S. B. Singh et al.55 synthesized
chaetomellic acids which are a class of alkyl dicarboxylic acids that were
isolated from Chaetomella acutiseta using starting step as aldol condensation.
Chaetomellic acids are potent and highly specific farnesyl-pyrophosphate (FPP)
mimic inhibitors of Ras farnesyl-protein transferase. The synthetic strategy of
chaetomellic acids involved a biomimetic-type aldol condensation of the
appropriate fatty acid ester with pyruvate followed by elimination of an
equivalent of water and hydrolysis of the ester groups. Aldol condensations (Scheme
21) of the appropriate fatty acid esters with methylpyruvate would give an
aldol product that would have the carbon skeleton of chaetomellic acids. The
aldol reactions in the standard conditions, addition of methylpyruvate to
enolate, resulted in very poor yields due to the insolubility of the enolate at
-78oC. This problem could not be circumvented by raising the
temperature due to the base catalyzed polymerization of methyl pyruvate at room
temperature. However, performing the aldol reaction in the reverse order easily
overcame this problem. The reaction of lithium diisopropylamide with methyl
palmitate gave an enolate that was slowly added to the cooled (-78oC)
solution of methylpyruvate. This gave a 1:1 diastereomeric mixture of aldol
products 113a and 114a in greater than 80% yield (Scheme 21).
The aldol reaction of methyl oleate with methyl pyruvate was performed in a
similar manner to give a 1:1 diastereomeric mixture of 113b and 114b with a
greater than 80% yield. Operationally this reaction was easier due to the
increased solubility of the unsaturated enolate at lower temperature. A similar
reaction of methyl myristate with methyl pyruvate gave 113c and 114.
________________
55. S. B. Singh, H.
Jayasuriya, K. C. Silverman, C. A. Bonfiglio, J. M. Williamson, and R. B. Lingham,
Bioorg. Med. Chem., 2000,8, 571.
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