Progress Toward the Total Synthesis of Salvadione-A and Related Diterpenoids Citation Greene, Blake Bennet (2004) Progress Toward the Total Synthesis of Salvadione-A and Related Diterpenoids. Master's thesis, California Institute of Technology. doi:10.7907/AAPZ-W246. https://resolver.caltech.edu/CaltechETD:etd-06252004-084128 Abstract Herein, we report our progress toward the total synthesis of salvadione-A, a structurally complex triterpenoid isolated from Salvia bucharica. We document a model system of our tandem Claisen/Cope/Diels-Alder strategy. Additionally, we describe the evolution of our strategy toward the synthesis of three structurally related diterpenoids-coulterone, cyclocoulterone, and komaroviquinone--from a cyclopropanation/Friedel-Crafts route to an anionic homo-Fries/intramolecular Barbier cyclization pathway. Item Type: Thesis (Master's thesis) Subject Keywords: Chemistry Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Unknown, Unknown Defense Date: 1 March 2004 Record Number: CaltechETD:etd-06252004-084128 Persistent URL: https://resolver.caltech.edu/CaltechETD:etd-06252004-084128 DOI: 10.7907/AAPZ-W246 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 2720 Collection: CaltechTHESIS Deposited By: Imported from ETD-db Deposited On: 28 Jun 2004 Last Modified: 08 Nov 2023 00:39 Thesis Files Preview PDF (Greene_bb_2004.pdf) - Final Version See Usage Policy. 1MB Repository Staff Only: item control page

Progress Toward the Total Synthesis of Salvadione-A and Related Diterpenoids Thesis by Blake Bennet Greene In Partial Fulfillment of the Requirements for the Degree of Master of Science California Institute of Technology Pasadena, California March, 2004 Acknowledgements I would first like to thank Brian Stoltz for giving me the opportunity of working in his lab. However, I certainly believe that his agreement to hire me had a lot to do with some serious convincing by John Wood. In any case, Brian provided me with much needed guidance over the course of my tenure here. He always seemed to have an answer to any question/problem that I would throw his way. I wish him the best of luck with his career and with his upcoming tenure. I would also like to thank Ryan, Ernie, and Uttam for treating me more like a friend than a co-worker. I appreciate the fact that they made my sixteen hours a day in lab as enjoyable as possible. While they still have a long road ahead of them, they must remember that no matter how badly their chemistry may go sometimes, there will always be Amigo’s. On a more general note, my thanks go to the Stoltz, Dougherty, Grubbs, and MacMillan groups for the help and chemicals they provided me with. Outside of Caltech, I would like to thank my family and friends for their support and encouragement. Without my mother and father, I certainly would not be where lam today. They selflessly offer their love, time, and support so that I could be the best that I can be. My appreciation also goes to Brett and Deven for their advice, help, and bad inside jokes. I would also like to give thanks to my good Yale friends, Ameet, Alan, Limor, Collin, Damian, Heather, and Mara. I could not ask for better friendship, loyalty, or support from any of them. I apologize to them for moving out to the West Coast, but I promise them that they are always in my thoughts. il I saved the best for last. I would like to thank Amy. For everything. No matter what, she always puts a smile on my face. She has been unbelievably supportive since the first day I met her and especially through my present career change. She continues to amaze me with her love, selfless acts, charm, intelligence, and incredibly good looks. Hands down, I am the luckiest guy in the world. ill Abstract Herein, we report our progress toward the total synthesis of salvadione-A, a structurally complex triterpenoid isolated from Salvia bucharica. We document a model system of our tandem Claisen/Cope/Diels-Alder strategy. Additionally, we describe the evolution of our strategy toward the synthesis of three structurally related diterpenoids—coulterone, cyclocoulterone, and komaroviquinone—from a cyclopropanation/Friedel-Crafts route to an anionic homo-Fries/intramolecular Barbier cyclization pathway. iv Table of Contents Acknowledgements Abstract List of Schemes List of Figures J. Introduction Isolation and biological activity Biogenetic pathway Retrosynthetic analysis II. Results and Discussion Model system Related diterpenoids Retrosynthetic analysis Cyclopropanation route Modified approach to the tricyclic core Final strategy: anionic homo-Fries/intramolecular Barbier III. Conclusion TV. Experimental Section V. References il iv vi Vii 10 11 16 19 23 23 34 List of Schemes Scheme 1. Scheme 2. Scheme 3. Scheme 4. Scheme 5. Scheme 6. Scheme 7. Scheme 8. Scheme 9. Scheme 10. Scheme 11. Scheme 12. Scheme 13. Scheme 14. Scheme 15. Scheme 16. Scheme 17. Scheme 18. Scheme 19. Scheme 20. Scheme 21. Scheme 22. Proposed biogenetic pathway to salvadione-A Majetich’s biomimetic approach to perovskone Retrosynthetic analysis of salvadione-A Model system for the tandem Claisen/Cope/Diels-Alder reaction Synthesis of hydroxyquinone 14 Conversion of geraniol to triene 10 Stille coupling route to afford triene 10 Cardillo’s synthesis of triene 10 Retrosynthetic analysis of the diterpenoids Synthesis of enal 41 Synthesis of phenol 42 Modified synthesis of diazoacetate 40 Synthesis of benzaldehyde 50 Synthesis of benzyl alcohol 51 Synthesis of diazoacetate 40 Two cyclopropanation routes Retrosynthetic analysis of tricycle 37 Grignard reaction Modified approach to tricycle 37 Final approach to tricycle 37 Anionic homo-Fries rearrangement Anionic homo-Fries rearrangement and endgame strategy 10 11 12 12 13 13 14 15 16 17 18 19 20 22 vi List of Figures Figure 1. Salvadione-A and other related triterpenoids from Salvia bucharica Figure 2. Coulterone, cyclocoulterone, and komaroviquinone Figure 3. Possible products of the attempted intramolecular cyclopropanation reaction Figure 4. Possible structures of the anionic homo-Fries rearrangement 15 21 vil I. Introduction Isolation and biological activity In 1999, Ahmad and co-workers isolated the triterpenoid, salvadione-A (1), from the Salvia bucharica plant in Quetta, Baluchistan, Pakistan’ (see Figure 1). While the biological activity of salvadione-A has yet to be tested, the Salvia bucharica plant has been utilized in traditional practices for the treatment of liver disorders and as a cooling medicine. Additionally, the plant is part of the Lamiaceae family, whose members generally possess compounds with antitumor activity. Despite its unknown biological activity, salvadione-A is attractive synthetically for its structural complexity. The natural product contains a challenging [6-7-6] tricyclic core as well as a propellene-like structural unit. Figure 1. Salvadione-A and other related triterpenoids from Salvia bucharica'” Salvadione-A (1) Salvadione-B Salvadiol Biogenetic pathway In the isolation of salvadione-A, Ahmad proposes that the biogenetic pathway of the natural product occurs through the addition of geranylpyrophosphate to an icetexone- type precursor.’ As shown in Scheme 1, the cycloaddition of these compounds yields tetracycle 2. Oxidation to the allylic cation and subsequent ring closure gives triketone 3. Simple ketone hydrolysis and ring closure then affords salvadione-A. Ahmad has proposed similar cycloaddition pathways to the biosyntheses of salvadione-B’ and salvadiol.? Scheme 1. Proposed biogenetic pathway to salvadione-A’ Precursor to Icetexone Geranyl Pyrophosphate 3 Salvadione-A Retrosynthetic analysis Having started our synthesis of salvadione-A in January of 2003, we assumed that other synthetic groups would be working on biomimetic approaches to the triterpenoid involving similar cycloadditions. In particular, Majetich’s total synthesis of (+)- perovskone, a triterpenoid structurally similar to salvadione-A, contained an intermolecular Diels-Alder reaction between trans-a-ocimene (4) and hydroxyquinone 5* (see Scheme 2). Thus, with hydroxyquinone 5 in hand, Majetich was theoretically on course to complete the biomimetic synthesis of salvadione-A. In order to avoid an analogous approach to salvadione-A, our retrosynthesis of the triterpenoid involved a tandem Claisen/Cope/Diels-Alder reaction to build the structurally complex carbon framework of the molecule (see Scheme 3). Salvadione-A Scheme 2. Majetich’s biomimetic approach to perovskone 5 Perovskone would be achieved by an oxidation of triol 6, which we envisioned would be produced by a tandem Claisen/Cope/Diels-Alder reaction of hydroquinone 9. Experimental evidence for the tandem Claisen/Cope rearrangement, also known as the para Claisen rearrangement, was well documented in the literature.°°’*° Certain trends that improve the rate and yield of the para Claisen rearrangement included substitution at both ortho positions,’ a hydroxyl substituent in the ortho position,® and the use of nonpolar solvents.” The tandem Claisen/Cope rearrangement had also been reported in total synthesis, such as in Danishefsky’s syntheses of Tricycloillicinone and Bicycloillicinone Aldehyde.” We also found evidence of a tandem Claisen/Cope/Diels-Alder reaction in Molina’s synthesis of fluoreno[2,3,4-i,j]isoquinoline ring derivatives.'' Given these precedents, the di-ortho substitution and the ortho hydroxyl group in hydroquinone 9, the difficulty of enolization for o-dienone 8, and the driving force for the formation of a conjugated triene in tricycle 7, we were convinced that the tandem Claisen/Cope rearrangement would proceed as outlined. Additionally, after the para Claisen rearrangement, tricycle 7 would be perfectly positioned for an intramolecular Diels-Alder reaction, which would construct the carbon framework of salvadione-A. In order to synthesize hydroquinone 9, triene 10 would be coupled to protected hydroquinone 11. Olefin reduction and deprotection of the product formed from a Grignard reaction between cyclohexanone 12 and benzyl bromide 13 and subsequent ring-closing metathesis would then yield protected hydroquinone 11. Scheme 3. Retrosynthetic analysis of salvadione A Diels-Alder —_ Claisen II. Results and Discussion Model system In order to test the utility of the tandem Claisen/Cope/Diels-Alder reaction in our synthetic route, we first developed a model system designed to examine the tandem sequence on a less complex, yet structurally similar version of hydroquinone 9. We therefore chose bicycle 16 as our model compound, which could be achieved from the coupling of hydroxyquinone 14 and triene 10 and subsequent reduction of the product, quinone 15 (see Scheme 4). Scheme 4. Model system for the tandem Claisen/Cope/Diels-Alder reaction OH 16 17 Despite the apparent simplicity of hydroxyquinone 14, there was neither a known route nor a direct method for synthesizing it. In fact, there was not even a literature precedent of the compound. Therefore, after much experimentation and optimization, an eight step synthesis of hydroxyquinone 14 with an overall yield of 29% was completed (see Scheme 5). Commercially available 2,6-dimethoxytoluene (18) was formylated with a,a-dichloromethyl methyl ether and TiCl, to provide benzaldehyde 19 in quantitative yield. An acid catalyzed Baeyer-Villager reaction of 19 also worked in excellent yield to afford phenol 20, which was oxidized with CAN to quinone 21 exclusively. A Diels- Alder reaction between 21 and 1,3-butadiene in glacial acetic acid provided di-enone 22."° Hydrogenation of 22 proceeded in moderate yield using 1 mol% Pd/C to furnish dihydroquinone 23. Homogeneous catalysis conditions were not attempted, although their use could have improved the yield of the hydrogenation step. Acid-catalyzed tautomerization to hydroquinone 24 followed by oxidation with FeCl,/HCl provided quinone 25. Finally, demethylation using BBr, afforded hydroxyquinone 14. It should be noted that only three steps of the synthesis (hydrogenation, tautomerization, and demethylation) required purification. Scheme 5. Synthesis of hydroxyquinone 14 ie) H OH OMe OMe OMe > a I CH,Cl, MeOH CH,CN -42 °C ——> RT OMe M OM (100% crude yield) OMe (97% crude yield) ° (100% crude yield) 18 19 20 ) ) OMe OMe OMe Vi 10% Pd/C, Hp __Hel AcOH EtOH THF (81% crude yield) ° (71% yield) 6 (70% yield) 21 22 23 OH ° fe) OMe OMe OH FeCly/HCl BBr, i -78 °C —> RT OH fe) fe) 24 (100% crude yield) 25 (74% yield) 14 Similar to the synthesis of hydroxyquinone 14, there was no straightforward route to synthesize triene 10. Noting that geraniol was simply the y,6-dihydro version of triene 10,'* we proposed that we could oxidize geraniol to triene 10 in a limited number of steps (see Scheme 6). After successfully oxidizing geraniol to citral under Swern conditions,we employed a number of dehydrogenation methods including Saegusa-Ito oxidation, organoselenium reagents, oxidation/elimination, Nicolaou’s hypervalent Scheme 6. Conversion of geraniol to triene 10 OH | —— =f Dehydrogenation. 7 Oxidation af 10 Citral Geraniol iodine, and x-allyl palladium chemistry” to oxidize citral to aldehyde 26. Unfortunately, none of these attempts were successful. We therefore modified our strategy to employ a Stille coupling reaction between vinyl iodide 27 and vinyl stannane 28 to afford methyl ester 29 (see Scheme 7). The synthesis of the coupling pieces proved synthetically ineffective, in that low yields and isomer impurities (for vinyl iodide 27) plagued the route. Nevertheless, with vinyl iodide 27 and vinyl stannane 28 in hand, the Stille reaction was attempted only to afford a low yield of an indeterminate isomer of methyl ester 29. Despite the futility of the two previous methods, we were fortunate to find Scheme 7. Stille coupling route to afford triene 10 OH (e) ia : Reduction Stille | Meo” | ——_ | ——— ¢ + aL | | | Bu,Sn 10 29 27 28 Cardillo’s four step synthesis of triene 10."° The route started with the formation of the 3,3-dimethylacrylic acid (30) dianion by LDA, which, under the right conditions, allowed for a C, attack on 3-methyl-2-butenal and subsequent lactonization to form lactone 31 (see Scheme 8). Despite numerous attempts at optimization, we were only able to produce 31 in 17% yield. Lactone 31 was then opened with z-BuOK to yield acid 32. Methylation of crude 32 with diazomethane gave methyl ester 33 in good yield. Finally, LAH reduction of 33 afforded triene 10 in 88% yield. It should be noted that 10 was formed exclusively as the a,f (Z)-y,6 (E) isomer. While modeling the coupling reaction between hydroxyquinone 14 and triene 10, we were able to successfully couple 14 with geraniol and to produce the hydroquinone by Scheme 8. Cardillo’s synthesis of triene 10 H f 1. LDA, THF G00 OH _0.°C --> reflux > ao -BuOK wey | 2. 3-methyl-2-butenal re) | THF HMPA, THF 0°C 0 °C —> reflux re) 30 ; 31 . 32 (17% yield) (100% crude yield) OH COOCH, CH,N, Z~Z~F LAH o~2~? i —<—$-_$? CH,Ci, Et,0 -10 °C 33 10 (90% yield) (88% yield) subjecting the coupled product to mild reduction conditions.’? We even attempted the tandem Claisen/Cope rearrangement’ but could not verify product formation in the reaction. However, no definitive conclusion about the para Claisen rearrangement could be drawn from this experiment, seeing that geraniol lacked the y,6 olefin and conjugation of triene 10, which could drastically affect its reactivity. Given the success of our model, we were therefore confident that hydroxyquinone 14 and triene 10 would couple. We initially attempted to combine the pieces under standard Mitsunobu conditions,’? but these reactions all failed and resulted in a variety of side products. Subsequent coupling reactions employing DCC or EDC conditions and atypical Mitsunobu conditions using PMe,, PBu;, or PCy, instead of PPh, were also unsuccessful and led to numerous side products. It therefore appeared that the triene functionality proved too unstable for the coupling reaction. The conjugation of the system presumably increased the acidity of the allylic hydrogens and thus facilitated the immediate elimination of either the coupled product or the activated electrophile. Because of the reactivity issues of the triene, it seemed that the formation of quinone 15 would require extremely mild coupling conditions or a different route altogether, such as the piecewise synthesis of the triene moiety onto hydroxyquinone 14. Related diterpenoids While our model system continued to be problematic, we faced more unfortunate news as Majetich published the total synthesis of (+)-salvadione-A.” As we had expected, Majetich employed a Diels-Alder reaction on his previously synthesized hydroxyquinone 5 to construct the triterpenoid. Given these setbacks, we decided to shift our focus to the synthesis of three related diterpenoids, coulterone (34)”’, cyclocoulterone (35)”, and komaroviquinone (36)” (see Figure 2). While coulterone was isolated in 1993 from Mexican Salvia coulteri,” cyclocoulterone and komaroviquinone were isolated from Dracocephalum komarovi in Uzbekistan in 2002.% Komaroviquinone was found to have strong in vitro trypanocidal activity against epimastigotes of Trypanosoma cruzi, which was responsible for Chagas’ disease in Central and South America.” As of March of 2004, no group has synthesized any one of these compounds. Notwithstanding slight functional group modifications on the aromatic ring, these natural products and the tricyclic core of salvadione-A (see protected hydroquinone 11) only differed by a benzylic ketone. Based on the biological activity of komaroviquinone and on the straightforward interconversion of these compounds to a salvadione-A intermediate, we Figure 2. Coulterone, cyclocoulterone, and komaroviquinone o™ ie] [e) Coulterone (34) Cyclocoulterone (35) Komaroviquinone (36) commenced the syntheses of these natural products en route to our total synthesis of salvadione-A. Retrosynthetic analysis Given the benzylic ketone functionality, we envisioned a different approach to access the tricyclic core of the diterpenoids. Coulterone could be accessed by the reduction of komaroviquinone (see Scheme 9). Subsequent functional group manipulation of coulterone could then afford cyclocoulterone. Komaroviquinone could be produced by the oxidation of tricycle 37, which could be synthesized by a Friedel- Crafts reaction and olefin hydrolysis of acid 38. The reductive opening of lactone 39 could yield 38. We sought to establish the carbon framework of the seven-membered Scheme 9. Retrosynthetic analysis of the diterpenoids R, Ro (o] Coulterone (34): R;=OH, R2==OMe Komaroviquinone (36) 37 ' Cyclocoulterone (35): Ry=Ro= -O-CH,-O- Reductive _ Intramolecular Opening ‘Gyclopropanation oO OH OMe H + OMe OMe 40 41 42 10 ring via an intramolecular cyclopropanation of diazoacetate 40. Finally, 40 could be accessed by the coupling of enal 41 and phenol 42 and consequent functional group manipulation of the product. Cyclopropanation route Enal 41 was afforded in only two steps from commercially available 3-methyl-2- cyclohexen-l-one (47) (see Scheme 10). We employed a cuprate trapping of 47 with Comins’ reagent to access vinyl triflate 48 in good yield.”? Enal 41 was then synthesized by a palladium catalyzed reductive carbonylation of 48 in low yield”* As shown in Scheme 10. Synthesis of enal 41 fe) ie] OTf 1. Me,CuLi, Et,0,0°C Pd(PPh,),, CO, LiCl, EtSiH H 2 THF, 50 °C 1ot oO 47 N* ~NTf 48 41 THF, 0 °C (76% crude yield) (43% yield) Scheme 11, the synthesis of phenol 42 was completed in four steps starting from commercially available 1,3-dimethoxybenzene (43). Original attempts to synthesize benzyl alcohol 44 resulted in low yields. However, subsequent optimization using Carreno’s ortho-directed metallation conditions on 1,3-dimethoxybenzene afforded 44 in good yield.” Acid-catalyzed hydrogenation of benzyl alcohol 44 yielded isopropylbenzene 45,” which, in turn, was formylated to provide benzaldehyde 46. Finally, crude 46 was subjected to acid-catalyzed Baeyer-Villager conditions to produce phenol 42 in 89% yield. With both enal 41 and phenol 42 in hand, we sought to couple the two pieces. 1] Scheme 11. Synthesis of phenol 42 OMe OMe OMe 1. n-BuLi, THF 10% Pd/C, Ho _ —_—_———— 2. ethyl chioroformate H,S0,, EtOAc THF, 0 °C —> RT OH aa OMe OMe OMe 3. MeMgBr, 0 °C —> RT 43 (85% yield) 4a (94% yield) 45 Ox LH OH ClxCHOMe, TiCl, OMe HzO, HO, _ OMe CHCl MeOH -42°C —> RT OMe OMe (100% crude yield) (89% yield) 46 42 Nevertheless, despite numerous attempts including a Et,AlCl promoted aldol and a Nagata coupling reaction,” we were unable to synthesize the coupled product. Because of this and the inefficient preparation of enal 41, we decided to slightly alter our approach to diazoacetate 40 (see Scheme 12). In our modified synthesis, vinyl bromide 49 would be reacted with benzaldehyde 50 to yield benzyl alcohol 51, which would then be elaborated to 40. Scheme 12. Modified synthesis of diazoacetate 40 N Se: oMe OH OMe ~ No OMe Br 4 OMe OMe OMe Cy Fa ee ~ So SI Q OMe OMe OMe 49 50 51 40 After Et,AICI promoted o-alkylation of phenol 42 afforded diol 52, methylation with Mel yielded trimethoxybenzene 53 (see Scheme 13). Subsequent benzylic oxidation of trimethoxybenzene 53 with MnO, provided benzaldehyde 50 in good yield. While we were unable to synthesize vinyl bromide 49 despite numerous attempts, we were able to couple dithiane 54 with benzaldehyde 50 in moderate yield using metal- 12 Scheme 13. Synthesis of benzaldehyde 50 OH OH OH OMe Et,AICI, (HCHO), OMe Mel, K,CO3 >» ——————— CH,Cl, Acetone, reflux 0°C ~> RT OMe (86% yield) OMe (93% yield) 42 52 OH OMe O OMe OMe OMe MnO, H TEA EERERRAIRDET onan CH,Cl, OMe © (84% yield) OMe 53 50 halogen exchange conditions (see Scheme 14). While further manipulations appeared promising, we discovered a much more effective and efficient route to benzyl alcohol 51. Using Takai’s alkenylchromium conditions, we were able to couple viny! triflate 48 with benzaldehyde 50 to afford 51 in good yield.”’ Scheme 14. Synthesis of benzyl alcohol 51 d \, d \ OH OMe Br OMe 1. #BuLi, Et,0,-78°C C7 (> 2. 50, Et,0, -78 °C 54 (53% yield) gy OMe O OMe OH OMe OTf H OMe CrCly, NiCly OMe * DMF Y OMe (82% yield) OMe 48 50 51 With the synthesis of benzyl alcohol 51 complete, we continued our synthesis of lactone 39. As shown in Scheme 15, esterification of 51 with diketene yielded ester 55 in 88% yield. Diazotization of 55 with mesyl azide followed by acetyl cleavage accessed diazoacetate 40 in high yield. With 40 in hand, we attempted the intramolecular cyclopropanation reaction using a variety of catalysts, including Rh,(OAc),, Cu(TBS),, 13 Scheme 15. Synthesis of diazoacetate 40 reflux —-> RT OMe Et,N, CH,CN —CH.cN OMe (88% yield) (93% yield) QO OMe OMe C7 So OMe 5% aq. KOH C7 oS ome CH,CN (90% yield) Cu(acac),, Cu Bronze, Cul*P(OEt);,” and Rh,(cap),.°° With the notable exception of Rh,(OAc),, the reactions yielded a similar variety of products, based on TLC analysis. While most of these products were unidentifiable, there appeared to be formation of lactone 39 in the reactions, albeit in low yield (less than 20%). It was possible that the unknown products of these reactions were a combination of aromatic C-H insertion and Buchner reaction products, although a number of different insertion reactions also could have occurred. It was well documented that reacting diazo compounds such as diazoacetate 40 with these transition metal catalysts could potentially yield three main products: lactone 39 (intramolecular cyclopropanation), bicycle 57 (aromatic C-H insertion), and cycloheptatriene 58 (Buchner reaction)” (see Figure 3). Because none of the catalysts seemed to favor intramolecular cyclopropanation over the other reactions, we sought a different synthetic route. We were still determined that we could access the seven-membered ring via a cyclopropanation pathway. Thus, with benzyl alcohol 51 in hand, we attempted both intramolecular and intermolecular cyclopropanation routes (see Scheme 16). Starting 14 Figure 3. Possible products of the attempted intramolecular cyclopropanation reaction 39 57 58 from protected benzyl alcohol 59, path A involved the installment of a diazoketone functionality onto the unsubstituted carbon of the aromatic ring, followed by intramolecular cyclopropanation to yield cyclopropane 62. The substitution of the diazoketone directly onto the aromatic ring would obviously limit the possibility of competitive aromatic C-H insertion or Buchner reactions. In path B, 59 could be intermolecularly cyclopropanated by ethyl diazoacetate with subsequent ring closure to afford cyclopropane 62. In either route, 62 could be manipulated to produce tricycle 37. Scheme 16. Two cyclopropanation routes ween, MeO ‘~ PO OMe wy” OMe 62 OEt OMe fe) 61 With P = TBS, SEM, or Ac in protected benzyl alcohol 59, we unfortunately were unable to functionalize the aromatic ring, despite numerous halogenation, formylation, 15 and carboxylation attempts. With the failure of these reactions, we proceeded with path B and encountered just as much difficulty. Using P = TBS or Ac, protected benzyl alcohol 59 was unreactive towards conditions using ethyl diazoacetate and either Rh,(OAc), or Cu(TBS), as a catalyst. Based on the persistent failure of the cyclopropanation route, we decided again to amend our synthetic plan. Modified approach to the tricyclic core Ironically, we returned to one of our original ideas to afford the [6-7-6] tricyclic core. As shown in Scheme 17, we envisioned that tricycle 37 could be quickly constructed from a Grignard and subsequent Friedel-Crafts reaction between t-butyl ester 63 and benzyl bromide 64, both of which could be efficiently prepared from commercially available starting materials. Based on steric arguments, the Grignard reaction would yield the correct relative stereochemistry of the trans-fused ring system. Scheme 17. Retrosynthetic analysis of tricycle 37 Me = ny OFBu | Cr A three component coupling reaction using 3-methyl-2-cyclohexen-1-one (47), 37 Me,CuLi, and tert-butyl bromoacetate yielded t-butyl ester 63 in excellent yield (see Scheme 18). Benzyl bromide 64 was also afforded in one step in 91% yield via the bromination of previously synthesized trimethoxybenzene 53. Our initial attempts of the Grignard reaction were unsuccessful and resulted mostly in the quenched Grignard reagent. This seemed reasonable given the number of acidic protons in t-butyl ester 63. 16 Thus, in order to limit competitive enolization, we employed Imamoto’s Grignard/CeCl, conditions and achieved addition to produce lactone 65, albeit in very low yield.” We anticipated the lactonization of the Grignard product, given the precedent of a related system,” and also expected subsequent ring closure to proceed without difficulty. Nevertheless, the lactone formation actually became detrimental to our synthetic route. Performing a Friedel-Crafts reaction directly on lactone 65 was unsuccessful using either AICI, or TiCl, Additionally, attempts at opening the lactone under saponification conditions worked, but the product was prone to lactonize back to starting material. To avoid lactonization issues, we even tried the Grignard/CeCl, conditions using an allyl group in place of the tert-butyl acetate in 63, but the reaction failed to yield any reasonable amount of product. Scheme 18. Grignard reaction fe) (o) 1. Me,CuLi, Et,0,0°C _ oO 2. HMPA, 0 °C a O#Bu 3. butyl bromoacetate Et,0, -78 °C ——> RT 47 oy cat 63 OMe (89% yield) Meo OH OMe Br OMe OMe OMe OMe PPhs, NBS 1. Mg®, Et,0, reflux 0 ° a EEE anneal cael >» THF, 0°C 2. CeCls, Et,O, 0 °C _ = 3. 63, Et,0, 0°C OMe (91% yield) OMe (9% yield) 53 64 65 Given the low yields of the Grignard reaction and the problems associated with lactonization, we reversed the order of our synthetic plan, such that we would first react arene 66 with acid chloride 67, and then close the seven membered ring using a Grignard or Barbier reaction to yield tricycle 37 (see Scheme 19). This approach would directly 17 address our difficulties with substituting the aromatic ring before attempting the addition reaction, which we had previously shown to work. Scheme 19. Modified approach to tricycle 37 MeO OM OMe Y OMe € OH OMe O74 ° OMe ro ee en | ee ee es Ge (ee | ee — x Cl é OMe OMe O OMe 8 66 67 68 37 We first attempted the simplest approach to accessing diketone 68, which was a Friedel-Crafts reaction between benzyl bromide 64 or acetylated arene 66 (X =H, Y = OAc) and acid chloride 67, synthesized by the hydrolysis and subsequent chlorination of t-butyl ester 63. Unfortunately, both of these reactions failed to afford 68 and instead yielded unidentifiable compounds that were presumably arene polymerization products. We therefore focused on a Stille reaction between ary! stannane 66 (X = SnBu,, Y = OAc) and acid chloride 67. We were able to easily access acetylated iodobenzene 66 (X =I, Y = OAc) by the iodination and acetylation of trimethoxybenzene 53. Nevertheless, despite numerous attempts, we could not perform the coupling reaction to make the aryl stannane. We believed that the steric encumbrance of the aromatic ring resulted in the lack of reactivity. Finally, we attempted a lithium-halogen exchange reaction between TBS-protected bromobenzene 66 (X = Br, Y = OTBS) and acid chloride 67, which succeeded in forming TBS-protected diketone 68 (Y = OTBS) in 7% yield. To achieve better reactivity, we attempted coupling TBS-protected bromobenzene 66 (X = Br, Y = OTBS) with the Weinreb amide version of acid chloride 67. Nevertheless, this reaction did not yield any product. 18 Final strategy: anionic homo-Fries/intramolecular Barbier Despite the poor yield of the initial lithium-halogen exchange reaction, we were satisfied with finally being able to substitute the aromatic ring. We concluded that the low product yield was a result of both competitive enolization and the poor reactivity of the acid chloride functionality with an organolithium species. Therefore, we designed a new synthesis of tricycle 37, which reduced the number of acidic protons and involved a more reactive electrophile (see Scheme 20). We envisioned synthesizing tricycle 37 through Molander’s SmI, promoted intramolecular Barbier cyclization on benzyl iodide 69.% Iodination and deprotection of keto-alcohol 70 could lead to 69, Keto-alcohol 70 could be accessed by an anionic homo-Fries rearrangement of ketal 71,** which, in turn, could be formed by the coupling of acid 72 and bromobenzene 73 and subsequent protection of the product. Scheme 20. Final approach to tricycle 37 | OMe 0 st OMe arieleela. ] OMe Barbier —> — Oo OMe OMe 37 69 Sonor? Fries Hydrolysis of t-butyl ester 63 with TFA yielded acid 72 in good yield (see Scheme 21). Bromination of trimethoxybenzene 53 with N-bromosuccinimide then afforded bromobenzene 73 in 91% yield. Mitsunobu coupling of 72 with 73 proceeded smoothly to yield ester 74, which was protected with ethylene glycol to afford ketal 71. 19 Scheme 21. Anionic homo-Fries rearrangement (o) (e) 9 TFA °) ——— > OtBu CHCl, OH (88% yield) 63 72 OMe fe) ie} OMe OMe Me HO NBS 72, BAD _72, DIAD, PPhy oO” OMe THE Br OMe (91% yield) (88% yield) OMe 53 74 ie 0 (¢] OMe Yo- ethylene glycol o OMe — Bulli ~~ at ee p-TSA, PhH —THF,-78°C -78 °C reflux Br (94% yield) OMe (82% yield) 71 With 71 in hand, we successfully performed the anionic homo-Fries rearrangement in 82% yield.*° Based on 'H NMR analysis, we assigned the structure of the product to be lactol 75 instead of keto-alcohol 70. Our next step to iodinate 75 proved to be quite difficult despite numerous attempts. We predicted that the stability of the lactol resulted in the poor reactivity of 75. Therefore, in an attempt to reduce lactol 75, we noted that a white solid precipitated when it was stirred in methanol. While TLC analysis confirmed a different R, value for the precipitate, "H NMR showed the same spectrum as lactol 75. We assumed that the solid was actually keto-alcohol 70 and that it cyclized into lactol 75 in certain solvents. An IR spectrum of the solid showed both hydroxyl (3448 cm”) and carbonyl! (1674 cm’) bands and therefore validated our hypothesis. With 70 in hand, we again attempted numerous iodination conditions, but these reactions failed to yield any product and resulted mostly in unreacted starting material. We then tried numerous functionalization reactions including mesylation, bromination, acetylation, and protection 20 with ethylene glycol, but these all afforded mostly unreacted keto-alcohol 70. When oxidation reactions using DMP, PDC, or MnO, and reduction attempts with LAH failed to react with 70, we reasoned that the product of the anionic homo-Fries rearrangement must be neither lactol 75 nor keto-alcohol 70. After further spectroscopic analysis, it was discovered that the product was actually enol ether 76 (see Figure 4).*%° The mistaken identification of the product resulted from ambiguous 'H NMR peaks and IR bands. What was believed to be diastereomeric benzylic hydrogen peaks (lactol 75) was actually a complex multiplet of benzylic and vinyl hydrogen peaks (enol ether 76). Additionally, the olefin band (enol ether 76) in the IR was mistaken for a carbonyl band (keto-alcohol 70). It was possible that the hydroxy] band (keto-alcohol 70) in the IR was a result of water contamination as it was fairly weak. High Resolution Mass Spectrometry confirmed the identification of the product as enol ether 76. While it is possible that the initial product of the rearrangement was keto-alcohol 70, lactol 75, or an equilibrium mixture of both, the reaction work-up and subsequent drying under methanol appeared to result in the exclusive formation of enol ether 76. Figure 4. Possible structures of the anionic homo-Fries rearrangement product OH OMe fo) [e} SU on De fA [ff \ ~ OMe O OMe = MeO 70 76 With the identity of the product finally resolved, we sought to iodinate, deprotect, and then cyclize enol ether 76 as shown in Scheme 20. Nevertheless, using a number of nucleophilic iodine sources such as Nal, KI, HI, TMSI, or Bu,N’*T and TsOH, enol ether 21 76 either was unreactive or resulted in a large number of. compounds, none of which was confirmed to be the iodinated product. Presuming that steric hindrance and/or competitive reaction participation of the ketal functionality resulted in the varied reactivity, we attempted to remove the protecting group. However, the deprotection step resulted in a number of products, which could not be isolated. We therefore concluded. that we would need to study the anionic homo-Fries of the unprotected cyclohexanone, ester 74 (see Scheme 22). An initial reaction did appear to afford enol ether 77, albeit in low yield and contaminated with trimethoxybenzene 53.*’ Further optimization therefore needed to be performed before making any definitive conclusions about the utility of this reaction. Assuming the success of the unprotected anionic homo-Fries rearrangement, we could access the tricyclic core either through our previous iodination/intramolecular Barbier cyclization route or through an elimination/reductive cyclization pathway. Scheme 22. Anionic homo-Fries rearrangement and endgame strategy fs) ie) OMe OMe . ti ° Anionic |. ee a Br Homo-Fries Barbier’ Cyclization OMe 74 . 37 MeQ OMe 9 OMe °] OH Za Demethylation ~ ZA Elimination OMe OMe MeO MeO 77 (o) OMe . Reductive Cyclization O OMe 78 22 Although we have only started our study of the reactivity of ester 74, we are optimistic that our new strategy will afford tricycle 37. IH. Conclusion In summary, we have reported our progress toward the total synthesis of salvadione-A. While we were not able to fully assess the utility of the tandem Claisen/Cope/Diels-Alder reaction in our model system, we learned valuable information about the reactivity of our triene moiety and future coupling strategies. Shifting our focus toward the total synthesis of the related diterpenoids en route to salvadione-A, we attempted a cyclopropanation/Friedel-Crafts approach to afford the [6-7-6] core of the compounds. Low yielding reactions and aromatic substitution issues caused us to modify our synthetic approach to an anionic homo-Fries rearrangement/intramolecular Barbier cyclization strategy. In this route, we successfully completed the synthesis of advanced intermediate 76 in ten linear steps from 1,3-dimethoxybenzene in 27% overall yield. Future research on this project should focus on the anionic homo-Fries rearrangement with ester 74 and subsequent aforementioned pathways to yield tricycle 37, the diterpenoids, and salvadione-A. IV. Experimental Section Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (either freshly distilled or passed through activated alumina columns). All commercially obtained reagents were used as received. HMPA was distilled over calcium hydride before use. N-bromosuccinimide 23 was recrystallized by hot gravity filtration in water. The following reagents were prepared according to literature procedure: Comins’ reagent,’ Cu(TBS)2,% and Rhy(cap)4.” Reaction temperatures were controlled using an IXKAmag temperature modulator. Thin-layer chromatography (TLC) was conducted with E. Merck silica gel 60 F254 pre-coated plates (0.25 mm) and visualized using a combination of UV and anisaldehyde staining. ICN silica gel (particle size 0.032-0.063 mm) was used for flash column chromatography. 'H NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz) and are reported relative to Me4Si (5 0.0). Data for 'H NMR spectra are reported as follows: chemical shift (6 ppm), multiplicity, coupling constant (Hz) and integration. '?C NMR spectra were recorded on a Varian Mercury 300 (at 75 MHz) and are reported relative to Me,Si (6 0.0). Data for °C NMR spectra are reported in terms of chemical shift. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm’'). High resolution mass spectra were obtained from the California Institute of Technology Mass Spectral Facility. 24 OMe OMe 1. n-BuLi, THF — 2. ethyl chioroformate THF, 0 °C —-> RT . OH OMe OMe 3. MeMgBr, 0 °C —-> RT 43 (85% yield) 44 Benzyl Alcohol 44. A solution of 1,3-dimethoxybenzene (1.0 mL, 7.6 mmol) in THF (6.0 mL) was added dropwise to n-BuLi (2.5 M in hexanes, 3.3 mL, 8.3 mmol) in THF (3.7 mL) under Ar. After stirring at room temperature for 1 h, the reaction mixture was cooled to 0 °C and charged with the dropwise addition of ethyl chloroformate (0.77 mL, 7.9 mmol) in THF (2.6 mL). After stirring at room temperature for 1 h, the reaction mixture was again cooled to 0 °C and charged with the dropwise addition of methylmagnesium bromide (3.0M in diethyl] ether, 15 mL, 45 mmol). The mixture was stirred at room temperature for 3 h and then slowly poured into cold saturated aq NH4Cl. After acidifying with 1 N HCl (aq), the reaction mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine (1x), dried with MgSO,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (5:1 hexanes:EtOAc) to yield benzyl alcohol 44 (1.3 g, 85% yield). Ry 0.37 (2:1 hexanes:EtOAc); ‘H NMR (300 MHz, CDCl3) 8 7.17 (t, J = 8.3 Hz, 1H), 6.62 (d, J = 8.3 Hz, 2H), 5.75 (s, 1H), 3.85 (s, 6H), 1.66 (s, 6H); °C NMR (75 MHz, CDCIs) 8 158.0, 127.8, 124.6, 106.2, 74.3, 56.3, 31.2; IR (film): 3529, 2970, 2942, 1593, 1582, 1474, 1451, 1434, 1387, 1367, 1273, 1247, 1215, 1160, 1098, 1071, 1032 cm’; HRMS- EI (m/z): [M]* cale’d for Cy);Hi¢03, 196.1100; found, 196.1090. 25 OMe . OMe 10% Pd/C, H, peeved Sele OH OMe OM e 4A (94% yield) aa Isopropylbenzene 45. Benzyl alcohol 44 (5.77 g, 29.4 mmol), 10% Pd/C (0.626 g, 0.588 mmol), conc. H2SO4 (39 drops), and EtOAc (84 mL) were combined, and the reaction vessel was evacuated and back-filled three times with hydrogen gas (1 atm). The reaction mixture was stirred under a hydrogen atmosphere overnight and then filtered through a plug of silica gel (EtOAc eluent). After concentrating the solution in vacuo, the crude product was diluted with Et,O and extracted with saturated aq NaHCO; (3x). The organic layer was washed with brine (1x), dried with MgSOu,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (20:1 hexanes:EtOAc) to yield isopropylbenzene 45 (4.96 g, 94% yield). Ry 0.65 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCI;) 7.12 (t, J = 8.3 Hz, 1H) 6.56 (d, J= 8.3 Hz, 2H), 3.82 (s, 6H), 3.70-3.55 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H); °C NMR (75 MHz, CDCI) § 158.8, 126.7, 124.7, 104.8, 55.9, 24.3, 20.9; IR (film): 2989, 2957, 2872, 2836, 1593, 1474, 1437, 1361, 1274, 1249, 1207, 1142, 1113, 1088, 1054, 1042 cm’'; HRMS- EI (m/z): [M]" cale’d for Cy;HisO2, 180.1150; found, 180.1153. Ox LH OH OMe OMe OMe Cl,CHOMe, TICl, HO,,H,SO, CHCl MeOH -42 °C —> RT Y OMe OMe OMe 46 45 (100% crude yield) (89% yield) 42 Phenol 42. To a solution of isopropyl benzene 45 (4.95 g, 27.5 mmol) in CH2Ch, (39 mL) was added a,a-dichloromethyl methyl ether (3.3 mL, 35.8 mmol). The reaction 26 mixture was cooled to -42 °C and charged with the dropwise addition of TiCl, (5.7 mL, 51.9 mmol). After stirring at -42 °C for 30 min and at room temperature for 40 min, the mixture was poured into cold H2O and extracted with EtOAc (3x). The combined organic layers were then dried with MgSO, and evaporated under reduced pressure to _ yield benzaldehyde 46. To a solution of crude 46 (5.72 g, 27.5 mmol) in MeOH (39 mL) was added conc. H2SO, (0.40 mL, 7.2 mmol) and H2O2 (30% “/y H20, 4.4 mL, 39 mmol). After stirring for 2.5 h, the reaction mixture was quenched with saturated aq NaHSO; and extracted with EtOAc (3x). The combined organic layers were washed with H20 (1x) and brine (1x), dried with MgSOu, and evaporated under reduced pressure. The crude product was purified by flash chromatography (5:1 hexanes:EtOAc) to yield phenol 42 (4.79 g, 89% yield over two steps). Ry 0.44 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl) 5 6.76 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 5.24 (s, 1H), 3.77 (s, 3H), 3.77 (s, 3H), 3.47-3.32 (m, 1H), 1.35 (d, J= 7.2 Hz, 6H); °C NMR (75 MHz, CDC13) 6 153.1, 145.4, 143.2, 130.0, 112.2, 108.3, 62.1, 56.0, 26.1, 21.2; IR (film): 3421 (br), 2990, 2958, 2907, 2836, 1485, 1458, 1431, 1361, 1258, 1218, 1190, 1150, 1105, 1052, 1013 em}; HRMS-EI (m/z): [M]" cale’d for C,H 1603, 196.1100; found, 196.1095, OH OH OH OMe Et,AICI, (HCHO), _ OMe ~ CHCl, a 0°C —->RT OMe (86% yield) OMe 42 52 Diol 52. To a solution of Et,AICI (1.0 M in hexanes, 28 mL, 28 mmol) in CH,Cl, (28 mL) was added phenol 42 (4.78 g, 24.4 mmol) in CH,Cl, (41 mL) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was charged with 27 paraformaldehyde (1.08 g, 34.1 mmol). The mixture was stirred at room temperature for 21.5 h, quenched with saturated aq NH,Cl, and extracted with CH,Cl, (3x). The combined organic layers were washed with H,O (1x), dried with MgSO,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (2:1 hexanes:EtOAc, then 1:1 hexanes:EtOAc) to yield diol 52 (4.73 g, 86% yield). Ry0.15 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDC1I;) 8 6.54 (s, 1H), 5.95 (s, 1H), 4.72 (s, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.46-3.31 (m, 1H), 2.39 (s, 1H), 1.33 (d, J = 6.9 Hz, 6H); °C NMR (75 MHz, CDCl) § 152.5, 145.6, 141.5, 129.6, 124.0, 107.6, 62.5, 62.0, 56.1, 26.0, 21.2; IR (film): 3537, 3407 (br), 3019, 2959, 1483, 1454, 1423, 1216, 1188, 1131, 1063 cm’; HRMS-EI (m/z): [M]" cale’d for C}2H)g04, 226.1205; found, 226.1211. OH OH OH OMe OMe OMe Mel, K,CO, Acetone, reflux OMe (93% yield) OMe 52 53 Trimethoxybenzene 53. A mixture of diol 52 (4.72 g, 20.9 mmol), K2CO3 (7.29 g, 52.8 mmol), acetone (64 mL), and iodomethane (4.0 mL, 64.3 mmol) was refluxed for 26.5 h at 60 °C. The reaction mixture was cooled to 0 °C, quenched with saturated aq NH,Cl, and extracted with EtOAc (3x). The combined organic layers were washed with brine (1x), dried with MgSOu, and evaporated under reduced pressure. The crude product was purified by flash chromatography (3:1 hexanes:EtOAc, then 2:1 hexanes:EtOAc, then 1:1 hexanes:EtOAc) to yield trimethoxybenzene 53 (4.66 g, 93% yield). Ry, 0.26 (2:1 hexanes:EtOAc); ‘H NMR (300 MHz, CDCl) & 6.61(s, 1H), 4.67 (d, J = 0.6 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.58-3.43 (m, 1H), 2.14 (s, 1H), 1.32 (s, 3H), 28 1.30 (s, 1H); 8C NMR (75 MHz, CDCls) 8 154.9, 151.8, 145.3, 131.8, 130.4, 106.6, 61.8, 61.0, 56.0, 25.4, 21.4; IR (film): 3385 (br), 2987, 2957, 2937, 2873, 1481, 1454, 1411, 1357, 1342, 1232, 1131, 1075, 1056, 1028 cm™; HRMS-EI (m/z): [MJ* cale’d for C13H2904, 240.1362; found, 240.1363. OMe OMe HO OMe NBS HO OMe THF Br OMe (91% yield) OMe 53 73 Bromobenzene 73. A reaction vessel covered in foil was charged with trimethoxybenzene 53 (933 mg, 3.88 mmol) in THF (33.9 mL). N-bromosuccinimide (725 mg, 4.07 mmol) was added portionwise every 5 min for 1 h. The reaction mixture was stirred for an additional hour and then concentrated in vacuo. The crude product was purified by flash chromatography (4:1 hexanes:EtOAc) to yield bromobenzene 73 (1.13 g, 91% yield). Ry0.37 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl;) 5 4.84 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H), 3.53-3.38 (m, 1H), 2.35 (s, 1H), 1.34 (d, J = 7.2 Hz, 6H); °C NMR (75 MHz, CDCl) & 151.6, 149.5, 137.0, 132.6, 114.1, 100.2, 61.8, 61.4, 60.6, 60.6, 27.1, 22.1; IR (film): 3475 (br), 3017, 2962, 2939, 1454, 1405, 1342, 1320, 1216, 1121, 1081, 1052, 1026 em”; HRMS-EI (m/z): [M]* cale’d for Cy3Hi9O4Br, 318.0467; found, 318.0464. 29 0 (e) 1. Me,CuLi, Et,0,0°C oO 2. HMPA, 0 °C i 3. tbutyl bromoacetate OfBu Et,0, -78 °C —-> RT 47 63 (89% yield) t-Butyl Ester 63. To a solution of copper iodide (3.08 g, 15.9 mmol) in EO (52 mL) was added methyllithium (1.6 M in Et,O, 19.8 mL, 31.7 mmol) dropwise at 0 °C under Ar. After stirring at 0 °C for 30 min, the mixture was charged with the dropwise addition of 3-methyl-2-cyclohexen-1-one (1.5 mL, 13 mmol) in Et,O (13 mL) and stirred at 0 °C for an additional 65 min. HMPA (9.2 mL, 53 mmol) was then added dropwise at 0 °C, and the mixture was slowly cooled to -78 °C. The reaction mixture was charged with the dropwise addition of tert-butyl bromoacetate (5.9mL, 40 mmol) in EO (10 mL) at —78 °C and was then warmed to room temperature. After stirring at room temperature for 2 h, the mixture was diluted with Et,O and extracted with 5% aq NHs,OH (3x) The organic layer was washed with brine (1x), dried with MgSO,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (20:1 hexanes:EtOAc, then 10:1 hexanes:EtOAc) to yield t-butyl ester 63 (2.8 g, 89% yield). Ry 0.50 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl) 6 2.80 dd, J = 9.9, 3.3 Hz, 1H), 2.62 (dd, J = 16.4, 10.0 Hz, 1H), 2.40-2.33 (m, 2H), 2.17 (dd, J= 16.4, 3.4 Hz, 1H), 2.02-1.54 (comp. m, 4H), 1.44 (s, 9H), 1.07 (s, 3H), 0.74 (s, 3H); °C NMR (75 MHz, CDC13) 6 211.5, 172.8, 80.5, 56.6, 41.4, 40.6, 39.2, 30.2, 29.9, 28.3, 23.0, 21.2; IR (film): 2966, 1731, 1714, 1368, 1156 cm’; HRMS-EI (m/z): [M]” cale’d for Cy4Ho403, 240.1726; found, 240.1715. 30 % 9 % 9 —lFA_ orpu CN2Cle OH (88% yield) 63 72 Acid 72. A solution of t-butyl ester 63 (2.83 g, 11.8 mmol), TFA (29 mL), and CH,Cl, (29 mL) was stirred for 45 min and then concentrated in vacuo. The crude product was purified by flash chromatography (2:1 hexanes:EtOAc, then 1:1 hexanes:EtOAc, then EtOAc) to yield acid 72 (1.91 g, 88% yield). Ry, 0.23 (1:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCI3) 8 10.98 (s, 1H), 2.84-1.52 (comp. m, 9H), 1.09 (s, 3H), 0.75 (s, 3H); °C NMR (75 MHz, CDC]3) § 211.3, 179.2, 56.4, 41.3, 40.5, 39,3, 30.0, 28.9, 22.9, 21.0; IR (film): 3413 (br), 2956, 1703, 1426, 1397, 1372, 1323, 1267, 1227, 1182, 1168, 1080 cm™?; HRMS-EI (m/z): [MJ cale’d for CioHi603, 184.1100; found, 184.1096. OMe DIAD, _DIAD, PPh; — Hr (88% yield) 72 73 74 OMe Ester 74. To a mixture of acid 72 (246 mg, 1.34 mmol), bromobenzene 73 (425 mg, 1.33 mmol), and PPh; (384 mg, 1.46 mmol) in THF (16.5 mL) was added DIAD (310 wL, 1.48 mmol) at 0 °C. After stirring overnight at room temperature, the mixture was concentrated in vacuo. The crude product was purified by flash chromatography (6:1 hexanes:EtOAc) to yield ester 74 (569 mg, 88% yield). Ry 0.52 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl3) 6 5.26 (dd, J = 19.9, 11.1 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.56-3.40 (m, 1H), 2.90 (dd, J= 9.8, 3.2 Hz, 1H), 2.77 (dd, J= 16.5, 9.9 Hz, 31 1H), 2.43-2.34 (m, 2H), 2.28 (dd, J = 16.5, 3.0 Hz, 1H), 2.06-1.53 (comp. m, 4H), 1.34 (d, J = 7.2 Hz, 6H), 1.08 (s, 3H), 0.72 (s, 3H); °C NMR (75 MHz, CDCl) & 211.2, 173.3, 152.5, 151.8, 150.4, 137.9, 127.9, 115.6, 61.7, 61.5, 60.6, 56.5, 41.4, 40.5, 39.3, 30.0, 29.0, 27.1, 23.0, 22.0, 22.0, 21.1; IR (film): 2961, 1737, 1713, 1455, 1405, 1342, 1323, 1242, 1163, 1122, 1083, 1028 cm?; HRMS-FAB (m/z): [M]* calc’d for C23H330¢6Br, 484.1460; found, 484.1468. PO ‘oie Sthylene glycol glycol 0 OMe p-TSA, PhH reflux Br aa (94% yieid) OMe 71 Ketal 71. Ester 74 (552 mg, 1.14 mmol), ethylene glycol (0.19 mL, 3.4 mmol), p-toluenesulfonic acid monohydrate (5.0 mg, 0.026 mmol), and benzene (12 mL) were combined and refluxed with a Dean-Stark apparatus at 110 °C for 21.5 h. The reaction mixture was then cooled to room temperature, diluted with Et,O, and extracted with H.O (3x). The organic layer was washed with brine (1x), dried with MgSOu,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (9:1 hexanes:EtOAc) to yield ketal 71 (569 mg, 94% yield). Ry 0.47 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl) 6 5.26 (dd, J = 22.0, 11.0 Hz, 2H), 4.02-3.78 (comp. m, 13H), 3.56-3.40 (m, 1H), 2.41 (dd, J = 14.7, 7.8 Hz, 1H), 2.31-2.15 (comp. m, 2H), 1.83-1.24 (comp. m, 12H), 0.98 (s, 3H), 0.87 (s, 3H); °C NMR (75 MHz, CDCl) & 174.6, 152.5, 151.7, 150.4, 137.8, 128.3, 115.7, 110.7, 65.3, 63.6, 61.7, 61.4, 61.4, 60.6, 50.0, 40.9, 35.3, 34.6, 31.6, 29.9, 27.1, 22.1, 21.7, 19.8; IR (film): 2939, 1736, 1455, 1405, 1341, 32 1323, 1272, 1242, 1170, 1138, 1087, 1056, 1030 cm’; HRMS-FAB (m/z): [MJ" calc’d for C23H3306Br, 528.1723; found, 528.1749. r tr Pa (e] OMe 0 [o) OMe ° OMe mBuLl a THF, -78 °C OMe Br MeO OMe (82% yield) 71 76 Enol Ether 76. To a solution of ketal 71 (569 mg, 1.07 mmol) in THF (4.3 mL) was added n-BuLi (1.6M in hexanes, 740 wL, 1.18 mmol) dropwise at —78 °C. After stirring for 2.5 h at -78 °C, the reaction mixture was quenched with saturated aq NH,Cl, warmed to room temperature, and extracted with EtOAc (3x). The combined organic layers were washed with brine (1x), dried with MgSOu,, and evaporated under reduced pressure. The crude product was purified by flash chromatography (5:1 hexanes:EtOAc) and dried under MeOH to yield enol ether 76 (378 mg, 82% yield). Ry 0.51 (2:1 hexanes:EtOAc); 'H NMR (300 MHz, CDCl) 8 5.36-5.18 (comp. m, 3H), 4.07-3.78 (comp. m, 10H), 3.74 (s, 3H), 3.56-3.40 (m, 1H), 2.80 (d, J = 10.7 Hz, 1H), 1.85-1.25 (comp. m, 12H), 1.01 (s, 3H), 0.96 (s, 3H); °C NMR (75 MHz, CDCl) 8 154.7, 152.4, 148.6, 144.0, 135.8, 131.6, 122.6, 111.1, 96.7, 71.2, 65.6, 64.5, 61.0, 60.8, 59.8, 50.7, 40.5, 36.5, 35.7, 31.7, 25.7, 22.3, 22.2, 22.2, 20.1; IR (KBr pellet): 3448 (br), 2954, 2870, 1674, 1468, 1422, 1413, 1382, 1365, 1343, 1322, 1288, 1249, 1192, 1167, 1153, 1131, 1116, 1094, 1066, 1034, 1014 cm’; HRMS-FAB (m/z): [M + HJ’ cale’d for C2sH3706, 433.2590; found, 433.2575. 33 V. References 1. Ahmad, V. U.; Zahid, M.; Ali, M. S.; Jassbi, A. R.; Abbas, M.; Clardy, J.; Lobkovsky, E.; Tareen, R. B.; Iqbal, M. Z. Salvadiones-A and —B: Two Terpenoids Having Novel Carbon Skeleta from Salvia bucharica. J. Org. Chem. 1999, 64, 8465-8567. 2. Ahmad, V. U.; Zahid, M.; Ali, M. S.; Choudhary, M. I.; Akhtar, F.; Ali, Z.; Iqbal, M. Z. Salvadiol: A Novel Triterpenoid from Salvia bucharica. Tetrahedron Lett. 1999, 40, 7561-7564. 3. Biosynthesis of salvadione-A modeled from the proposed biosynthesis of perovskone: Parvez, A.; Choudhary, M. I.; Akhter, F.; Noorwala, M.; Mohammad, F. V.; Hasan, N. M.; Zamir, T.; Ahmad, V. U. Perovskone: A Triterpene with a Novel Carbon Skeleton from Perovskia abrotanoides. J. Org. Chem. 1992, 57, 4339-4340. 4. Majetich, G.; Zhang, Y. Concise Synthesis of (+)-Perovskone. J. Am. Chem. Soc. 1994, 716, 4979-4980. 5. Marvell, E. N.; Burreson, B. J.; Crandall, T. Influence of Alkyl Groups on the Rate of the para Claisen Rearrangement. J. Org. Chem. 1965, 30, 1030-1032. 6. Marvell, E. 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It is important to note that we are unsure of which olefin geometry (E or Z) of the a, olefin in triene 10 will lead to the correct framework of salvadione-A in the tandem Claisen/Cope/Diels-Alder reaction due to uncertainties in transition state configurations (no theoretical calculations were performed to determine the most stable configuration). Because of this, I refer to both the EF and Z isomers as triene 10. If the wrong isomer were to be synthesized, olefin isomerization could potentially be utilized to form the other isomer. . 14. IBX Chemistry: a. Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. A New Method for the One-Step Synthesis of a,§-Unsaturated Carbonyl Systems from Saturated Alcohols and Carbonyl Compounds. J. Am. Chem. Soc. 2000, 122, 7596-7597. b. Nicolaou, K. C.; Montagnon, T.; Baran, P.S. Modulation of the Reactivity Profile of IBX by Ligand Complexation: Ambient Temperature Dehydrogenation of Aldehydes and Ketones to a,B-Unsaturated Carbonyl Compounds. Angew. Chem. 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Standard Mitsunobu conditions: DIAD or DEAD with PPh, in THF or Toluene. 20. Majetich, G.; Wang, Y.; Li, Y.; Vohs, J. K.; Robinson, G. H. A Synthesis of (+)- Salvadione-A. Org. Lett. 2003, 5, 3847-3850. 21. Frontana, B.; Cardenas, J.; Rodriguez-Hahn, L. Diterpenoids from Salvia coulteri. Phytochemistry 1994, 36, 739-741. 35 22. Uchiyama, N.; Kiuchi, F.; Ito, M.; Takeda, Y.; Khodzhimatov, O. K.; Ashurmetov, O. A. New Icetexane and 20-Norabietane Diterpenes with Trypanocidal Activity from Dracocephalum komarovi. J. Nat. Prod. 2003, 66, 128-131. 23. Comins, D. L.; Dehghani, A. Pyridine-Derived Triflating Reagents: An Improvised Preparation of Vinyl Triflates from Metallo Enolates. Tetrahedron Lett. 1992, 33, 6299- 6302. 24. Thompson, S. K.; Heathcock, C. H. Total Synthesis of Some Marasmane and Lactarane Sesquiterpenes. J. Org. Chem. 1992, 57, 5979-5989. 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Reactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chloride. J. Am. Chem. Soc. 1989, 117, 4392-4398. 33. Molander, G. A.; Huerou, Y. L.; Brown, G. A. Sequenced Reactions with Samarium(II) Iodide. Sequential Intramolecular Barbier Cyclization/Grob Fragmentation for the Synthesis of Medium-Sized Carbocycles. J. Org. Chem. 2001, 66, 4511-4516. 34. I would like to thank Richmond Sarpong, Ph.D. for his suggestion to use the Anionic Homo-Fries Rearrangement. 35. Piettre, A.; Massardier, C.; Chevenier, E.; Gimbert, Y.; Greene, A. Efficient Preparation of Polysubstituted Naphthyl Phenyl and Dinaphthyl Ketones from Napththalenic Esters by Anionic Homo-Fries Rearrangement. Syn/ett 2002, 12, 2086- 2088. 36. lam grateful to Uttam Tambar for suggesting the possibility that the product was an enol ether. 37. I believe that trimethoxybenzene 53 was yielded in the reaction, because too much n- BuLi was used. This caused the excess to act as a nucleophile and open the desbromo- starting material to yield 53. 38. Charles, R. G. Copper (IJ) and Nickel (IJ N-(n-alkyl)salicylaldimine Chelates. J. Org. Chem. 1957, 22, 677-679. 39. Doyle, M. P.; Westrum, L. J.; Wolthius, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. Electronic and Steric Control in Carbon-Hydrogen Insertion Reactions of Diazoacetoacetates Catalyzed by Dirhodium (II) Carboxylates and Carboxamides. J. Am. Chem. Soc. 1993, 115, 958-964. 37