Expeditious Stereoselective Synthesis of l-Iminosugar Precursors via a Mitsunobu Reaction

Abstract

An efficient stereoselective synthesis of l-imino-C-gulosides is disclosed. Starting from the 2,3:4,6-di-O-isopropylidene-d-mannopyranose the synthetic pathway involves first a Wittig reaction with CMPP to introduce the carbon at the pseudo-anomeric position, followed by a Michael reaction under ultrasound activation to introduce the nitrogen center, and finally a Mitsunobu reaction for the ring closure leading to the C-iminosugar from the l-series.

Key words

carbohydrates - azasugars - stereoselective - Mitsunobu reaction - glycosidase

References and Notes

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24

Synthesis of Compound 2
To a solution of 2,3:4,6-Di-O-isopropylidene-d-manno-pyranose (1 equiv, 23 mmol, 6 g) in anhyd benzene was added(cyanomethylene) triphenylphosphorane (3 equiv, 69 mmol, 21 g). The mixture was stirred and refluxed under argon atmosphere for 3 h. The reaction mixture was diluted with CH₂Cl₂ (200 mL) and washed twice with brine (50 mL). The organic layer was dried over anhyd Na₂SO₄ for 30 min and concentrated under vacuum to give pale yellowish oil. The crude was chromatographed on SiO₂ (PE-Et₂O, 5:5) to afford the two isomers (6.5 g, 70% for Z-isomer) as colorless oils. R _f  = 0.16 (Z-isomer, major), 0.08 (E-isomer, minor; PE-Et₂O, 5:5). ^¹H NMR (400 MHz, acetone-d ₆):
δ (Z-isomer) = 6.81 (dd, J _1-7 = 11.26 Hz, J _1-2 = 8.00 Hz, H₁), 5.77 (dd, J _7-1 = 11.27 Hz, J _7-2 = 1.30 Hz, H₇), 5.16 (dt,
J _2-1 = 7.85 Hz, J _2-3 = 7.80 Hz, J _2-7 = 1.27 Hz, H₂), 4.72 (dd, J _3-2 = 7.48 Hz, J _3-4 = 1.45 Hz, H₃), 4.29 (d, J _OH-5 = 6.01 Hz, -OH), 3.81-3.70 (m, H₅, H_6a), 3.58 (dd, J = 10.16, 9.07 Hz, H_6a), 3.48 (dd, J _4-5 = 9.17 Hz, J _4-3 = 1.43 Hz, H₄), 1.48, 1.41, 1.37, 1.31 (4 s, 12 H, H₁₀, H₁₁, H₁₃, H₁₄). ^¹³C NMR (100 MHz, acetone-d ₆): δ (Z-isomer) = 153.45 (C₁), 117.16 (C₈), 111.70 (C₉), 102.34 (C₇), 99.90 (C₁₂), 77.87 (C₂), 77.64 (C₃), 74.44 (C₄), 66.48 (C₆), 63.94 (C₅), 30.09, 27.90, 26.89, 19.96 (C₁₀, C₁₁, C₁₃, C₁₄). MS (ESI⁺): m/z = 306.22 [M + Na]⁺.

31

Typical Procedure for the Synthesis of Compounds 3-5
Compound 2 (1 equiv) was dissolved in dry amine in excess. The mixture was placed in an ultrasound bath under an argon atmosphere for 10 h. The unreacted amine was removed under reduced pressure and the byproducts removed by flash chromatography on SiO₂ (PE-Et₂O, 8:2) to afford compounds 3, 4, or 5 as colorless oils in 80% yield.
Compound 3: R _f  = 0.11 (PE-Et₂O, 8:2). ^¹H NMR (400 MHz, acetone-d ₆): δ = 7.46-7.19 (m, 5 H, H_c, H_d, H_e), 4.48 (dd, J _3-2 = 6.29 Hz, J _3-4 = 1.55 Hz, H₃), 4.28 (dd, J _2-1 = 8.85 Hz, J _2-3 = 6.29 Hz, H₂), 4.22 (d, J _OH-5 = 5.88 Hz, OH), ν₀ = 3.82 (ABq, 2 H, ν_A = 4.03, ν_B = 3.87, Δν = 64.2 Hz, J _AB = 14.0 Hz, H_a), 3.79-3.68 (m, H₅, H_6a), 3.63-3.50 (m, H_6b), 3.61 (dd, J _4-5 = 8.93 Hz, J _4-3 = 1.57 Hz, H₄), 3.33 (ddd, J _1-2 = 8.92 Hz, J _1-7b = 5.18 Hz, J _1-7a = 4.49 Hz, H₁), 2.81 (dd, J _7a-7b = 17.39 Hz, J _7a-1 = 4.44 Hz, H_7a) 2.58 (dd, J _7b-7a = 17.40 Hz, J _7b-1 = 5.29 Hz, H_7b), 1.48, 1.33, 1.23, 1.20 (4 s, 12 H, H₁₀, H₁₁, H₁₃, H₁₄). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 142.55 (C_b), 130.07 and 129.87 (2 C, C_c, C_d), 128.55 (C_e), 119.67 (C₈), 110.31 (C₉), 99.82 (C₁₂), 80.65 (C₂), 75.79 (C₃), 74.44 (C₄), 66.48 (C₆), 63.92 (C₅), 53.73 (C₁), 52.16 (C_a), 29.98, 27.75, 27.20, 20.03 (4C, C₁₀, C₁₁, C₁₃, C₁₄), 22.03 (C₇). MS (ESI⁺): m/z = 391.13 [M + H]⁺, 413.13 [M + Na]⁺. MS (ESI^-): m/z = 425.46 [M + Cl]^-.
Compound 4: R _f  = 0.28 (Et₂O). ^¹H NMR (400 MHz, acetone-d ₆): δ = 4.48 (dd, J _3-2 = 6.26 Hz, J _3-4 = 1.56 Hz, H₃), 4.20 (dd, J _2-1 = 8.53 Hz, J _2-3 = 6.26 Hz, H₂), 3.84-3.67 (m, H₄, H₅, H_6a), 3.64-3.56 (m, H_6b), 3.28 (ddd, J _1-2 = 8.52 Hz, J _1-7b = 5.54 Hz, J _1-7a = 4.52 Hz, H₁), 2.73 (dd, J _7a-7b = 17.31 Hz, J _7a-1 = 4.53 Hz, H_7a), 2.55 (dd, J _7b-7a = 17.32 Hz, J _7b-1 = 5.54 Hz, H_7b), 2.78-2.70 (m, H_9a), 2.68-2.61 (m, H_9b), 1.49-1.32 (m, H₁₀, H₁₁), 1.50, 1.48, 1.33, 1,32 (4 s, 12 H, H₁₄, H₁₅, H₁₇, H₁₈), 0.91 (t, J _12-11a = 7.20, J _12-11b = 7.20 Hz, H₁₂). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 119.83 (C₈), 110.15 (C₁₃), 99.91 (C₁₆), 80.26 (C₂), 75.83 (C₃), 74.45 (C₄), 66.57 (C₆), 64.07 (C₅), 55.36 (C₁), 48.30 (C₉), 34.09 (C₁₀), 30.15, 27.75, 27.13, 20.45 (4 C, C₁₄, C₁₅, C₁₇, C₁₈), 21.95 (C₁₁), 15.25 (C₁₂). MS (ESI⁺): m/z = 357.31 [M + H]⁺, 379.33 [M + Na]⁺. MS (ESI^-): m/z = 355.36 [M - H]^-, 391.28
[M + Cl]^-.
Compound 5: R _f  = 0.08 (PE-Et₂O, 9:1). ^¹H NMR (400 MHz, acetone-d ₆): δ = 5.90 (dddd, J _{10-11 trans}  = 17.29 Hz, J _{10-11 cis} = 10.33 Hz, J = 6.15 Hz, J = 5.19 Hz, H₁₀), 5.25 (qd, J _{11 trans -10} = 17.29 Hz, J = 1.80, 1.80, 1.79 Hz, H_{11 trans} ), 5.08 (ddd, J _{11 cis -10} = 10.34 Hz, J = 3.42 Hz, J = 1.48 Hz, H_{11 cis} ), 4.48 (dd,
J _3-2 = 6.28 Hz, J = 1.57 Hz, H₃), 4.24 (dd, J = 8.68 Hz, J _2-3 = 6.27 Hz, H₂), 3.82-3.55 (m, 4 H, H₄, H₅, H_6a, H_6b), 3.47-3.29 (m, 3 H, H₁, H_9a, H_9b), 2.75 (dd, J _7a-7b = 17.35 Hz, J = 4.49 Hz, H_7a), 2.55 (dd, J _7b-7a = 17.35 Hz, J = 5.41 Hz, H_7b), 1.48, 1.32 (2 d, 12 H, H₁₃, H₁₄, H₁₆, H₁₇). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 139.48 (C₁₀), 119.76 (C₈), 116.70 (C₁₁), 110.26 (C₁₂), 99.90 (C₁₅), 80.52 (C₂), 75.85 (C₃), 74.52 (C₄), 66.54 (C₆), 63.96 (C₅), 53.15 (C₁), 51 (C₉), 30.16, 27.74, 27.74, 20.34 (C₁₃, C₁₄, C₁₅, C₁₇), 22.26 (C₇). MS (ESI⁺): m/z = 341.27 [M + H]⁺, 363.29 [M + Na]⁺.

32

Typical Procedure for the Synthesis of Compounds 6-8
Compounds 3, 4, or 5 (1 equiv) and Ph₃P (2 equiv) were dissolved in a minimum amount of dry toluene. The mixture was stirred under argon at r.t. DEAD (2 equiv, 2.56 mmol, 1.2 mL) was added dropwise, and the mixture was stirred further 3 h. The crude product was purified by chromatog-raphy on SiO₂ (PE-Et₂O, 7:3) to afford compounds 6, 7, or 8 in 70% yield.

Compound 6: R _f  = 0.2 (PE-Et₂O, 7:3); [α]_D +5.86 (c 1, HCCl₃, 25 ˚C). ^¹H NMR (400 MHz, acetone d ₆ ): δ = 7.42 (m, 2 H, H_c), 7.30 (m, 2 H, H_d), 7.23 (m, 1 H, H_e), 4.43 (dd, J _3-4 = 2.5 Hz, J _3-2 = 8.0 Hz, H₃), 4.25 (dd, J _4-3 = 2.7 Hz, J _4-5 = 5.6 Hz, H₄), 4.23 (dd, J _2-1 = 2.1 Hz, J _2-3 = 8.1 Hz, H₂), ν₀ = 3.99 (ABq, 2 H, ν_A = 4.13, ν_B = 3.85, Δν = 112.3 Hz, J _AB = 14.3 Hz, H_a), 3.85 (ddd, J _1-2 = 2.2 Hz, J _1-7b = 7.3 Hz, J _1-7a = 7.4 Hz, H₁), 3.38 (dd, J _6a-5 = 6.1 Hz, J _6a-6b = 11.7 Hz, H_6a), 3.33 (dd, J _6b-5 = 6.4 Hz, J _6b-5 = 11.8 Hz, H_6b), 2.99 (dd, J _7a-1 = 7.7 Hz, J _7a-7b = 17.0 Hz, H_7a), 3.00 (ddd, J _5-6a = 6.3 Hz, J _5-6b = 6.4 Hz, J _5-4 = 5.7 Hz, H₅), 2.91 (dd, J _7b-1 = 7.2 Hz, J _7b-7a = 17.0 Hz, H_7b), 1.61 (s, CH₃), 1.38 (d, J = 0.4 Hz, CH₃), 1.30 (s, CH₃), 1.30 (s, CH₃). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 143.17 (C_b), 130.49, 129.94 (C _{ortho / meta} ), 128.71 (C _para ), 120.32 (C₈), 110.60 (C₉), 101.23 (C₁₂), 75.99 (C₃), 73.64 (C₄), 65.87 (C₂), 63.77 (C₆), 56.87 (C_a), 56.15 (C₅), 53.49 (C₁), 27.67, 27.25, 24.44, 22.68 (C₁₀, C₁₁, C₁₃, C₁₄), 19.81 (C₇). MS (ESI⁺): m/z = 373.32 [M + H]⁺, 395.28 [M + Na]⁺, 411.18 [M + K]⁺, 767.57 [2 M + Na]⁺.
Compound 7: R _f  = 0.6 (PE-Et₂O, 8:2); [α]_D +6.52 (c 1, HCCl₃, 25 ˚C). ^¹H NMR (400 MHz, acetone-d ₆): δ = 4.38 (dd, J _3-4 = 26.0 Hz, J _3-2 = 8.0 Hz, H₃), 4.26 (dd, J _4-3 = 2.6 Hz, J _4-5 = 5.6 Hz, H₄), 4.15 (dd, J _2-1 = 2.2 Hz, J _2-3 = 8.0 Hz, H₂), 3.78 (dd, J _6a-5 = 6.2 Hz, J _6a-6b = 11.7 Hz, H_6a), 3.69 (ddd, J _1-2 = 2.2 Hz, J _1-7a = 7.7 Hz, J _1-7b = 8.4 Hz, H₁), 3.56 (dd, J _6b-5 = 6.6 Hz, J _6b-6a = 11.7 Hz, H_6b), 3.05 (q, J _5-4 =
J _5-6a = J _5-6b = 6.1 Hz, H₅), 2.86-2.64 (m, 4 H, H_7a, H_7b, H_9a, H_9b), (s, 3 H, CH₃), 1.41-1.20 (m, 4 H, H_10a, H_10b, H_11a, H_11b), 1.47, 1.36, 1.33, 1.30 (4 s, 12 H, H₁₄, H₁₅, H₁₇, H₁₈). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 120.20 (C₈), 110.46 (C₁₃), 101.13 (C₁₆), 75.97 (C₃), 73.47 (C₂), 65.69 (C₄), 64.57 (C₆), 57.07 (C₅), 53.58 (C₁), 52.66 (C₉), 35.35 (C₁₀), 27.60, 27.08, 24.47, 22.85 (C₁₄, C₁₅, C₁₇, C₁₈), 21.60 (C₁₁), 19.81 (C₇), 15.38 (C₁₂). MS (ESI⁺): m/z = 339.36 [M + H⁺], 361.26
[M + Na]⁺, 699.47 [2 M + Na]⁺.
Compound 8: R _f  = 0.28 (PE-Et₂O, 8:2); [α]_D +8.34 (c 1, HCCl₃, 25 ˚C). ^¹H NMR (400 MHz, acetone-d ₆): δ = 5.76 (dddd, J _{10-11 trans}  = 17.19 Hz, J _{10-11 cis}  = 10.07 Hz, J _10-9b = 7.99 Hz, J _10-9a = 4.40 Hz, H₁₀), 5.15 (dtd, J _{11 trans -10} = 17.21 Hz, J = 2.03 Hz, J _{11 trans -11 cis}  = 1.11 Hz, H_{11 trans} ), 5.00 (dtd, J _{10-11 cis}  = 10.07 Hz, J = 1.88 Hz, J _{11 cis -9a} = 1.87 Hz, J _{11 cis -11 trans}  = 0.92 Hz, H_{11 cis} ), 4.37 (dd, J _3-2 = 7.94 Hz, J _3-4 = 2.60 Hz, H₃), 4.25 (dd, J _4-5 = 5.27 Hz, J _4-3 = 2.60 Hz, H₄), 4.17 (dd, J _2-3 = 7.95 Hz, J _2-1 = 2.12 Hz, H₂), 3.78 (td, J = 8.17 Hz, J _1-2 = 1.94 Hz, J = 1.94 Hz, H₁), 3.74 (dd, J _6a-6b = 11.82 Hz, J = 5.63 Hz, H_6a-6b), 3.60 (tdd, J _9a-9b = 14.88 Hz, J _9a-10 = 4.12 Hz, J _{9a-11 cis}  = 1.87 Hz, J = 1.87 Hz, H_9a), 3.57 (dd,
J _6b-6a = 11.76 Hz, J = 5.85 Hz, H_6a-6b), 3.26 (tdd, J _9b-9a = 14.88 Hz, J _9b-10 = 7.99 Hz, J = 1.04, 1.04 Hz, H_9b), 2.99 (q, J _5-4 = 5.59 Hz, J _5-6a = 5.59 Hz, J _5-6b = 5.59 Hz, H₅), 2.84 (d, J = 0.65 Hz, H_7a), 2.82 (s, H_7b), 1.50, 1.37, 1.34, 1.30 (4 d, 12 H, J = 0.58 Hz, H₁₃, H₁₄, H₁₆, H₁₇). ^¹³C NMR (100 MHz, acetone-d ₆): δ = 140.93 (C₁₀), 120.04 (C₈), 116.88 (C₁₁), 110.53 (C₁₂), 101.04 (C₁₅), 75.88 (C₃), 73.75 (C₂), 66.04 (C₄), 64.51 (C₆), 55.81 (C₉), 55.67 (C₅), 53.38 (C₁), 28.07, 27.20, 24.50, 22.38 (C_14, C₁₃, C₁₆, C₁₇), 19.77 (C₇). MS (ESI⁺): m/z = 323.27 [M + H]⁺, 345.21 [M + Na]⁺, 361.20
[M + K]⁺.