The Acyl-Claisen Rearrangement: Development of a Novel Metal-Catalyzed Claisen Rearrangen1ent and Enantioselective Variants of the Acyl-Claisen Rearrangement Citation Yoon, Tehshik Peter (2002) The Acyl-Claisen Rearrangement: Development of a Novel Metal-Catalyzed Claisen Rearrangen1ent and Enantioselective Variants of the Acyl-Claisen Rearrangement. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JNTK-2387. https://resolver.caltech.edu/CaltechTHESIS:01282010-153053761 Abstract The development of a versatile new variant of the Claisen rearrangement is described. In this new Lewis acid-catalyzed process, the condensation of an allylic amine with a ketene (generated in situ from dehydrohaolgenation of an acid chloride) results in formation of a zwitterionic intermediate. Sigmatropic rearrangement via a highly organized cyclic transition state allows stereospecific access to a diverse range of α,β-disubstituted-γ,δ-unsaturated amides in excellent yields and diastereoselectivities for a range of alkyl-, aryl-, and heteroatom-substituted substrates. The ability of this new methodology to generate quaternary carbon stereocenters on both cyclic and acyclic carbon frameworks is demonstrated. An enantioselective variant of the acyl-Claisen rearrangement employing a chiral magnesium(II)-bis(oxazoline) Lewis acid has been developed. The use of chelating acid chlorides provides excellent organizational control over the transition state, allowing the rearrangement of a range of allyl morpholine substrates to proceed in up to 97% ee. Excellent levels of complementary diastereocontrol can be achieved in a predictable and highly selective manner from the rearrangement of the (E)- and (Z)-isomers of the allyl amine substrates. This reaction is also proficient at accessing quaternary carbon stereocenters. The scope of the enantioselective acyl-Claisen has been expanded by the use of a new chiral boron Lewis acid. This rearrangement does not require chelating acid chloride substrates for good enantioinduction. Thus, a range of α-alkyl-, α-alkoxy-, α-thio-, and α-halogen-substituted Claisen adducts can be produced in up to 93% ee. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Chemistry Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Awards: The Herbert Newby McCoy Award, 2002 Thesis Availability: Public (worldwide access) Research Advisor(s): MacMillan, David W. C. Thesis Committee: Dougherty, Dennis A. (chair) Grubbs, Robert H. Stoltz, Brian M. MacMillan, David W. C. Defense Date: 17 May 2002 Record Number: CaltechTHESIS:01282010-153053761 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:01282010-153053761 DOI: 10.7907/JNTK-2387 ORCID: Author ORCID Yoon, Tehshik Peter 0000-0002-3934-4973 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 5542 Collection: CaltechTHESIS Deposited By: Tony Diaz Deposited On: 29 Jan 2010 15:50 Last Modified: 14 Jan 2022 01:55 Thesis Files Preview PDF - Final Version See Usage Policy. 6MB Repository Staff Only: item control page

The Acyl-Claisen Rearrangement. Development of a Novel Metal-Catalyzed Claisen Rearrangement and Enantioselective Variants of the Acyl-Claisen Rearrangement Thesis by Tehshik Peter Yoon In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2002 (Defended May 17, 2002) © 2002 Tehshik Peter Yoon All Rights Reserved Acknowledgments First, I would like to thank my advisor, Prof. Dave MacMillan, who adopted me- when I was adrift and allowed me to join his group right at the very beginning. That first, sleepless year at Berkeley was an amazing experience, and I will always consider it one of the best times of my life. Dave has been a tremendous advisor; he’s been my harshest critic and my best advocate, and I’ve learned an incredible amount under his mentorship. I’m grateful to him for believing in my potential and for encouraging me to constantly push the limits of my imagination. Most of all, ’'d be remiss if I didn’t thank him for bringing me back home to Caltech. I also want to thank his wife, Selina Fong, for her support over the years in her dual roles as group administrator and unofficial morale officer. The talented bunch of people who make up the MacMillan group have been my friends, coworkers, and surrogate family for the past four years. I’d like to thank my baymates, Chris Borths, Julie Park, and Jim Falsey, and my roommate Jake Wiener, who have been among my closest friends in graduate school and consequently have had to bear the brunt of my eccentricities. Sorry about all the NPR. Vy Dong, who was my partner in all of the early Claisen work (Ch. 2-3), Sung-gon Kim, who contributed to the boron chemistry (Ch. 5), and the rest of Team Claisen (Jeongbeob Seo, Jim, Naomi Anker, Wendy Jen) have been instrumental in the development of the Claisen project. I’d also like to acknowledge the very first group—Borths, Vy, Wendy, Jake, Jeongbeob, Tristan Lambert, and Kateri Ahrendt—I’l] always remember fondly that first year when it was just the eight of us with our bizarre set of inside jokes working those insane hours to make a name for our fledgling group. I am indebted in a million ways to the entire group, past and present. It was a privilege to work with all of you. I’ve relied heavily on the advice of many excellent postdocs during the past few years. Drs. Justin Gallivan, Steve Goldberg, Jen Love, Claudia Roberson, Chris Sinz, and iv Dean Toste have been especially generous with their time and expertise. Very special thanks to Steve, Chris S., and Eric Ferreira for their carful prooffreading of this disseratation. I owe a tremendous debt of gratitude to my first graduate advisor at Caltech, Prof. Erick Carreira. It was his infectious passion for science that drew me to Caltech in the first place. In his group, I had the opportunity to get to know a remarkable bunch of coworkers. I'd like especially to acknowledge Justin Du Bois, Mary Shepard, Mike Johnson, Jay Dritz, and Don Gauthier for teaching me one end of a sep funnel from the other, and my classmates Jeff Bode, Mike Mish, Jeremy Starr and Craig Tomooka for their friendship. I'd also like to express my gratitude to my undergraduate advisor at Harvard, Prof. Dave Evans. He is a scholar, teacher, and artist of the highest caliber, whose elegant approach to science first taught me to appreciate the beauty of our craft. I’ve been privileged to work with many talented undergraduates during my graduate career, both in the lab and the classroom. I’d particularly like to mention the awesome talent of Naomi Anker, whose development of the sulfur acyl-Claisen contributed so much to the Claisen effort. I only hope she learned half as much from me as I did from her. Caltech has been a great place to be a graduate student. I’d like to thank the members of my thesis committee, Prof. Dennis Dougherty, Prof. Bob Grubbs, and Prof. Brian Stoltz for their encouragement and advice. Special thanks must also to go to the division staff—especially Dian Buchness and Chris Smith, who make the world go ‘round. My first teachers were my parents, who have been actively involved in my education since the very beginning. Their first lessons—honor, loyalty, compassion, persistence, hard work—are still the most precious to me. I can only begin to express my appreciation for all the sacrifices they made in their lives so that my sister and I could flourish. So I'd like to dedicate this dissertation to my mom and dad, who are still my greatest inspiration. Abstract The development of a versatile new variant of the Claisen rearrangement is described. In this new Lewis acid-catalyzed process, the condensation of an allylic amine with a ketene (generated in situ from dehydrohaolgenation of an acid chloride) results in formation of a zwitterionic intermediate. Sigmatropic rearrangement via a highly organized cyclic transition state allows stereospecific access to a diverse range of a,f-disubstituted- y,6-unsaturated amides in excellent yields and diastereoselectivities for a range of alkyl-, aryl-, and heteroatom-substituted substrates. The ability of this new methodology to generate quaternary carbon stereocenters on both cyclic and acyclic carbon frameworks is demonstrated. An enantioselective variant of the acyl-Claisen rearrangement employing a chiral magnesium(II)-bis(oxazoline) Lewis acid has been developed. The use of chelating acid chlorides provides excellent organizational control over the transition state, allowing the rearrangement of a range of allyl morpholine substrates to proceed in up to 97% ee. Excellent levels of complementary diastereocontrol can be achieved in a predictable and highly selective manner from the rearrangement of the (£)- and (Z)-isomers of the allyl amine substrates. This reaction is also proficient at accessing quaternary carbon stereocenters. The scope of the enantioselective acyl-Claisen has been expanded by the use of a new chiral boron Lewis acid. This rearrangement does not require chelating acid chloride substrates for good enantioinduction. Thus, a range of o-alkyl-, a-alkoxy-, a-thio-, and a- halogen-substituted Claisen adducts can be produced in up to 93% ee. Table of Contents AcknowledgmenttS.......... 00. ccc cece cece ee ence cette eee ne eee e tee eee eee eee ence teeeneeeee tees il FN 8 0: soca Vv Table of Contents....... 0... ccc cece cece eee c eect eee ence ee ene eee e ea eeneteeeeeeeeeeeeeaeeaes vi List of Schemes........... ccc cece cece nce e tence eee ee eee ence eens senor tennessee eeeeeaeeane sees Vili List Of Figures..... 0... cece cee cece eee e nnn nee ence eee en E ee Ee ene EEE EEE EEE EE eee ix List of Tables....... 0... cece cece ene eee n eee eee ence eee eee eeeeeeeeeteceeaseeneeeeeeaeegs x Chapter 1. The Asymmetric Claisen Rearrangement...........................055 1 Introduction. ..... 00... ce eee ee eee e eee ence ene eens eneeneeeeeeeeeeeeeeeeeeee rena ] Stereoinduction in the Claisen Rearrangement...................0.:0: cee ceee eee 6 Chapter 2. Development of the Lewis Acid-Catalyzed Ketene-Claisen......... 14 Rearrangement Reaction Design............ cece cece ence erence eect eee neeneeeeeeeeeeeeeeeneenee ence 14 Results and Discussion. ...........cccceeeeeceee eee ee eee ee eects eee ne eee eee ne eee enes 18 Origins of Stereoselectivity in the Ketene-Claisen Rearrangement............. 20 Scope of the Ketene-Claisen Rearrangement.................ccee cece eee eeeeeeees 22 Experimental Section. ..........cc cece ccc cc cece cece eee n eect eee eeeeaeea eee ee ena eees 25 Chapter 3. Development of the Acyl-Claisen Rearrangement.................... 32 Reaction Design....... 0.0... cece cece cence ence eee e see ee tees teense enee ene eesenee eee 32 Results and Discussion. ........... 0... cece cee seeceee ence eens eee ene ee eee eee ne ene enes 33 Scope of the Acyl-Claisen Rearrangement................eeeeeeeeeeeeeeeeeeeeeeee 4l Analysis of the Acyl-Claisen Rearrangement by ReactIR......ccccccceseeeeeen 49 £000.) LISS (0) | eee 54 Experimental Section.............. cece ccc cece eter e ee eee eee e eee eee eee naan 56 Vil Chapter 4. Development of a First-Generation Enantioselective ................ 70 Acyl-Claisen Rearrangement Reaction Design.......... 0... ccc ce cece nee e eee ceee en eeeneeeenenseseeeeeeeeneneenens 70 Results and Discussion..............cccccec ene ecee cece eee ee eee eeaeneeneeaeen sen eenes 71 Scope of the First-Generation Enantioselective Acyl-Claisen..................5 78 Rearrangement Stereochemical Models....... 0.0... ccccecece cece ne ee eee eee ee eneeeeeeneeeee en eees 83 Limitations of the First-Generation Enantioselective Acyl-Claisen............. 85 Rearrangement £000) 10d TS (0) | ce 87 Experimental Section......... 0.0... cccececccceeeec ence tec eeeeceeaeneeseeeneeeeenes 88 Chapter 5. Development of a Second-Generation Enantioselective.............. 104 Acyl-Claisen Rearrangement Reaction Design.......... 0. cece eee cece cece eee ne eee ee eben eee eneneeeene enone ea ena 104 BINOL-Aluminum-Promoted Enantioselective Acyl-Claisen................... 106 Rearrangements Boron-Bis(sulfonamide)-Promoted Enantioselective Acyl-Claisen............. 107 Rearrangements Results and Discussion............cccccceeceeeecee eee eneeeeeeeaeaeeeeseaeesen sense 109 Evaluation of Reaction Scope...........cccecececeeceeeeeseceeeeeeeeeeneesenenaeees 113 Stereochemical Model....... 0. cece cee cc eee e eee eeeceee ence eens eases seen es eeeenes 118 Limitations of the Methodology.................cccccccesceececeseeeeneenteneneeess 120 £0) Te) 1S 0) | cee 122 Experimental .......... 0.00. c cece eee ence ence cece ence tees eeeees eee ee een eeaeenens 123 Appendix 1. X-Ray Crystallographic Data for (2S*,3S*)-N-2-Methyl- ...... 137 3-phenyI-4-pentenoyl)-morpholine Appendix 2. X-Ray Crystallographic Data for (2S*,3S*)-N-3-Methyl- ...... 156 2-phthalimido-4-pentenoyl)-morpholine Chapter 1 Scheme |. Scheme 2. Scheme 3. Scheme 4. Scheme 5. Scheme 6. Scheme 7. Scheme 8. Scheme 9. Scheme 10. Chapter 2 Scheme 1. Chapter 3 Scheme 1. Scheme 2. Scheme 3. Scheme 4. Chapter 4 Scheme 1. Scheme 2. Chapter 5 Scheme 1. Scheme 2. Scheme 3. List of Schemes The Carroll rearrangement. The Eschenmoser Claisen in the synthesis of thromboxane B,. The Johnson Claisen in the synthesis of zaragozic acid C. Diastereoselectivity in the Ireland Claisen. Enantiospecificity in the Claisen rearrangement. Kurth’s oxazoline-based chiral auxiliary. Metz’s binaphthyl-based chiral auxiliary. Yamamoto’s enantioselective oxonia-Claisen. Corey’s enantioselective Ireland Claisen. Hiersemann’s catalytic enantioselective oxonia-Claisen. Proposed Lewis acid-catalyzed ketene-Claisen rearrangement. Tertiary amine-catalyzed formation of ketene dimers. Allyl morpholines in the acyl-Claisen rearrangement. Reactivity differences between cis and trans olefins. Acyl-ammonium vs. ketene mechanisms. Chelation control in the enantioselective acyl-Claisen rearrangement. Von Braun fragmentation. Synthesis of the boron-stien complexes. Catalyst inhibition by product. Catalyst inhibition by chloride ion. 16 35 39 44 50 71 81 109 121 122 Chapter 1 Figure |. Figure 2. Chapter 2 Figure 1. Figure 2. Figure 3. Chapter 3 Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Chapter 4 Figure 1. Figure 2. Figure 3. Chapter 5 Figure |. Figure 2. Figure 3. Figure 4. ix List of Figures The Claisen rearrangement. Charge-accelerated Claisen rearrangements. Dipole-accelerated ketene-Claisen rearrangement. (Z)-Enolate selectivity in additions to monosubstituted ketenes. Origins of diastereoselectivity in acyclic Claisen rearrangements. ReactIR: Crotyl-pyrrolidine-catalyzed dimerization of methylketene. ReactIR profile of the absorbance of the ketene stretch. ReactiR: The AICl,-catalyzed acyl-Claisen rearrangement. ReactIR: The AIC1,-catalyzed acyl-Claisen rearrangement (profile). ReactIR: Thé TiC1,(THF),-catalyzed acyl-Claisen rearrangement. ReactIR: The TiCl,(THF),-catalyzed acyl-Claisen rearrangement (profile). ArBox ligands assayed in the enantioselective acyl-Claisen. Substituted ArBox ligands. Semiempirical (PM3) computational transition state model. Comparison of benzyloxyacety] chloride and propionyl chloride. Rationale for design of chiral Group 13 Lewis acids. Tetrahedral and trigonal geometries for boron Lewis acids. Stereochemical rationale for the enantioselective acyl-Claisen rearrangement. 17 21 716 77 84 105 105 118 119 Chapter 2 Table 1. Table 2. Chapter 3 Table 1. Table 2. Table 3. Table 4. Table 5. Table 6. Table 7. Chapter 4 Table 1. Table 2. Table 3. Table 4. Table 5. Table 6. Table 7. List of Tables Ketene-Claisen rearrangement between cinnamy] pyrrolidine and methylketene. Ketene-Claisen rearrangements of representative allyl pyrrolidines. Effect of Lewis acid on the acyl-Claisen rearrangement. Effect of amine base on the acyl-Claisen rearrangement. Allyl morpholines in the acyl-Claisen rearrangement. Acyl-Claisen rearrangements of representative allyl morpholines. Acyl]-Claisen rearrangements of representative acid chlorides. Optimization of reactions using benzyloxyacety] chloride. Acyl-Claisen rearrangements of heteroatom-substituted acid chlorides. Chiral bis(oxazoline)*MgBr, Lewis acids in the enantioselective acyl-Claisen rearrangement. Effect of counterion on the enantioselective acyl-Claisen. ArBox ligands in the enantioselective acyl-Claisen. Effect of electron-donating and -withdrawing ArBox substituents on the enantioselective acyl-Claisen. Acid chloide scope in the enantioselective acyl-Claisen. Alkyl- and aryl-substituted allyl morpholines. Electron-deficient allyl morpholines. 19 23 33 34 40 42 45 46 47 72 74 76 78 79 80 82 Chapter 5 Table 1. Table 2. Table 3. Table 4. Table 5. Table 6. Table 7. Xi Effect of boron complex structure on the enantioselective acyl-Claisen rearrangement. Variation of diamino ligand backbone. Variation of sulfonamide structure. Alkyl- and aryl-substituted ally] morpohlines. Heteroatom-substituted allyl morpholines. Alkyl- and aryl-substituted acid chlorides. Heteroatom-substituted acid chlorides. 110 111 112 114 115 116 117 “Fate, it seems, is not without a sense of irony.” -Morpheus, The Matrix Chapter 1 The Asymmetric Claisen Rearrangement Introduction Since its initial discovery in 1912,’ the Claisen rearrangement has become recognized as one of the most powerful carbon-carbon bond-forming reactions available for the construction of complex organic molecules.” In its most basic formulation, this reaction is the [3,3]-sigmatropic rearrangement of an allyl vinyl ether to a y,6-unsaturated carbonyl compound (Figure 1). Formally, the bond reorganization event can be regarded as an intramolecular S,,' reaction between an enol ether (Claisen), thiocarbony! enol (thio-Claisen), or enamine (aza-Claisen) and an allylic ether, sulfide, or amine, respectively. The formation of anew carbon-carbon bond in the rearrangement results in the concomitant formation of up to two new stereogenic carbon centers. As a result of its potential to generate dense stereochemical motifs on cyclic and acyclic frameworks in a predictable and highly diastereoselective manner, the Claisen rearrangement has found extensive application in the + ay Za Ry X=O0 Clai aN ; x aisen LA ——___> Le*Ln, ied X=S_ Thio-Claisen ZA Re A, S OR, X =NR Aza-Claisen Figure 1. The Claisen rearrangement. 1. Claisen, B. Chem. Ber. 1912, 45, 3157 2. For recent reviews of the Claisen rearrangement, see: (a) Moody, C.J. Adv. Hetrocycl. Chem. 1987, 42, 203. (b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (c) Blechert, S.; Synthesis 1989, 71. @ Kallmerten, J.; Wittman, M. D. Stud. Nat. Prod. Chem. 1989, 3, 233. (e) Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M. and Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.2. (f) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron 1996, 7, 1847. total synthesis of natural products and has been the target of numerous methodological studies in the nine decades since its first report. & ML, ML re Z~o, n J VJ anion-accelerated cation accelerated Ireland Claisen oxonia—Claisen Figure 2. Charge-accelerated Claisen rearrangements. The thermal sigmatropic rearrangement of allyl vinyl ethers typically occurs at elevated temperatures (ca. 150-200 °C). In contrast to the reversible Cope rearrangement of 1,5-dienes, the Claisen rearrangement results in the energetically favorable formation of a C=O x-bond. Therefore, the Claisen rearrangement is typically a strongly exothermic process (ca. 20 kcal/mol)’* with a correspondingly earlier transition state and a lower activation barrier than the Cope rearrangement.” Incorporation of anionic charge at position 2a° or cationic charge at position 3’ can accelerate the Claisen rearrangement, which has resulted in Claisen variants that occur at temperatures as low as -78 °C (Figure 2). 3. (a) Schuler, F. W.; Murphy, G. W. J. Am. Chem. Soc. 1950, 72, 3155. (b) Vittorelli, P.; Winkler, T.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta. 1968, 5/7, 1457. 4. Estimation of the enthalpy of transformation of allyl vinyl ether to 5-hexenal using Benson’s group additivity method predicts AH® = -17 kcal/mol. Cohen, N.; Benson, S. W. Chem. Rev. 1993, 93, 2419. 5. Aviyente, V.; Yoo, H. Y.; Houk, K. N. J. Org. Chem. 1997, 62, 6121. 6. (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1972, 94, 5897. (b) Denmark, S. E.; Harmata, M. A. J. Am. Chem. Soc. 1982, 104, 4972. Traditionally, the sensitive allyl vinyl ether moiety is generated by the mercury- or acid-catalyzed transetherification of enol ethers with allylic alcohols.* However, the toxicitiy of mercury salts and the low yields typically associated with these procedures limit their practical utility. The development of new Claisen methodology in the century since its initial discovery has been significantly assisted by the discovery of Claisen variants that allow the vinyl ether moiety to be generated in situ and the rearrangement to be conducted under milder conditions. The first such variant of general utility was serendipitously discovered by Carroll in 1940 (Scheme 1).’ An attempt to effect the base-promoted transesterification of B-ketoester 1 with allyl alcohol 2 resulted instead in the enolization of the allyl ester and subsequent [3,3]-rearrangement, resulting in the isolation of methyl ketone 3 after decarboxylation. Scheme 1 AL O ONa oO ONa oO M OM ° * NaOAc AK 1 Me’ 2” ~O | —*~ | Me fe) NN Me 7. (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 3985. (b) Stevenson, J. W.S.; Bryson, Tetrahedron Lett. 1982, 23, 3143. (c) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull, Chem. Soc. Jpn. 1984, 57, 446. (d) Takai, K.; Mori, 1.; Oshima, K.; Nozaki, H. Tetrahedron 1984, 40, 4013. 8. (a) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828. (b) Burgstahler, A. W.,; Nordin, I. C. J. Am. Chem. Soc. 1961, 83, 198. (c) Church R. F.; Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1966, 31, 2526. (d) Thomas, A. F. J. Am. Chem. Soc. 1969, 9/7, 3281. (e) Dauben. W. G.; Dietsche, T. J. J. Org. Chem. 1972, 37, 1212. 9. (a) Carroll, M. F. J. Chem. Soc. 1940, 704. (b) Carroll, M. F. J. Chem. Soc. 1940, 1266. (©) Carroll, M. F. J. Chem. Soc. 1941, 507. In 1964, Eschenmoser'’ reported a Claisen variant in which the allyl vinyl ether moiety is generated in situ by condensation of an N,O-ketene acetal with an allylic alcohol (Scheme 2). The resulting transacetylated intermediate rearranges under the reaction conditions to produce a y,6-unsaturated amide. This Claisen variant was utilized as the key step in Corey’s synthesis of thromboxane B,, in which the cyclic allylic alcohol 4 was treated with N,N-dimethylacetamide dimethy] acetal at 160 °C to give the rearranged product 5! | Scheme 2 Me.N_ Me HOw, AS MeO~ ~OMe TT or Meo" ~o 25-160 °C OH 4 L_ OH - Nee —_—_—_—_——> Me Thromboxane A Me B HO (@) 2 10. (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425. (b) Wick, A. E.; Felix, D.; Gschwend-Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1969, 52, 1030. © Jenkins, P. R.; Gut, R.; Wetter, H.; Eschenmoser, A. Helv. Chim. Acta 1979, 62, 1922. 11. (a) Corey, E. J.; Shibasaki, M.; Knolle, J.; Sugahara, T. Tetrahedron Lett. 1977, 785. (b) Corey, E. J.; Shibasaki, M.; Knolle, J. Tetrahedron Lett. 1977, 1625. Subsequently, Johnson'* demonstrated that orthoesters also undergo acid-catalyzed condensation with allylic alcohols to afford ketene acetals. Rearrangement occurs under the reaction conditions necessary for transacetalization to afford ester products (Scheme 3).: This reaction continues to be an important, operationally simple variant of the Claisen rearrangement, and has been featured recently in Santini’s synthesis of the zaragozic acid C C(6) O-acyl sidechain 6 (Scheme 3)."* Scheme 3 EHO, [08 OEt EtO~ ~Me ue ott + OH = ——» AWAY py Vt ANA 9% | Pn : ’ Ph : Me Me Me — 7 6 The most influential advance in Claisen technology was the rearrangement of silylated ester enolates first introduced by Ireland and coworkers in 1972 (Scheme 4).'* The key feature of the Ireland Claisen is the ability to direct the diastereoselectivity of the process in a highly predictable fashion by controlling the geometry of enolization. Thus, enolization of crotyl ester 7 with LDA in THF at —78 °C leads to selective formation of the 12. Johnson, W. S.; Werthemann, L. Bartlett, W. R.; Brockson, T. J.; Li, T.-T.; Faulkner, D. J.: Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741. 13. Santini, C.; Ball, R. G.; Berger, G. D. J. Org. Chem. 1994, 59, 2261. 14. (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897. (b) Ireland, R. E.; Willard, A. K. Tetrahedron Lett. 1975, 3975. (c) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. (E)-silyl ketene acetal. In general, the transition state of the Claisen rearrangement of acyclic substrates demonstrates a strong preference for a highly organized, chair-like topography; therefore, the (Z)-enolate methyl substituent adopts a pseudo-axial position in the chair-like transition state, leading predominantly to the anti-substituted product 8 in 79% yield and 87:13 dr. The complementary diastereomer can be similarly accessed by (Z)- selective enolization in a 23% HMPA/THF solvent system followed by rearrangement to syn-2,3-dimethyl-5-hexenoic acid (9) in 73% yield and 81:19 dr.'** Scheme 4 Me THF O- > Me CO.H TMSO 79% Me ~Z O (E)-enolate 8 86:14 anti:syn Mi HK, LDA a TMSCI Me 7 O Me, CO2H 65 °C ae THF/HMPA = [MSO Me 73% Me” \7 (Z)-enolate 9 81:19 syn:anti Stereoinduction in the Claisen Rearrangement In addition to being highly diastereospecific, Claisen rearrangements with a stereogenic center at the oxygen-bearing allylic carbon are generally highly enantiospecific. In the Johnson orthoester Claisen rearrangement of the enantiopure secondary alcohol 10 depicted in Scheme 5, for example, the reaction proceeds predominantly through the transition state geometry depicted in Ia, in which the allylic methyl substituent adopts an equatorial configuration, rather than through transition state 11b, which is significantly destabilized by the 1,3-diaxial interaction between the methyl and the alkoxy substituents. The rearranged product 12 can therefore be isolated from the reaction in >90% ee.'° Importantly, loss of stereochemical fidelity in this process must be due to a small proportion of rearrangement through a high-energy boat topography, as the disfavored chair transition state 11b leads to the isomeric (Z)-alkene 13. Scheme 5 Me Me Me MeC(OEt)s O favored SN OEt CO,Et lla 12 OH 10 > : Me Me. ee disfavored ~ Ie + -------- > Me sel \ H | ---------- > Me MeC(OEt)3 O CO.Et tib 13 The efficiency of stereochemical relay in the highly organized transition state of the Claisen rearrangement has enabled to the development of several highly asymmetric variants that employ chiral auxiliaries." In 1985, Kurth'’ described an oxazoline-based aza-Claisen variant (Scheme 6). N-Alkylation of the valinol-derived oxazoline 14 with crotyl tosylate 15. Hill, R. K.; Soman, R.; Sawada, S. J. Org. Chem. 1972, 37, 3737. ‘16. For reviews of asymmetric Claisen rearrangements, see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847. (b) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43. 17. (a) Kurth, M. J.; Decker, O. H. W.; Hope, H.; Yanuck, M. D. J. Am. Chem. Soc. 1985, 107, 443. (b) Kurth, M. J.; Decker, O. H. W. J. Org. Chem. 1985, 50, 5769. followed by in situ deprotonation of the intermediate iminium salt gives (Z)-ketene acetal 15. Rearrangement at 155 °C affords imidate 16 as a 83:17 mixture of syn to anti isomers in 75% yield, where the syn isomers are isolated in 95% de with respect to the chiral auxiliary. Scheme 6 [ Me 7] Me. Me 1) OTs Me Me Me | Me N 155°C oN ‘ 2) n-BuLi, | Z~o | 6 me AL -~78 °C Me Me : LL Me 2 Me 14 15 16: 75% yield 83:17 syn:anti 95% de In 1997, Metz and coworkers'* reported a chiral auxiliary strategy with greater generality (Scheme 7). Crotyl imidate 17, derived from binaphthyl-derived amine 18, can be deprotonated with lithium diethylamide at -78 °C. Upon warming the reaction to 0 °C, the resulting (Z)-ketene acetal 19 rearranges to the anti-substituted amide 20, which can be isolated in 78% yield and 94% de. The chiral auxiliary can be cleaved and recovered by hydrolysis of the amide product to the carboxylic acid 21 via a two-step iodolactonization- reduction protocol. 18. (a) Metz, P.; Hungerhoff, B. GIT Fachz. Lab. 1996, 40, 690. (b) Metz, P.; Hungerhoff, B. J. Org. Chem. 1997, 40, 690. Scheme 7 NAr* LN art NHAr* Me . Me Oo LINEts 07 >= fe) 78% yield ° Me ° : LA ve ~78 °C LAX, O° SNe 979." 17 20 19 ome OH HO/EtOH 0 Me 2. Zn°, ACOH + S Me 20 18 "Ar*NHo" Enantioselective rearrangement of achiral allyl vinyl ethers has also been achieved. In 1995, Yamamoto'’ described a cation-accelerated Claisen rearrangement that employs the bulky aluminum(III]) complex 21 as a chiral Lewis acid. Allyl vinyl ethers 22a—c rearrange at -78 °C in the presence of a stoichiometric quantity of 21 to afford the corresponding y,é- unsaturated aldehydes 23a—c in 70-97% yield and 76-92% ee. While enantioselectivities observed for substrates bearing bulky substituents (22a, R = t-Bu, 91% ee; 22b, R = Me,Si, 92% ee) are generally good, significantly lower selectivities are observed in the rearrangement of less sterically demanding allylic substrates (22c, R = Ph, 76% ee). 19. Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 1165. 10 Scheme 8 F Car 14+ O—)sAl » | CHO CO 22a R= t-Bu 23a 70% yield, 91% ee b R= SiMe, b 78% yield, 92% ee 21 (R)-ATBN-F c R=Ph c 97% yield, 76% ee A further brilliant advance in asymmetric Claisen technology is represented by Corey’s”° report of a chiral Lewis acid for the first enantioselective and diastereospecific rearrangement of achiral ester enolates (Scheme 9). In the presence of the stilbenediamine- derived bis(sulfonamido)boron Lewis acid 24, crotyl propionate (25) is enolized by i- Pr,NEt at —78 °C to afford (£)-ketene acetal 26. Upon warming the reaction to —20 °C, the rearranged syn-2,3-dimethyl-5-hexenoic acid product 27 predominates over the anti diastereomer in a 99:1 ratio and may be isolated in 75% yield and >97% ee. Importantly, Corey’s system allows the complementary anti diastereomer to be selectively generated by controlling the conditions under which the enolization event occurs. Thus, by deprotonating the Lewis acid-activated ester with triethylamine in a toluene-hexane solvent system, the (Z)- ketene acetal 28 can be generated selectively. After rearrangement of this geometric isomer at —20 °C, the anti isomer 29 predominates in a 90:10 ratio and can be isolated in 65% yield and 96% ee. 20. Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1986, 113, 4026. Scheme 9 Me Ph ; F3C 9 CF3 gNA NS no catalyst \ turnover Br F5C 24 R*,BBr CF, oluene Me hexane Me —20°C LA oe A Me -~78°C LA, 14 days 25 26 - 27 99:1 syn:anti >97% ee, 75% yield : Ro*By i-ProNEt ° fe) CH2Clo AY -20°C Me ° ie 78°C ZA Me 14 days ~ :, This methodology is successful with a range of alkyl-, aryl-, and heteroatom- substituted substrates, and Corey has demonstrated the synthetic utility of this reaction in elegant total syntheses of two natural products, (+)-fuscol’' and dolabellatrienone.”* In each synthesis, the key Claisen event is employed to install a quaternary carbon stereocenter in a 28 29 90:10 anti:syn 96% ee, 65% yield 21. Corey, E. J.; Roberts, B. E.; Dixon, B. R. J. Am. Chem. Soc. 1995, 117, 193. 22. Corey, E. J.; Kania, R. S. J. Am. Chem. Soc., 1996, 178, 1229. 12 highly enantio- and diastereoselective manner.’* However, stoichiometric quantities of the Lewis acid 24 are required for a successful reaction. Catalyst turnover in this reaction is likely inhibited by the formation of stable boron-carboxylate complex 30 as the direct: product of the rearrangement event. Scheme 10 31 i-Pr-O Oo 5 mol% i-Pr-O ne catalyst me CuL,* wD » Me Z oO” ee nee ow 100% yield 82% ee 86:14 synmanti Despite the synthetic importance of the Claisen rearrangement and the efforts of several groups towards the development of novel asymmetric Claisen variants, the development of catalytic asymmetric Claisen rearrangements has proven to be a difficult goal. In fact, the first example of an enantioselective Claisen rearrangement catalyzed by a chiral Lewis acid was only recently reported in the literature. Hiersemann** has demonstrated that copper(II) bisoxazoline complex 31 catalyzes the oxonia-Claisen rearrangement of allyl vinyl ethers capable of binding in a bidentate fashion to the metal 23. Enantioselective construction of quaternary carbon stereocenters continues to be a challenging objective for synthetic organic chemists. For reviews of recent methods, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001, 40, 4591. 24. Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem. Int. Ed. 2001, 40, 4700. 13 center (Scheme 10). Enantioselectivities as high as 88% and diastereoselectivity as high as 97:3 can be achieved. However, the requirement for a chelating ester at the 2-position and the nontrivial synthesis of the ally! vinyl ether substrates limit the scope and synthetic utility of this reaction methodology. “Thus, the development of a highly enantioselective catalytic Claisen variant of general synthetic utility continues to be an important yet elusive goal. Our approach to the discovery of an enantioselective catalytic Claisen rearrangement therefore begins with the design of a new Claisen variant that is more readily amenable to Lewis acid catalysis than the Ireland Claisen, with greater substrate scope and more facile substrate synthesis than the metal-mediated oxonia-Claisen reaction. 14 Chapter 2 Development of the Lewis Acid-Catalyzed Ketene Claisen Rearrangement Reaction Design The intial phase of this research program took its inspiration from the conceptually novel ketene-Claisen rearrangement reported by Bellus in 1978.' In an attempt to perform a [2+2] cycloaddition, the authors discovered that allylic ethers and sulfides will instead condense with dichloroketene to form zwitterionic enolates, which subsequently undergo [3,3]-sigmatropic rearrangement to produce y,6-unsaturated esters and _ thioesters, respectively (eq 1). C=O o va 23°C Age [3,3] ( \ ether Cl R “\~™ome Iw A broad range of allylic substrates can be used successfully in this Claisen rearrangement, including both cyclic and acyclic ethers and sulfides. The range of ketenes that could be used, however, was reported to be relatively narrow. Only highly electron- deficient ketenes such as dichloroketene and chloro(trichloroethyl)ketene were found to participate readily in the ketene-Claisen rearrangement. However, detailed inspection of these reports revealed that successful rearrangements only occurred when ketenes were 1. (a) Malherbe, R.; Bellus, D. Helv. Chim. Acta 1978, 61, 3096. (b) Malherbe, R.; Rist, G.; Bellus, D. J. Org. Chem. 1983, 48, 860. 15 generated in situ by zinc-promoted dehalogenation of a-chloro acid chlorides,” in which zinc(II) chloride is generated as a byproduct (eq 2). In fact, when the highly electron- deficient chlorocyanoketene was generated by thermolysis’ in the absence of any metal species (eq 3), less than 5% of the product arising from Claisen rearrangement could be isolated, even at elevated temperatures. oN ——+ 0-0 + AC (2) 23 °C rer cil Cl OMe Ng 85 °C cl | o ———+ y=c=0 unreactive (3) Cl NC Oo These observations suggested that the ZnCl, byproduct of zinc-promoted ketene formation might constitute an integral component of the ketene-Claisen rearrangement, perhaps serving as a Lewis acid that activates ketenes towards nucleophilic attack. Indeed, Lewis acid activation of ketenes is well precedented,* and Brady” has suggested such a 2. (a) Staudinger, H. Chem. Ber. 1905, 38, 1735. (b) Hassner, A.; Krepski, L. R. J. Org. Chem. 1978, 43, 2879. (c) Mehta, G.; Rao, H. 8. P. Svath. Commun. 1985, 15, 991. ) Depres, J.; Greene, A. E. Org. Synth. 1989, 68, 41. (ec) Wulferding, A.; Wartchow, R.; Hoffmann, H. M. R. Synlett. 1992, 476. 3. (a) Moore, H. W.; Hernandez, L.; Sing, A. J. Am. Chem. Soc. 1976, 98, 3728. (b) Moore, H. W.; Hernandez, L.; Chambers, R. J. Am. Chem. Soc. 1978, 100, 2245. 4. For example, BF,*OEt, catalyzes the acylation of -BuOH with trimethylsilylketene. Ruden, R. A. J. Org. Chem. 1974, 39, 3607. 5. (a) Brady, W. T.; Lloyd, R. M. J. Org. Chem. 1979, 44, 2 560. (b) Brady, W. T.; Lloyd, R. M. J. Org. Chem. 1980, 45, 2025. - 16 mechanism in the [2+2] cycloaddition of dichloroketene with silyl enol ethers. Brady has reported that the cycloaddition proceeds smoothly when dichloroketene is generated in situ ** while the reaction fails from zinc-promoted dehalogenation of trichloroacetyl chloride, when the ketene is generated by amine-promoted dehydrohalogenation of dichloroacetyl chloride under metal-free conditions.°” Although the initial reports of the ketene-Claisen reaction did not make any mention of this mechanistic possibility, we speculated that a wider range of less electron-poor ketenes could potentially be induced to participate in the ketene- Claisen reaction by addition of the appropriate Lewis acid catalyst. Scheme 1 LA Re Some ~o We therefore proposed the hypothetical catalytic cycle for a general Lewis acid- catalyzed ketene-Claisen rearrangement shown in Scheme 1. Lewis acid activation of ketene 17 1 towards nucleophilic attack by allylic ether 2 should generate the metal-bound zwitterionic enolate species 3. This intermediate should then undergo [3,3]-sigmatropic rearrangement to afford the metal-bound ester 4. Release of the free ester product 5 would then regenerate the Lewis acid and complete the catalytic cycle. If this hypothesis is correct, there are several features of the ketene-Claisen rearrangement that would render it an attractive platform for the development of a new asymmetric catalytic process. First, Claisen rearrangements are known to be accelerated both by cationic charge at the 3-position (e.g., the oxonia-Claisen) and by anionic charge at the 2a-position (e.g., the Ireland Claisen).° The zwitterionic intermediate generated by condensation of a ketene with an allylic ether will possess charge at both the 2a- and 3- positions, and should therefore be optimally poised to undergo charge-accelerated sigmatropic rearrangement. anion-accelerated cation accelerated zwitterionic ireland Claisen oxonia—Claisen ketene—Claisen Figure 1. Dipole-accelerated ketene-Claisen rearrangement. Second, we anticipated that the ketene-Claisen rearrangement should be amenable to catalysis using a substoichiometric amount of a Lewis acidic metal species. In Corey’s 6. Chapter 1, Footnotes 6-7. 18 boron-mediated ester enolate Claisen rearrangement,’ the anionic carboxylate product binds irreversibly to the boron Lewis acid, thereby inhibiting catalyst turnover (see Chapter 1, Scheme 9). The product of the ketene-Claisen reaction, on the other hand, is a neutral ester species (i.e., 5) and should therefore be able to dissociate readily from a range of Lewis acidic metal salts. Results and Discussion We began our experiments by examining the reaction of methylketene (7) with cinnamy! methyl ether (6). Methylketene (7) can be generated free of metal salts by treatment of bromoacetyl bromide with zinc in THF and codistillation of the ketene-THF solution at reduced pressure into a liquid nitrogen-cooled Schlenk flask.* Unfortunately, the ether 6 failed to react with methylketene to produce the desired ester product 8 in the presence of a variety of Lewis acids (eq 4). As methylketene is considerably less electrophilic than the halogenated ketenes employed by Bellus, we reasoned that a more reactive nucleophile might be required to condense with the less reactive ketene. Ph~ Some Lowis acid ewis aci 6 ene een - eee > not observed (4) Ma THF —= C=O 7 8 7. Chapter 1, Footnotes 19-21. 8. (a) Smith, C. W.; Norton, D. G. Organic Syntheses, Coll. Vol. IV; Rabjohn, N., Ed.; Wiley: New York, 1963, pp. 348-350. (b) McCarney, C. C.; Ward, R. S. J. Chem. Soc., Perkin Trans. 1, 1975, 1600. 19 Table 1. Ketene-Claisen rearrangement between cinnamy] pyrrolidine and methylketene. “yO Me Lewis acid mA WN Nice Huse THF Ph O . acest (5) Me > 10 9 7 entry Lewis acid equiv % conv“ synianti? 1 - - NR -- 2 AIC; 1.0 90 >99:1 3 MgBro 1.0 80 >99:1 4 Yb(OTf)2 1.0 90 >99:1 5 ZnBr2 1.0 89 >99:1 6 TiCl4(THF), 1.0 83° >99:1 7 ZnBry 0.2 87 >99:1 8 A\MeCl) 0.2 90° >99:1 9 TiCl,(Oi-Pr)2 0.2 72° >99:1 10 TiCl4(THF), 0.1 83° >99:1 @ Conversion based on 'H NMR analysis of the Product ratios determined by GLC using a Bodman CC1701 column. “Isolated yield. unpurified reaction mixture. We therefore turned our attention to reactions involving allylic amine nucleophiles. Subsequent to the initial demonstration of the ketene-Claisen of allylic ethers by Bellus and Malherbe,' the ability of allylic tertiary amines to participate in this reaction was 20 demonstrated in studies by Mariano,”* Edstrom,’” Roberts,”* Vedejs,?* Nubbemeyer,”* and Hegedus.” To our delight, we discovered that cinnamyl pyrrolidine undergoes an efficient ketene-Claisen rearrangement at room temperature under the influence of Lewis acid catalysts (Table 1). As illustrated by entries 2-10, a variety of oxophilic metal salts, including AICI,, MgBr,, Yb(OTf),, ZnBr,, TiCl,(Oi-Pr),, and TiCl,(THF), successfully catalyze this process at catalyst loadings as low as 10 mol% (entry 10, TiCl,(THF),). Importantly, reactions conducted in the absence of a Lewis acid catalyst failed to produce any observable Claisen product (entry 1). Origins of Stereoselectivity in the Ketene-Claisen Rearrangement This new Lewis acid-catalyzed ketene-Claisen rearrangement was found to be highly stereoselective. Only one diastereomer of the product was observable by 'H NMR in each example listed in Table 1. Indeed, GC analysis demonstrated that the syn diastereomer was generated preferentially over the anti isomer with >99:1 diastereoselectivity in the presence of every Lewis acid that was successful in this process. The high levels of stereoselectivity observed are the result of two sequential, highly selective steps. First, additions of nucleophiles to monosubstituted ketenes typically result in exclusive formation of the (Z)-enolate (Figure 2).'° Because the lowest unoccupied molecular orbital (LUMO) is the C=O x* orbital, which lies in the plane defined by the 9. (a) Kunng, F.-A.; Gu, J.-M.; Chao, Y.; Mariano, P. S. J. Org. Chem. 1983, 48, 4262. (b) Edstrom, E. D. J. Am. Chem. Soc. 1991, 113, 6690. (c) Maruya, R.; Pittol, C. A.; Pryce, R. J.; Roberts, S. M.; Thomas, R. J.; Williams, J. O. J. Chem. Soc., Perkin Trans. 1 1992, 1617. (d) Vedejs, E.; Gringas, M. J. Am. Chem. Soc. 1994, 116, 579. (e) Diederich, M.; Nubbemeyer, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 1026. (f) Deur, C. J.; Miller, M. W.; Hegedus, L. S. J. Org. Chem. 1996, 61, 2871. 10. Seikaly, H. R.; Tidwell, T. T. Tetrahedron 1986, 42, 2613. ‘ 21 ketene, '' nucleophiles that react with the ketene encounter a destabilizing steric interaction with one of the substituents on the terminal carbon. Thus, approach of the nucleophile occurs preferentially from the less-hindered trajectory opposite the bulkier substitutent of the ketene, resulting in selective formation of the (Z)-enolate. N Nu oO” “oY o7 R 4 99 v9 _ A Nu c=o — art 00 I / 06 | disfavored (E )-enolate favored (Z)-enolate Figure 2. Origins of (Z)-enolate geometry in additions to monosubstituted ketenes. Second, the carbon-carbon bond-forming event is also highly diastereoselective. In a typical Claisen rearrangement of an acyclic allyl vinyl ether, the activation energy for rearrangement through a chair-like topography to the syn product is typically ~3 kcal/mol lower than that of the complementary boat transition state leading to the anti diastereomer.'” At the elevated temperatures required for the traditional Claisen rearrangement of unactivated allyl vinyl ethers (150-200 °C), products can typically be isolated with up to 98:2 diastereoselectivity. However, this Lewis acid-promoted ketene-Claisen rearrangement proceeds smoothly at room temperature, presumably due to acceleration from the dipolar 11. Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am. Chem. Soc. 1993, 115, 995. 12. (a) Vitorelli, P.; Winkler, T.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1968. 51. 1457. (b) Vitorelli, P.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1975, 58. 1293. (c) Vance, R. L.; Rondan, N. G.; Houk, K. N.; Hensen, F.; Borden, W. T.; Komornicki, A.; Wimmer, E. /. Am. Chem. Soc. 1988, 110, 2314. 22 charge distribution of the zwitterionic intermediate, and as a consequence, considerably higher levels of stereocontrol can be achieved. H Me\ oA 142°C Men ANG Cr Mle SUR favored H Me” ZA chair an 98:2 J } ~3 kcal/mol chair:boat Me H H O-|— 142 °C Me Sy Veeeneee---- > ian ww eee > disfavored Me Me Me A boat Figure 3. Origins of diastereoselectivity in acyclic Claisen rearrangements. Scope of the Ketene-Claisen Rearrangement The scope of this new ketene-Claisen reaction was investigated by Vy Dong, and the results of this investigation are summarized in Table 2. A range of substituted allylic pyrrolidines react with methylketene in the presence of 20 mol% TiCl,(THF),, allowing access to alkyl-, aryl-, and even halogen-substituted products (entries 14). The diastereoselectivities observed in each case are uniformly excellent. In addition, a quaternary carbon center can be generated at the position B to the amide moiety in the Claisen adduct by starting with prenyl pyrrolidine as the allyl component (entry 5). Similarly, quaternary substitution at the a-position can be achieved by using dimethyl ketene as the electrophilic reaction partner (entry 6). 23 Table 2. Ketene-Claisen rearrangement of representative allyl pyrrolidines. 20 mol% Cy TiCl4(THF)2 ake 6 oh THF, 23 °C Cy (6) R! entry amine® ketene product* yield syn:anti?“ fe) 1 nN Me 84 _ | \=c=o RoN A Me Oo Me RoN Me . 2 2 I \ecxo an YO 84 >99:1 Me Me RN O Ph 3°? Me 85 399:1 lL \=c=o an Ph Me o 6UCCl RoN Me 77 9:1 ‘ “L \=c=0 “t~ 799: cl Me fe) 5 \=c=o RoN ~ Me Me Me O Ph Me RoN 6 Re L c=o aed 86 ~ Ph Me Me Me “NR, = N-pyrrolidine. ’ Product ratios determined by GLC using a Bodman CC1701 column. ‘Relative configurations assigned by chemical correlation to known compounds (See Experimental section). However, this reaction proved to be somewhat limited in the substrate scope. While trans-substituted allylic pyrrolidines rearrange efficiently with high levels of syn stereoselectivity, cis-alkenes appeared to react much more slowly. For example, as shown in eq 7, treatment of (Z)-2-pentenyl pyrrolidine (11) with methylketene in the presence of 20 24 mol% TiCl,(THF), resulted in <10% conversion to an amide product 12 of low diastereopurity (85:15 anti:syn as measured by 'H NMR). Me 20 mol% Et AZ + \=c= fe) N NA . (7) { N 4 TiCl4(THF)> C i le 12 <10% conversion 85:15 anti:syn A more critical limitation was the necessity of generating and isolating ketene solutions free of metal salts, which further limits the range and synthetic utility of this new methodology. First, because the ketenes used in this study are isolated by codistillation with ethereal solvents, only ketenes of relatively low molecular weight can be used. Second, because the concentrations of these solutions are difficult to ascertain, the ketene reaction partner is typically added to the reaction in vast excess. A more economical procedure would allow the ketene component to be added in only slight excess. Finally, the Lewis acidity of certain metal salts can be buffered by the presence of the strongly donating ethereal solvents in which the ketene is generated. These concerns led us to consider a new strategy that generates ketenes in situ from more readily available, bench-stable precursors. 25 Experimental Section General Information. All non-aqueous reactions were performed using flame- or oven-dried glassware under an atmosphere of dry nitrogen. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego.' Non-aqueous reagents were transferred under nitrogen via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Biichi rotary evaporator. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl prior to use. N,N- diisopropylethylamine and dichloromethane were distilled from calcium hydride prior to use. Air sensitive solids were dispensed in an inert atmosphere glovebox. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still.’ Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching or KMn0O, stain. 'H and '*C NMR spectra were recorded on Bruker DRX-500 (500 MHz and 125 MHz, respectively), AMX-400 (400 MHz and 100 MHz), or AMX-300 (300 MHz and 75 MHz) instruments, as noted, and are internally referenced to residual protio solvent signals. Data for 'H are reported as follows: chemical shift (8 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for '*C are reported in terms of chemical shift. IR spectra were recorded 1. Perrin, D. D.; Armarego, W. L. F. Purificaion of Laboratory Chemicals; 3" ed., Pregamon Press, Oxford, 1988. 2. Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923. 26 on an ASI React-IR 1000 spectrometer and are reported in terms of frequency of absorption (cm). Mass spectra were obtained from the UC Berkeley Mass Spectral facility. Gas chromatography was performed on Hewlett-Packard 5890A and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using a C&C Column Technologies CC-1701 column (30 m x 0.25 mm). General Procedure A: A round bottom flask containing TiCl,(THF), was charged with THF and the allyl pyrrolidine. The solution was stirred for 10 min before the ketene was added in portions of approximately 30 drops every 15 min via a 22 gauge teflon cannula. Addition of ketene (S—7 mL) was continued (1.5—2 h) until the allyl pyrrolidine was completely consumed (1.5-2 h) as determined by TLC (5% Et,N:EtOAc). The resulting dark red solution was quenched with ether and aqueous | N NaOH. The aqueous layer was then extracted with ether, and the combined organic layers were washed with brine, dried, and concentrated. The resulting residue was purified by flash chromatography with 50% Et,O/hexanes to provide the title compounds. General Procedure B: A round-bottomed flask containing TiCl,(THF), was charged with CH,Cl,, then treated with the allyl morpholine, followed by iPr,NEt. The solution was stirred for 5 min before a solution of the acid chloride in CH,Cl, was added dropwise over | min. The resulting dark red solution was stirred until the allyl morpholine was completely consumed (2-6 h) as determined by TLC (EtOAc). The reaction mixture was then diluted with an equal volume of Et,O and washed with aqueous 1 N NaOH. The aqueous layer was then extracted with ether, and the combined organic layers were washed with brine, dried (Na,SO,), and concentrated. The resulting residue was purified by silica gel chromatography (Et,O) to afford the title compounds. 27 General Procedure C: A round-bottomed flask containing TiCl,(THF), was charged with CH,Cl,, then treated with the allyl morpholine, followed by iPr,NEt. The solution was stirred for 5 min before a solution of the acid chloride in CH,Cl, was added slowly by syringe pump over 16 h. The resulting dark red solution was stirred until the allyl morpholine was completely consumed (2—5h) as determined by TLC (EtOAc). The reaction mixture was then diluted with an equal volume of Et,O and washed with aqueous 1 N NaOH. The aqueous layer was then extracted with ether, and the combined organic layers were washed with brine, dried (Na,SO,), and concentrated. The resulting residue was purified by silica gel chromatography (Et,O) to afford the title compounds. Methylketene: Methylketene was freshly prepared for each use according to the procedure of Ward.* Zinc powder was activated by washing with aqueous | N HCl, water, methanol, and ether and was subsequently dried under vacuum. The activated zinc powder (1.0 g, 15.3 mmol) was suspended in THF in a 100 mL receiving flask. The flask was fitted with a short-path distillation apparatus with a 50 mL Schlenk flask connected to the receiving end. The pressure within the apparatus was reduced to 110 torr, and a solution of freshly distilled 2-bromopropionyl bromide (0.52 mL, 5.0 mmol) in THF (3.5 mL) was then added dropwise via a 22 gauge teflon cannula tightened with a metal clamp. The ketene formed immediately and codistilled with the THF. The distillate was collected in the liquid nitrogen cooled Schlenk flask. After addition of acid bromide was complete (8-10 minutes), the distillation was continued for another 5 min. The distillate was then warmed to ~78 °C in a dry ice/acetone bath under nitrogen, resulting in a bright yellow solution that was used without further purification. The IR spectrum of the solution displays an intense ketene band at 2130 cm’. 3. McCarney, C. C.; Ward R. S. J. Chem. Soc., Perkin Trans. 1, 1975,/6, 1600. 28 N-(2-Methyl-4-pentenoyl)-pyrrolidine (Table 2, entry 1). Prepared according to general procedure A from (£)-N-2-propenyl-pyrrolidine (76 mg, 0.68 mmol), TiCl,(THF),, (44 mg, 130 umol), and methylketene to provide the pure product as a yellow oil in 84% yield (96 mg, 0.57 mmol); IR 2980, 2880, 1629, 1463, 1440, 919 cm'; 'H NMR (500 MHz) 6 5.76 (m, 1H, CHCH,), 5.05 (dd, J = 1.5, 3.4 Hz, 1H, CHCH,), 5.01 (dd, J = 1.5, 3.4 Hz, 1H, CHCH,), 3.40-3.49 (m, 4H, (CH,),N), 2.57 (m, 1H, CHC=O), 2.43 (m, 1H, CH,CH=CH,), 2.11 qm, 1H, CH,CH=CH,), 1.93 (m, 2H, CH,CH,N), 1.83 (m, 2H, CH,CH,N), 1.10 (d, J = 6.8 Hz, 3H, CH,CH=O); '°C NMR (125 MHz) 6 174.49, 136.27, 116.30, 46.38, 45.62, 38.02, 37.88, 26.08, 24.26, 16.86; LRMS (FAB) m/z 168 . (MH)*; HRMS (FAB) exact mass calcd for (C, ,H,,NO) requires m/z 167.1310, found m/z 167.1308. N-(2,3-Dimethy-4-pentenoyl)-pyrrolidine (Table 2, entry 2). Prepared according to general procedure A from (£)-N-2-buteny]-pyrrolidine (94.4 mg, 0.753 mmol), TiCl,(THF),, (50 mg, 150 umol), and methylketene to provide the pure product as a yellow oil in 84% yield (114 mg, 0.628 mmol). All spectral data were in complete agreement with those previously reported for N-(2-methyl-4-pentenoy])-pyrrolidine.* (2R*,3R*)-N-(3-Phenyl-2-methyl-4-pentenoyl)-pyrrolidine (Table 2, entry 3). Prepared according to general procedure A from (£)-N-3-Phenyl-2-propeny]l pyrrolidine (107 mg, 0.571 mmol), TiCl,(THF),, (19 mg, 57 umol), and methylketene to ‘ provide the pure product as a white solid in 80% yield (111 mg, 0.46 mmol); mp 85-86 °C; 4. Welch, J. T.; Eswarakrishnan, S. J. Org. Chem. 1985, 50, 26, 5909. 29 IR 2980, 2880, 1629, 1459, 1440, 923 cm''; 'H NMR (400 MHz) 6 7.16-7.30 (m, 5H, Ph), 5.95-6.04 (ddd, J = 8.05, 10.9, 16.5 Hz, 1H, CHCH,), 4.97 (d, J = 0.8 Hz, 1H, CHCH.), 4.93-4.94 (m, 1H, CHCH,), 3.56 (t, J = 9.0 Hz, 1H, CHCH=CH,), 3.40-3.47 (m, 4H, (CH,)O), 2.87 (m, 1H, CHC=O), 1.78-1.91 (m, 4H, CH,CH,N), 0.90 (d, J = 6.8 Hz, 3H, CH,); '*C NMR (100 MHz) 8 173.79, 141.90, 139.76, 128.45, 128.30, 126.44, 115.43, 53.46, 46.59, 45.60, 42.99, 26.01, 24.28, 16.14; LRMS (FAB) m/z 244 (MH)*; HRMS (FAB) exact mass calcd for (C,,.H,,NOH)* requires m/z 244.1702, found m/z 244.1702; Anal. Calcd for C, H, ,NO: C, 78.97; H, 8.70; N, 5.76. Found C, 79.02; H, 8.41; N, 5.71. N-3-Chloro-2-propenyl pyrrolidine (Table 2, entry 4). Prepared according to the procedure of Butler.” (E)-1,3 dichloropropene was added dropwise to a refluxing mixture of pyrrolidine (6.3 mL, 110 mmol), NaHCO, (6.4 g, 76 mmol) and water (6 mL). After stirring the reaction at reflux for 3 h, the organic layer was separated from the aqueous layer and distilled to provide pure product as a colorless oil in 20 % yield (2.2 g, 15 mmol): bp (72 °C, 10 torr); IR 2814, 1637, 1455, 1297, 116, 907 cm'; 'H NMR (400 MHz) 8 6.15 (dt, J = 13.2, 1.2 Hz, 1H, CICHD), 6.03 (m, 1H, CICH=CH), 3.10 (d, J = 7.0 Hz, 1H, CH,CH=CH), 2.50 (m, 4H, (CH,),N), 1.80 (m, 4H, (CH,CH,)N); '*C NMR (100 MHz) 6 Anal. Calcd for C,H, CIN: C, 57.73; H, 8.31; N, 9.62. Found C, 57.41; H, 8.66; N, 9.85. (2R*,3R*)-N-(3-Chloro-2-methyl-4-pentenoyl)-pyrrolidine (Table 2, entry 4). Prepared according to general procedure A from (£)-N-3-Chloro-2-propenyl- pyrrolidine (81.1 mg, 0.557 mmol), TiCl,(THF),, (36 mg, 11 umol), and methylketene to provide 77% yield of the pure product (86.4 mg, 0.431 mmol) as a yellow oil; IR 2980, 5. Butler, G. B.; Ingley, F. L. J. Am. Chem. Soc. 1951, 895. 30 2880, 1633, 1459, 1440, 934 cm'; 'H NMR (500 MHz) 6 5.90 (ddd, J = 8.4, 10.2, 16.9 Hz, 1H, CH=CH,), 5.29 (dt, J = 16.9, 0.9 Hz, 1H, CH=CH), 5.14 (dd, J = 10.3, 19.7 Hz, 1H, CH=CH), 4.50 (t, J = 8.8 Hz, 1H, CHCC), 3.38-3.59 (m, 4H, (CH,),N), 2.83 (m, 1H, CHC=0), 1.79-1.98 (m, 4H, (CH,CH,)N, 1.29 (d, J = 6.8 Hz, 3H, CH,); '*C NMR (125 MHz) 6 171.47, 136.37, 117.83, 65.29, 46.74, 45.68, 45.53, 25.97, 24.25, 15.95; LRMS (FAB) m/z 201 (M)"; HRMS (FAB) exact mass calcd for (C,,H,.CINO)* requires m/z 201.0920, found m/z 201.0917. (2-Methy-3,3-dimethyl-4-pentenoyl)-pyrrolidine (Table 2, entry 5). Prepared according to the general procedure A from (£)-N-3-methy]l-2-butenyl-pyrrolidine (87 mg, 0.62 mmol), TiCl,(THF),, (42 mg, 126 umol), and methylketene to provide 68% yield of the pure product (81 mg, 0.42 mmol) as a yellow oil; IR 2976, 2880, 1725, 1629, 1455, 1436, 1193, 919 cm"; 'H NMR (500 MHz) 6 5.93 (dd, J = 10.3, 17.9 Hz, 1H, CH=CH,), 4.95 (dd, J = 1.4, 6.2 Hz, 1H, CH=CH,), 4.92 (s, 1H, CH=CH), 3.38-3.52 (m, 4H, (CH,),N), 2.44 (q, J = 7.0 Hz, 1H, (CH)C=O), 2.26 (m, 2H, CH,CH,N), 1.86 (m, 2H, CH,CH,N), ), 1.07 (s, 3H, (CH,),C©), 1.03 (d, J = 5.6 Hz, 6H, (CH,),CH=O); '*C NMR (100 MHz) 6 174.04, 146.77, 111.25, 47.25, 45.91, 45.52, 39.35, 26.21, 24.71, 24.38, 23.80, 13.06; LRMS (FAB) m/z 195 (M)"; HRMS (FAB) exact mass calcd for (C,,H,,NO)* requires m/z 195.1623, found m/z 195.1626. (2,2 Dimethy-3-phenyl-4-pentenoyl)-pyrrolidine (Table 2, entry 6). Prepared according to general procedure A from -(E)-N-3-phenyl-2-propenyl-pyrrolidine (68 mg, 0.36 mmol), TiCl,(THF),, (22 mg, 66 umol), and dimethylketene to provide 86% yield of the pure product (111 mg, 0.46 mmol) as a colorless oil; IR 3057, 2980, 2883, 1602, 1471, 1409 cm; 'H NMR (500 MHz) 6 7.18-7.27 (m, 5H, Ph), 6.30 (m, | H, CHCH,), 5.13 (d, J= 10.1 Hz, 1H, CH=CH,), 5.09 (d, J = 16.9 Hz, 1H, CH=CH,), 3.64 (d, J = 9.6 Hz, 1H, 31 CHCH=CH,), 3.07-3.48 (m, 4H, (CH,),O0), 1.65 (m, 4H, (CH,CH,),N), 1.27 (s, 3H, (CH,),CC=0), 1.22 (s, 3H, (CH,),CC=O); '*C NMR (125 MHz) 8 174.86, 141.08, 137.16, 129.09, 127.89, 126.56, 117.09, 57.17, 48.56, 47.36, 27.18, 25.22, 23.61, 22.87; LRMS (FAB) m/z 257 (M)*; HRMS (FAB) exact mass calcd for (C,,H,,NO)* requires m/z 257.1780, found m/z 258.1775; Anal. Calcd for C,H, NO: C, 79.33; H, 9.01; N, 5,44. Found C, 79.01; H, 9.28; N, 5.40. 32 Chapter 3 Development of the Acyl-Claisen Rearrangement’ Reaction Design The research described in Chapter 2 successfully validated our hypothesis that the ketene-Claisen rearrangement is susceptible to Lewis acid catalysis. Indeed, a range of Lewis acidic metal salts were shown to catalyze the reaction of alkyl-substituted ketenes with a variety of allylic tertiary amine substrates. However, the inherent instability of most ketenes and the difficulty with which they are prepared, stored, and isolated limited the utility of this methodology and prompted us to investigate alternate methods of ketene generation. In this context, the amine-promoted dehydrohalogenation of acid chlorides, first demonstrated by Staudinger,’ is a widely used method of generating a broad range of mono- and disubstituted ketenes. Reactive ketenes generated in this manner have been trapped in situ with a variety of reaction partners, including alkenes, enol silanes, imines, and carbonyl! compounds.’ Importantly, this reaction generates ketenes without concomitant formation of a Lewis acidic metal byproduct. We reasoned that the utilization of acid chlorides as ketene surrogates in our Claisen methodology would (1) allow access to a 1. Portions of the research described in this chapter have been published as a communication: Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 1/2], 9726. 2. Staudinger, H. Chem. Ber. 1911, 44, 1619. 3. For recent comprehensive reviews of ketene cycloadditions, see: (a) Clemens, R. J. Chem. Rev. 1986, 86, 241. (b) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159. 33 broader range of a-substituted Claisen adducts, (2) allow the reaction to be conducted without a large excess of the electrophilic reaction partner, and (3) permit the use of non- coordinating solvents that would be less likely to buffer the Lewis acidity of the catalytic: metal salts. Results and Discussion This hypothesis was initially evaluated in the reaction of crotyl pyrrolidine (1) with propiony! chloride (2) in the presence of i-Pr,NEt (Table 1). Gratifyingly, under the influence of 1 equiv dimethylaluminum chloride, the reaction proceeds smoothly to produce the desired Claisen adduct with good conversion (entry 2). Unfortunately, the reaction was Table 1. Effect of Lewis acid on the acyl-Claisen rearrangement of cinnamy] pyrrolidine. Ph O oO . : “y™ Lewis acid Ph” SS i? + me A (1) Cl i-ProNEt Me 3 1 2 CHe2Clo entry Lewis acid equiv % conv“ syn:anti? 1 -- -- -- -- 2 AlMe,Cl 1.0 94 >99:1 3 AlMe,Cl 0.1 34 >99:1 4 MgBr 0.1 20 >99:1 5 Zn(OTf)o 0.1 <5 >99:1 6 TiCl4(THF), 0.1 13 >99:1 7 Yb(OTS)3 0.1 84 >99:1 “ Conversion based on 'H NMR analysis of the unpurified reaction mixture. > Product ratios determined by GLC using a Bodman CC1701 column. 34 less efficient using catalytic amounts of various Lewis acids (entries 3-6). When the catalyst loading of a range of Lewis acidic metal salts is lowered to 10 mol%, the level of conversion as measured by 'H NMR is generally quite low. Good catalytic efficiency is only observed using Yb(OTPf), as the Lewis acid (entry 7). ’ We were concerned that the tertiary amine base might be interacting with the metal center and interfering with the course of the reaction. Table 2 summarizes the results of reactions investigating the effect of base structure on reaction efficiency. To our surprise, high levels of conversion were only observed when i-Pr,NEt was used as the base (entry 1). The use of triethylamine resulted in lower conversion (entry 2), while only traces of the desired product could be observed in the presence of pyridine, DMAP, and DBU (entries 3-5). The success of the reaction did not seem to correlate well to the basicity of the amine used. Table 2. Effect of amine base on the acyl-Claisen rearrangement of cinnamyl pyrrolidine. 0 1 equiv Ph O ein AlMe2Cl Ph N + SA > oo base L> (2) Me CHo2Clo 1 2 3 entry amine base % conv® 1 i-PryNEt 04 2 Et3N 44 3 pyridine <5 4 DMAP 5 “ Conversion based on 'H NMR analysis of the unpurified reaction mixture. 35 More revealingly, TLC analysis of the unsuccessful reactions indicated that a new product was generated. Cinnamyl! pyrrolidine could be recovered unchanged from the reaction, suggesting that the byproduct was the result of decomposition of the acid chloride component. Indeed, the formation of B-lactone 4 by dimerization of methylketene is known to be catalyzed by nucleophilic tertiary amines (Scheme 1).*° Thus, we speculated that the poor conversions observed in the acyl-Claisen rearrangement could be due to consumption of the ketene intermediate in a nonproductive amine-catalyzed dimerization process that is competitive with the desired Claisen rearrangement. Scheme 1 =O | e) Me NRz WAT 3 Me ie) wat J ‘ Me, " ort 7 Me 4 4 Me 4. (a) Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444. (b) Farnum, D. G.; Johnson, J. R.; Hess, R. E.; Marshall, T. B.; Webster, B. J. Am. Chem. Soc. 1965, 87, 5191. (c) Dehmlow, E. V.; Fastabend, U. Synth. Commun. 1993, 23, 79. 5. Enantioselective dimerization of ketenes has been achieved using a chiral tertiary amine catalyst: (a) Calter, M. A. J. Org. Chem. 1996, 61, 8006. (b) Calter, M. A.; Guo, X. J. Org. Chem. 1998, 63, 5308. 36 We became concerned that the N-cinnamyl pyrrolidine substrate itself could be serving as a nucleophilic catalyst for ketene dimerization. Because our initial investigations of the Lewis acid-catalyzed ketene-Claisen utilized ketene solutions added to the reaction in large excess, a competitive pyrrolidine-catalyzed ketene dimerization process would have been less detrimental to the overall yield of the reaction with respect to the limiting pyrrolidine substrate and may have gone unnoticed. In order to investigate this concern, the reaction of propiony! chloride, i-Pr,NEt, and crotyl pyrrolidine was investigated and monitored by ReactIR analysis. This in situ, real- time method of analyzing the course of a chemical reaction by IR spectroscopy proved to be ideal for the analysis of the acyl-Claisen reaction, as distinct characteristic IR signals could be observed for the acid chloride starting material (ca. 1790 cm’'), the ketene intermediate (ca. 2115 cm’), and the amide product (ca. 1635 cm'').° By collecting a number of spectra at uniform intervals over the course of the reaction, the concentration of various species in solution can be monitored by observing changes in the absorbance of the corresponding peaks in the IR spectra.’ 6. Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral Data for Structure Determination of Organic Compounds, 2™ ed.; Springer—Verlag: New York, 1989. 7. The concentration of a species in solution is linearly related to its absorbance by Beer’s Law (A=ecl, where A is absorbance, € is the molar extinction coefficient, c is concentration, and 1 is the path length). 37 propionyl chloride abs 0.04 methylketene ~5.Q00E-2~ 0.10004 0.15004 0.2000 -0, 2500-4 2260 2100 2000 2360 1860 1700 1660 wavenumber (cnr hy time imin) Figure 1. ReactIR spectrum of the crotyl pyrrolidine-catalyzed dimerization of ketene. -0.1606-+ ONE -0.1766- “osaool/ -0.1900- -0.2000-1 -0.2100- -0.2200- -0.2300- -0.2400- -0.2500- -0.2606~ addition of crotyl pyrrolidine —— 200.0 259.0 time cmin} Figure 2. ReactIR profile of the absorbance of the ketene stretch (2115 cm’!). 38 Upon addition of propiony] chloride to a solution of i-Pr,NEt in CH,CI, at -20 °C, ReactIR analysis indicates the appearance of a strong stretch corresponding to the acid chloride carbonyl, which decays gradually as a peak corresponding to the methylketene stretch emerges (Figure 1). When crotyl pyrrolidine is added to the solution, the ketene stretch immediately disappears and the acid chloride stretch becomes greatly diminished in intensity. These results lend credence to our supposition that the N-allyl pyrrolidine substrates can cause ketene dimerization to occur competitively with the Claisen process. In addition, because ketene could be observed in the presence of the sterically encumbered i-Pr,NEt base, it was clear that less nucleophilic amines would be poor catalysts for ketene dimerization and therefore could be present in the reaction without obstructing the Claisen process. As a result, we began to consider other allylic amines that might engage in a facile acyl-Claisen rearrangement without significantly promoting a detrimental ketene dimerization process. In this context, N-allyl morpholine compounds appeared to be ideal candidates for investigation, as the presence of an electron-withdrawing oxygen in the six- membered ring reduces the basicity and nucleophilicty of the morpholine nitrogen relative to pyrrolidine.* Therefore, allyl morpholines are expected to be less efficient catalysts for the dimerization of ketenes (Scheme 2). 8. The pKa of protonated N-methylpyrrolidine is 10.3, while protonated N-methylmorpholine exhibits a pKa of 7.4. Perrin, D. D. Dissociation Constants of Organic Bases in Aqueous Solution; Butterworths: London, 1965. 39 Scheme 2 Me _np—/ OLA Z Oo=-C=—= ~~ oe N~ ~~™Me _ Ls N AL Me oJ Lewis LA acid (LA) Me weaker nucleophile destablized ammonium slower dimerization faster rearrangement catalyst [3,3] LA O Me ~o * Me my _ mh oJ Me —LA oJ Me greater synthetic weaker Lewis base utility faster catalyst turnover In addition, the morpholine substrates would be superior to allyl pyrrolidines for several other reasons. First, the electron-withdrawing effect of the morpholine oxygen would destabilize the cationic charge on the nitrogen of the zwitterionic intermediate and could thereby increase the rate of the sigmatropic rearrangement. Second, the poorer electron-donating ability of the morpholine nitrogen should render the amide carbonyl] of the product less Lewis basic, which would accelerate dissociation of the product from the metal center and improve catalyst turnover. Third, morpholine-derived amides possess 40 greater synthetic utility than their pyrrolidine-derived counterparts. Like Weinreb amides,’ morpholine-derived amides can be directly converted to ketones by treatment with alkylmetal nucleophiles'° and to aldehydes by reduction with LAH."! Table 3. Effect of Lewis acid on the acyl-Claisen rearrangement of crotyl morpholine. Me O Me . he Lewis acid HAAN (3) Lo Cl -ProNEt Me Lo 5 9 CHo2Clo 6 entry Lewis acid equiv yield synianti* 1 -- ~ NR - 2 Y(OTE)3 0.1 59° >99:1 3 MgBry*OEty 0.1 39° >99:1 4 Yb(OTP)3 0.1 80 >99:1 5 AlCl; 0.1 90 >99:1 6 Ti(Oi-Pr)4 0.1 76 >99:1 7 TiCl,(THF)> 0.1 99° >99:1 8 TiCl,(THF)» 0.05 92 >99:] “ Product ratios determined by GLC using a Bodman CC1701 column. ’ Conversion based on 'H NMR analysis of the unpurified reaction mixture. 9. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b) Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15. (c) Williams, J. M.; Jobson. R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1996, 36, 5461. (d) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685. 10. Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997, 1414. 11. Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000, 41, 37. 4] The results of experiments designed to test the effectiveness of morpholine-based substrates in the acyl-Claisen rearrangement are described in Table 3. In accord with our hypothesis, N-crotyl morpholine rearranges efficiently in the presence of catalytic quantities of a range of Lewis acids, including Yb(OTf),, AICl,, Ti(Oi-Pr),Cl,, and TiCl,(THF),. The desired Claisen product 6 was formed in high yield (>75%, entries 4-8) and with the same excellent levels of stereocontrol observed in previous experiments (>99:1 syn:anti). Notably, no products from Claisen rearrangement can be observed when the reaction is performed in the absence of a Lewis acid (entry 1). In analogy to the ketene-Claisen methodology discussed in Chapter 2, TiCl,(THF), again proved to be the most effective Lewis acid for this transformation and could be used in as little as 5 mol% catalyst loading (entry 8). We therefore selected this metal salt for further exploration of the scope of the acyl-Claisen rearrangement. Scope of the Acyl-Claisen Rearrangement Experiments that probe the scope of the allyl morpholine reaction component are summarized in Table 2. Significant structural variation in the allyl substituent (R, = H, alkyl, aryl or halogen, entries 1-4) is possible in the reaction of trans-substituted allylic morpholines while maintaining good yields and excellent levels of diastereoselectivity (>76% yield, >99:1 syn:anti). Notably, the B-chloro-substituted morpholine amide 9 can be isolated in 95% yield without any observable decomposition to the conjugated a,f,y,5- unsaturated B-elimination product. While trans-disubstituted allylic morpholines reacted smoothly with propionyl chloride under the influence of 5-10 mol% of TiCl,(THF),, experiments involving the corresponding cis isomers were initially unsuccessful. Addition of propiony] chloride to cis-crotyl morpholine in the presence of 10 mol% TiCl,(THF), (entry 5) failed to produce the desired Claisen adduct, as indicated by TLC and 'H NMR. However, when 1 equiv 42 TiC1,(THF), was used to promote the reaction, the desired anti-|,2-dimethyl-substituted Claisen product 10 was formed with >95% conversion after 2 h (entry 6). Table 4. Acyl-Claisen rearrangement of representative allyl morpholines and propionyl chloride. . oO OR @) mn TiCl4(THF)> Ae N + Me > 4 4 ion oo FPreNEL CHacl [N o R 23 °C oJ Me entry amine mol% cat product” yield syn:anti?.“ fe) 1 i 10 95 - ie l an YO Me 7 O Me 2 con | 5 ZA 9 >99:1 oJ RoN . : Me Me 6 QO Ph 3 Sal 10 aa 16 >99:1 Ph , Me 8 o ¢ 4 oa N | 10 Z 9 >99:] o J RoN Cl Me 9 oO M 5 J | 10 AZ NR -- fe) RoN Me Me 10 O Me N = 6 Cy? 100 ew YO >954 <5:954 Me ; = oO — o “NR, =N-morpholine. ? Product ratios determined by GLC using a Bodman CC1701 column. ‘ Relative configurations assigned by chemical correlation to a known compound (See Experimental section). “Conversion and diastereoselectivity determined by 'H NMR analysis of unpurified reaction mixture. 43 These results can be understood from an examination of the transition states involved in the rearrangement of each isomer (Scheme 3). Assuming that addition of the allylic morpholine occurs from the less hindered side of the ketene,'* the zwitterionic enolate intermediate should be formed with high (Z) selectivity. In the case of the trans- crotyl morpholine, a low-energy chair-like transition state is accessible that places the methyl substituents in pseudo-equatorial orientations. The corresponding chair-like transition state for the rearrangement of the cis isomer, however, positions one of the methyl substituents in a pseudoaxial orientation, which suffers from a destabilizing 1,3-diaxial interaction with the bulky metal-bound enolate oxygen. Thus, the rate of rearrangement for the cis-croty] morpholine would be expected to be slower than the rate of the trans isomer. As a result, ketene dimerization can compete with the desired rearrangement process, resulting in diminished yields of the desired acyl-Claisen adducts. Scheme 3 _ye \a/ Me O oy ie o=C= —~Ie fast HAA 12. See Chapter 2, Figure 2. 44 We speculated that the reaction of the cis-croty! morpholine isomer could be rendered catalytic in titanium if the rate of ketene dimerization could be diminished with respect to the rate of the desired acyl-Claisen process. Since ketene dimerization is presumably second-order with respect to ketene, while the acyl-Claisen rearrangement involves only one equivalent of ketene, we reasoned that the undesired dimerization process could be avoided by maintaining a relatively low concentration of ketene in solution. We further surmised that the concentration of ketene could be minimized by slow addition of the acid chloride precursor to the reaction over a long period of time. Indeed, as shown in eq 5, when propiony! chloride is added by syringe pump over the course of 10 h, the reaction of cis-croty] morpholine proceeds smoothly to give the desired anti product in 74% yield (95:5 anti:syn) using only 20 mol% TiCl,(THF), O 20 mol% O Me TiCl4(THF % yi Cy ?> + me ye, aw 74% yield oJ Me Cl -ProNEt, CH2Clo o J the 95:5 anti:syn (5) 10h 23 °C addition The scope of acid chlorides tolerated by the reaction was also investigated (Table 5). The reaction is successful using a variety of sterically unhindered alkyl-substituted acid chlorides, such as acetyl chloride, propionyl chloride, and hexenoy! chloride (entires 1-3). Sterically encumbered acid chlorides such as isovaleroyl chloride react much more sluggishly (entry 4), and the a-disubstituted isobutyroyl chloride produced no observable Claisen product (entry 5)."* 13. As dimethyl ketene participates readily in the ketene-Claisen (Chapter 2), we presume that the failure of isobutyroyl chloride in the acyl-Claisen is due to a slow rate of ketene formation. Indeed, ReactIR analysis of the reaction of isobutyroyl chloride with i-Pr,NEt does not provide evidence of the 45 Table 5. Acyl-Claisen rearrangement of allyl morpholines and representative acid chlorides. 1@) Me fe) ZA aaa 0 10 10 molt TiCla rN od (6) oO R -ProNEt, CHCl; CH2Clo © oJ entry allyl amine® — acid-Cl product” yield syn:anti? 0 0 Me 1 RIN SMe oe anor Ae 81 -- 11 O Me 7 2° BINT? Se cl aw 92 >99:] e Me 6 vad 93 >99:1 cl nmBu nBu 12 ie) [e) Me 4. RN~ S7~Me oN aw 284 5 99:1 iPr #Pr 13 O [@) Me M -- 5 RoN~ ~~Me oN e ad NR Me. Mé Me 14 “ NR» = N-morpholine. ? Product ratios determined by GLC using a Bodman CC1701 column. “ Relative stereochemistry assigned by analogy to results summarized in Table 4. ¢ Reaction conducted with 5 mol% TiCl,(THF),. ° 32% conversion as assayed by 'N NMR of the unpurified reaction mixture. formation of dimethylketene (Dong, V. M.; Hughes, C. H.; MacMillan, D. W. C.., unpublished results). 46 As shown in Table 6, heteroatom-substituted acid chlorides also participate in the acyl-Claisen rearrangement. Initial experiments demonstrated that benzyloxyacetyl chloride reacts with trans-crotyl morpholine to afford the expected Claisen product 15 in good yield but with poor diastereoselectivity (entry 1, 92% yield, 67:33 syn-anti). Importantly, it was discovered that when employing the o-benzyloxy acid chloride as the ketene equivalent, Claisen rearrangement product was formed over 24 h even in the absence of a Lewis acid. This background reaction pathway was poorly selective for the production of the anti isomer 16 (entry 2, 26:74 syn:anti). However, when stoichiometric amounts of TiCl,(THF), were employed, good levels of syn selectivity were observed, suggesting that the Lewis acid-mediated process itself is highly diastereoselective (entry 3, 90:10 syn-anti). In attempts to diminish the non-Lewis acid-activated background process, the reaction was Table 6. Optimization of reactions using benzyloxyacetyl chloride. O Me 0 ZA cl JL _osn cy fe) OBn 15 + 23 °C " Z -ProNEt, CHoClo rn i (7) Nite HProNEt, CHoClo o ow oJ fe) Opn 16 entry conditions % yield 15:16 1 10 mol% TiCl,(THF)» 92 78:22 2 no Lewis acid 24° 26:74 3 100 mol% TiCl4(THF) 83? 90:10 4 10 mol% TiCl4(THF)», 10h addition 91 86:14° “ Product ratios determined by 'H NMR. ? Conversions determined by 'H NMR analysis of the unpurified reaction mixture. “ Product ratio determined by GLC using a Bodman CC1701 column. 47 conducted with slow addition of the acid chloride. At lower concentrations of the reactive ketene component, the Lewis acid-catalyzed pathway is favored, resulting in formation of the Claisen product 15 in high yield and diastereoselectivity (91% yield, 86:14 syn:anti). Table 7. Acyl-Claisen rearrangement of allylic morpholines with representative heteroatom-substituted acid chlorides. 3 Oo Rt ZA aan ol 10 10 mol TICla (oN aoe (8) O I iProNEt, CHaCl> 0 oJ entry allylamine® acid-Cl product yield syn:anti?“ O O Me 1 RN SF Me oN ow 91 86:14 OBn Opn 15 oO O Me 2 RN~ ~7>Me ZA 81 92:8 Cl RoN SPh SsPh 17 fe) Oo Me 3. RN~ ~7~Me oN nw 77 >99:1 NPht NPht 18 9 o cl 4° RN Scr oN aw OZ 83 90:10 OBn OBn 19 5 wT? oN RN NF 70 10:90 OBn OBn 20 “NR, = N-morpholine. ? Product ratios determined by GLC using a Bodman CC1701 column. ‘ Relative stereochemistry assigned by analogy to results summarized in Table 4. “ 32% conversion as assayed by 'N NMR of the unpurified reaction mixture. 48 In addition to benzyloxyacetyl chloride, other o-heteroatom-substituted acid chlorides participate successfully in the acyl-Claisen rearrangement (Table 7). Thus, reaction of crotyl morpholine with benzyloxy- and phenylthio-substituted acid chlorides results in the formation of the corresponding c-alkoxy- and o-alkylthio-substituted Claisen adducts (entries 1-2, 81-91% yield, 86:14 to 92:8 syn:anti). This methodology also provides a new strategy for the catalytic production of unnatural B-substituted o-amino acids using a-phthalylglycyl chloride (entry 3, 77% yield, 98:2 syn:anti). Finally, both the syn and anti o-oxy-B-chloro Claisen isomers 19 and 20 can be accessed in high yield and stereoselectivity from chloro-substituted ally! morpholines and benzyloxyacetyl chloride (entries 4-5). The ability to easily generate halogen-bearing stereocenters on an acyclic carbon framework in a highly stereospecific manner using this new Claisen methodology further highlights its value in the construction of otherwise elusive structural motifs.'4 The success of both cis- and trans-disubstituted allyl morpholines in this reaction suggested to us that quaternary carbon centers might also be accessible using this methodology from the rearrangement of 3,3-disubstituted allyl morpholine substrates. Thus, N-prenyl morpholine 21 reacts with propionyl chloride to give 2,3,3-trimethy]- substituted Claisen product 22 in good yield (eq 9). In addition, the propensity for the acyl-Claisen rearrangement to proceed via a highly organized chair-like transition suggested that quaternary carbon stereocenters could be generated stereospecifically from 3,3- disubstuted allyl morpholine substrates. Indeed, as shown in eq 10, reaction of propionyl chloride with 1-methyl-3-N-morpholino-cyclohexene (23) provides very high levels of diastereocontrol in the formation of the quaternary carbon bearing cyclic adduct 24 (70% yield, 95:5 anti:syn). Finally, as illustrated in equation 3, the reaction is also highly 14. A review of chiral auxiliary-based methods for construction of halogenated stereocenters has recently been published: Duhamel, P. Ind. Chem. Libr. 1996, 8, 176. 49 diastereoselective in the rearrangement of acyclic olefins, furnishing 26 with excellent syn selectivity (eq 11, >99:1 syn:anti). Me Oo ak 40 mo!% TiCl4(THF)> i Me Me ZA — rN Me oN -Pr>NEt, CHCl. wy (9) 0 _ Me 23 °C oJ Me 21 22 70% yield me f I% TiCl4(THF) Tr 10 mol% Ti Oo N oN — : N (10) \ / i-ProNEt, CHoCl Me Me 2 23 °C ame oJ Me 23 24 75% yield anti:syn 95:5 Me fe) ~O Et Me AA 10 mol% TiCl4(THF)o. ; a ZA ct cI > awe (11) -ProNEt, CHoClo oJ Me 23°C oe, Me 25 26 72% yield syn:anti>99:1 Analysis of the Acyl-Claisen Rearrangement by ReactIR Our initial investigations of the acyl-Claisen rearrangement were predicated on the mechanistic hypothesis shown in Scheme 4, path B. We surmised that acid chlorides would undergo rapid dehydrohalogenation in the presence of i-Pr,NEt to produce ketenes, which would condense with allylic amines under the influence of a Lewis acid catalyst to generate a zwitterionic intermediate 28. However, we could not rule out the possibility of an alternate “mechanism in which the key zwitterionic intermediate 28 is produced instead by Lewis acid- promoted enolization of acyl ammonium species 27 (path A). 50 Scheme 4 Mes SS N > ° Co a i we KT + oe " AJ path A Me cr 27 Lewis | ;PrNEt Lewis | iPr NEt acid 2 acid 2 ae PAL / oO O MA Me 2A Ss —=C=O > 2) aN path B , A ie L. _ 28 compound IR cm! [3,3] acyl-ammonium 1840 methylketene 2115 O Me acid chloride 1790 awh\yh amide 1635 oJ Me As previously mentioned, the ketene (2115 cm'') and acyl ammonium carbonyl (1840 cm’) produce absorbance peaks in the IR spectrum that are strong and easily distinguishable both from one another and from the acid chloride starting material (1790 cm’') and amide product (1635 cm'') carbony! stretches.° Consequently, we recognized that analysis of reaction progress by ReactIR could potentially identify which reactive intermediates are generated during the course of the reaction. Thus, we monitored the AICl,-catalyzed reaction of crotyl morpholine and propiony] chloride by ReactIR. The region of the IR absorbance, spectrum from 1600-2200 cm'' is shown in Figure 3. Upon addition of propiony! chloride, a peak corresponding to the acid chloride carbonyl appears at 1790 cm’! and decays as a peak corresponding to the product amide develops at 1635 cm”. Additionally, a third peak appears at 2115 cm’', indicating 51 that ketene is indeed generated under the reaction conditions and could lie along the reaction pathway. / product —~- Abs / methylketene ,05900- .04500-| .04600- .03500-4 .03000- 02500- .02000- .01500- .01000- : §,.0008-3-| 9. propionyl chioride ono 8G mR Of OHO FO 2 2260 2106 2060 1900 1800 wavenumber (env! } Figure 3. ReactIR analysis of the AlCl,-catalyzed acyl-Claisen rearrangement. However, the presence of ketene in the reaction solution does not necessarily demonstrate that ketene is directly involved as an intermediate in the reaction. The ketene peak observed under the reaction conditions could simply be the result of an equilibrium concentration of ketene that reverts to acid chloride before forming an acyl ammonium intermediate.'’ In fact, a plot of absorbance vs. time for the acid chloride and ketene peaks suggests that the ketene and the acid chloride are consumed at the same rate (Figure 4), which would be consistent with a rapid pre-equilibrium between the ketene and acid chloride species followed by a slow rate-determining step through either reaction manifold. 15. Ketene formation is known to be reversible: Brady, W. T.; Scherubel, G. A. J. Am. Chem. Soc. 1973, 95, 7447. abs 0,05000-~ 9.04800- 9.04000. 0.03800 0.030004 9.02800- 0.02090 0.01560~ Q.51000- 5. 000E~3-4 product” propionyl chioride 0.0-+ Figure 4. ReactIR profile of the AlCl,-catalyzed acyl-Claisen rearrangement. 3,069 time (h) Ei 4.006 5.060 52 The analysis of the acyl-Claisen rearrangement catalyzed by TiCl,(THF), shown in Figure 5 is more informative. As in the AICl,-catalyzed reaction, addition of propiony] chloride results in the appearance of an acid chloride stretch that decays as an amide signal grows in. However, in this case, the ketene stretch remains constant at a relatively low absorbance throughout the course of the reaction (Figure 6). This profile is inconsistent with a mechanism in which ketene and acid chloride remain in equilibrium throughout the course of the reaction. It is more likely that the ketene is a steady-state intermediate that is generated and consumed rapidly in the subsequent formation of the zwitterionic intermediate 28. Thus, these data discount the intermediacy of an acyl 53 ammonium species and lend additional support for the ketene mechanism we initially proposed. product ~j~ i Abs methyiketene propionyl 9.04560- chloride 0.04000 6,03500-4 ' 0.03000- —— 0.025004 She ) & 4 6.92000- 4 6.91500- = &.01000- ore 5.000E-3- Gf 0.0. ~5. Q00K~-3- 3 a E : b ; { a j 2200 2100 2000 1906 1800 wavenumber (cm!) Figure 5. ReactIR analysis of the TiCl,(THF),-catalyzed acyl-Claisen rearrangement. 54 abs ment gerry cota NEN DN a NASR AOR RL 0.04000- a product a» Y” a 0.93500~ / 0,.03000- / ; oh 0.02500-] \ / \ 0.02000- \ . 4 \ \ 2 0,01500-+ \ propionyt es chloride 0.01000-4 \ | ketene ~~~ §. Q00E+-3- an Oe T y t ¥ T r 1.000 2,000 3.000 time (h) Figure 6. ReactIR profile of the TiCl,(THF),-catalyzed acyl-Claisen rearrangement. Conclusion We have developed a powerful new acyl-Claisen rearrangement that susceptible to Lewis acid catalysis. This methodology tolerates a wide range of alkyl-, aryl-, and heteroatom-substituted acid chloride and allylic morpholine reaction partners. Slow addition of acid chloride to the reaction allows the successful rearrangement of less reactive allyl morpholine substrates without consumption of the intermediate ketene in a non- productive dimerization process. The acyl-Claisen rearrangement is highly stereospecific using allyl morpholine substrates bearing cis- and trans-disubstituted double bonds, and can be employed to establish quaternary carbon stereocenters in a highly diastereoselective manner on both cyclic and acyclic carbon frameworks. Analysis of the reaction by ReactIR 55 spectroscopy supports a mechanism in which ketene generated in situ is directly involved in the reaction pathway. Importantly, this reaction is catalytic in the presence of a variety of metal species and presents an attractive platform for the development of an asymmetric catalytic Claisen variant. 56 Experimental Section General Information. All non-aqueous reactions were performed using flame- or oven-dried glassware under an atmosphere of dry nitrogen. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego.' Non-aqueous reagents were transferred under nitrogen via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Biichi rotary evaporator. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl prior to use. N,N- diisopropylethylamine and dichloromethane were distilled from calcium hydride prior to use, Air sensitive solids were dispensed in an inert atmosphere glovebox. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still.’ Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching or KMn0O, stain. 'H and '°C NMR spectra were recorded on Bruker DRX-500 (500 MHz and 125 MHz, respectively), AMX-400 (400 MHz and 100 MHz), or AMX-300 (300 MHz and 75 MHz) instruments, as noted, and are internally referenced to residual protio solvent signals. Data for 'H are reported as follows: chemical shift (5 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for '°C are reported in terms of chemical shift. IR spectra were recorded “1. Perrin, D. D.; Armarego, W. L. F. Purificaion of Laboratory Chemicals; 3" ed., Pregamon Press, Oxford, 1988. 2. Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923. 57 on an ASI React-IR 1000 spectrometer and are reported in terms of frequency of absorption (cm'). Mass spectra were obtained from the UC Berkeley Mass Spectral facility. Gas chromatography was performed on Hewlett-Packard 5890A and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using the following columns: Bodman Chiraldex T-TA (30 m x 0.25 mm) and C&C Column Technologies CC-1701 (30 m x 0.25 mm). General Procedure A: A round-bottomed flask containing TiCl,e«(THF), was charged with CH,CL,, then treated with the allyllic morpholine, followed by i-Pr,NEt. The solution was stirred for 5 min before a solution of the acid chloride in CH,Cl, was added dropwise over | min. The resulting dark red solution was stirred until the allyllic morpholine was completely consumed (2-6 h) as determined by TLC (EtOAc). The reaction mixture was then diluted with an equal volume of Et,O and washed with aqueous 1N NaOH (5 mL). The aqueous layer was then extracted with ether, and the combined organic layers washed with brine, dried (Na,SO,), and concentrated. The resulting residue was purified by silica gel chromatography (Et,O) to afford the title compounds. General Procedure B: A round-bottomed flask containing TiCl,«(THF), was charged with CH,CL,, then treated with the allyllic morpholine, followed by i-Pr,NEt. The solution was stirred for 5 min before a solution of the acid chloride in CH,Cl, was added slowly by syringe pump over 4-10 h. The resulting dark red solution was stirred until the allylic morpholine was completely consumed (2—6h) as determined by TLC (EtOAc). The reaction mixture was then diluted with an equal volume of Et,O and washed with aqueous 1N NaOH (5 mL). The aqueous layer was then extracted with ether, and the combined organic layers washed with brine, dried (Na,SO,), and concentrated. The resulting residue was purified by silica gel chromatography (Et,O) to afford the title compounds. 58 N-(2-Methyl-4-pentenoyl)-morpholine (Table 4, entry 1). Prepared according to general procedure A from N-ally! morpholine (161 mg, 1.3 mmol), TiCl,e(THF), (42 mg, 0.13 mmol), i-Pr,NEt (336 wL, 0.94 mmol), and propionyl chloride (1.5 mL, 1 M solution in CH,CL,, 1.5 mmol) in CH,Cl, (13 mL) to provide the pure product as a clear oil in 95% yield (221 mg, 1.2 mmol); IR (CH,CL,) 2976, 2864, 1640, 1467, 1436 cm'; 'H NMR (400 MHz) 6 5.66-5.77 (m, 1H, CH=CH,), 4.96-5.05 (m, 2H, CH=CH,), 3.47-3.64 (m, 8H, N(CH,CH,),), 2.64-2.72 (m, 1H, CHCH,), 2.35-2.42 (m, 1H, CH,CH=CH.,), 2.06-2.13 (m, 1H, CH,CH=CH,), 1.08 (d, 3H, CH,); '*C NMR (100 MHz) 8 174.5, 136.0, 116.7, 67.0, 66.8, 46.0, 42.1, 38.1, 35.1, 17.3; LRMS (FAB) m/z 183 (M)*; HRMS (FAB) exact mass calcd for (C, ,H,,NO,) requires m/z 183.1259, found m/z 183.1253. (2R*,3S*)-N-(2,3-Dimethyl-4-pentenoyl)-morpholine (Table 4, entry 2). Prepared according to general procedure A from (£)-N-but-2-enyl morpholine (115 mg, 0.81 mmol), TiCl,°(THF), (27 mg, 81 pmol), i-Pr,NEt (213 wL, 1.22 mmol), and propionyl chloride (980 wL, 1 M solution in CH,Cl,, 0.98 mmol) in CH,Cl, (8.1 mL) to provide the pure product as a colorless oil in 92% yield (148 mg, 0.75 mmol); >99:1 syn-anti. Syn isomer: IR (CH,Cl,) 2972, 2926, 2860, 1633, 1459, 1436 cm'; 'H NMR (300 MHz, CDCI,) 6 5.68 (ddd, J = 7.3, 10.4, 17.5 Hz, 1H, CH=CH,), 4.87-4.96 (m, 2H, CH=CH,), 3.34—3.60 (m, 8H, N(CH,CHL),), 2.52 (dq, J= 7.1, 7.1 Hz, 1H, CHCH,), 2.37 (q, J = 7.1 Hz, 1H, CHCH,), 1.01 (d, J = 6.7 Hz, 3H, CH,), 0.94 (d, J = 6.8 Hz, 3H, CH,); '*C NMR (75 MHz, CDClI,) 5 174.7, 142.3, 114.3, 67.3, 67.0, 46.5, 42.3, 40.5, 40.3, 16.3, 14.8; LRMS (FAB) m/z 197 (M)*; HRMS (FAB) exact mass calcd for (C,,H,,.NO,) requires m/z 197.1416, found m/z 197.1414. Product ratio was determined by GLC with a Bodman T-TA column (70 °C, 2 °C/min gradient, 23 psi); syn adduct (2R,3S and 2S,3R) t,= 39.7 min and 40.8 min, anti adduct (2R,3R and 25,3S) t, = 39.9 min and 40.5 min. 59 1.11 OME 440 wh Ke te 2. Zn, AcOH. 8G °C a Determination of the Relative Configuration of (2R*,3S*)-N-(2,3-Dimethyl- 4-pentenoyl)-morpholine by Correlation with (2R*,3S*)-2,3-Dimethyl-4-pentenoic acid. A solution of (2R*,3S*)-N-(2,3-dimethyl-4-pentenoyl)-morpholine (22 mg, 0.11 mmol) in 1,2-DME (0.25 mL) and H,O (0.25 mL) was placed in an 8 mL scintillation vial equipped with a magnetic stir bar. The solution was treated with iodine (61 mg, 0.24 mmol) and was stirred in the absence of light. After 30 min, the reaction was diluted with Et,O (1 mL) and washed sequentially with 10% aqueous Na,S,O, (1 mL) and brine (1 mL). The resulting organic layer was dried (Na,SO,) and concentrated to give (25*,3S*,4R*)-4- iodomethy]-2,3-dimethyl-y-butyrolactone as a yellow oil. This crude residue was dissolved in glacial ACOH (1 mL) and placed in an 8 mL scintillation vial equipped with a magnetic stir bar. The solution was treated with zinc dust (65 mg, 1.0 mmol) and stirred at 65 °C for 3h. After allowing the reaction to cool to rt, | N HCl (aq) (1 mL) was added, and the mixture was extracted with ether (3 x 1 mL). The organic extracts were combined, dried (Na,SO,), and concentrated to give a light pink oil that exhibited spectral data identical in all respects to those reported for (2R*,3S*)-2,3-dimethyl-4-pentenoic acid.’ (2S*,3S*)-N-(2-Methyl-3-phenyl-4-pentenoyl)-morpholine (Table 4, entry 3). Prepared according to general procedure A from (£)-N-(3-phenyl-2-propeny!)-morpholine (201 mg, 0.99 mmol), TiCl,«(THF), (33 mg, 99 pmol), i-Pr,NEt (258 pwL, 1.43 mmol), and propionyl chloride (1.48 mL, 1 M solution in CH,Cl,, 1.48 mmol) in CH,Cl, (10 mL) at 3. Metz, P. Tetrahedron 1993, 49, 6367. 60 0 °C to provide the pure product as white needles in 74% yield (194 mg, 0.75 mmol); >99:1 syn:anti. Syn isomer: IR (CH,Cl,) 3057, 2988, 2968, 2930, 1637, 1436 cm'; 'H NMR (400 MHz, CDCI,) 6 7.15-7.31 (m, 5H, Ph), 5.99 (ddd, J = 7.8, 10.4, 17.9 Hz, 1H, CH=CH,), 4.95-5.02 (m, 2H, CH=CH,), 3.48-3.66 (m, 9H, N(CH,CH,),, CHPh), 3.04 (dq, J = 6.8, 9.9 Hz, 1H, CHCH,), 0.90 (d, 3H, CH,); '*C NMR (100 MHz, CDCI,) 6 174.0, 141.7, 139.8, 128.6, 128.3, 126.7, 115.7, 67.0, 66.7, 53.4, 46.2, 42.1, 39.7, 16.7; LRMS (FAB) m/z 259; HRMS (FAB) exact mass calcd for (C, H,,NO,) requires m/z 259.1572, found m/z 259.1569. Diastereomer ratio was determined by GLC with a CC- 1701 column (70 °C, 5 °C/min gradient, 25 psi); syn adduct t, = 31.3 min, anti adduct t, = 30.2 min. (2R*,3S*)-N-(3-Chloro-2-methyl-4-pentenoyl)-morpholine (Table 4, entry 4). Prepared according to general procedure A from (E)-N-(3-chloro-2-propenyl) morpholine (112 mg, 0.69 mmol), TiCl,°(THF), (23 mg, 69 pmol), i-Pr,NEt (181 pL, 1.04 mmol), and propionyl chloride (1.04 mL, 1 M solution in CH,Cl,, 1.04 mmol) in CH,Cl, (7 mL) to provide the pure product as a pale yellow oil in 95% yield (143 mg, 0.66 mmol); >99:1 syn:anti . Syn isomer: IR (CH,Cl,) 3057, 2976, 2864, 1640, 1463, 1440 cm'; 'H NMR (300 MHz, CDC1,) 5 5.87 (ddd, J = 8.3, 10.2, 18.5 Hz, 1H, CH=CH,), 5.12-5.31 (m, 2H, CH=CH), 4.51 (t, J = 8.4 Hz, 1H, CHCl), 3.50-3.65 (m, 8H, N(CH,CH,),), 2.98 (dq, J = 6.8, 8.8 Hz, 1H, CHCH,), 1.27 (d, J = 6.8, 3H, CH,); '*C NMR (75 MHz) 6 172.0, 136.6, 118.4, 67.2, 67.0, 65.4, 46.7, 42.7, 42.5, 16.7; LRMS (FAB) m/z 217 (M)*; HRMS (FAB) exact mass calcd for (C,H, CINO,) requires m/z 217.0870, found m/z 217.0868. Product ratio was determined by GLC with a Bodman T-TA column (70 °C, 7 °C/min gradient, 23 psi); syn adduct (2R,3S and 25,3R) t, = 18.7 min and 19.2 min, anti adduct (2R,3R and 25,35) t,= 19.6 min and 19.8 min. Relative configuration assigned by analogy. 61 (2R*,3R*)-N-(2,3-Dimethyl-4-pentenoyl)-morpholine (eq 5). Prepared according to general procedure B from (Z)-N-but-2-enyl morpholine (88 mg, 0.62 mmol), TiCl,°(THF), (42 mg, 0.13 mmol), i-Pr,NEt (163 wL, 0.94 mmol), and propiony! chloride: (750 pL, 1 M solution in CH,Cl,, 0.75 mmol), added over 8h, in CH,Cl, (4.2 mL) to provide the pure product as a clear oil in 74% yield (91 mg, 0.46 mmol); 95:5 anti:syn. Anti isomer: IR (CH,CL,) 2976, 2864, 1637, 1463, 1436 cm'; 'H NMR (400 MHz, CDCI,) 5 5.61 (ddd, J = 8.2, 10.2, 18.3 Hz, 1H, CH=CH,), 4.96-5.12 (m, 2H, CH=CH,), 3.44-3.66 (m, 8H, N(CH,CH,),), 2.36-2.49 (m, 2H, CHCH3), 1.02 (d, J = 6.5 Hz, 3H, CH,), 0.94 (d, J = 6.3 Hz, 3H, CH;); '*C NMR (100 MHz, CDCI,) 8 174.9, 141.6. 115.4, 67.4, 67.1, 46.5, 42.4, 41.8, 40.4, 19.3; LRMS (FAB) m/z 197 (M)"; HRMS (FAB) exact mass for (C, ,H,,NO,) requires m/z 197.1416, found 197.1414. Product ratio was determined by GLC with a Bodman I-TA column (70 °C, 2 °C/min gradient, 23 psi); syn adduct (2R,3S and 25,3R) t,= 39.7 min and 40.8 min, anti adduct (2R,3R and 25,3S) t, = 39.9 min and 40.5 min. N-(3-Methyl-4-pentenoyl)-morpholine (Table 5, entry 1). Prepared according to general procedure A from (£)-N-but-2-enyl morpholine (147 mg, 1.04 mmol), TiCL,°(THF), (35 mg, 0.10 mmol), i-Pr,NEt (255 yL, 1.56 mmol), and propionyl chloride (1.25 mL, 1 M solution in CH,CL,, 1.25 mmol) in CH,Cl, (10 mL) to provide the pure product as a clear oil in 81% yield (155 mg, 0.846 mmol); 'H NMR (300 MHz, CDCI,) 8 5.78 (ddd, J = 6.6, 10.3, 17.2 Hz, 1H, CH=CH,), 4.91-5.03 (m, 2H, CH=CH.), 3.43-3.65 (m, 8H. N(CH,CH,),), 2.61-2.74 (m, 1H, CHCH,), 2.35 (dd, J = 6.8, 14.8 Hz, 1H CH,CH), 2.23 (dd, J = 7.4 Hz, 14.8 Hz, 1H CH,CH), 1.04 d, J = 6.8 Hz, 3H, CH,); '°C NMR (75 MHz, CDCI,) 6 170.8, 143.3, 113.5, 67.3, 67.0, 46.5, 42.2, 39.9, 34.8, 20.1; LRMS (FAB) m/z 183 (M)"; HRMS (EID) exact mass for (C,,H,,NO,) requires m/z 183.1259, found 183.1254. 62 (2R*,3S*)-N-(2-Butyl-3-methyl-4-pentenoyl)-morpholine (Table 5, entry 3). Prepared according to general procedure A from (£)-N-but-2-enyl morpholine (129 mg, 0.914 mmol), TiCl,«(THF), (31 mg, 91 umol), i-Pr,NEt (239 Lb, 1.37 mmol), and hexanoyl chloride (154 uL, 1.10 mmol) in CH,Cl, (9 mL) to provide the pure product as a yellow oil in 93% yield (204 mg, 0.852 mmol); 'H NMR (300 MHz, CDCl,) 6 5.69 (ddd, J = 7.5, 10.3, 17.3 Hz, 1H, CH=CH,), 4.87-4.97 (m, 2H, CH=CH,), 3.40-3.63 (m, 8H. N(CH,CH,),), 2.35—2.46 (m, 2H, CHCH,, CHCH=CH.,), 1.63 (m, 1H, butyl), 1.42 (m, 1H, butyl), 1.02-1.24 (m, 4H, butyl), 0.97 (d, J = 6.7 Hz, 3H, CH,), 0.82 (t, J = 6.8 Hz, 3H, CH,CH,); '°C NMR (75 MHz, CDCI,) & 174.0, 142.3, 114.3, 67.5, 67.1, 46.7, 46.2, 42.3, 40.6, 30.3, 29.8, 23.2, 17.1, 14.3; LRMS (FAB) m/z 239 (M)*; HRMS (EI) exact mass for (C,,H,,NO,) requires m/z 239.1885, found 239.1886. (2R*,3S*)-N-(2-Benzyloxy-3-methyl-4-pentenoyl)-morpholine (Table 7, entry 1). Prepared according to general procedure B from (£)-N-but-2-eny! morpholine (60 mg, 0.43 mmol), TiCl,«(THF), (14 mg, 43 pmol), i-Pr,NEt (111 pL, 0.64 mmol), and benzyloxyacetyl chloride (0.51 mL, 1 M solution in CH,Cl,, 0.51 mmol), added over 2h, in CH,Cl, (8.5 mL) to provide the pure product as a pale yellow oil in 91% yield (112 mg, 0.39 mmol); 86:15 syn:anti. Syn isomer: IR (CH,Cl,) 3068, 2746, 2864, 1640, 1455 cm’!; 'H NMR (400 MHz, CDCl,) 5 7.27-7.36 (m, 5H, Ph), 5.68 (ddd, J = 8.3, 10.2, 18.5 Hz, 1H, CH=CH,), 5.00-5.08 (m, 2H, CH=CH), 4.62 (d, J = 11.7, 1H, CH,Ph), 4.43 (d, J = 11.7, 1H, CH,Ph), 3.92 (d, J = 8.9, 1H, CHOCH,Ph), 3.55~3.70 (m, 8H, N(CH,CH,),), 2.55~2.62 (m, 1H, CHCH,), 1.15 (d, J = 6.6 Hz, 3H, CH,); '*C NMR (100 MHz, CDCI,) 5 169.5, 138.9, 137.3, 128.5, 128.0, 115.8, 84.2, 72.2, 67.1, 66.8, 45.7, 42.5, 41.5, 17.0; LRMS (FAB) m/z 290 (MH)*; HRMS (FAB) exact mass calcd for (C,,H,,NO,) requires m/z 289.1756, found m/z 290.1755. Diastereomer ratios were determined by 'H NMR analysis. Relative configuration assigned by analogy. 63 (2R*,3S*)-N-(3-Methyl-2-phenylthio-4-pentenoyl)-morpholine (Table 7, entry 2). Prepared according to general procedure B from (£)-N-but-2-enyl morpholine (67 mg, 0.48 mmol), TiCl,«(THF), (15.9 mg, 47.5 pmol), i-Pr,NEt (124 wl, 0.71 mmol), and phenylthioacetyl chloride (569 wL, 1 M solution in CH,Cl,, 0.57 mmol), added over 4h, in CH,Cl, (9.5 mL) to provide the pure product as a light orange oil in 81% yield (107 mg, 0.39 mmol); syn:anti 92:8. Syn isomer: IR (CH,Cl,) 3053, 2976, 2864, 1640, 1436 em; 'H NMR (400 MHz, CDCI,) 5 7.47—7.49 (m, 2H, Ph), 7.28-7.30 (m, 3H, Ph), 5.75 (ddd, J = 7.5, 8.8, 16.3 Hz, 1H, CH=CH,), 4.99-5.10 (m, 2H, CH=CH,), 3.73 (d, J = 9.7 Hz, 1H, CHSPh), 3.11-3.58 (m, 8H, N(CH,CH,),), 2.76-2.82 (m, 1H, CHCH,), 1.28 (d, J = 6.8 Hz, 3H, CH,); '*C NMR (100 MHz, CDCI,) 5 169.7, 140.3, 134.0, 129.1, 128.4, 115.6, 78.3, 66.9, 66.4, 53.9, 46.4, 42.3, 39.7, 17.9; LRMS (FAB) m/z 292 (MH)"; HRMS (FAB) exact mass calcd for (C,,~H,,NO,S) requiresm/z 292.1371, found m/z 292.1373. Diastereomer ratios were determined by 'H NMR analysis. Relative configuration assigned by analogy. (2R*,3S*)-N-(Methyl-2-phthalimido-4-pentenoyl)-morpholine (Table 7, entry 3). Prepared according to general procedure B from (£)-N-but-2-enyl morpholine (75 mg, 0.53 mmol), TiCl,«(THF), (17.7 mg, 53 pmol), i-Pr,NEt (139 wL, 0.80 mmol), and phthalylglycyl chloride (1.3 mL, 0.5 M solution in CH,Cl,, 0.64 mmol), added over 3h, in CH,Cl, (10.6 mL) to provide the pure product as white crystals in 77% yield (134 mg, 0.41 mmol); 98:2 syn:anti. Syn isomer: IR (CH,CL,) 3065, 2976, 2864, 1776, 1718, 1660, 1459, , 1436, 1382, 1359 cm''; 'H NMR (400 MHz, CDCI,) 5 7.69-7.81 (m, 4H, PhH), 5.79 (ddd, J=7.6, 10.4, 17.5 Hz, 1H, CH=CH,), 5.04—-5.18 (m, 2H, CH=CH,), 4.76 (d, J = 10.2 Hz, 1H, CHNR,), 3.63—3.71 (m, 1H, CHCH;), 3.39-3.56 (m, 8H, N(CH,CHL),), 0.95 (d, J = 6.8 Hz, 3H, CH,); '°C NMR (100 MHz, CDCI,) 8 167.8, 166.5, 139.6, 134.4, 131.3, 123.6, 64 116.6, 66.8, 66.5, 54.5, 46.3, 42.5, 36.5, 16.5; LRMS (FAB) m/z 329 (MH)*; HRMS (FAB) exact mass calcd for (C,,H,,N,O,)" requires m/z 329.1501, found m/z 329.1504. Diastereomer ratio was determined by GLC with a CC-1701 column (50 °C, 5 °C/min gradient, 25 psi); syn adduct t,= 51.8 min, anti adduct t, = 49.2 min. (2R*,3S*)-N-(2-Benzyloxy-3-chloro-4-pentenoy!)-morpholine (Table 7, entry 4). Prepared according to the general procedure A from (E)-N-(3-chloro-2-propeny])- morpholine (100 mg, 0.62 mmol), TiCl,°(THF),, (21 mg, 62 umol), i-Pr,NEt (151 uL, 86.7 mmol), and propionyl chloride (0.74 mL, | M solution in CH,Cl,, 0.74 mmol) in CH,Cl, (12 mL) to provide the pure product as a yellow oil in 84% yield (160 mg, 0.52 mmol); 90:10 syn:anti. Syn isomer: IR (CH,CL,) 3053, 2976, 2907, 2864, 1648, 1444, 1274, 1247, 1116 cm'; 'H NMR (400 MHz) 8 7.30-7.40 (m, 5H, Ph), 5.92 (ddd, J = 8.5 Hz, J = 10.1 Hz, J = 16.9 Hz, 1H, CH=CH,) 5.39 (d, J = 16.9 Hz, 1 H, CH=CH), 5.26 (d, J = 10.2 Hz, 1 H, CH=CH), 4.72-4.73 (m, 1H, CHCl), 4.71 (d, J = 11.7 Hz, 1H, CH,Ph), 4.57 (d, J = 11.7 Hz, 1H, CH,Ph), 4.33 (d, J = 7.4 Hz, 1H, CHOCH,Ph), 3.50-3.65 (m, 8H, N(CH,CH,),); '*C NMR (100 MHz) 6 167.0, 136.5, 134.4, 128.5, 128.3, 128.1, 119.5, 82.4, 72.5, 66.9, 66.7, 62.4, 45.8, 42.8; LRMS (FAB) m/z 310 (MH)*; HRMS (FAB) exact mass calcd for (C,,H,,CINO,)° requires m/z 310.1210, found m/z 310.1213. Diastereomer ratio was determined by GLC with a CC-1701 column (80 °C, 20 °C/min gradient for 1 min, then 10 °C/min, 23 psi); syn adduct t, = 19.2 min, anti adduct t, = 19.3 min. (2R*,3R*)-N-(2-Benzyloxy-3-chloro-4-pentenoyl)-morpholine (Table 7, entry 5). Prepared according to the general procedure A from (Z)-N-(3-chloro-2-propenyl)- morpholine (82 mg, 0.51 mmol), TiCl,«(THF),, (17 mg, 51 umol), i-Pr,NEt (290 uL, 1.66 mmol), and propionyl chloride (1.52 mL, 1 M solution in CH,CL,, 1.52 mmol) in CH,Cl, 65 (10 mL) to provide the pure product as a yellow oil in 71% yield (110 mg, 0.36 mmol); 90:10 anti:syn. Anti isomer: IR (CH,Cl,) 3057, 2976, 2907, 1652, 1444, 1239, cm'; 'H NMR (400 MHz) 6 7.29-7.38 (m, 5H, Ph), 6.00 (ddd, J = 8.4 Hz, J = 10.1 Hz, J = 16.9 Hz, 1H, CH=CH,), 5.48 (dd J = 0.9 Hz, J = 16.0 Hz, | H, CH=CH,), 5.35 (d, J = 10.2 Hz, 1 H, CH=CH,), 4.75 (t, J = 8.3 Hz, 1H, CHCl), 4.63 (d, J = 12.0 Hz, 1H, CH,Ph), 4.51 (d, J = 12.0 Hz, 1H, CH,Ph), 4.33 (d, J = 8.3 Hz, 1H, CHOCH,Ph), 3.50-3.70 (m, 8H, N(CH,CH,),); '3C NMR (100 MHz) 8 167.3, 136.7, 134.5, 128.6, 128.3, 128.1, 119.8, 78.5, 71.9, 66.9, 66.6, 60.5, 46.0, 42.7; LRMS (FAB) m/z 310 (MH)*; HRMS (FAB) exact mass calcd for (C, ,H, ,CINO,)* requires m/z 310.1210, found m/z 310.1213. Diastereomer ratio was determined by GLC with a CC-1701 column (80 °C, 20 °C/min gradient for 1 min, then 10°°C/min, 23 psi); syn adduct t,= 19.2 min, anti adduct t, = 19.3 min. N-(2,3,3-Trimethyl-4-pentenoyl)-morpholine (22). Prepared according to general procedure B from (£)-N-(3,3-dimethyl-2-propenyl)-morpholine (150 mg, 0.97 mmol), TiCl,(THF),, (32 mg, 96 umol), iPr,NEt (0.70 mL, 4.0 mmol), and propionyl chloride (2.5 mL, 1 M solution in CH,CL,, 2.5 mmol) in CH,Cl, (3 mL) to provide the pure product as a yellow oil in 70% yield (141 mg, 0.667 mmol); IR 2972, 2864, 1633, 1463, 1432, 1239, 1116, 1027,919 cm'; 'H NMR (400 MHz) 6 5.91 (dd, J = 11.0 Hz, 17.2 Hz, 1H, CH=CH,), 4.99 (s, J = 1.47, 1H, CH=CH,), 4.95 (dd, J = 8.72 Hz, 1H, CH=CH,), 3.52-3.67 (m, 8H, morpholine), 2.63 (q, J = 6.9 Hz, 1H, CHC=O), 1.09 (s, 3H, CH,CCH=CH,), 1.07 (d, J = 6.0 Hz, 3H, CH,CHC=0), 1.06 (s, 3H, CH,CCH=CH,); '*C NMR (100 MHz) 6 174.03, 146.49, 111.59, 67.11, 66.74, 46.90, 42.34, 41.91, 39.35, 24.66, 24.10, 13.61; LRMS (FAB) m/z 212 (MH)*; HRMS (FAB) exact mass calcd for (C, ,H, ,NO,H)* requires m/z 212.1651, found m/z 212.1655. 66 3-Methyl-1-morpholinocyclohexene (23). To a solution of 3-methyl-2- cyclohexen-1-one (1.50 g, 13.7 mmol) and morpholine (3.57 g, 41.0 mmol) in CH,Cl, (120 mL) was added Ti(Oi-Pr),. The reaction was monitored by IR for disappearance of the ketone. After 6 h the solution was concentrated and EtOH (45 mL) was added followed by Na(CN)BH, (1.81 g, 28.8 mmol). The solution was stirred for 1 h before 1N NaOH (30 mL) was added. The resulting mixture was extracted with EtOAc (3 x 50 mL), and the combined organic extracts were dried over Na,SO, and concentrated to give an orange oil. The residue was purified by column chromatography on silica gel using EtOAc to furnish the product as a brown oil in 19% yield (0.47 g). The spectral data for 24 were in complete agreement with previously reported literature values.’ (E)-N-(3-Ethyl-3-methyl-2-propenyl)-morpholine (25). 2-Methyl-3-penten-1- ol was prepared using a modification of the procedure outlined by Corey and coworkers:° To a solution of 2-pentyn-1-ol (2.5 mL, 27 mmol) in THF (100 mL) was added Red-Al (8.1 mL of a 3.5 M solution in toluene, 28 mmol). The resulting solution was warmed to reflux for 3.5 h and then cooled to —78 °C, before a solution of iodine (20.5 g, 81.0 mmol) in THF (50 mL) was added dropwise by syringe. The resulting solution was then allowed to warm to rt before Et,O (200 mL) was added, and the reaction mixture washed with 5% Na,SO, (3 x 200 mL), dried (Na,SO,), and concentrated to afford 3-iodo-2-penten-1-ol as a crude product that was used without further purification. To a solution of copper(Diodide (20.1 g, 0.11 mol) and methyl lithium (162 mL of a 1.3 M solution in Et,O, 0.21 mol) in Et,O (60 mL) at 0 °C was added a solution of the 4. Birch, A. J.; Hutchinson, E. G.; Rao, G. S. J. Chem. Soc. Comm. 1971, 2409. 5. Corey, E. J.; Chen, H. K.; Tetrahedron Lett., 1973, 18 , 1611. 67 crude 3-iodo-2-penten-!-ol. The reaction mixture was stirred at 0 °C for 62 h and then washed with sat. aq. NH,C1 (3 x 200 mL), dried (Na,SO,), and concentrated to provide 2- methy]l-3-penten-1-ol in 91% yield (2.1 g, 21 mmol) as a pure oil by 'H NMR analysis. Spectroscopic data of this material were in complete agreement with reported literature values.° Morpholine 25 was prepared using a modification of the procedure outlined by Froyen and coworkers:’ To a solution of 2-methyl-3-peten-1-ol (1.3 g, 13 mmol) and triphenylphosphine (3.6 g, 14 mmol) in THF (10 mL) was added N-bromosuccinimide (2.5 g, 14 mmol). After 15 min, morpholine (2.7 mL, 31 mmol) was added dropwise and the resulting brown solution was heated to 70 °C for 2.5 h. Upon cooling to rt, the reaction mixture was diluted with Et,O (25 mL) and filtered through a pad of Celite®. The filtrate was then extracted with aqueous 1N HCl (100 mL). The product containing aqueous layer was then washed with Et,O (3 x 100 mL), and then made alkaline by the addition of NaOH (4 g). The aqueous solution was then extracted with Et,O (3 x 100 mL), the combined organic layers dried (Na,SO,), and then concentrated by rotary evaporation at 0 °C under reduced pressure. The resulting residue was then distilled (110 °C, 20 mm) to afford (E)-N- (3-ethyl-3-methyl-2-propenyl)-morpholine (25) as a colorless oil in 49% yield (1.0 g, 6.0 mmol); IR 2968, 1455, 1293, 1116, 1004, 907 cm’; 'H NMR (400 MHz) 6 5.21-5.25 (m, 1H, CH=CCH,), 3.65-3.77 (m, 4H, O(CH,),), 2.96 (d, J = 7.0 Hz, 2H, CH,C=CH), 2.44 (m, 4H, N(CH,),), 2.01 (q, J = 7.3 Hz, 2H, CH,CH,), 1.63 (s, 3H, CH,C=CH), 0.97-1.04 (m, 3H, CH,CH,); '*C NMR (100 MHz) 6 141.1, 118.7, 67.0, 56.0, 53.5, 32.4, 16.4, 12.5; 6. Normant, J.F.; Cahiez, G.; Chuit, C.; Villieras, J.; Tetrahedron Lett.; 1973, 26, 2407. 7. Froyen P.; Juvvik, P. Tetrahedron Lett. 1995, 36, 9555. 68 LRMS (FAB) m/z 169 (M)*; HRMS (FAB) exact mass calcd for (C,,H,,NO)* requires m/z 169.1467, found m/z 169.1464. (1°S*,2R)-N-(2-(1-Methylcyclohex-2’-enyl)-propanoyl)-morpholine —_ (24). - Prepared according to general procedure A from 1-methyl-3-N-morpholino-cycohexene 23 (50 mg, 0.28), TiCl,*(THF),, (9 mg, 27 umol), i-Pr,NEt (71 uL, 0.41 mmol), and propionyl chloride (0.41 mL, 1M solution in CH,Cl,, 0.41 mmol) in CH,Cl, (3 mL) to provide the product as a yellow oil in 72% yield (45 mg, 0.36 mmol); 95:5 dr. Major isomer: IR (CH,CL1,) 2968, 2934, 2864, 1633, 1459, 1432, 1239, 1116 cm'; 'H NMR (400 MHz) & 5.72 (d, J = 10.2 Hz, 1H, CH,CH=CH), 5.64 (m, 1H, CH,CH=CH), 3.54-3.70 (m, 8H, N(CH,CH,),), 2.62 (q, J = 6.9 Hz, 1H CHC=O), 1.92 (m, 2H, CH,CH=CH), 1.68-1.73 (m, 1H, CH,), 1.53-1.67 (m, 2H, CH,), 1.34-1.39 (m, 1H, CH,), 1.09 (d, J = 6.9Hz, 3H, CH,CHC=0), 1.06 (s, 3H, CH,CCH=CH); '*C NMR (100 MHz) 6 174.5, 134.1, 126.4, 67.1, 66.8, 50.1, 46.9, 42.1, 37.4, 33.2, 25.0, 24.7, 19.2, 13.3; LRMS (FAB) m/z 237 (M)*; HRMS (FAB) exact mass calcd for (C,,H,,NO,) requires m/z 237.1729, found m/z 237.1731. Diastereomer ratios were determined by 'H NMR analysis. (2R*,3R*)-N-(2,3-Dimethyl-3-ethyl-4-pentenoyl)-morpholine (26). Prepared according to general procedure B from (£)-N-(3-ethyl-3-methyl-2-propeny!l)-morpholine (135 mg, 0.80 mmol), TiCl,°(THF),, (27 mg, 81 umol), i-Pr,NEt (0.56 mL, 3.2 mmol), and propiony! chloride (2.4 mL, 1 M solution in CH,Cl,, 2.4 mmol) in CH,Cl, (2.7 mL) to provide the pure product as a yellow oil in 72% yield (130 mg, 0.58 mmol); >99:1 syn-anti. Syn isomer: IR (CH,C1,) 2972, 1633, 1459, 1432, 1235 cm''; 'H NMR (400 MHz) 6 5.88 (dd, J = 10.9 Hz, 17.6 Hz, 1H, CH=CH,), 5.03 (dd, J = 1.5, 10.9 Hz, 1H, CH=CH,), 4.88 (dd, J = 1.4, 17.6 Hz, 1H, CH=CH,), 3.49-3.64 (m, 8H, N(CH,CH,),), 2.63 (q, J = 6.9 Hz, 1H, CHC=O), 1.32-1.49 (m, 2H, CH,CH,), 1.02 (d, J = 6.9 Hz, 3H, CH,CHC=0O), 0.99 (s, 3H, CH,C), 0.73 (t, J = 7.5 Hz, 3H, CH,CH,); '*C NMR (100 MHz) 8 174.1, 143.8, 67.0, 69 66.7, 66.6, 46.8, 42.7, 42.2, 41.8, 30.9, 18.7, 13.3, 8.3; LRMS (FAB) m/z 225 (M)*; HRMS (FAB) exact mass calcd for (C,,H,,NO,)” requires m/z 225.1710, found m/z 225.1727. ’ ReactIR Analysis of Ketene Dimerization (Figures 1-2). The ReactIR probe was fitted with a Schlenk flask, to which was added CH,Cl, and i-Pr,NEt. The reaction was cooled to —78 °C, and spectra were collected every 1 min. Propionyl chloride was added dropwise to the solution, and the reaction was then gradually allowed to warm to room temperature. After 210 min, crotyl pyrrolidine was added as a solution in CH,Cl.. Monitoring of the reaction was continued for an additional 90 min. The resulting spectra are displayed in Figures 1-2. ReactIR Analysis of the AICI,-Catalyzed Acyl-Claisen Rearrangement (Figure 3-4). The ReactIR probe was fitted with a Schlenk flask containing (£)-crotyl moropholine (130 mg, 0.921 mmol), AICI, (12.3 mg, 92 umol), i-Pr,NEt (240 uL, 1.39 mmol), and CH,Cl, (9 mL). Spectra were collected every | min. Propionyl chloride (120 uL, 1.38 mmol) was added dropwise to the solution, and the reaction was monitored for 5 h. The resulting spectra are displayed in Figures 34. ReactIR Analysis of the TiCl,-Catalyzed Acyl-Claisen Rearrangement (Figure 5-6). The ReactIR probe was fitted with a Schlenk flask containing (E)-crotyl moropholine (196 mg,1.39 mmol), TiCl,(THP), (46 mg, 139 umol), i-Pr,NEt (362 uL, 2.08 mmol), and CH,Cl, (14 mL). Spectra were collected every | min. Propionyl! chloride (145 uL, 1.67 mmol) was added dropwise to the solution, and the reaction was monitored for 4 h. The resulting spectra are displayed in Figures 5-6. 70 Chapter 4 Development of a First-Generation Enantioselective Acyl-Claisen Rearrangement! Reaction Design The Lewis acid-catalyzed acyl-Claisen rearrangement described in Chapter 3 is a highly diastereospecific and functional group tolerant new methodology that is capable of generating a rapid increase in molecular complexity on both cyclic and acyclic carbon frameworks. A variety of Lewis acidic metal salts were shown to be capable of promoting this reaction. Consequently, we believed that this new methodology would be an attractive platform for the development of a new enantioselective variant of the Claisen rearrangement. In the initial design of such a reaction, we drew inspiration from previous successful examples of chiral Lewis acid-mediated reactions.” In particular, chelation of a substrate to a metal center has been demonstrated to be a useful organizational control element in various enantioselective Lewis acid-catalyzed processes.’ We speculated that an a- heteroatom-substituted acid chloride capable of two-point binding could provide a highly organized transition state for an enantioselective Claisen rearrangement. Our initial efforts therefore focused on the reaction involving benzyloxyacetyl chloride as the acid chloride component (Scheme 1). 1. Portions of the research described in this chapter have been published as a communication: Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 2911. 2. For arecent survey of the field, see: Comprehensive Asymmteric Catalysis, Vol 1-3. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Springer, New York, 1999. 3. For example: Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. 71 Scheme 1 Lewis acid fe) 3 osn Chiral Cl + Ry R Results and Discussion A variety of metal-ligand combinations were assayed for their ability to produce the products of the acyl-Claisen rearrangement in enantioenriched form. The metal salts selected for this preliminary investigation were those that proved to be effective catalysts for the acyl-Claisen rearrangement in our initial metal screen, described in Chapter 3. We further chose to focus on chiral ligands that are members of “privileged” classes of ligands; that is, ligand architectures such as binaphthyls,* bis(oxazolines),’ and salens® that have demonstrated the ability to generate an effective chiral environment about a metal center for a wide range of enantioselective processes. 4. For recent reviews of binaphthyl derivatives as ligands in organic synthesis, see: (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992, 503. (b) Akutaqawa, S. App. Cat. A 1995, 128, 171. 5. For recent reviews of chiral bis(oxazoline) ligands in organic synthesis, see: (a) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (b) Pfaltz, A.; In Encyclopedia of Reagents for Organic Synthesis, Vol. 3; Wiley: New York, 1995; p 2094. (b) Ghosh, A. K.; Packiarajan, M.; Cappiello, J. Tetrahedron: Asymm. 1998, 9, 1. 6. For a recent review of chiral metal(salen) colmplexes in organic synthesis, see: Canali, L.;: Sherrington, D. C. Chem. Soc. Rev. 1999, 28, 85. 72 An extensive screen of ligand-metal combinations revealed that magnesium bromide etherate complexes of various isopropylidene bisoxazoline (box) and pyridine bisoxazoline (pybox) ligands’ could promote the acyl-Claisen reaction of benzyloxyacetyl chloride and Table 1. Effect of chiral bis(oxazoline)eMgBr, Lewis acids on the enantioselective acyl- Claisen rearrangement. . S Me Me | oA 0 0 N70 | | > | | | > N. LN N——Mg——N Mgt /\ 2 R Br ‘Br R R Br Br R Mg(box)Bre Mg(pybox)Bro 1 2 1 equiv fe) Me ¢) Lewis acid ANY a N + ZA ————— N oJ “ aw OBn -ProNEt iS bon (1) Me CH2Clo 3 4 ~20 °C 5 entry complex ligand R % conv? % ee? 1 la box t-Bu >95 21 2 1b box Ph 95 24 3 2a pybox t-Bu 37 18 4 2b pybox Ph 70 46 5 2c pybox i-Pr 51 15 6 2d pybox Bn 93 0 “ Conversion of 3 determined by GLC on a Bodman CC1701 using an internal tridecane standard. ” Enantiomeric excess was determined by chiral HPLC using a Chiralcel AD column. 7. Box and pybox ligands were purchased from Aldrich and used as supplied or were prepared by the method of Evans and coworkers: Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541. 73 crotyl morpholine with poor to moderate levels of enantioselectivity. The results of this survey of bis(oxazoline) ligands are summarized in Table 1. In general, the bidentate box ligands (entries 1-2) gave higher levels of conversion than the pybox ligands (entries 3-6). Notably, the phenyl-substituted pybox was the most enantioselective ligand in this preliminary assay, affording the Claisen product in 46% ee, while reactions employing other ligands proceeded in less than 25% ee. Unfortunately, the complexes prepared in situ from phenyl pybox and MgBr,*OEt, were only moderately soluble in methylene chloride and resulted in the formation of heterogeneous slurries. As a consequence, results of reactions employing this complex suffered from poor reproducibility, depending on the concentration of the reaction and the length of time the ligand was allowed to stir with MgBr,*OEt, before the allylic morpholine and acid chloride reaction components were added to the solution. The solubility of the magnesium pybox Lewis acid, however, proved to be dependent on the identity of the metal salt from which the complex was derived. Experiments probing the effect of counterion on the reaction are summarized in Table 2. In contrast to the bromide complex, the phenyl pybox*Mgl,* complex was readily soluble in CH,Cl,, and reproducibly gave superior conversions without significantly impacting the enantioselectivity of the reaction. Other counterions were less successful in promoting the acyl-Claisen rearrangement. 8. The purity of the Mgl, used proved to be important for the reproducibility of the reaction. Optimal results could be obtained using anhydrous powdered Mgl, (99.998%) available from Aldrich (catalog no. 46,610-7). 74 Table 2. Effect of magnesium(II) source on the enantioselective acyl-Claisen rearrangement. 1 equiv O Me O Ph-pybox:MgXo 9) a N | + J o8n 2 a ZA (2) oJ cl EProNEt oJ OBn Me CHClo, -20 °C 3 4 5 entry MgX; salt % conv@ % ee? 1° MgBr7*°OEty 70 46 2° MgBry 72 9 3 Mgl, 89 45 4 Mg(OTf)2 52 30 5 MgsO4 NR -- “ Conversion of 3 determined by GLC on a Bodman CC1701 using an internal tridecane standard. ? Enantiomeric excess was determined by chiral HPLC using a Chiralcel AD column. ‘ Heterogeneous reaction mixture. Having identified the bis(oxazoline)e Mgl, complex as a promising framework for the development of an enantioselective Lewis acid for the acyl-Claisen rearrangement, we next embarked on a more focused exploration of ligand architecture on the enantioselectivity of the reaction. In considering possible ligand designs, we speculated that the additional L- type nitrogen ligand present in the pybox complexes rendered them less Lewis acidic and consequently less efficient promoters than the corresponding box complexes. Thus, we focused our efforts in ligand design on bidentate bis(oxazoline) ligands. In this context, we considered alternate ligand architectures in which the distance and bite angle between the oxazoline nitrogens can be adjusted by systematic variation of the backbone that links the oxazoline units. One of the ligand architectures that initially attracted our interest was the |,2-bis(oxazolinyl)benzene (ArBox) ligands, first described by 75 Bolm and coworkers in 1991.° A variety of these ligands bearing different oxazoline substituents are readily accessible via condensation of 1,2-phthalonitrile with the appropriate enantiopure amino alcohol, as outlined in eq 3. Although the initial report describing this: class of ligands reported the isolation and crystallographic determination of the zinc complex of the phenyl-substituted ArBox ligand, no successful enantioselective processes using these ligands had been reported in the literature prior to our disclosure of the present work. !° oN ok NH»s — CN N ZnCl Cx ro, ; 3) CN chlorobenzene N 2 equiv — ani Table 3 summarizes the results of experiments using members of the ArBox class of ligands. A survey of various substituents on the oxazoline rings revealed that the phenyl- substituted ArBox complex (entry 1, ligand 6) was more reactive and gave significantly higher levels of enantioinduction than the corresponding isopropyl, benzyl, and t-butyl analogs (entries 2-4), in analogy to the results of experiments employing the pybox family of ligands. We therefore speculated that the phenyl substituents could be exerting an electronic, rather than a purely steric, influence over the geometry of the transition state, perhaps through an attractive cation-m interaction with the ammonium cation. 9. Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173. 10. ArBox ligands have given poor results in those reactions in which it has been assayed: (a) Diels—Alder (2% ee): Davenport, A. J.; Davies, D. L.; Fawcett, J.; Garratt, S. A.; Lad, L.; Russell, D. R. Chem. Commun. 1997, 2347. (b) Diels-Alder (racemic): Takacs, J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R., IIL Tetrahedron: Asymm. 1997, 8, 3079. (c) Ketone hydrosilylation (10% ee): Mimoun, H.; de St. Laumer, J. Y.; Giannini, L.; Scopelliti, R.; Floriani, C. J. Am. Chem. Soc. 1999, 121, 6158. (d) Aldol (13% ce): Wiener, J. J. M.; MacMillan, D. W. C.; unpublished results, 76 N N 6 R=FfBu 7 R=Ph 8 R=HPr 10 9 R=Bn Figure 1. ArBox ligands assayed in the enantioselective acyl-Claisen rearrangement. Table 3. Effect of ArBox ligands in the enantioselective acyl-Claisen rearrangement. 1 equiv Oo cl O ligand-Mgl2 Abe 1S) oy , oo 08n i-ProNEt Ss o 11 CHpCly, -20°C © OBn 12 entry ligand % conv % ee? 1 6 30 37 2 7 95 72 3 8 40 57 4 9 87 24 5 10 53 5 “ Conversion of 11 determined by GLC on a Bodman CC1701 using an internal tridecane standard. ? Enantiomeric excess was determined by chiral HPLC using a Chiralcel OJ column. 771 Thus, the effect of electron-withdrawing and -donating substituents on the ArBox framework was also investigated. The results of these experiments are summarized in Table 4.'' In general, the reaction gives better results when 2 equiv of the chiral promoter is used. The presence of electron-withdrawing groups on the benzene backbone results in higher levels of enantioinduction (entries 2-3),'° while electron-donating groups appear to diminish both the efficiency and enantioselectivity of the acyl-Claisen rearrangement (entry 6). Alkoxy groups on the phenyl oxazoline substituents further increased the selectivity of the reaction (entries 7-8). Thus, the p-methoxyphenyl-substituted 4,5-dichloro-1,2- bis(oxazolinyl)benzene ligand 16 resulted in optimal levels of reactivity and oe) a~ Oa = Cl = O N ( 0 =N Cl aN 15 SC) 16 S( ome Figure 2. Modified ArBox ligands assayed in the acyl-Claisen rearrangement. 11. Synthesized by the method of Bolm by condensation of the appropriate amino alcohol with 2,3- naphthalenedicarbonitrile, 3,4-dichloro-1,2-phthalonitrile, or 3,4-dicyano-1,2-methylenedioxybenzene. See ref. 9. 12. Attempts to synthesize more electron-deficient ligands with a perchlorinated benzene backbone were unsuccessful, as the amino alcohols failed to cyclize with 2,3,4,5-tetrachlorophthalonitrile, 78 enantioselectivity and was selected for further investigation of the scope of this new enantioselective Claisen variant. Table 4. Effect of electron-donating and -withdrawing ArBox substituents on the enantioselective acyl-Claisen rearrangement (@) N . 9 ligand-Mgl, BO wg O “7 oI 3A onn i PrNEt 1S e (S) CHeClo, -20 °C " 17 18 equiv entry ligand — ligand*Mgly ~~ % conv % ee? 1 7 2.0 87° 83 2 13 1.0 97 73 3 13 2.0 97 83 4 14 1.0 74 84 5 14 2.0 65° 86 6 15 2.0 12 17 7 16 1.0 63° 81 8 16 2.0 80° 9] “ Conversion of 17 determined by GLC on a Bodman CC1701 using an internal tridecane standard. ° Enantiomeric excess was determined by chiral HPLC using a Chiralcel OJ column. ‘© Isolated yield. Scope of the First-Generation Enantioselective Acyl-Claisen Rearrangement. Having identified ArBoxeMglI, complex 19 as a successful asymmetric promoter of the acyl-Claisen rearrangement depicted in eq 6, we next investigated the effect of acid chloride structure on the selectivity of the reaction (Table 5). In line with our reaction design criteria, the level of enantioselectivity correlates with the ability of the acid chloride to participate in metal chelation. Thus, the highest levels of asymmetric induction were observed using those substrates bearing the most nucleophilic a-alkoxy substituents (entry 1, R=Bn, 91% ee: entry 2, R=Me, 80% ee). Conversely, poorly chelating substrates such as 79 acetoxyacetyl and (t-butyldimethylsilyloxy)acetyl chloride (entries 5 and 6) demonstrate only modest levels of selectivity (37% and 38% ee, respectively). Given this trend, benzyloxyacetyl chloride was chosen for further investigation of the reaction scope. Table 5. Effect of acid chloride structure on the enantioselective acyl-Claisen rearrangement. 19 PMP-CiArBox-Mglo Cl Cl on + Son 2 equiv 19 : awe (6) i-ProNEt : CHClp, -20 °C o OR 17 entry OR % yield % ee 1 OBn 80 91 2 OMe 28 80 3 OPh 48 78 4 OPhCI-4 59 71 5 OTBS 67 38 6 OAc 44 37 “ Enantiomeric excess was determined by chiral GC or HPLC. 80 Table 6. Enantioselective acyl-Claisen rearrangement with alkyl- and aryl-substituted allyl morpholines 9 , 0 or 2 equiv 19 Nn? 7) + > 6 | oN i-ProNEt, CH2Clo an : OBn 23 °C oO OBn R entry amine product* % yield % ee? fe) o J 2 z OBn @) Me 2 ome aN 78 91 oJ 2 : OBn Me Ph fe) N 3° Ss oT 79 91 fe) R2N~ ~Y OBn Ph O Me ; Sel ow <104 _¢ ro, oN : Me - OBn O Ph 5f iS | R PQA 264 79 Pho : OBn “NR, = N-morpholine. ? Enantiomeric excess was determined by chiral GLC or HPLC. ‘Reaction performed using 3 equiv 19. @ Significant quantities of 20 were isolated from this reaction. ° Not determined. / Reaction conducted at 40 °C using 1 equiv 19. The results of an investigation of allyl morpholine structure on the reaction are shown in Table 6. As demonstrated by entries 2 and 3, alkyl and aryl substituents at the methallyl position are tolerated. However, crotyl and cinnamyl morpholine (entries 4 and 5) 81 primarily undergo von Braun fragmentation'* under the reaction conditions, evidenced by the formation of morpholine amide 20 (Scheme 2). We reasoned that electron-withdrawing substituents on the allylic amine would disfavor S,2-type nucleophilic attack on the acyl ammonium species and partition the reaction towards the desired Claisen rearrangement pathway.'* Indeed, as shown in Table 7, electron-deficient allylic morpholines are excellent substrates for this reaction, giving the desired Claisen rearrangement products in good yield with very high levels of enantio- and diastereoselectivity (entries 1-5, 74-95% yield, 86-97% ee, 92-99% dr). Moreover, we determined that relatively mild electronic perturbations on the allylic component could dramatically impact the course of the reaction; whereas crotyl morpholine undergoes predominantly von Braun fragmentation under the reaction conditions (Table 3, entry 4), the corresponding 4-benzoyloxy-substituted compound gives the desired Claisen-rearrangement product in good yield and selectivity (Table 4, entry 3, 13. (a) Von Braun, J.; Engelbertz, P. Ber. 1923, 56, 1573. (b) von Braun, J.; Friedsam, A. Ber. 1930, 63, 2407. (c) von Braun, J.; May, M.; Michaelis, R. Ann. 1931, 490, 189. (d) Hagemann, H. A. Org. React. 1953, 7, 198. . 14. The benzyl ether is easily cleaved under mild conditions (BF,*OEt,, Me,S). Ishizaki, M.; Hoshino, O.; litaka, Y. Tetrahedron Lett. 1991, 32, 7079. This method is being applied in our group in a total synthesis of callipeltoside A: Wiener, J. J. M.; Seo, J. B.; MacMillan, D. W. C., unpublished results. 82 95% yield, 98:2 syn:anti, 91% ee). Importantly, the enantioselective acyl-Claisen reaction remains diastereospecific. Thus, while (£)-(3-chloro-2-butenyl)morpholine yields predominantly the syn Claisen product (entry 4, 95% yield, 98:2 syn:anti, 91% ee), the (Z)-- isomer affords the corresponding anti product with similar levels of stereocontrol (entry 5, 74% yield, 3:97 syn:anti, 91% ee). As in the corresponding TiCl,(THF),-catalyzed reactions described in Chapter 3, formation of the o,8,y,6-unsaturated amide resulting from B-elimination of the chloride substituent is not observed in either case, highlighting the mild reaction conditions employed in this asymmetric Claisen process. Table 7. Electron-deficient allyl morpholine substrates in the enantioselective acyl-Claisen rearrangement. oO R O ; A 3 equiv 19 : 8 oJ cl i-ProNEt, CHoClo : R OBn 23 °C © OBn entr amine roduct® 9% yield syn:anti? % ee? y p y y QO CO.Et 1 TN AZ RA 8 973.96 o J RN = CO.Et Bn O —- PhNO>-4 2 con JAA 2 1 97 o J RoN* PhNO3-4 6Bn 3° 86 92:8 86 CH,OBz OQ QO DD DDD ano 95 98:2 91 Cl N J o anor KZ 74 3:97 91 OBn O + “NR, =N-morpholine. ’ Product ratios determined by chiral GLC or HPLC. Absolute stereochemistry determined by chemical correlation or by analogy. ‘ Reaction performed using 2 equiv 19. 83 A further example of the ability of this new asymmetric acyl-Claisen methodology to access elusive acyclic structural motifs is illustrated in eq 9. The rearrangement of the trisubstituted alkene 21 using 3 equiv 19 results in the formation of Claisen product 22 bearing a quaternary carbon stereogenic center. The geometry of the prochiral olefin is translated with excellent stereochemical fidelity, providing the expected Claisen adduct 22 in 97% ee and 94:6 syn:anti selectivity. fe) Me 0 ALA e088 Se rN A ~co,8t > a y (9) 3 equiv 19 - oJ i-ProNEt, -20 °C oS ben CHeClo 21 22 94:6 syn:anti, 97% ee 75% yield Stereochemical Models'* On the basis of the excellent, predictable diastereoselectivity observed in these reactions, we presume that this asymmetric acyl-Claisen rearrangement proceeds via a cyclic chair-like transition state, in accord with previously established Claisen methodology (see Chapter 1). Additionally, the results of the acid chloride survey summarized in Table 5 strongly suggest that coordination of the a-alkoxy substituent. Taking these considerations into account, semiempirical computational modeling of the presumed transition state was performed at the PM3 level (Figure 3).'° On the basis of the resulting minimized structure 23, we have developed a preliminary working model to explain the origins the 15. Several attempts to produce crystals of complex 19 failed to provide crystals of sufficient quality for X- ray analysis. The 'H NMR spectrum of 19 in CD.Cl, indicated fluxional behavior in solution. 16. PM3 method, MacSpartan, Wavefunction, Inc. 84 enantioinduction observed in this reaction. Coordination of the transition state to the tetrahedral magnesium(IJ) center in a bidentate manner orients one of the PMP substituents over the enolate olefin, blocking the si face and leaving the re diastereoface open for attack, as shown. This model is consistent with the absolute sense of stereoinduction observed in this reaction. si face shielded Figure 3. Transition state model generated by semiempirical computation (PM3). Limitations of the First-generation Enantioselective Acyl-Claisen 85 As demonstrated by the results outlined in Table 6, crotyl morpholine is not successful in the asymmetric acyl-Claisen rearrangement promoted by 19 because of the propensity of the acyl ammonium species to undergo von Braun fragmentation in the presence of the highly nucleophilic iodide counterion. We reasoned that a Lewis acidic metal species with less nucleophilic counterions might be able to successfully promote the acyl-Claisen rearrangement of crotyl morpholine. Unfortunately, the Mg(OTf), and MgCl, complexes of 16 were not successful at promoting this reaction. Use of the corresponding MgBr,*OEt, complex resulted in less von Braun fragmentation, but the reaction was less efficient (eq 10, 21% conv, 73% ee). fe) oa OBn 22% conv Cl 16*MgBro-OEts i. O M OBn (10) fe) After a screen of alternate metal centers, we discovered that the complex of 16 with AICI, could promote the reaction with promising levels of enantioinduction (eq 11, 82% ee). Importantly, no von Braun cleavage was observed by analysis of the unpurified reaction mixture by capillary GC. However, the reaction requires 3 equiv of the chiral promoter; reactions employing fewer equivalents of the chiral aluminum Lewis acid fail to yield products exhibiting substantial ee’s.'’ 17. For example, use of 1 equiv 16*AIC1, results in formation of a Claisen product in only 31% ee. 86 fe) AL oan P O Me Cl 3 equiv 16°AICl, = 70% conv ; = awh 94:6 syn:anti (11) Z /-ProNEt, CH2Cle = 82% (No te -20 °C oJ 6Bn 6 ee 0 Indeed, enantioselective catalysis of acyl-Claisen rearrangements involving benzyloxyacety] chloride proved to be an elusive goal in general. Reactions using only 50 mol% 19 gave the Claisen product in considerably poorer enantioselectivity (eq 12, 42% ee). fe) fe) oa 088 50 mol% 19 A ~A 81% yield - N 9 (12) -ProNEt, CH2Clo : 42% ee (ow 20°C oJ OBn (@) Because the in situ generation of ketenes from acid chlorides results in the formation of an ammonium chloride byproduct, we speculated that the Mgl, promoter could undergo a detrimental salt metathesis reaction to a poorly reactive MgCl, species. In addition, as discussed in Chapter 3, acyl-Claisen reactions involving benzyloxyacetyl chloride exhibit a slow but significant background reaction in the absence of a Lewis acid catalyst. The uncatalyzed reaction of ally! morpholine with benzyloxyacetyl chloride, for example, afforded the Claisen adduct in 42% yield after 24 hours. These concerns prompted us to reconsider bidentate chelation as a design element in the investigation of our second-generation approach to an enantioselective acyl-Claisen rearrangement. 87 Conclusion A first-generation approach to the development of an enantioselective variant of the acyl-Claisen has resulted in the discovery of a magnesium(IIebis(oxazoline) complex 19. The selectivity of the reaction is high when Lewis basic a-alkoxy-substituted acid chlorides are used. Although 2-3 equiv of the chiral promoter are required for optimal levels of enantioselectivity, this chiral Lewis acid successfully promotes the enantioselective and stereospecific reaction of a range of allyl morpholine substrates in 86-97% ee, including alkyl-, aryl-, ester-, and heteroatom-substituted substrates. Quaternary carbon stereocenters can also be accessed in a highly stereoselective fashion. 88 Experimental Section General Information. All reactions were performed using flame- or oven-dried glassware under an atmosphere of dry nitrogen. Commercial reagents were purified prior to use according to the guidelines of Perrin and Armarego.' Non-aqueous reagents were transferred under nitrogen by syringe. Organic solutions were concentrated under reduced pressure using a Biichi rotary evaporator. Methylene choride and N,N- diisopropylethylamine were distilled from calcium hydride immediately prior to use. Chlorobenzene was used as supplied by Acros. (R,R)-1,2-bis(2-phenyloxazolin-4- yl)benzene was prepared as described by Bolm and coworkers.’ Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still.’ Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching or KMnO, stain. 'H and '*C NMR spectra were recorded on Bruker DRX-500 (500 MHz and 125 MHz, respectively), AMX-400 (400 MHz and 100 MHz), AMX-300 (300 MHz and 75 MHz), Varian 1500 (500 MHz and 125 MHz), or Mercury 300 (300 MHz and 75 MHz) as noted, and are internally referenced to residual protio solvent signals. Data for 'H NMR are reported as follows: chemical shift (6 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for 1. Perrin, D. D.; Armarego, W. L. F. Purificaion of Laboratory Chemicals; 3" ed., Pregamon Press, Oxford, 1988. 2. Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173. 3. Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923. 89 '°C NMR are reported in terms of chemical shift. IR spectra were recorded on a Perkin- Elmer 1600 Series spectrometer using NaCl salt plates, and reported in terms of frequency of absorption (cm''). Mass spectra were obtained from the UC Irvine Mass Spectral: Facility. Optical rotations were recorded on a Jasco P-1010 polarimeter (WI lamp, 589 nm, 25°C). Gas chromatography was performed on Hewlett-Packard 5890A and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using the following columns: Bodman Chiraldex T-TA (30 m x 0.25 mm) and C&C Column Technologies CC-1701 (30 m x 0.25 mm). HPLC analysis was performed on a Hewlett-Packard 1100 Series HPLC at 254nm using the following Chiralcel columns: OD-H (25 cm) and OD guard (5 cm), AD (25 cm) and AD guard (5 cm), OJ (25 cm) and OJ guard (5 cm). (R,R)-1,2-Dichloro-4,5-bis(2-phenyloxazolin-4-yl)benzene (14). A solution of 4,5-dichloro-1,2-phthalonitrile (500 mg, 2.5 mmol), (R)-phenylglycinol (1.04 g, 7.6 mmol), and anhydrous ZnCl, (17 mg, 130 umol) in chlorobenzene (9 mL ) was warmed to reflux for 12 h. After cooling to room temperature, the solvent was removed by rotary evaporation, and the residue was partitioned between CH,Cl, (15 mL) and water (15 mL ). The organic phase was dried (Na,SO,), concentrated, and purified by flash chromatography (66:33 hexanes:EtOAc) to afford 579 mg (1.32 mmol, 52% yield) of 2b as a viscous yellow oil. IR (thin film) 3061, 3030, 2898, 1652, 1505, 1488, 1393, 1034 cm'!; 'H NMR (300 MHz, CDC1,) 6 7.26-7.33 (m, 10H, PhH), 6.07 (s, 2H, CIPhH), 5.32 (dd, J = 9.2, 9.2 Hz, 2H, OCH,CHN), 4.67 (dd, J = 8.5, 9.9 Hz, 2H, OCH,CHN), 4.16 (dd, J = 8.2, 8.5 Hz, 2H, OCH,CHN). '°C NMR (75 MHz, CDCI,) & 149.5, 142.4, 128.8, 128.6, 127.7, 127.1, 110.5, 102.5, 75.5, 70.8; HRMS (FAB) exact mass calcd for (C,,H, CILN,O, + H"*) requires m/z 437.0824, found m/z 437.0817. [a], = +68.1 (c = 1.0, CHC1,). 90 (R,R)-1,2-Dichloro-4,5-bis(2-(p-methoxyphenyl)oxazolin-4-yl)benzene (ArCl2-PMPBox 16). (R)-(p-Methoxyphenyl)glycinol was prepared as previously described.* A solution of 4,5-dichloro-1,2-phthalonitrile (2.4 g, 12 mmol), (R)-(p- methoxyphenyl)glycinol (5.0 g, 30 mmol), and anhydrous ZnCl, (160 mg, 1.2 mmol) in chlorobenzene (120 mL) was warmed to reflux for 7 h. After cooling to room temperature, the solvent was removed by rotary evaporation, and the residue was partitioned between CH,Cl, (15 mL) and H,O (15 mL ). The organic phase was dried (Na,SO,), concentrated, and purified by flash chromatography (66:33 to 50:50 hexanes:EtOAc gradient). The resulting solid was recrystallized from EtOAc and hexanes to give 4.0 g (8.0 mmol, 67%) of 2c a white crystalline material. IR (thin film) 1955, 1906, 1833, 1669, 1649, 1514, 1247, 951, 832 cm'; 'H NMR (300 MHz, CDCI,) 6 7.96 (s, 2H, CIPhH), 7.24 (d, J = 8.8 Hz, 4H, MeOPhH), 6.82 (d, J = 8.8 Hz, 4H, MeOPhH), 5.30 (dd, J = 8.5, 9.9 Hz, 1H, OCH,CHN), 4.67 (dd, J = 8.5, 10.2 Hz, 2H, OCH(H)CHN), 4.18 (dd, J = 8.5, 8.5 Hz, 2H, OCH(H)CHN), 3.78 (s, 6H, OCH,). '°C NMR (75 MHz, CDCI,) 5 162.6, 159.0, 134.9, 133.8, 131.8, 128.0, 127.9, 114.0, 75.6, 70.1, 55.3; HRMS (CI) exact mass calcd for (C,,H,,C1,N,O,") requires m/z 496.0957, found m/z 496.0956; [a], = +72.9 (c = 1.0, CHC1,). General Procedure. To a flask charged with ArCl,-PMPBox 16 and anhydrous MglI, in an inert atmosphere, was added CH,Cl, (4 mL) and the resulting pale yellow solution was stirred vigorously for 1 h under an inert atmosphere. The allyl morpholine (0.4 mmol) was then added via syringe as a solution in CH,Cl, (1 mL ). The syringe was rinsed with CH,Cl, (3 x 1 mL), and the combined rinses were added to the reaction flask. The reaction mixture was then treated with i-Pr,NEt, then cooled to -20 °C. At this point, a 4. Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994, 50, 9457. 91 solution of the acid chloride (1.0 M in CH,Cl,) was added over 12 h. After a further 12 h at —20 °C, the reaction mixture was washed with a mixture of EtOAc (25 mL) and 1 N NaOH (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were then washed with saturated aq. NaCl (50 mL), dried (Na,SO,), and then concentrated. The resulting residue was then added to EtOH (15 mL) and set aside. After 6-10 h, the precipitated ArCl,-PMPBox ligand was removed by filtration, and the resulting supernatant solution was concentrated by rotary evaporation. The resulting residue was then purified by preparative HPLC or by flash chromatography. (2S)-N-(2-Benzyloxy-4-pentenoyl)-morpholine (Table 5, entry 1). Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and benzyloxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using MgI, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.1 1 mL, 0.60 mmol) to afford the product as a colorless oil in 80% yield (88 mg, 0.32 mmol); 91% ee. IR (thin film) 2916, 2854, 1643, 1457, 1436, 1114 cm'; 'H NMR (400 MHz, CDCI,) 8 7.27-7.37 (m, 5H, PhH), 5.83 (ddd, J = 7.0, 10.2, 17.1 Hz, 1H, CH=CH,), 5.10-5.17 (m, 2H, CH=CH, ), 4.62 (d, J = 11.7 Hz, 1H, CH,Ph), 4.45 (d, J = 11.7 Hz, 1H, CH,Ph), 6.54 (dd, J = 6.0, 8.0 Hz, 1H, CHOCH,Ph), 3.57-3.83 (m, 8H, N(CH,CH,),), 2.47-2.62 (m, 2H, CH,CH=CH,); '*C NMR (100 MHz, CDCI,) 6 169.6, 137.3, 133.4, 128.5, 128.0, 128.0, 118.0, 79.0, 71.4, 67.1, 66.8, 45.7, 42.6, 36.7; HRMS (CI exact mass calcd for (C,,H,,NO, + H"*) requires m/z 276.1599, found m/z 276.1594; [a], = +30.2 (c = 1.0, CHC1,). The enantiomeric purity was determined by HPLC with a Chiralcel OJ column -and OJ guard column (10% EtOH:hexanes, 1 mL/min flow); t.= 16.8 min and 19.3 min. (2S)-N-(2-Methoxy-4-pentenoyl)-morpholine (Table 5, entry 2). Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and methoxyacetyl 92 chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using Mgl, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 28% yield (22 mg, 0.11 mmol); 80% ee. IR (thin film) 2946, 2853, 2812, 1721, 1659, 1119 cm'; 'H NMR (400 MHz, CDCI,) 8 5.81 (ddd, J=7.0, 10.2, 17.1 Hz, 1H, CH=CH,), 5.09-5.16 (m, 2H, CH=CH.), 4.07 (dd, J = 6.0, 7.8 Hz, 1H, CHOCH,), 3.64-3.78 (m, 8H, N(CH,CHL),), 3.35 (s, 3H, CH,), 2.44-2.55 (m, 2H, CH,CH=CH,); '*C NMR (100 MHz, CDCI,) 8 169.5, 133.4, 117.9, 81.1, 67.1, 66.9, 56.9, 45.6, 42.6, 36.4; HRMS (CI) exact mass calcd for (C,,H,,NO,*) requires m/z 199.1208, found m/z 199.1211; [a], = +2.1 (c = 1.0, CHCI,). The enantiomeric purity was assayed by derivitization of a portion of the product to the iodolactone (I,, 1:1 H,O:DME, 15 min) and analysis by GC with a Bodman Chiraldex T-TA column (50 °C, 1 °C/min gradient, 1 mL/min); minor diastereomer, t, = 92.9 min and 107.7 min. (2S)-N-(2-Phenoxy-4-pentenoyl)-morpholine (Table 5, entry 3). Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and phenoxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using MglI, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 48% yield (50 mg, 0.19 mmol); 78% ee. IR (thin film) 3072, 2968, 2916, 2854, 1643, 1597, 1228 cm’; 'H NMR (400 MHz, CDCl,) 6 7.25- 7.29 (m, 2H, PhH), 6.96-7.00 (m, 1H, PhH), 6.89 (d, J = 8.8 Hz, 2H, PhH), 5.88 (ddd, J = 7.0, 10.0, 17.0 Hz, 1H, CH=CH,), 5.14-5.22 (m, 2H, CH=CH, ), 4.85 (dd, J = 6.5, 7.5 Hz, 1H, CH,OPh), 3.36-3.78 (m, 8H, N(CH,CH,),), 2.70-2.72 (m, 2H, CHCH=CH,); '°C NMR (100 MHz, CDC1,) 6 168.8, 157.2, 132.7, 129:8, 121.8, 118.5. 114.9, 78.5, 67.0, 66.7, 45.8, 42.9, 36.8; HRMS (CI) exact mass calcd for (C,;H,,NO, + H*) requires m/z 262.1443, found m/z 262.1438; [a], = -26.3 (c = 1.0, CHCI,). The enantiomeric purity 93 was determined by HPLC with a Chiralcel OJ column and OJ guard column (3% EtOH:hexanes, | mL/min flow); t, = 28.3 min and 32.6 min. (2S)-N-(2-(p-Chlorophenoxy)-4-pentenoyl)-morpholine (Table 5, entry 4). Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and (p- chlorophenoxy)acetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using Mgl, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 59% yield (70 mg, 0.24 mmol); 71% ee. IR (thin film) 3072, 2968, 2916, 2854, 1643, 1597, 1493, 1234 cm'; 'H NMR (400 MHz, CDC1,) 6 7.23 (d, J = 9.0 Hz, 1H, PhH), 6.83 (d, J = 9.0 Hz, 1H, PhH), 5.87 (ddd, J = 7.0, 10.0, 17.0 Hz, 1H, CH=CH,), 5.15-5.23 (m, 2H, CH=CH,), 4.80 (dd, J = 6.2, 7.5 Hz,, 1H, CH-O(PhCl)), 3.39-3.75 (m, 8H, N(CH,CH,),), 2.68-2.76 (m, 2H, CHCH=CH,); '*C NMR (100 MHz, CDCI,) 5 168.4, 155.8, 132.4, 129.7, 118.7, 116.2, 114.9, 78.9, 67.0, 66.7, 45.8, 42.9, 36.7, HRMS (CI) exact mass caled for (C, ,H, ,NO;CI") requires m/z 295.0975, found m/z 295.0969; [a], = -17.7 (c = 1.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel AD column and AD guard column (3% i-PrOH:hexanes, | mL/min flow); t, = 36.2 min and 41.8 min. (2S)-N-(2-(¢-Butyldimethylsilyloxy)-4-pentenoyl)-morpholine (Table 5, entry 5) Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and (t- butyldimethylsilyl)oxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using Mgl, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 67% yield (81 mg, 0.27 mmol); 38% ee. IR (thin film) 5/77, 2911, 2854, 1643, 1462, 1436, 1249, 839 cm'; 'H NMR (400 MHz, CDCI,) 6 5.75 (ddd, 7.0, 10.1, 17.2 Hz, 1H, CH=CH,), 5.06-5.10 (m, 2H, CH=CH), 4.38-4.45 (m, 1H, CH-OTBS), 3.56-3.85 (m, 8H, N(CH,CH.),), 2.24-2.45 (m, 94 2H, CH,CH=CH,), 0.86 (s, 9H, SiC(CH,);), 0.04 (s, 4H, Si(CH,),); '*C NMR (100 MHz, CDCI,) 6 171.1, 133.5, 118.1, 75.7, 67.1, 67.0, 45.9, 42.7, 39.9, 25.7, 18.1, -4.7, -5.2; HRMS (CD) exact mass calcd for (C, ,H,,NO,Si + H"*) requires m/z 300.1995, found m/z 300.1986; [a], = +6.2 (c = 1.0, CHCl,). The enantiomeric purity was assayed by derivitization of a portion of the product to the deprotected secondary alcohol (2N HCL, MeOH, 30 min) and analysis by GC with a Bodman Chiraldex [-TA column (70 °C, 3 °C/min gradient, 1 mL/min); minor diastereomer, t, = 34.5 min and 35.8 min. (2S)-N-(2-Acetoxy-4-pentenoyl)-morpholine (Table 5, entry 6). Prepared by the general procedure from N-allyl morpholine (51 mg, 0.40 mmol) and acetoxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using Mg], (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 44% yield (40 mg, 0.18 mmol); 37% ee. IR (thin film) 2968. 2926, 2864, 1737, 1654, 1451, 1239 cm'; 'H NMR (400 MHz, CDCI,) 8 5.74 (ddd, J = 7.1, 10.1, 17.1 Hz, 1H, CH=CH,), 5.29 (m, 1H, CHOAc), 5.11-5.13 (m, 2H, CH=CH, ), 3.48-3.69 (m, 8H, N(CH,CH.),), 2.48-2.57 (m, 2H, CH,CH=CH,), 2.10 (s, 3H, OAc); ); '*C NMR (100 MHz, CDCI,) 6 171.0, 168.2, 132.3, 119.3, 69.6, 67.2, 66.8, 46.4, 42.8, 36.0, 21.0; HRMS (CI) exact mass calcd for (C,,H,,NO,") requires m/z 227.1158, found m/z 257.1152; [a], = -4.3 (c = 1.0, CHCI,). The enantiomeric purity was assayed by derivitization of a portion of the product to the deprotected secondary alcohol (NaBH,, MeOH, 2 h) and analysis by GC with a Bodman Chiraldex [-TA column (70 °C, 3 °C/min gradient, 1 mL/min); minor diastereomer, t, = 34.6 min and 35.9 min. (2S)-N-(2-Benzyloxy-5-methyl-4-pentenoyl)-morpholine (Table 6, Entry 2). Prepared by the general procedure from N-methallyl morpholine (57 mg, 0.40 mmol) and benzyloxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using Mg], 95 (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 78% yield (90 mg, 0.31 mmol); 91% ee. IR (thin film) 3072, 3030, 2968, 2916, 2854, 1643, 1457, 1436 cm'; 'H NMR (400 MHz, CDCI,) 5 7.21—7.34 (m, 5H, PhH), 4.83 (s, 1H, CMe=CH,), 4.77 (s, CMe=CH,), 4.60 (d, 1H, J = 11.6 Hz, 1H, CH,Ph), 4.43 (d, 1H, J = 11.6 Hz, 1H, CH,Ph), 4.33 (dd, J = 5.5, 8.7 Hz, 1H, CHOCH,Ph), 3.56-3.75 (m, 8H, N(CH,CH.),), 2.52 (dd, J = 8.7, 14.3 Hz, 1H, CH,CMe=CH,), 2.41 (dd, J = 5.4, 14.3 Hz, 1H, CH,CMe=CH,); '*C NMR (100 MHz, CDCI,) 6 169.9, 141.1, 137.3, 128.5, 128.0, 128.0, 113.6, 78.5, 71.6, 67.1, 66.8, 45.7, 42.5, 40.6, 22.5; HRMS (CI) exact mass calcd for (C,,H,,NO, + H*) requires m/z 290.1756, found m/z 290.1764; [a], = +30.0 (c = 1.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel OJ column and OJ guard column (6% i- PrOH:hexanes, 1 mL/min flow); t,= 14.8 min and 16.4 min. (2S)-N-(2-Benzyloxy-5-phenyl-4-pentenoyl)-morpholine (Table 6, entry 3). Prepared by the general procedure from N-(2-phenyl-2-propenyl)morpholine (81 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,Cl,, 1.0 mmol), using Mgl, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i-Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 79% yield (111 mg, 0.32 mmol); 90% ee. IR (thin film) 3030, 1926, 1854, 1716, 1643, 1509, 1451, 1244 cm'; 'H NMR (300 MHz, CDC1,) 5 7.20-7.40 (m, 10H, PhH), 5.39 (d, J = 1.4 Hz, CPh=CH,), 5.20 (d, J = 1.1 Hz, CPh=CH,), 4.55 (d, J= 11.5 Hz, 1H, CH,Ph), 4.35 (d, J = 11.5 Hz, 1H, CH,Ph), 4.28 (dd, J = 6.9, 7.1 Hz, 1H, CHOCH,Ph), 3.42-3.63 (m, 8H, N(CH,CH,),), 3.00 (dd, J = 0.8, 6.9 Hz, 2H, CH,CPh=CH,); '*C NMR (75 MHz, CDCI,) 8169.6, 143:5, 139.9, 137.1, 128.3, 128.2, 127.8, 127.6, 126.0, 115.8, 99.9, 77.0, 71.4, 67.0, 66.6, 45.6, 42.4, 38.5; HRMS (CI) exact mass caled for (C,,H,,NO, + H*) requires m/z 352.1912, found m/z 359.1919; la], = +4.9 (c = 1.0, CHCI,). The enantiomeric purity was determined by 96 HPLC with a Chiralcel AD column and AD guard column (10% i-PrOH:hexanes, 1 mL/min flow); t,= 13.4 min and 16.0 min. (28,3S)-N-(2-Benzyloxy-3-(ethoxycarbonyl)-4-pentenoyl)-morpholine (Table 7, entry 1) Prepared by the general procedure from (E)-ethyl 4-morpholinocrotonate (74 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,CL,, 1.0 mmol), using MgI, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i- Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 84% yield (111 mg, 0.32 mmol); syn:anti 97:3; syn 96% ee. Syn isomer: IR (thin film) 2968, 2916, 2864, 1737, 1649, 1457, 1441 cm''; 'H NMR (400 MHz, CDCl,) 6 7.27-7.37 (m, 5H, PhH), 5.75 (ddd, J = 9.1, 10.1, 17.1 Hz, 1H, CH=CH,), 4.61 (d, J= 11.7 Hz, 1H, CH,Ph), 4.60 (d, J = 10.5 Hz, 1H, CH-OBn), 4.51 (d, J = 11.7 Hz, 1H, CH,Ph), 4.11-4.25 (m, 2H, OCH,CH,), 3.50-3.65 (m, 9H, CH-CH=CH,), N(CH,CH,),), 1.24 (t, J = 7.1 Hz, OCH,CH,); '°C NMR (100 MHz, CDC1,) 6 171.1, 167.6, 136.9, 130.7, 128.4, 128.1, 128.1, 120.6, 79.4, 72.3, 67.0, 66.7, 61.2, 54.0, 45.7, 42.5, 14.1; HRMS (CD exact mass calcd for (C,,H,,.NO, + H*) requires m/z 348.1811, found m/z 348.1804; [a], = -31.8 (c = 1.0, CHCI,). The enantiomeric purity and diastereomer ratio were determined by HPLC with a Chiralcel AD column and AD guard column (10% EtOH:hexanes, 1 mL/min flow); syn isomer, t.= 15.5 min and 20.6 min; anti isomer, t, = 14.1 min and 19.5 min. (2S,3S)-N-(2-Benzyloxy-3-(p-nitrophenyl)-4-pentenoyl)-morpholine (Table 7, entry 2) Prepared by the general procedure from (£)-N-(p-nitrocinnamyl])morpholine (99 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,CL, 1.0 mmol), using Mgl, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i- Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 82% yield (136 mg, ().33 mmol); syn:anti 99:1; syn 97% ee. Syn isomer: IR (thin film) 3061, 2968, 2911, 2854, 97 1737, 1649, 1519, 1457, 1436, 1348, 1239 cm'; 'H NMR (300 MHz, CDCI,) 6 8.14 (d, J = 8.8 Hz, 2H, (NO,)PhH), 7.35 (d, J = 8.8 Hz, 2H, (NO,)PhH), 7.21-7.25 (m, 3H, CH,PhH), 6.99 (d, J = 7.7 Hz, 2H, CH,PhH), 5.94 (ddd, J = 8.8, 10.4, 17.0 Hz, 1H, CH=CH,), 5.08- 5.18 (m, 2H, CH=CH,), 4.52 (d, J = 12.1 Hz, 1H, CH,Ph), 4.44 (d, J = 9.6 Hz, 1H, CHOBn), 4.27 (d, J = 11.8 Hz, 1H, CH,Ph), 3.87 (dd, J = 9.1, 9.1 Hz, 1H, CH-CH=CH.,), 3.51-3.76 (m, 8H, N(CH,CH,),); ‘°C NMR (75 MHz, CDC1,) 8 168.0, 147.8, 146.6, 136.1, 135.1, 129.1, 128.3, 128.0, 127.8, 123.5, 118.7, 81.8, 72.0, 67.0, 66.6, 53.0, 45.6, 42.7; HRMS (CI) exact mass calcd for (C,,H,,N,O, + H*) requires m/z 397.1763, found m/z 397.1756; [a]p = +4.0 (c = 1.0, CHCI,). The enantiomeric purity and diastereomer ratio were determined by HPLC with a Chiralcel AD column and AD guard column (15% i- PrOH:hexanes, 1 mL/min flow); syn isomer, t = 16.7 min and t = 26.1 min; anti isomer, t, = 21.9 min and 29.5 min. (2S,3R)-N-(2-Benzyloxy-3-(benzoyloxymethyl)-4-pentenoyl)-morpholine (Table 7, entry 3). Prepared by the general procedure from (E)-N-(4-benzoyloxy-2- butenyl)morpholine (105 mg, 0.40 mmol) and benzyloxyacetyl chloride (0.48 mL, 1.0 M solution in CH,Cl,, 0.48 mmol), using MgI, (222 mg, 0.80 mmol), ArCl,-PMPBox 2c (398 mg, 0.80 mmol), and i-Pr,NEt (0.11 mL, 0.60 mmol) to afford the product as a colorless oil in 86% yield (140 mg, 0.34 mmol); syn:anti 92:8; 86% ee. Syn isomer: IR (thin film) 3072, 3030, 2968, 2916, 2854, 1716, 1643, 1451, 1275 cm'; 'H NMR (400 MHz, CDCI,) 6 7.94 (d, J = 7.1 Hz, 2H, C(O)PhH), 7.53 (t, J = 7.4 Hz, 1H, C(O)PhH), 7.39 (dd, J = 7.9, 7.5 Hz, 2H, C(O)PhH), 7.18-7.28 (m, 5H, CH,(PhH)), 5.78 (ddd, J = 9.3, 10.2, 17.1 Hz, 1H, , CH=CH,), 5.15-5.21 (m, 2H, CH=CH), 4.65 (d, J = 11.7 Hz, 1H, CH,Ph), 4.49-4.51 (m, 2H, CH,OBz), 4.42 (d, J = 11.7 Hz, 1H, CH,Ph), 4.27 (d, J = 9.5 Hz, 1H, CHOBn), 3.54-3.73 (m, 8H, N(CH,CH,),), 2.91-2.96 (m, 1H, CH-CH=CH,); '*C NMR (100 MHz, CDC1,) 6 168.6, 166.3, 136.8, 134.0, 133.0, 130.0, 129.6, 129.5, 128.5, 128.4, 128.2, 128.2, 98 120.3, 97.4, 72.3, 67.1, 66.7, 64.5, 46.7, 45.6, 42.6; HRMS (CI) exact mass caled for (C,,H,,NO,; + H*) requires m/z 410.1967, found m/z 410.1952; [a], = +8.6 (c = 1.0, CHCI,). The enantiomeric purity and diastereomer ratio were determined by HPLC with a Chiralcel OD-H column and OD guard column (10% i-PrOH:hexanes, | mL/min flow); syn isomer, t, = 20.1 min and 29.5 min; anti isomer, t, = 23.2 min and 26.0 min. (2S,3R)-N-(2-Benzyloxy-3-chloro-4-pentenoyl)-morpholine (Table 7, entry 4). Prepared by the general procedure from (E£)-N-(3-chloro-2-propenyl)morpholine (65 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,CL, 1.0 mmol), using Mgl, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i- Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 95% yield (118 mg, 0.38 mmol); syn:anti 98:2; 91% ee. 'H NMR, '*C NMR, IR, and mass spectral data for this compound were consistent with those previously reported.’ [a], = —5.8 (c = 1.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel OJ column and OJ guard column (10% EtOH:hexanes, 0.5 mL/min); syn isomer, t = 53.0 min and t = 61.5 min. The diastereomer ratio was determined by GC with a CC-1701 column (70 °C, 7 °C/min gradient, 1 mL/min); syn isomer, t, = 29.8 min, anti isomer, t, =30.3 min. (2S,3S)-N-(2-Benzyloxy-3-chloro-4-pentenoyl)-morpholine (Table 7, entry 5). Prepared by the general procedure from (Z)-N-(2-phenyl-2-propenyl)morpholine (81 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,CL,, 1.0 mmol), using Mgl, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i-Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 79% yield (111 mg, 0.32 mmol). 'd NMR, '*C NMR, IR, and mass spectral data for this compound were consistent 5. Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726. 99 with those previously reported.” [a], = +54.9 (c = 1.0, CHCI,). The enantiomeric purity and diastereomer ratio were determined by HPLC with a Chiralcel OJ column and OJ guard column (6%:1% i-PrOH:EtOH:hexanes, | mL/min flow); anti isomer, t, = 37.6 min and 51.0 min; syn isomer, t, = 48.2 min. (2S,3S)-N-(2-Benzyloxy-3-(ethoxycarbonyl)-3-methyl-4-pentenoyl)- morpholine (22). Prepared by the general procedure from ethyl (£)-4-morpholino-2- methylcrotonate (85 mg, 0.40 mmol) and benzyloxyacetyl chloride (1.0 mL, 1.0 M solution in CH,Cl,, 1.0 mmol), using MglI, (334 mg, 1.2 mmol), ArCl,-PMPBox 2c (597 mg, 1.2 mmol), and i-Pr,NEt (0.21 mL, 1.2 mmol) to afford the product as a colorless oil in 75% yield (109 mg, 0.30 mmol); syn:anti 94:6; syn 97% ee. IR (thin film) 3093, 3051, 2968, 2906, 2854, 1732, 1654, 1457, 1441, 1239 cm'; 'H NMR (300 MHz) 6 7.26-7.34 (m, 5H, Ph), 5.94 (dd, J = 10.7, 17.3 Hz, 1H, CH=CH,), 5.11-5.18 (m, 2H, CH=CH), 4.76 (s, 1H, CHOBn), 4.59 (d, J = 11.8 Hz, CH,Ph), 4.43 (d, J = 11.8 Hz, CH,Ph), 4.06-4.21 (m, 2H, OCH,CH;), 3.34-3.60 (m, 8H, N(CH,CH,),), 1.44 (s, 3H, CH), 1.21 (tj J = 7.1 Hz, OCH,CH,); '*C NMR (75 MHz, CDCI,) 5 173.0, 167.2, 137.1, 136.8, 128.2, 127.9, 127.9, 116.3, 79.2, 72.5, 67.0, 66.4, 61.3, 53.9, 46.4, 42.4, 15.4, 14.1; HRMS (CI) exact mass calcd for (C,,H,,NO, + H*) requires m/z 362.1967, found m/z 362.1960; [a], = —33.6 (c = 1.0, CHC1,). The enantiomeric purity and diastereomer ratio were determined by HPLC with a Chiralcel AD column and AD guard column (6% i-PrOH:hexanes, 1 mL/min flow); syn isomer, t, = 15.7 min and 17.6 min; anti isomer, t, = 16.5 min. 100 O O 1. lo, 1:1 H2O:DME wee 2. Zn®, AcOH, 65 °C Meo NF oJ on 3. TMS-CHNo, MeOH 6Bn $1 Determination of the absolute configuration of (2S)-N-(2-benzyloxy-4- pentenoyl)-morpholine by correlation with (2S)-2-benzyloxy-4-pentenoic acid methyl ester (S1). A solution of (25)-N-(2-benzyloxy-4-pentenoyl)-morpholine (23 mg, 84 umol) in 2 mL 1:1 water/ DME was placed in an 8 mL scintillation vial equipped with a magnetic stir bar. The solution was treated with iodine (53 mg, 0.21 mmol) and stirred at 23 °C for 10 min. The reaction was then quenched with 10% aqueous Na,S,O, (1 mL) and extracted into Et,O. The resulting organic layer was dried (Na,SO,) and concentrated. The unpurified iodolactone product was then taken up in glacial ACOH (i mL). The resulting solution was then treated with zinc dust (55 mg, 0.84 mmol) and stirred at 65 °C for 1.5 h. Upon cooling to ambient temperature, 1 N HCl (aq) (1 mL) was added, and the resulting mixture was extracted with Et,O (3 x 1 mL). The organic extracts were combined, dried (Na,SO,), and concentrated. The resulting carboxylic acid was then taken up in MeOH and TMS-CHN, (2.0 M in hexanes) was added dropwise until a bright yellow color persisted. The reaction was then treated with a drop of AcOH and concentrated. The residue was purified by flash chromatography (5:1 hexanes:EtOAc) to afford 9.5 mg (43 umol, 52% yield) of a clear oil that was spectroscopically identical in all respects to the compound (25)- 2-benzyloxy-4-pentenoic acid methy] ester.° [a], (literature) = +46 (c = 1.0, CHCI,); [oa], (observed) = +55 (c = 1.0, CHC). 6. Kato, Y.; Ohta, H.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 1303. 101 (e) 1?) O O 2 He, PdiC BL Ae Ho, Pd/C st ~0 ‘ Determination of the absolute stereochemistry of (25,3S)-N-(2-benzyloxy-3- chloro-4-pentenoyl)-morpholine by correlation with (2S)-N-(2-hydroxy- pentanoyl)-morpholine (S1). A suspension containing (2S)-N-(2-benzyloxy-4- pentenoyl)-morpholine (19 mg, 68 umol) of known absolute configuration (vide supra) and 10% palladium on carbon (25 mg) in 1 mL ethanol was stirred under an atmosphere of H, for 30 min. The catalyst was removed by filtration through a short plug of celite, and the filtrate was concentrated. Purification of the residue by flash chromatography (1:1 hexanes:EtOAc) afforded 12 mg (68 umol, 96% yield) of a colorless film. [a], = + 4.0 (c = 1.0, CHC1,). A suspension containing of (25,35)-N-(2-benzyloxy-3-chloro-4-pentenoyl)- morpholine (43 mg, 0.14 mmol) and 10% palladium on carbon (50 mg) in EtOH (2 mL) was stirred under at atmosphere of H, for 1 h. The catalyst was then removed by filtration through a short plug of celite, and the filtrate was concentrated. Purification of the residue by flash chromatography (1:1 hexanes:EtOAc) afforded 25.4 mg (0.14 mmol, 97%) of a colorless oil that was spectroscopically identical to $1 in all respects. [a], = + 2.4 (c = 1.0, CHCI,). 102 oO Cl oJ 6Bn o J 6H $2 Determination of the absolute stereochemistry of (25,3R)-N-(2-benzyloxy-3- chloro-4-pentenoyl)-morpholine by correlation with (2S)-N-(2- hydroxypentanoyl)-morpholine (S2). A suspension containing of (25,3R)-N-(2- benzyloxy-3-chloro-4-pentenoyl)-morpholine (26.2 mg, 84.6 umol) and 10% palladium on carbon (50 mg) in EtOH (2 mL) was stirred under at atmosphere of H, for 1.5 h. The catalyst was then removed by filtration through a short plug of celite, and the filtrate was concentrated. Purification of the residue by flash chromatography (1:1 hexanes:EtOAc) afforded 15 mg (81 umol, 96% yield) of a colorless film that was spectroscopically identical to $2. [a], = + 1.0 (c = 1.0, CHCI,). 9 COnEt O CO, Et O COW a AZ 1. lp, 1:1 DME:H,0 ieNAF 1. Ho, Pd/C oo : 2. Zn°, ACOH, 65 °C : 2. LIOH, HpO/THF : ‘e) OBn OBn OH Determination of the absolute stereochemistry of (25,3S)-N-(2-benzyloxy-3- (ethoxycarbonyl)-4-pentenoyl)-morpholine by correlation with (25S,3R)-3- ethylmalic acid. A solution of (25,3S)-N-(2-benzyloxy-3-(ethoxycarbonyl)-4-pentenoy])- morpholine (34 mg, 0.1 mmol) in 2.4 mL 1:1 H,O/DME was treated with iodine (64 mg, 0.25 mmol) and stirred at 23 °C for 1 h. The resulting solution was then treated with 10% aqueous Na,S,O, (1 mL) and extracted into Et,O. The resulting organic layer was dried (Na,SO,) and concentrated. The iodolactone residue was then taken up in glacial ACOH (2.5 mL) and treated with zinc dust (65 mg, 1.0 mmol) and stirred at 65 °C for 1.5 h. Upon cooling to ambient temperature, | N HCl (aq) (1 mL) was added, and the mixture was 103 extracted with Et,O (3 x | mL). The organic extracts were combined, dried (Na,SO,), and then concentrated. The resulting carboxylic acid was taken up in THF (4 mL) and treated with 10%. palladium on carbon (50 mg) and stirred under an H, atmosphere for | h. The catalyst was then removed by filtration through a short plug of celite, and the filtrate was concentrated. The resulting residue was then taken up in 3:1 THF:H,O (4 mL) and treated with LiOH*H,O (42 mg, 1.0 mmol). The solution was warmed to 65 °C for 14 h. After cooling to ambient temperature, the reaction mixture was added to Dowex 50X80-200 (H* form) resin. The resin was removed by filtration and washed with H,O. The combined filtrate was concentrated to afford 7 mg of a yellow oil (43 umol, 43% for 4 steps) that was identical to (2R,3S)-3-ethylmalic acid’ in all regards except for optical rotation, which was opposite in sign. [a], (literature) = -3.1 (c = 1.0, H,O); [a], (observed) = +1.4 (c = 1.0, H,0). 7. Kakinuma, K.; Terasawa, H.; Li, H.-Y.; Miyazaki, K.; Oshima, T. Biosci. Biotech. Biochem., 1993, 57, 1916. ; 104 Chapter 5 Development of a Second-Generation Enantioselective Acyl-Claisen Rearrangement Reaction Design The design of our first-generation approach to an enantioselective acyl-Claisen rearrangement focused on the use of benzyloxyacetyl chloride in order to take advantage of the well-established ability of bidentate chelating substrates to confer a high level of organizational control in the transition state of Lewis acid-catalyzed transformations.' Indeed, the research described in Chapter 4 employs this strategy to produce Claisen products in up to 97% ee. However, the requirement for an acid chloride substrate capable of two-point binding to a metal center limits the scope of the reaction to transformations using benzyloxyacetyl chloride as the ketene precursor; reactions employing acid chlorides with less Lewis basic a-substitutents gave poorer results, and the use of propiony] chloride resulted in racemic products. In addition, benzyloxyacetyl chloride suffers from a significant uncatalyzed background reaction that significantly reduces the enantioselectivity of the products when a substoichiometric quantity of the chiral Lewis acid is used. Acyl-Claisen rearrangements using non-chelating acid chlorides such as propionyl chloride, on the other hand, suffer from neither of these disadvantages. As demonstrated in Chapter 3, propionyl chloride does not participate in an uncatalyzed background reaction. Furthermore, chiral Lewis acids that achieve high levels of organizational control over the transition state without a specific requirement for two-point binding could potentially be 1. Chapter 4, reference 3. 105 tolerant of a range of a-substituents on the acid chloride component of the reaction, greatly expanding the utility of this process (Figure 1). 0 ce) 2A _oen me Cl Cl good transition poor transition state organization state organization background reaction no background reaction limited scope broader potential scope Figure 1. Comparison of benzyloxyacety] chloride and propiony] chloride. Initially, we speculated that electronic interactions between the zwitterionic intermediate and the metal center could be exploited to diminish the conformational flexibility of the transition state. In particular, we predicted that the presence of an energetically low-lying empty p-orbital on the metal center could potentially induce anisotropy about the enolate oxygen-metal bond (Figure 2). Therefore we chose to focus on Group 13 Lewis acids in our initial investigations toward the development of a second- generation enantioselective acyl-Claisen rearrangement involving non-chelating acid chlorides. Q Mw —tL* 07 0 ve ODN Low-lying empty p orbitals on the metal center could result in anisotropy about the M-O bond. Figure 2. Rationale for design of propionate acyl-Claisen around Group 13 Lewis acids. 106 BINOL-Aluminum-Promoted Enantioselective Acyl-Claisen Rearrangements In our preliminary studies of the acyl-Claisen rearrangement described in Chapter 3, Bu,B(OTf) did not successfully catalyze the acyl-Claisen rearrangement of propionyl chloride and crotyl morpholine, while AICl, proved to be a very effective catalyst for this reaction. Consequently, chiral aluminum Lewis acids were first screened for their ability to promote the asymmetric reaction. A screen of ligand-metal salt combinations revealed that BINOL-AICI complex 1, generated in situ by the reaction of BINOL and dimethylaluminum chloride in methylene chloride, exerted promising levels of enantiocontrol over the reaction of crotyl pyrrolidine (2) with propionyl chloride (eq 1, 29% ee).** Upon further optimization, involving variation of the amine substituents as well as reaction conditions, the enantioselectivity of the reaction could be improved to 53% ee (eq 2).’ iL oe. ot on Ake w oS 1 equiv 1, -ProNEt 0 2 CHaCle, -20 °C 3 Done ee >95% conv \ oO” CO oO Ph Me cl AL Me, ZA Me. Z BINOL-AICI (1) “SNS ™ bh ~ N (2) the 1 equiv 1, -Pr.NEt Me Me 4 —20°C 5 538% ee 90% conv 2. Relative stereochemistry shown. The absolute sense of stereoinduction was not determined. 3. Surprisingly, the reaction of crotyl morpholine was racemic under these conditions. 107 However, optimization of this system was complicated by two factors. First, the success of the reaction was highly dependent on the order of addition and the solvent in which the Lewis acid complex was generated. In particular, optimal results were obtained when the BINOL-aluminum complex was generated in Et,O and the allyl amine substrate was next added as a solution in CH,Cl,. This behavior is consistent with the formation of complex aluminum-BINOLate aggregates in solution.* Second, the BINOL ligand structure is relatively difficult to functionalize, rendering the optimization of ligand architecture in this system synthetically intensive. Boron-Bis(sulfonamide)-Promoted Enantioselective Acyl-Claisen Rearrangements We therefore sought a new Lewis acid bearing a ligand framework that was modular and correspondingly more easily derivatized than BINOL. We also considered Lewis acid systems that had proven successful in other asymmetric reactions involving one-point binding between substrates and the metal center. In particular, Corey’s® chiral boron Lewis acid-promoted ester enolate Claisen rearrangement appears to meet both of these criteria. Corey has shown that the boron bromide complex 6 can be used to promote the Ireland- 4. Related aluminum-BINOLate complexes demonstrate complex aggregation behavior in solution: (a) Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L. Tetrahedron: Asymm. 1997, 8, 3403. (b) Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 441. Similar behavior has also been observed for other Group 13 BINOLate complexes: (c) Chitsaz, S.; Neumiiller, B. Organometallics 2001, 20, 2338. Titanium BINOLates are similar: (d) Davis, T. J.; Balsells, J.; Carroll, P.; Walsh, P. J. Org. Lert. 2001, 3, 699. 5. (a) Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1979, 10], 3035. (b) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1988, 61, 2975. (c) Yamamoto, K.; Murase, N.; Yamamoto, H. J. Org. Chem. 1993, 58, 2938. (d) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamaoto, H. J. Am. Chem. Soc. 1998, 120, 6920. (e) Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 1095. 6. Chapter 2, references 19-21. 108 Claisen rearrangement of the monodentate propionate substrate 7 to give the rearranged carboxylic acid 8 with excellent levels of enantiocontrol (eq 3, >97% ee). We speculated that a structurally similar Lewis acid could provide similarly high levels of organizational control in acyl-Claisen rearrangements with propiony] chloride. AS, a SS “7 SS 6 R*,B-Br fe} 6 [Fr fo) ] o 2k me a ; A_Me 20 °C 3) LA ve ~78 °C LA, 7 ~ 7 8 (>97% ee) The synthesis of the boron complex described by Corey® is straightforward (Scheme 1). Chiral ligand 11 can be produced by condensation of commercially available stilbenediamine (stein, 9) with 2 equiv sulfonyl chloride 10. The boron bromide complex 6 is generated by complexation of ligand 11 with BBr,. Importantly, this synthesis is modular and can be easily modified by variation of either the parent diamine’ or the sulfonyl chloride* component. Additionally, the halide component of the Lewis acid can be exchanged for more labile counterions (e.g., triflate or perchlorate) by treatment of the bromide with the appropriate silver salt.° 7. Corey, E. J.; Lee, D. H.; Sarshar, S. Tetrahedron: Asymm. 1995, 6, 1995. 8. Guo, C.; Qiu, J.; Zhang, X.; Verdugo, D.; Larter, M. L.; Christie, R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145. 109 Scheme 1 CF CF, CF, Ph Ph DMAP Pn a f 4 EtsN HaN WH Clg CF. CH-Cl ae 7NH HN CF 2 2 o” No 3 avle 3 oO” SS 0” No 3 9 10 11 (2 equiv) BBs OL, AgOTt Bets Ck, a Ny N, an ~ B ow” SS, Br ne 6 12 Results and Discussion The results of a survey of Lewis acid structures in the acyl-Claisen reaction of propionyl chloride and allyl-morpholine (13) are summarized in Table 1. As shown in entry 1, the boron complex most useful for Corey’s Ireland Claisen was not a competent promoter for the asymmetric acyl-Claisen rearrangement. The toluene sulfonamide derivative was more successful, providing the desired Claisen adduct 14 in 44-70% ee, albeit with very low conversion due to the undesired formation of propionyl morpholine (15) through a von Braun fragmentation process (entries 2-3). We speculated that this nucleophilic cleavage pathway could be avoided by replacement of the bromide counterion with a less nucleophilic anion. Indeed, no products from von Braun fragmentation were observed in reactions using the boron chloride, triflate, and perchlorate complexes, which promoted the reaction in 50-77% ee (entries 4-6). However, the PF, and BF, complexes were not successful promoters for the acyl-Claisen rearrangement (entries 7~8). 9. Evans has demonstrated that weakly coordinating counterions can be beneficial to Lewis acid-catalyzed enantioselective processes: Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798. 110 Table 1. Effect of boron complex structure on enantioselective acyl-Claisen rearrangement. Ph Ph fe) . ( A me ° 0 R. UN. UN. OR Cl VX SB° 7 Zz Ame oo xy 00 rN c N "= oJ cy <= PrgNEt, CHeClp Ne 40 15 “ —20 °C Claisen product von Braun product entry R X equivLA %14° %ee? %15° . CF; 1 HO Br 1 50 5 0 CF3 4 i )-ne cl 2 >99 50 0 5 i )-Me OTf 2 >99 71 0 6 i )-Me ClO, 2 >99 77 0) 7 i )-Me BF, 2 40 0 ) 8 i )rwe PFs —s-_-2 9 ¢ 0 “ Product ratios determined by GLC using a Bodman CC1701 column. © Enantiomeric excess was determined by chiral GLC using a Chiraldex T-TA column. ° Not determined. 11] Several ligands containing alternate diamino backbones were also synthesized, and the results of experiments assaying their effectiveness in the enantioselective acyl-Claisen rearrangement are summarized in Table 2. Both the trans-1,2-diaminocyclohexane and 2,2’-diaminobinaphthyl backbones resulted in boron complexes that were less enantioselective than the stilbene diamine-derived boron Lewis acids (entires 2-3, 8—19% ee). Thus, ligands containing the stien backbone were chosen for further investigation of this reaction. Table 2. Effect of diamino ligand backbone structure on the enantioselective acyl-Claisen rearrangement. fe) O 2 equiv LA Oy Je meee cy ry (° oJ Cl e /-ProNEt, CH2Clo J 13 -20 °C ° Me 44 entry LA % conv % ee? Ts Pho on 1 as ‘B—oT1 >99 71 ph’ oN Ts Ts / N 2 or BOOT 75 19 ‘\ Ts Cer, N 3 B-OTt 61 8 Con Ts “ Product ratios determined by GLC using a Bodman CC1701 column. ? Enantiomeric excess was determined by chiral GLC using a Chiraldex T-TA column. 112 Experiments probing variations on the sulfonamide portion of the ligand structure are summarized in Table 4. Electron-deficient ligands give poor results; the 3,5- bis(trifluoromethyl)benzene-substituted ligand gives very poor conversion and ee. As demonstrated in entry 2, the enantioselectivity of the reaction could be increased slightly at Table 3. Effect of sulfonamide structure on the enantioselective acyl-Claisen rearrangement. 2equiv Ph, Ph R N N R a i Te a J% | S% i oN r OCIO; N A (6) o oN 13 FPraNEt, CH2Clp oJ Me 14 entry R % conv? % ee? s . 1 TC. >99 71 Me nn CFs 3 Ww 15 -- CF3 : CO 18 0 64 Ne 72 7 way Mn 4 Conversion of 13 determined by GLC using a Bodman CC1701 column. ? Enantiomeric excess determined by GLC using a Chiraldex T-TA column. © Not determined. “ Reaction conducted using boron triflate complex. 113 the expense of reaction efficiency by using bulkier sulfonamide groups (41% conv, 80% ee). Surprisingly, naphthylene sulfonamide-derived ligands gave poor conversions and no enantioselectivity under identical conditions (entries 3-4). Given these results, we selected the bis(toluenesulfonamido) boron species (entry 1) as the optimal Lewis acid for further exploration of this reaction process. Upon further optimization of the reaction conditions, we found that the use of CHCI, as solvent and a lower reaction temperature of —30 °C resulted in improved yields and selectivities (eq 7). Under these conditions, allyl morpholine reacts with propionyl chloride in the presence of the boron perchlorate complex 16 to give the Claisen adduct 14 in 88% ee (74% isolated yield). These conditions were employed in reactions to examine the scope of this second-generation enantioselective acyl-Claisen methodology. Ph, Ph 2equiv *% eM gehts O fe) 16 ocio ae 5 N A 74 %yield (7) J Me 88% ee O 13 cl -PraNEt, CHCl3 oJ Me 44 —30 °C Evaluation of Reaction Scope The scope of this methodology was investigated by Dr. Sung-Gon Kim. Table 4 summarizes the results of experiments probing the range of alkyl- and aryl-substituted ally] morpholine structures tolerated in the reaction. In accord with the results of our first- generation magnesium-promoted asymmetric acyl-Claisen rearrangement, a variety of alkyl- substituted morpholines rearrange with good levels of enantio- and diastereocontrol (entries 1-4, 86-92% ee, >99:1 syn:anti). The enantioselectivity of the reaction increases slightly with increasing steric bulk of the alkyl substituent. However, carbocation-stablizing 114 substituents had a deleterious effect on the rearrangement, and reaction of cinnamyl morpholine resulted in decomposition of the morpholine substrate (entry 5). Table 4. Enantioselective acyl-Claisen rearrangement of representative alkyl- and aryl- substituted allyl morpholines. O O R 2 equiv 16 aaa > a oO (8) J cl FProNEt, CHCls ~ (@) Me —30 °C @) Me entry amine product® % yield syn:anti” % ee* 9 Me 1 eet aw YZ 66 - 86 Me Me O Me d con ZA ah | FN 81 >99:1 9 Me Me ie] iPr N 34 CL awd 84 >99:1 92 Pr M ie O Bn N 4d cy an 83 > >99:1 90 Bn Me Q Ph N ° Pho the “ NR, = N-morpholine. ? Product ratios determined by GLC using a Bodman CC1701 column. ‘ Enantiomeric excess determined by chiral HPLC or GLC. ¢ Reaction conducted using c-Hex,NMe as amine base. ° Substrate decomposition observed. Heteroatom-substituted ally] morpholine substrates were also investigated (Table 5). As demonstrated by entry 1, halogen-substituted ally! morpholines react successfully, providing the B-chloro-substituted amide in 93% ee (>99:1 syn:anti, 77% yield) without any observable products of B-elimination. Although cinnamyl morpholine decomposes under 115 the reaction conditions, the electron-poor p-nitrocinnamyl] derivative rearranges efficiently, providing the expected Claisen adduct in 84% yield and 90% ee (entry 3). Finally, the ester-substituted allyl morpholine substrate shown in entry 4 reacts sluggishly, requiring higher temperatures for reasonable reaction times, and consequently providing the desired Claisen product in diminished enantioselectivity (entry 4, 79% ee), albeit with excellent diastereoselectivity. Table 5. Enantioselective acyl-Claisen rearrangement of representative heteroatom- functionalized allyl morpholines. O 2 equiv 16 7 - Z “NE N o~R yon he (9 ea cl #PrgNEt, CHC! e O 2 8 oJ M Me -30 °C ° entry amine product* % yield syn:anti? % ee 9 «a N +f | RAN Z 77 > 99:1 98 fe) 2 Cl Me Q CH,OBz N 2 om naw 72 >99:1 87 CHOBz Me ie} PhNO.-4 N 3 Sm oN Z 90 >99:1 90 PhNO,-4 Me QO CO,Et N d . 4 Sm nw 45 > 991 79 COzEt the “NR, = N-Morpholine. ? Product ratio determined by GLC using a Bodman CC1701 column. © Enantiomeric excess determined by chiral GLC or HPLC. “ Reaction performed at -10 °C. 116 In accord with our design plan, a range of acid chlorides participate in this reaction and rearrange with moderate to good levels of enantioselectivity (Table 6). As demonstrated by the results of entries 2-4, a variety of alkyl-substituted acid chlorides participate in the reaction, although the enantioselectivity of the process seems to decrease as the bulk of the alkyl substituent increases (entry 2, R = Me, 91% ee; entry 3, R = Et, 84% ee; entry 4, R = Bn, 74% ee; entry 5, R = Ph, 10% ee). Acetyl chloride gave only von Braun fragmentation products. Table 6. Enantioselective acyl-Claisen rearrangement with representative alkyl- and aryl- substituted acid chlorides. ie) Me Oo 2 equiv 16 (NSF ie 2 ay (10) oS cl -ProNEt, CHCl; J 0 R ~30 °C ° R entry R % yield = syn:anti" = % ee? H --6 -- -- 2 Me 81 >99:1 91 3¢ Et 71 >99:1 84 4¢d Bn 44 97:3 74 5 Ph 71 99:1 10 “ Product ratios determined by GLC using a Bodman CC1701 column. ? Enantiomeric excess determined by chiral HPLC or GLC. ¢ Allyl morpholine decomposition observed. “ Reaction conducted using c-Hex,NMe as amine base. Heteroatom-substituted acid chlorides were also assayed. Benzyloxyacetyl chloride, which proved to be the optimal acid chloride for the magnesium-promoted chemistry described in Chapter 4, gave poor results under these conditions; the powerful Lewis acidity of the boron perchlorate Lewis acid 11 facilitated cleavage of the benzyl group, and the resulting a-hydroxyamide product was isolated with only 18% ee (entry 1). The Claisen 117 products resulting from rearrangement of a-phenoxy-derived acid chlorides, which are not susceptible to a similar fragmentation process, were formed in higher ee (entries 2-3, 53-69% ee). As evidenced by entries 4-5, reasonable levels of stereocontrol could be- achieved in rearrangements that produce a-halogenated products (entry 4, R = Cl, 80% ee; entry 5, R = Br, 79% ee). These results establish that this new boron Lewis acid provides a promising chiral environment for the further development of a general enantioselective Claisen rearrangement. Table 7. Enantioselective acyl-Claisen rearrangement of representative heteroatom- substituted acid chlorides. Oo 2 equiv 16 Gf Me fl (Nie oN iPryNEt, CHCls i: ama “ o R -30 °C oJ R entry R % yield = syn:anti"” —% ee? 1 OBn 55° 97:3 18 2d OPh 84 92:8 69 34 OPhCI-4 69 98:2 53 4 SPh 75 >99:1 77 54 Cl 78 >99:1 80 6° Br 74 99:1 719 “Product ratios determined by GLC using a Bodman CC1701 column. ? Enantiomeric excess determined by chiral HPLC or GLC. “The debenzylated a-hydroxyamide (R = OH) was isolated. ¢@ Reaction conducted using c-HexzNMe as amine base. © The acid halid used in this reaction was bromoacetyl bromide. 118 Stereochemical Model The transition state geometry about the Lewis acidic center of boron halide-mediated '° or trigonal (18),° depending on Lewis acidic processes can be either tetrahedral (17) whether the counterion is dissociated or covalently bound to the boron center (Figure 3).'' While ‘the neutral trigonal species should possess greater Lewis acidicty than the anionic tetrahedral ate complex, boron-halogen bonds are generally very strong (B-Cl = 128 kcal /mol),'* and dissociation of the halide counterion could be energetically prohibitive. However, in our new enantioselective acyl-Claisen methodology, the perchlorate and triflate counterions that provide optimal results are excellent leaving groups and should dissociate easily from boron. Indeed, addition of 2 equiv NaClO, results in slower reaction rates without significantly impacting the enantioselectiivty of the rearrangement, which is consistent with a mechanism requiring dissociation of the perchlorate counterion prior to the rate-limiting rearrangement event. Therefore, we speculate that the boron center likely adopts a trigonal geometry in the transition state of the sigmatropic event. ear a ee “4 D+ ns —_ “D+ / R _ R RO +X tetrahedral trigonal borate complex neutral complex Figure 3. Tetrahedral and trigonal geometries for boron Lewis acids. 10. For example: (a) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794. (b) Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116, 1657. 11. Corey has investigated divergent stereochemical consequences from the trigonal and tetrahedral geometries of boron Lewis acids in the context of the aldol reaction: Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. 12. Barrow, R. F. Trans. Faraday Soc. 1960, 56, 962. 119 Based on this assumption, we have proposed a preliminary transition state model based on PM3 semiempirical calculations to explain the observed sense of stereoinduction. As shown in Figure 4, the lowest energy structure computed for complex 16 displays an attractive =-7t interaction between the aryl groups of the sulfonamide substituent and the stien backbone. In this conformation, the re face of a bound enolate is effectively shielded by one of the oxygen atoms of the sulfonamide, leaving the si face open for rearrangement. An attempt to enforce rearrangement from the si face forces the sulfonamide substituent to rotate 107° out of alignment, disrupting the attractive m—-m interaction. The sense of enantioenduction predicted by this model is consistent with the observed outcome. —_—p_- attractive zs interaction Figure 4. Preliminary rationale for the observed sense of stereoinduction.'* 13. The opposite antipode of the ligand is shown. 120 Limitations of the Methodology At present, stoichiometric quantities of the Lewis acid promoter are required for optimal yields and levels of enantioselectivity. While the reaction of allyl morpholine and propionyl chloride proceeds in the presence of 2 equiv 16 under our optimized conditions to give the rearranged product in 88% ee and 74% yield (eq 7), the reaction gives dramatically poorer results when the stoichiometry of the Lewis acid is reduced to 20 mol% (eq 12). Ph Ph 20mol% 7 Ts“ NaN“ Ts I ° 16 ocio NN oe 3 awh\y 10% yield (12) oJ 13 Cl i-ProNEt, CHCl, oJ Me 14 18% ee -30 °C We speculate that there are two key reasons that explain the finding that 16 does not serve as a competent Claisen catalyst in substoichiometric quantities. First, the catalyst suffers from product inhibition. As outlined in Scheme 2, the progress of the reaction is impeded by the addition of the product to the reaction mixture. When conducted in the presence of | equiv of racemic 14, the reaction proceeds to 58% conversion. Amide 14 is isolated from the reaction in 31% ee, indicating that the product formed in the course of the reaction is generated in 53% ee. Conducting the reaction in the presence of 2 equiv of 14 resulted in even poorer results (10% conversion, 35% ee). 121 Scheme 2 Product inhibition: O 0 we ow ane oJ 0 Me 5 oJ Me 13 (+)-14 (1 equiv) JL Me 14 58% conv, 31% ee Cl (53% ee, corrected) 2 equiv 16 0 0 -ProNEt, CHCl, Z aon aw -30°C aA VY 0 13 (+)-14 (2 equiv) 14 10% conv, 3.5% ee (35% ee, corrected) Second, we speculate that the ammonium chloride salt generated from dehydrohalogenation of the acid chloride can inhibit the reaction by participating in a salt metathesis reaction with the boron perchlorate Lewis acid (Scheme 3). As demonstrated by the results summarized in Table 1, the boron chloride salt 17 is a less effective promoter of the acyl-Claisen rearrangement. Furthermore, in the presence of an excess of ammonium chloride, the vacant coordination site on boron in 17 can accept a second halide ligand to afford the boron ate complex 18, which is coordinatively saturated and cannot act as a Lewis acid. A competent acyl-Claisen catalyst based on this system, therefore, will likely require a method of removing chloride ion from the solution. Experiments are underway in our group to explore this possibility. 122 Scheme 3 Inhibition by chloride ion: Ph, Ph Ph, Ph Ph, Ph ! iProEtNH*Cl- / 7ProEtNH*Cr H ( Ts“Ns N= Ts ———_-————> Ts“ NR /N~Ts —_--e— Ts“ Nv a2N~Ts | { fe 16 =ocio, 17 «a 18 Cl Cl #Pr.EtNHt effective decreased no vacant chiral Lewis selectivit coordination acid y sites Conclusion Our investigations of a second-generation strategy towards an enantioselective acyl- Claisen rearrangement have resulted in the discovery that stilbenediamine-derived boron Lewis acid 16 is an effective enantioselective promoter for acyl-Claisen rearrangements involving propionyl choride. In analogy to the magnesium-ArBox-promoted variant disclosed in Chapters 3-4, this boron-mediated process enables the rearrangement of a variety of allyl morpholine substrates with good enantiocontrol. In addition, bidentate chelation is not an essential criterion for effective control of transition state geometry, and a range of alkyl-, aryl-, and heteroatom-substituted acid chlorides participate in this reaction with moderate to good levels of enantioselectivity. This new methodology provides convenient access to complex, stereochemically dense acyclic motifs and represents an important step towards the development of the first enantioselective catalytic Claisen rearrangement of general utility. 123 Experimental Section General Information. All non-aqueous reactions were performed using flame- or oven-dried glassware under an atmosphere of dry nitrogen. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego.' Non-aqueous reagents were transferred under nitrogen via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Biichi rotary evaporator. diisopropylethylamine, dicyclohexylmethylamine, dichloromethane, and chloroform were distilled from calcium hydride prior to use. Air-sensitive solids were dispensed in an inert atmosphere glovebox. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still.’ Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching or KMn0O, stain. Melting points were determined on a Tomas Hoover capillary melting point apparatus and are uncorrected. 'H and '*°C NMR spectra were recorded on Mercury 300 (300 MHz and 75 MHz) as noted, and are internally referenced to residual protio solvent signals. Data for 'H NMR are reported as follows: chemical shift (5 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for '*C NMR are reported in terms of chemical shift. IR spectra were recorded on a Perkin-Elmer 1600 Series spectrometer using NaCl salt plates, 1. Perrin, D. D.; Armarego, W. L. F. Purificaion of Laboratory Chemicals; 3" ed., Pregamon Press, Oxford, 1988. 2. Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923. 124 and reported in terms of frequency of absorption (cm’'). Mass spectra were obtained from the UC Irvine Mass Spectral Facility. Optical rotations were recorded on a Jasco P-1010 polarimeter (WI lamp, 589 nm). Gas chromatography was performed on Hewlett-Packard: 5890A gas chromatograph equipped with a split-mode capillary injection system and flame ionization detectors using the following columns: Bodman Chiraldex T-TA (30 m x 0.25 mm). HPLC analysis was performed on a Hewlett-Packard 1100 Series HPLC at 254nm using the following Chiralcel columns: OD-H (25 cm) and OD guard (5 cm), AD (25 cm) and AD guard (5 cm). Bis(sulfonamide) ligands. (R,R)-Bis(3,5-ditrifluoromethyl-benzenesulfonyl)-1,2- diphenyl-1,2-diaminoethane* and (R,R)-bis(4-methylbenzene-sulfonyl)-1,2-dipheny]-1,2- diaminoethane* were synthesized as previously described and were spectroscopically identical in all respects to the reported materials. The syntheses of other bis(sulfonamide) ligands were accomplished analogously by condensation of the appropriate diamine with a sulfonyl! chloride. (R,R)-2-Bromo-4,5-diphenyl-1,3-bis-(toluene-4-sulfonyl)-[1,3,2]diaza- borolidine (16). In a flame-dried 250 mL round-bottomed Schlenk flask was placed (R,R)- bis(4-methylbenzene-sulfony])- 1 ,2-diphenyl-1,2-diaminoethane (2.28g, 4.38 mmol). The flask was sealed with a rubber septum and then evacuated and flushed three times with nitrogen. The flask was then charged with 50 mL dry CH,Cl,. A 1.0 M solution of boron tribromide in hexanes (8.8 mL, 8.8 mmol) was added by syringe, and the reaction mixture 3. Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. 4. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xing, YJ. J. Am. Chem. Soc. 1989, 111, 5493. 125 was stirred at 23 °C for 24 h. The flask was immersed in a water bath, and the solvent and residual boron compounds were carefully removed under reduced pressure through a sodium hydroxide trap. After admission of nitrogen, the flask was charged with 20 mL dry CH,Cl,, and the suspension was stirred until the solution became homogenous. The solvent was removed under reduced pressure, and the residue was dried under vacuum for 8 h to provide an orange amorphous solid in 99% yield (2.63 g, 4.32 mmol). This material was used in acyl-Claisen rearrangements without further purification. General Procedure A. A dry flask in an inert atmosphere glovebox was charged with 16 and anhydrous AgClO,. The flask was sealed with a rubber septum and removed from the glovebox. CHC1, (1 mL) was introduced by syringe, and the resulting pale yellow mixture was stirred vigorously for 1 h under nitrogen. The resulting mixture was take up in a disposable 2.5 mL syringe, which was then fitted with an Acrodisc® PTFE syringe filter and an 18 gauge disposible needle. The filtered solution was added directly to a solution of allyl morpholine (0.2 mmol) in CH,Cl, (1 mL ). The reaction mixture was then treated with i-Pr,NEt or Cy,MeN, and cooled to —30 °C. The solution was stirred for 10 min before acid chloride was added dropwise over 0.5 min. After 18 h at —30 °C, the reaction mixture was poured onto a mixture of EtOAc (5 mL) and 20% sodium potasium tartrate solution (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with saturated aq. NaCl (50 mL), dried (Na,SO,), and concentrated by rotory evaporation. The resulting residue was purified by silica gel chromatography to afford the title compounds and recovered R,R)-bis(4- methylbenzene-sulfony])-1,2-diphenyl-1,2-diaminoethane. General Procedure B. A dry flask in an inert atmosphere glovebox was charged with 16 and anhydrous AgClO,. The flask was sealed with a rubber septum and removed 126 from the glovebox. CHCI, (1 mL) was introduced by syringe, and the resulting pale yellow mixture was stirred vigorously for 1 h under nitrogen. The resulting mixture was take up in a disposable 2.5 mL syringe, which was then fitted with an Acrodisc® PTFE syringe filter and an 18 gauge disposible needle. The filtered solution was added directly to a solution of allyl morpholine (0.2 mmol) in CH,Cl, (1 mL ). The reaction mixture was then treated with i-Pr,NEt or Cy,MeN, and cooled to -30 °C. The solution was stirred for 10 min before a solution of the acid chloride in CHCl, was added by syringe pump over 12 h. After addition was complete, the reaction was stirred 6 h at -30 °C then quenched by pouring onto a mixture of EtOAc (5 mL) and 20% sodium potasium tartrate solution (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 5 mL). The combined organic layers were washed with saturated aq. NaCl (50 mL), dried (Na,SO,), and concentrated by rotory evaporation. The resulting residue was purified by silica gel chromatography to afford the title compounds and recovered R.R)-bis(4-methylbenzene- sulfony])-1,2-dipheny]-1,2-diaminoethane. (2R)-N-(2-Methyl-4-pentenoyl)-morpholine (14). Prepared by general procedure A from N-allyl morpholine (25 mg, 0.20 mmol) and propiony] chloride (21 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and i-Pr,NEt (53 uL, 0.30 mmol) to afford the product as a colorless oil in 74% yield (27 mg); 88% ee. 'H NMR, '*C NMR, IR, and mass spectral data for this compound were consistent with those previously reported.” [a],°* = -21.2 (c = 0.9, CHCI,). The enantiomeric purity was determined by GC with a Bodman Chiraldex T-TA column (100 °C, 2.0 mL/min, 25 psi); t, = 37.1 min and 39.7 min. 5. Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726. 127 (2R)-N-(2-Methyl-4-methyl-4-pentenoyl)-morpholine (Table 4, entry 1). Prepared by general procedure A from N-methallylmorpholine (28 mg, 0.20 mmol) and propionyl chloride (21 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and i-Pr,NEt (53 uL, 0.30 mmol) to afford the product as a colorless oil in 66% yield (26 mg); 86% ee. IR (thin film) 2968, 2918, 2856, 1643, 1433, 1233, 1116 cm’; 'H NMR (300 MHz, CDCl,) 8 4.78 (s, 1H, CH,CCH,=CH,), 4.68 (s, 1H, CH,CCH,=CH,), 3.53-3.69 (m, 8H, N(CH,CH.),), 2.80- 2.91 (m, 1H, CHCH,), 2.41 (dd, J = 7.2, 14.7 Hz, 1H, CH,CCH,=CH,), 2.07 (dd, J = 7.2, 14.1 Hz, 1H, CH,CCH,=CH,), 1.72 (s, 3H, CH,CCH,=CH,), 1.11 (d, J = 6.6 Hz, 3H, CHCH,); '*C NMR (75 MHz, CDCI,) 6 174.9, 143.2, 112.1, 67.3, 67.1, 46.3, 42.4, 42.0, 33.6, 23.1, 17.7; [a],°? = -6.8 (c = 1.1, CHCI,). The enantiomeric purity was determined by GC with a Bodman Chiraldex '-TA column (115 °C, 2.0 mL/min, 25 psi); t, = 36.5 min and 42.3 min. (2R,3S)-N-(2,3-Dimethyl-4-pentenoyl)-morpholine (Table 4, entry 2). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and propionyl chloride (21 uwL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a colorless oil in 81% yield (32 mg); syn:anti >99:1 syn 91% ee. 'H NMR, '*C NMR, IR, and mass spectral data for this compound were consistent with those previously reported.” [a],°° = -39.8 (c = 1.3, CHClI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex T-TA column (115 °C, 2.0 mL/min, 25 psi): syn isomer, t, = 32.7 min and 39.5 min; anti isomer, t. = 41.9 min and 43.0 min. 128 (2R,3S)-N-(2-Methyl-3-isopropyl-4-pentenoyl)-morpholine (Table 4, entry 3). Prepared by general procedure A from (E)-N-4-methylpent-2-enyl morpholine (34 mg, 0.20 mmol) and propionyl chloride (23 uL, 0.26 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a colorless oil in 84% yield (38 mg); syn:anti >99:1 syn 92% ee. Syn isomer: IR (thin film) 2961, 2925, 28541641, 1432, 1267, 1250, 1117, 1026cm'; 'H NMR (300 MHz, CDCI,) 6 5.63 (ddd, J = 10.2, 17.1, 20.1 Hz, 1H, CH=CH,), 5.03 (ddd, J = 2.4, 10.2, 20.1 Hz, 2H, CH=CH,), 3.50-3.66 (m, 8H, N(CH,CH,),), 2.81 (dq, J = 6.6, 9.6 Hz, 1H, CHCH,), 2.20 (ddd, J = 3.9, 9.6, 17.1 Hz, 1H, CHCH=CH,), 1.81-2.02 (m, 1H, CH(CH,),), 1.10 (d, J = 6.6 Hz, 3H, CHCH,), 0.83 (dd, J = 6.6, 21.6 Hz, 6H, CH(CH,),); '5C NMR (75 MHz, CDCI,) 5 175.0, 136.6, 117.8, 67.3, 67.0, 53.2, 46.6, 42.3, 36.7, 27.0, 22.0, 16.8, 16.1; [a],* = +4.5 (c = 1.6, CHCI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex T-TA column (125 °C, 1.7 mL/min, 23 psi); syn isomer, t, = 37.5 min and 40.0 min; anti isomer, t, = 41.5 min and 43.0 min. (2R,3S)-N-(3-Benzyl-2-methyl-4-pentenoyl)-morpholine (Table 4, entry 4). Prepared by general procedure A from (£)-N-4-phenylbut-2-enyl morpholine (44 mg, 0.20 mmol) and propionyl chloride (23 uL, 0.26 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a white solid in 83% yield (45 mg); syn:anti >99:1 syn 90% ee. Syn isomer: mp 69-70 °C; IR (thin film) 2967, 2931, 2856, 1641, 1433, 1267, 1227, 1116 cm’; 'H NMR (300 MHz, CDCI,) 6 7.10-7.29 (m, 5H, CH,C,H,), 5.81 (ddd, J = 8.1, 10.2, 16.8 Hz, 1H, CH=CH,), 4.90 (ddd, J = 1.8, 10.2, 16.8 Hz, 2H, CH=CH,), 3.38-3.66 (m, 8H, N(CH,CH,),), 2.89-2.96 (m, 1H, CHCH,), 2.71-2.75 (m, 1H, CHCH=CH,), 2.50-2.60 (m, 2H, CH,C,H,), 1.19 (d, J = 7.2 Hz, 3H, CHCH,); '*C NMR (75 MHz, CDCI,) 8 174.2, 140.3, 139.7, 129.4, 128.3, 126.1, 116.5, 67.3, 67.0, 49.2, 46.5, 42.3, 38.6, 38.0, 15.7. The 129 enantiomeric purity was determined by HPLC with a Chiralcel AD column and AD guard column (3% i-PrOH:hexanes, 1 mL/min flow); t, = 17.7 min and 22.8 min. (2R,3R)-N-(3-Chloro-2-methyl-4-pentenoyl)-morpholine (Table 5, entry 1). Prepared by general procedure A from (£)-N-(3-chloro-2-propenyl) morpholine (32 meg, 0.20 mmol) and propiony! chloride (21 pL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a colorless oil in 77% yield (33 mg); syn:anti >99:1 syn 93% ee. 'H NMR, '*C NMR, IR, and mass spectral data for this compound were consistent with those previously reported.” [a],°*° = -42.8 (c = 1.5, CHCI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex T-TA column (135 °C, 1.7 mL/min, 24 psi); syn isomer, t, = 26.3 min and 32.8 min; anti isomer, t, = 28.9 min and 31.0 min. (2R,3S)-N-(3-(Benzoyloxymethyl)-2-methyl-4-pentenoyl)-morpholine (Table 5, entry 2). Prepared by general procedure B from (£)-N-(4-benzoyloxy-2- butenyl)morpholine (104 mg, 0.40 mmol) and propiony! chloride (480 uL, 1.0 M solution in CHCL,, 0.48 mmol), using AgClO, (168 mg, 0.80 mmol), (R,R)-bromoborane reagent 16 (488 mg, 0.80 mmol), and i-Pr,NEt (106 uL, 0.60 mmol) to afford the product as a colorless oil in 72% yield (92 mg); syn:anti >99:1 syn 87% ee. Syn isomer: IR (thin film) 2969, 2923, 2857, 1718, 1641, 1451, 1273, 1115 cm; 'H NMR (300 MHz, CDCl,) 8 7.41- 8.02 (m, 5H, CH,OCOC,H,), 5.89 (ddd, J = 8.1, 10.5, 17.1 Hz, 1H, CH=CH,), 5.14 (ddd, J = 1.2, 10.5, 17.1 Hz, 2H, CH=CH,), 4.37-4.48 (m, 2H, CH,OCOC,H.,), 3.51-3.65 (m, 8H, N(CH,CH,),), 2.91-3.00 (m, 1H, CHCH,), 2.82-2.86 (m, 1H, CHCH=CH,), 1.20 (d, J = 6.9 Hz, 3H, CHCH,); ‘°C NMR (75 MHz, CDCI,) 5 173.6, 166.4, 137.0, 133.2, 130.3, 129.7, 128.6, 117.9, 67.3, 67.0, 65.5, 46.6, 46.2, 42.4, 36.5, 15.7; [a], > = -30.6 (c = 1.0, 130 CHCIl,). The enantiomeric purity was determined by HPLC with a Chiralcel AD column and AD guard column (5% i-PrOH:hexanes, | mL/min flow); t, = 25.5 min and 27.4 min. (2R,3R)-N-(2-Methyl-3-(p-nitrophenyl)-4-pentenoyl)-morpholine (Table 5, entry 3). Prepared by general procedure A from (£)-N-4-phenylbut-2-enyl morpholine (50 mg, 0.20 mmol) and propiony] chloride (21 wL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 2# (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a colorless oil in 87% yield (89 mg); syn:anti >99:1 syn 90% ee. Syn isomer: IR (thin film) 3081, 2970, 2923, 2858, 1637, 1529, 1463, 1435, 1352, 1245, 1220, 1116 cm'; 'H NMR (300 MHz, CDCI,) 8 8.06-8.13 (m, 2H, CH,C,H,NO.), 7.47-7.57 (m, 2H, CH,C,H,NO,), 5.98 (ddd, J = 7.8, 10.5, 18.0 Hz, 1H, CH=CH,), 5.04 (ddd, J = 1.2, 10.5, 18.0 Hz, 2H, CH=CH,), 3.82 (dd, 1H, J = 3.6, 7.8 Hz, CHCH=CH,), 3.58-3.74 (m, 8H, N(CH,CH,),), 3.10 (dq, 1H, J = 3.6, 6.9 Hz, CHCH,), 0.91 (d, J = 6.9 Hz, 3H, CHCH,); '*C NMR (75 MHz, CDCI,) 6 173.3, 148.6, 144.0, 138.8, 135.4, 129.7, 123.0, 122.0, 117.0, 67.3, 67.0, 53.0, 46.6, 42.6, 40.0, 16.9; [a],,”* = -53.4 (c = 1.9, CHCL,). The enantiomeric purity was determined by HPLC with a Chiralcel AD column and AD guard column (5% i-PrOH:hexanes, 1 mL/min flow); t,= 35.5 min and 42.0 min. (2R,3R)-N-(3-(Ethoxycarbonyl)-2-methyl-4-pentenoyl)-morpholine (Table 5, entry 4). Prepared by general procedure A from (£)-ethyl 4-morpholinocrotonate (40 mg, 0.20 mmol) and propionyl chloride (21 wL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and i-Pr,NEt (53 wL, 0.30 mmol) to afford the product as a colorless oil in 45% yield (23 mg); syn:anti >99:1 syn 79% ee. Syn isomer: IR (thin film) 2977, 2935, 2868, 1731, 1643, 1435, 1252, 1173, 1116 cm'; 'H NMR (300 MHz, CDCI,) 6 5.80 (ddd, J = 8.7, 10.5, 17.1 Hz, 1H, CH=CH.,), 5.16 (ddd, J = 1.8, 10.5, 17.1 Hz, 2H, CH=CH,), 4.11-4.22 (m, 2H, CO,CH,CH,), 3.49-3.658 (m, 8H, 131 N(CH, CH,),), 3.38 (dd, J = 8.7, 9.0, Hz, 1H, CHCH=CH,), 3.10-3.20 (m, 1H, CHCH,), 1.27 (t, J = 7.2 Hz, 3H, CO,CH,CH,), 1.13 (d, J = 7.2 Hz, 3H, CHCH,); '*C NMR (75 MHz, CDCI,) 6 173.0, 172.7, 134.2, 119.0, 67.3, 67.1, 61.1, 53.9, 46.6, 42.5, 38.0, 16.7,- 14.6; [a],°* = -52.1 (c = 1.0, CHCI,). The enantiomeric purity was determined by GC with a Bodman Chiraldex I-TA column (130 °C, for 40 min, then 1 °C/min, 1.7 mL/min, 23 psi); t, = 57.9 min and 58.7 min. (2R,3R)-N-(2-Ethyl-3-methyl-4-pentenoyl)-morpholine (Table 6, entry 3). Prepared by general procedure A from (E)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and butyryl chloride (25 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a colorless oil in 71% yield (30 mg); syn:anti >99:1 syn 84% ee. Syn isomer: IR (thin film) 2945, 2928, 2857, 1637, 1442, 1271, 1225, 1117 cm'; 'H NMR (300 MHz, CDCI1,) 6 5.70 (ddd, J = 7.8, 10.5, 17.7 Hz, 1H, CH=CH,), 5.10 (ddd, J = 1.8, 10.5, 17.7 Hz, 2H, CH=CH,), 3.40-3.67 (m, 8H, N(CH,CH,).,), 2.35-2.43 (m, 1H, CHCH,CH,), 1.44- 1.70 (m, 2H, CHCHCH=CH,), 0.97 (d, J = 6.0 Hz, 3H, CHCH,), 0.78 (dd, J =3.3, 7.8 Hz, 3H, CHCH,CH,); '*C NMR (75 MHz, CDCI,) 5 173.7, 142.1, 114.2, 67.5, 67.1, 47.9, 46.7, 42.3, 40.4, 23.1, 17.2, 12.6; [a],”* = -9.90 (c = 1.2, CHCI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex T-TA column (120 °C, 2.0 mL/min, 25 psi); syn isomer, t, = 28.5 min and 29.7 min; anti isomer, t, = 36.6 min and 37.5 min. (2S,3R)-N-(2-Benzyl-3-methyl-4-pentenoyl)-morpholine (Table 6, entry 4). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and hydrocinnamoy! chloride (36 wL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to 132 afford the product as a white solid in 44% yield (24 mg); syn:anti 97:3 syn 74% ee. Syn isomer: mp 69-70 °C; IR (thin film) 2960, 2917, 2857, 1622, 1460, 1266, 1111 cm’; 'H NMR (300 MHz, CDC1,) 6 7.14-7.28 (m, 5H, CH,C,H,), 5.77 (ddd, J = 7.8, 10.5, 17.7 Hz, 1H, CH=CH,), 4.99 (ddd, J = 1.5, 10.5, 17.7 Hz, 2H, CH=CH,), 2.56-3.69 (m, 12H, N(CH;CH,),, CHCH,C,H,, CHCH=CH,), 1.15 (d, J = 6.6 Hz, 3H, CHCH,)); '*C NMR (75 MHz, CDC1,) 8 172.7, 141.7, 140.2, 129.3, 128.6, 126.5, 114.6, 67.1, 66.5, 49.2, 46.4, 42.2, 40.7, 37.2, 17.7; [a], * = +28.7 (c = 1.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel ODH column and ODH guard column (1% i- PrOH:hexanes, 1 mL/min flow); t, = 22.7 min and 26.5 min. (2S,3R)-N-(3-Methyl-2-phenyl-4-pentenoyl)-morpholine (Table 6, entry 5). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and phenylacetyl chloride (32 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and iPr,NEt (59 uL, 0.30 mmol) to afford the product as a white solid in 77% yield (40 mg); syn:anti 99:1 syn 10% ee. Syn isomer: mp 72-73 °C; IR (thin film) 2964, 2922, 2856, 1641, 1456, 1430, 1224, 1115 cm’; 'H NMR (300 MHz, CDC1,) 6 7.08-7.33 (m, 5H, CHC,H,), 5.91 (ddd, J = 7.2, 10.5, 17.4 Hz, 1H, CH=CH,), 5.04 (ddd, J = 1.2, 10.5, 17.4 Hz, 2H, CH=CH,), 3.36-3.69 (m, 8H, N(CH,CH,),), 3.02-3.18 (m, 2H, CHCHCH,), 0.77 (d, J = 6.9 Hz, 3H, CHCH,); ‘°C NMR (75 MHz, CDCI,) 8 171.2, 142.7, 138.2, 128.9, 128.7, 127.4, 114.3, 67.1, 66.7, 54.6, 46.6, 42.7, 40.5, 17.7; [a],’* = +2.35 (c = 1.7, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel AD column and AD guard column (5% i-PrOH:hexanes, | mL/min flow): t, = 11.5 min and 12.4 min. (2R,3S)-N-(3-Methyl-2-phenyloxy-4-pentenoyl)-morpholine (Table 7, entry 2). Prepared by the general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 133 mmol) and phenyloxyacetyl chloride (33 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a white solid in 84% yield (46 mg); syn:anti 92:8 syn 69% ee. Syn isomer: mp 65-66 °C; IR (thin film) 2967, 2922, 2857, 1641, 1599, 1588, 1495, 1439, 1227, 1116 cm'; 'H NMR (300 MHz, CDCI,) 8 6.89-7.31 (m, 5H, OC,H,), 5.80 (ddd, J = 8.4, 9.9, 17.1 Hz, 1H, CH=CH, ), 5.12 (ddd, J = 1.5, 9.9, 17.1 Hz, 2H, CH=CH,), 4.57 (d, J = 9.0 Hz, 1H, CHOC,H,), 3.34-3.85 (m, 8H, N(CH,CH,),), 2.70-2.84 (m, 1H, CHCH,), 1.24 (d, J = 6.6 Hz, 3H, CHCH,); '*C NMR (75 MHz, CDCI,) & 168.6, 157.7, 138.5, 129.9, 121.9, 116.5, 115.1, 83.8, 67.3, 67.0, 46.1, 43.2, 42.1, 17.6; [a],”* = -12.2 (c = 2.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel ODH column and ODH guard column (3% i-PrOH:hexanes, | mL/min flow); t, = 11.2 min and 12.1 min. (2R,3S)-N-(3-Methyl-2-p-chlorophenyloxy-4-pentenoyl)-morpholine (Table 7, entry 3). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and p-chlorophenyloxyacetyl chloride (37 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and iPr,NEt (59 uL, 0.30 mmol) to afford the product as a white solid in 86% yield (53 mg); syn:anti 97:3 syn 47% ee. Syn isomer: mp 85-86 °C; IR (thin film) 2968, 2924, 2857, 1642, 1595, 1491, 1439, 1232, 1116 cm'; 'H NMR (300 MHz, CDCI,) 8 6.81-7.24 (m, 4H, OC,H,C)), 5.78 (ddd, J = 8.1, 9.9, 17.1 Hz, 1H, CH=CH,), 5.12 (ddd, J = 1.2, 9.9, 17.1 Hz, 2H, CH=CH,), 4.50 (d, J = 9.0 Hz, 1H, CHOC,H,Cl), 3.36-3.74 (m, 8H, N(CH,CH,),), 2.64-2.82 (m, 1H, ‘CHCH,), 1.21 (d, J = 6.6 Hz, 3H, CHCH,); '°C NMR (75 MHz, CDCI,) 5 168.2, 156.3, 138.5, 130.7, 128.9, 116.7, 115.6, 83.3, 67.3, 67.0, 46.0, 43.1, 41.7, 17.5; [a], * = -46.0 (c = 1.5, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel ODH 134 column and ODH guard column (2% EtOH:hexanes, 1 mL/min flow); t, = 15.2 min and 16.1 min. (2R,3S)-N-(3-Methyl-2-phenylthio-4-pentenoyl)-morpholine (Table 7, entry 4). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and phenylthioacetyl chloride (36 wL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)-bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a white solid in 86% yield (50 mg); syn:anti >99:1 syn 72% ee. 'H NMR, '*°C NMR, IR, and mass spectral data for this compound were consistent with those previously reported.” [a], * = +68.4 (c = 2.0, CHCI,). The enantiomeric purity was determined by HPLC with a Chiralcel ODH column and ODH guard column (1% i- PrOH:hexanes, 1 mL/min flow); t, = 36.7 min and 43.2 min. (2R,3R)-N-(2-Chloro-3-methyl-4-pentenoyl)-morpholine (Table 7, entry 5). Prepared by general procedure A from (E)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and chloroacetyl chloride (19 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a white solid in 78% yield (34 mg); syn:anti >99:1 syn 80% ee. Syn isomer: mp 47-48 °C; IR (thin film) 2969, 2925, 2858, 1655, 1458, 1439, 1276, 1234, 1116 cm’; 'H NMR (300 MHz, CDC1,) 6 5.76 (ddd, J = 7.5, 10.2, 17.4 Hz, 1H, CH=CH,), 5.12 (ddd, J = 2.4, 10.2, 17.4 Hz, 2H, CH=CH,), 4.21 (d, J = 8.7 Hz, 1H, CHCl), 3.46-3.79 (m, 8H, N(CH,CH,),), 2.90-3.02 (m, 1H, CHCH=CH,), 1.24 (d, J = 6.6 Hz, 3H, CHCH,)); '*C NMR (75 MHz, CDCI,) 8 166.9, 138.9, 117.0, 67.0, 66.8, 58.5, 46.9, 43.0, 40.8, 17.0: [a], = -46.0 (c = 1.5, CHCI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex I-TA column (135 °C, 1.7 mL/min, 24 psi); syn isomer, t, = 23.0 min and 27.4 min; anti isomer, t, = 28.7 min and 31.7 min. 135 (2R,3R)-N-(2-Bromo-3-methyl-4-pentenoyl)-morpholine (Table 7, entry 6). Prepared by general procedure A from (£)-N-but-2-enyl morpholine (28 mg, 0.20 mmol) and bromoacetyl bromide (21 uL, 0.24 mmol), using AgClO, (84 mg, 0.40 mmol), (R,R)- bromoborane reagent 16 (244 mg, 0.40 mmol), and Cy,MeN (64 uL, 0.30 mmol) to afford the product as a white solid in 88% yield (46 mg); syn:anti >99:1 syn 76% ee. Syn isomer: mp 48-49 °C; IR (thin film) 2968, 2923, 2857, 1650, 1457, 1438, 1274, 1232, 1116 cm’; 'H NMR (300 MHz, CDCI,) 8 5.74 (ddd, J = 7.2, 10.5, 17.4 Hz, 1H, CH=CH,), 5.10 (dd, J = 10.5, 17.4 Hz, 2H, CH=CH,), 4.20 (d, J = 9.0 Hz, 1H, CHBr), 3.42-3.76 (m, 8H, N(CH,CH,),), 2.94-3.05 (m, 1H, CHCH=CH,), 1.26 (d, J = 6.6 Hz, 3H, CHCH,)); '°C NMR (75 MHz, CDCl,) 6 167.0, 138.8, 117.0, 67.0, 66.6, 49.1, 47.0, 42.9, 40.5, 18.6; [a],> = -50.7 (c = 2.0, CHCI,). The enantiomeric purity and diastereomer ratio was determined by GC with a Bodman Chiraldex [-TA column (135 °C, 1.7 mL/min, 24 psi); syn isomer, t, = 33.2 min and 37.6 min; anti isomer, t, = 42.0 min and 45.8 min. Determination of the absolute configuration of (2R,3S)-N-(2,3-Dimethyl-4- pentenoyl)-morpholine by Correlation with (2R,3S)-2,3-Dimethyl-4-pentenoic acid. A solution of (2R,3S)-N-(2,3-dimethyl-4-pentenoy]l)-morpholine (16 mg, 81 umol) in 1,2-DME (0.8 mL) and H,O (0.8 mL) was placed in a 2 mL scintillation vial equipped with a magnetic stir bar. The solution was treated with iodine (52 mg, .203 wmol) and was stirred in the absence of light. After 30 min, the reaction was diluted with Et,O ( mL) and washed sequentially with 10% aqueous Na,S,O, (2 mL) and brine (2 mL). The resulting organic layer was dried (Na,SO,) and concentrated to give 4-iodomethyl-2,3-dimethyl-y- butyrolactone as a yellow oil. The residue was dissolved in glacial ACOH (0.8 mL) and placed in a 2 mL scintillation vial equipped with a magnetic stir bar. The solution was treated with zinc dust (53 mg, 810 umol) and stirred at 65 °C for 3 h. After allowing the reaction to cool to rt, 1 N HCl (aq) (2 mL) was added, and the mixture was extracted with 136 ether (5 x 2 mL). The organic extracts were combined, dried (Na,SO,), and concentrated to give a light pink oil that exhibited spectral data identical in all respects to those reported for (2R,3S)-2,3-dimethyl-4-pentenoic acid.° [a], (literature) = 48.9 (c = 1.0, CHCl,); [a], (observed) = ~29.9 (c = 1.0, CHC1,). 6. Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y.; Ito, S. Tetrahedron Lett. 1992, 33, 1651. Sample: tpyii92 P.O. # 1736 X-ray Structure Report for Tehshik Yoon 204 Lewis Hall 3-8419 MacMillan Thu Apr 1 1999 137 138 Introduction The compound C,;gNO2Hg29 crystallizes in the non-centrosymmetric space group Pna2; with four molecules in the unit cell. The correct enantiomorph of the space group could not be determined. This ambiguity is inconsequential, however, as both enantiomorphs of the molecule are present in the space group regardless of the handedness of the space group. The relative stereochemistry of the molecule is as expected. There are no unusually close intermolec- ular contacts. -DLC 139 Experimental Data Collection A fragment of a colorless plate-like crystal of CygNOoHag having approximate dimensions of 0.35 x 0.30 x 0.12 mm was mounted on a quartz fiber using Paratone N hydrocarbon oil. All measurements were made on a SMART!° CCD area detector with graphite monochromated Mo-Ka radiation. Cell constants and an orientation matrix , obtained from a least-squares refinement using the measured positions of 99 reflections in the range 3.00 < 28 < 52.00° corresponded to a primitive orthorhombic cell with dimensions: a = 10.343(2) A b = 14.736(4) A c = 9.399(2) A V = 1432.5(6) A? For Z = 4 and F.W. = 258.34, the calculated density is 1.20 g/cm. Based on the systematic absences of: Okl: k+] ¥ 2n hol: h 4 2n packing considerations, a statistical analysis of intensity distribution, and the successful solution and refinement of the structure, the space group was determined to be: Pna2, (#33) The data were collected at a temperature of -135 + 1°C. Frames corresponding to an arbitrary hemisphere of data were collected using w scans of 0.3° counted for a total of 10.0 seconds per frame. Data Reduction Data were integrated by the program SAINT" to a maximum 26 value of 52.3°. The data were corrected for Lorentz and polarization effects. Fourteen reflections with AI/oI > 7 were treated as outliers, resulting in 0.20% of the data being removed. Data were analyzed for agreement and possible absorption using XPREP!”. An absorption correction was not necessary. Structure Solution and Refinement The structure was solved by direct methods! and expanded using Fourier techniques”. The non- hydrogen atoms were refined anisotropically. Hydrogen atoms were included in calculated idealized positions but not refined. The final cycle of full-matrix least-squares refinement? was based on 1640 140 observed reflections (I > 3.000(I)) and 171 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of: R =\|Fo| ~ |Fel|/E|Fo| = 0.034 Ry = (fw (|Fo| — |Fc])?/SwFo*)] = 0.037 The standard deviation of an observation of unit weight? was 1.37. The weighting scheme was based on counting statistics and included a factor (p = 0.030) to downweight the intense reflections. Plots of Dw(|Fol| — |Fc|)? versus |Fo|, reflection order in data collection, sin @/ and various classes of indices showed no unusual trends. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.12 and -0.13 e7 / A®, respectively. Neutral atom scattering factors were taken from Cromer and Waber® . Anomalous dispersion effects were included in Fealc®; the values for Af’ and Af’ were those of Creagh and McAuley’. The values for the mass attenuation coefficients are those of Creagh and Hubbel®. All calculations were performed using the teXsan® crystallographic software package of Molecular Structure Corporation. References (1) SIR92: Altomare, A., Cascarano, M., Giacovazzo, C., Guagliardi, A. (1993). J. Appl. Cryst., 26, 343. (2) DIRDIF94: Beurskens, P.T., Admiraal, G., Beurskens, G., Bosman, W.P., de Gelder, R., Israel, R. and Smits, J.M.M. (1994). The DIRDIF-94 program system, Technical Report of the Crystallography Laboratory, University of Nijmegen, The Netherlands. (3) Least-Squares: Function minimized: Sw(|Fo| — |Fc|)? (4) Standard deviation of an observation of unit weight: J dw(|Fo| — |Fc})?/(No — Nv) where: No = number of observations Nv = number of variables (5) Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography”, Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974). (6) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964). (7) Creagh, D. C. & McAuley, W.J .; ”International Tables for Crystallography” , Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992). (8) Creagh, D. C. & Hubbell, J.H..; ” International Tables for Crystallography”, Vol C, (A.J.C. 141 Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992). (9) teXsan: Crystal Structure Analysis Package, Molecular Structure Corporation (1985 & 1992). (10) SMART: Area-Detector Software Package, Siemens Industrial Automation, Inc.: Madison, WI, (1995) (11) SAINT: SAX Area-Dectector Integration Program, V4.024; Siemens Industrial Automa- tion, Inc.: Madison, WI, (1995) (12) XPREP:(v 5.03) Part of the SHELXTL Crystal Structure Determination Siemens Industrial Automation, Inc.: Madison, WI, (1995) 142 EXPERIMENTAL DETAILS A. Crystal Data Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group Z value Deate Fooo p(MoKa) Diffractometer Radiation Detector Position Exposure Time Scan Type 26 max CigNO2H 29 258.34 colorless, plates 0.35 X 0.30 X 0.12 mm orthorhombic Primitive a = 10.343(2)A_ b= 14.736(4) A c= 9.399(2) A V = 1432.5(6) A? Pna2, (#33) 4 1.198 g/cm? 556.00 14.08 em7! B. Intensity Measurements SMART CCD MoKa (A = 0.71069 A) graphite monochromated 60.00 mm 10.0 seconds per frame. w (0.3 degrees per frame) 02.3° No. of Reflections Measured Corrections 143 Total: 6560 Unique: 1658 (Rinz = 0.047) Lorentz-polarization C. Structure Solution and Refinement Structure Solution Refinement Function Minimized Least Squares Weights p-factor Anomalous Dispersion No. Observations (I>3.000(I)) No. Variables Reflection/Parameter Ratio Residuals: R; Rw; Rall Goodness of Fit Indicator Max Shift/Error in Final Cycle Maximum peak in Final Diff. Map Minimum peak in Final Diff. Map Direct Methods (SIR92) Full-matrix least-squares Ew(|Fo| — |Fel)? w= SFo) == [o2(Fo) + BF o?|-} 0.0300 All non-hydrogen atoms 1640 171 9.59 0.034 ; 0.037; 0.053 1.37 0.00 0.12 e~ / AS -0.13 e~ /A® 144 Table 1. Atomic coordinates and Biso/Beq atom x y Zz Beg O(1) 0.59157(14) 0.18906(10) 0.9976 2.55(4) O(2) 0.90038(16) 0.13627(13) 0.6126(3) 8.53(5) N(1) 0.77688(17) 0.16092(13) 0.8791(3) 2.27(5) CQ) 0.7711(2) 0.35837(16) 1.3063(3) 2.31(6) C(2) 0.6941(2) 0.38136(16) 1.4214(4) 2.61(6) C(3) 0.7457(3) 0.42685(18) 1.5374(3) 3.28(7) C(4) 0.8758(3) 0.44891(17) 1.5399(3) 3.49(7) C(5) 0.9530(3) 0.42585(16) 1.4266(4) 3.23(7) C(6) 0.9019(2) 0.38096(16) 1.3103(3) 2.74(6) C(7) 0.7110(2) 0.31772(17) 1.1739(3) 2.57(6) C(8) 0.6949(2) 0.39285(17) 1.0639(4) 2.71(6) C(9) 0.7625(3) 0.40555(18) 0.9492(4) 3.61(7) C(10) 0.7850(2) 0.23570(16) 1.1152(3) 2.36(6) C(11) 0.8044(2) 0.16220(16) 1.2303(4) 2.98(6) C(12) 0.7104(2) 0.19376(16) 0.9918(3) 2.13(5) C(13) 0.9168(2) 0.15072(17) 0.8681(3) 2.85(6) C(14) 0.9622(2) 0.18423(17) 0.7258(4) 3.39(7) C(15) 0.7639(3). 0.1495(2) 0.6224(3) 3.15(7) C(16) 0.7103(2) 0.11646(15) 0.7620(4) 2.45(6) H(1) 0.6050 0.3658 1.4208 3.1891 H(2) 0.6918 0.4429 1.6153 3.9349 H(3) 0.9114 0.4798 1.6194 4.1916 H(4) 1.0423 0.4409 1.4282 3.8708 H(5) 0.9563 0.3654 1.2326 3.2831 H(6) 0.6269 0.2974 1.1989 3.0858 H(7) 0.6276 0.4353 1.0813 8.2485 H(8) 0.7434 0.4552 0.8882 4.3376 H(9) 0.8311 0.3652 0.9264 2887 H(10) 0.8672 0.2552 1.0820 2.8290 H(11) 0.7227 0.1390 1.2587 8.5778 H(12) 0.8468 0.1881 1.3103 3.5773 H(13) 0.8557 0.1143 1.1928 B78 H(14) 0.9574 0.1849 0.9412 3.4165 (15) 0.9390 0.0885 0.8782 3.4165 H(16 0.9426 0.2470 0.7176 4.0721 ( ) 17) 1.0530 0.1757 0.7189 4.0721 Table 1. Atomic coordinates and Bjso/Beq (continued) atom x y Zz Beg H(18) 0.7231 0.1173 0.5472 3.7789 H(19) 0.7458 0.2125 0.6132 3.7789 H(20) 0.6206 0.1301 0.7667 2.9378 H(21) 0.7223 0.0527 0.7689 2.9378 8 5 Beg = 3% Ui (aa*)? +U29(bb*)?+Usa(cc*)? +20 200" bb" cos ¥+-2Uj3aa* cc* cos 3+2U23bb* cc* cos a) Table 2. Anisotropic Displacement Parameters atom O(1) q229229a0%20 2222228299292 99999%8 Q ~] Q Ko) on owwmww wre Se area e w a a ee Qaqan0n0d eS Se Fe oo Ll ol ed Q = a Un 0.0244(9) 0.0420(11) 0.0232(11) 0.0312(14) 0.0384(15) 0.063(2) 0.070(2) 0.0421(16 0.0354(15 0.0245(13 0.0379(14 0.060(2) 0.0256(1 ws U2. 0.0369(1 0.0541( 0.0352( 0.0267( 0.0316( 0.0370(16) 0.0332(15) 0.0372(16) 0.0331(16) 0.0390(16) 0.0310(15) 0.0335(15) 0.0353(16) 0.0326(15) 0.0263( 0.0440( ( ( ( 0) ) ) ) ) 12 12 14 15 0.0478 0.0466 0.0291(1 13) 17) 17) 18) 4) U33 0.0355(10) 0.0381 (12) 0.0279(13) 0.0297(16) 0.0291 (16) 0.0245(17) 0.0293(18) 0.0432(18) 0.0354(17) 0.0343(16) 0.0339(17) 0.043(2) 0.0287(15) 0.0352(17) 0.0262(14) 0.0367(17) 0.046(2) 0.0280(17) 0.0321(16) The general temperature factor expression: exp(—2 na “207, h? + b*?Ug9k? + CU 331? + 2a*b*Uy2hk + 2a* Uj -0.0020(8) -0.0069(9) -0.0003(9) -0.0043(10) -0.0059(12) -0.0037(13) -0.0017(14) 0.0019(12) 0.0013(11) -0.0042(11) 0.0012(11) -0.0036(13) -0.0016(11) -0.0010(11) -0.0003(11) 0.0025(12) -0.0069(11) -0.0054(13) -0.0008(10) Ui3 0.0016(8) 0.0083(9) -0.0013(10) 0.0011(13) 0.0037(13) 0.0062(14) -0.0175(16) -0.0151(14) -0.0037(13) 0.0004(11) -0.0120(14) -0.0044(16) 0.0004(12) -0.0018(15) -0.0023(12) -0.0007(13) 0.0092(14) -0.0045(14) -0.0010(13) 146 U93 -0.0074(& -0.0144 -0.0090 I jon) Oo coms) =~ ay Zz CPC PPC CC CP CO CO COC Cl COCO OT ay w CUyghl + 2b*c*Uo3kl)) 147 Table 3. Bond Lengths(A) atom atom distance atom atom distance O(1) C(12) 1.232(2) O(2) C(14) 1.428(3) O(2) C(15) 1.428(3) N(1) C(12) 1.352(3) N(1) C(13) 1.459(3) N(1) C(16) 1.455(3) CQ) C(2) 1.385(3) C(1) C(6) 1.394(3) C(1) C(7) 1.515(4) C(2) C(3) 1.387(4) C(3) C(4) 1.384(4) C(4) C(5) 1.374(4) C(5) C(6) 1.383(4) C(7) C(8) 1.524(4) C(7) C(10) 1.533(3) C(8) C(9) 1.299(4) C(10) C(11) 1.544(3) C(10) C(12) 1.524(3) C(13) C(14) 1.500(4) C(15) C(16) 1.505(4) 148 Table 4. Bond Lengths(A) atom atom distance atom atom distance C(2) H(1) 0.95 C(3) H(2) 0.95 C(4) H(3) 0.95 C(5) H(4) 0.95 C(6) H(5) 0.95 C(7) H(6) 0.95 C(8) H(7) 0.95 C(9) H(8) 0.95 C(9) H(9) 0.95 C(10) H(10) 0.95 C(11) H(11) 0.95 C(11) H(12) 0.95 C(11) H(13) 0.95 C(13) H(14) 0.95 C(13) H(15) 0.95 C(14) H(16) 0.95 C(14) H(17) 0.95 C(15) H(18) 0.95 C(15) H(19) 0.95 C(16) H(20) 0.95 C(16) H(21) 0.95 149 Table 5. Bond Angles(°) - atom atom atom angle atom atom atom angle C(14) O(2) C(15) 109.1(2) C(12) N(1) C(13) 126.7(2) C(12) N(1) C(16) 120.86(17) C(13) N(1) C(16) 111.67(18) C(2) C(1) C(6) 118.6(2) C(2) C(1) C(7) 120.2(2) C(6) C(1) C(7) 121.0(2) C(1) C(2) C(3) 120.7(2) C(2) C(3) C(4) 120.0(2) C(3) C(4) C(5) 119.6(2) C(4) C(5) C(6) 120.6(2) C(1) C(6) C(5) 120.4(2) C(1) C(7) C(8) 108.4(2) C(1) C(7) C(10) 113.8(2) C(8) C(7) C(10) 112.5(2) C(7) C(8) C(9) 127.5(2) C(7) cio) C(41)—s111.5(2) C(7) C(10) = C(12).—Ss«:109.94(18) C(11) C(10) C(12) 108.4(2) O(1) C(12) N(1) 121.5(2) O(1) C(12) C(10) 119.6(2) N(1) C(12) C(10) 118.91(18) N(1) C(13) C(14) 109.9(2) O(2) C(14) C(13) 111.18(18) O(2) C(15) C(16) 112.1(2) N(1) C(16) C(15) 109.85(18) 150 Table 6. Bond Angles(°) atom atom atom angle atom atom atom angle C(1) C(2) H(1) 119.6 C(3) C(2) H(1) 119.6 C(2) C(3) H(2) 120.0 C(4) C(3) H(2) 120.0 C(3) C(4) H(3) 120.2 C(5) C(4) H(3) 120.2 C(4) C(5) H(4) 119.7 C(6) C(5) H(4) 119.7 Cc(1) C(6) H(5) 119.8 C(5) C(6) H(5) 119.8. C(1) C(7) H(6) 107.3 C(8) C(7) H(6) 107.3 C(10) C(7) H(6) 107.3 C(7) C(8) H(7) 116.2 C(9) C(8) H(7) 116.2 C(8) C(9) H(8) 120.0 C(8) C(9) H(9) 120.0 H(8) C(9) H(9) 120.0 C(7) C(10) H(10) 109.0 C(11) C(10) H(10) 109.0 C(12) C(10) H(10) 109.0 C(10) C(11) H(11) 109.5 C(10) C(11) H(12) 109.5 C(10) C(11) H(13) 109.5 H(11) C(11) H(12) 109.5 H(11) C(1i1) H(13) 109.5 H(12) C(11) H(13) 109.5 N(1) C(13) H(14) 109.4 N(1) C(13) H(15) 109.4 C(14) C(13) H(14) 109.4 C(14) C(13) H(15) 109.4 H(14) C(13) H(15) 109.5 O(2) C(14) H(16) 109.0 O(2) C(14) H(17) 109.0 C(13) C(14) H(16) 109.0 C(13) C(14) H(17) 109.0 H(16) C(14) H(17) 109.5 O(2) C(15) H(18) 108.8 O(2) C(15) H(19) 108.8 C(16) C(15) H(18) 108.8 C(16) C(15) H(19) 108.8 H(18) C(15) H(19) 109.5 N(1) C(16) H(20) 109.4 N(1) C(16) H(21) 109.4 C(15) C(16) H(20) 109.4 C(15) C(16) H(21) 109.4 H(20) C(16) H(21) 109.5 151 Table 7. Torsion Angles(°) atom atom atom atom angle atom atom atom atom angle O(1) C(12) N(1) C(13) — -170.7(2) O(1) C(12) =N(1) C(16) -1.7(3) O(1) (12) (10) ~C(7) ~——-38.7(3) O41) C(12) ~~ C(10)—«C(11)—«83.3(3) O(2) (14) C(13) N(1) — -58.2(3) O(2) (15) C(16) N(4) 56.2(3) N(1) (12) (10) ~C(7)~—-142.5(2) N(Q1) (12) C(40), C11) ~—-95.5(2) c(t) C(2),—s« C3) (4) -0.7(4) cal) (6) (5B) 4) 0.0(4) c(1) (7) (8) ~—C(9)—«106..4(3) c(i) C(7)— (40), C41). 13) c(1) C(7)—-e(a0),—s C42) ~-—s«174.3(2) cj) cl) C6) C65) -0.4(3) c2) Cc) (7) (8) 99.2(2) c(2) C1) €(7)—s (0) 14.9(2) c(2) G3), (4) C55) 0.3(4) c(3) -«C(2),— ca) CG) 0.8(4) c(3) (2), C4) (7)—-173.5(2) c(3) (4) C(5) C6) 0.1(4) C(5) = C(6) = C(4).—sC(7)—s«173.8(2) c(6) (1) (7) ~—C(8)_—«-75.0(3) c(6) CQ) (7) C~0)_—_—=51.0(3) c(8) (7), (40), C(1)—_=«*177.9(2) c(8) (7) (10) (12) ~—-62.0(3) c(9) —«C(8),— (7), C(40)_——~- 20.34) c(10) (12) N(1) (13) ——_—-8.0(3) c(10) C2) ~N(1) C(16) —-177.1(2) c(i2) N(1) (13) (14) -135.3(2) c(i2) N(1) (16) (15) ~—-135.9(2) c(13) N(1) (46) (15) -53.5(2) c(13) C(14), ~O(2) ~~ (15) —s«60.1(3) c(14) O22) (15) C16) — -59.3(3) c(i4) C13) N(Q) C(16) — 54.8(3) 152 Table 8. Non-bonded Contacts out to 3.75 A atom atom distance ADC atom atom distance ADC O(1) C(13) 3.213(3) 45504 O(1) C(14) 3.435(3) 45504 O(1) C(10) 3.537(3) 45504 O(1) C(4) 3.577(3) 64403 O(1) C(6) 3.681(3) 45504 O(1) C(9) 3.706(3) 45504 O(2) C(2) 3.540(3) 55404 O(2) C(11)—3.747(3) 55401 O(2) C(8) 3.748(3) 64403 C(4) C(16) 3.703(4) 65503 C(4) C(12) 3.744(3) 65503 C(5) C(16) 3.625(4) 65503 C(6) C(16) —3.687(3) 65503 C(8) C3) —-3.474(4) 45504 C(9) C(13) —-3.749(4) 45504 C(l) C45) 3.714(4) 55601 153 The ADC (atom designator code) specifies the position of an atom in a crystal. The 5-digit number shown in the table is a composite of three one-digit numbers and one two-digit number: TA (first digit) + TB (second digit) + TC (third digit) + SN (last two digits). TA, TB and TC are the crystal lattice translation digits along cell edges a, b and c. A translation digit of 5 indicates the origin unit cell. If TA = 4, this indicates a translation of one unit cell length along the a-axis in the negative direction. Each translation digit can range in value from 1 to 9 and thus +4 lattice translations from the origin (TA=5, TB=5, TC=5) can be represented. The 5N, or symmetry operator number, refers to the number of the symmetry operator used to generate the coordinates of the target atom. A list of symmetry operators relevant to this structure are given below. For a given intermolecular contact, the first atom (origin atom) is located in the origin unit cell and its position can be generated using the identity operator (SN=1). Thus, the ADC for an origin atom is always 55501. The position of the second atom (target atom) can be generated using the ADC and the coordinates of the atom in the parameter table. For example, an ADC of 47502 refers to the target atom moved through symmetry operator two, then translated -1 cell translations along the a axis, +2 cell translations along the b axis, and 0 cell translations along the c axis. An ADC of 1 indicates an intermolecular contact between two fragments (eg. cation and anion) that reside in the same asymmetric unit. Symmetry Operators: (1) X, Y, Z (2) -X, -Y, 1/2+Z (3) 1/2-X, 1/2+Y, 1/242 (4) 1/2+X, 1/2Y, Z Table 9. Least Squares Planes Plane number 1 Atoms defining plane Distance C(1) -0.003(3) C(2) 0.004(3) C(3) -0.003(3) C(4) -0.001(3) (5) 0.001(3) C(6) 0.000(2) Additional Atoms Distance C(7) -0.144 Plane number 2 Atoms defining plane Distance C(7) 0.0 C(8) 0.0 C(9) 0.0 Additional Atoms Distance C(10) -0.491 Plane number 3 Atoms defining plane Distance C(10) 0.002(3) C(12) -0.007(2) O(1) 0.0011(14) N(1) 0.001(2) Additional Atoms Distance C(13) 0.181 C(16) 0.056 Summary plane mean deviation x? 1 0.0020 5.4 0.0000 0.0 3 0.0028 11.1 plane 2 3 1 98.71 8.26 2 104.31 Dihedral angles between planes (°) Sample: tpy128 P.O. # 1736 X-ray Structure Report for Tehshik Yoon 204 Lewis Hall 3-8419 MacMillan Thu May 20 1999 156 Introduction The compound C;gN2O4Hig crystallizes in the triclinic space group P1 with four molecules in the unit cell. There are two crystallographically unique but chemically identical molecules in the asymmetric unit. The relative stereochemistry of the molecule is as expected. The morpholine moiety on one of the molecules is disordered over two possible chair conformations. The disorder was modeled using half occupancy isotropic carbon and oxygen atoms and one full occupancy anisotropic nitrogen atom. There are no unusually close intermolecular contacts. -DLC 158 Experimental Data Collection A fragment of a colorless blocky crystal of C1gN2O4Hj9 having approximate dimensions of 0.35 x 0.17 x 0.05 mm was mounted on a quartz fiber using Paratone N hydrocarbon oil. All measurements were made on a SMART! CCD area detector with graphite monochromated Mo-Ka radiation. Cell constants and an orientation matrix , obtained from a least-squares refinement using the measured positions of 2880 reflections in the range 3.00 < 26 < 46.00° corresponded to a primitive triclinic cell with dimensions: a = 9.1819(9) A a = 90.855(2)° b = 11.3667(10) A B = 90.623(2)° c = 16.8867(17) A 7 = 110.369(2) V = 1651.8(3) A# {\ For Z = 4 and F.W. = 327.36, the calculated density is 1.32 g/cm. Based on a statistical analysis of intensity distribution, and the successful solution and refinement of the structure, the space group was determined to be: Pl (#2) The data were collected at a temperature of -122 + 1°C. Frames corresponding to an arbitrary hemisphere of data were collected using w scans of 0..3° counted for a total of 10.0 seconds per frame. Data Reduction Data were integrated by the program SAINT!! to a maximum 26 value of 49.4°. The data were corrected for Lorentz and polarization effects. Data were analyzed for agreement and possible absorption using XPREP!?. An empirical absorption correction based on comparison of redundant and equivalent reflections as applied using SADABS!° (Tmax = 0.96, Tmin = 0.76). Structure Solution and Refinement The structure was solved by direct methods! and expanded using Fourier techniques”. The full occupancy non-hydrogen atoms were refined anisotropically, while the partial occupancy non- hydrogen atoms were refined isotropically. The disordered morpholine moiety was modeled as de- scribed in the Introduction. Hydrogen atoms were included in calculated idealized positions but not refined. The final cycle of full-matrix least-squares refinement? was based on 3025 observed reflections (I > 3.00c(I)) and 428 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of: R=2D||Fo| —|Fc}|/=|Fo| = 0.052 159 Ry = / (Zw(|Fo| — |Fc])?/SwFo2)] = 0.062 The standard deviation of an observation of unit weight? was 2.06. The weighting scheme was based on counting statistics and included a factor (p = 0.030) to downweight the intense reflections. Plots of Hw(|Fo| —|Fc|)? versus |Fo|, reflection order in data collection, sin 9/ and various classes of indices showed no unusual trends. The maximum and minimum peaks on the final difference - Fourier map corresponded to 0.36 and -0.19 e7 / AB, respectively. Neutral atom scattering factors were taken from Cromer and Waber® . Anomalous dispersion effects were included in Fcalc®; the values for Af’ and Af’ were those of Creagh and McAuley’. The values for the mass attenuation coefficients are those of Creagh and Hubbel®. All calculations were performed using the teXsan® crystallographic software package of Molecular Structure Corporation. References (1) SIR92: Altomare, A., Cascarano, M., Giacovazzo, C., Guagliardi, A. (1993). J. Appl. Cryst., 26, 343. (2) DIRDIF94: Beurskens, P.T., Admiraal, G., Beurskens, G., Bosman, W.P., de Gelder, R., Israel, R. and Smits, J.M.M. (1994). The DIRDIF-94 program system, Technical Report of the Crystallography Laboratory, University of Nijmegen, The Netherlands. (3) Least-Squares: Function minimized: Ew(|Fo| — |Fe|)? (4) Standard deviation of an observation of unit weight: /=w(|Fo| ~ |Fel)?/(No — Nv) where: No = number of observations Nv = number of variables (5) Cromer, D. T. & Waber, J. T.; ”International Tables for X-ray Crystallography”, Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974). (6) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964). (7) Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography”, Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992). (8) Creagh, D. C. & Hubbell, J.H..; ’International Tables for Crystallography”, Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992). (9) teXsan: Crystal Structure Analysis Package, Molecular Structure Corporation (1985 & 1992). 160 (10) SMART: Area-Detector Software Package, Siemens Industrial Automation, Inc.: Madison, WI, (1995) (11) SAINT: SAX Area-Dectector Integration Program, V4.024: Siemens Industrial Automa- tion, Inc.: Madison, WI, (1995) (12) XPREP:(v 5.03) Part of the SHELXTL Crystal Structure Determination Siemens Industrial Automation, Inc.: Madison, WI, (1995) (13) SADABS: Siemens Area Detector ABSsorption correction program, George Sheldrick, (1996). Advance copy, private communication. Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group Z value Deate Foo u(MoKa) Diffractometer Radiation ‘ Detector Position Exposure Time Scan Type 161 EXPERIMENTAL DETAILS A. Crystal Data CigN204Hi9 327.36 colorless, blocks 0.35 X 0.17 X 0.05 mm triclinic Primitive a= 9.1819(9)A b= 11.3667(10) A c = 16.8867(17) A a = 90.855(2)° B = 90.623(2)° y = 110.369(2)° V = 1651.8(3) A® Pl (#2) 4 1.316 g/cm? 692.00 16.21 cm7! B. Intensity Measurements SMART CCD ~ MoKa (A = 0.71069 A) graphite monochromated 60.00 mm 10.0 seconds per frame. w (0.3 degrees per frame) No. of Reflections Measured Corrections 162 49.4° Total: 8645 Unique: 5563 (Ring = 0.028) Lorentz-polarization Absorption (Tmax = 0.96 Tmin = 0.76) C. Structure Solution and Refinement Structure Solution Refinement Function Minimized Least Squares Weights p-factor Anomalous Dispersion No. Observations (I>3.000(I)) No. Variables Reflection/Parameter Ratio Residuals: R; Rw; Rall Goodness of Fit Indicator Max Shift/Error in Final Cycle Maximum peak in Final Diff. Map Minimum peak in Final Diff. Map Direct Methods (SIR92) Full-matrix least-squares Lw(|Fo| — |Fel)? w w= Fo = [o2(Fo) + &Fo?|7! 0.0300 All non-hydrogen atoms 3025 428 7.07 0.052 ; 0.062; 0.105 2.06 0.00 0.36 e~ /A® -0.19 e~ /A8 163 Table 1. Atomic coordinates and Bjs5,/Beg and occupancy atom x y Zz Beg occ O(1) 0.1090(3) 0.7756(3) 0.72420(17) 3.41(7) O(2) -0.1954(4) 0.8561(3) 0.51169(17) 3.87(8) O(3) 0.1956(3) 0.5541(3) 0.79701(17) 3.79(8) O(4) 0.1124(3) 0.3896(2) 0.57795(16) 2.91(7) O(5) 0.4106(3) 0.2483(3) 0.22739(17) 3.30(7) O(6) 0.7248(7) 0.1527(6) 0.0221(4) 2.83(14) 1/2 O(7) 0.6627(8) 0.1088(6) 0.0110(4) 3.38(15) 1/2 O(8) 0.6300(3) 0.5987(3) 0.08320(17) 3.52(7) O(9) 0.2862(3) 0.4628(3) 0.28574(16) 3.56(7) N(1) -0.0551(4) 0.7387(3) 0.61895(18) 2.32(8) N(2) 0.0568(4) 0.5034(3) 0.67708(18) 2.33(8) N(3) 0.5224(5) 0.2363(3) 0.1116(2) 3.95(10) N(4) 0.4424(4) 0.4976(3) 0.1744(2) 2.57(8) C(1) 0.4673(6) 0.8858(4) 0.6007(3) 4.39(13) C(2) 0.3613(5) 0.7797 (4) 0.5815(2) 3.08(11) C(3) 0.3033(4) 0.6702(3) 0.6349(2) 2.44(9) C(4) 0.1249(4) 0.6195(4) 0.6318(2) 2.37(9) C(5) 0.0580(5) 0.7177(4) 0.6621(3) 2.41(10) C(6) -0.1352(5) 0.6720(4) 0.5480(2) 2.84(10) C(7) 0.1295(5) 0.7664(4) 0.4851(3) 3.40(11) C(8) 0.1180(5) 0.9187(4) 0.5823(3) 3.61(12) C(9) 0.1239(5) 0.8286(4) 0.6475(2) 2.87(10) C(10) 0.3687(5) 0.5699(4) 0.6095(3) 3.83(11) c(11) 0.0954(5) 0.4823(4) 0.7552(3) 2.87(11) C(12) 0.0086(5) 0.3532(4) 0.7738(2) 2.55(10) C(13) 0.0224(5) 0.2858(4) 0.8424(3) 3.41(12) Cc(14) 0.1263(6) 0.1642(4) 0.8416(3) 3.64(12) C(15) -0.2130(5) 0.1117(4) 0.7742(3) 3.72(12) C(16) -0.2017(5) 0.1802(4) 0.7057(3) 3.04(11) C(17) 0.0990(4) 0.3018(4) 0.7070(2) 2.43(10) C(18) 0.0591(5) 0.3975(4) 0.6451(3) 2.36(10) C(19) 0.0490(7) 0.1072(5) 0.0990(3) 5.95(15) C(20) 0.1375(5) 0.2147(4) 0.0747(3) 3.21(11) C(21) 0.1958(5) 0.3318(4) 0.1249(2) 2.69(10) C(22) 0.3756(5) 0.3820(4) 0.1274(2) 2.49(10) C(23) 0.4384(5) 0.2835(4) 0.1590(3) 2.65(10) Table 1. Atomic coordinates and B;;, /Beg and occupancy (continued) atom C(24) C(25) Ww ho xX 0.6181(12) 0.5555(11) 0.7190(10) 0.5956(11) 0.6825(11) 0.5935(11) 0.6077 jem) fo) fon) for) bd ON NNN NNN RON y 0.1633(9) 0.1239(9) 0.1453(7) 0.0597(8) 0.2576(9) 0.1973(8) 0.3025(8) 0.2345(9) 0.5984(4) 0.6984(4) 0.8179(4) 0.8919(4) 0.8460(4) 0.7260(4) 0.6546(4) 0.5273(4) 0.4315(4) 0.9514 0.8981 0.7708 0.6971 0.6006 0.6164 0.6254 0.8091 0.7233 0.9638 0.9756 0.8732 0.7857 0.5422 0.6039 0.5009 0.3219 0.1158 0.0270 Z 0.1461(6) 0.1400 0.1087(5 0.0855 (6 -0.0019(5 -0.0198(5 0.0364(5 0.5707 0.5998 0.6925 0.6616 0.5569 0.6115 0.6441 0.8886 0.8881 0.7749 (5 (5 ) ) ) ) ) ) ) ) ) 3) ) ) ) ) ) ) Beg 3.2(2) 2.6(2) 2.76(16) 4.0(2) 3.5(2) 3.26(18) 3.05(17) 3.8(2) 2.77(11) 2.78(10) 3.63(12) 4.47(13) 3.95(13) 3.35(11) 2.56(10) 2.77(11) 3.91(12) 5.2730 5.2730 3.6965 2.9334 2.8403 3.4075 3.4075 4.0828 4.0828 4.3338 4.3338 3.4381 3.4381 4.5967 4.5967 4.5967 4.0910 4.3734 4.4604 oce 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 164 Table 1. Atomic coordinates and Bjs./Beg and occupancy (continued) atom x y Zz Beg occ H(20) -0.2625 0.1444 0.6598 3.6522 H(21) 0.0167 0.0369 0.0636 7.1431 H(22) 0.0159 0.0982 0.1524 7.1431 H(23) 0.1681 0.2202 0.0210 3.8508 H(24) 0.1590 0.3128 0.1772 3.2324 H(25) 0.4102 0.3994 0.0746 2.9826 H(26) 0.7848 0.8482 0.1675 4.3576 H(27) 0.7963 0.9753 0.2803 5.3683 H(28) 0.6382 0.8972 0.3870 4.7436 H(29) 0.4476 0.6949 0.3812 4.0254 H(30) 0.1740 0.5054 0.1243 4.6949 H(31) 0.1716 0.4504 0.0394 4.6949 H(32) 0.0258 0.4007 0.0918 4.6949 8 Beq = 37 (Ou (aa*)? + Ug(bb*)? +U33(cc*)? +2U 200° bb* cos ¥+2U3aa*cc* cos G-+2U23bb* cc* cos a) 166 Table 2. Anisotropic Displacement Parameters atom Uy Ung Us3 Une Uy Uo3 O(1) 0.051(2) 0.051(2) 0.0322(18) 0.0240(16) -0.0086(16) —-0.0103(16) O(2) 0.069(2) 0.054(2) 0.039(2) 0.0409(18) -0.0025(17) 0.001216) O(3) 0.049(2) 0.044(2) 0.039(2) 0.0004(16) -0.0158(17) —_0.0058(15) O(4) 0.0373(17) 0.0360(17) 0.0334(18) — 0.0082(14) -0.0029(15) — -0.0032(14) O(5) 0.0442(18) 0.056(2) 0.0292(18) 0.0222(16) 0.0075(15) — 0.0106(15) O(8) 0.0386(17) 0.054(2) 0.038(2) 0.0120(16) 0.0078(16) —-0.0106(16) O(9) 0.046(2) 0.040(2) 0.040(2) 0.0037(16) 0.0142(16) -0.0025(15) N(1) 0.031(2) 0.029(2) 0.030(2) 0.0121(17) -0.0028(17) -0.0006(16) N(2) 0.030(2) 0.029(2) 0.027(2) 0.0067(17) -0.0004(16) — 0.0040(16) N(3) 0.082(3) 0.067(3) 0.024(2) 0.055(3) 0.012(2) 0.009(2) N(4) 0.034(2) 0.032(2) 0.031(2) 0.0092(18) 0.0064(18) — -0.0003(17) c(1) 0.060(3) 0.049(3) 0.053(3) 0.013(3) 0.002(3) 0.011(3) C(2) 0.033(3) 0.040(3) 0.040(3) 0.006(2) -0.004(2) 0.002(2) C(3) 0.029(2) 0.027(2) 0.034(3) 0.006(2) -0.001(2) 0.003(2) C(4) 0.032(2) 0.032(2) 0.023(2) 0.008(2) -0.002(2) 0.003(2) C(5) 0.032(2) 0.027(2) 0.029(3) 0.005(2) 0.004(2) 0.007(2) C(6) 0.034(2) 0.037(3) 0.037(3) 0.014(2) -0.003(2) -0.003(2) C(7) 0.052(3) 0.045(3) 0.036(3) 0.023(3) 0.000(2) -0.003(2) C(8) 0.060(3) 0.044(3) 0.042(3) 0.028(3) 0.007(3) 0.004(2) C(9) 0.039(3) 0.041(3) 0.033(3) 0.019(2) 0.003(2) 0.000(2) C(10) 0.030(2) 0.047(3) 0.067(3) 0.013(2) -0.002(2) -0.003(3) C(11) 0.034(3) 0.041(3) 0.036(3) 0.015(2) 0.000(2) 0.004(2) C(12) 0.036(2) 0.030(3) 0.035(3) 0.016(2) 0.006(2) 0.009(2) C(13) 0.042(3) 0.046(3) 0.046(3) 0.020(3) 0.004(2) 0.009(3) c(14) 0.048(3) 0.042(3) 0.051(3) 0.018(3) 0.017(3) 0.018(3) C(15) 0.041(3) 0.033(3) 0.066(4) 0.010(2) 0.017(3) 0.007(3) C(16) 0.035(3) 0.032(3) 0.047(3) 0.009(2) 0.009(2) 0.004(2) C(17) 0.028(2) 0.028(3) 0.037(3) 0.011(2) 0.008(2) 0.003(2) C(18) 0.027(2) 0.033(3) 0.032(3) 0.012(2) 0.002(2) 0.002(2) C(19) 0.119(5) 0.047(3) 0.044(3) 0.008(4) 0.013(3) 0.002(3) C(20) 0.046(3) 0.040(3) 0.035(3) 0.014(2) 0.004(2) 0.002(2) C(21) 0.038(3) 0.035(3) 0.031(3) 0.014(2) 0.002(2) 0.002(2) C(22) 0.036(2) 0.034(3) 0.025(2) 0.013(2) 0.004(2) 0.000(2) C(23) 0.036(3) 0.036(3) 0.030(3) 0.014(2) 0.000(2) 0.002(2) (32) 0.032(3) 0.041(3) 0.035(3) 0.016(2) 0.002(2) 0.008(2) C(33) 0.033(2) 0.033(3) 0.041(3) 0.013(2) 0.007(2) 0.004(2) 167 Table 2. Anisotropic Displacement Parameters (continued) atom Uy Uae Us Ue Ui Uo3 (34) 0.034(3) -0.034(3) —-—(0,066(3) 0.006(2) — -0.003(3) —-:0.006(3) (35) 0.047(3) -0.036(3) —-0.080(4) 0.007(3) -0.008(3) —--0.002(3) C(36) 0.047(3) -0.043(3) —«0.064(4) 0.022(3) -0.018(3) _—_-0.016(3) (37) 0.045(3) :0.040(3) —:0.046(3) 0.019(3) -0.005(2) —_—-0.002(2) (38) 0.034(2) :0.029(3) —:0.036(3) 0.015(2) -0.001(2) ——-0.001(2) (39) | 0.035(3) 0.036(3) —:0.035(3) 0.014(2) -0.004(2) —0.000(2) (40) 0.043(3) :0.043(3) ~—=—«0.065(3) 0.019(2) -0.001(3) _—--0.001(3) The general temperature factor expression: exp(—2 n(a “207 he + b*? Ugo k? + ?Us3l? + 2a*b*Ughk + 2a*c* Uy 3hl + 2b* c*Uo3kl)) 168 Table 3. Bond Lengths(A) ot atom atom distance atom NNN ot tn n ers OOo wow Aan ww wom wo OO wd Oo Wa ae ee se Os Ol Ol Ol lf WS sO ees OS OSs OS sO sO SES ON ss OS Os OSs SS LS ES OS OSs SS OSs Oa es OSs aes ase es OO eS OS OO ON ee st &F- or wotnonrseanwtwawuoernwreoedaqiewHyN-wryrwoaoonnwmntvoc$c’”owodoc’kcowrocrT tft NON O MN YO Fr OwWoenwroanwkwrannmrimmr ononok wareoanmeoeeqoc”r”roeoorvocn % © tt VAN ATT SCN MYY BMT eY A ee oennanat re SMM a| MAT MM © ON NNN NNN PONENT NN NNN NN aa sa el —™~ Aa 7 O OO ON aa We YD 1D DW NR Om mR OS OM OOD a lt OWL OS OO Ot lll | OU NCD MmrqI NNN NN MUM DANN MANA TFWM Ds SB se wMrNnNTNNNN OM OOM NM OM ooo 0o 00 0U~00€=2ue0=0=du022—@ —~ 6eBOmMOOOC—COOOO —hOUmU Cm oe mo Cm be moe mom meme meme mob Cm em Ue Oo. ee eee SOS OOO TOT TOT OTN Tee Nee eee eee ee a aa Oa aa eae a NN oN ON EN NN NNT eT a a a a ees es TI NOD rT ND Neem a 0s De ee 0 00 0 Sn Ce Ks <0 Vn eS cc on 0 Sn Dn eS ee eee ee TO OO OT OO Oe C©Cm- COMO Tr TO OMA THR UA OW aA FH revo weomMmMvwnMonrekr oavUuUu Banat nN MW Ow NNN DW ODN OM ODA OM AANA YwnmeoenTnn iv WO Owe DAhTFT DTN DM vo DAwWDOAHAADA HD Ww NHN OO Ot Tt N MH HH id wo HT Ty ww HTH HM MN OM MAM AAA OM HO HY SH ee ee ee es ee ee or ee ee] — NN NNN NN NNN os OR ION NN NN NNN Dom OH mae De DOD DmnrweowWdtonrdnroonwnrirworoedndrdi aD oOo or OOGa tt YOY ID OWE NANANNA MOMMA N MN DMM ARPT Dr DT TAT NNNNN ANH OM HM HO MD OM Nee eee OOO Oe Oe OT OOOO OOOO OT OT OO OT OTT OT Oe OTe Oe ae ae ON NNN NNN NTN TN TNR TR Nn NNN NN NNN NN NN NNN Se ail ee nl tad alla e e ee 169 Table 4. Bond Lengths(A) atom atom distance atom atom distance c(1) H(1) 0.95 C(1) H(2) 0.95 C(2) H(3) 0.95 C(3) H(4) 0.95 C(4) H(5) 0.95 C(6) H(6) 0.95 C(6) H(7) 0.95 C(7) H(8) 0.95 C(7) H(9) 0.95 C(8) H(10) 0.95 C(8) H(11) 0.95 C(9) H(12) 0.95 C(9) H(13) 0.95 C(10) H(14) 0.95 C(10) H(15) 0.95 C(10) H(16) 0.95 C(13) H(17) 0.95 C(14) H(18) 0.95 C(15) H(19) 0.95 C(16) H(20) 0.95 C(19) H(21) 0.95 C(19) H(22) 0.95 C(20) H(23) 0.95 C(21) H(24) 0.95 C(22) H(25) 0.95 C(34) H(26) 0.95 C(35) H(27) 0.95 C(36) H(28) 0.95 C(37) H(29) 0.95 C(40) H(30) 0.95 C(40) H(31) 0.95 C(40) H(32) 0.95 170 Table 5. Bond Angles(°) atom atom angle atom atom atom angle atom en -een ACR aAananntroaeaeanaereraoara awa os MS HO tHe es eae iets ees a Oe Oa aS as OS ae a ar eoUwenreTvreeaeTaen en SON LTPT HMSO SOS OM HDT HHDAHEHAKEAHMOA SHS w ane His MAR OSC S Soe Hi nNnoO Hew oH COBH eH KD He KR OH HN wD HAT GD SFP WOO THN VO DODO Heme NT NNN NAN TP TD AN Ft CO HF TON Wr ZF TON DANN TF ON OC CO pa ee co EV Vn = ee oS Dee ee ee Fae a eae es eee a a en ee ae Fae eee ae ae cae eel ae ae — Cla ei ae ae a a amie aii Oo OMe DAA ODO OMe DD a ~~ OH CO MN WD N DS Damm em er NO OY we ORE SN NWNNNNNNNN OU DHF NMA MN N MN Yr Ort Oo DOH Hn eT NBN HN Ne ee Oe Oe ONO ee OOOO OT OTN OT OO OT OTOL OT OTN OWN OW OM i [aaa iat i aS ati li a ee Nee NNN Ne Oe ea eee eee eee Nee eee eee eee eae eee eae eae ee Ne a Oe Nee ee es eae as Os eee eae ee eee ee eee TOOT COT ae aa ae ea DN NNN NNN NN NN ST Som CO Nm ODO a ee ae a © ev © 0) 0 0 ns ns Ds Ss ss Ms ss SY OD OK He OO) OL Tt iii ii ie Tt ie in ini ir i i i i er Oe a Oar ae a2 tT en ASn 2 ZPHN SG Ko or wr nr tA HBP HMAH BANKS BG werKH HOw H moron MonwvornnmwANnNnrADt NO st ERAN N Orn Fr OoOTWA NTO TW NN DN N Sen Ye a ee ra ee © I A ee ee ee ee | ON NNN ON NNN o—~ ON NNN mr~r- OwmwwWDr-e DOH ORD aH DH WO tt CO CO WD mae Dam mm ee OO NCU Ee UT CU OUlULDOLUCUCOOUMDN! UD ONNNNANNN NN AN Drre DN DM NAnMmMn DM as Oo WO HMHAh DN tnt ntn na Tt NN Ne Ne Le Ne eee ee eee eee eee ee eee eee eee OO OT OO OT OT Oa ae ae ae ON NN TNT NN NN NN NTN TN TR NN NNN NNN NTN NN NN NT eee eee OO OO eee Oe eee eee eee eee eee eee ae Nee Oe Nae ee Oe eee eee eee eee OT OO Oi OD ODO aN OT Oa aa aa Oa Table 5. Bond Angles(°) (continued) atom C(20) N(4) C(21) O(5) N(3) = WwW w Ne Ne OT NS ele) ~I ~~ fon) wee 1) a ~~ atom C(21) C(22) C(22) C(23) C(24) C(24) C(24) C(25) C(25) C(25) C(26) C(26) C(26) C(26) C(26) C(27) C(27) C(27) C(27) C(27) C(28) C(28) C(28) C(28) C(28) C(29) C(29) C(29) C(29) C(29) C(30) C(30) C(30) C(31) C(31) C(31) atom C(40) C(21) C(23) C(22) angle 110.2(3) 113.4(3) 111.1(3) 119.2(4) 76.2(14) 102.8(7) 58.8(15) 80.8(15) 115.4(8) 98.0(17) 21.1(3) 112.3(6) 111.3(7) 55.0(5) 75.3(8) 21.6(3) 112.4(8) 111.3(7) 79.0(7) 50.4(6) 22.4(3) 124,3(9) 61.7(8) 92.5(6) 50.6(8) 23.1(3) 96.6(7) 85.1(9) 120.6(8) 93.9(11) 121.0(8) 69.8(8) 91.8(10) 101.5(7) 73.2(8) 49.2(7) fon) wa OO No Nh oo a a a SNe atom 171 46.0(14 52.1(6) 122.5(8) 76.1(6) 96.1(6) 21.1(6) 54.3(6) 94.0(6) 57.4(5) 124.8(8) 23.3(5) 73.6(7) 84.1(9) 109.4(7) 119.1(8) 89.4(11) 39.0(5) 62.0(8) 119.2(8) 113.0(7) 52.8(8) 41.2(5) 104.0(6) 37.8(5) 54.2(8) 121.9(8) 35.5(5) 84.6(10) 172 Table 5. Bond Angles(°) (continued) atom atom atom angle atom atom atom angle O(8) C(32) N(4) 124,.4(4) O(8) C(32) C(33) 129.1(4) N(4) C(32) C(33) 106.4(4) C(32) C(33) C(34) 130.4(4) C(32) —-C(33) C(38) 108.1(4) c(34)—s-C(33)~—s C(38) 121.4(4) C(33) C(34) C(35) 117.3(4) C(34) C(35) C(36) 121.0(4) C(35) C(36) C(37) 121.4(4) C(36) C(37) C(38) 117.1(4) C(33) C(38) C(37) 121.6(4) C(33) C(38) C(39) 108.5(4) C(37) C(38) C(39) 129.9(4) O(9) C(39) N(4) 126.1(4) O(9) C(39) C(38) 127.6(4) N(4) C(39) C(38) 106.3(4) 173 Table 6. Bond Angles(°) atom atom atom angle atom atom atom angle C(2) C(1) H(1) 120.0 C(2) C(1) H(2) 120.0 H(1) C(1) H(2) 120.0 C(1) C(2) H(3) 117.6 C(3) C(2) H(3) 117.6 C(2) C(3) H(4) 109.0 C(4) C(3) H(4) 109.0 c(10) ~—C(3) H(4) 109.0 N(2) C(4) H(5) 107.8 C(3) C(4) H(5) 107.8 C(5) C(4) H(5) 107.8 N(1) C(6) H(6) 109.6 N(1) C(6) H(7) 109.6 C(7) C(6) H(6) 109.6 C(7) C(6) H(7) 109.6 H(6) C(6) H(7) 109.5 O(2) C(7) H(8) 108.9 O(2) C(7) H(9) 108.9 C(6) C(7) H(8) 108.9 C(6) C(7) H(9) 108.9 H(8) C(7) H(9) 109.5 O(2) C(8) H(10) 108.8 O(2) C(8) H(11) 108.8 C(9) C(8) H(10) 108.8 C(9) C(8) H(11) 108.8 H(10) C(8) H(11) 109.5 N(1) C(9) H(12) 109.8 N(1) C(9) H(13) 109.8 C(8) C(9) H(12) 109.8 C(8) C(9) H(13) 109.8 H(12) C(9) H(13) 109.5 C(3) C(10) H(14) 109.5 C(3) C(10) H(15) 109.5 C(3) C(10) H(16) 109.5 H(14) C(10) H(15) 109.5 H(14) C(10) H(16) 109.5 H(15) C(10) H(16) 109.5 C(12) C(13) H(17) 121.2 C(14) C(13) H(17) 121.2 C(13) C(14) H(18) 119.5 C(15) C(14) H(18) 119.5 C(14) C(15) H(19) 119.3 C(16) C(15) H(19) 119.3 C(15) C(16) H(20) 121.3 C(17) C(16) H(20) 121.3 C(20) C(19) H(21) 120.0 C(20) C(19) H(22) 120.0 H(21) C(19) H(22) 120.0 C(19) C(20) H(23) 117.6 C(21) C(20) H(23) 117.6 C(20) C(21) H(24) 108.9 C(22) C(21) H(24) 108.9 c(40) ss C(21),—s«wY(24)—s«i108.9 N(4) C(22) = H(25) ~—:107.7 C(21) C(22) H(25) 107.7 C(23) C(22) H(25) 107.7 C(33) C(34) H(26) 121.3 C(35) C(34) H(26) 121.3 C(34) C(35) H(27) 119.5 C(36) C(35) H(27) 119.5 C(35) C(36) H(28) 119.3 C(37) C(36) H(28) 119.3 C(36) C(37) H(29) 121.4 C(38) C(37) H(29) 121.4 C(21) C(40) H(30) 109.5 C(21) C(40) H(31) 109.5 C(21) C(40) H(32) 109.5 H(30) C(40) H(31) 109.5 H(30) C(40) H(32) 109.5 H(31) C(40) H(32) 109.5 174 Table 7. Torsion Angles(°) atom atom atom atom angle * atom atom atom atom angle O(1) (5) =N() ~~ C(6) ~~ -175.0(4) oq) =C(5) NG) (9) -2.4(6) O(1) (5) = C(4)—s N(Q) 78.3(4) O(1) (5) =C(4) C3) -46.9(5) o(2) C(7)—sC(6) ss N(Q)_—s«-57.0(4) O(2) (8) ~=c(9)— N(1) 57.3(4) O(3) C(11) N(2) C(4) -3.3(6) O(3) C(i1) -N(2) C(18) 176.7(4) O(3) C(11) C12) (13) 3.0(7) O(3) C11) -C(12)——C(17)_~—s-176.2(4) o(4) C(1gs) =~N(2)—C(4) 1.3(6) O(4) C(18) -N(2).—sC(11)_~—s-178..8(4) O(4) C18) C17) C12) -179.9(4) O(4) C(18) =C(17) ~—s C16) 1.5(7) O(5) (23) ~N(3) (24) -15.1(7) O(5) G(23),—-N(3)——sC(25)~——«10.8(7) O(5) C(23) N(3) C30) -159.4(5) O(5) (23) N(3)—s C(31)_—s155.6(5) O(5) C(23) C(22) -N(4) 61.9(5) O(5) C(23) -C(22) ~~ C(21) -63.7(5) O(8) C(32) N(4) C(22) 1.1(6) O(8) C(32) N(4) C(39) —-178.6(4) O(8) C(32) C(33) -C(34) 1.0(7) O(8) C(32) C(33) C38) -179.6(4) O(9) —-C(39) —-N(4).——s C22) 4.2(7) O(9) (39) N(4) C32) «175.5 (4) O(9) C(39) C(38) -C(33) 174.5(4) O(9) C(39) -C(38) = C(37) 4.5(7) N(1) (5) = C(4), Ss N(2)_—s-102.2(4) N(1) (5) (4) CB)“ 12.5(3) N(2) C(4) (3), C(2)—s«*174.6(3) N(2) C(4) (3), C0) —s=53.8(4) N(2) C1) C(12)) =C(13) _—-178.7(4) N(2) C41) C12) C17) 2.1(4) N(2). C(18) C17) (12) 0.8(4) N(2) G(18) C(17),—s«C(16)~—-177.7(4) N(3) C(23) (22) N(4) 118.4(4) N(3) C(23) C(22) C21) 116.0(4) N(4) -C(22) C21) C(20)_~——«179.1(3) N(4) C(22)-- (21), C(40)~—s25:7.7(4) N(4) G(32) -C(33)—« C34) -177.9(4) N(4) C(32)-—- (33) C(38) 1.5(4) N(4) (39) C(38)—« C33) 2.8(4) N(4) C(39) (38) C(37)_—-178.2(4) cil) C(2),—s« (3) C(4)—s«82.7(5) cil) (2), (3), G10). -105.4(5) c(2) -C(3),— C4) (5B) S62. (4) c(3)C(4) ss N(2),—s (1) 48.75) C(3) C(4) N(2) C(18) 131.4(3) C(4) N(2) C(11) (12) 178.4(3) C(4) N(2) C18) C(17)_—-179.4(3) c(4) -C(5)—N(1)—s C6) 5.6(6) c(4) C5) = N(1)—C(9)_—s«*178.1(3) C(5) N(1) C(6)—C(7)_—-129.1(4) C(5) N(1) C9) C(8)_—s«128.5(4) C(5) (4) =N(Q) C(1l) — -75.7(4) C(5) C(4)—N(2),—s C48) -——:104.3(4) C(5) (4) C(3),—sC(10)——«2176.7(3) c(6) Nl) C9) C8) 57.8(4) C(6) C(7) Of) C8) 57.0(4) c(7) -O(2),—s«e(8)—s (9) 57.5(4) c(7) -c(6) —N(1)—sC(9) 57.9(4) C(i1)—-N(2) C(18) -C(17) 0.5(4) C11) C(12)) C43) (14) © -177.5(4) c(l1) C(12) «C(17)—«C(16)~—«:176.9(4) C(11) C(12)) «C(17), (48) -1.8(4) c(12) (11) -N(2))C(18)—-1.6(4) C12) (13) C44) C(15) 0.4(6) cz) c(17) ~C(16)~—-C(45) 1.0(6) C(13) C(12) C17) C16) -2.4(6) C13) C(12) C(17) C(18) 178.9(4) C(13) =C(14) =C(15) C16) -1.8(7) Table 7. Torsion Angles(°) (continued) atom C(14) i) Ww atom C(13) C(16) C(20) C(22) N(4) C(23) C(23) C(22) C(22) C(33) C(33) C(34) C(33) C(35) C(36) atom C(12) C(17) atom angle 1.6(6) 179.4(4) -118.0(5) -135.8(4) -179.9(3) 165.2(5) 20.9(7) 99.9(4) -179.2(3) 179.9(4) -2.6(4) atom C(15) C(20) C(21) C(22) N(4) C(23) C(23) C(22) N(4) C(33) (32) (38) (33) (34) ) Q Qa0 34 (37 Q atom C(17) C(22) C(23) C(39) C(38) C(25) C(31) C(39) C(38) C(37) C(39) C(36) C(39) C(38) C(39) 175 angle 1.0(6) 120.7(5) -57.7(4) 43.9(5) 178.4(3) -168.9(5) -24.1(7) -80.4(5) -1.9(4) 178.3(4) 0.6(6) -177.5(4) 176 Table 8. Non-bonded Contacts out to 3.75 A atom atom distance ADC atom atom distance ADC O(1) C(26) —-3.178(8) 66602 O(1) C(24) ——-3.190(10) 66602 O(1) C(35) —-3.550(5) 67602 O(1) C(25) ——-3.657(10) 66602 O(1) 0(9) 3.697(4) 56602 O(1) C(21) —-3.699(5) 56602 O(2) C(36) —-3.277(5) 45501 O(2) C(8) 3.528(5) 57602 O(2) C(1) 3.575(6) 45501 0(3) C(24) ——-3.196(10) 66602 0(3) N(3) 3.205(5) 66602 0(3) C(23) —-3.292(5) 66602 0(3) C(32) ——-3.345(5) 66602 0(3) C(30) —-3.396(9) 66602 0(3) O(8) 3.412(4) 66602 0(3) O(5) 3.563(4) 66602 O(3) C(26) —-3.574(9) 66602 O(3) N(4) 3.599(4) 66602 O(3) C(40) —-3.644(6) 56602 0(3) C(25) ——-3.709(10) 66602 O(4) , C(6) 3.369(5) 56602 O(4) C(7) 3.457(5) 56602 O(4) O(9) 3.533(4) 56602 0(4) C(4) 3.541(5) 56602 O(4) C(2) 3.581(5) 56602 O(5) C(9) 3.275(5) 56602 O(5) C(3) 3.358(4) 66602 O(5) C(10) —-3.572(5) 66602 O(5) C(1) 3.641(5) 66602 O(6) C(14) —-3.339(8) 65401 O(6) C(19) —-3.439(8) 65501 O(6) C(27) —-3.549(11) 65502 O(6) C(20) —-3.701(7) 65501 O(7) C(27) —-2.935(11) 65502 0(7) O(7) 3.161(14) 65502 O(7) C(14) ——-3.414(8) 65401 O(7) C(29) ——-3.463(12) 65502 O(7) C(25) —-3.677(12) 65502 O(7) C(31) 3.695(11) 65502 O(8) C(31) 3.183(9) 66502 0(8) C(30) —-3.433(9) 66502 0(8) C(22)—-3.567(5) 66502 O(8) C(13) 3.583(5) 66602 O(8) C(20) 3.648(5) 66502 O(9) N(1) 3.023(4) 56602 O(9) C(18) —-3.245(5) 56602 O(9) C(5) 3.252(5) 56602 O(9) C(6) 3.299(5) 56602 O(9) C(9) 3.342(5) 56602 O(9) N(2) 3.366(4) 56602 O(9) C(17) ——-3.649(5) 56602 O(9) C(10) —-3.745(5) 66602 C(1) C(36) —-3.579(7) 67602 C(1) C(8) 3.711(7) 65501 C(7) C(36) —-3.616(6) 45501 C(7) C(18) _3.676(6) 56602 C(7) C(8) 3.713(6) 57602 C(8) C(8) 3.651(9) 57602 C(10) C(39) 3.634(6) 66602 C(11) C(40) 3.693(6) 56602 C(13)——C(34)—3.520(6) 66602 C(13) —-C(28)-~—s:3.732(10) 45601 C(i4) C28) ~—3.536(10) 45601 c(l4)-C(19)—s3.554(7) 55602 cd4) = C(29) ~~ 3.608(10) 45601 C(15) —-C(25)~—s-3.676(11) 55602 C(16) —-C(37)~—s«3.476(6) 56602 C19) C(26)~—3.213(10) 45501 C(20) C(26) * 3.698(9) 45501 C(27) C(29) 3.019(13) 65502 C(27) (27) ~—s«3.373(18) 65502 C(27) —-C(31)~—s«3.591(13) 65502 C(28) (40) ~—-3.700(10) 66502 C(31) —-C(32)~—:3.642(10) 66502 177 The ADC (atom designator code) specifies the position of an atom in a crystal. The 5-digit number shown in the table is a composite of three one-digit numbers and one two-digit number: TA (first digit) + TB (second digit) + TC (third digit) + SN (last two digits). TA, TB and TC are the crystal lattice translation digits along cell edges a, b and c. A translation digit of 5 indicates the origin unit cell. If TA = 4, this indicates a translation of one unit cell length along the a-axis in the negative direction. Each translation digit can range in value from 1 to 9 and thus +4 lattice translations from the origin (TA=5, TB=5, TC=5) can be represented. The SN, or symmetry operator number, refers to the number of the symmetry operator used to generate the coordinates of the target atom. A list of symmetry operators relevant to this structure are given below. For a given intermolecular contact, the first atom (origin atom) is located in the origin unit cell and its position can be generated using the identity operator (SN=1). Thus, the ADC for an origin atom is always 55501. The position of the second atom (target atom) can be generated using the ADC and the coordinates of the atom in the parameter table. For example, an ADC of 47502 refers to the target atom moved through symmetry operator two, then translated -1 cell translations along the a axis, +2 cell translations along the b axis, and 0 cell translations along the c axis. An ADC of 1 indicates an intermolecular contact between two fragments (eg. cation and anion) that reside in the same asymmetric unit. Symmetry Operators: (1) X, Y, Z, (2) -X, -Y, -Z Table 9. Least Squares Planes Plane number 1 Atoms defining plane Additional Atoms O(3) O(4) C(4) Distance Distance 0.116 -0.032 -0.012 Plane number 2 Atoms defining plane Additional Atoms plane O(8) (9) (22) Summary mean deviation 0.0165 0.0194 Distance Distance 0.041 -0.148 0.013 156.0 188.1 178 179 Dihedral angles between planes (°) plane 1 2 43.63