Total Synthesis of Neooxazolomycin

Abstract

Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayNeooxazolomycin and oxazolomycin A, originally isolated from a strain of Streptomyces by Uemura and co-workers in 1985, [1] together with the seven other congeners identified to date constitute a family of structurally unique oxazole polyene lactam-lactone antibiotics. These oxazolomycins were found to exhibit wide-ranging and potent antibacterial and antiviral activities as well as in vivo antitumor activity. Their intriguing molecular architectures and biological activities make these compounds attractive targets for synthesis. [2,3] In 1990, Kende et al. disclosed the synthesis of neooxazolomycin, [4] and this superb achievement is the first and only total synthesis of any member of this family; however the stereocontrolled construction of the right-hand core has remained an unanswered challenge.Our synthetic plan for neooxazolomycin makes a disconnection at the amide linkage to give the left-hand segment 1 and right-hand segment 2 (Scheme 1). Since Kende et al. had already demonstrated an effective method for the synthesis of 1 [4] by a Reformatsky-type aldol reaction [5] and Stille coupling, [6] the major challenge in the synthesis resided in the stereoselective construction of 2. From the retrosynthetic perspective, we envisioned pyrrolidinone 4 as a precursor of 2 with considerably less structural complexity which would lead to 2 through a Nozaki-Hiyama-Kishi reaction [7] and stereoselective dihydroxylation with concomitant lactonization. We postulated that this precursor could be accessed by a palladium-catalyzed cyclization of amide 5. This approach is particularly appealing since the three contiguous stereogenic centers including two quaternary centers could be created by one dihydroxylation process. The required amide 5 was synthesized in a completely stereoselective manner by taking advantage of the intramolecular hydrosilylation [8] developed by Tamao et al. [9] (Scheme 2). Thus, alkynol 8 was first prepared by the coupling of alkyne 6 [10] and triflate 7, [11] both readily available from (S)hydroxy-2-methylpropanoate, followed by desilylation. Reaction of 8 with tetramethyldisilazane provided hydrodimethylsilyl ether 9, which upon hydrosilylation with [Pt(dvds)] [12] as a catalyst in THF at room temperature followed by exposure of the resulting siloxane 10 to iodine in the presence of CsF in Scheme 1. Retrosynthetic analysis of neooxazolomycin. Bn = benzyl, Fmoc = 9-fluorenylmethyloxycarbonyl.

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).…”

“…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). 84) Recently, Taylor and colleagues have also reported the formal synthesis of neooxazolomycin (74).…”

“…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. Our synthetic plan for this natural product made the obvious disconnection at the amide linkage to the left-hand segment 96 and the right-hand segment 97 (Chart 22).…”

“…The left-hand segment 96 was prepared by the method outlined in Chart 24, which featured a marked improvement of the procedure 82) we previously reported. The synthesis began with a Cinchona alkaloid-catalyzed asymmetric cyclocondensation of an aldehyde and an acid chloride.…”