Stereoselective Conjugate Additions to γ-Lactams: Synthesis of Polysubstituted Benzo-Fused Indolizidine Systems

Abstract

The stereoselectivity of the conjugate addition of carbon nucleophiles to the bicyclic γ-lactam unit of dihydropyrrolo[2,1-a]isoquinolones depends on the nature of the nucleophile and the substituent at the angular position.

conjugate addition reactions - lactams - stereoselective synthesis - nucleophiles - carbanions

References and Notes

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11 Conjugate addition reaction of enolates and cuprates to the unactivated dihydropyrroloisoquinolones always failed, and unreacted starting material was always recovered: González-Temprano I. PhD Thesis   Universidad del País Vasco; Spain: 2003. 

12

See reference 6c.

13 See for instance: Osante I. Abdullah MN. Arrasate S. Sotomayor N. Lete E. ARKIVOC  2007,  (iv):  206 

14

Typical Procedure: MeLi (1.50 mL of a 1.6 M solution, 2.4 mmol) was added dropwise over a suspension of CuI (228 mg, 1.2 mmol) in anhyd THF (5 mL) at 0 °C. After 30 min, the mixture was cooled to -78 ºC, and a solution of lactam 2a (157 mg, 0.4 mmol) in THF (10 mL) was added. The reaction mixture was stirred for 3 h, allowed to warm to 0 ºC, and stirred at this temperature for 12 h. The reaction was quenched by sequential addition of 12% aq NH₄OH (20 mL) and sat. NH₄Cl (10 mL) at 0 °C. After the mixture was allowed to warm to r.t., the organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. Flash column chromatography (silica gel, 70% hexane-EtOAc) afforded the pyrroloisoquinolone 6a as a colorless oil (140 mg, 85%) as a single diastereomer. IR (CHCl₃): 1736, 1692 cm^-1. ¹H NMR (CDCl₃): δ = 1.36 (t, J = 6.7 Hz, 3 H), 1.41 (s, 3 H), 2.61-3.04 (m, 4 H), 3.36 (d, J = 11.9 Hz, 1 H), 3.84 (s, 6 H), 4.29-4.32 (m, 1 H), 5.21 (s, 2 H), 6.57 (s, 1 H), 6.69 (s, 1 H), 7.25-7.35 (m, 5 H). ¹³C NMR (CDCl₃): δ = 13.9, 21.9, 28.8, 34.8, 44.2, 55.6, 55.7, 55.9, 61.5, 66.9, 107.6, 11.7, 124.9, 127.8, 128.0, 128.4, 133.2, 135.4, 147.6, 147.7, 166.3, 169.2. MS (EI): m/z (rel. intensity) = 409 (8) [M⁺], 395 (26), 394 (100), 259 (32), 258 (14), 244 (20), 206 (10), 204 (10), 91 (52). Anal. Calcd for C₂₄H₂₇NO₅: C, 70.40; H, 6.65; N, 3.42. Found: C, 70.35; H, 6.43; N, 3.16.

15

We have observed that adducts, once formed, do not appear to undergo reversal to the unsaturated lactam, precluding the possibility of thermodynamic factors being responsible for the stereochemical results.

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