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

Donald Craig; Christopher J. T. Hyland; Simon E. Ward

doi:10.1055/s-2006-949605

LETTER

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

Donald Craig*^a, Christopher J. T. Hyland^a, Simon E. Ward^b
^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;

Abstract

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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

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References

References and Notes

1 Craig D. Hyland CJT. Ward SE. Chem. Commun. 2005, 3439

2 Liddell JR. Nat. Prod. Rep. 2002, 19: 773

3 Kennewell PD. Miles NJ. Sammes PG. Westwood R. J. Chem. Soc., Perkin Trans. 1 1985, 11: 2299

4 Moriwake T. Hamano S. Miki D. Saito S. Torii S. Chem. Lett. 1986, 815

5a

PyBOP = (Benzotriazol-1-yloxy)tripyrrolidinophospho-nium hexafluorophosphate

5b Castro B. Dormoy JR. Evin G. Selve C. Tetrahedron Lett. 1975, 1219

6

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

7 Wada M. Higashizaki S. Chem. Commun. 1984, 482

8 For a review on steric and electronic effects of phosphorus ligands, see: Tollman CA. Chem. Rev. 1977, 3: 313

9 Broeker JL. Reinhard WH. Houk KN. J. Am. Chem. Soc. 1991, 113: 5006

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.

12 For desulfonylation of a structurally similar substrate, see: Chang M.-Y. Hsu R.-T. Tseng T.-W. Sun P.-P. Chang N.-C. Tetrahedron 2004, 60: 5545

For previous syntheses of (-)-trachelanthamidine see:

13a Nagao Y. Dai W.-M. Ochiai M. Tsukagoshi S. Fujita E. J. Org. Chem. 1990, 55: 1148

13b Robins DJ. Sakdarat S. J. Chem. Soc., Perkin Trans. 1 1981, 909

13c Rüeger H. Benn M. Heterocycles 1982, 19: 1677

13d Moriwake T. Hamano S. Saito S. Heterocycles 1988, 27: 1135

14

Data for 4: R _f = 0.51 (10% MeOH-CH₂Cl₂); [α]_D ²² -104.6 (c 1.0, CHCl₃). IR (film): ν_max = 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 ₂OCO₂Me), 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 ₂CH ₂CHN). 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): ν_max = 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.