Sunday, June 17, 2012

E. J. Corey's Synthetic Approach to Germanicol

In 2008, E. J. Corey's laboratory disclosed a formal synthesis of germanicol (see previous post) that was enantioselective. The work was characterized by the authors as 'a major advance over the original route to [germanicol] in terms of brevity, efficiency, and enantiocontrol.' The Corey route is initiated by the Corey-Zhang dihydroxylation of 2,6-E,E-farnesyl acetate (1), a reaction that, to its credit, delivers multigram quantities of the chiral diol 2, but that necessitates a complex cinchona catalyst that is not commercially available (catalyst A). This rationally designed ligand is capable of molecular recognition of a polyolefin substrate and delivers the terminal dihydroxylation product (2) in good yield and with outstanding stereoinduction. Three subsequent operations then secured the acyl silane 3.
Nucleophilic addition of 2-propenyllithium to 3 generated an intermediate (Int-I) that readily underwent Brook rearrangement under the specified conditions. In situ benzylation of the resultant allylic lithio species then provided 4. This triene (4) was the substrate for an epoxide-initiated pi-cation/olefin polyannulation reaction that occurred upon exposure to Lewis acidic conditions at low temperature. O-Silylation of the cation-olefin polyannulation product delivered 5, which cyclized further to give 6 under conditions that were reported by Ireland and co-workers during their germanicol campaign. The pentacycle 6 intersects with an Ireland-Johnson synthetic intermediate en route to germanicol. It is noteworthy that the laboratory of Corey has provided access to 6 as a single stereoisomer. However, no less than eight additional steps are required (as per the Ireland-Johnson protocol) to convert 6 into germanicol. Additionally, upon inspection of the supporting information of the Corey JACS publication (JACS, 2008), it was found that the conversion of 4 into 6 was conducted on 100 milligram scale, providing only 25 milligrams of 6 over the course of three synthetic steps. It is not clear from the data provided by Corey and co-workers that this sequence would work well on large (gram) scale. Therefore, while the Corey protocol is indeed an advancement with regard to 'brevity,' if I were tasked with the synthesis of one gram (arbitrary quantity) of germanicol, I would probably start reproducing Bob Ireland's total synthesis, which, to reiterate, was published in 1970. Clearly, unmet challenges to present day synthetic science persist.

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