Zirconium based approaches to nitrogen heterocycles. A synthesis of Tecomanine.

Mark I. Kemp, Richard J. Whitby* (RJW1@soton.ac.uk)

Department of Chemistry, Southampton University, Southampton, HANTS, SO17 1BJ, U.K.

Steven J. Coote

Glaxo Group Research, Gunnels Wood Road, Stevenage, HERTS, SG1 2NY, U.K.

Abstract: Intramolecular cocyclisation of N-methyl-N-(2-methyl-but-3-ynyl)-but-2-enylamine using zirconocene ethylene followed by carbonylation affords a 4 : 1 mixture of (+/-)-Tecomanine and (+/-)-4-epi-Tecomanine.
The formation of zirconabicycles by the intramolecular cocyclisation of 1,n-dienes and -enynes with `zirconocene' has received much attention in recent years[1]. The co-cyclisation is most conveniently carried out using the `zirconocene' equivalent zirconocene 1-butene (the Negishi reagent[2]) formed in situ from dibutylzirconocene (Scheme 1).

Zirconabicycles are versatile intermediates which may be elaborated into a wide range of mono- and bi-cyclic organic compounds[3]. The formation of pyrrolidines by co-cyclisation of diallyl- or N-propargyl allylamines is well known[4] and we recently reported that 3,4-disubstituted piperidines could be made from homologues of these precursors[5]. We now report an application of this method to the synthesis of the hypoglycemic agent Tecomanine 1[6,7].

The known carbonylation of zirconacyclopentenes to give cyclopentenones suggested alkyne 2 as the the immediate precursor of Tecomanine. Terminal alkynes are reported to fail to co-cyclise with the Negishi reagent[1] (the terminal proton is too acidic) but we were attracted by a report[8] that zirconocene ethylene successfully added to terminal alkynes, and that thermal elimination of ethylene from the so-formed unsaturated zirconacycles gave a zirconocene-alkyne complex which could be trapped, a potential solution to this limitation[9].

Reaction between N-crotylmethylamine[10] (80 : 20 mixture of E : Z isomers) and the p-toluenesulphonate of 2-methyl-3-butyne-1-ol[11] gave the required enyne 2. Reaction with in situ generated zirconocene ethylene 3 at room temperature gave the monocyclic products 4 and 5 (3 : 1). Heating at reflux in THF for 3 hours gave complete conversion to the zirconabicycles 6 and 7 which gave the piperidines 8 and 9 on methanolysis, the major of which was easily assigned as cis[12]. This demonstrated that the more stable zirconabicycle was 6 as required for Tecomanine synthesis. Carbonylation (1 atm CO, r.t. 16h) gave an easily separated 4 : 1 mixture of (+/-)-tecomanine 1[13] and (+/-)-4-epi-tecomanine 10[14] in a disappointing 21% overall yield from 2. The yield was slightly increased to 31% by carrying out the carbonylation at -78deg.C for 2h then working up with iodine (2 eq.).

Of note is that products from the (Z)-crotyl moiety were not isolated. This is probably due to rapid epimerisation of the supposed intermediate zirconocene h2-ketone complex 11[16] via the hydride 12[17] although epimerisation on work-up has not been ruled out.

An alternative solution to the problem of the failure of terminal alkynes in the zirconocene 1-butene induced co-cyclisation reaction is to use trimethylsilyl or trimethylstannyl alkynes instead. Unfortunately it was predictable[18] that this would not give the correct stereochemistry for Tecomanine. 1,3-Interaction between the large alkyne substituent and the equatorial methyl group in the zirconacycle 15 destabilises it with respect to the isomer 14 where the methyl is axial. In confirmation of this prediction cocyclisation of the trimethylstannyl alkyne 13 followed by protonolysis gave exclusively the piperidine 16.

Overall we have described a concise synthesis of the hypoglycemic agent (+/-)-Tecomanine using a zirconocene induced co-cyclisation / carbonylation.

Acknowledgements. We wish to thank Glaxo Group Research and the EPSRC for support of this work through the CASE scheme.

References and Notes.

1. Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124; Negishi, E. I. In Comprehensive Organic Synthesis; Trost, B.M.; Fleming, I. Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5; p 1163; RajanBabu, T. V.; Nugent, W.A.; Taber, D.F.; Fagan, P. J. J. Am.Chem. Soc. 1988, 110, 7128-7135.[back]

2. Negishi, E.; Cederbaum, F.E.; Takahashi, T. Tetrahedron Lett. 1986, 27, 2829. For assignment of structure see: Buchwald, S.L.; Watson, B.T.; Huffman, J.C. J. Am. Chem. Soc. 1987, 109, 2544. Binger, P.; Müller, P.; Benn, R.; Rufinska, A.; Gabor, B; Krüger, C.; Betz, P. Chem. Ber., 1989, 122, 1035-1042.[back]

3. Carbonylation: Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi, T.; Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521; Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E.Tetrahedron Lett. 1989, 30, 5105. Aldehyde insertion: Copéret, C.; Negishi, E.; Xi, Z.; Takahashi, T. Tetrahedron Lett. 1994, 35, 695. Tandem isocyanide / (alkyne, alkene, ketone, isocyanate) insertion: Davis, J. M.; Whitby, R. J.; Jaxa-Chamiec, A. Tetrahedron Lett. 1992, 33, 5655; idem, ibid, 1994, 35, 1445; idem, Synlett 1994, 111; Probert, G. D.; Whitby, R. J.; Coote, S. J. Tetrahedron Lett. in press. Halogenation: Nugent, W. A.; Taber, D. F. J. Am. Chem. Soc. 1989, 111, 6435. Metathesis with other elements (S, Se, Si, Sn, Ge, B, P, As, Sb, Bi): Fagan, P. J.; Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1994, 116, 1880. Copper catalysed elaboration: Kasai, K.; Kotora, M.; Suzuki, N.; Takahashi, T. J. Chem. Soc., Chem. Commun. 1995, 109. Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51, 4407-4420. Tandem lithium chloroallylide / electrophile elaborations: Luker, T.; Whitby, R. J. Tetrahedron Lett. 1994, 35, 785. Luker, T.; Whitby, R. J. Tetrahedron Lett. 1994, 50, 9465. Luker, T.; Whitby, R. J. Tetrahedron Lett. 1995, in press. c. Gordon, G. J.; Whitby, R. J. Synlett 1995, 77. [back]

4. For the reductive coupling of diallylamines see: Rousset, C.J.; Swanson, D.R.; Lamaty, F.; Negishi, E. Tetrahedron Lett. 1989, 30, 5105; Nugent, W.A.; Taber, D.F. J. Am.Chem. Soc. 1989, 111, 6435; Mori, M; Uesaka, N.; Shibasaki, M. J. Org. Chem. 1992, 57, 3519; Uesaka, N.; Mori, M.; Saitoh, F.; Uesaka, N.; Shibasaki, M. Chem. Lett. 1993, 213-216; Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59, 5643-5649; Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633-5642. For the coupling of N-propargyl-allylamines see Negishi, E.; Holmes, S.J.; Tour, J.M.; Miller, J.A.; Cederbaum, F.E.; Swanson, D.R.; Takahashi, T. J. Am.Chem. Soc. 1989, 111, 3336. For the formation of N-heterocycles using catalytic zirconocene and titanocene reagents see: Wischmeyer, U.; Knight, K.S.; Waymouth, R.M. Tetrahedron Lett. 1992, 33, 7735; Berk, S.C.; Grossman, R.B.; Buchwald, S.L. J. Am. Chem. Soc. 1993, 115, 4912; Uesaka, N.; Mori, M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 4542-4547.[back]

5. Kemp, M. I.; Whitby, R. J.; Coote, S. J. Synlett 1994, 451.[back]

6. Tecomanine. Isolation and structure: Dickinson, E. M.; Jones, G. Tetrahedron, 1969, 25, 1523 and refs therin, Jones, G.; Fales, H. M.; Wildman, W. C. Tetrahedron Lett. 1963, 397. Jones, G. et al J. Chem. Soc., Chem. Commun. 1971, 994 (X-ray). Ferguson, G.; Marsh, W. C. J. Chem. Soc., Perkin trans 1 1975, 1124.

Hypoglycemic activity: Hammouda, Y.; Rashid, A. K.; Amer, M.S. J. Pharm. Pharmacol., 1964, 16, 833; Hammouda, Y.; Amer, M.S. J. Pharm. Sci., 1966, 55, 1452. Lozoyameckes, M; Melladocampos, V. J. Ethnopharm. 1985, 14, 1-9.[back]

7. Previous synthesis of (+/-)-Tecomanine: (a) Imanishi, T.; Yagi, N.; Hanaoka, M. Chem. Pharm. Bull. 1983, 31, 1243-1253. (b) idem, Tetrahedron Lett. 1981, 22, 667-670. (c) Miyashita, M.; Tanaka, D.; Shiratani, T.; Irie, H. Chem. Pharm. Bull. 1992, 40, 1614-1615. Synthesis of (+)-Tecomanine: Kametani, T.; Suzuki, Y.; Ban, C.; Honda, T. Heterocycles 1987, 26, 1491-1493.[back]

8. Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E. Tetrahedron Lett., 1993, 34, 687-690.[back]

9. An alternative approach to the coupling of terminal alkynes is to form the zirconocene alkyne complex in situ by C-H activation from a vinyl zirconocene species: Broene, R. D.; Buchwald, S. L. Science 1993, 261, 1696-1701. Barluenga, J.; Sanz, R.; Fananas, F. J. Z. Naturforschung Sect. B 1995, 50, 312-314. Barluenga, J; Sanz, R.; Fananas, F. J. Chem. Soc., Chem. Commun. 1995, 1009-1010.[back]

10. N-Methyl crotylamine was prepared as in Scheme 4. Of note is that the crotyl chloride used (Aldrich) is an 80 : 20 mixture of E : Z isomers. The reaction of triflouroacetic anhydride with methylamine hydrochloride initially gave mostly (CF3CO)2NMe but heating overnight with an excess of the amine salt gave the required compound.[back]

11. The 2-methyl-but-3-yne-1-ol tosylate was prepared from 3-butyn-2-ol as shown in Scheme 5. [back]

12. Data for 8. 1H NMR (300 MHz, CDCl3) 4.73 (1H, s), 4.71 (1H, s), 3.01 (1H, dd, J = 11 & 4 Hz), 2.90 (1H, dd, J = 10 & 4 Hz), 2.28 (3H, s), 1.6-1.8 (2H, two obscured multiplets), 1.62 (1H, t, J = 11 Hz*), 1.57 (1H, t, J = 11 Hz*), 1.26 (2H, m), 1.02 (3H, d, J = 7 Hz), 0.96 (3H, t, J = 7 Hz). *- These signals are due to the axial protons on the carbons next to nitrogen and the vicinal di-axial couplings show that the substituents on the adjacent carbons must both be equatorial. 13C NMR (75MHz, CDCl3) 154.30 (C), 102.59 (C), 65.62 (CH2), 62.97 (CH2), 45.94 (CH3), 44.14 (CH), 37.33 (CH), 22.71 (CH2), 15.63 (CH3), 12.16 (CH3).[back]

13. Data for (+/-)-Tecomanine 1. Picrate m.p. 184-186deg.C (lit<[7a] 184.5-185.5deg.C); IR (thin film) 2962 m, 2934 m, 2876 m, 2781 m, 1704 s, 1620 m, 1464 m, 1373 m, 868 m cm-1; 1H NMR (270 MHz, CDCl3) 5.85 (1H, s), 3.17 (1H, ddd, J = 11, 6 & 2 Hz), 2.94 (1H, ddd, J = 11, 6 & 2 Hz), 2.64 (1H, m), 2.50 (1H, m), 2.27 (3H, s), 1.89 (1H, qd, J = 8 & 3 Hz), 1.74 (2H, t, J = 11 Hz), 1.19 (3H, d, J = 7 Hz), 1.16 (3H, d, J = 6 Hz); 13C NMR (75 MHz, CDCl3) 210.63 (C), 183.68 (C), 124.39 (CH), 63.25 (CH2), 62.05 (CH2), 49.70 (CH), 45.63 (CH3), 45.16 (CH), 35.24 (CH), 15.06 (CH3), 15.00 (CH3); UV (EtOH) λmax 224 nm (log ε 3.98). MS (EI) m/e (% base) 180 (15), 179 (100, M+), 164 (32), 111 (35), 93 (43), 58 (39), 57 (94), 42 (46); HRMS (EI) Calc. for C11H17NO 179.1310. Found 179.1306. Anal of picrate. C11H17NO.C6H3N3O7 requires C, 50.00; H, 4.90; N, 13.73%. Found C, 50.29; H, 4.76; N, 13.52%.[back]

14. Data for (+/-)-epi-Tecomanine: IR (thin film) 2962 m, 2931 m, 2783 m, 1704 s, 1625 m, 1462 m, 1368 m cm -1; 1H NMR (270 MHz, CDCl3) 5.86 (1H, s), 3.23 (1H, dd, J = 11 & 6 Hz), 2.97 (1H, m), 2.80 (1H, d plus further coupling, J = 11 Hz), 2.78 (1H, obscured multiplet), 2.30 (3H, s), 2.18 (1H, dd, J = 11 & 4 Hz), 1.94 (1H, qd, J = 7 & 3 Hz), 1.70 (1H, t, J = 11 Hz), 1.35 (3H, d, J = 7 Hz), 1.19 (3H, d, J = 8 Hz); 13C NMR (67.5 MHz, CDCl3) 183.39 (C), 125.65 (CH), 62.70 (CH2), 62.07 (CH2), 46.30 (CH & CH3), 45.28 (CH), 34.51 (CH), 19.09 (CH3), 14.73 (CH3) carbonyl carbon not observed; UV (EtOH) λmax 226 nm (log ε 4.00); MS (CI, NH3) m/e 180 (MH+); HRMS (CI, NH3) calc for C11H18NO 180.1388, found 180.1391. NMR data in complete agreement with that reported in ref. 15.[back]

15. Alazard, J. P.; Leboff, A.; Thal, C. Tetrahedron 1991, 47, 9195-9206.

16. Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Takahashi, T.; Swanson, D. R. J. Am. Chem. Soc. 1989, 111, 3336.[back]

17. Coles, N.; Harris, M.C.J.; Whitby, R. J.; Blagg, J. Organometallics 1994, 13, 190.[back]

18. Lund, E. C.; Livinghouse, T. J. Org. Chem. 1989, 54, 4487-4488.[back]

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