The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(II)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(II) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(IV)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.

[reaction: see text] Hydroxy alkene 12, synthesized stereoselectively from 2-methyloxazole-4-carboxaldehyde, underwent intramolecular methoxy carbonylation in the presence of palladium(II) acetate to give 13 in which all five stereogenic centers around the tetrahydropyran correspond to those in ring C of phorboxazole A. Aldehyde 15, derived from 13, was linked to hydroxy alkene 23 via a Wittig coupling, and the composite 25 was subjected to a second palladium(II) acetate mediated methoxy carbonylation to yield 26, accompanied by acetoxy ester 27.

[Structure: see text] Subunits of phorboxazole A containing C1-C2, C3-C8, C9-C19, C20-C32, C33-C41, and C42-C46 were connected in a sequence that first linked C32 with C33 and then C41 with C42. A C3-C8 fragment was joined to C9-C19, and the assembled unit was then joined with the left half of 1. Closure of the macrolide was accomplished by esterification of the C24 alcohol followed by intramolecular Horner-Wadsworth-Emmons condensation to set the (E)-C2-C3 alkene.

[Structure: see text] Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20-C32 and C9-C19 containing tetrahydropyrans A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.

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