antibiotic-associated pseudomembranous colitis, a leading
cause of infectious diarrhea in hospitals worldwide.7
Given the biological activity of castanospermine, it is
understandable that almost 30 years after its initial isolation
this alkaloid remains a relevant and popular synthetic
target.8,9 That minor structural/stereochemical alterations to
1 lead to dramatic alterations in glycosidase selectivity only
adds further impetus to the development of new synthetic
routes to this natural product.10 In light our of our ongoing
interest in the synthesis of R-glucosidase inhibitors11,12 and
having recently reported a versatile oxamidation method for
the preparation of R-hydroxyalkyl lactams involving the
intramolecular addition of acylnitrenium ions to alkenes,13
we were prompted to consider whether this methodology
might be gainfully employed in the enantioselective prepara-
tion of (+)-castanospermine. Herein, we report the successful
implementation of this idea through the use of a substrate-
controlled nitrenium ion oxamidation reaction.
closure (Scheme 1). In turn, this compound would be
accessed through the cyclization of the nitrenium ion
generated upon the oxidation of methyl D-gluco-hydroxamate
6. Since singlet nitrenium ions are known to undergo
concerted addition to alkenes,14 this reaction would generate
bicyclic aziridinium ion 3, which upon concerted, regiose-
lective ion-pair collapse at the external (R) position15 and
hydrolysis of the resulting triflouroacetate ester adduct would
provide δ-lactam 2 and thereby establish the C-1/8a erythro
stereodiad of the natural product. Regarding the diastereo-
selectivity of the addition process, we anticipated that
cyclization of the nitrenium ion generated from 6 would
preferentially proceed via a transition state resembling
pseudochair 4, thereby avoiding the 1,3-allylic strain16
present in boatlike conformer 5.17
Our initial route toward (+)-castanospermine (1) com-
menced from tribenzyl D-glucono-δ-lactone (7),18 which
underwent ring opening with the methoxylamine in the
presence of Me3Al19 to provide O-methyl hydroxamate 8 in
excellent yield (Scheme 2). Chemoselective oxidation of the
From a reterosynthetic perspective, we envisioned that the
indolizidine ring of 1 could be generated from R-hydroxy-
alkyl lactam 2 through a sequence of reduction and ring
(3) (a) Gloster, T.; Meloncelli, P.; Stick, R.; Zechel, D.; Vasella, A.;
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Scheme 2. Initial Route to (+)-Castanospermine (1)
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