Stereochemical assignment of the mycalolides and the ulapualides: Studies directed toward the total synthesis of ulapualide A

Ulapualide A belongs to an important class of trisoxazole-containing marine natural products, which includes mycalolides, kabiramides, halichondramides, haligishamides, and jaspisamides. Chiral (E)-crotylsilane bond construction methodology was used to provide a C20--C35 subunit based upon the initial reported stereochemical assignment of ulapualide A. The reported relative and absolute stereochemistry of the ulapualides was corrected through combination of synthesis of an elaborated C20--C35 subunit and chemical degradation of the natural product. The stereochemistry of the ulapualides and mycalolides was determined to be identical in the C20--C35 portion of the compounds. The synthesis of the C20--C35 subunit was then modified to prepare the fragment more efficiently, bearing the stereochemical relationships found in the natural product.; The stereocontrolled synthesis of a C1--C19 fragment of ulapualide A was also accomplished. The C3 hydroxyl-bearing stereocenter was established by Jacobsen's hydrolytic kinetic resolution (HKR) of a terminal epoxide, while the C9 methyl stereocenter was introduced through an asymmetric crotylation using a chiral organosilane reagent. Union of the C1--C6 and the C7--C19 fragments by a Kishi-Nozaki coupling followed by oxidation and conjugate addition of hydride completed the preparation of this fragment.; The viability of a modified Schlosser-Wittig olefination was established to install the C19--C20 trans-olefin, characteristic of this class of trisoxazole containing marine natural products. Preliminary model studies utilizing mono-, bis-, and trisoxazoles with various alpha,beta-unsaturated and branched aldehydes for the formation of trans-olefins provided good precedence for extension to the natural product.