Kuwajima Taxol total synthesis



 The Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the Tokyo Institute of Technologyis one of several efforts in organic synthesis.

This synthesis is truly synthetic without any help from small biomolecule precursors and also a Ojima lactam.

The 20 carbon frame is constructed from several pieces: propargyl alcohol (C1, C2, C14), diethylaluminum cyanide (C19) and trimethylsilylmethyl bromide (C20)

Synthesis A ring

Ring A synthesis (scheme 1) starts by joining the Peterson olefination to the sulfide 1.17 followed by deprotection to completed ring A 1.18. The A ring is now complete with the aldehyde group and de sulfide group in place for anchoring with ring C forming ring B.

Synthesis B ring

The bottom part of ring B is constructed by Grob fragmentation-like reaction.

After deprotection (pinacol) to diol 2.6, Swern oxidation of 2.10 to ketone 2.11

Synthesis C ring

Completion of the C ring requires complete reduction of the arene, placement of para oxygen atoms and importantly introduction of the C19 methyl group. The first assault on the aromatic ring in 3.1 (scheme 3) is launched with Samarium(II) iodide gives ring-opening finally putting the C19 methyl group in place in 3.14 and deprotection (TBAF) and enol-ketone conversion gives hydroxyketone 3.15

Synthesis D ring

By protecting the diol group in triol 4.1 (scheme 4) as the phenyl boronic ester 4.2, the remaining alcohol group can be protected as the TBS ether 4.3. After deprotecting the diol group (nucleophilic aliphatic substitution to oxetane 4.14.

Tail addition

The C1, C2 and C4 functional groups are put in place next and starting from oxetane 5.1 (scheme 5) the MOM protecting group is removed in 5.2 (PPTS) and replaced by a TES group TESCl) in 5.3. The acetylated in 5.6 and in the final step the carbonate group is opened by reaction with phenyllithium to the hydroxyester 5.7.

Prior to tail addition the TES protective group is removed in 5.8 (acetic acid) to taxol 5.13.

References

  1. ^ Enantioselective Total Synthesis of Taxol Koichiro Morihira, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Nobuhito Nakamura, Hiroyuki Kusama, and Isao Kuwajima J. Am. Chem. Soc.; (Communication); 1998; 120(49); 12980-12981. DOI 10.1021/ja9824932
  2. ^ Enantioselective Total Synthesis of (-)-Taxol Hiroyuki Kusama, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Hajime Kashima, Nobuhito Nakamura, Koichiro Morihira, and Isao Kuwajima. J. Am. Chem. Soc.; (Article); 2000; 122(16); 3811-3820. DOI: 10.1021/ja9939439
 
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