11 Total Synthesis of Leustroducsin B
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Leustroducsin B (LSN-B, 1b) is a potent colony-stimulating factor inducer isolated from the culture broth of Streptomyces platensis SANK 60191 by Sankyo's groups. LSN-B is known to exhibit a variety of biological activities and is likely to be developed as a new drug candidate. These interesting biological activities coupled with its unique structural features have attracted our attention as a target for total synthesis. We designed the construction of a carbon framework of LSN-B by coupling the aldehyde 2 and the enyne 3. The key point of synthesis of 2 was construction of C8, C9 stereocenters. The stereochemistry of C8 of 2 was controlled by lipase-mediated desymmetrization of 2,2-disubstituted propanediol 10. Chelation-controlled addition of allylmagnesium bromide to the aldehyde 12 in Et_2O at -78℃ afforded the desired sec-alcohol 13 as a single diastereomer. Upon treatment with a catalytic amount of Ti(Oi-Pr)_4 in refluxing benzene, 20 underwent smooth cyclization to give lactone 21. Synthesis of the enyne 3 involves optical resolution of racemic hydroxy ester 23 by lipase, (Z)-selective Horner-Wadsworth-Emmons reaction and Sonogashira coupling reaction. It was found that Zn reagents were very effective for the coupling reaction between the aldehyde 22 and the enyne 25. The alkynylzinc bromide 26, which was prepared from 25, underwent smooth addition to 22 in toluene-Et_2O to give the desired adduct 27 as a single diastereomer. Partial reduction of the conjugated triple bond was best carried out with Zn/LiCuBr_2 according to the method of Brandsma to yield the Z,Z-diene 28. The final stage of our synthesis involves a series of functional group manipulations without disturbing the other delicate functionalities. For the reason mentioned above, we devised this new benzylidene group, which can be deprotected safely under weakly acidic conditions from densely functionalized substrates. The protecting group was easily removed in a 2-step procedure (30 to 31, (HF)_3・Et_3N; AcOH-THE-H_2O). Finally, removal of the phenoxyacetyl group on C11-OH with Er(OTf)_3 in MeOH followed by treatment with Pd(PPh_3)_4, HCO_2H and Et_3N furnished leustroducsin B (1b).
