AsymmetricSynthesisof(+)-Negamycin.PDFVIP

Asymmetric Synthesis of ()-Negamycin Rajendra P. Jain and Robert M. Williams* Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523 rmw@ Received February 20, 2002 An asymmetric synthesis of the antibiotic ()-negamycin ( 1) has been achieved, starting from commercially available (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one (2). The synthesis involved the stabilized Wittig olefination of the lactone carbonyl group of 2 and subsequent asymmetric hydrogenation to generate the corresponding all-syn oxazine 4 with excellent diastereoselectivity. Conversion of 4 into -alkoxy imine 7 and subsequent CeCl3-promoted chelation-controlled allylation of 7 generated the corresponding homoallylamine 8 with good diatereoselectivity, which was readily converted into ()-negamycin ( 1) in 25% overall yield over 11 steps. Introduction ()-Negamycin ( 1, 2-[(3R,5R)-3,6-diamino-5-hydroxy- hexanoyl]-1-methylhydrazinoacetic acid) (Figure 1) is an unusual antibiotic containing a hydrazido peptide link- age.1 First isolated in 1970 by Umezawa and co-workers2 FIGURE 1. from culture filtrates of three strains closely related to Streptomyces purpeofuscus, the structure of negamycin of optically active negamycin described in these literature was confirmed in 1972 by total synthesis from D-galac- procedures required 820 steps, with yields ranging turonic acid.3 Negamycin exhibits considerable inhibitory between 7 and 32%.6 Herein, we report a