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Mukaiyama Taxol total synthesis
The Mukaiyama taxol total synthesis published by the group of Teruaki Mukaiyama of the Tokyo University of Science between 1997 and 1999 was the 6th successful taxol total synthesis. The total synthesis of Taxol is considered a hallmark in organic synthesis.
This version is a linear synthesis with ring formation taking place in the order B, C, A, D. Contrary to the other published methods, the tail synthesis is by an original design. Teruaki Mukaiyama is an expert on aldol reactions and not surprisingly his Taxol version contains no less than 5 of these reactions. Other key reactions encountered in this synthesis are a pinacol coupling and a Reformatskii reaction. In terms of raw materials the C20 framework is built up from L-serine (C3), isobutyric acid (C4), glycolic acid (C2), methyl bromide (C1), methyl iodide (C1), 2,3-dibromopropene (C3), acetic acid (C2) and homoallyl bromide (C4).
==Synthesis B ring==
The lower rim of the cyclooctane B ring containing the first 5 carbon atoms was synthesized in a semisynthesis starting from naturally occurring L-serine (''scheme 1''). This route started with conversion of the amino group of the serine methyl ester (1) to the diol ester 2 via diazotization (sodium nitrite/sulfuric acid). After protection of the primary alcohol group to a (t-butyldimethyl) TBS silyl ether (TBSCl / imidazole) and that of the secondary alcohol group with a (Bn) benzyl ether (benzyl imidate, triflic acid), the aldehyde 3 was reacted with the methyl ester of isobutyric acid (4) in an Aldol addition to alcohol 5 with 65% stereoselectivity. This group was protected as a PMB (p-methoxybenzyl) ether (again through an imidate) in 6 which enabled organic reduction of the ester to the aldehyde in 7 with DIBAL.
Completing the cyclooctane ring required 3 more carbon atoms that were supplied by a C2 fragment in an aldol addition and a Grignard C1 fragment (''scheme 2''). A Mukaiyama aldol addition (magnesium bromide / toluene) took place between aldehyde 7 and ketene silyl acetal 8 with 71% stereoselectivity to alcohol 9 which was protected as the TBS ether 10 (TBSOTf, 2,6-lutidine). The ester group was reduced with DIBAL to an alcohol and then back oxidized to aldehyde 11 by Swern oxidation. Alkylation by methyl magnesium bromide to alcohol 12 and another Swern oxidation gave ketone 13. This group was converted to the silyl enol ether 14 (LHMDS, TMSCl) enabling it to react with NBS to alkyl bromide 15. The C20 methyl group was introduced as methyl iodide in a nucleophilic substitution with a strong base (LHMDS in HMPA) to bromide 16. Then in preparation to ring-closure the TBS ether was deprotected (HCl/THF) to an alcohol which was converted to the aldehyde 17 in a Swern oxidation. The ring-closing reaction was a Reformatskii reaction with Samarium(II) iodide and acetic acid to acetate 18. The stereochemistry of this particular step was of no consequence because the acetate group is dehydrated to the alkene 19 with DBU in benzene.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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