Kishi’s synthesis

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Kishi s synthesis 290 ring closing metathesis 302 ring expansion 65, 98... 

Based on the method used in Kishi s synthesis, a diene moiety can be connected to 77 through routine synthetic chemistry, and this finishes the C-15 to C-19 subunit of intermediate 66. Conversion of 77 to 66 is briefly depicted in Scheme 7-19. 

Kishi s synthesis of aklavinone (625) (Section 4.1.8.4) exploits the regiodirecting bias of a bromide substituent in dienophile (94) (which parallels that of the phenylthio group in 90) (Scheme 26). The initially formed cycloadduct underwent spontaneous elimination of HBr (neutralized by SrCOa) and oxidation (air, Pt 2NEt) to give the anthraquinone product (97) as the exclusive regioisomer. 

This strategy was adopted in the synthesis of halicondrin [231]. A related strategy was also developed in Kishi s synthesis of halicondrin [232,233]. Finally, it should be noted that this same strategy can be performed on ketoses, thus forming gem-di-substituted C-glycosyl compounds. The ketose variation was used in an approach to the synthesis of verrucosidin [234]. 

For a full discussion of Kishi s synthesis of Monensin see Nicolaou and Sorenson p. 185. 

Scheme 16 Kishi s synthesis-3. Intramolecular Diels-Alder reaction and completion of the total synthesis...

Not long after Kishi s synthesis was completed, Jacobi published an equally impressive campaign featuring the development of an intramolecular 1,3-dipolar cycloaddition of an azomethine imine to a 2-imidazolone to... 

The case was strongly made that, in spite of the recent significant achievements in the arena of total synthesis, we still have far to go before we can accomplish practical syntheses of any desired structure, no matter how complicated. We have come a long way from Wohler s synthesis of urea to the Woodward-Eschenmoser synthesis of vitamin B12 and Kishi s synthesis of palytoxin. However, even these monumental synthetic feats are only big steps along the long road toward synthetic perfection. It will probably take another 150 years before chemists will be able to prepare non-biological compounds of... 

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