Total Syntheses of 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 • 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 • (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 (PAF) • Potent and selective antagonists for inhibitory 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 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 / 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. J.; Gavai, A. V. Tet. Lett. 1988, 29 (26), 3201-3204. Enantioselective Synthesis of Ginkgolide B

HO O OMe OMe OMe 1. BH3•THF PDC OMe o 2. H2O2 OMe 4Å sieves, 0 C OMe t-Bu 89% t-Bu CH2Cl2 t-Bu 79% KH, TBSCl 94% O O O OMe 1. TiCl , TBSO t-Bu steps O 4 O CH Cl , –78 oC OMe O 2 2 2. MeOH OMe O O H 68% t-Bu t-Bu enantiopure ABDF ring system

Purity established by NMR in the presence of the chiral shift reagent (+)-[Eu(hfc)3]. Racemic mixture showed two t-Bu peaks while product of the above route showed only one. Crimmins’ Synthesis of (±)-Ginkgolide B

O Me O Me OH OH O C O O O H O H O O D O H E H HO HO O B F O

t-Bu t-Bu OH O OH O

Crimmins M. T.; Pace, J.M.; Nantermet, P.G.; Kim-Meade, A.S.; Thomas. J.B.; Watterson, S.H.; Wagman, A.S. J. Am. Chem. Soc. 1999, 121, 10249-10250.

Crimmins M. T.; Pace, J.M.; Nantermet, P.G.; Kim-Meade, A.S.; Thomas. J.B.; Watterson, S.H.; Wagman, A.S. J. Am. Chem. Soc. 2000, 122, 8453-8463. Retrosynthetic Analysis a la Crimmins

Me O O O O H O OH OMe O OH O O H O O O O O O O OMe OMe H O OH OH HO t-Bu t-Bu OH t-Bu

O O O CO2Et EtO C CO2Et O 2 O

OH t-Bu HO OTMS t-Bu t-Bu Synthesis of the Photosubstrate

O Ph3P CHCO2Et t-Bu CuCNLi O O 2

CH Cl Et O, TMSCl EtO2C 2 2 EtO2C 2 OHC o 94% –78 ! 0 C t-Bu

O EtO2C O i-Bu AlH O 2 Li CO2Et A Toluene t-Bu EtO C OHC o OH 2 –78 oC THF, –78 C t-Bu t-Bu 95% 2 steps 86% anti:syn 3.3 : 1 O EtO2C

B OH t-Bu

CuBr•SMe O 2 CO Et EtO OTMS 2 O ZnCl2•OEt2 HMPA CO2Et Zn 2 + A ultrasound Et2O, THF 81% OTMS t-Bu [2+2] Photocycloaddition: Round I - The Phantom Menace

O O O O CO CH CO2CH3 2 3 CO CH H3CO2C O h! O 2 3 O or H O 6 8 OTMS > 350 nm TMSO OTMS H TMSO single diastereomer

O O O CO2CH3 CO2CH3 CO2CH3 O h! O O + 1.5 : 1 > 350 nm

t-Bu t-Bu t-Bu

O O CO2Et CO2Et O h! O The wrong diastereomer!! > 350 nm hexanes TMSO OTMS t-Bu t-Bu [2+2] Photocycloaddition: Round II - A New Hope

O O O CO2Et CO2Et CO2Et O h! O O + 1.1 : 1 > 350 nm 77% hexanes HO HO OH t-Bu t-Bu t-Bu

OEt PPTS, O O Benzene H O oC O O O 80 74% H O O t-Bu t-Bu

O O O CONMe2 CONMe2 CONMe2 O h! O O + 3 : 1 > 350 nm 85% hexanes HO HO OH t-Bu t-Bu t-Bu A New Photosubstrate

O O O H H H MgBr + OHC THF, 0 oC OH t-Bu t-Bu 97% OH t-Bu

1. DEAD, Ph3P, p-NO2C6H4CO2H, tol.

2. NaOH, THF, H2O

O 1. Et3SiCl, Et3N O H EtO C CH2Cl2 2

2. n-BuLi, ClCO2Et o OH t-Bu THF, –78 C OTES t-Bu 95%

O CO Et CuBr•SMe2, 2 O O EtO2C HMPA CO2Et + Zn 2 Et2O, THF 82% OTES t-Bu OTES t-Bu [2+2] Photocycloaddition: Round III - The Empire Strikes Back

OEt O O O O CO2Et CO2Et O h! single diastereomer O H O > 350 nm H quantitative yield hexanes RO TESO OTES t-Bu t-Bu t-Bu

O O O O CO2Et CO2Et EtOH, reflux; O O 1. 5% HF, CH3CN O PPTS, benzene O 2. MsCl, Et3N reflux TESO MsO 63% - 3 steps t-Bu t-Bu t-Bu

Me O OHO This [2+2] reaction has O O H completely formed the A, B, O D H O D, and F rings! Only two A F rings remain. HO B O t-BuOH Cleavage of Cyclobutane

Initial analysis: In actuality, the !-overlap of the Good acceptors at C4 lone pair of the enol oxygen with the alkene greatly reduces the O O Good donor at C12 oxygen's donor ability O O DMDO O O O O O O O R O HCl H2O, acetone O O O 94% MeOH t-Bu t-Bu R=CO2Me t-Bu t-Bu p-TsOH O OH H2O OH O O O O OH O H O O O O O 2 O –H O O OH OH OH O OH OH OH OH t-Bu t-Bu t-Bu t-Bu

MeOH O HC(OMe) 3 O NSO2Ph O O Ph O p-TSA OMe t-BuLi OH OMe 95% O Et NH (20 mol%) O O 2 O OMe oC THF, –20 OMe OH 98% OH t-Bu t-Bu "Unexpected and Devastating Events"

O O O O O O OH OMe O O p-TsOH O O O OMe O O OMe OMe 4Å mol. sieves O OH OH CH2Cl2 OH t-Bu t-Bu t-Bu desired product

H

O O O O O OMe O OMe O O O OMe O –H O H H O OH OH OH OH OH O t-Bu t-Bu t-Bu ene-diol rearrangement Evidence for the intermediate: O O O OH OMe O O p-TsOH O OMe O O OMe 4Å mol. sieves CHO OAc CH2Cl2 OAc t-Bu t-Bu A Corey and Crimmins Convergence?

O O O O OH O OMe O O O p-TsOH, O OMe O OMe benzene, O O reflux OMe OH OH O O t-Bu t-Bu t-Bu O

Recall the Corey Synthesis: The C10 hydroxyl group produces the unwanted rearrangement and O O derails this attempt to cyclize. O 1. dioxane, CSA O * OMe O O sealed tube, 120 oC O CHO 2. MeOH, CSA OMe The C3 carbonyl causes the C1 * position to be far too reactive t-Bu t-Bu

O O O O O O OH OMe O O O O O O CSA OMe O O O O + O O OMe MeOH CHO 1 : 1 mixture OH t-Bu t-Bu t-Bu t-Bu O Retrosynthetic Revision

O Me O Me O OH O O OH Me O O H O H HO O OMe O O O O O O O H H O O HO HO OMe OH t-Bu t-Bu t-Bu

O O O OH CO2Et OMe O O O OMe HO OH t-Bu t-Bu

O CO Et O 2 O EtO2C

OH t-Bu OTES t-Bu Intramolecular Aldol: Masking the C3 Carbonyl

O O O O O OMe OMe O O O OMe O O O OMe CS , DBU, OMe Bu3SnH, AIBN 2 O MeI, DMF; benzene, OMe OH OCS2Me t-Bu 91% t-Bu 75% t-Bu

O O O O O O OH O O O OMe OMe NSO Ph O O O 2 O OMe Ph t-BuLi O O O O OMe O OMe o Et2NH THF, Et N, CH Cl , 40 C 3 2 2 OMe –78 oC 0 oC t-Bu ! t-Bu 66% t-Bu

O O O Me Li O O O O OMe O LDA O HO OMe O O O O THF, –78 oC Me O OMe 100% OMe t-Bu t-Bu Closure of the E Ring

O O Me O O Me O Me HO O OMe NaOMe O H HO HO O OMe CSA, MeOH O O O MeO2C O O O 65 oC MeOH OMe OMe OMe 88% 50% t-Bu t-Bu t-Bu MeOH O Me Me O Me MeO OH O O O O HO HO H HO O O H O O O O O O OMe OMe OMe t-Bu t-Bu t-Bu

O O HO Me H Me HO O PPTS, pyridine O H O O MeO2C O MeO C chlorobenzene, 2 O OMe reflux 85% t-Bu t-Bu To the Finish...

Me O O O HO HO Me HO Me H H O H VO(acac)2, O p-TSA O O O MeO O O MeO C O O O O 2 t-BuOOH 81% 2 steps O O HO t-Bu t-Bu t-Bu

O Me Me O Me O OH HO HO O H H Br O O O DMDO O O 2 O O H O O O O O O HOAc, NaOAc H acetone HO 51% - 2 steps O HO HO O t-Bu t-Bu t-Bu OH O Ginkgolide B

Crimmins Total Synthesis from 3-furaldehyde - 25 steps, 2.5% overall yield Conclusions • Corey’s synthesis – A selective [2+2] ketene - olefin cycloaddition and a Baeyer Villiger oxidation to make caprolactone – Mukaiyama Aldol to create spirocenter – Difficulties with allylic oxidation (“mosaic” approach) • Crimmins’ synthesis – [2+2] used to form 2 spirocenters (Corey - 1 spirocenter) – Solves oxidation problem by using intramolecular aldol to mask the C3 carbonyl and its reactive β position. • t-butyl group – Installed early in all cases (Corey - 3rd step, Crimmins - 2nd step, first stereocenter in enantioselective synthesis) – Plays important role in setting stereocenters throughout all syntheses • Forbids Corey’s intramolecular photolysis to close E ring • Crimmins’ [2+2] photocycloaddition • Epoxidations, protecting group strategies