Sugar-Pirating as an Enabling Platform for the Synthesis of 4,6-Dideoxyhexoses

Abstract

An efficient divergent synthetic strategy that leverages the natural product spectinomycin to access uniquely functionalized monosaccharides is described. Stereoselective 2′and 3′-reduction of key spectinomycin-derived intermediates enabled facile access to all eight possible 2,3-stereoisomers of 4,6-dideoxyhexoses as well as representative 3,4,6-trideoxysugars and 3,4,6-trideoxy-3-aminohexoses. In addition, the method was applied to the synthesis of two functionalized sugars commonly associated with macrolide antibioticsthe 3-O-alkyl-4,6-dideoxysugar D-chalcose and the 3-N-alkyl-3,4,6-trideoxysugar D-desosamine.

Synthesis and Structural Characteristics of all Mono- and Difluorinated 4,6-Dideoxy-d-xylo-hexopyranoses

“…[α] D 20 +34 ( c 1, H 2 O); IR (neat) 3315 (br), 2971 (w), 2923 (w), 1443 (w), 1045 (s), 815 (s) cm –1 ; 1 H NMR (500 MHz, CD 3 OD, α/β 49:51) δ 5.08 (1H, d, J = 3.8 Hz, H 1α ), 4.39 (1H, d, J = 7.8 Hz, H 1β ), 4.14 (1H, dqdd, J = 11.4, 6.3, 2.2, 0.3 Hz, H 5α ), 3.84 (1H, ddd, J = 11.4, 9.4, 5.0 Hz, H 3α ), 3.63 (1H, dqd, J = 11.5, 6.2, 2.0 Hz, H 5β ), 3.55 (1H, ddd, J = 11.4, 9.0, 5.2 Hz, H 3β ), 3.25 (1H, dd, J = 9.4, 3.7 Hz, H 2α ), 3.01 (1H, dd, J = 9.0, 7.8 Hz, H 2β ), 1.94 (1H, ddd, J = 12.8, 4.9, 2.2 Hz, H 4(eq)α ), 1.92 (1H, ddd, J = 12.8, 5.2, 2.0, 0.3 Hz, H 4(eq)β ), 1.31 (1H, dt, J = 12.8, 11.4 Hz, H 4(ax)β ), 1.25 (1H, dt, J = 12.7, 11.5 Hz, H 4(ax)α ), 1.21 (3H, d, J = 6.2 Hz, H 6β ), 1.14 (3H, d, J = 6.3 Hz, H 6α ) ppm; 13 C­{ 1 H} NMR (126 MHz, CD 3 OD) δ 98.4 (C 1β ), 94.7 (C 1α ), 78.3 (C 2β ), 75.8 (C 2α ), 72.4 (C 3β ), 69.3 (C 5β ), 68.8 (C 3α ), 64.8 (C 5α ), 42.5 (C 4α ), 42.3 (C 4β ), 21.52 (C 6α ), 21.50 (C 6β ) ppm; 1 H NMR (500 MHz, D 2 O, α/β 27:73) δ 5.06 (1H, d, J = 3.8 Hz, H 1α ), 4.40 (1H, d, J = 7.9 Hz, H 1β ), 4.02 (1H, dqdd, J = 11.8, 6.2, 2.2, 0.5 Hz, H 5α ), 3.75 (1H, ddd, J = 11.5, 9.8, 5.0 Hz, H 3α ), 3.62 (1H, dqd, J = 11.3, 6.2, 2.0 Hz, H 5β ), 3.55 (1H, ddd, J = 11.5, 9.2, 5.3 Hz, H 3β ), 3.29 (1H, dd, J = 9.8, 3.8 Hz, H 2α ), 2.98 (1H, dd, J = 9.3, 7.9 Hz, H 2β ), 1.91 (dddt, J = 12.9, 5.0, 2.3, 0.5 Hz, H 4(eq)α ), 1.88 (1H, ddd, J = 13.0, 5.2, 2.0 Hz, H 4(eq)β ), 1.24 (dt, J = 13.0, 11.5 Hz, H 4(ax)β ), 1.26–1.17 (1H, m, H 4(ax)α ), 1.08 (3H, d, J = 6.3 Hz, H 6β ), 1.05 (3H, d, J = 6.3 Hz, H 6α ) ppm; 13 C­{ 1 H} NMR (126 MHz, D 2 O) δ 95.9 (C 1β ), 92.6 (C 1α ), 78.0 (C 2β ), 73.2 (C 2α ), 70.4 (C 3β ), 68.6 (C 5β ), 66.9 (C 3α ), 64.6 (C 5α ), 40.0 (C 4α ), 39.9 (C 4β ), 19.87 (C 6α ), 19.85 (C 6β ) ppm; MS (ESI+) 171.4 [M + Na] + . Spectroscopic data corresponds with the literature …”

“…46−49 Thorson et al recently described an elegant approach for the synthesis of all eight possible 2,3-diastereomers of 4,6-dideoxyhexoses in enantiomerically pure form from a single natural product source. 50 The best known 4,6-dideoxysugar in nature is chalcose (Figure 1), which is an essential constituent of lankamycin and the chalcomycin macrolide antibiotics, which without chalcose do not show bioactivity. 51−53 The nonmethylated 4,6-dideoxy-Dxylo-hexopyranose has been found as part of the macrolide neutramycin.…”

“…Their synthesis − and conformational analysis continue to be the subject of much study. Hexoses with dideoxygenation at the 4- and 6-positions are rarer sugars yet have been reported to play key roles in macrolide antibiotic pharmacokinetics, pharmacodynamics, and molecular target recognition. − Thorson et al recently described an elegant approach for the synthesis of all eight possible 2,3-diastereomers of 4,6-dideoxyhexoses in enantiomerically pure form from a single natural product source . The best known 4,6-dideoxysugar in nature is chalcose (Figure ), which is an essential constituent of lankamycin and the chalcomycin macrolide antibiotics, which without chalcose do not show bioactivity. − The nonmethylated 4,6-dideoxy- d - xylo -hexopyranose has been found as part of the macrolide neutramycin.…”

A Unified Strategy to Access 2- and 4-Deoxygenated Sugars Enabled by Manganese-Promoted 1,2-Radical Migration

“…While it is broadly recognized that the use of protecting groups adds multiple steps to a synthetic scheme, a more nuanced drawback is that the protecting group strategy itself is highly specific to the site of reaction, the identity of the sugar, and chemical compatibility with subsequent reaction conditions. As a result, the synthesis of diversely functionalized deoxygenated sugars requires bespoke multistep synthetic sequences reliant upon nuanced protecting group-based strategies (Figure B). − Common existing strategies for sugar deoxygenation include (a) de novo synthesis − and (b) modification of monosaccharide precursors, − especially those (c) stemming from glycals. − Divergent semisynthetic strategies capable of accessing a broad scope deoxygenated sugars are exceedingly rare. − …”

Regiospecific Synthesis of Calcium‐Independent Daptomycin Antibiotics using a Chemoenzymatic Method

“…[16,[18][19][20] Biocatalysis has gained much interestl ately and has been used to catalyzed ifficult and uncommon reactions due to its enhancement of regio-and stereospecificity. [21][22][23][24][25] Indole prenyltransferases (IPTs) are enzymes that utilize naturallyo ccurring allyl pyrophosphate donors (OPP) to catalyzet he transfer of the prenyl group to Trp/indole or indole-containing acceptor.T he significance of IPTsa rises from their relaxed acceptora nd donor specificity in addition to their ability to catalyzeC ÀCb ond formation. [26,27] Amongt hese promiscuous IPTsi sC dpNPT,afungal IPT that has shown broad substrate specificity.I tc atalyzes normal( C-1')a nd/or reverse (C-3')p renylation of Trp-containing cyclic dipeptides at N-1 or C-3 of the indole, respectively using native and nonnative OPPs.…”