Total Syntheses of Ginkgolide B O HO O HO O H O t-Bu Me O HO O O H Brooks Maki May 23, 2005 Outline • What? – Background of Ginkgolides • Why? – Points of interest concerning Ginkgolide B • Who? (When?) – Corey’s racemic synthesis (1988) – Corey’s enantioselective synthesis (1988) – Crimmins’ racemic synthesis (2000) • How? – 2 total syntheses – 1 formal synthesis Isolation and Characterization • Ginkgolides A, B, C, and M were isolated from O HO O the root bark of Ginkgo biloba by Furukawa in R2 O H O 1932. t-Bu Me O R1 • Nakanishi and co-workers identified structures R3 of these diterpenes in 1967. O O H Ginkgolide A - R1 = OH, R2 = H, R3 = H Ginkgolide B - R1 = OH, R2 = OH, R3 = H • Also in 1967, Okabe and colleagues published Ginkgolide C - R1 = OH, R2 = OH, R3 = OH X-ray crystallography studies confirming Ginkgolide M - R1 = H, R2 = OH, R3 = OH structure and absolute stereochemistry of the Ginkgolide J - R1 = OH, R2 = H, R3 = OH ginkgolides. H O O O • Bilobalide (in 1971) and Ginkgolide J (in O O 1987) have been discovered as other members OH O t-Bu of the ginkgolide family. H OH Furukawa, S. Sci. Papers Inst. Phys. Chem. Res. Tokyo 1932, 19, 27. Bilobalide Nakanishi, K. Pure Appl. Chem. 1967, 14, 89-113. Sakabe, N.; Takada, S.; Okabe, K. J. Chem. Soc., Chem. Commun. 1967, 259-261 Ginkgo Biloba: The Source • Oldest fossil records from 270 million years ago • Basically unchanged since the Jurassic period. • Extracts known to have medicinal value for nearly 2500 years (China, Japan, and India) • Survived atomic blast at Hiroshima in 1945. Medicinal Value of the Ginkgolides • Anti-inflammatory • Prevent blood clotting (improves circulation) • Antagonists of Platelet Activating Factor Receptor (PAF) • Potent and selective antagonists for inhibitory glycine receptor • Possible neuroprotective effects (Alzheimer’s, dementia) • EGb761 - extract of Ginkgo biloba containing 6% terpene trilactones (ginkgolides and bilobalide) – Sales exceed $500 million worldwide Jaracz, S.; Nakanishi, K.; Jensen, A.; Strømgaard, K. Chem. Eur. J. 2004, 10, 1507-1518. Vogensen, S.B.; Strømgaard, K.; Shindou, H.; Jaracz, S.; Suehiro, M.; Ishii, S.; Shimizu, T.; Nakanishi, K. J. Med. Chem. 2003, 46, 601-608. Ginkgolide B: The Molecule • Six 5-membered rings – Spiro[4.4]nonane O – 3 lactones HO O – 1 tetrahydrofuran ring HO O H O * * • Cage structure * * * t-Bu • 11 stereogenic centers * * * * O Me * – 4 tetra-substituted HO * stereocenters O O H – All 5 carbons of the A ring • tert-Butyl group Corey’s Total Synthesis of (±)-Ginkgolide B O O HO O HO O HO HO O O F O O t-Bu t-Bu C A E Me O Me OB HO HO D O O H O O H Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649-651. Nicolaou, K. C.; Sorensen, E. J. Classics In Total Synthesis. 1996. 451-464. Desai, M. C.; Ghosh, A. K.; Kang, M.; Houpis, I. N. Strategies and Tactics in Organic Synthesis. 1991, 3, 89-119. Corey's Retrosynthetic Analysis MeO O MeO O HO O O HO HO O O O t-Bu O t-Bu t-Bu O Me O Me O O HO HO O O H O O H O O H MeO O MeO O t-Bu O MeO t-Bu O O H O MeO O MeO O H O t-Bu O t-Bu t-Bu HO O O H CO2H Spirocyclic B-F ring system OMe OMe O MeO O 1. t-Bu2Cu(CN)Li2, 1. OMe o o OMe N MeO Et2O, –78 C ! –45 C toluene O TMSO t-Bu 2. TMSCl, Et3N, 2. HCl o o 75% –45 C ! –10 C O OMe MeO O O HO O HO OMe , TiCl4 O O O O O t-Bu TMSO t-Bu o Me O CH2Cl2, –78 C t-Bu 65% 3 steps HO O O H LA TiCl4 O O O OMe OMe MeO H LA LA O H H O O OMe O O OMe t-Bu H O O t-Bu O t-Bu t-Bu Me3Si MeO OMe [2+2] Cycloaddition MeO O MeO MeO LDA, DME, O Me O O O –78 ! 0 oC; O O TfO t-Bu PhNTf2 Pd(PPh3)4, CuI, t-Bu o t-Bu OBO 0 C ! RT n-PrNH2, benzene 80% 84% MeO MeO O O MeO 1. Cy BH, THF, 0 oC O 2 1. (COCl)2, benzene t-Bu t-Bu 2. AcOH; H2O2, pH 10 t-Bu 2. n-Bu3N, toluene 3. HCl (pH 3 ! 11 ! 3) 80% OBO 86% H H CO2H O Inside the [2+2] Ketene - Olefin Cycloaddition MeO MeO MeO O O O 1. (COCl)2, benzene t-Bu t-Bu t-Bu 2. n-Bu3N, toluene 80% H H H CO2H O O MeO MeO MeO O O O t-Bu t-Bu t-Bu H H H H O O O MeO MeO O MeO O PEROXIDE O A : B peroxide, t-Bu t-Bu NaOH t-Bu HOOH 1 : 1 acetone, –30 oC H H Me3COOH 3 : 1 86% A O B H H H O O H exclusively A O O Ph3COOH E Ring Through Intramolecular Photolysis MeO OMe MeO H h!, (tungsten) O O O Pb(OAc)4, I2, pyr. H H H 1,2-dichloroethane O H O t-Bu OH t-Bu O t-Bu o 25 C, 10 min. O H H O O 80% O O no desired product observed t-butyl group pseudoequitorial Lowest energy transition structure for the desired product was calculated to be 5.2 kcal/mol higher than the lowest energy transition structure leading to the observed product. Replacement of t-butyl group with hydrogen causes the transition state leading to the desired product to be favored by Ground State of starting material 1.9 kcal/mol Houk, K. N.; Tucker, J. A.; Dorigo, A. E. Acc. Chem. Res. 1990, 23, 107-113. Moving in the General Direction of the E Ring O MeO HO O O HO S S O O t-Bu HS SH OH t-Bu t-Bu O TiCl , CH Cl , 0 oC Me H 4 2 2 HO quant. H O H O O H O O O H PDC = pyridinium dichromate o MeO O 1. HIO4, –30 C ! RT, S S S S MeOH, CH Cl , OMe PDC, AcOH 2 2 OH t-Bu O trace H2O o t-Bu 4Å sieves, 0 C t-Bu 75% 2. CSA, MeOH H H H 80% O O H O O H O O H O MeOH HO O CSA O t-Bu t-Bu H O H SO H H 3 O O O O H E Ring Construction MeO H MeO O MeO O O OMe 1. LiNEt2, THF OMe o o t-Bu –25 C ! 0 C t-Bu CSA t-Bu O O 2. CH2Cl2 H HO NSO2Ph 75% 3 steps H Ph H O O O O O O H N Et Et MeO MeO O O OMe OMe OMe O t-Bu t-Bu t-Bu HO Ph OLi O Ph O H PhO2S N H O H O O N LiO O SO2Ph Oxaziridine undergoes addition to the more accessible convex face A Short Detour MeO H MeO O O MeO O OMe Davis oxaziridine OMe CSA, solvent t-Bu t-Bu t-Bu O A H HO O O H H O O O O H + 2 : 1 separable mixture O of epimers Starting Material Solvent A : B Major epimer MeOH 1 : 1 OMe Minor epimer MeOH only B t-Bu O Major epimer DCM only A B O O H Minor epimer DCM 3 : 1 An adumbrative example: Treatment of the minor epimer with CSA in CH2Cl2 produced the epimer of A as the O major product. Epimerization was effected MeO H by treatment with CSA in MeOH. OMe 1. dioxane, CSA O sealed tube, 120 oC t-Bu t-Bu O 2. CSA, MeOH O adumbrative: adj. indistinctly prophetic; foreshadowing O O H O O H Allylic Oxidation via a Mosaic Route MeO H MeO H MeO H MeO H O O O O Br h!, NBS t-Bu t-Bu t-Bu t-Bu O o Br O O O CCl4, 10 C Br Br 80% H O O H O O H O O H O O 1 : 3 : 6 10M AgNO3, MeCN PPTS = pyridinium p-toluenesulfonate MeO H MeO H MeO H O O O O NO O 2 PPTS, pyr. t-Bu t-Bu t-Bu t-Bu O O O o O chlorobenzene, 135 C O O2NO O 40% from irradiation O O H O O H O O H O O H 1. Zn, AcOH 2. PDC, CH2Cl2 1. 20 eq. DBU, 20 eq. H2O, benzene / methanol 2. PDC, CH2Cl2 Installation of the C Ring O O O O Ph3COOH, O O Me O BnMe3Ni-PrO, t-BuO t-BuO t-Bu THF, –10 oC t-Bu t-Bu LDA, THF, O O Me O O (MeO)3P O HMPA HO o o O O H 72% O O H –78 C ! –30 C O O H 68% dr = 8 : 1 CSA CH2Cl2 O O O OH OH O H O H t-BuO O O O t-BuO t-Bu H2O t-Bu t-Bu Me O – t-BuOH Me O Me O HO HO HO O O H O O H O O H 92% Finally Finishing - Facile Functionalization of the F Ring HO O HO OH O O O H TBSO TBSO TBSOTf, O O O t-Bu O OsO4 2,6-lutidine t-Bu O t-Bu Me O pyridine CH CN Me O Me O HO 3 65% 89% HO HO O O H O O H O O H HO O O HO O HO O TBSO TBSO HO O O I , CaCO , O HO O 2 3 O O t-Bu t-Bu BF3•OEt2 O MeOH t-Bu Me O Me O dr = 2 : 1 CH Cl O HO HO 2 2 Me 89% HO O O H O O H O O H Ginkgolide B Corey's Total Synthesis from 4-cyclopentenylmorpholine - 32 steps, 0.31% overall yield Enantioselective Synthesis of Ginkgolide B O O O O HO 10 mol% CBS O OMe OMe t-Bu BH3•THF t-Bu O t-Bu OMe NEt , DMAP OMe THF OMe 3 88% CH2Cl2 OMe 93% ee 91% Ph t-BuMgCl H Ph 3 mol% CuCN o O ether, –20 C N B 87% Ph Me H Ph OMe chiral oxazaborolidine O catalyst OMe N B t-Bu H B 3 Me Ph Ph H Ph H Ph O H OBH2 HO O N N B Me BH OMe B Me H B 3 2 O H2B H OMe H O OMe MeO OMe OMe MeO MeO Corey, E.