Total Synthesis of (±)-Ginkgolide B

Extracts of the ginkgo tree, Ginkgo biloba, now widely recommended in Asian and European medicine (annual sales ca. $500 000 000 per annum), have been found to antagonize platelet activating factor (PAF),¹ a very fundamental mammalian regulator.² Ginkgo extracts increasingly find therapeutic use in the treatment of cerebrovascular and peripheral circulatory problems of the elderly and asthma. The most active anti-PAF agent in the ginkgo extract is the hexacyclic C₂₀ trilactone ginkgolide B (1)³ (IC₅₀ 10⁻⁷–10⁻⁸ M in various tests),¹ which appears to antagonize all known PAF-induced membrane events. The first total synthesis of ginkgolide B (racemic form) is described herein. A recent paper from these laboratories⁴ has reported the total synthesis of the related C₁₅ ginkgolide, (±)-bilobalide,⁵ by a totally different approach.

Reaction of 1-morpholinocyclopentene with dimethoxyacetaldehyde in benzene at 23 °C for 18 h, stirring of the resulting solution with 6 N hydrochloric acid at 0 °C for 30 min, extractive isolation and distillation (145–146 °C at 15 Torr) provided enone 2 in 70% yield.^6–8 Enone 2 was converted into the end silyl ether 3 (93% yield) by reaction in ether with the cuprate reagent t-Bu₂CuCNLi₂ (1.5 equiv relative to 2; prepared from reaction of cuprous cyanide and tert-butyllithium in a 1:2 ratio at −78 °C for 50 min and then at −45 °C for 30 min) at −78 °C for 10 min and then at −45 °C for 30 min, followed by silylation of the resulting enolate with 5 equiv each of trimethylchlorosilane and triethylamine (−45 °C for 45 min, then −10 °C for 5 min) and extractive isolation. Addition of 3 in methylene chloride to a solution of 1,3,5-trioxane (1.2 mol equiv) and titanium tetrachloride (3.6 equiv) in methylene chloride at −78 °C (over 20 min), further reaction (−78 °C for 2 h and −45 °C for 1 h), and finally treatment with one-half volume of methanol (0 °C initially then 23 °C for 12 h) produced stereoselectively⁹ cyclopentanone 4, mp 25–27 °C, as a 2:1 mixture of two C(11) anomeric methyl acetals (ginkgolide numbering) in 65% yield. Deprotonation of 4 with 1.25 equiv of lithium diisopropylamide (LDA) in dimethoxyethane (−78 °C for 1 h, 0 °C for 20 min) and subsequent reaction with N-phenyltriflimide¹⁰ (0 °C for 1.5 h, 23 °C for 1 h) afforded after isolation and silica gel chromatography (SGC) an 80% yield of enol triflate 5. A solution of 5 and Pd(PPh₃)₄ (5.7 mol%) in benzene was stirred at 16 °C for 15 min and then treated successively with a benzene solution of acetylenic OBO ester 6¹¹ (1 equiv), n-propylamine (2.3 equiv), and 0.5 equiv of cuprous iodide, all at 16 °C to give after 4 h at 16 °C, extractive isolation and SGC 76–84% of the coupling product 7 (2:1 mixture of anomers), mp 44–47 °C.¹² The triple bond of 7 was reduced by reaction with 1.5 equiv of dicyclohexylborane in tetrahydrofuran (THF) (0 °C for 2 h, 23 °C for 0.5 h), followed by protonolysis (acetic acid 23 °C for 16 h), and decomposition of residual boranes (H₂O₂, 23 °C, pH 10). The resulting solution was acidified to pH 3 with 1 N hydrochloric acid, brought to pH 11 (vigorous stirring, 4 h) and reacidified to pH 3 to cleave the OBO ester unit,¹³ and the (Z)-olefinic acid 8 was isolated by extraction and removal of solvent (70% yield, colorless oil). Conversion of 8 to the corresponding acid chloride (5 equiv of oxalyl chloride in benzene at 23 °C for 2 h) and addition of the acid chloride in toluene solution (0.2 M) over 2 h to a stirred solution of tri-n-butyiamine (10 equiv) in toluene at reflux, followed by further reaction at reflux for 1 h, furnished stereospecifically (71–87% yield) the tetracyclic ketone 9, mp 59 °C. Structure 9, which results from internal ketene–olefin cycloaddition¹⁴ and elimination of the anomeric methoxy group (under tri-n-butylammonium chloride catalysis), follows from spectroscopic data and the transformation 11 → 12 described below.¹⁵

Addition of 9 in acetone (at −30 °C) to a stirred solution of triphenylmethyl hydroperoxide in 8:1 acetone–1 N aqueous sodium hydroxide at −30 °C over 10 min and a further reaction time of 2 h at −30 °C produced a single Baeyer–Villiger product 10, mp 163 °C, in 86% yield.¹⁵ Lactone 10 was transformed into 4-hydroxylactone 11 (ginkgolide numbering as in 1) by a two-step sequence: (1) deprotonation (1.5 equiv of sodium bis(trimethylsilyl)amide in THF at −50 °C for 20 min) followed by reaction of the resulting anion with 2 equiv of (E)-2-(phenylsulfonyl)-3-phenyloxaziridine¹⁶ (at −50 °C for 5 min and then at −50 °C to 0 °C over 10 min) to afford the corresponding α-hydroxylactone (73% after SGC) and (2) exposure to a 1% solution of camphorsulfonic acid (CSA) in methanol at 23 °C for 48 h to give 11, mp 155 °C (75%).¹⁷ Reaction of 11 with lead tetraacetate (4.5 equiv) and iodine (3 equiv) in pyridine-1,2-dichloroethane at 5 °C under sunlamp irradiation for 10 min resulted in complete conversion to a single product, determined by 500-MHz ¹H NMR analysis to be the cyclic ether 12,¹⁸ rather than the hoped for product of functionalization at C(12). Although this result was not useful as a synthetic step, it did provide conformation of the stereochemistry of intermediates 9, 10, and 11.

The required oxygen bridge between C(4) and C(12) was established by an alternative route starting from 10. Reaction of 10 with 1.2 equiv of propane-1,3-dithiol and excess titanium tetrachloride in methylene chloride at 0 °C for 10 min and then at 23 °C for 40 min produced the thioacetal–primary alcohol 13, mp 230 °C (98%), which was transformed into the aldehyde 14, mp 165–166 °C (75% yield), by treatment with pyridinium dichromate (PDC, 1 mol equiv), powdered 3-Å molecular sieves and acetic acid in methylene chloride at 0 °C for 1 h. The aldehyde 14 was converted into the bis-acetal 15 (80% overall yield as a 2:1 mixture of C(12) anomers) (major anomer from SGC, mp 107 °C) by the following process: (1) oxidative dithiane cleavage by reaction of 14 with 0.5 mol equiv of periodic acid in 1:1 methanol–methylene chloride containing ca. 1% water at −30 °C initially then at 0 °C for 20 min and 23 °C for 40 min and (2) stirring of the resulting product with methanolic CSA at 23 °C. The C(4)–C(12) oxygen bridge was generated by the following sequence: (1) deprotonation of bis-acetal 15 with use of 1.9 equiv of lithium diethylamide initially at −25 °C and then at 0 °C for 15 min and subsequent oxygenation with (E)-2-(phenylsulfonyl)-3-phenyloxaziridine¹⁶ (2 equiv, 0 °C for 30 min) to form the α-hydroxylacetone 16, mp 115–116 °C, and (2) reaction with a solution of CSA in methylene chloride (20 mg/100 mL) at 23 °C for 24 h to afford 17, mp 151–153 °C (75%).²⁰ The introduction of an oxo function at C(3) was accomplished in 50% overall yield by the following transformations: (1) allylic bromination with 1.3 equiv of N-bromosuccinimide in carbon tetrachloride (0.02 M) under external tungsten lamp irradiation at 10 °C for 2–3 h (monitored by SG TLC) to give a mixture of 60% of the C(3) brominated product (Br³), 30% of the C(l) brominated product (Br¹), and 10% of the 3,3-dibrominated product (Br^3,3); (2) reaction of the mixture with 10 M silver nitrate in acetonitrile at 23 °C for 15 min which generates a mixture of the enone 18, mp 267–268 °C (from Br^3,3), the 1-nitrate ester (from Br³), and the 3-nitrate ester (from Br¹), easily separated by SGC; (3) conversion of the 3-nitrate ester to 18 by nitrate cleavage with zinc–acetic acid followed by oxidation of the resulting C(3) alcohol with PDC in methylene chloride at 23 °C for 5 h; (4) conversion of the 1-nitrate ester to 18 by exposure to 20 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 equiv of water in 10:1 benzene–methanol at 23 °C for 30 h followed by oxidation of the resulting C(3) alcohol (from overall S_N2′ reaction) by PDC.

The final γ-lactone ring was affixed starting with epoxy ketone 19 which was obtained from 18 in the following two steps: (1) elimination of methanol from C(10)–C(11) by heating 18 under argon with 5 equiv of pyridinium tosylate and 2.5 equiv of dry pyridine in chlorobenzene at 135 °C for 16 h (80% yield)^21,22 and (2) enone epoxidation with triphenylmethyl hydroperoxide (5 equiv) and benzyltrimethylammonium isopropoxide (0.5 equiv) in THF at −10 °C for 3 h to give after reduction of excess hydroperoxide by trimethyl phosphite (10 equiv) and SGC 72% of 19. Reaction of 19 with 7 equiv of the lithium enolate of tert-butyl propionate (from LDA) in 4:1 THF–hexamethylphosphorictriamide, at −78 °C to −30 °C for 2 h and then at −30 °C for 10 h, furnished the desired aldol adduct 20 in 60% yield after SGC.²³ Exposure of 20 to 4 equiv of CSA in methylene chloride (23 °C for 15 h) afforded bis-lactone 21 (82%) which was converted to the tert-butyldimethylsilyl (TBMS) ether 22 upon treatment with 2.5 equiv of TBMS triflate and 5 equiv of 2,6-lutidine in acetonitrile at 23 °C for 1 h (89%). Hydroxylation of 22 using osmium tetroxide in pyridine followed by oxidation of the resulting product with excess iodine in methanol in the presence of CaCO₃ (23 °C for 12 h) produced trilactone 23 (ca. 40% from 22)²¹ along with a small amount of the C(10) epimer. Desilylation of 23 (5 equiv of BF₃·Et₂O in methylene chloride at 23 °C for 14 h) gave 89% yield of (±)-ginkgolide B (1), identical with an authentic sample by 500-MHz ¹H NMR, FT-IR, SG-TLC analysis in several solvent systems, and mass spectral comparison.²⁴