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.

Beidseitig gearbeitet: Neooxazolomycin, das zu den Oxazolomycin‐Antibiotika gehört, wurde mit einem konvergenten Ansatz in der natürlich vorkommenden Form synthetisiert. Die hoch stereoselektive Strategie umfasst eine Tamao‐Hydrosilylierung, eine palladiumkatalysierte Enolatalkenylierung, eine Dihydroxylierung mit Lactonbildung und eine Nozaki‐Hiyama‐Kishi‐Reaktion für das rechte Segment sowie einen verbesserten Weg zum linken Segment.

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Beidseitig gearbeitet: Neooxazolomycin, das zu den Oxazolomycin‐Antibiotika gehört, wurde mit einem konvergenten Ansatz in der natürlich vorkommenden Form synthetisiert. Die hoch stereoselektive Strategie umfasst eine Tamao‐Hydrosilylierung, eine palladiumkatalysierte Enolatalkenylierung, eine Dihydroxylierung mit Lactonbildung und eine Nozaki‐Hiyama‐Kishi‐Reaktion für das rechte Segment sowie einen verbesserten Weg zum linken Segment.