Total synthesis of the marine toxin phorboxazole A using palladium(ii)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesisElectronic supplementary information (ESI) available: Preparations and analytical details of synthetic compounds. See DOI: 10.1039/c2ob25766a

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 3 was 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%. 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 ).