M. Suzuki et al.46 synthesized a
series of 3,5-dihydroxyheptenoic acid derivatives containing pyrazolopyridine,
isoxazolopyridine, thienopyridine, and pyrazolopyrimidine as a key scaffold
from condensed pyridine and condensed pyrimidine carboxylic acid esters by
homologation, aldol condensation with ethyl acetoacetate dianion, and
stereoselective reduction of the 5-hydroxyketone. Several compounds in the
series were found to have potent HMG-CoA reductase inhibitory activities in vitro and marked cholesterol
biosynthesis inhibitory activities in
vivo. Scheme 14 shows the elaboration of 3, 5-dihydroxyheptenoic acid
derivatives 63(a–d) starting from 57(a–d). The Dibal reduction of 57(a–d),
followed by PCC oxidation of the resulting alcohol 58(a–d) provided
aldehydes 59(a–d). Homologation of 59(a–d) to propenal 47(a–d) was accomplished
by utilizing cis-(2-ethoxyvinyl) lithium and subsequent hydrolysis with
p-toluenesulfonic acid. An aldol condensation of 60(a–d) with the
sodium/lithium dianion of ethyl acetoacetate afforded the racemic
3-keto-5-hydroxy esters 61(a–d) and further converted in 62(a-d)
and than in 63(a-d).
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46. M. Suzuki, H. Iwasaki, Y. Fujikawa, M. Sakashita, M. Kitahara, and R. Sakoda, Bioorg. Med. Chem. Lett., 2001, 11, 1285
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