Mukaiyama Taxol total synthesis

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).

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).

After removal of the TES group (HCl, THF), the alcohol 26 was oxidized to aldehyde 27 (TPAP, NMO)which enabled the intramolecular Aldol reaction to bicycle 28.

This compound was alkylated to 32 at the C1 ketone group with the Grignard homoallyl magnesium bromide (C4 fragment completing the carbon framework) and deprotected at C11 (TBAF) to diol 33.

Finally the C15 hydroxyl group was introduced by oxidation at the allyl position with in two steps PPC and sodium acetate (to the enone) and with K-selectride to alcohol 43 which was protected as a TES ether in 44.

Osmium tetroxide added two hydroxyl groups to the exocyclic double bond in diol 47 and oxetane ring-closure to 48 took place with DBU in a nucleophilic substitution.

This formed the silyl enol ether 55 (n-butyllithium, trimethylsilyl chloride, Diisopropylamine) which reacted with chiral amine catalyst 58, tin triflate and nBu2(OAc)2 in a Mukaiyama aldol addition with benzaldehyde to alcohol 59 with 99% anti selectivity and 96% ee.

In the final synthetic steps (scheme 8) the amide tail 62 was added to ABCD ring 52 in an esterification catalysed by o,o'-di(2-pyridyl) thiocarbonate (DPTC) and DMAP forming ester 63.

Mukaiyama Taxol total synthesis overview from raw material perspective
Ring B synthesis scheme 1
Ring B synthesis scheme 1
Ring B synthesis scheme
Ring B synthesis scheme
Ring C synthesis scheme 3
Ring C synthesis scheme 3
Ring A synthesis scheme 4
Ring A synthesis scheme 4
Ring A synthesis part 2 scheme 5
Ring A synthesis part 2 scheme 5
Ring D synthesis scheme 6
Ring D synthesis scheme 6
Tail synthesis scheme 7
Tail synthesis scheme 7
Tail addition scheme 8
Tail addition scheme 8