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Synlett 2006(8): 1181-1184  
DOI: 10.1055/s-2006-932488
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Entry to Polysubstituted Pyrrolizidines, Indolizidines and ­Quinolizidines via a Sequential Reaction Process

Dawei Ma*, Wei Zhu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax: +86(21)64166128; e-Mail: madw@mail.sioc.ac.cn;
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Publication History

Received 29 November 2005
Publication Date:
10 March 2006 (online)

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Abstract

A sequential SN2-Michael addition-Michael addition ­reaction process between ω-iodo-α,β-alkynoates and δ- or γ-amino α,β-unsaturated esters is developed, which affords polysubstituted pyrrolizidines, indolizidines or quinolizidines in good yields.

Key words

cascade reactions - pyrrolizidines - indolizidines - quinolizidines

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General Procedure for Reaction of Iodides 1 with δ- or γ-Amino α,β-Unsaturated Esters 2: A mixture of 1 (0.22 mmol), 2 (0.23 mmol), anhyd K2CO3 (95 mg), and 4 Å MS (40 mg) in 3 mL of MeCN was refluxed until the starting materials disappeared as monitored by TLC. The cooled solution was concentrated and partitioned between brine and Et2O. The organic phase was dried over MgSO4 and concentrated. The residue was purified via chromatography to give 3.

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Selected data for 3a: [α]D 18 +138.0 (c 0.75, CHCl3). IR (film): 1734, 1664, 1573 cm-1. 1H NMR (300 MHz, CDCl3): δ = 4.18-4.02 (m, 4 H), 3.28 (t, J = 3.6 Hz, 1 H), 3.22-3.18 (m, 1 H), 3.12-3.10 (m, 1 H), 3.03-2.99 (m, 1 H), 2.81 (dt, J = 18.0, 6.5 Hz, 1 H), 2.64 (dd, J = 14.0, 3.4 Hz, 1 H), 2.36 (dd, J = 14.0, 8.8 Hz, 1 H), 2.02-1.96 (m, 1 H), 1.82-1.61 (m, 5 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.88 (d, J = 8.7 Hz, 3 H), 0.77 (d, J = 6.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 172.6, 166.7, 162.4, 161.2, 95.5, 73.2, 60.1, 58.1, 44.9, 40.7, 38.0, 24.8, 23.4, 20.0, 17.3, 15.8, 14.8, 14.4. MS: m/z = 323 [M+]. ESI-HRMS: m/z calcd for C18H29NO4Na: 346.1979 [M + Na]+; found: 346.1989.

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Selected data for 3h: [α]D 14 +53.6 (c 0.95, CHCl3). IR (film): 2934, 1730, 1675, 1552 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.31-7.21 (m, 8 H), 7.12-7.10 (m, 2 H), 4.74 (d, J = 12.6 Hz, 1 H), 4.56 (d, J = 12.6 Hz, 1 H), 4.18-4.09 (m, 4 H), 3.74-3.73 (m, 1 H), 3.48 (d, J = 9.6 Hz, 1 H), 3.41-3.36 (m, 1 H), 3.28 (dt, J = 17.0, 5.0 Hz, 1 H), 3.07-2.99 (m, 1 H), 2.83-2.74 (m, 3 H), 2.61 (dd, J = 13.2, 4.7 Hz, 1 H), 2.52 (dt, J = 11.9, 5.0 Hz, 1 H), 2.38 (dd, J = 16.4, 11.0 Hz, 1 H), 1.69-1.64 (m, 1 H), 1.56-1.47 (m, 3 H), 1.29-1.19 (m, 6 H). 13C NMR (75 MHz, CDCl3): δ = 173.0, 169.2, 154.7, 139.0, 138.9, 129.0 (2 C), 128.5 (2 C), 128.3 (2 C), 127.4 (2 C), 127.3, 126.5, 93.0, 75.9, 70.1, 66.2, 60.2, 58.8, 52.6, 38.1, 36.9, 33.8, 27.8, 23.3, 20.5, 14.6, 14.3. MS (EI): m/z = 491 [M+]. ESI-HRMS: m/z calcd for C30H37NO5Na: 514.2586 [M + Na]+; found: 514.2564.

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Selected data for 3m: [α]D 18 -12.3 (c 0.5, CHCl3). IR (film): 2930, 1728, 1665, 1574 cm-1. 1H NMR (300 MHz, CDCl3): δ = 6.88 (q, J = 7.5 Hz, 1 H), 5.90 (d, J = 15.5 Hz, 1 H), 4.22-4.03 (m, 6 H), 3.47 (q, J = 3.9 Hz, 1 H), 3.22-3.16 (m, 1 H), 3.09-2.96 (m, 2 H), 2.86-2.74 (m, 3 H), 2.52-2.47 (m, 2 H), 2.29 (dd, J = 15.6, 9.9 Hz, 1 H), 1.79-1.74 (m, 2 H), 1.65-1.59 (m, 2 H), 1.31-1.19 (m, 9 H). MS (EI): m/z = 393 [M+]. ESI-HRMS: m/z calcd for C21H32NO6: 394.2252 [M + H]+; found: 394.2224.