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Kuwajima Taxol total synthesis
The Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the Tokyo Institute of Technology is one of several efforts in taxol total synthesis published in the 1990s. 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)
==Synthesis A ring==
Ring A synthesis (''scheme 1'') started 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 reduced the alkyne to the alkene in 1.4 and Swern oxidation converted the alcohol group to the enone group in 1.5. Fragment C11-C15-C16-C17 1.6 was then added as the lithium enolate of isobutyric acid ethyl ester in a conjugate addition to gamma keto ester 1.7. A Claisen condensation closed the ring to 1.8 and the intermediate enol is captured by pivaloyl chloride (piv) as a protective group. The THP group was 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 was 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 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.
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