Tunable Approach for the Stereoselective Synthesis of 1-C-Diethylphosphono(difluoromethyl) Iminosugars as Glycosyl Phosphate Mimics

Abstract

An efficient methodology for the stereoselective and tunable addition of LiCFP(O)(OEt) and BrMgCFP(O)(OEt) reagents to N-t-butanesulfinyl glycosylamines is described with details on the stereochemical effects at play in this process. It provides a practical route to various 1-C-diethylphosphono(difluoromethyl) iminosugars as glycosyl phosphate and sugar nucleotide mimics.

Glycoside Mimics from Glycosylamines: Recent Progress

“…in dry toluene. The reaction mixture is heated at 70 °C to give compounds 81a , 81b and 81d in moderate to excellent yields (45–94%) [99,100,101]. …”

“…The N - tert -butanesulfinyl glycosylamines undergo addition reactions with a range of Grignard and lithium reagents to give related 1,2- syn or 1,2- anti -aminoalditols in good yields and moderate to excellent diastereoselectivities [99,101,102,103]. Their reactivity was found to be similar to that of N -alkyl- N -glycosides and of N -benzyl- N -glycosylhydroxylamines with a chemical stability similar to that of the N -Cbz-analogues [99].…”

“…Importantly, however, the process can be scaled-up (up to 1.9 g of product 82 ) [102], without erosion of the diastereo-selectivity. The method was implemented to a variety of organomagnesium species (see Table 3) [99], including propargyl Grignard reagents [101]. It may be possible to further enrich the diastereoselectivity significantly by adding LiCl, which resulted in d.r.…”

“…greater than 90% (entries 3, 7, 12). The addition reactions were extended to different series, namely on glycosylamines derived from 2,3,4-tri- O -benzyl- d -xylopyranose [99] (e.g., 81d ), 2,3,5-tri- O -benzyl- d -xylofuranose (e.g., 81b ), [101], and the acid-sensitive furanose derivative 81c [99] to afford compounds ( S S )- 82dD , ( S R )- 82bE , and ( S S )- 82cD , respectively, in good yields and good diastereoselectivities (Scheme 26). …”

“…Afterwards, the sulfinyl protecting group was removed with mild acid (HCl in MeOH) to generate the corresponding 1,2- cis imino- C -glycosyl derivatives 83 in good yields (see procedure C) [99,102]. Alternatively, the sulfinyl group may be cleaved first and cyclization promoted from the free amine, which occurs spontaneously (procedure D) [101,103]. …”