Total Synthesis of Ginkgolide B
Ginkgo biloba, termed the "living fossil" by Darwin, has ancestors dating to 230 million B.C. Extracts of ginkgo biloba, which have been used as herbal medicines for 5000 years to treat a variety of conditions such as coughs, asthma, and circulatory disorders, are currently undergoing clinical evaluation for treatment of dementia.
Ginkgolide B is the most potent platelet activating factor (PAF) antagonist of the ginkgo extracts, with an IC50of 0.6μM. The complex molecular architecture of ginkgolide B which includes six rings, eleven stereogenic centers, ten oxygenated carbons, and four contiguous fully substituted carbons is a daunting challenge or chemical synthesis. The diabolical disposition of functionality dictates that introduction of functional groups be judiciously orchestrated. The total synthesis of ginkgolide B has been completed utilizing the zinc-copper homoenolate and stereoselective intramolecular [2+2] photocycloaddition methodologies developed in our laboratories.
The key steps in the synthesis are outlined in the scheme above. A conjugate addition-cyclization on acetylene 1 provided the photosubstrate 2 in excellent yield. Irradiation of the enone 2 resulted in a highly diastereoselective [2+2] photocycloaddition to establish the two contiguous quaternary centers at the core of the ginkgolide skeleton. The cyclobutane of 3 was fragmented to produce the propionate 4 that underwent an intramolecular aldol addition to establish the stereochemistry of the tertiary alcohol. An acid catalyzed reorganization to the ginkgolide skeleton produced the pentacyclic intermediate 6 which was converted to ginkgolide B in just 3 steps. The overall synthesis for this extraordinarily complex molecule required only 25 steps.
A detailed account of the synthesis can be found in J. Am. Chem. Soc. 2000, 122, 8453-8463.
Total Synthesis of (-)-Isolaurallene
Medium ring ethers of various structural types have been isolated from marine organisms. While medium ring ethers such as the ladder ethers toxins have important implications with regard to their biological impact, it is the exquisite structures of naturally occurring medium ring ethers that has provoked the imagination of synthetic chemists. Nine membered ethers are perhaps less common, but are present in the ladder toxins brevetoxin A, ciguatoxin, gambieric acid A, the eunicellins and in the simpler metabolites obtusenyne, neolaurallene and isolaurallene.
Isolaurallene, which contains a nine membered cyclic ether, as well as a bromoallene substituted tetrahydrofuran, was isolated by Kurata from laurencia nipponica yamada collected in Izumihama near Hiroo on the Pacific Coast of Hokkaido. As part of our continuing program directed toward the development of flexible strategies for the asymmetric construction of medium ring ether metabolites, we designed an approach to the synthesis of (-)-isolaurallene that focused on the preparation of the medium ring ether through an asymmetric glycolate alkylation followed by an olefin metathesis without the aid of a cyclic conformational constraint. The key steps in the synthesis are summarized in the scheme below.
Treatment of oxazolidinone 1 under our standard asymmetric glycolate alkylation conditions provided the diene 3, which was converted in a series of steps to the epoxy-diene 4. Exposure of the diene to the Grubbs catalyst effected rapid and efficient closure of the nine-membered ether to produce 5. Hydrolysis of the acetate 5 with potassium carbonate in methanol resulted in concomitant closure of the tetrahydrofuran ring. The basic skeleton incorporating both the oxonene and the tetrahydrofuran had been completed in just 11 steps from oxazolidinone 1. The synthesis was completed by conversion of the diol 6 to the chloroepoxide 7 through a series of standard operations and then elimination of the chloroepoxide to the acetylene 8 which was converted to the required bromoallene in a highly selective manner. Synthetic (-)-isolaurallene was spectroscopically identical to the natural material.
A detailed account of the synthesis can be found in J. Am. Chem. Soc. 2000, 123
Total Synthesis of Callystatin A
Callystatin A, 1, was isolated from the marine sponge, Callyspongia truncata, in the Nagasaki Prefecture and shows remarkable in vitro cytotoxicity (IC50 = 0.01 ng/mL) against KB cells. The relative and absolute stereostructure of callystatin A was established by a combination of spectroscopic methods and chemical synthesis. The limited quantities of callystatin A available from natural sources, as well as the possibility for a carrying out syntheses and structure elucidation of the related antitumor antibiotics, prompted us to pursue a total synthesis of callystatin A.
The asymmetric total synthesis of (-)-callystatin A exploiting our recently developed asymmetric aldol protocol with chlorotitanium enolates of acyl oxazolidinethiones is summarized in the scheme below.
The synthesis of the C13 to C22 propionate fragment was predicated on the application of our recent success with asymmetric aldol additions using chlorotitanium enolates of acyloxazolidinethiones. Thus, treatment of propionyloxazolidinethione 2 with titanium tetrachloride and (-)-sparteine followed by addition of S-2-methylbutanal 3 resulted in the formation of syn aldol adduct 4 in 83% yield and greater than 98% d.e. In preparation for the second asymmetric aldol to construct the C16-C17 bond, the secondary alcohol was protected as its TBS ether, the chiral auxiliary was reductively removed with lithium borohydride and the resultant alcohol was oxidized to the aldehyde 5 in 83% overall yield. Execution of the second asymmetric aldol, under identical conditions to the first, produced an 81% yield of the syn aldol adduct 6 (98:2 d.s.). Conversion of the aldol adduct 6 to the key phosphonium salt 8 was accomplished under standard conditions.
The two key fragments were assembled by a highly selective Wittig olefination to produce the tetraene 12, which was converted to callystatin A in 2 steps.
A detailed account of the synthesis is available: J. Am. Chem. Soc. 1998, 120, 9084-9085.