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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 taxol total synthesis published in the 1990's [1] [2]. The total synthesis of Taxol is considered a landmark in organic synthesis.

This synthesis is truly synthetic without any help from small biomolecule precursors and also a linear synthesis with molecule ring construction in the order of A, B, C, D. At some point chirality is locked into the molecule via an 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: 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)

Additional recommended knowledge

Contents

Synthesis A ring

Ring A synthesis (scheme 1) starts by joining the THP protected propargyl alcohol 1.1 (the C2-C1-C14 fragment) and propionaldehyde 1.2 (fragment C13-C12-C18) in a nucleophilic addition with n-butyllithium to alcohol 1.3. The Lindlar catalyst then reduces the alkyne to the alkene in 1.4 and Swern oxidation convert the alcohol group to the enone group in 1.5. Fragment C11-C15-C16-C17 1.6 is then added as the lithium enolate of isobutyric acid ethyl ester in a conjugate addition to gamma keto ester 1.7. A Claisen condensation closes 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 TsOH to 1.9 and the formed alcohol oxidized by Swern oxidation to aldehyde 1.10. The TIPS silyl enol ether 1.11 is formed by reaction with the triflate TIPSOtf and DBU in DMAP setting the stage for asymmetric dihydroxylation to hydroxyaldehyde 1.12. The piv protecting group is 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 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 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 nucleophilic addition to the aldehyde of 2.1 (scheme 2) with dibenzyl acetal of 2-bromobenzaldehyde 2.2 as its aryllithium. This step is much in common with the B ring synthesis in the Nicolaou Taxol total synthesis except that the aldehyde group is located at ring A and not ring B. The diol in 2.3 is protected as the boronic ester 2.4 preparing the molecule for upper part ring closure with tin tetrachloride to tricycle 2.5 in a Grob fragmentation-like reaction.

After deprotection (pinacol) to diol 2.6, DIBAL reduction 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 hydride and AIBN(see Barton-McCombie deoxygenation) to alcohol 2.9. Palladium on carbon hydrogenation removes the benzyl protecting group allowing the 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 Birch reduction (potassium, ammonia, tetrahydrofuran, -78°C, then ethanol) to diene 3.2. Deprotection (TBAF) to diol 3.3, reprotection as the benzaldehyde acetal 3.4 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 oxygen is generated from oxygen and rose bengal and 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 acetal 3.7 (PMP stands for p-methoxyphenyl) allowing the oxidation of the C4 alcohol to ketone 3.8 with the Dess-Martin periodinane. Diethylaluminum cyanide reacts in a conjugate addition to the enone group to nitrile 3.9. The enol is protected as the TBS ether 3.10 allowing for the reduction of the nitrile group first to the aldehyde with DIBAL and then on to the alcohol 3.11 with Lithium aluminium hydride. The alcohol group is replaced by bromine in a Appel reaction which causes an elimination reaction (loss of HBr) to cyclopropane 3.12. Treatment with hydrochloric acid forms ketone 3.13, reaction 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 (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-propenylmethylether and PPTS and the C7 ketone is converted to its enolate 4.7 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 silane 4.8. The trimethylsilyl group eliminates on addition of NCS to organochloride 4.9. Prior to ring-closing the D ring there is some unfinished business in ring C. A C10 alcohol is introduced by MoOPH oxidation to 4.10 but with the wrong stereochemistry. After acetylation to 4.11 and inversion of configuration with added base DBN this problem is remedied in compound 4.12. Next dihydroxylation with Osmium(VIII) oxide forms the diol 4.13 with the primary alcohol on addition of base DBU displacing the chlorine atom in a 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 acetal group is removed in 5.4 (hydrogenation PdOH2, H2) and replaced by a carbonate ester group 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 phenyllithium to 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 lactam 5.11 (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.

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
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Kuwajima_Taxol_total_synthesis". A list of authors is available in Wikipedia.
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