We will develop and demonstrate a powerful new strategy for bicyclic acetal synthesis and elaboration. We will apply this ketalization/ring-closing metathesis technique to the synthesis of four natural products of varying structure to illustrate its versatility. Key attributes of this strategy that act in concert to afford extremely short synthetic routes to the chosen targets are: . Subunit convergence by intermolecular ketalization (a reliable, high-yielding net dehydration); . Intramolecular C-C bond formation via ring-closing metathesis; . Production of a dissymmetric bicyclic acetal from a C2-symmetric diene-diol; . Conformational locking of a dihydropyran within the bridged bicyclic acetal, allowing exploitation of steric and stereoelectronic biases for hydropyran functionalization; . Potential for chain elaboration in two directions in the residual vinyl group of the diene-diol and the ketone """"""""R"""""""" group in convergence subunits; . Internal masking of three functional groups (hydroxyl, hydroxyl, and carbonyl), thus avoiding extra steps for protection and deprotection. We will synthesize the targets below by expeditious sequences enabled by these considerations: . 20-Deoxybryostatins, representative of the clinically-significant bryostatin class of anticancer agents; . Didemniserinolipid B, containing the 6,8-dioxabicyclo[3.2.1]octane skeleton common in bioactive agents; . Thromboxane B2-(TXBz)., natural degradation product of platelet aggregation mediator TXA2and model for clinical development of thrombosis inhibitors for cardiovascular disease treatment; . Kendomycin, a recently isolated ansa macrocyclic quinone methide that has exhibited biological activity as an endothelin receptor antagonist, as an antibacterial against MRSA strains, and as a potent anticancer agent with cytotoxicities similar or superior to doxorubicin and cisplatin against several cell lines. The proposed syntheses are one-third to one-half as long as comparative benchmarks for these targets, illustrating the effectiveness of this developing strategy for dramatically affecting synthetic efficiency.
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| Voight, Eric A; Seradj, Hassan; Roethle, Paul A et al. (2004) Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis. Org Lett 6:4045-8 |
