Deacetoxyalcyonin acetate synthesis

Deacetoxyalcyonin acetate synthesis 76 Dendrobatid alkaloid 25 IF synthesis 112, 168... 

Deacetoxyalcyonin acetate 1 and cuncellin 2 are representative members of the euniccllin class of diterpenes. The synthesis of deacetoxyalcyonin acetate 2 by Gary Molander of the University of Pennsylvania (J. Am. Chem. Soc. 2004, /26,1642) illustrates the power of intramolecular organometallic carbonyl addition for ring construction. 

A general synthetic route toward the marine metabolite eunicellin diterpenes was developed by G.A. Molander and co-workers.The power of this method was demonstrated by the completion of the asymmetric total synthesis of deacetoxyalcyonin acetate. A tricyclic (3-keto ester intermediate was methylated in the y-position with complete diastereoselectivity using dianion chemistry and the crude product was subjected to the Krapcho decarboxylation. This was one of the rare cases when the transformation did not only remove the methoxycarbonyl group, but at the same time epimerized the newly formed stereocenter to yield a separable mixture of methyl ketones. 

In the laboratory of G.A. Molander, a general route for the synthesis of eunicellin diterpenes was developed and was applied for the asymmetric total synthesis of deacetoxyalcyonin acetate. One of the key steps was an inramolecular NHK coupling reaction between an enol triflate and an aldehyde. The cyclopentenol product was formed in high yield as a 2 1 mixture of diastereomers. The undesired diastereomer could be transformed to the desired one using a Mitsunobu reaction. 

An excellent synthetic example of the Prins reaction is found in MacMillan and Overman s total synthesis of (-)-7-deacetoxyalcyonin acetate (21), in which the core of the natural product is assembled via the Prins-pinacol reaction sequence.16 Treatment of diol 17 with aldehyde 18 in the presence of BF3 Et20 presumably gives oxonium ion 19, which then undergoes the Prins-pinacol reaction sequence to generate 20 in 79% yield, thereby establishing the entire core bicycle of 21 in one step. Intermediate 20 was then carried forward to complete the total synthesis of 7-deacetoxyalcyonin acetate (21).16... 

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