Stereoselective Synthesis of the A,E-Ring Bicyclic Core of Calyciphylline B-Type Alkaloids

Abstract

A stereoselective synthesis of the bicyclic unit constituting the A and E rings of calyciphylline B-type alkaloids is disclosed. The propionate ester of (1R)-cyclohex-2-en-1-ol, obtained by enzymatic resolution, is subjected to an Ireland–Claisen rearrangement. Subsequent reduction of the acid, Mitsunobu reaction to introduce a nitrogen functionality, oxidative cleavage to a dialdehyde, and intramolecular aldol and aza-Michael reactions afford the bicyclic subunit.

Key words

asymmetric synthesis - alkaloids - chiral resolution - electrocyclic reaction - Michael addition - Mitsunobu reaction

• References and Notes

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• 13 N-[(1S)-1-Cyclohex-2-en-1-ylpropyl]-4-nitrobenzenesulfonamide (17) To a solution of alcohol 16 (1.4 g, 10 mmol) in anhyd THF (200 mL) were added Ph₃P (5.24 g, 20 mmol), (4-nitrobenzene)sulfonamide (4.04 g, 20 mmol), and DIAD (3.16 mL, 20 mmol) at 0 °C, and the mixture was stirred for 12 h at rt. H₂O (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography [silica gel (100–200 mesh), 10% EtOAc–hexane] to give a colorless solid; yield: 2.21 g (6.5 mmol, 65%); mp 98–100 °C; [α]_D ²⁰ –15.3 (c 0.31, CHCl₃); R_f = 0.2 (15% EtOAc–hexane). IR (neat): 3282, 2926, 2850, 1608, 1530, 1351, 1156, 753, 611 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.37 (d, J = 8.8 Hz, 2 H), 8.05 (d, J = 8.9 Hz, 2 H), 5.74 (ddd, J = 9.7, 6.5, 2.9 Hz, 1 H), 5.43 (d, J = 10.2 Hz, 1 H), 4.65 (t, J = 6.1 Hz, 1 H), 3.07–2.98 (m, 1 H), 2.92–2.83 (m, 1 H), 2.18–2.07 (m, 1 H), 2.00–1.89 (m, 2 H), 1.77–1.68 (m, 1 H), 1.67–1.59 (m, 2 H), 1.53–1.41 (m, 1 H), 1.31–1.13 (m, 1 H), 0.88 (d, J = 6.9, Hz, 3 H).¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.1, 146.0, 129.2, 128.6, 128.31, 124.4, 46.8, 38.1, 37.6, 25.7, 25.2, 22.1, 14.8. MS (ESI–TOF): m/z = 325 [M + H]⁺; HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₅H₂₁N₂O₄S: 325.1222; found: 325.1227.
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• 16 Allyl Ester 8 Et₃N (80 μL, 0.56 mmol) and allyl bromide (25 μL, 0.28 mmol) were added to a solution of acid 19 (50 mg, 0.14 mmol) in anhyd CH₂Cl₂ (1.5 mL) cooled to 0 °C. The mixture was stirred for 30 min at rt then concentrated in vacuo and extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography [silica gel (100–200 mesh), 10% EtOAc–hexanes] to give a colorless solid; yield: 44 mg (0.11 mmol, 80%); mp 124–126 °C; [α]_D ²⁰ +2.6 (c 1.3, CHCl₃); R_f  = 0.6 (20% EtOAc–hexane). IR (KBr): 3096, 2927, 2860, 1727, 1531, 1351, 1167, 1115, 1026, 613 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.42 (d, J = 8.8 Hz, 2 H), 8.07 (d, J = 8.8 Hz, 2 H), 5.99 (ddd, J = 17.2, 10.7, 5.7 Hz, 1 H), 5.40 (dd, J = 17.2, 1.5 Hz, 1 H), 5.31 (dd, J = 10.4, 1.2 Hz, 1 H), 4.70–4.66 (m, 2 H), 4.12 (dd, J = 9.0, 3.8 Hz, 1 H), 3.73 (dd, J = 9.3, 6.3 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.57 (t, J = 9.3 Hz, 1 H), 2.21–2.11 (m, 2 H), 1.99–1.90 (m, 2 H), 1.83–1.75 (m, 1 H), 1.55–1.50 (m, 1 H), 0.86 (d, J = 6.6 Hz, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 174.0, 150.3, 141.4, 132.2, 129.3, 124.3, 118.4, 67.0, 65.5, 57.5, 51.7, 38.0, 30.4, 30.0, 16.5. MS (ESI–TOF): m/z = 395 [M + H]⁺. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O₆S: 395.1277; found: 395.1275.