Diastereoselective Synthesis of Polyfunctional-Pyrrolidines via Vinyl Epoxide Aminolysis/Ring-Closing Metathesis: . . .

Karl B. Lindsay; Minyan Tang; Stephen G. Pyne

doi:10.1055/s-2002-25337

LETTER

Diastereoselective Synthesis of Polyfunctional-Pyrrolidines via Vinyl Epoxide Aminolysis/Ring-Closing Metathesis: Synthesis of Chiral 2,5-Dihydropyrroles and (1R,2S,7R,7aR)-1,2,7-Trihydroxypyrrolizidine

Karl B. Lindsay, Minyan Tang, Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia
Fax: +61(2)42214287; e-Mail: stephen_pyne@uow.edu.au;

Abstract

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Abstract

This paper describes an efficient and diastereoselective method for preparing 2-substituted-2,5-dihydropyrroles in racemic and optically active form via acid catalysed or microwave assisted aminolysis of vinyl epoxides with allyl amine followed by ring-closing metathesis. Using this method, (1R,2S,7R,7aR)-1,2,7-trihydroxypyrrolizidine could be prepared by elaboration of a chiral 2-substitited-2,5-dihydropyrrole.

Key words

2,5-dihydropyrroles - vinyl epoxide - aminolysis - ring-closing metathesis

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References

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(3S,4R)-3-Allylamino-6-(4-methoxybenzyloxy)-1-hexen-4-ol (8b): (2R,3R)-3-[2-(4-Methoxybenzyloxy)ethyl]-2-ethenyloxirane (7b) (1.647 g, 6.98 mmol) was dissolved in allylamine (11.5 mL, 153.56 mmol), then pTsOH.H₂O (355 mg, 1.87 mmol) was added. The mixture was heated at 110 °C under nitrogen in a sealed tube for 4 d. After cooling, all volatiles were removed in vacuo to give a red solid that was purified by column chromatography (gradient elution from 0-12.5% MeOH-CH₂Cl₂) to give the title compound (1.83 g, 90%) as a pale yellow solid. Mp 61.5-62.5 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, 2 H, J = 9.0 Hz), 6.86 (d, 2 H, J = 9.0 Hz), 5.94-5.81 (m,1 H), 5.71 (ddd,1 H, J = 8.4, 10.5, 17.4 Hz), 5.22 (dd,1 H, J = 1.8, 10.5 Hz), 5.19-5.18 (m,1 H), 5.13-5.12 (m,1 H), 5.08 (dd,1 H, J = 1.2, 9.9 Hz), 4.43 (s, 2 H), 3.85 (dt,1 H, J = 3.3, 6.6 Hz), 3.79 (s, 3 H), 3.69-3.56 (m, 2 H), 3.28 (apparent dd,1 H, J = 6.0, 13.8 Hz), 3.12 (apparent dd,1 H, J = 6.3, 14.4 Hz), 3.07 (dd,1 H, J = 3.3, 8.4 Hz), 1.80-1.61 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 159.00 (C), 136.40 (CH), 136.04 (CH), 130.05 (C), 129.18 (CH), 118.28 (CH₂), 116.00 (CH₂), 113.67 (CH), 72.84 (CH₂), 71.38 (CH), 68.27 (CH₂), 65.18 (CH), 55.25 (CH₃), 49.55 (CH₂), 32.76 (CH₂); [α]_D ²⁵+2.0 (c 2.3 CHCl₃); MS (CI +ve) m/z 292 (M-1⁺. 100%); HRMS (CI +ve) Calcd for C₁₇H₂₆NO₃ (MH⁺) 292.191. Found: 292.194.

N -Boc Protection: To a solution of 8b (1.17 g, 4.01 mmol) in dry THF (70 mL) were added triethylamine (0.98 mL, 7.00 mmol) and di-tert-butyldicarbonate (1.53 g, 7.00 mmol) under nitrogen. The mixture was stirred at r.t. for 24 h. All volatiles were then removed in vacuo to give a yellow oil which was purified by column chromatography (gradient elution from 20-40% EtOAc-petroleum ether) to give the N-Boc derivative of 8b (1.507 g, 96%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, 2 H, J = 8.4 Hz), 6.87 (d, 2 H, J = 8.4 Hz), 6.08 (ddd,1 H, J = 6.9, 9.9, 17.1 Hz), 5.85-5.72 (m,1 H), 5.30-5.21 (m, 2 H), 5.16-5.06 (m, 2 H), 4.44 (s, 2 H), 4.09 (m,1 H), 3.93-3.89 (m,1 H), 3.82 (m, 2 H), 3.80 (s, 3 H), 3.73-3.57 (m, 2 H), 1.76 (br s, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ CO not observed, 159.00 (C), 134.96 (CH), 129.98 (CH), 129.12 (CH), 118.38 (CH₂), 116.27 (CH₂), 113.65 (CH), 80.14 (C), 72.84 (CH₂), 70.06 (CH), 68.32 (CH₂), 65.11 (CH), 55.21 (CH₃), 50.12 (CH₂), 33.93 (CH₂), 28.42 (CMe₃); [α]_D ²⁵ -19.2 (c 2.4 CHCl₃); MS (CI +ve) m/z 392 (M + 1⁺); HRMS (CI +ve) Calcd for C₂₂H₃₄NO₅ (MH⁺) 392.244. Found: 392.244. RCM: Grubbs’ Catalyst (0.219 g, 0.266 mmol) was added to a solution of the above N-Boc derivative (1.039 g, 2.634 mmol) in dry DCM (500 mL) under nitrogen. The mixture was heated to reflux for 24 h. The solution was cooled and the solvent was removed in vacuo to give a brown oil which was purified by column chromatography (gradient elution with 20-55% EtOAc-petroleum ether) to give 9b as a clear oil (0.877 g, 91%). ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, 2 H, J = 8.4 Hz), 6.86 (d, 2 H, J = 8.4 Hz), 5.80 (apparent dd,1 H, J = 1.5, 6.3 Hz), 5.64 (apparent dd,1 H, J = 2.1, 6.3 Hz), 4.85 (d,1 H, J = 8.4 Hz), 4.83-4.80 (m,1 H), 4.44 (s, 2 H), 4.19 (dd,1 H, J = 2.1, 15.6 Hz), 4.04-3.97 (m,1 H), 3.87 (apparent t,1 H, J = 9.6 Hz), 3.8 (s, 3 H), 3.71-3.56 (m, 2 H), 1.69-1.53 (m, 2 H), 1.48 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 158.91(CO), 156.14 (C), 130.39 (C), 129.25 (CH), 127.12 (CH), 126.53 (CH), 113.62 (CH), 80.50 (C), 72.84 (CH₂), 71.33 (CH), 71.51 (CH), 67.87 (CH₂), 55.26 (CH₃), 54.68 (CH₂), 31.79 (CH₂), 28.48 (CH₃); [α]_D ²³ -80.3 (c 2.4 CHCl₃); MS (CI +ve) m/z 364 (M + 1⁺); HRMS (CI +ve) Calcd for C₂₀H₃₀NO₅ (MH⁺) 364.212. Found: 364.199.

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17: ¹H NMR (300 MHz, CDCl₃) δ 5.40 (ddd,1 H, J = 2.1, 4.2, 4.5 Hz), 5.12 (m,1 H), 4.99 (dd,1 H, J = 4.5, 7.8 Hz), 3.50 (dd,1 H, J = 2.1, 7.8 Hz), 3.27 (dd,1 H, J = 2.1, 11.7 Hz), 3.21 (ddd,1 H, obscured), 2.87 (dd,1 H, J = 4.2, 11.7 Hz), 2.71 (ddd,1 H, J =6.0, 9.0, 11.1 Hz), 2.07 (s, 3 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.95-1.86 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 170.34 (CO), 170.11 (CO), 170.07 (CO), 77.13 (CH), 74.09 (CH), 73.16 (CH), 71.58 (CH), 57.12 (CH₂), 52.91 (CH₂), 30.54 (CH₂), 21.11 (CH₃), 20.94 (CH₃), 20.75 (CH₃); [α]_D ²⁵ +5.0 (c 0.8 CHCl₃); 16: ¹H NMR (300 MHz, D₂O) δ 4.23-4.15 (m, 2 H), 3.86 (dd,1 H, J = 4.2, 6.3 Hz), 3.10 (dd,1 H, J = 1.8, 6.3 Hz), 3.04-2.98 (m, 2 H), 2.71 (dd,1 H, J = 4.2, 11.7 Hz), 2.61 (apparent quint,1 H), 2.08-1.95 (m,1 H), 1.77-1.67 (m,1 H); ¹³C NMR (75 MHz, D₂O) δ 77.78 (CH), 77.64 (CH), 77.41 (CH), 74.81 (CH), 60.51 (CH₂), 54.85 (CH₂), 35.13 (CH₂).

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