Azetidine 2-carboxylic acid (Aze) is a naturally occurring amino acid and is toxic by mis-incorporation in place of prolines in human. Aze analogues may be useful building blocks for novel peptidomimetics. It is not possible to make peptides with 3-hydroxy Aze as a component since at pH >8, the ring is fragmented by a retro-aldol reaction. This paper describes the synthesis of 3-fluoro-Aze intermediates to form stable peptide analogues. D-Glucose can be efficiently transformed into the ditriflates 1  and 2 , which with benzylamine give good yields of the bicyclic azetidines 3  and 4 . Elaboration gives either enantiomer of trans, trans-fluoro Aze 5D  and 5L  in good yield. The ester 5L  can undergo displacement of the OH group to give the azido Aze 6  for incorporation of d-amino Aze into peptides. Alternatively, ring expansion during the nucleophilic displacement gives the trans, trans-difluoro proline 7  as a novel building block. Meanwhile, novel fluoro iminosugars such as 8  and 9  are also accessible. None of the fluoro iminosugars affect any glycosidase. However one of them is comparable to 5-fluoruracil and Gemcitabine in its effect on human pancreatic cancer cell growth.

Fluoro azetidines and difluoro prolines from D-glucose: Inhibition of pancreatic cancer cell growth by a fluoro azetidine

248th National Meeting (2014)

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