Toward the Total Synthesis of Disorazole A₁ and C₁:  Asymmetric Synthesis of a Masked Southern Segment

Abstract

[reaction: see text] A highly convergent asymmetric synthesis of the masked southern segment of the antimitotic agent disorazole A(1) involves a Sonogashira coupling between a C1'-C10' enyne and a suitably protected C11'-C19' vinyl iodide. The central E,Z,Z-triene moiety is masked as a more stable ynediene.

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“…Solvent evaporation, alcoholysis with i-PrOH (80°C), gives a 4:1 mixture of stereotriade 57 and its α,β,γ-anti,anti stereomer. This mixture is converted into their kinetic silyl enol ethers and oxidized with mCPBA (Rubottom oxidation [157]), giving 58, which undergoes Mukaiyama aldol coupling with aldehyde 59 [158][159][160] producing alkene 60 (73 %). Ozonolysis of 60 provides an aldehyde that is allylated under Brown's conditions [161].…”

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“…7). 36 Additionally, positioning the alkyne at C-9/C-10 did not significantly affect the relative energies of tetradehydrodisorazole C 1 ( 44 ) and disorazole C 1 (465.8 kJ/mol vs 463.3 kJ/mol, respectively).…”

“…The stereochemical information gained from these studies was undoubtedly unavailable to Meyers and co-workers at the time of their work on disorazole C 1 29,33. In 2002, Hoffmann and co-workers first reported the synthesis of a masked fragment of disorazole C 1 with the correct absolute and relative configurations at all stereocenters 36. Hoffmann adopted a synthetic strategy that utilized a strategically placed alkyne along the C-7/C-12 backbone to mask the labile triene moiety of disorazole C 1 , thereby allowing for a more efficient cyclodimerization of dienyne 41 (Fig.…”

“…Previous work by Meyers29,33 and Hoffmann36,40,41 revealed important synthetic parameters, including the instability of the triene backbone and the significance of the position of the alkyne which served both to mask the ( Z )-olefin(s) of the triene unit as well as facilitate the macrolactonization. Wipf and Graham were able to capitalize on these important findings and devise a synthetic approach that utilized a Sonogashira coupling to construct the carbon–carbon bonds at C-8/C-9 of the dienyne monomer 66 (Fig.…”

“…Swern oxidation of the primary alcohol proceeded smoothly, but, unfortunately the subsequent alkyne addition using 1-lithiopropyne proved problematic, resulting in formation of a 1.1: 1.0 ( syn: anti ) ratio of separable diastereomers at C-16. Hoffmann also reported difficulties in the selective formation of the neopentyl anti -1,3-diol 36,41,46. Attempts at improving the diastereoselectivity for the generation of this diol segment have thus far proved unsuccessful.…”