Synthesis of demethylallosamidin, a yeast chitinase inhibitor; use of disaccharide glycosyl donor carrying novel neighboring group

Synthesis and Biological Activity of Natural Aminocyclopentitol Glycosidase Inhibitors: Mannostatins, Trehazolin, Allosamidins, and Their Analogues

“…Pseudotrisaccharide 416, an "all-gluco" analogue of allosamidin (4), is apparently susceptible to hydrolysis by chitinases themselves (Table 3). 115 That the C-3 hydroxyl group of the central sugar in allosamidin (4) might mimic an incoming nucleophilic water molecule, as has previously been suggested, 25 seems a less plausible explanation: the glucoallosamidins (286a and 286b), both of which contain a central D-glucosamine unit rather than D-allosamine, are better inhibitors of certain chitinases than allosamidin (4) itself, 95 and the "all-gluco" analogue 418 of demethylallosamidin shows activity 108 comparable to that of the natural compound 284 toward Candida albicans chitinase (see Table 3).…”

“…Takahashi and co-workers 108 have synthesized the aminocyclopentitol 345, a protected derivative of demethylallosamizoline, used subsequently in the only reported total synthesis (see Section IV.D.4) of the natural compound demethylallosamidin (284). The synthesis of the carbocycle 345 is described here (Scheme 44).…”

“…Takahashi and collaborators, 108 using alcohol 345 (see Section IV.C.10, Scheme 44) and a strategy paralleling their approach to allosamidin (4) (see Section IV.D.3), reported the first total synthesis of the natural product demethylallosamidin (284) (Scheme 50). Isopropylidenation of the known intermediate 365 was achieved with 2-methoxypropene in the presence of camphorsulfonic acid to give acetal 369 in high yield.…”

Natural product family 18 chitinase inhibitors

“…Trost's synthesis of 2 also paved the way for a total synthesis of 1, achieved in collaboration with the group of Vasella. 62,63 This employs a more conventional, but nonetheless innovative solution to the problem of generating the unusual allosamine stereochemistry, which has been paralleled in subsequent total syntheses described by Kuzuhara et al 75,76 and Ferrier et al 51 The well-known trichloroacetimidate methodology of Schmidt and Kinzy 77 was employed for the key glycosylation steps. Preparation of the disaccharide moiety was achieved in a convergent fashion from D-glucosamine.…”

“…Takahashi, Kuzuhara and Terayama 76 have also described the synthesis of the aglycone 79 (Scheme 12) of the naturally occurring N-demethylated allosamidin analogue 4 and the preparation of the natural product using intermediates from the preceding synthesis of 1. Vasella and Trost had observed that treatment of pseudotrisaccharide 40 with hydrazine hydrate led not only to dephthaloylation, but also cleavage of the oxazoline ring system, 63 and this was exploited as shown in Scheme 12 by Takahashi and Kuzuhara to convert 76 to amino alcohol 77.…”