Easy Access to Configurationally Controlled C-Glycofuranoside-Based Building Blocks by Means of Formyl C-Glycofuranosides

Abstract

A general approach to enantiopure C-glycofuranoside-based hybrid α/β-amino acids and nitrones, among other valuable building blocks, has been established via formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glycopyranosides by DAST-promoted ring contraction.

C-glycofuranoside-based building blocks - formyl C-glycofuranosides - DAST-promoted ring contraction - C-glycofuranosyl nitrones - C-glycofuranosyl amino acids

References and Notes

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Preparation and More Relevant Data of Compound 10
A soln of 9 (105 mg, 0.340 mmol) in dry THF (4.8 mL) containing 3 Å MS was treated with NaCNBH₃ (273 mg, 4.35 mmol). The mixture was stirred for 15 min, and then Et₂O-HCl (3.5%, 6 mL) was added. After 5 min, the reaction was diluted with H₂O (20 mL) and CH₂Cl₂ (20 mL). After separation, the organic layer was successively washed with sat. aq NaHCO₃ (50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated. Column chromatography (hexane-EtOAc, 3:1) gave pure 10 (64 mg, 64%).
Analytical Data
[α]_D ^²4 +16.2 (c 0.63, CH₂Cl₂). IR: ν_max = 2108 (N₃) cm^-¹. ^¹H NMR (500 MHz, acetone-d ₆): δ = 7.36-7.26 (m, 5 H, Ph), 4.75 (s br, 1 H, OH_C4), 4.55 (s, 2 H, CH₂Ph), 4.55-4.53 (m, 1 H, H-4), 4.17 (ddd, 1 H, J _1,2 = J _{1 ′ ,2} = 5.7 Hz, J _2,3 = 3.7 Hz, H-2), 4.14 (dd, 1 H, J _3,4 = 4.2 Hz, H-3), 3.93 (ddd, 1 H, J _4,5 = 7.5 Hz, J _{5,6 ′} = 4.5 Hz, J _5,6 = 3.0 Hz, H-5), 3.65 (dd, 1 H, J _{6,6 ′} = 11.0 Hz, H-6), 3.58 (dd, 1 H, H-6′), 3.56 (dd, 1 H, J _{1,1 ′} = 10.0 Hz, H-1), 3.43 (dd, 1 H, H-1′), 3.31 (s, 3H, OCH₃) ppm. HRMS (CI): m/z calcd for C₁₄H₁₉N₃O₄ + H: 294.1454; found: 294.1462.

The calculations were performed at the University of Barcelona. Lowest-energy conformer were calculated by performing Monte Carlo conformational searches (50000 steps) with MacroModel 8.5 (MM2*, CHCl₃, GB/SA):

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The ratio of 24/25 was calculated by the ^¹H NMR (CDCl₃) of the mixture, in particular from the signals of H-4 of both stereoisomers: δ = 5.65 ppm (dd, 1 H, J _4,5 = 7.8 Hz, J _3,4 = 4.5 Hz, H-4) observed for the major stereoisomer 24, and that observed at δ = 4.80 ppm (dd, 1 H, J _4,5 = 7.2 Hz, J _3,4 = 4.8 Hz, H-4) for 25.

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More Relevant Data Compound 16: [α]_D ^²¹ +37 (c 0.77, acetone). ^¹H NMR (500 MHz, acetone-d ₆): δ = 7.36-7.33 (m, 5 H, Ph), 7.09 (d, 1 H, J _NH,3 = 7.0 Hz, CCONH), 6.43 (s br, 1 H, OCONH), 4.58-4.53 (m, 1 H, H-3), 4.57 and 4.58 (each 2 d, 1 H, J _{H,H ′} = 12.9 Hz, CH₂Ph), 4.45 (d, 1 H, J _OH,4 = 8.0 Hz, OH_C4), 4.31 (ddd, 1 H, J _2,3 = 8.0 Hz, J _{1 ′ ,2} = 4.5 Hz, J _1,2 = 3.0 Hz, H-2), 4.17-4.14 (m, 1 H, H-4), 4.01 (ddd, 1 H, J _5,6 = J _{5,6 ′} = 4.0 Hz, J _4,5 = 3.0 Hz, H-5), 3.77 (dd, 1 H, J _gem = 16.5 Hz, J _NH,CH2a = 6.0 Hz, NHCH ^a ₂), 3.72 (dd, 1 H, J _NH,CH2b = 6.0 Hz, NHCH ^b ₂), 3.55 (dd, 1 H, J _{6,6 ′} = 10.5 Hz, H-6), 3.52 (dd, 1 H, H-6′), 3.50 (dd, 1 H, J _{1,1 ′} = 10.5 Hz, H-1), 3.40 (dd, 1 H, H-1′), 3.35 (s, 3 H, OCH₃), 1.43 [s, 9 H, C(CH₃)₃] ppm. ^¹³C NMR (125.7 MHz, acetone-d ₆): δ = 170.5, 157.0, 139.6-128.2, 85.2, 79.6, 78.9, 73.8, 73.1, 72.9, 72.0, 59.3, 53.9, 44.9, 28.6 ppm. HRMS (CI): m/z calcd for C₂₁H₃₂N₂O₇ + H: 425.2288; found: 425.2291. Anal. Calcd for C₂₁H₃₂N₂O₇: C, 59.42; H, 7.60; N, 6.60. Found: C, 59.12; H, 7.45; N, 6.72.
Compound 20: [α]_D ^²4 +52 (c 0.66, CH₂Cl₂). IR: ν_max = 2114 (N₃) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.07 (dd, 1 H, J _NH,CH2a = 5.0 Hz, NH), 5.22 (dd, 1 H, J _4,5 = 8.5 Hz, J _3,4 = 4.5 Hz, H-4), 4.68 (dd, 1 H, J _2,3 = 4.5 Hz, H-3), 4.62 (d, 1 H, H-2), 4.40-4.36 (m, 1 H, H-5), 4.36 (dd, 1 H, J _{6,6 ′} = 12.5 Hz, J _5,6 = 2.5 Hz, H-6), 4.23 (q, 2 H, J = 7.0, C₂H₅), 4.13 (dd, 1 H, J _{5,6 ′} = 4.0 Hz, H-6′), 4.11 (dd, 1 H, J _gem = 18.0 Hz, NHCH ^a ₂), 4.07 (dd, 1 H, NHCH ^b ₂), 2.16, 2.09 (2 s, each 3 H, COCH₃), 1.29 (t, 3 H, C₂H₅) ppm. HRMS (CI): m/z calcd for C₁₄H₂₀N₄O₈ + H: 373.1359; found: 373.1349.
Compound 22: [α]_D ^²4 -1.2 (c 0.75, CH₂Cl₂). IR: ν_max = 2112 (N₃) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.41 (s, 5 H, Ph), 6.79 (d, 1 H, J _1,2 = 4.5 Hz, H-1), 5.20 (dd, 1 H, J _4,5 = 8.0 Hz, J _3,4 = 5.0 Hz, H-4), 5.15 (dd, 1 H, J _2,3 = 4.5 Hz, H-2), 4.94 (dd, 1 H, H-3), 4.91 (s, 2 H, CH₂Ph), 4.34 (dd, 1 H, J _{6,6 ′} = 12.0, J _5,6 = 3.0 Hz, H-6), 4.24 (ddd, J _{5,6 ′} = 4.5 Hz, H-5), 4.04 (dd, 1 H, H-6′), 2.14, 2.08 (2 s, each 3 H, 2 COCH₃) ppm. ^¹³C NMR (125.7 MHz, CDCl₃): δ = 170.7, 170.2, 136.2, 132.0-129.2, 77.2, 77.0, 73.5, 69.3, 63.3, 62.7, 20.9, 20.4 ppm. HRMS (CI): m/z calcd for C₁₇H₂₀N₄O₆ + H: 377.1461; found: 377.1454.