Catalytic Asymmetric Synthesis of (R)-(-)-Calycotomine, (S)-(-)-Salsolidine and (S)-(-)-Carnegine

Abstract

A simple and efficient procedure for a synthesis of isoquinoline alkaloids is described. The key step of the synthesis was a hydrocyanation of 6,7-dimethoxy-3,4-dihydroisoqunoline giving the corresponding 1-cyano-1,2,3,4-tetrahydroisoquinoline. The asymmetric Strecker reaction was accomplished in high yield and high enantiomeric excess using Jacobsen’s thiourea-containing ­catalyst. The 1-cyanoisoquinoline thus obtained was transformed to natural products, (R)-(-)-calycotomine, (S)-(-)-salsolidine and (S)-(-)-carnegine.

isoquinoline alkaloid - asymmetric synthesis - Strecker reaction - Jacobsen’s catalyst - calycotomine

References and Notes

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12

Synthesis of ( R )-(+)-1-Cyano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (3).
A 50 mL round-bottom flask equipped with a stir bar was charged with 6,7-dimethoxy-3,4-dihydroisoquinoline (1, 190 mg, 0.994 mmol), the catalyst 2 (28 mg, 0.049 mmol, 0.05 equiv), and toluene (15 mL). The reaction was cooled to -70 °C by means of a constant-temperature bath. In another 30 mL flask equipped with a stir bar, 10 mL of toluene and 200 µL of TMSCN (1.5 mmol, 1.5 equiv) were combined. This solution was cooled to 0 °C and 60 µL of MeOH (1.5 mmol, 1.5 equiv) were added. The solution was allowed to stir for 2 h at 0 °C and then added to the reaction flask by syringe addition over 20 h at -70 °C. The reaction was allowed to stir for 40 h at -70 °C. To the reaction mixture, an excess of TFAA (560 µL, 4.0 mmol, 4 equiv) was added and the mixture was stirred for 2 h at -60 °C. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with 40% EtOAc in hexanes to afford 3 (269 mg, 86%) as colorless needles, mp 96 °C; [α]_D ¹⁸ +127.1 (c 1.05, CHCl₃). HPLC: t _R (S) = 16.7 min; t _R (R) = 19.5 min [Chiralpak OD (0.46 cm ¥ 25 cm, Daicel Chemical Ind., Ltd.), hexane-i-PrOH, 90:10, 1.0 mL/min] 95% ee. ¹H NMR (CDCl₃): δ = 6.82 (s, 1 H), 6.67 (s, 1 H), 6.28 (s, 1 H), 4.24-4.20 (m, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.81-3.73 (m, 1 H), 3.07-2.99 (m, 1 H), 2.91-2.87 (m, 1 H). ¹³C NMR (CDCl₃): δ = 156.96 (q, J = 37.2 Hz), 149.85, 148.79, 125.18, 118.17, 116.47, 111.33, 109.17, 56.05, 55.92, 44.60, 41.72, 41.69, 27.79. Anal. Calcd for C₁₄H₁₃F₃N₂O₃: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.62; H, 3.96; N, 8.63.

13

Analytical Data for ( R )-(-)-Calycotomine (8).
Colorless solid; mp 138 °C; [α]_D ²¹ -37.9 (c 0.13, H₂O); lit.¹⁷ [α]_D ²⁹ +33.7 (c 1.05, H₂O); lit.¹⁸ [α]_D ²⁵ +37.9 (c 0.2, H₂O), both of these values referred to the S enantiomer. ¹H NMR (CDCl₃): δ = 6.59 (s, 1 H), 6.58 (s, 1 H), 4.00 (dd, 1 H, J = 4.1, 9.3 Hz), 3.850 (s, 3 H), 3.846 (s, 3 H), 3.77 (dd, 1 H, J = 4.1, 10.7 Hz), 3.63 (dd, 1 H, J = 9.5, 10.7 Hz), 3.13-3.02 (m, 2 H), 2.76-2.63 (m, 2 H). ¹³C NMR (CDCl₃): δ = 147.82, 147.49, 127.49, 126.77, 111.96, 109.13, 63.98, 56.00, 55.97, 55.86, 38.70, 28.95. HRMS-FAB: m/z calcd for C₁₂H₁₈NO₃: 224.1287 [M + H]⁺; found: 224.1294.

14

Analytical Data for ( S )-(-)-Salsolidine (11).
Colorless oil; [α]_D ²⁰ -57.9 (c 0.11, EtOH); lit.¹⁸ [α]_D ²⁵ +59.5 (c 0.9, EtOH); lit.¹⁹ [α]_D ²⁵ +54.0 (c 0.63, EtOH), both of these values referred to the R enantiomer. ¹H NMR (CDCl₃): δ = 6.62 (s, 1 H), 6.58 (s, 1 H), 4.13 (q, 1 H, J = 6.8 Hz), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.33-3.27 (m, 1 H), 3.06 (ddd, 1 H, J = 4.9, 8.3, 13.2 Hz), 2.89-2.82 (m, 1 H), 2.75-2.68 (m, 1 H), 1.51 (d, 3 H, J = 6.8 Hz). ¹³C NMR (CDCl₃): δ = 148.16, 147.88, 127.53, 124.40, 111.38, 108.74, 55.94, 55.79, 50.32, 39.40, 26.34, 20.52. HRMS-FAB: m/z calcd for C₁₂H₁₈NO₂: 208.1338 [M + H]⁺; found: 208.1359.

15

( S )-(-)-Carnegine (12).
Colorless oil. [α]_D ²⁰ -47.8 (c 0.10, EtOH); lit.²⁰ [α]_D ²⁵ -51.5 (c 1.70, EtOH). ¹H NMR (CDCl₃): δ = 6.59 (s, 1 H), 6.57 (s, 1 H), 3.848 (s, 3 H), 3.845 (s, 3 H), 3.57 (q, 1 H, J = 6.6 Hz), 3.04 (ddd, 1 H, J = 4.9, 6.6, 11.7 Hz), 2.85-2.72 (m, 2 H), 2.65 (ddd, 1 H, J = 4.9, 7.1, 12.0 Hz). 2.49 (s, 3 H), 1.39 (d, 3 H, J = 6.6 Hz). ¹³C NMR (CDCl₃): δ = 147.28, 147.23, 131.38, 125.77, 111.17, 109.86, 58.66, 55.94, 55.78, 48.80, 42.80, 27.37, 19.73. HRMS-FAB: m/z calcd for C₁₃H₂₀NO₂: 222.1494 [M + H]⁺; found: 222.1502.

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