Synthesis of Deacetoxyalcyonin Acetate

Deacetoxyalcyonin acetate 1 and euncellin 2 are representative members of the eunicellin class of diterpenes. The synthesis of deacetoxyalcyonin acetate 2 by Gary Molander of the University of Pennsylvania (/ Am. Chem. Soc. 2004, 126, 1642) illustrates the power of intramolecular organometallic carbonyl addition for ring construction. 

Three-carbon ring expansion was carried out in two stages. First, two-carbon homologation of the exo methylene ketone 8 followed by trapping of the intermediate etiolate as the criflate led to 9. Nozaki-Hiyama-Kishi coupling followed by acetylation smoothly converted 9 into 10. 

The trisubstituted alkene of 10 was more readily oxidized than was the congested telrasubstituted alkene, so the more reactive alkene was temporarily epoxidized. After ozonolysis, the epoxide was reduced off using the Sharpless protocol. It is a tribute to the specificity of this reagent that the easily-reduced a-acetoxy ketone is not affected. Selective silylation of the more accessible ketone followed by methylenation, hydrolysis and addition of methyl lithium to the outside face of the previously protected carbonyl then delivered 1. 

As new drug entities must be usually be prepared as single enantiomers, and as many contain one or more heterocyclic or carbocyclic rings, there is an increased emphasis on the development of practical methods for the construction of enantiomerically pure cyclic systems. In this three-part series, we will cover the most important recent advances. 

While enantioselective transition metal catalysis continues to be important, several useful all-organic catalysts have been developed over the past few years. Tomislav Rovis of Colorado State University has reported (J. Am. Chem. Soc. 2004,126,8876) that the triazolium salt 5 catalyzes the enantioselective Stetter-type cyclization of 4 to 6. The cyclization also works well for the enantioselective construction of azacyclic, Ihiacyclic and carbocyclic rings. 

---

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... 

---