5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars: application to the stereoselective synthesis of d-galacto-isofagomine

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

“…Isogalactofagomine (4- epi -isofagomine) is one of the most interesting members of azasugars and is an extremely potent and selective β-galactosidase inhibitor (IC 50 = 12 nM; Ki = 4 nM). 22 While several synthetic routes have been reported to access such azasugars, these approaches rely on chiral starting materials 23 and chiral resolution by enzymes. 24 The gram-scale asymmetric hydrogenation of 7x with ( R )- 6b provided (+)- 8x in 97% yield with 98% ee and 98 : 2 cis -selectivity within 12 h. The reduction of (+)- 8x with LiAlH 4 followed by the reaction with 2,2-dimethoxypropane yielded the cyclic imino derivative (+)- 18 in 76% yield.…”

A remarkable change in inhibition potency and selectivity of isofagomine by simple N-modification

“…Another sugar-based approach was published by Chmielewski who provided the (-) enantiomer [31]. In addition, a range of de novo syntheses were published starting, for example, from dihydrouracil [32], from butadiene monoxide [33][34][35], from enantiomerically enriched tris(hydroxymethyl)methane (2-hydroxymethyl-1,3-dihydroxypropane) [36,37], and from chiral (lipase-resolved) N-BOC-5-hydroxy-3-piperidene [38]. Parent compound 1 was also accessed by intramolecular delivery of a d-tartaric acid-derived α-trimethylsilylmethylamine radical cation to a tethered acetylene moiety [39,40], or starting from arecoline [41] and related intermediates [42,43], as well as from methyl nicotinate [44].…”

“…Thus, simple and straight forward, in this approach, virtually stereo selective as well as high yielding reactions enabled a convenient access to IFG (1) in nine steps and 35% overall yield. In the following, we prepared a selected set of differently N-modified isofagomine derivatives (27)(28)(29)(30)(31)(32)(33)(34)(35) for in-depth biological evaluations with a series of different glycoside hydrolases. Two types of spacer arms providing a terminal azide functionality were introduced by simple N-alkylation reactions.…”