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Synlett 2002(5): 0731-0734
DOI: 10.1055/s-2002-25337
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 19 February 2002
Publication Date:
07 February 2007 (online)

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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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(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.

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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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Reactions were performed on a Milestone, ETHOS SEL microwave labstation in sealed teflon vessels with strict control of the internal reaction temperature.

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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).