Kuwajima Taxol total synthesis

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Taxol is considered a landmark in organic synthesis
.

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

asymmetric synthesis step which is unique compared to the other efforts. In common with the other efforts the tail addition is based on the Ojima lactam
.

The 20 carbon frame is constructed from several pieces:

diethylaluminum cyanide
(C19) and trimethylsilylmethyl bromide (C20)

Synthesis A ring

Ring A synthesis (scheme 1) started by joining the

asymmetric dihydroxylation to hydroxyaldehyde 1.12. The piv protecting group was then replaced by a TIPS group in 1.14 after protecting the aldehyde as the aminal 1.13 and as this group is automatically lost on column chromatography, the step was repeated to aminal 1.15. The C10 fragment was then introduced by the lithium salt of Trimethyl(phenylthiomethyl)silane 1.16 in a 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.

Kuwajime Taxol scheme 1
Kuwajime Taxol scheme 1
Scheme 1

Synthesis B ring

The bottom part of ring B was constructed by

tin tetrachloride to tricycle 2.5 in a Grob fragmentation
-like reaction.

After deprotection (

Barton-McCombie deoxygenation) to alcohol 2.9. Palladium on carbon hydrogenation removed the benzyl protecting group allowing the Swern oxidation
of 2.10 to ketone 2.11

Kuwajime Taxol scheme 2
Kuwajime Taxol scheme 2
Scheme 2

Synthesis C ring

Completion of the C ring required 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) was launched with

DIBAL and then on to the alcohol 3.11 with Lithium aluminium hydride. The alcohol group was replaced by bromine in an Appel reaction which caused an elimination reaction (loss of HBr) to cyclopropane 3.12. Treatment with hydrochloric acid formed ketone 3.13, reaction with Samarium(II) iodide
gave ring-opening finally putting the C19 methyl group in place in 3.14 and deprotection (TBAF) and enol-ketone conversion gave hydroxyketone 3.15

Kuwajime Taxol scheme 3
Kuwajime Taxol scheme 3
Scheme 3

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 could be protected as the TBS ether 4.3. After deprotecting the diol group (

nucleophilic aliphatic substitution to oxetane
4.14.

Kuwajime Taxol scheme 4
Kuwajime Taxol scheme 4
Scheme 4

Tail addition

The C1, C2 and C4 functional groups were 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 acetal group was removed in 5.4 (hydrogenation PdOH2, H2) and replaced by a carbonate ester group in 5.5 (triphosgene, pyridine). The tertiary alcohol group was acetylated in 5.6 and in the final step the carbonate group was opened by reaction with phenyllithium to the hydroxyester 5.7.

Prior to tail addition the TES protective group was removed in 5.8 (

TASF) enabling the tail addition of Ojima lactam 5.11 (this step is common with all total synthetic efforts to date) to 5.12 with Lithium bis(trimethylsilyl)amide. The synthesis was completed with TROC removal (zinc, acetic acid
) to taxol 5.13.

Kuwajime Taxol scheme 5
Kuwajime Taxol scheme 5
Scheme 5

See also

External links

References

  1. doi:10.1021/ja9824932
    .
  2. doi:10.1021/ja9939439
    .
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