Condensation of the aryllithium reagents,
prepared from the bromides 10 and 11 and
tert-butyllithium, with lactone 19 and acid-catalyzed
spirocyclization gave the papulacandin spiroketals
14 and 15. Subsequent protection using
di-tert-butylsilyl bis(trifluoromethanesulfonate) gave
the
diols 31 and 30. Isoleucine (37)
was converted using a double Wittig reaction sequence and
propargylation of the intermediate aldehyde 46 into the
alkynol 47. Separation of the C-7 epimers
of 47 was achieved using kinetic resolution via
Sharpless epoxidation. Both alkynol epimers
53
and 57 were converted into the papulacandin side chain
esters 65 and 66 using a
hydrozirconation
and palladium(0)-catalyzed coupling sequence. Comparisons of
Mosher ester derivatives of 65 and
66 with the Mosher ester derivative of the natural
papulacandin side chain and further degradation
were consistent with the stereochemistry of the natural product being
7S,14S. Esterification of
the spiroketals with the mixed anhydride 70 and global
deprotection gave papulacandin D (1).
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