Total Synthesis of Oxazolomycin A

Abstract

The first total synthesis of oxazolomycin A, a structurally novel oxazole polyene γ-lactam/β-lactone antibiotic, is described. Key features include the stereocontrolled construction of the right-hand heterocyclic core by taking advantage of an In(III)-catalyzed Conia-ene type cyclization and the asymmetric synthesis of the left-hand segment starting with a Cinchona alkaloid-catalyzed cyclocondensation of an aldehyde with an acid chloride.

Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies

“…79,80) The importance of nitrogen-containing heterocycles as drugs and other various chemical entities continues to inspire the development of tactical methods for their synthesis. In connection with a project [81][82][83][84] directed toward the synthesis of biologically intriguing natural products with highly functionalized pyrrolidinone cores such as lactacystin (72), salinosporamide A (73), neooxazolomycin (74), and oxazolomycin A (75), we became interested in developing a novel approach relying upon the Conia-ene reaction of amidomalonate 76 to give 78 via 77 (Chart 16). We envisaged that the suitably functionalized pyrrolidinone skeletons useful for the synthesis 4.1 Indium-Catalyzed Cyclization 83) Conia-ene reactions 85) usually require harsh conditions so that racemization of the product and isomerization of the exo olefin from the β,γ-to α,β-position are serious matters of concern in the reaction shown in Chart 16.…”

“…Finally, the synthesis of salinosporamide (73) was achieved from 95 in a six-step sequence involving the removal of the p-methoxybenzyl group, reductive opening of the cyclic acetal, (Me 2 AlTeMe) 2 -promoted dealkylative cleavage 101) of the methyl ester, β-lactonization, and chlorination. 82,84) Oxazolomycin A and neooxazolomycin, originally isolated from a strain of Streptomyces by the group of Uemura in 1985, 102,103) constitute a family of structurally unique oxazole polyene lactam-lactone antibiotics together with seven other congeners identified to date (Chart 21). These oxazolomycins exhibit wide-ranging, potent inhibitory activity against Gram-positive bacteria and antiviral activity against vaccinia, herpes simplex type I, and influenza A (WSN; H1N1) as well as in vivo (74) had long been the only achievement until we have recently reported the syntheses of neooxazolomycin (74) 82) and oxazolomycin A (75).…”

“…These oxazolomycins exhibit wide-ranging, potent inhibitory activity against Gram-positive bacteria and antiviral activity against vaccinia, herpes simplex type I, and influenza A (WSN; H1N1) as well as in vivo (74) had long been the only achievement until we have recently reported the syntheses of neooxazolomycin (74) 82) and oxazolomycin A (75). 84) Recently, Taylor and colleagues have also reported the formal synthesis of neooxazolomycin (74). 107) 82) To develop an effective general method for the synthesis of the oxazolomycin family of compounds, we initially selected neooxazolomycin (74) as a target.…”

“…Finally, following Kende et al's procedure exactly, 106) condensation of 96 with the free amine in situ generated from the right-hand segment 97 followed by deacetylation allowed us to complete the total synthesis of neooxazolomycin (74). 84) Taking into account the labile nature of oxazolomycin A (75) under various deprotection conditions, we focused on a challenging strategy wherein the final step is the selective construction of the β-lactone ring from the unprotected tetrahydroxy acid 121 (Chart 25). Based on the methodology developed in the synthesis of neooxazolomycin (74), we envisioned the assembly of 121 from the aforementioned two parts 96 and 108 and the right-hand core 122.…”

Asymmetric Synthesis of the Fully Elaborated Pyrrolidinone Core of Oxazolomycin A

“…4 The sole total synthesis of oxazolomycin A was reported in 2011 by Hatakeyama et al in 34 linear steps, utilizing a Conia-ene type cyclization to construct the central γ-lactam ring. 5 Elsewhere, the groups of Kende in 1990 and Hatakeyama in 2007 have † University of Oxford. ‡ GlaxoSmithKline.…”