Pyrrolidines glycosidase inhibitors

An efficient and straightforward synthesis of isomers of DMDP 36 (2,5-dihy-droxymethyl-3,4-dihydroxypyrrolidine), a known naturally occurring glycosidase inhibitor, has been recently reported. o-Xylose is converted into nitrone 37 in a few steps. Vinylation of 37 gives hydroxyamine 38 which is reduced into the corresponding pyrrolidine with zinc. N-Protection, alkene ozonolysis, and reduction with NaBH4 lead to compound 39. Final deprotection gives 2,5-dideoxy-2,5-imino-L-mannitol (e f-36) (Scheme 14) [92]. 

The plant alkaloid castanospermine 155 and the related piperidine alkaloid 1-deox-ynojirimicin 160, like several other polyhydroxylated octahydroindolizidines, piperidines and pyrrolidines, are potent glycosidase inhibitors. These nitrogen bases are of considerable interest for the study of biosynthetic processes and, in addition, castanospermine and some of its derivatives may be of clinical value as antineo-plastic agents and as drugs in the treatment of AIDS. 

When a mixture of acetic anhydride and trimethylsilyl triflate was used, the opening of the Cl - O bond took place to yield the corresponding acy-lated polyhydroxy pyrrolidines 11 as mixtures of a- and b-anomers [43], compounds of interest as potential glycosidase inhibitors. However, when the opening of the pyranose ring is carried out in methanol containing lithium perchlorate, followed by addition of a 2 1 mixture of TFA and trifluoroacetic anhydride, only 12 was obtained as a single diastereoisomer (Scheme 4). 

Enzyme Inhibition - 2-Acetamido-2-deoxy-D-glucopyranose, chitobiose and chitotriose were P-glycosidically linked to various exo-glycosidase inhibitors, and evaluated as chitinase inhibitors. Good inhibition was found for an JV-formyl-pyrrolidine analogue (transition state mimic) and epoxybutyl chitobioside (an irreversible inhibitor). ... 

The reaction of MBFI adduct with alkane-amines also provided an effective protocol to synthesize pyrrolidin-2-one derivatives via nucleophilic reaction and subsequent cyclization processes. Ayed et al. first reported the direct condensation of MBH adduct with primary amines in methanol to afford 3-hydroxyl pyrrolidin-2-ones 410 in good to excellent yields (Scheme 4.130). The reaction of (5)-phenylethylamine with MBH adduct 411 was reported to generate an equimolar mixture of the 4,5-ci5-disubstituted pyrrolidin-2-ones 412 and 413 (Scheme 4.131). Interestingly, pyrrolidin-2-one 413 could be further used to synthesize the glycosidase inhibitor 414. ... 

Elbein and Molyneux (36) in an earlier review emphasized that three structural features are common in all alkaloid glycosidase inhibitors (AGI) which are toxic to mammals they have a secondary or tertiary nitrogen atom in a pyrrolidine, piperidine or indolizidine ring they have at least three hydroxyl groups in a jS-position relative to the nitrogen and they have fixed stereochemical relationships between the hydroxyl groups, which likely accounts for the specificity of the enzyme inhibition observed. Data from insect studies suggest that these same structural constraints may apply. Clearly there is much yet to be learned empirically about specificity of these compounds. 

Similar strategies have been used for the synthesis (286) of the tetrahydro-pyrrolizidine 323 from 2,3 5,6-di-O-isopropylidene-D-g/yccroD-ta/o-hep-tono-1,4-lactone (322). These polyhydroxylated pyrrolidines and pyrrolizi-dines are potential specific inhibitors of glycosidases. The stereochemistry of the hydroxyl groups have a profound effect on the selectivity of the inhibition (286-288). 

M. Shibano, S. Kitagawa, S. Nakamura, N. Akazawa, and G. Kusano, Studies on the constituents of Broussonetia species. II. Six new pyrrolidine alkaloids, broussonetine A, B, E, F and broussonetine A and B, as inhibitors of glycosidases, from Broussonetia kazinoki SIEB., Chem. Pharm. Bull., 45 (1997) 700-705. 

Heteroatom-substituted carbohydrates are efficiently assembled by the enzymatic aldol condensation of DHAP with an appropriately appended aldehyde. Iminocyclitols that are inhibitors of glycosidases, such as deoxynojirimycin and deoxymannojirimycin, are simply prepared by condensation of azo-substituted aldehydes under the FDP protocol followed by dephosphorylation and palladium mediated reductive animation (Scheme 5.18a).39 In addition a number of polyhydroxylated pyrrolidines that are efficient glucosidase inhibitors have been synthesized by this chemo-enzymatic strategy (Scheme 5.18 ).1" 30,40 If the palladium mediated hydrogenation is done in the presence of hydrochloric acid, an amino-sugar intermediate is formed as its hydrochloride salt. Treatment with base then forms polyhydroxylated imines, instead of iminocyclitols (Scheme 5.19).41... 

Doddi and Vankar have described efficient syntheses of two pyrrolidine-based imino sugars, 431 and 432, beginning from the MBH adduct of (R)-2, 3-0-isopropylideneglyceraldehydes. The key steps included regiospecific amination via successive S n2 --S n2 displacement reactions), RCM and diastereospecific dihydroxylations (Scheme 3.192). These azasugars were reported to be moderate inhibitors of glycosidase. ... 

All these advances allowed the preparation of a collection of polyhydroxy-lated piperidine, pyrrolidine, pyrrolizidines, indolizidine, and quinolizidine type iminocyclitols (e.g.. Scheme 16.9) which were widely investigated against a panel of commercial glycosidases as well as inhibitors of intestinal rat disaccharidases [16, 19, 21]. 

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