- Kuwajima Taxol total synthesis
This synthesis is truly synthetic without any help from small biomolecule precursors and also a
linear synthesiswith molecule ring construction in the order of A, B, C, D. At some point chiralityis locked into the molecule via an asymmetric synthesisstep 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:
propargyl alcohol(C1, C2, C14), propionaldehyde(C13, C12, C18), isobutyric acid(C15, C16, C17, C11), Trimethyl(phenylthiomethyl)silane (C10), 2-bromobenzaldehyde (C3 to C9), diethylaluminum cyanide(C19) and trimethylsilylmethyl bromide (C20)
ynthesis A ring
Ring A synthesis ("scheme 1") starts by joining the THP protected
propargyl alcohol1.1 (the C2-C1-C14 fragment) and propionaldehyde1.2 (fragment C13-C12-C18) in a nucleophilic additionwith "n"-butyllithium to alcohol1.3. The Lindlar catalystthen reduces the alkyneto the alkenein 1.4 and Swern oxidationconvert the alcohol group to the enonegroup in 1.5. Fragment C11-C15-C16-C17 1.6 is then added as the lithium enolate of isobutyric acidethyl esterin a conjugate additionto gamma keto ester1.7. A Claisen condensationcloses the ring to 1.8 and the intermediate enol is captured by pivaloyl chloride (piv) as a protective group. The THP group is removed with TsOHto 1.9 and the formed alcoholoxidized by Swern oxidationto aldehyde1.10. The TIPS silyl enol ether1.11 is formed by reaction with the triflateTIPSOtf and DBU in DMAPsetting the stage for asymmetric dihydroxylationto hydroxyaldehyde 1.12. The piv protecting group is then replaced by a TIPS group in 1.14 after protecting the aldehyde as the aminal1.13 and as this group is automatically lost on column chromatography, the step is repeated to aminal 1.15. The C10 fragment is then introduced by the lithium salt of "Trimethyl(phenylthiomethyl)silane" 1.16 in a Peterson olefinationto the sulfide1.17 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.
ynthesis B ring
The bottom part of ring B is constructed by
nucleophilic additionto the aldehyde of 2.1 ("scheme 2") with dibenzyl acetalof "2-bromobenzaldehyde" 2.2 as its aryllithium. This step is much in common with the B ring synthesis in the Nicolaou Taxol total synthesisexcept that the aldehyde group is located at ring A and not ring B. The diolin 2.3 is protected as the boronic ester2.4 preparing the molecule for upper part ring closure with tin tetrachlorideto tricycle 2.5 in a Grob fragmentation-like reaction. After deprotection ( pinacol) to diol 2.6, DIBALreduction to triol 2.7 and TBS reprotection (TBSOtf, lutidine) to alcohol 2.8 it is possible to remove the phenylsulfide group in a with tributyltin hydrideand AIBN(see Barton-McCombie deoxygenation) to alcohol 2.9. Palladium on carbon hydrogenationremoves the benzyl protecting group allowing the Swern oxidationof 2.10 to ketone 2.11
ynthesis 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
Birch reduction( potassium, ammonia, tetrahydrofuran, -78°C, then ethanol) to diene3.2. Deprotection ( TBAF) to diol 3.3, reprotection as the benzaldehyde acetal3.4 and reduction ( sodium borohydride) to alcohol 3.5 allows the oxidation of the diene to the 1,4-butenediol 3.6. In this photochemical[4+2] cycloaddition, singlet oxygenis generated from oxygen and rose bengaland the intermediate peroxide is reduced with thiourea. The next order of business is introduction of the C19 fragment: the new diol group is protected as the PMP acetal3.7 (PMP stands for "p-methoxyphenyl") allowing the oxidation of the C4 alcohol to ketone 3.8 with the Dess-Martin periodinane. Diethylaluminum cyanidereacts in a conjugate additionto the enone group to nitrile3.9. The enol is protected as the TBS ether 3.10 allowing for the reduction of the nitrile group first to the aldehydewith DIBALand then on to the alcohol3.11 with Lithium aluminium hydride. The alcohol group is replaced by bromine in a Appel reactionwhich causes an elimination reaction(loss of HBr) to cyclopropane3.12. Treatment with hydrochloric acidforms ketone 3.13, reaction with Samarium(II) iodidegives ring-opening finally putting the C19 methyl group in place in 3.14 and deprotection (TBAF) and enol-ketone conversion gives hydroxyketone 3.15
ynthesis 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 (
hydrogen peroxide, sodium bicarbonate) again in 4.4 it is possible to oxidize the C19 alcohol to the ketone 4.5 with Dess-Martin periodinane. In a new round of protections the C7 alcohol is converted to the "2-methoxy-2-propyl" (MOP) ether 4.6 with 2-propenylmethyletherand PPTSand the C7 ketone is converted to its enolate4.7 by reaction with KHMDS and N,N-bis(trifluoromethylsulfonyl)aniline. These preambles facilitate the introduction of the final missing C20 fragment as the Grignard reagent"trimethylsilylmethylmagnesium bromide" which couples with the triflate in a tetrakis(triphenylphosphine)palladium(0)catalysed reaction to the silane4.8. The trimethylsilylgroup eliminates on addition of NCS to organochloride4.9. Prior to ring-closing the D ring there is some unfinished business in ring C. A C10 alcohol is introduced by MoOPH oxidationto 4.10 but with the wrong stereochemistry. After acetylationto 4.11 and inversion of configurationwith added base DBNthis problem is remedied in compound 4.12. Next dihydroxylationwith Osmium(VIII) oxideforms the diol4.13 with the primary alcohol on addition of base DBU displacing the chlorine atom in a nucleophilic aliphatic substitutionto oxetane4.14.
The C1, C2 and C4 functional groups are put in place next and starting from
oxetane5.1 ("scheme 5") the MOM protecting group is removed in 5.2 ( PPTS) and replaced by a TES group TESCl) in 5.3. The acetalgroup is removed in 5.4 ( hydrogenationPdOH2, H2) and replaced by a carbonate estergroup in 5.5 ( triphosgene, pyridine). The tertiary alcohol group is acetylated in 5.6 and in the final step the carbonate group is opened by reaction with phenyllithiumto the hydroxyester 5.7.
Prior to tail addition the TES protective group is removed in 5.8 (
hydrogen fluoride pyridine) and replaced by a TROC (trichloroethyl carbonate, TROCCl ) group in 5.9. The C13 alcohol protective group is removed in 5.10 ( TASF) enabling the tail addition of Ojima lactam5.11 (this step is common with all total synthetic efforts to date) to 5.12 with Lithium bis(trimethylsilyl)amide. The synthesis is completed with TROC removal ( zinc, acetic acid) to taxol 5.13.
Wikimedia Foundation. 2010.