A Facile and General Entry to C-Glycosyl (R)- and (S)-β-Amino Acid Pairs from Glycosyl Cyanides through Enamino Ester Intermediates

Abstract

Four O-perbenzylated glycosyl cyanides (α- and β-d-mannopyranosyl, α-d-galactopyranosyl, and α-d-arabinofuranosyl) were converted by treatment with BrCH₂CO₂Et/Zn in THF at reflux (Blaise-Kishi reaction) into the corresponding C-glycosyl β-en­amino esters which in turn were reduced by NaBH(OAc)₃ to give four pairs of C-glycosyl (R)- and (S)-β-amino esters.

Key words

amino acids - glycopeptides - glycosides - reductions - ­nitriles

References and Notes

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• 1e Varki A. Cummings R. Esko J. Freeze H. Hart G. Marth J. Essentials of Glycobiology   Cold Spring Harbor Laboratory Press; New York: 1999. 
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• 3b

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10

Typical Procedure for Entry to β-Enamino Esters ( 2). A suspension of zinc dust (588 mg, 9.00 mmol) in anhyd THF (8 mL) was heated under reflux then a few drops of ethyl bromoacetate were added. After a green color had appeared (ca. 15 min), a solution of glycosyl cyanide 1 (1.50 mmol) in anhyd THF (2 mL) was added in one portion. The remaining bromoacetate was added dropwise over 50 min (total amount of bromoacetate: 0.66 mL, 6.0 mmol). The reaction mixture was cooled to r.t., treated with sat. aq NaHCO₃ solution (10 mL) and filtered through a pad of Celite^®. The filtrate was extracted with Et₂O (3 × 75 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The residue was eluted from a column of silica gel using a suitable elution system to afford the corresponding β-enamino ester 2 as a single stereoisomer.
Analytical data for compound 2b: [α]_D 12.7 (c 1.4, CHCl₃). ¹H NMR (CDCl₃ + D₂O): δ = 7.45-7.10 (m, 20 H, Ph), 4.92 and 4.68 (2 d, 2 H, J = 11.2 Hz, PhCH ₂), 4.84 and 4.59 (2 d, 2 H, J = 11.5 Hz, PhCH ₂), 4.73 and 4.66 (2 d, 2 H, J = 11.0 Hz, PhCH ₂), 4.63 and 4.56 (2 d, 2 H, J = 12.0 Hz, PhCH ₂), 4.47 (s, 1 H, H-2), 4.15 (q, 2 H, J = 7.0 Hz, OCH ₂CH₃), 4.00 (dd, 1 H, J _4,5 = ca. 0.5 Hz, J _5,6 = 3.0 Hz, H-5), 3.93 (dd, 1 H, J _6,7 = 9.1 Hz, J _7,8 = 9.0 Hz, H-7), 3.91 (d, 1 H, H-4), 3.77 (dd, 1 H, J _8,9a = 2.5 Hz, J _9a,9b = 10.8 Hz, H-9a), 3.73 (dd, 1 H, J _8,9b = 4.8 Hz, H-9b), 3.66 (dd, 1 H, H-6), 3.51 (dd, 1 H, H-8), 1.30 (t, 3 H, OCH₂CH ₃). Anal. Calcd for C₃₉H₄₃NO₇: C, 73.45; H, 6.80; N, 2.20. Found: C, 73.48; H, 6.81; N, 2.24. MALDI-TOF MS: 638.5 [M⁺ + H], 660.9 [M⁺ + Na].

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Typical Procedure for Entry to β-Amino Esters ( 3).
A solution of NaBH(OAc)₃ was prepared by adding NaBH₄ (57 mg, 1.50 mmol) to glacial AcOH (1.5 mL) while the temperature was kept at 10 °C. After the H₂ evolution ceased (30 min), a solution of β-enamino ester 2 (0.50 mmol) in glacial AcOH (0.5 mL) was added slowly. The solution was stirred at r.t. for an additional 1 h, and then concentrated in vacuo. The residue was suspended in EtOAc (80 mL) and washed with sat. aq NaHCO₃ solution (2 × 10 mL). The organic phase was dried (Na₂SO₄), concentrated, and purified by column chromatography on silica gel using a suitable elution system to give the corresponding (R)- and (S)-β-amino esters 3 in a variable diastereomeric ratio (see Table [1] ).
Analytical data for compound (S)-3b: ¹H NMR (CDCl₃): δ = 7.50-7.10 (m, 20 H, Ph), 5.09 and 4.78 (2 d, 2 H, J = 11.8 Hz, PhCH ₂), 4.92 and 4.60 (2 d, 2 H, J = 10.8 Hz, PhCH ₂), 4.86 and 4.77 (2 d, 2 H, J = 11.5 Hz, PhCH ₂), 4.64 and 4.54 (2 d, 2 H, J = 12.0 Hz, PhCH ₂), 4.21 (dd, 1 H, J _4,5 = ca. 0.5 Hz, J _5,6 = 2.5 Hz, H-5), 4.20-4.08 (m, 2 H, OCH ₂CH₃), 3.96 (dd, 1 H, J _6,7 = 9.0 Hz, J _7,8 = 9.2 Hz, H-7), 3.80-3.70 (m, 2 H, 2 H-9), 3.67 (dd, 1 H, H-6), 3.44 (ddd, 1 H, J _2a,3 = 3.2 Hz, J _2b,3 = 8.8 Hz, J _3,4 = 8.5 Hz, H-3), 3.42 (m, 1 H, H-8), 3.12 (dd, 1 H, H-4), 2.88 (dd, 1 H, J _2a,2b = 16.2 Hz, H-2a), 2.37 (dd, 1 H, H-2b), 2.00 (bs, 2 H, NH₂), 1.26 (t, 3 H, J = 7.0 Hz, OCH₂CH ₃). Anal. Calcd for C₃₉H₄₅NO₇: C, 73.22; H, 7.09; N, 2.19. Found: C, 73.20; H, 7.05; N, 2.15. MALDI-TOF MS: 640.8 [M⁺ + H], 662.8 [M⁺ + Na].

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Typical Procedure for Entry to N -Boc Derivatives ( 4). To a stirred mixture of β-amino ester 3 (0.50 mmol), dioxane (8 mL), and Boc₂O (546 mg, 2.50 mmol) a few drops of sat. aq NaHCO₃ solution (until basic pH) were added. The solution was stirred at r.t. for an additional 12 h then diluted with Et₂O (100 mL) and washed with a 10% aq solution of citric acid (2 × 10 mL). The organic phase was separated, washed with brine (2 × 10 mL), dried (Na₂SO₄) and concentrated in vacuo. The residue was then purified by column chromatography on silica gel with the suitable elution system to give the corresponding N-Boc derivative 4 in almost quantitative yield.
Analytical data for compounds 4: (S)-4a: [α]_D 1.7 (c 1.3, CHCl₃). (R)-4a: [α]_D -5.8 (c 1.0, CHCl₃). (S)-4b: [α]_D -12.0 (c 1.5, CHCl₃). (R)-4b: [α]_D -11.5 (c 1.2, CHCl₃). (S)-4c: [α]_D 22.1 (c 0.9, CHCl₃). (R)-4c: [α]_D 37.0 (c 0.8, CHCl₃). (S)-4d: slightly contaminated by uncharacterized by-products. (R)-4d: [α]_D 8.2 (c 0.7, CHCl₃). ¹H NMR (CDCl₃) for (S)-4b: δ = 7.50-7.10 (m, 20 H, Ph), 5.17 (br d, 1 H, J _3,NH = 8.5 Hz, NH), 5.02 and 4.70 (2 d, 2 H, J = 10.5 Hz, PhCH ₂), 4.90 and 4.75 (2 d, 2 H, J = 11.0 Hz, PhCH ₂), 4.82 and 4.60 (2 d, 2 H, J = 11.5 Hz, PhCH ₂), 4.62 and 4.51 (2 d, 2 H, J = 12.0 Hz, PhCH ₂), 4.30-4.20 (m, 1 H, H-3), 4.11 (q, 2 H, J = 7.0 Hz, OCH ₂CH₃), 4.02 (dd, 1 H, J _4,5 = ca. 0.5 Hz, J _5,6 = 2.5 Hz, H-5), 3.88 (dd, 1 H, J _6,7 = 9.2 Hz, J _7,8 = 9.5 Hz, H-7), 3.76 (dd, 1 H, J _8,9a = 3.5 Hz, J _9a,9b = 12.0 Hz, H-9a), 3.70 (dd, 1 H, J _8,9b = 3.8 Hz, H-9b), 3.65 (dd, 1 H, H-6), 3.53 (dd, 1 H, J _3,4 = 8.5 Hz, H-4), 3.42 (ddd, 1 H, H-8), 2.83 (dd, 1 H, J _2a,2b = 16.5 Hz, J _2a,3 = 6.0 Hz, H-2a), 2.66 (dd, 1 H, J _2b,3 = 4.0 Hz, H-2b), 1.42 (s, 9 H, t-Bu), 1.22 (t, 3 H, OCH₂CH ₃). Anal. Calcd for C₄₄H₄₃NO₉: C, 71.43; H, 7.22; N, 1.89. Found: C, 71.40; H, 7.20; N, 1.80. MALDI-TOF MS: 762.5 [M⁺ + Na], 778.5 [M⁺ + K].

15

The removal of benzyl groups was essential to guarantee Δδ^RS values with a regular sign distribution for all protons of Mosher’s amides 5.