Concise synthesis of the C15-C38 fragment of okadaic acid: application of the Suzuki-Miyaura reaction to spiroacetal synthesis.

A concise synthetic entry to the C15-C38 fragment of okadaic acid by exploiting a Suzuki-Miyaura reaction for the rapid assembly of the spiroacetal substructures has been developed. The present synthesis was completed in 19 linear steps from a commercially available material, showcasing the efficiency of our synthetic strategy.

Formal total synthesis of okadaic acid via regiocontrolled gold(I)-catalyzed spiroketalizations.

Both C19 and C34 spiroketal domains of okadaic acid were assembled using gold(I) chloride catalyzed spiroketalizations, and the two resulting fragments were coupled to give the C15-C38 fragment of okadaic acid, a known intermediate for the total synthesis of this important natural product.

Versatile synthesis of the C3-C14 domain of 7-deoxyokadaic acid.

Described is a flexible synthesis of the C3-C14 domain of 7-deoxyokadaic acid that is amenable to facile structural diversification. Treatment of ynone 10 under acidic conditions led to net bis-conjugate addition of the latent diol to give the thermodynamically favored spiroketal 27, a versatile intermediate, en route to 7-deoxyokadaic acid and analogs.

DTX5c, a new OA sulphate ester derivative from cultures of Prorocentrum belizeanum.

Prorocentrum belizeanum is a dinoflagellate known for its okadaic acid (OA) and dinophysitoxins (DTXs) production, both OA and DTX are polyether toxins of the Diarrhetic Shellfish Poisoning (DSP) group. We have recently published the isolation of a new diol-ester of okadaic acid from cultures of P. belizeanum. On this occasion we present a new sulphated water-soluble derivative, DTX-5c, isolated from this microalga, whose structure was established on the basis of its spectroscopical data.

Expedient access to the okadaic acid architecture: a novel synthesis of the C1-C27 domain.

A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constitutent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.