Chiron approaches to polyhydroxylated piperidines: promising glycosidase inhibitors

Abstract

New chiron approaches towards the syntheses of polyhydroxylated piperidine analogues are described. The methodologies involve 1,3-addition of methyl magnesium bromide and silyl ketene acetal to D-glucose derived nitrone, intramolecular Michael addition to D-glucose derived α,β-unsaturated ester and double reductive amination of 5-keto aldose as key steps.

Asymmetric Dihydroxylation of d-Glucose Derived α,β-Unsaturated Ester: Synthesis of Azepane and Nojirimycin Analogues

“…Asymmetric Dihydroxylation of 3. The required ( E )-ethyl-1,2- O -isopropylidene-3- O -benzyl-5,6-dideoxy-α- d - xylo -5-enoheptofuranuronate ( 3 ) was prepared from d -glucose as reported earlier 7f. The dihydroxylation of 3 with potassium osmate (catalytic), potassium ferricyanide, potassium carbonate, and methane sulfonamide in tert -butyl alcohol−water (1:1) afforded a diastereomeric mixture of vicinal diols 4a and 4b in the ratio 2:1 (eq 1).…”

“…Although the physical and spectral data of 1c , d were found to be consistent with the structures, the configurational assignment at each carbon atom in 1c was based on the X-ray analysis of 4a while in the case of 1d the configurational assignment was tentatively made on the expected syn -dihydroxylation from the other face of 3 leading to 4b . The 1 H NMR spectrum of 1c and 1d did not give any supportive information on the conformational and configurational assignment due to the flexibility in seven-membered ring systems. 7j,k As an alternative, we thought of converting 4a , b to the corresponding six-membered piperidine analogues 2c , d wherein the configurational assignment at each carbon atom will be clearly evident from the six-membered cyclic structure, with either 4 C 1 or 1 C 4 conformations, and the same configurational assignments would be applicable to azepane analogues. For this, the amino alcohols 7a , b (obtained from 4a , b ) were found to be the true intermediates wherein cleavage of the anomeric carbon atom (C1) and reductive aminocyclization would afford the corresponding six-carbon azasugars 2c , d .…”

“…The development of new azasugars thus opened a dynamic research field at the interface between glycobiology and synthetic organic chemistry. During the course of our investigations in the area of nojirimycin, castanospermine, and azepane analogues, we thought of synthesizing altogether different one-carbon ring homologues of 1-deoxynojirimycin namely azepanes 1c and 1d , with −CH 2 OH functionality at C5, as well as piperidine alkaloids 1-deoxy- d -altronojirimycin 2c , a recently reported natural product from the bark extract of Angylocalyx pynaertii (Leguminosae), and 2d (1-deoxy- l -nojirimycin), the enantiomer of 1-deoxynojirimycin 2b .

1 Azepane and nojirimycin anlogues.

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