A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.
[Show abstract][Hide abstract] ABSTRACT: A highly stereoselective joint total synthesis of the potent polyketide macrolide antibiotics etnangien and etnangien methyl ester was accomplished by a convergent strategy and proceeds in 23 steps (longest linear sequence). Notable synthetic features include a sequence of highly stereoselective substrate-controlled aldol reactions to set the characteristic assembly of methyl- and hydroxyl-bearing stereogenic centers of the propionate portions, an efficient diastereoselective Heck macrocyclization of a deliberately conformationally biased precursor, and a late-stage introduction of the labile side chain by means of a high-yielding Stille coupling of protective-group-free precursors. Along the way, an improved, reliable protocol for a Z-selective Stork-Zhao-Wittig olefination of aldehydes was developed, and an effective protocol for a 1,3-syn reduction of sterically particularly hindered beta-hydroxy ketones was devised. Within the synthetic campaign, a more detailed understanding of the intrinsic isomerization pathways of these labile natural products was elaborated. The expedient and flexible strategy of the etnangiens should be amenable to designed analogues of these RNA-polymerase inhibitors, thus enabling further exploration of the promising biological potential of these macrolide antibiotics.
The Journal of Organic Chemistry 03/2010; 75(8):2429-44. DOI:10.1021/jo100201f · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Even though the macrolides of the iejimalide family are of marine origin, whereas those of the archazolid series derive from terrestrial myxobacteria, a comparison of their constitution, stereochemistry, and biological activity suggests that these natural products are close structural and functional relatives. Guided by this perception, compound 5 was prepared, which hybridizes the macrolactone core of iejimalide B (2) with the tail of archazolid A (3). The cytotoxicity profile of this chimera, as determined with a panel of 12 human cancer cell lines, corresponds to that of the parent compound 2, although its potency is lower. This outcome may be interpreted on the basis of molecular dynamics calculations, which suggest that the low energy conformations of 2 and 5 are similar but the energetic barriers between the relevant conformers are distinctly higher for the hybrid structure. The synthesis of 5 hinged on a regioselective functionalization of 2,4-dibromothiazole 6, a highly selective CBS-reduction of ketone 8, a Suzuki cross coupling of vinyl boronate 17 with the elaborate alkenyl iodide 16, and a productive closure of the macrocycle by RCM, which requires the selective activation of two out of eight double bonds present in the cyclization precursor 20 by the second-generation Grubbs catalyst 21.
[Show abstract][Hide abstract] ABSTRACT: Reactions of thioamide dianions, derived from secondary N-arylmethyl thioamides using BuLi, with thioformamides followed by the addition of iodine to yield 5-amino-2-thiazolines are described. Treatment of the 5-amino-2-thiazolines with iodine leads to a highly efficient production of 5-aminothiazoles. When N,N-diarylthioformamides are employed in this process, fluorescent 5-N,N-diarylthiazoles are obtained.
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