Asymmetric synthesis of 2-mono- and 2,3-trans-disubstituted azetidines

Article abstract of DOI:10.1002/ejoc.200400473

A versatile and efficient asymmetric synthesis of 2-mono-and 2,3-trans-disubstituted azetidines with excellent diastereomeric (de = 93 to ≥ 96%) and enantiomeric excesses (ee ≥ 96%) in good overall yields is described. Virtually stereoisomerically pure differently N,O-protected 3-amino-1-alkanols were prepared as intermediates. Key steps are a diastereoselective α-alkylation of aldehyde SAMP-hydrazones with benzyloxymethyl chloride as the electrophile, and a nucleophilic 1,2-addition of various organocerium reagents to the hydrazone CN double bond. An epimerisation-free reductive removal of the auxiliary gave O-benzyl-protected 3-amino-1-alkanols. After N-tosylation and hydrogenolytic cleavage of the benzylic protecting group, ring closure to the corresponding N-tosylazetidines was achieved in good yields under Mitsunobu conditions. Detosylation was easily accomplished employing sodium/naphthalene. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.