The Total Synthesis of (±)-Ginkgolide B

Abstract

The total synthesis of the potent PAF antagonist ginkgolide B has been accomplished. The complex architecture of ginkgolide B which includes six rings, eleven stereogenic centers, ten oxygenated carbons, and four contiguous fully substituted carbons is a daunting challenge for chemical synthesis. The synthesis of ginkgolide B was accomplished through a stereoselective intramolecular photocycloaddition of enone 5 to construct the congested core of the molecule. The photocycloaddition substrate was prepared through technology for the construction of carboalkoxycyclopentenones previously reported from these laboratories. Regioselective cyclobutane fragmentation and further functionalization of the photoadduct 4 provided the key pentacyclic intermediate. Acid-catalyzed rearrangement and epoxide opening were key transformations in the production of ginkgolide B from the pentacyclic intermediate.Ginkgo biloba, one of the oldest surviving flora with ancestors dating to 230 million B.C., flourished during the Jurassic Period and has been called the "living fossil" by Charles Darwin. 1 The ginkgo tree survives today because of its extraordinary resilience, having endured several planetary mass extinctions of plant life. Its regenerative powers are supported by a report that a ginkgo tree sprouted anew from its roots at ground zero Hiroshima. Extracts of G. biloba have been used as herbal medicines for approximately 5000 years to treat a variety of ailments including coughs, asthma, and circulatory disorders. The traditional Hindu medicine "soma" also contains ginkgo extracts, and recent clinical studies attest to possible benefits of ginkgolides in the delay in the onset of dementia. 2 Ginkgolides A, B, C, and M (Figure 1), which differ only in the number and location of hydroxyl groups, were first isolated as "bitter principles" of the root bark by Furukawa and co-workers in 1932. 3 The structures of the ginkgolides were first elucidated in 1967 by a series of spectroscopic studies by Nakanishi. 4 The assigned structures were independently confirmed by X-ray crystallography by the Okabe group at Nagoya University. 5 A related C15 compound, bilobalide, was discovered in 1971, 6,7 and in 1987, another member of the ginkgolide family, ginkgolide J, was isolated and characterized. 8 Ginkgolide B is the most potent platelet-activating factor (PAF) antagonist of the ginkgo extracts with an IC 50 value of 0.6 mM. 9 Because of its portentous molecular architecture, ginkgolide B is an intimidating challenge for chemical synthesis. Included in the ginkgolide skeleton are six rings, eleven stereogenic centers, ten oxygenated carbons, an unusual tert-butyl group, 10 and four contiguous fully substituted carbon atoms. At the sterically congested core of the molecule are quaternary carbons C5 and C9, which are jointly embodied in five of the six rings of the molecule. The stereogenically correct installation of the C5 and C9 quaternary carbons and the proper orchestration of functional group manipulation are the most critical iss...

Five‐Membered Heterocycles: Furan

“…A remarkable example is the pivotal intramolecular cyclization to form 216 (Scheme 6.100), as employed in the total synthesis of ginkgolide B [196].…”

Epoxides in Complex Molecule Synthesis

“…Apparently, hydrolysis of the epoxide produces the hemiacetal 207, which undergoes retroaldol fragmentation of the cyclobutane to afford the dialdehyde, which forms the stable hydrate 208 (Scheme 8.52) [94].…”

Chemistry and Biology of Terpene Trilactones fromGinkgo Biloba

“…[126] In a recently completed total synthesis of GB (2, Scheme 9), a photocycloaddition was again used as a key transformation. [127,128] First, 66 was treated with a zinc-copper homoenolate to give 67, which was then subjected to irradiation at 366 nm in hexanes, leading to 68 in high yield and excellent diastereoselectivity, establishing two quaternary centers and rings A, B, and C of GB (2) (Scheme 9). In three steps, lactone ring F was generated by hydrolysis of the triethylsilyl ether, mesylation of the resulting alcohol, and treatment with pyridinium p-toluenesulfonic acid (PPTS) to give 69 in 63 % overall yield.…”