Progress on the synthesis of a model system for neocarzinostatin chromophore Citation Fuhry, Mary Ann M. (1989) Progress on the synthesis of a model system for neocarzinostatin chromophore. Master's thesis, California Institute of Technology. doi:10.7907/tj6s-2x96. https://resolver.caltech.edu/CaltechTHESIS:04072010-111308897 Abstract No abstract. 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): Unknown, Unknown Thesis Committee: Unknown, Unknown Defense Date: 8 June 1989 Record Number: CaltechTHESIS:04072010-111308897 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:04072010-111308897 DOI: 10.7907/tj6s-2x96 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 5698 Collection: CaltechTHESIS Deposited By: Tony Diaz Deposited On: 14 Jun 2010 20:23 Last Modified: 19 Apr 2021 22:26 Thesis Files Preview PDF - Final Version See Usage Policy. 1MB Repository Staff Only: item control page

Progress on the Synthesis of a Model System for the Neocarzinostatin Chromophore Mary Ann M. Fuhry In partial fulfillment of the requirements for the degree of Master of Science California Institute of Technology Pasadena, California 1989 Submitted June 8, 1989 Table of Contents INtrOdUCtiON oo... eee ceecccecce ceca eeeeeeseceusceuccaueeens 1 DISCUSSION oo. ceeececeeeccecceseueeeeecueceeecaecueeaees 3 REfETENCES eee ec ccecceecee cee seeesenaceeusaueceueeues 20 Experimental ooe..cecceccccccceccceccaseceueccuascansceeeeaes 21 SPECIAL ccc ecc cece eee eea eee eeessssuecaeeueeaeeaess 52 Introduction The antitumor antibiotic neocarzinostatin (NCS)1.2 is known to cleave DNA. This reaction is greatly stimulated by the addition of thiols, and, in the absence of DNA, preincubation with thiols rapidly inactivates the drug!@. NCS consists of two components, a protein of MW 10,700, and a very labile, methanol-extractable nonprotein component, chromophore 1. The separated chromophore has been shown to be at least as active as NCS in inducing single-strand breaks in DNA and in inhibiting DNA synthesis; the protein component protects the chromophore and controls its release}. Both the isolated chromophore and NCS require thiols for optimal reactivity. The mechanism by which nucleophiles activate 1 toward DNA cleavage has been proposed*.5 to proceed via a diradical species (Scheme I). Scheme | CH, CH,0 CH, ro) CH;0 CH,0 OH Osu R,O NCH Ry = H3C OH OH Re = CH2CO,CH, The focus of this research is the synthesis of the chromophore analog, 2. This model system may react with thiols in an analogous manner to the natural product, as shown in scheme II. Scheme Il tBuCO, RS r\\OH TI A successful synthesis of the core component would outline the strategy for the total synthesis of NCS chromophore. Finally, diyne 2 may be developed into new, non- diffusable DNA-cleaving reagents by tethering it to known DNA binders. Herein, progress on the synthesis of the NCS chromophore analog 2 will be reported. Discussion Compounds 3, 4, and 5 were investigated as possible precursors to the NCS chromophore model system, 2. Each was prepared from multistep syntheses to be described in the following sections. Preliminary ring-closure studies were conducted on all systems. Aldehyde 3 Precursor 3 was designed to allow closure of the 9-membered ring by intramolecular addition of an acetylenic anion to an o,B-unsaturated aldehyde. Treatment with a hindered lithium base would metallate at the terminal acetylene position, as shown in Scheme HI. The resulting alcohol could be eliminated to form the target compound, 2. Scheme Il fe) ; fe) tBucO, tBuCO, N N | 4 LINR2 Li —> CHO CHO 3 LL _ P. H tBuCO, OH H The synthesis of compound 3 is outlined in Scheme IV. Cyclopentanone was converted to the trimethylsilyl (TMS) enol ether, 6, using TMSCI, Nal, and NEt3 in CH3CN®, This, on reaction with trimethylorthoformate and a catalytic amount of TMSOSO>CF3 (TMS triflate), gave the dimethyl acetal, 77, which, on addition of lithium acetylide gave a 4:1 diastereomeric mixture of alcohols, 8. The corresponding ¢ - butyldimethylsilyl (TBS) ethers, 9, were prepared with TBS triflate? and 2,6-lutidine. Although both stereocenters were eliminated later in the synthesis, separation of the isomers simplified analysis of the structures that followed. It was found most convenient to separate the diastereomers as TBS ethers by flash chromatography. The stereochemistry of the two ethers was determined by NOE difference studies. The acetylene group was selectively reduced to the olefin with H2 over NEt3-poisoned Pd(C); the arrows in the diagram below indicate the protons whose signals were enhanced on irradiation of protons a and b, respectively. CH(OMe)a OTBS H H ( Ha H major The second starting material, bromide 10, was prepared by bromination of ethyl propiolate with Br7 and KyCO3 in CCly, followed by Pd-catalyzed coupling with TMS acetylene!0, Coupling of acetylide 9 and bromide 10 with Cul, PrNHp, and a Pd catalyst under oxygen-free conditions lead to enediyne 11 in 85% yield. Diisobutyl aluminum (DIBAL) in toluene was used to reduce the carbony], and, in the same pot, the trimethylsilyl group was removed with methanolic KOH to provide alcohol 12. A Sharpless oxidation was employed! 1 to give a 95% crude yield of epoxide 13; treatment Scheme IV ° OTMS fe) TMSCI, Nal,EtsN, CH3CN TMSOTH, HC(OMe)3 OMe 35-40°C, 93% -78°C, 81% OMe TBSOTF, 2,6-lutidine | SSH NH,C! CH2Cle, 0°C ee —— > THF, -78°C 99% 80% OMe OMe 9 fo) Oo fe) Bro, K2CO3, CCly, 70°C Br TMS —S =H Br Eto NN ——__——» FIO m= EtO xs 75% i ProNeét, Pd(PPh3)4, | H Cul, DMF, 0°C, 90% H Br H 10 TMS Scheme IV (cont) EtO — Pd(PPha)4, Cul, PrNHa, 1. DIBAL, toluene, OMe toluene, RT, 83% -78°C om 10 2. KOH/MeOH ° 86% 9 re) | | H (+)-DET, Ti(Q/ Pr)4, TBHP, = 3A sieves, CH2Clo -20 ——™ -5°C, 65% 12 (racemic) t BuCOs 1, H202, ClgCCO2H, CHoClo/t BUQH, 0°C —= RT 2. DMS, MeOH 85% Scheme IV (cont.) DBU, toluene 65% PhSeNEts, CH2Cla, RT 15 26% with trimethylacetylchloride in pyridine gave compound 14 in 60% yield from 12. Attempts to hydrolize the dimethylacetal protecting group under conventional acidic conditions required high concentrations of acid and lengthy reaction times, resulting in poor yields. A much milder method was developed using H2O9 in CHClg / rt BuOH and trichloroacetic acid to give a hydroperoxide (see Appendix); treatment with dimethyl sulfide (DMS) gave aldehyde 15 in 66-85% yield. Elimination to the final product, 3, was accomplished with diazabicycloundecene (DBU) in toluene (65%). Some preliminary cyclization attempts are shown in Table 1. Reaction of 15 with lithium tetramethylpiperidide (LiTMP) gave dimers or the elimination product 3. In order to prevent enolization of the aldehyde, compound 16 was prepared in low yield from 15 with PhSeNEt3 12. Again, treatment with base resulted largely in elimination. Reaction of 3 with LiN(TMS)? resulted in formation of dimers, both acyclic and cyclic. Most recently, the epoxide of 3 has been opened and the resulting diol protected!3; conditions for closure of this system are being investigated. Table 1. Ring Closure Studies 3 Substrate Conditions Results 15 LITMP, CeCl,, THF, -78°C mixture of acyclic base added to substrate dimers 15 LiTMP, THF, -78°C mostly 3; unidentified substrate added to base side products 16 LITMP, THF, -78°C mostly 3; some substrate added to base unreacted 16 3 LiN(TMS)>, THF, -78°C cyclic and substrate added to base acyclic dimers LO Bis-epoxide 4 The ring-closure strategy of compound 4 relies on intramolecular addition of a cuprous acetylide to a vinyl epoxide. Addition to the olefin would result in epoxide opening, as shown in Scheme V, possibly through a 10-membered intermediate with Cull, followed by reductive elimination. Elimination of the alcohol would provide the NCS chromophore model compound, 2. Scheme V fe) [ fa) 7 tBuCO, tBuCO, —_ _ H i Cul O Cu : NEt; re) —_—_— $a 4 LL a QO - _ tBuCO, o t Buco, a ; \ Oo Cul! —x HO LL am Ll Precursor 4 was prepared from aldehyde 15 as shown in Scheme VI. The aldehyde was reduced with K-selectride to give of alcohol 16, and the tertiary alcohol deprotected with fluoride to give diol 18 in 82% yield. The primary alcohol was converted to 19 in 97% yield by selective protection with rbutyldiphenylsily1 chloride / imidazole. The tertiary alcohol was eliminated with POCIs3 in pyridine, providing a 67% yield of a 4:1 mixture of olefins of which 20 was the major isomer. After desilylation, the double bond was epoxidized with mCPBA to give a 63% yield of a mixture of the two syn epoxides, 32. The alcohol was converted to 23 by treating the corresponding triflate (formed from Tf,0 / i PryNEt) with PhSeH!4. Elimination to the exo-methylene was accomplished by oxidation with mCPBA at -78°C, followed by treatment with DMS, and warming to room temperature, to give 4 in 40% yield from 22. Ring-closure studies of 4 are summarized in Table 2. Most conditions resulted in decomposition. Table 2. Ring Closure Studies of 4 Conditions Results CuCl, NEts, THF, RT mostly starting material CuCl, PrNHp, toluene, RT . decomposition Cul, NEty/NEty HCI, OMF, THF decomposition CuCl, PrNH>, HJNOH HCI, EtOH, RT decomposition 12 Scheme VI H k-selectride, THF TBAF, THF. 0°C - er -78°C, 76% 82% Nn, t Buco, . Ht BuPhSicl, POCI,, pyridine imidazole -20°C, 67% LT ——_._.__ DMF, 97% Oo fo) 4 tBuCO,~ TBAF, THF, 0°C OSiPhot Bu 83% 20 21 13 Scheme VI (cont.) 34 mCPBA, NaHCOs3, CH2Clo, 0°C 63% 1. MCPBA, CH2Cly,-78°C 2. OMS 3. K2CO3, PRT 40% from 22 1. TioO, i ProNEt, CHoCle, -78°C 2. PhSeH, -35°C 14 Aldehyde dichloride 5 The most recently-studied system involves formation of the epoxide of 2 during the ring-closure step. Unlike compounds 3 and 4, the double bond of 5 holds the reactive ends of the molecule together in an unambiguous way. The planned strategy was to cyclize 5 through nucleophilic attack at the aldehyde functionality, forming an alkoxide anion which, through loss of Cl-, should close to form a 10-membered heterocycle (Scheme VII). Subsequent deprotonation at the acidic site should kinetically favor epoxide formation, displacing the second chlorine anion. As in the preceding systems, elimination of the protected alcohol would give the precursor to the final product, 2. Scheme VII fe) H O- H Cl NC c™ 4 CHCl, La cl ae —_ a 5 = — 7 Z H 0 H | NC cl base | | —_—— — L5 Aldehyde dichloride 5 was prepared as outlined in Scheme VII. Cyclopentanone was o-alkylated!5 (NaOMe, HCOEt, Et2O, 20%) to give ketoaldehyde 24 ; treatment with triflic anhydride / triethylamine resulted in a clean conversion to enol triflate, 25. Protected propargyl alcohol, 26, (prepared from propargyl alcohol and TBSC1 / NEt3 in 83% yield) was coupled with 25 (Pd(PPh3)2Cl2, Cul, NEt3, THF, RT, 78%) to give enone 27, with the geometry shown. Photoisomerization gave a poor yield (18%) of enone 28 ; the geometry was confirmed through NOE experiments. Addition of propiolaldehyde diethylacetal anion to the ketone gave alcohol 29 in good yield (81%). Protection of the tertiary alcohol (TBSOTE, 2,6-lutidine, CH2Clp, OCC RT, 98%), followed by selective deprotection (1 eq TBAF, THF, 0°C, 87%), revealed primary alcohol, 31. Oxidation under standard Swern conditions (oxalyl chloride, DMSO, NEt3, CH)Clo, -78°C, 75%) to aldehyde 32 was followed by treatment with PCls5 / dirbutylmethylpyridine!6 which, after workup with saturated aqueous ammonium chloride, provided aldehyde dichloride 5 (87%). Preliminary cyclization studies of 5 are summarized in Table 3!7. Continued research will involve elimination of the protected tertiary alcohol to give a planar system. Ring-closure experiments on this system will be conducted in due course. 16 Scheme VII fo) OH 41,0, NEts, OSO2CF3 NaOMe, HCO2Et = CHeClo, -78°C = Et2O, 20% 47% 24 25 oTBS Cul, NEts, | | Pd(PPh3}2Clo, e) (e) THF, RT : h 20 nm 78% Z v, 2920 ZA — SS toluene, 18% —"\ OTBS OTBS 26 27 28 Eto OEt OTBS Eto OEt OTBS cL | | _——— OF io TBSOTH, CH2Cla, TaS0 — 3 a 2,6-lutidine THF, -78°C o°C——> AT 1% a 29 98% 30 17 Scheme VI (cont.) EtO OEt OH Eto OEt CHO | | | | oxaly! chloride, DMSO | | | | TBAF, THF,O°C TBSO NEtg, CHpClz, -78°C TBSO 87% 75% 31 32 CHO = CHCla Me Ion | | 1. PCls, tBu N tBu CHeCh, 0°C TBSO —_ 2. NH4CI, 57% 18 Table 3. Ring Closure Studies of 5 NC OH CHO CHCl NYY CHCI, TBSO TBSO — —_ 5 33 substrate conditions results 5 KCN, HOAc, THF, 0°C cyanchydrins 33 33 pyridine, CH2Clo no reaction mostly starting material 5 KCN, DMF, 0°C + uncharacterized mixture of products 5 KCN, EtOH / H,0, 0°C ethyl ester, 34, below 2:1 cis:trans 34 19 References and Notes 1) a) Napier, M. A.; Holmquist, B.; Strydom, D. J.; Goldberg, I. H.; Biochem. Biophys. Res. Comm. 1979, 89, 635. b) Alders-Schonberg, G.; Dewey, R. S.; Hensens, O. D.; Liesch, J. M.; Napier, M. A; Goldberg, I. H. Biochem. Biophys. Res. Comm. 1980, 95, 1351. 2) Koide, Y.; Ishii, F.; Hasuda, K.; Koyam, Y.; Edo, K.; Kitamine, F.; Ishida, N. J. Antibiot. 1980, 33, 342. 3) Kappen, L. S.; Napier, M. A.; Goldberg, I. H. Proc. Natl. Acad. Sci. USA 1980, 77, 1970. 4) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493. 5) Myers, A. G.; Proteau, P. J. J. Am. Chem. Soc. 1989, 111, 1146. 6) Walshe, N. D. A.; Goodwin, G. B. T.; Smith, G. C.; Woodward, F. E. Organic Synth. 1987, 1. 7) Hara, S.; Suzuki, A. Tetrahedron Lett. 1983, 24, 735. 8) Midland, M. M. J. Org. Chem. 1975, 40, 2250. 9) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. Tetrahedron Lett. 1981, 22, 3455. 10) Bromide 10 was prepared by Dr. Mian M. Alauddin. 11) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. 12) Jefson, M.; Meinwald, J. Tetrahedron Lett. 1981, 22, 3561. 13) Diol formation and subsequent ring- closure studies are being conducted by Philip J. Proteau. 14) Org. Synth. Coll. Vol. II p. 771. 15) Michael R. Lewis, 1987, I-13. 16) Dr. Paul Kamer, 1988, I-199. 17) Cyanohydrin 33 was prepared from aldehyde dichloride 5 by treatment with an excess of KCN in THF / acetic acid at room temperature. 18) Coulson, D.R. /norg. Synth. Vol. 13, p. 121. 20 Experimental All solvents used in the following reactions were distilled under moisture- and oxygen-free conditions. Dichloromethane and acetonitrile were distilled over CaHp. Toluene was distilled over sodium, and tetrahydrofuran (THF), over sodium and benzophenone. Ethyl acetate and hexanes used for extractions and chromatography were purchased from J. T. Baker (HPLC grade) and used without drying. , Amines distilled from CaHz included triethylamine, 2,6-lutidine, propylamine, pyridine, diisopropylethylamine, and 2,6-ditbutyl-4-methylpyridine. Other reagents distilled from CaH2 were diazabicycloundecene (DBU), dimethylsulfoxide (DMSO), and trimethylsilyl chloride (TMSCl). Dimethylformamide (DMF) was distilled from BaO, and imidazole and oxalyl chloride were distilled directly. Triflic anhydride (Tf2O) was prepared from distillation of triflic acid from P20s. Reagents prepared according to literature procedures included rbutyldimethylsilyltriflate (TBSOTE£)9, PhSeNEt,!2, PhSeH!4, and Pd(PPh3)418. Sodium iodide was dried at 120°C / .6 mm Hg for 12 h before use. The remaining reagents were purchased and used without further purification, including trichloroacetic acid (Mallinkrodt), methanol (Fisher), meta-chloroperbenzoic acid (mCPBA, Fluka), phosphorus pentoxide (EM), and the following reagents from Aldrich: rbutyl alcohol, dimethyl] sulfide (DMS), K-selectride (potassium tri-sec-butylborohydride), tetrabutylammonium fluoride (TBAF), tbutyldiphenylsilylchloride, phosphorus oxychloride, bis(triphenylphosphine) palladium(IDchloride, propiolaldehyde diethylacetal, trimethylsilyltriflate (TMSOTD), trimethylorthoformate, copper(II)iodide, diisobutylaluminum hydride (DIBAL), (+)-diethyl tartrate (DET), titanium(IV) isopropoxide, tbutylhydroperoxide (TBHP), and trimethylacetyl chloride. Glassware was dried in a 100°C oven for at least 6 h or flame-dried before use. An argon atmosphere was standard for all procedures. IR spectra were obtained on a Perkin- Elmer 1600 FTIR instrument, all as neat films. A JEOL 400MHz or a Bruker 500MHz spectrometer was used for 1H NMR spectra. An Oriel 1000-watt arc lamp was used for photochemistry in the synthesis of 5. 21 OTMS TMSCI, Nal, EtsN, CH3CN 35-40°C, 93% Cyclopentanone (22.2 ml, .251 mol, 1 eq) and NEt3 (40.0 ml, .287 mol, 1.14 eq) were placed in a three-neck flask and treated with TMSCI (34.1 ml, .269 mol, 1.07 eq). A solution of Nal (35.1 g, .234 mol, .93 eq) in CH3CN (270 ml) was introduced over 1.5 h through an addition funnel. After 1 h, the reaction was complete by IR. The mixture was poured carefully into 500 ml pentane / 15 ml NEt3 / 500 ml brine / ice, extracted once, dried over Na2SO4q, and concentrated. The crude product was used directly in the following reaction. IR: — 3080, 2970, 2860, 1643, 1350, 1250, 1195, 1040, 970, 930, 900, 870, 850. 22 OTMS 9 TMSOTHE, HC(OMe)3 OMe -78°C, 81% OMe A solution of 6 (40.6 g crude, .26 mol, 1 eq) and HC(OMe)3 (34.2 ml, .313 mol, 1.2 eq) in 270 ml CH2Clp at -78 OC was treated with TMS-triflate (9.0 ml, .046 mol, 0.18 eq). The reaction was quenched with NEt3 (2.0 ml, .014 mol, .06 eq) and allowed to warm to room temperature. A small amount of anhydrous K7CO3 was added and the mixture was filtered and concentrated. The product was distilled at 0.6 mm Hg, and the fraction at 63-69°C was collected to give 31.93 g 7(82%). FTIR: 2965, 2834, 1741, 1452, 1357, 1069, 968. 1HNMR (90 MHz, CDCl3): 4.53 (d, J=1Hz, 1H, CH(OMe)); 3.34 (s, 6H, OMe); 2.58-1.59 (m, 7H). TLC (20% EtOAc / hexanes): product: .21 MS(ED): 158, 127, 97, 84, 75, 67, 57, 49, 43. 23 OMe *, OMe {i= NH,Cl OMe » % THF, -78°C 99% H OMe 7 8 4:1 Deoxygenated THF (250 ml) was cooled to -78°C. Approximately 2L acetylene (purified by passing through first a -78°C trap, then concentrated sulfuric acid, and finally a KOH tower) was bubbled through, then BuLi (50.5 ml, 110.5 mmol, 1.9 eq, cooled to -789°C) in 5 ml THF was added by cannula below the level of the liquid. Ketone 7 (9.0438 g, 57.17 mmol, 1.0 eq) was added dropwise by syringe, and the mixture stirred for 3h. Saturated NH4Cl solution was added (45 ml), and the mixture allowed to warm to room temperature. Dilution with 50% EtOAc / hexanes followed, and the separated organic layer washed several times with water. The combined washings were extracted again, and the organic portions were dried over sodium sulfate and concentrated under vacuum; the ratio of isomers was 4:1 by NMR. The product was purified by flash chromatography (40% EtOAc / hexanes ), collecting both isomers of 8 together in near quantitative yield. FTIR: 3595-3385, 3315-3215, 2095. 1HNMR (400MHz, CDCl3): 4.62 (d, J=3Hz, 1H, CH(OMe)9); 3.71 (s, 1H, OH); 3.48 (s, 3H, OCH3); 3.30 (s, 3H, OCH3); 2.51 (s, 1H, acetylene-H); 2.18 (m, 2H); 1.88 (m, 2H); 1.73 (m, 2H); 1.55 (m, 1H). TLC (20% EtOAc / hexanes): SM: .21 product: .19 24 % OH TBSOTH, 2,6-lutidine 4, gores om * OMe CHeCla, 0°C ° Oy % “4 ‘ome 80% H OMe 8 41 9 A solution of alcohol 8 (3.030 g, 16.45 mmol, 1.0 eq) in 15 ml CH2Cl9 at 0°C was treated with 2,6-lutidine (4.2 ml, 20.20 mmol, 1.23 eq) and TBS-triflate (5.60 ml, 24.36 mmol, 1.48 eq). After 1 h, the reaction was quenched with methanol, diluted in 1 :1 EtOAc / hexanes, washed twice with water, dried over NazSOq, and concentrated under vacuum. The product was purified by flash chromatography (50% to 75% EtOAc / hexanes), collecting 2.400 g of the major isomer of 9 and 1.549 g of a mixture of both isomers (80% yield). FTIR: 3310, 2090, 1250. 1HNMR (400MHz, CDC13): major: 4.50 (d, J=6Hz, 1H,CH(OMe) ); 3.33 (s, 3H, OCH3); 3.32 (s, 3H, OCH3); 2.54 (s, 1H, acetylene-H); .26 (m, 1H); 1.98 (m, 2H); 1.83 (m, 2H); 1.64 (m, 2H); 0.84 (s, 9H, Si-t Bu); 0.17 (s, 3H, Si-CH3); 0.15 (s, 3H, Si-CH3). minor: 4.52 (d, J=6Hz, 1H, CH(OMe)9); 3.40 (s, 3H, OCH3); 3.29 (s, 3H, OCH3); 2.51 (s, 1H, acetylene-H); 2.30 (m, 1H); 1.99 (m, 2H); 1.78 Gm, 2H); 1.68 (m, 2H); 0.88 (s, 9H, Si-t Bu); 0.21 (s, 3H, Si-CH3); 0.20 (s, 3H, Si-CH3). TLC (10% EtOAc / hexanes ): SM: .11 major: .42 minor: .38 25 \ EtO =< \ Pd(PPha)4, Cul, PrNHa, NN toluene, RT, 838% | ws [e} z= *, OMe _ = oTBS TMS 2, OMe mM » i , CH(OMe), 3 Eto %, H 11 (racemic) 10 TMS A solution of acetylide 9 (7.5602 g, 25.13 mmol, 1 eq) and propylamine (3.10 ml, 37.71 mmol, 1.50 eq) in 10 ml toluene was prepared in a dry Schlenk flask. Bromide 10 (8.3451 g, 30.32 mmol, 1.21 eq) was stirred with the Pd catalyst (1.4492 g, 1.25 mmol, 0.05 eq, protected from light) in 20 ml toluene for 45 min, then transferred by cannula to the acetylide Solution. After heating to 60°C for 1 h, the mixture was poured into 150 ml saturated NH4Cl/ 60 ml 5% NaHCO3 and stirred for 1 h. Dilution in 1:1 EtOAc / hexanes followed; the aqueous layer was separated and extracted twice. The combined organic layers were washed with saturated NH4Cl, then H20, dried over sodium sulfate, and concentrated under vacuum. The product was purified by flash chromatography (3% EtOAc / hexanes) to give the desired compound in 83% yield (10.2351 g, 20.77 mmol ). FTIR: 1735, 1575, 1255. 'HNMR (500MHz, CDCI3): 6.96 (s, 1H, vinyl-H); 4.62 (d, J=7.4Hz, 1H, CH(OMe)9); 4.27 (m, 1H, CH3CH9); 3.35 (s, 3H, OCH3); 3.34 (s, 3H, OCH3); 2.36 (m, 1H, CHCH(OMe)9); 2.11 (m, 1H); 1.93 (dt, J=7.9, 12.9Hz, 1H); 1.84 (m, 1H); 1.72 (m, 3H); 1.32 (t, J=7.9Hz, 3H, CH3CH3); 0.87 (s, 9H, Si-t Bu); 0.22 (s, 15H, Si-CH3). 26 TLC7% EtOAc / hexanes): MS(DCT): RBr: .34 acetylide: .30 product: .24 448, 262, 240, 225, 183, 169, 73. 27 i aN 1. DIBAL, toluene, \, lil -78°C | 5 OTBS Z OTBS H(OMe)> 2. anaes H(OMe}, a 11 (racemic) (racemic) A solution of 11 (2.3522 g, 4.773 mmol, 1 eq) in 16 ml toluene at -78°C was treated with DIBAL (10.0 ml, 10.0 mmol, 2.1 eq) and warmed to 0°C. After reduction of the ester was complete (10 min), freshly prepared 3N KOH / MeOH (30.0 ml, 90.0 mmol, 18.8 eq) was cooled to 0°C and added by cannula. After 30 min, the reaction mixture was poured into 5:1 H2O / brine, stirred for 10 min, extracted with 1:1 EtOAc / hexanes, dried (Na2SOg4), and concentrated. Purification on a short flash column (20% EtOAc / hexanes) gave 1.5490 g allylic alcohol 12 (4.09 mmol, 86% yield). FTIR: 3436, 3309, 2929, 1598, 1251. HNMR (400MHZ, CeDe): 5.72 (dd, J=1.8, 4.0Hz, 1H, vinyl-H); 4.76 (d, J=6.8Hz, 1H, CH(OMe)2); 3.83 (br s, 2H, CH2OH); 3.28 (s, 3H, OCH3); 3.21 (s, 3H, OCH3); 2.92 (d, J=2.4Hz, 1H, acetylene-H); 2.50 (dd, J=7.1, 8.7Hz, 1H, CHCH(OMe)2); 2.15-2.10 (m, 1H); 1.96-1.62 (m, 5H); 1.03 (s, 9H, Si- t Bu); 0.38 (s, 3H, Si-CH3); 0.31 (s, 3H, Si-CH3). TLC (10% EtOAc / hexanes): SM: .76 intermediate: .15 product: .47 | 28 HH. (+)-DET, Ti(O/ Pr}4, TBHP, OTBS 3A sieves, CH2Clo CH(OMe}, ~ “y -20 —™ -5°C, 65% H 12. (racemic) The catalyst was prepared by adding (+)-DET ( 3.0 ml, 17.53 mmol), Ti(Oi Pr)3 (4.8 ml, 16.13 mmol), and TBHP (37.08 mmol) to a dry flask at -20°C containing 30 ml CH2Cl2 and 0.2 g 3A molecular sieves. After 30 min, a solution of alcohol 12 (1.549 g, 4.09 mmol) in 18 ml CH2Cly at -20°C was introduced by cannula to the catalyst; the reaction mixture was warmed to -5°C. After 24 h, the mixture was warmed to 0°C, added to 300 ml of a solution of FeSO4 (99 g) and tartaric acid (30 g), and stirred for 10 min. The organic layer was separated; the aqueous layer was extracted twice with 100-ml portions of ether. The combined organic layers were then cooled to 0°C and treated with 30% NaOH in brine (30 ml). After stirring for 1 h, the mixture was diluted in H2O; the aqueous layer was separated and extracted with ether. The combined organic layers were dried and concentrated to give 1.5286 g crude product (3.87 mmol, 95% yield). FTIR: 3411, 3310, 2930, 1252. "HNMR (200MHz, CgD6): 4.76 (t, J=6Hz, 1H, CH(OMe)); 3.56 (m, 2H, CH»OH); 3.41 (2s, 1H, epoxy-H); 3.34 (2s, 3H, OCH3); 3.28 (2s, H, OCH3); 2.51 (m, 1H, CHCH(OMe)3); 2.12 (m, 1H): 2.40 (2s, 1H, acetylene-H); 1.90 (m, 5H); 1.10 (2s, 9H, Si- t Bu); 0.44 (2s, 3H, Si-CH3); 0.36 (2s, 3H, Si-CH3). TLC (20% EtOAc / hexanes; 4 elutions): SM: .62 product: .52, .48 29 OTBS Nes CH(OMe)2 pyridine, 60% 14 A solution of alcohol 13 (6.3637 g, 16.13 mmol, 1 eq) in 20 ml pyridine was treated with trimethylacetyl chloride (5.0 ml, 40.60 mmol, 2.52 eq ) at room temperature. After 20 min, during which a light brown precipitate formed, the reaction mixture was diluted in 1:1 EtOAc / hexanes, washed 3 times with H20, dried over Na2SQq, and concentrated. The product was purified by flash chromatography (10% EtOAc /hexanes), giving 4.635 g 14 as a yellow oil (60% yield from alcohol 12). FTIR: 3311, 2957, 2129, 1742, 1251. 1HNMR (500MHz, CeDe): TLC(20% EtOAc / hexanes): MS (DCD: 4.74 (2d, J=6.7Hz, 1H, CH(OMe)2); 4.33 (2d, J=12.3Hz, 1H, OCH2); 3.92 (2d, J=12.3Hz, 1H, OCH); 3.30, 3.29 (2s, 3H, OCH3); 3.28, 3.26 (2d, J=9.0Hz, 1H, epoxy-H); 3.25, 3.23 (2s, 3H, OCH3); 2.43 (dd, J=6.9, 8.7Hz, 1H, CHCH(OMe)3); 2.10 (m, 1H); 1.98 (s, 1H, acetylene-H); 1.92-1.80 (m, 3H); 1.72-1.55 (m, 2H); 1.08 (s, 9H, CO- t Bu); 1.00 (s, 9H, Si-t Bu); 0.38 (2s, 3H, Si-CH3); 0.30 (2s, 3H, Si-CHs3). SM: .17 product: .45 447, 387, 361, 345, 315, 175. 30 H OTBS \gs 1. H2O2, ClgCCO3H, fe) CH(OMe)> CHe2Cla/t BUOH, 0°C = RT _ H 2. DMS, MeOH 85% 14 A solution of epoxide 14 (0.2089 g, 0.436 mmol, 1 eq) in 5 ml CH2Cl2 / 3 ml t BuOH at O°C was treated with 85% H202 (1.0 ml, 35.16 mmol, 81.0 eq, 8.1%) and trichloroacetic acid (0.054 g, 0.33 mmol, 0.76 eq). The homogeneous solution was warmed to room temperature and stirred for 24h. The mixture was then poured into 10% brine / ice and diluted in a minimum volume of 1:1 EtOAc /hexanes. The organic layer was separated and washed sequentially with brine, 1M Na2S203, and saturated NaHCO3. After drying over Na2SOq, it was transferred to a larger flask, treated with 3 ml DMS in 15 ml MeOH, and stirred for 1 h. The solution was concentrated, dissolved in 1:1 EtOAc / hexanes, and washed twice with water. The organic layer was dried and concentrated; purification was by flash chromatography, pretreating the column first with 3% NEt3 / hexanes, then eluting with 10% EtOAc / hexanes, to give 0.1246 g aldehyde 15 (0.299 mmol, 66% yield). FTIR: 3314, 2960, 2743, 1739, 1726, 1251. 'HNMR (400MHz, CgDe6): 9.96 (2d, J=1.7, 2.1Hz, 1H, aldehyde-H); 4.21 (2d, J=12.3Hz, 1H, OCH2); 3.78 (2d, J=12.31Hz, 1H, OCH); 3.17 (2d, J=1.7Hz, 1H, epoxy-H); 2.58 (m, 1H, CHCHO); 2.00 (2d, J=1.7Hz, 1H, acetylene-H); 1.79 (m, 2H); 1.57 (m, 4H); 1.09 (2s, 9H, CO- Bu); 0.94 (2s, 9H, Si-t Bu); 0.28 (2s, 3H, Si-CH3); 0.22 (2s, 3H, Si-CH3). TLC(20% EtOAc / hexanes): SM: .45 peroxides: .37, .33 31 TLC(20% EtOAc / hexanes): SM: .45 peroxides: .37, .33 product: .48 MS(DC)D: 433, 391, 375, 347, 289, 273, 245, 215, 187, 159, 85, 75, 57. Exact mass: calculated: 433.2410281 found: 433.2390000 A= 4.7 ppm 32 DBU, toluene 65% A solution of aldehyde 15 (0.084 g, 0.19 mmol, 1 eq) in 3 ml toluene at 0°C was treated with DBU (1501, 1.00 mmol, 5.3 eq) and warmed to room temperature. After 1.5 h, the mixture was diluted in 1:1 EtOAc / hexanes, washed first with 1:1 saturated citric acid / water, then with water, dried over Na2SOq, and concentrated under vacuum. The crude product was run through a small flash silica gel column (20% EtOAc / hexanes) to give 0.0373 g pure 3 (65% yield). FTIR: 3266, 2973, 2727, 2129, 1739, 1674. 1HNMR (400MHz, C6D6): 10.32 (s, 1H, aldehyde-H); 4.24 (d, J=11.7Hz, 1H, OCH); 3.73 (d, J=11.7Hz, 1H, OCH2); 3.23 (2s, 1H, epoxy-H); 2.32 (t, J=7.5Hz, 2H); 2.18 (t, J=7.5Hz, 2H); 1.89 (2s, 1H, acetylene-H); 1.29 (p, J=7.5Hz, 2H); 1.09 (s, 9H, ¢t Bu). TLC (20% EtOAc / hexanes): SM: .48 product: .32 MS(DCD: 301, 275, 261, 248, 217, 199, 162, 135, 115, 103, 85, 57. Exact mass: calculated: 301.1439844 found: 301.1445000 A= 1.7 ppm 33 4, a tBuCO,~ PhSeNEts, CH2Cle, RT 26% PhSeNH? (approx. 50 eq) was added to a solution of aldehyde 15 (0.021 g, 0.046 mmo!) in 0.2 ml CH2Cl» at room temperature. After 5 h, the solvent was removed under vacuum and the residue purified by prep-TLC (10% EtOAc / hexanes ) to give 0.007 g of 16 (0.012 mmol, 26% yield). FTIR: 3306, 3057, 2956, 2722, 1742, 1705, 1251. THNMR (500MHz, CgDe): 10.07 (2s, 1H, aldehyde-H); 7.54 (m, 1H, p-ArH); 7.14- 6.90 (m, 4H, 0, m -ArH); 4.24, 4.17 (2d, J=12.3Hz, 1H, OCH); 3.83, 3.80 (2d, J=12.3Hz, 1H, OCH2); 3.22, 3.18 (2s, 1H, epoxy-H); 2.50 (m, 2H); 2.12, 2.07 (2s, 1H, acetylene-H); 1.76 (m, 2H); 1.63 (m, 2H); 1.15, 1.14 (2s, 9H, COr Bu); 1.10, 1.09 (2s, 9H, Si-t Bu); 0.42, 0.40 (2s, 3H, Si-CH3); 0.30, 0.27 (2s, 3H, Si-CH3). TLC (10% EtOAc / hexanes; 2 elutions): SM: .40 product: .33 34 {e) H RS > Mn, . t puco,~ tBuCO,~ l ' | H CHO 78°C, 76% %, 15 17 A solution of aldehyde 15 (0.1749 g, 0.404 mmol, 1 eq) in 5 ml THF was cooled to -78°C and treated with a 1-M solution of K-selectride (0.400 mmol, 1 eq). After 10 min, the reaction was quenched with 1 ml of saturated NaHCO3 solution and allowed to warm to room temperature. The mixture was poured into brine and diluted with 1:1 EtOAc /hexanes ; the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over Na2SOq and concentrated. Purification by flash chromatography (20% EtOAc / hexanes) gave 0.1338 g of alcohol 17 (0.308 mmol, 76%). FTIR: 3312, 2958, 2858, 1738, 1463, 1281, 1251, 1143, 1045, 839, 778. IHMNR (400MHz, CgDe): 4.28, 4.23 (2d, J=12.2Hz, 1H, t BuCO2CH2); 3.96-3.93 (m, 1H, CH2OH); 3.81 (d, J=12.2Hz, 1H, t BuCO2CH2); 3.80 (d, J=12.2Hz, 1H, t BuCO2CH2); 3.19 (t, J=0.7Hz, 1H, epoxy-H); 2.20-2.05 (m, 1H, CHCH20H); 1.98 (2d, J=0.7Hz, acetylene-H); 1.87-1.72 (m, 1H); 1.72-1.48 (m, 4H); 1.42-1.28 (m, 1H); 1.10 (2s, 9H, t BuCOz2); 0.96 (s, 9H, Si-t Bu); 0.32 (s, 3H, Si-CH3); 0.21 (s, 3H, Si-CH3). TLC (20% EtOAc / hexanes): SM: .43 product: .21 35 TBAF, THF, 0°C ni 82% Alcohol 17 (0.0667 g, 0.153 mmol, 1 eq) in 2 ml deoxygenated THF at 0°C was treated with 1-M TBAF (0.920 mmol, 6.0 eq). After 40 min, the mixture was partitioned between 1:1 EtOAc / hexanes and brine. The organic layer was separated, dried over Na2SQOq, and concentrated under vacuum. Diol 18 was purified by flash chromatography (40% EtOAc / hexanes) to give 0.0425 g (0.125 mmol, 82% yield). FTIR: 3285, 2966, 1732, 1481, 1282, 1143, 1033. IHNMR (400MHz, C6D6): 4.34, 4.25 (2d, J=12.2Hz, 1H, t BuCO2CH2); 3.86-3.77 (m, 1H, CH2OH); 3.80 (d, J=12.4Hz, 1H, t BuCO2CH2); 3.68 (d, J=12.2Hz, 1H, tf BuCO2CH2); 3.58-3.50 (m, 1H, CH2OH); 3.20, 3.16 (2d, J=1.6Hz, 1H, epoxy-H); 2.13- 2.07 (m, 2H); 1.94 (2d, J=1.7Hz, 1H, acetylene-H); 1.93- 1.87 (m, 1H); 1.64-1.47 (m, 4H); 1.09 (2s, 9H, t-Bu). TLC (60% EtOAc / hexanes): SM: .72 product: .34 36 "Y, tBuCO,~ “ t BuPhaSiCl, imidazole al DMF, 97% 19 A solution of diol 18 (0.0415 g, 0.122 mmol, 1 eq) and imidazole (0.3555 g, 5.22 mmol, 42.8 eq) in DMF (3 ml) at room temperature was treated with BuPh2SiCl (0.160 ml, 0.615 mmol, 5.10 eq) and allowed to stir for 1h. The mixture was poured into 75 ml water and extracted 4 times with 50-ml portions of hexanes. The combined organic layers were dried (Na2SQOq4) and concentrated; the residue was purified by flash chromatography (20% EtOAc / NEt3 / hexanes) to give 0.0684 g alcohol 19 (0.118 mmol, 97% yield). FTIR: 3431, 3319, 3071, 2931, 1740, 1472, 1428, 1391, 1362, 1262, 1113, 938, 822, 738. 1HNMR (400MHz, C6De6): 7.18 (s, 10H, Si-Ph2); 4.28, 4.25 (2d, J=12Hz, 1H, tBuCO2CHg); 4.15-4.08 ( m, 1H, CH2OH); 3.83-3.71 (m, 2H, tBuCO2CH?2 + CH20OH); 3.62 (brs , 1H, OH); 3.22 (br s, 1H, epoxy-H); 2.28-2.60 (m, 3H); 2.04-1.88 (m, 2H); 1.68 (2s, 18H, Si-tBu + tBuCQ2). TLC (40% EtOAc / hexanes): SM: .13 product: .60 37 POC}, pyridine -20°C, 67% A solution of alcohol 19 (0.1341 g, 0.231 mmol, 1 eq) in 5 ml dry pyridine at -20°C was treated with OPCl3 (0.50 ml, 5.36 mmol, 23.0 eq). The mixture was allowed to stir overnight, while slowly warming to 0°C. The reaction was quenched carefully with water, poured into 1:1 water / brine (50 ml), and extracted twice with 100-ml portions of EtOAc /hexanes. The combined organic layers were washed again with water / brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (15% EtOAc / hexanes) gave 0.0866 g (0.154 mmol, 67% yield) of a 4.5:1 mixture of elimination products, of which the major isomer was 20. FTIR: 3283, 3072, 2931, 2858, 2224, 2130, 1959, 1889, 1823, 1739, 1721, 1590, 1473, 1428, 1282, 1149, 1113, 998, 823, 741, 702, 608. JHNMR (400MHz, C6D6): 7.15 (s, 10H, Si-Ph2); 6.08 (d, J=3Hz, 1H, vinyl-H); 4.34, 4.29 (2d, J=13Hz, 1H, t BuCO2CHp2); 3.96-3.80 (m, 1H, CH2OSiR3); 3.87-3.74 (m, 2H, t BuCO2CH?2 + CH2SiR3); 3.31 (br s, 1H, epoxy-H); 2.40-2.32 (m, 1H); 2.28-2.17 (m, 1H); 2.10-2.01 (m, 1H); 1.93-1.84 (m, 1H); 1.75 (2 br s, 1H, acetylene-H); 1.18 (s, 9H, t BuCO2); 1.06 (s, 9H, Si-t Bu). TLC (20% EtOAc / hexanes): SM: .21 product: .46 38 In t Buco, | TBAF, THF, 0°C OSIPh,t Bu 83% 20 21 Silyl ether 20 (0.1111 g, 0.198 mmol, leq) in 3 ml deoxygenated THF at -10°C was treated with a 1-M solution of TBAF (1.00 mmol, 5.05 eq). The reaction was warmed to -59C and allowed to stir overnight. The mixture was diluted in 1:1 EtOAc / hexanes, washed twice with brine, dried over Na2SQOq, and concentrated. Purification by flash chromatography (20% EtOAc / hexanes) afforded alcohol 21 in 83% yield (0.0494 g, 0.163 mmol). FTIR: 3286, 2960, 2224, 2128, 1739, 1481, 1400, 1282, 1143, 1035. {HNMR (400MHz, C6D¢6): 6.01 (d, J=2.7Hz, 1H, vinyl-H); 4.34, 4.28 (2d, J=12.0Hz, 1H. t BuCO2CH2); 4.19 (s, 1H, OH); 3.84, 3.76 (2d, J=12.2Hz, 1H,t BuCO2CH2); 3.61-3.57 (m, 2H, CH20OH); 3.25, 3.23 (2d, J=1.6Hz, epoxy-H); 2.06-1.96 (m, 1H); 2.10 (d, J=1.7Hz, 1H, acetylene-H); 1.70-1.64 (m, 1H); 1.60-1.52 (m, 1H); 1.45-1.41 (m, 1H); 1.35-1.31 (m, 1H); 1.10 (s, 9H, ¢ Bu). TLC (40% EtOAc / hexanes): SM: .70 product: .35 39 4 . tBuCO,~ , mCPBA, NaHCOs, CHCle, 0°C fe) 63% 22 Alcohol 21 (0.0623 g, 0.206 mmol, 1 eq) in 4 ml CHCl, with 0.5 ml saturated aqueous NaHCO3 at 0°C was treated with mCPBA (0.2572 g, 1.490 mmol, 7.2 eq) and stirred vigorously for 2 h. Saturated K2CO3 was added (2 ml), followed by 2M Na2S203 (2 ml), and the mixture was diluted in 1:1 EtOAc /hexanes. After washing with 5% NaOH, the organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (25% EtOAc / 5% NEt3 / hexanes) to give 0.0411 g epoxide 22 (0.129 mmol, 63% yield). IEINMR (400MHz, C6D6): 4.27, 4.21 (2d, J=12.4Hz, 1H, ¢ BuCO2CH2); 3.90-3.82 (m, 1H, CH20H); 3.74, 3.63 (2d, J=12.2Hz, 1H, ¢ BuCQ CH); 3.68-3.59 (m, 1H, CH2OH); 3.31, 3.27 (2s, 1H, ring epoxy-H); 3.16, 3.14 (2d, J=1.6Hz, 1H, diyne epoxy-H); 2.12-2.05 (m, 1H, CHCH20H); 1.50-1.42 (m, 2H); 1.26-1.18 (m, 2H); 1.10 (s, 9H, ¢ Bu). TLC (40% EtOAc / hexanes): SM: .28 product: .18 40 1. TO, i ProNEt, CH2Ch, -78°C 2. PhSeH, -35°C A solution of alcohol 22 (0.021 g, 0.066 mmol, 1 eq) andi Pr2NEt (0.140 ml, 0.804 mmol, 12.18 eq) in 1 ml CH2Cl2 at -78°C was treated with triflic anhydride (0.030 ml, 0.18 mmol, 2.69 eq). After conversion to the triflate was complete (10 min), PhSeH (0.034 ml, 0.32 mmol, 4.8 eq) was introduced and the reaction mixture was warmed to -35°C for 5h. The reaction was quenched with Ig, diluted in 1:1 EtOAc / hexanes, washed twice with water, dried (Na2SOq), and concentrated. The product was filtered through a short plug of silica gel (20% EtOAc /5% NEt3 / hexanes), and used crude for the elimination reaction. FTIR: 3283, 2960, 2928, 2253, 2129, 1738, 1579, 1479, 1282, 1143, 1073, 1022, 890, 801, 738. HNMR (400MHz, C6D6): 7.48-7.42 (m, 2H, Ar-H); 7.02-6.91 (m, 3H, Ar-H); 4.24 (dd, J=12.2, 10.5Hz, 1H, t BuCO2CH9); 3.75, (dd, J=12.2, 4.9Hz, 1H, t BuCO2CH9); 3.66-3.56 (m, 1H, CH2SePh); 3.33, 3.29 (2s, 1H, ring epoxy-H); 3.20, 3.19 (2d, J=1.7Hz, diyne epoxy-H); 2.87-2.79 (m, 1H, CH»SePh); 2.26-2.18 (m, 1H); 1.89 (br s, 1H, acetylene- H); 1.58-1.52 (m, 2H); 1.49-1.42 (m, 2H); 1.08 (s, 9H, t Bu). 41 TLC (40% EtOAc / hexanes): (60% EtOAc / hexanes): SM: .05 triflate: .18 triflate: .23 product: .36 42 1. MCPBA, CH2Clz,-78°C 2. DMS 3. KeCOs3, RT 40% from 22 Crude epoxide 23 in 6 ml CH2Cl2 / 1 ml saturated NaHCO3 at -78°C was treated with mCPBA (0.3199 g, 1.854 mmol, 14.05 eq vs. 22 ). Oxidation was complete after 3h; the reaction was quenched with 1 ml DMS and allowed to stir for 1.25 h. A large | excess of solid K2CO3 was added, and the mixture slowly warmed to room temperature overnight. The mixture was partitioned between saturated K2CO3 and 1:1 EtOAc / hexanes; the organic layer was washed sequentially with water, 5% NaOH, and saturated NaHCO3, dried over Na2SOu, and concentrated. Purification by flash chromatography (10% EtOAc / 5% NEt3 / hexanes) gave 0.0080 g 4 (0.027 mmol, 40% yield from 22). FTIR: 3286, 2924, 2256, 2130, 1736, 1275, 1129. 1THNMR (400MHz, C6D6): 5.75 (dd, J=19.4, 2.3Hz, 1H, vinyl-H); 5.01 (br s, 1H, vinyl-H); 4.28 (dd, J=7.1, 12.2Hz, 1H, t BuCO2CH2); 3.72 (dd, J=6.0, 12.3Hz, 1H, t BuCO2CHz2); 3.65, 3.56 (2d, J=1.3Hz, 1H, ring epoxy-H); 3.20, 3.17 (2d, J=1.7Hz, 1H, diyne epoxy-H); 2.04-1.80 (m, 1H); 1.82- 1.73 (m, 1H); 1.64 (br s, 1H, acetylene-H); 1.52-1.41 (m, 2H); 1.08 (s, 9H, ¢ Bu). TLC (20% EtOAc / hexanes): SM: .36 product: .35 43 OH THO, NEts, OSO2CF, —_— CH2Clo, -78°C —_ I 47% 24 25 A solution of ketoaldehyde 24 (1.0039 g, 8.95 mmol, 1 eq) and NEt3 (2.4 ml, 17.22 mmol, 1.92 eq) in 30 ml CH2Cl at -78°C was treated with triflic anhydride (2.9 ml, 17.24 mmol, 1.93 eq). After 30 min, the reaction was quenched with water, extracted twice with 100-ml portions of diethyl ether, dried over Na2SOq , and concentrated to about 5 ml. The crude product was purified by flash chromatography (20% EtOAc / hexanes) to give 1.0276 g enol triflate 25 (4.208 mmol, 47%). IHNMR (400MHz, CDCl3): 7.41 (m, 1H, vinyl-H); 2.60 (m, 2H); 2.34 (m, 2H); 1.94 (m, 2H). TLC (20% EtOAc / hexanes): SM: .13 product: .37 44 Cul, NEts, fe) Pd(PPhg)2Clo, fe) OSO,CF, THF, RT 78% —_ ——$_<_ oO OTBS OTBS 25 27 A solution of triflate 25 (1.0276 g, 4.208 mmol, 1 eq) and Pd(PPh3)2Clo (0.1205 g, 0.125 mmol, 0.03 eq) in 6 ml THF was added to a stirred solution of acetylide 26 (0.9316 g, 5.469 mmol, 1.30 eq), NEt3 (1.8 ml, 12.914 mmol, 3.07 eq), and Cul (0.0607 g, 0.319 mmol, 0.075 eq) in 6 ml THF. After 1 h, the reaction mixture was poured into saturated NH4Cl solution, extracted twice with 1:1 EtOAc / hexanes, dried over Na2SOq, and concentrated. Purification by flash chromatography (10% EtOAc / hexanes) gave 0.8730 g enone 27 (3.30 mmol, 78% yield). FTIR: 2956, 2858, 2210, 1718, 1618, 1254, 1157, 1086, 837. IHNMR (400MHz, CDCl3): 6.38 (m, 1H, vinyl-H); 4.50 (d, J=1Hz, 2H, CH2OTBS); 2.76 (td, J=7.3, 2.7Hz, 2H); 2.37 (t, J=7.8Hz, 2H); 1.95 (p, J=7.6Hz, 2H); 0.90 (s, 9H, Si-t Bu); 0.12 (s, 6H, Si- CH3). TLC (20% EtOAc / hexanes): SM: .32 product: .45 45 OTBS ; | ie) hv, 2320 nm SS toluene, 18% 27 OTBS 28 Enone 27 (1.0153 g) in 12 ml toluene was irradiated through a 320-nm filter for 45 min with stirring. The solvent was removed, and the isomers separated by flash chromatography (10% EtOAc / hexanes) to give 0.1808 g of cis -enone 28 (18%), and 0.7485 g of recovered 27 (74%). FTIR: 2957, 2857, 1996, 1721, 1613, 1258, 1161, 1083, 837, 779. 'HNMR (400MHz, CDCl3): 5.88 (m, 1H, vinyl-H); 4.55 (d, J=1Hz, 2H); 2.72 (m, 2H); 2.37 (t, J=7.7Hz, 2H); 1.93 (p, J=7.6Hz, 2H); 0.91 (s, 9H, Si-t Bu); 0.14 (s, 6H. Si-CH3). TLC (20% EtOAc / hexanes): SM: .39 product: .29 Difference NOE: OTBS | a 4 46 E oTBS Eto OEt OTBS OEt HO THF, -78°C 81% 28 29 A solution of enone 28 (0.1534 g, 0.580 mmol, 1 eq) in 6 ml THF at -78°C was treated with (EtO)2HCC2Li (prepared from (EtO)2HCC2H (0.420 ml, 2.93 mmol, 5.05 eq) and n BuLi (2.0 ml, 2.94 mmol, 5.06 eq) in 6 ml THF at -78°C). After 30 min, the reaction was quenched cold with saturated NH4CI solution, extracted with 1:1 EtOAc / hexanes, dried (Na2SOq4), and concentrated. Alcohol 29 was purified by flash chromatography (15% EtOAc / hexanes) to give 0.1850 g (0.471 mmol, 81%). FTIR: 3543, 2930, 2858, 2210, 1473, 1255, 1081, 1055, 837, 778. IHNMR (500MHz, CDCl3): 5.57 (m, 1H, vinyl-H); 5.30 (s, 1H, CH(OEt)2); 4.48 (d, J=1.8Hz, 2H, CH2OTBS); 3.76-3.70 (m, 2H, OCH2CH3); 3.61-3.55 (m, 2H, OCH2CH3); 3.48 (s, 1H, OH); 2.55- 2.52 (m, 2H); 2.24-2.21 (m, 1H); 2.10-2.04 (m, 1H); 1.81- 1.72 (m, 2H); 1.22 (t, J=7.1Hz, 6H, OCH2CH3); 0.91 (s, 9H, Si-t Bu); 0.12 (2s, 6H, Si-CH3). TLC (5% EtOAc / hexanes): SM: .34 product: .25 47 Eto OEt oTBS Eto OEt OTBS HO TBSOTI,CH2Ch, = s- tg50 2,6-lutidine oec——s RT A solution of alcohol 29 (0.1850 g, 0.471 mmol, 1 eq) and 2,6-lutidine (1.10 ml, 9.44 mmol, 20.0 eq) in 8 ml CH2Cl2 at 0°C was treated with TBSOTE (0.75 ml, 3.26 mmol, 6.92 eq) and warmed to room temperature. After 1.5 h, the reaction was quenched with 5 ml MeOH, diluted in 1:1 EtOAc / hexanes, washed with water, dried over Na2SOq, and concentrated. Purification by flash chromatography (10% EtOAc / hexanes) gave 0.2348 g of 30 (0.463 mmol, 98% yield). FTIR: 2956, 2929, 2886, 2857, 2211, 1599, 1472, 1360, 1252, 1167, 1122, 1080, 1056, 1006, 838, 778. IHNMR (400MHz, CDCl3): 5.56 (t, J=2.2Hz, 1H, vinyl-H); 5.30 (s, 1H, CH(OEt)2); 4.46 (d, J=2.2Hz, 2H, CH2OTBS); 3.76-3.69 (m, 2H, OCH?2CH3); 3.60-3.55 (m, 2H, OCH2CH3); 2.50-2.42 (m, 2H); 2.09-2.01 (m, 2H); 1.75-1.67 (m, 2H); 1.21 (t, J=7.1Hz, 6H, OCH2CH3); 0.90 (s, 9H, Si-t Bu); 0.87 (s, 9H, Si-t Bu); 0.22 (s, 3H, Si-CH3); 0.19 (s, 3H, Si-CH3); 0.11 (s, 6H, Si-CH3). TLC (20% EtOAc / hexanes): SM: .35 product: .54 48 EtO OEt _oTBS EtO OE OH TBAF, THF,0°C TBSO —_ —_ 87% TBSO 31 30 A 10-ml solution of 30 (0.2348 g, 0.463 mmol, 1 eq) in THF at 0°C was deoxygenated and treated with 1- M TBAF (0.46 ml, 0.46 mmol, 1.0 eq). The reaction was quenched after 10 min with brine, extracted twice with 1:1 EtOAc / hexanes, dried over Na2SOq4, and concentrated. The crude product was purified by flash chromatography (10% EtOAc / hexanes) to give 0.1584 g alcohol 31 (0.403 mmol, 87% yield). THNMR (400MHz, CDCl3): 5.54 (m, 1H, vinyl-H); 5.35 (s, 1H, CH(OEt)2); 4.43-4.29 (m, 2H, CH2OH); 3.82-3.71 (m, 2H, OCH2CH3); 3.65- 3.56 (m, 2H, OCH2CH3); 3.09 (t, J=8Hz, 1H, OH); 2.60- 2.51 (m, 1H); 2.44-2.33 (m, 1H); 2.14-2.07 (m, 1H); 2.03- 1.95 (m, 1H); 1.87-1.76 (m, 1H); 1.73-1.64(m, 1H); 1.25 (m, 6H, OCH2CH3); 0.86 (s, 9H, Si-t Bu); 0.25 (s, 3H, Si-CH3); 0.22 (s, 3H, Si-CH3). TLC (20% EtOAc / hexanes): SM: .72 product: .26 49 OEt EtO Eto OEt OH CHO oxalyt chloride, DMSO TBSO NEts, CH2Clo, -78°C TBSO 75% 31 32 DMSO (0.150 ml, 2.11 mmol, 73 eq) was added to a solution of oxalyl chloride (0.10 ml, 1.15 mmol, 40 eq) in 2 ml CH2Cly at -78°C, causing gas evolution for 1 sec. Alcohol 31 (0.0115 g, 0.029 mmol, 1 eq) in 1 ml CH2Clo was introduced; the mixture was stirred for 15 min, then treated with NEt3 (0.5 ml, 3.59 mmol, 124 eq). After 15 min, the reaction was warmed to 0°C, stirred for 10 min, then partitioned between brine and 1:1 EtOAc / hexanes. The organic layer was separated, dried over NazSOq, and concentrated. The residue was run through a short flash column (20% EtOAc / hexanes) to give 0.0085 g aldehyde 32 (0.022 mmol, 75% yield). FTIR: 2955, 2856, 2177, 1661, 1630, 1472, 1251, 1169, 1020, 1054, 1013, 839, 779. IHNMR (400MHz, CDCl3): 9.38 (s, 1H, aldehyde-H); 5.69 (br s, 1H, vinyl-H); 5.31 (s, 1H, CH(OEt)2); 3.74-3.68 (m, 2H, OCH2CH3); 3.60- 3.55 (m, 2H, OCH2CH3); 2.60-2.53 (m, 2H); 2.23-2.05 (m, 2H); 1.82-1.74 (m, 2H); 1.22 (m, 6H, OCH2CH3):; 0.86 (s, 9H, Si-t Bu); 0.27 (s, 3H, Si-CH3); 0.22 (s, 3H, Si-CH3). TLC (20% EtOAc / hexanes): SM: .42 product: .47 50 EtO Oet CHO CHO CHC, Me | | OL. I | 1. PCls, tBu~ “N° “tBu TBSO CHL, 0°C ____—-TBSO —_— — 2. NH4Cl, 57% 32 A solution of aldehyde 32 (0.0992 g, 0.254 mmol, 1 eq, dried with toluene) and ditbutylmethylpyridine (1.60 ml, 6.93 mmol, 27.27 eq) in 16 ml CH2Cl2 at 0°C was treated with PCls5 (0.260 g, 1.248 mmol, 4.91 eq) in 4 ml CHCh. The reaction was quenched cold after 10 min with saturated aqueous NH4Cl and extracted with 1:1 EtOAc / hexanes. The organic layer was separated, washed with water, dried (Na2SO4), and concentrated. Purification by flash chromatography (100% hexanes to 10% EtOAc / hexanes) afforded aldehyde dichloride 5 in 87% yield (0.0821 g, 0.221 mmol). FTIR: 2956, 2857, 2216, 1674-1668, 1472, 1253, 1084, 839, 779, 722. 1HNMR (500MHz, CDCl3): 9.28 (s, 1H, aldehyde-H); 6.43 (d, J=1.8Hz, 1H, CHCl2); 5.69 (m, 1H, vinyl-H); 2.67-2.60 (m, 1H); 2.53-2.44 (m, 1H); 2.17-2.10 (m, 2H); 1.92-1.73 (m, 2H); 0.88 (s, 9H, Si-t Bu); 0.29 (s, 3H, Si-CH3); 0.23 (s, 3H, Si-CH3). TLC (10% EtOAc / hexanes): SM: .31 product: .40 51 OTMS 172.794 6 xT yl | 4 I | | 4 4 { -411.33 1 1 T T T T T T 4000 3500 3000 2500 2000 4500 4000 cm! 500 52 OMe OMe 74 Ges 53 300 140 go S22B8eBEIGe = xl_—«Agd=1222-JUN-88 BB:5+-81°35 —78E El BpM=@ = =t.ly Hee@ ——T1C=87344000 Acnt UCR Sys: 7878 HAR: = 7339088 AYERS FUNDY CCIT) $6) 78€Y PT= @° Cal 62208818 ASS 75 188, 45 95] 90. 95 | O 96 | 754 704 , OMe OMe 65 J 7 66 55 58 | 45 | 404 5 6 1 ub Lily y— tl min i dda 48 68 88 108 128 148 168 188 288 cee 248 54 xt sa « e a3 Fil <2 6 ; bo : 1 L 381i} 8 2s Fi -_ z \ a =< 27. § a ee a [ +o 1 Z r™ oF Fy qs Le 9 t i : b L te i LL r i} “ r MULTIPUER TIME CONSTANT SCANTIME 8. SUT PROGRAM _ | Lil or 1600 5 = + i nee nee ee L 1800 2000 REMARKS R major isomer -{ minor isomer — — 2500 CONCENTRATION _. CELL PATH REFERENCE | lf i SOLVENT __. .. fan 3000 WAVENUMBER(CM—'} ili L 3500 SAMPLE Pens ONG. | 200 55 MICRONS PRY 1000 1200 1400 1800 2000 2500 3500 Bea L 2 ° aa 22 =§ [ im b ! Ln Tle 1 t = | L wy i F = V4 r 3] « ly bo 2 a x 8 | . o 1 | i toy it i \ } I] H b ry ol | : Lin z, f a.e8. _ t 8225 @ r fzeg. [wo ere = ‘ Q b 3 eo) f * ” [ _ _ eo) Vf inal L wo & | w r L L - : Ln | ‘ KN = { i | i: r 1 | ' roy I r i : 1 r i - iy . - } S| a5. ew SZ ls -- oa Sat os|/8S 8 2 7S r S$ if > ~ Pa ate %. @ J isomer r iso mino u \ JSS ae z c ce ve. Zz. 1000 WAVENUMRERICM *') 100 VENUMBER(CM- *} HAR ‘ E i E ] | \ i} t { i {& ss le E #8 ra ge a = H i = < & 2 of: : 3 z 5 z g < = £2 ard 22 - ec ef fot arene fP- A L eas BRS La Dna A ee ee 3.0 2.5 2.0 1.5 1.0 5 0.0 -.5 3.5 PPM es Sin ie das ton ion nn en ie ie ne ee ee ee ee ee 5.0 4.5 4.0 5.5 7.0 6.5 6.0 7.5 Pg rr ry as a 57 HO Ll t I 1 1 1 1 ] afar{e? 4000 3500 2800 2000 1600 1200 800 600 Nes} CM-4 ; / t tf uJ c [ PPM | T T T Tt ~~ oT ae ~ | | / - } i / [re a T 7 T T T T | t 5 4 f } ; | | | | { ¢ rd ; i we . V | PPM T ¥ T T T t T T T T T T T T T T T T [ T T T T T T T T T T T T 4 } e i Q 58 674 2000 Ort i 8.00 4 000 ‘ -o 2 ! 3 ee 59 Ma, tBucO2 oTBS CH(OME)z 14 | wet t H 1 Be } 4202 3600 2800 2000 1800 4200 704 ces T T aa T v ¥ T T 4.50 4.00 3.50 - 3.00 2.50 2.00 PPM 8.5 6.0 7.5 7.0 6.5 6.0 5.5 5.0 4.0 3.5 3.0 2.5 2.0 4, 0.5 60 168, 35 J 98 J 85 | 88 | Ay 78, 65 J 68 | 35 be 149 by 175 345 158 288 ty, tBuCOs~ OTBS CH(OMe)e H 14 61 U .____., gf 3 62 ke re ak 588 63 4 = L l 1 1 j qoee 300 3800 2006 1500 1200 TOO CAA r T ‘ T Toren 4.0 3.0 2.0 t ‘ T iu q ‘ T v q T T J q v T T t ‘ T r 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 PPM 64 ——_ = = 65 8, 135 275 5] 248 58 188 158 288 208 388 386 488 90.52 ST 78.95 (Peaks | 1044.9 cmt 4 65.077 T T T T T T T 4000 3500 3000 2500 2000 41500 1000 cm! anne ee eee ee 9 8 7 C 5 67 ' “a7.33-4 st 67.44 T T T y y ¢ 4000 3800. «= 3000S 500-—S—S—«2000 1500 1000 all np a 1 een ae ie 2 4 6 5 i ne es ne a 7 68 —r T T T —— T 4 TT 3 F La ee — T — an na ne mt TT 7 G yO 5 4 3 2 69 @9. 38-4 aT | 4 j H ) ‘ 4 H \ i . | 758-4 OSiPhot Bu 20 4000 1000 em! Ue Toycrce or 0 aan — i oe TT tr re eee TT ae esr ae 5 3 é 1 70 89.66 aT 60.63-+-—— t 1 t 41500 4000 em! 4000 3500 3000 2600 2000 PPM 71 TO ee 4 | ere prereneece apci peaer epee T r TI oor 4 a } id . 4 j , 72 88. 18- 4000 cat (Orere try peer perry pore ry ree scerprenepreyereceepere spores pve se cprereprerepenrs peereperyepereeperciy ore peeve peavepeere eit 4342 4) 40 Feo $4 sr be ne ph ey ae ¢ PM 29 PH FP eT aL LE Oe, ly Gs ai Ts Chr pore rg rr rrr peep er per . fined /.4 fot fog ? oy im i 7.0 a Ga 1PM Tr re pn ry pe ppt mp rt pea pe poe pe te pa : 4 a A & 5 4 4 c l t 73 t BuCO2 74,43 3500 3000 2500 2000 1500 1000 cat tana " "i J ile Noy rents Creepers greateennirnrpres genes peerigtcng rer iorttsree prey pore ses rpreryprensprere ten prem pian crear ct it i z 1 | 1 od Lopomer Spo em epee pepe ect tor y 5 4 J PPM vor 74 OSO2CF3 — 25 f° m Tepeererrrrt Tere Oar Pore rr errrp rr creer PTT pit EVETT TET S PPEV TET PPP rrr erry erry ce OTBS a ng LS Se ee epatdiataetatiaet-- me setae, ES ee ca! T 1000 T 1500 T T 2500 2000 3000 T 3500 20.44 yet i SrA TA Td A Ld Lae > qtr PEEL EET ETRE TT TT TTT TET PPT CTY PETE e © >» e 1 ¢ 76 OTBS ee) wo | xT ee" i (\ i a | | ly ) 3s ; | a 46.17 T t t T T T 4000 3500 3000 2500 2000 1500 1000 cat Ve Lae” my bom 546, oy Or ae - toy 4 a7 a4 aegad 4.414 a 'f / if “aaa ray 4 ‘ Due dota fe de eer lettn eS Ce! = lt TL eprevertperresm aya PPC ECUDPeeorrr rstiaptererinerprreeerert ‘ we ' : } , © 4 4. a6 SACASA SEARLS DAASED AU OA UASERUOEAS SOR ABAOR SI ASRER AA ARSGAGARA0000 COERAEEAO I “oe ey ‘ ¢ oe 1s PEPE TPP rer ret Perea Peer ery c 5 be 77 92.40 RT 42.39- T T T T 1 T > 4000 3500 3000 2500 2000 4500 2000 cm F T T —~ T T T 1 T T + - 3.8 3.6 a4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 - = [eliediei iis mete oe wyatt qa BO 7.5 7.0 6.5 60 95 5.0 4.5 AI EtO O€&t OTBS 29 spo ps 0.0 78 EtO OEt OTBS P-E 83.674 4 TBSO 30 38.62-+— T T T T t r 4 4000 3500 3000 2500 2000 41500 1000 cma | ! \ i iperrnir 1 [ fenaeiy remy Tse ream grerapverne reer pree eer pe rereg fm AA eer ge ‘ fot ford Fede ad at aa ea lave Gays ing hade sted lace che foto te dee eles bode b spite en oe vo a Sad a - cme a oan 7.5 7.0 6.5 6.0 5.5 5.0 45 4.0 3.9 3.0 2.5 2.0 1.5 1.0 06 0.0 79 = SJ EtO OEt OH TBSO 31 80 Ae ah AL uh Le 81 CHO CHCia TBSO 40.044 t T or a: - T —T 4000 3500 3000 2500 2000 41500 | ' as a CT pores ' ‘ 24 24 aod ail faze) 1.9 Lon . a = ML a _ __ - TeTePP pT Prersrreprr een eee eri eerp rere rere pre rrers ERTL POTEET PTT PRETTY Ve 1 ' = fe , bn eral Hou 45 41 ao 41000 cm! PPM ttt beM PRTeRRTEDTOTTT TTY POPE CTT eres Pet eT es PTET CPP T PETES [TTT EEE PRET TPT Tf? eu 14 Le wh ae 82 Appendix MILD CONDITIONS FOR THE REMOVAL OF ACID-LABILE PROTECTIVE GROUPS Andrew G. Myers,* Mary Ann M. Fundy and Peter A. Lindstrom, Jr. Contribution No. 7819 from the Amold and Mabel Beckman Laboratories of Chemical Synthesis California Institute of Technology, Pasadena, California 91125 Summary: Hydrogen peroxide-trichloroacetic acid is an effective reagent combination for the mild cleavage of acid-labile protective groups. In the course of research directed towards a synthesis of neocarzinostatin chromophore and related compounds, we required a means to transform the dimethyl acetal 1 into the aldehyde 2.) An extensive survey of aqueous acid-cosolvent combinations failed to reveal conditions which would effect hydrolysis of the dimethyl acetal group of 1 without competitive opening of the epoxide ring. The ability of hydrogen peroxide to enter into acetal exchange reactions has long been recognized, though reported reaction conditions (acetal and hydrogen peroxide, neat, 70 °C, 15 h)? have perhaps dissuaded wider exploration of the method. We find that 1 is cleanly transformed into the mixed hydroperoxy methyl acetal (stereochemistry not determined) upon treatment with 70% hydrogen peroxide (caution--see below)-trichloroacetic acid in 1:1 t-butyl alcohol-dichloromethane at 0-23 °C. This hydroperoxide was stable to isolation and could be purified by flash column chromatography, but for convenience and safety was typically directly reduced by treatment with methanolic dimethyl sulfide solution,? providing the aldehyde 2 in 80% (overall) yield after chromatographic purification. The presence of water in the H Ox; Buco,” | | NN 70% HpO2, ClaCCO2H H OCH, CH2Cb, EBUOH (CHa)2S, CH30H TBSO OCH3 + Dedicated to the memory of our friend and colleague, Peter A. Lindstrom, Jr. 83 reaction mixture is markedly deleterious; use of 90% hydrogen peroxide leads to faster reaction with a slight increase in yield whereas reaction with 30% hydrogen peroxide is prohibitively slow and epoxide- ring-opening is observed. The substantial hazard in working with the former reagent and its removal from the commercial market have led us to develop our procedure around the commercially available (FMC), and safer, 70% solution. A particular advantage of this sequence are the mild conditions of final deprotection;3 neither aldehyde epimerization nor elimination of the B-silyloxy group are observed. By contrast, subjection of the acetal 3 to acidic hydrolysis conditions (1 M p-toluenesulfonic acid, 3:1 THF:H20, 23 °C, 3 days) produces competitively the o,B-unsaturated aldehyde 4. It should be noted that this alternative preparation of hydroperoxy alkyl acetals provides access to a number of useful oxidative transformations as well.4 We have also found that the tetrahydropyranyl group of 5 (9 h, 80%)! and the trityl group of 6 (24 h, 85%)° are smoothly removed under similar reaction conditions, suggesting potential for wider application of the method in the removal of acid-labile protective groups and indicating that complications arising from free-radical or peracid impurities are, at best, minor. H H CeHs(CHa)an ee CeHe(CHa)a. ee TMS %, N \ ~ | | TMS | | TMS | TBSO OCHs 0 SS OCH 4 CHEOTHP —(Cet4e)400 4 5 6 Extreme caution should be exercised in handling mixtures of organic materials and high-strength hydrogen peroxide.6 Explosions have resulted upon distillation of hydrogen-peroxide-treated tetrahydropyranyl ethers.’ For this reason we have made it a practice not to concentrate organic solutions which have been in contact with hydrogen peroxide without first treating with dimethyl sulfide-methanol and then only after obtaining a negative indication with EM Quant® Peroxide Test Paper.7 All manipulations with high-strength hydrogen peroxide solution should be carried out behind a good safety shield. Employing these and other safety precautions, described in greater detail in the experimental procedure which follows, we have never experienced a mishap in the laboratory. The superior nucleophilicity of hydrogen peroxide (relative to water)® is evident in the smooth transacetalization of 1 under conditions too weakly acidic for reaction with water. A more subtle distinction is the difference in relative rates of attack exhibited by these two nucleophiles towards the epoxide and acetal groups of 1.9 With care in execution, we feel that the procedure described herein provides a useful addition to existing methods for the removal of acid-labile protective groups.1° Experimental All manipulations with hydrogen peroxide and peroxide-treated solutions are carried out behind a sturdy blast shield. A 50-mL round-bottom flask was charged with dimethyl acetal 1 (327 mg, 0.683 mmol), anhydrous t-butyl alcohol-dichloromethane solution (1:1, 15 mL) and a teflon-coated magnetic stir bar which had been carefully cleaned to remove adhering metal contaminants. The mixture was cooled in an ice bath and 70% hydrogen peroxide solution (FMC, 2.80 mL) was administered slowly from a 5-mL glass syringe fitted with a polyethylene needle (gloves should be worn as hydrogen peroxide causes severe chemical burns). A solution of trichloroacetic acid in anhydrous dichloromethane (3 M, 0.36 mL, 1.6 equiv) was added and the ice bath was removed. After stirring at 23 °C for 35 h, the clear, homogeneous solution was carefully poured into ice-cold brine (100 mL). The organic layer was brought to 60 mL volume by the addition of 1:1 ethyl acetate:hexanes and the layers were separated (this and all subsequent aqueous layers were treated with 2 M aqueous sodium thiosulfate solution prior to disposal). The organic layer was washed again with ice-cold brine (100 mL), then slowly added to an ice-cold mixture of 1 M aqueous sodium bicarbonate solution and 2 M aqueous sodium thiosulfate solution (1:1, 100 mL). After separation, the organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL) and then treated with methanolic dimethyl sulfide solution (5:1 methanol:dimethy] sulfide, 24 mL). The progress of hydroperoxide reduction was conveniently monitored by thin-layer chromatography (Rf values 0.45, 0.35 and 0.48, respectively, for 1, the hydroperoxy methyl acetal and 2, 20% ethyl acetate-hexanes) and was judged complete after 45 min. Peroxide analysis at this point with EM Quant® Peroxide Test Paper was negative. The solution was concentrated and the product purified by flash column chromatography (87:10:3 hexanes:ethyl acetate:triethylamine) to provide the aldehyde 2 as a colorless oil (236 mg, 80%). 85 Acknowledgement Generous financial assistance from the National Institutes of Health (CA-47148-01) and Merck & Co., Inc., a Dreyfus New Faculty Award (to AGM) and a Summer Undergraduate Research Fellowship (to PAL) are gratefully acknowledged. References (1) Our synthetic materials, here designated as 1 and 2, are composed of a 1:1 mixture of diastereomers, cis about the cyclopentane ring with S,S epoxide stereochemistry. Preparation of compounds 1, 3 and 5 will be described elsewhere. (2) Rieche, A.; Bischoff, C. Chem. Ber. 1961, 94, 2722. (3) Pappas, J.J.; Keaveney, W.P.; Gancher, E.; Berger, M. Tetrahedron Lett. 1966, 4273. (4) Schreiber, S.L.; Liew, W-F. Tetrahedron Lett. 1983, 2363. (5) Blickenstaff, R.T. J. Am. Chem. Soc. 1960, 82, 3673. (6) Shanley, E.S.; Perrin, J.R. Jet Propul. 1958, 28, 382; available within FMC Technical Bulletin 46. (7) Meyers, A.L; Schwartzman, S.; Olson, G.L.; Cheung, H-C. Tetrahedron Lett. 1976, 2417. (8) Hiatt, R. In Organic Peroxides; Swern, D. Ed.; Wiley: New York, 1971; Vol. 2, Chapter I. (9) For interesting examples of relative rate differences in base-catalyzed reactions of hydrogen peroxide and water, see: Evans, D.A.; Britton, T.C.; and Ellman, J.A. Tetrahedron Lett. 1987, 28, 6141. (10)The a-effect nucleophile semicarbazide has recently been used for acetonide removal in an advanced intermediate in the total synthesis of Forskolin: Corey, E.J.; Jardine, P.D.S.; Rohloff, J.C. J. Am. Chem. Soc. 1988, 110, 3672. 86