Chemical synthesis of the (25R)- and (25S)-epimers of 3α,7α,12α-trihydroxy-5α-cholestan-27-oic acid as well as their corresponding glycine and taurine conjugates

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• 作者：Shoujiro Ogawa^a ; Kuniko Mitamura^b ; Shigeo Ikegawa^b ; Matthew D. Krasowski^c ; Lee R. Hagey^d ; Alan F. Hofmann^d ; ^{afhofmann@gmail.com"" rel=""nofollow} ; Takashi Iida^a ; ^{takaiida@chs.nihon-u.ac.jp"" rel=""nofollow}
• 关键词：Allo-bile acid ; 5&#x3b1 ; -Bile acid ; 3&#x3b1 ; 7&#x3b1 ; 12&#x3b1 ; -Trihydroxy-5&#x3b1 ; -cholestan-27-oic acid ; Bile acid biosynthesis ; Chemical synthesis ; NMR
• 刊名：Chemistry and Physics of Lipids
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：164
• 期：5
• 页码：368-377
• 全文大小：889 K

文摘

The (25R)- and (25S)-epimers of C₂₇ 3α,7α,12α-trihydroxy-5α-cholestan-27-oic acid as well as their corresponding N-acylamidate conjugates with glycine or taurine were prepared starting from cholic acid in 14 steps. The principal reactions involved were (1) reduction of a key intermediary C₂₄ allo-cholic acid performate with NaBH₄/triethylamine/ethyl chloroformate, (2) iodination of the resulting 3,7,12-triformyloxy-5α-cholan-24-ol with I₂/triphenylphosphine; (3) nucleophilic substitution of the iodo derivative with diethylmethyl malonate/NaH; and (4) hydrolysis of the resulting 3,7,12-triformyloxy-25-methyl-26,27-diethyl ester with KOH, followed by decarboxylation of the geminal dicarboxylic acid with LiCl. N-Acylamidation of the resulting (25R)/(25S)-3α,7α,12α-trihydroxy-5α-cholestan-27-oic acid mixture with glycine or taurine afforded the corresponding epimeric mixtures of the glycine and taurine conjugates. The (25R)- and (25S)-epimers of the three variants of unconjugated and conjugated 3α,7α,12α-trihydroxy-5α-cholestan-27-oic acid were efficiently separated by HPLC on a reversed-phase C₁₈ column and their structural characteristics, particularly the chiral center at C-25, delineated using ¹H and ¹³C NMR. These synthetic compounds should be useful as authentic reference standards for establishing their presence in bile as well as being useful in studies on the biosynthesis of allo-bile acids from cholesterol.