Synthesis of Discodermolide Subunits by S(E)2' Addition of Nonracemic Allenylstannanes to Aldehydes.
Three subunits, 15, 29, and 34, of the immunosuppressant discodermolide were prepared starting from (S)-3-[(tert-butyldimethylsilyl)oxy]-2-methylpropanal ((S)-1) and the enantioenriched allenylstannanes (P)-2a, (P)-2b, and (P)-31. The route to 15 involved BF(3)-promoted addition of stannane (P)-2a to aldehyde (S)-1 which afforded the syn,syn-homopropargylic alcohol adduct 3 in 97% yield. The derived p-methoxybenzylidene acetal 5 was treated with Red-Al to effect cleavage of the pivalate and reduction of the double bond leading to the (E)-allylic alcohol 6. Sharpless epoxidation and subsequent addition of Me(2)CuCNLi(2) yielded the syn,syn,syn,anti stereopentad, diol 8. Protection of the secondary alcohol and oxidation of the primary gave aldehyde 12, which was treated with the alpha-bromo allylsilane 13 and CrCl(2), followed by NaH to effect elimination to the diene 15. A similar sequence was employed to prepare aldehyde 29. In this case aldehyde (S)-1 was converted to the anti,syn-homopropargylic alcohol 20 by treatment with the allenyl indium reagent formed in situ from allenylstannane (P)-2b and InBr(3). Epoxy alcohol 24, prepared from alcohol 20 by the above-described sequence, was reduced with Red-Al to afford diol 25. Protection of the secondary alcohol and oxidation of the primary completed the synthesis of 29. The anti,syn-homopropargylic alcohol 32 was obtained through addition of the allenic indium reagent, from allenylstannane (P)-31, to aldehyde (S)-1. Protection of the derived diol 33 as the p-methoxybenzylidene acetal afforded the third subunit, acetylene 34. Addition of the lithio derivative of 34 to aldehyde 29 gave alcohol 35 with the carbinyl stereochemistry needed for C7 of discodermolide as the major product.
Marshall
James A.
JA
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901.
Lu
Zhi-Hui
ZH
Johns
Brian A.
BA