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Synlett 2006(13): 2142-2144  
DOI: 10.1055/s-2006-949605
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Synthesis of (-)-Trachelanthamidine via Palladium-Catalysed Intramolecular Allylation

Donald Craig*a, Christopher J. T. Hylanda, Simon E. Wardb
a Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
b GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Fax: +44(20)75945868; e-Mail: d.craig@imperial.ac.uk;
Further Information

Publication History

Received 23 May 2006
Publication Date:
09 August 2006 (online)

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Abstract

A stereoselective synthesis of (-)-trachelanthamidine has been developed, employing a palladium-catalysed cyclisation as the key step.

Key words

allyl complexes - cyclisations - lactams - palladium - ­stereoselective synthesis

    References and Notes

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  • 5a

    PyBOP = (Benzotriazol-1-yloxy)tripyrrolidinophospho-nium hexafluorophosphate
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  • For previous syntheses of (-)-trachelanthamidine see:
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6

TTMPP = tris(2,4,6-trimethoxyphenyl)phosphine.

10

A referee has made the reasonable suggestion that in the cyclisations of 1, the same conformation is adopted as for cyclisation of 4, but that for 1 Pd approaches the π-bond from the opposite face due to the absence of the constraining ring and the consequent ability of the N-acyl moiety to rotate. This would necessitate a subsequent change in the conformation of the π-allyl complex to allow cyclisation to take place.

11

We thank Dr. A. J. P. White (Imperial College) for the X-ray structure determination. Full details will be reported elsewhere.

14

Data for 4: R f = 0.51 (10% MeOH-CH2Cl2); [α]D 22 -104.6 (c 1.0, CHCl3). IR (film): νmax = 2956, 1747, 1649, 1439, 1269, 1269, 1153, 1086, 941, 793, 729 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.78-7.76 (2 H, m, ortho Ts), 7.38-7.28 (2 H, m, meta Ts), 5.83-5.61 (2 H, m, CH=CH), 4.78-4.62 (3 H, m, CHN and CH 2 OCO2Me), 4.28-3.47 (4 H, m, CH 2Ts and CH2N), 3.81-3.80 (3 H, m, OMe), 2.45 (3 H, s, Me of Ts), 2.21-1.69 (4 H, m, CH 2 CH 2 CHN). 13C NMR (75 MHz, CDCl3): δ = 160.4, 159.8, 155.6, 155.5, 145.3, 145.2, 136.2, 135.7, 134.3, 133.4, 129.8, 128.7, 125.3, 123.0, 67.7, 66.9, 61.7, 61.4, 59.1, 58.0, 55.0, 54.8, 48.1, 46.8, 32.6, 30.4, 23.7, 21.8. MS (CI): m/z = 382 [M + H]+, 306, 228, 152. HRMS: m/z calcd for C18H23NO6S [M + H]+: 382.1324; found [M + H]+: 382.1328. Anal. Calcd for C18H23NO6S (%): C, 56.68; H, 6.08; N, 3.67. Found: C, 56.53; H, 6.08; N, 3.53.

15

Preparation of 9a,b.
To a solution of allylic carbonate 4 (59.0 mg, 0.156 mmol, 1.0 equiv) in MeCN (2 mL) was added Pd2(dba)3 (7.30 mg, 0.008 mmol, 0.05 equiv) and triisopropyl phosphite (20.0 µL, 0.078 mmol, 0.5 equiv) at r.t. After 12 h the reaction was concentrated under reduced pressure and the residue purified by chromatography (Et2O) to yield an inseparable 94:6 mixture of the pyrrolizidinones 9a and 9b (34 mg, 72%) as a colourless oil; R f = 0.2 (Et2O). IR (film): νmax = 2972, 1703, 1421, 1317, 1177, 1086, 910, 814, cm-1. 1H NMR (400 MHz, CDCl3): δ (major isomer) = 7.83 (2 H, d, J = 8.0 Hz), 7.34 (2 H, d, J = 8.0 Hz), 5.96 (1 H, ddd, J = 16.0, 10.0, 7.0 Hz), 5.26 (1 H, d, J = 17.0 Hz), 5.21 (1 H, d, J = 9.0 Hz), 4.16 (d, J = 9.0 Hz, 1 H), 3.64-3.55 (m, 2 H), 3.47 (q, J = 7.0 Hz, 1 H), 3.09-3.03 (m, 1 H), 2.44 (s, 3 H), 2.27-1.97 (m, 3 H), 1.56-1.46 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ (major isomer) = 163.9, 145.1, 135.1, 136.0, 129.7, 129.4, 118.0, 73.5, 63.7, 45.5, 41.8, 30.6, 26.2, 21.7. MS (CI): m/z calcd for C16H19NO3S [M + H]+: 306.1164; found [M + H]+: 306.1174.