Synthesis of Nagstatin and its Analogues

• Main Author: Abdulmalek, Emilia
• Published: University of Oxford 2007
• Subjects: 547.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487215

Nagstatin is a naturally occurring carbohydrate mimic with glycosidase inhibiting properties. It was isolated from the fermentation broth of Streptomyces amakuensis and was shown to be specific inhibitor of N-acetyl-~-D-glucosaminidase.1 The aims of the described study were to establish an efficient and versatile approach towards the synthesis of nagstatin that would be applicable for a rapid synthesis ofa library of nagstatin analogues. In the initial approach, a key lactam intermediate was generated via ring-closing metathesis of an amide, which was derived from both enantiomers of methionine. An Nisoxazolylmethyl group served the dual purpose of protecting group and as a direct precursor of the imidazole unit. Unfortunately, suitable conditions for the transformation of the resulting ~-ketonitrile into the desired fused piperidine-imidazole were not found. In the next approach, a protected, optically active, vinylglycinol derivative was prepared in 6 steps from L-methionine via sulfi1imine elimination and converted into an unsaturated lactam intermediate via ring-closing metathesis. Elaboration into the fullyfunctionalized lactam ofnagstatin was envisaged but not performed. A gluco-analogue of the fully-functionalized lactam was later synthesized in 6 steps from sorbyl alcohol via tethered aminohydroxylation, cross metathesis, dihydroxylation and base-induced cyclization. Finally, a key unsaturated lactam intermediate was accessed via Pd-catalyzed decarboxylative carbonylation of 5-vinyloxazolidinone at low pressure on N-tosyl protection. Directed epoxidation attempted on a homoallylic alcohol with mCPBA later resulted in the almost exclusive formation of the trans-epoxy alcohol. Directed dihydroxylation attempted on the resulting allylic alcohol failed and the diol was recovered as a lactone on hydrolysis or thiolysis ofthe osmate ester.