Synthesis of Two Nuphar Alkaloids by Allenic Hydroxylamine Cyclisation

Abstract

A highly diastereoselective silver-catalysed cyclisation of a 2-substituted β-allenic hydroxylamine is reported. The resulting trans-isoxazolidine is converted into two Nuphar alkaloids by a sequence involving cross-metathesis and intramolecular reductive amination.

Key words

piperidines - allenes - cyclisation - silver - alkaloids

References and Notes

• 1a Arata Y. Ohahshi T. Yakagaku Zasshi  1957,  77:  792 
• 1b Maurer B. Ohloff G. Helv. Chim. Acta  1976,  59:  1169 
• 2a Lalonde RT. Muhammad N. Wong CF. Sturiale ER. J. Org. Chem.  1980,  45:  3664 
• 2b Ohnuma T. Tabe M. Shiiya K. Ban Y. Tetrahedron Lett.  1983,  24:  4249 
• 2c Tufariello JJ. Dyszlewski AD. J. Chem. Soc., Chem. Commun.  1987,  1138 
• 2d Shimizu I. Yamazaki H. Chem. Lett.  1990,  777 
• 2e Clive DJL. Bergstra RJ. J. Org. Chem.  1991,  56:  4976 
• 2f Aoyagi S. Shishido Y. Kibayashi C. Tetrahedron Lett.  1991,  32:  4325 
• 2g Honda T. Ishikawa F. Yamane S. J. Chem. Soc., Chem. Commun.  1994,  499 
• 2h Honda T. Ishikawa F. Yamane S. Heterocycles  1999,  52:  313 
• 2i Barluenga J. Aznar F. Ribas C. Valdés C. J. Org. Chem.  1999,  64:  3736 
• 2j Gebauer J. Blechert S. Synlett  2005,  2826 
• 2k Davis F. Santhanaraman M. J. Org. Chem.  2006,  71:  4222 
• 2l Stoye A. Quandt G. Brunnhöfer B. Kapatsina E. Baron J. Fischer A. Weymann M. Kunz H. Angew. Chem. Int. Ed.  2009,  48:  2228 
• 3a Bates RW. Satchareon V. Chem. Soc. Rev.  2002,  12 
• For a review of silver in heterocycle synthesis, see:
• 3b Álvarez-Corral M. Muñoz-Dorado M. Rodríguez-García I. Chem. Rev.  2008,  108:  3174 
• 4 Bates RW. Nemeth J. Snell RH. Synthesis  2008,  1033 
• 5 Bates RW. Lu Y. J. Org. Chem.  2009,  74:  9460 
• 6a Crandall JK. Tindell GL. J. Chem. Soc., Chem. Commun.  1970,  1412 
• 6b Konegawa T. Ohtsuka Y. Ikeda H. Sugai T. Ohta H. Synlett  1997,  1297 
• 6c Ma S. Gao W. J. Org. Chem.  2002,  67:  6104 
• 7a Grochowski E. Jurczak J. Synthesis  1976,  682 
• 7b Iwagami H. Yatagai M. Nakazawa M. Orita H. Honda Y. Ohnuki T. Yukawa T. Bull. Chem. Soc. Jpn.  1991,  64:  175 
• 9 Wabnitz TC. Yu J.-Q. Spencer JB. Chem. Eur. J.  2004,  10:  484 
• 10a Cicchi S. Got A. Brandi A. Guarna A. Sarlos FD. Tetrahedron Lett.  1990,  31:  3351 
• 10b Zhang D. Süling C. Miller MJ. J. Org. Chem.  1998,  63:  885 
• 10c Mulvihill MJ. Gage JL. Miller MJ. J. Org. Chem.  1998,  63:  3357 
• 10d Li F. Brogan JB. Gage JL. Zhang D. Miller MJ. J. Org. Chem.  2004,  69:  4538 
• 10e Yang Y.-K. Choi J.-H. Tae J. J. Org. Chem.  2005,  70:  6995 
• 10f Calvet G. Blanchard N. Kouklovsky C. Synthesis  2005,  3346 
• 13 Sinisterra JV. Mouloungui Z. Delmas M. Gaset A. Synthesis  1985,  1097 
• 14 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183 
• 15 Connon SJ. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 
• 16 Bieniek M. Michrowska A. Usanov DL. Grela K. Chem. Eur. J.  2008,  14:  806 
• 17 Hoye TR. Jeffrey CS. Tennakoon MA. Wang J. Zhao H. J. Am. Chem. Soc.  2004,  126:  10210 

8

NMR spectroscopic data for the trans isomer: ^¹H NMR (300 MHz, CDCl₃): δ = 1.08 (3 H, d, J = 6.8 Hz, CH₃), 1.45 (9 H, s, t-Bu), 2.39 (1 H, m, CH), 3.41 (1 H, t, J = 8.3 Hz, CH₂), 3.93 (1 H, t, J = 6.9 Hz, CH), 4.10 (1 H, t, J = 7.2 Hz,CH₂), 5.13 (1 H, J = 10.1 Hz, =CH), 5.22 (1 H, J = 17.0 Hz, =CH), 5.76 (1 H, ddd, J = 7.2, 10.2, 16.8 Hz, =CH). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 28.2, 43.8, 69.1, 75.0, 81.8, 115.8, 136.7, 157.0.

11

A suitable crystal was obtained from EtOAc-hexane. Empirical formula: C₁₁H₂₁NO₃; formula weight: 215.29; temp: 173 (2) K; wavelength: 0.71073 Å; crystal system: monoclinic; space group: P2 (1)/n; unit cell dimensions: a = 11.1651 (4) Å, α = 90˚, b = 11.2768 (4) Å, β = 115.343 (2)˚, c = 11.1785 (5) Å, γ = 90˚; volume: 1272.00(9) Å^³; Z: 4; density(calcd): 1.124 Mg/m^³; absorption coefficient: 0.081 mm^-¹; F(000): 472; crystal size: 0.30 × 0.30 × 0.14 mm^³; θ range for data collection: 2.16-27.67˚; index ranges: -14 ≤ h ≤ 14, -12 ≤ k ≤ 14, -14 ≤ l ≤ 14; reflections collected: 12787; independent reflections: 2983 [R(int) = 0.0586]; completeness to θ = 27.67˚: 99.9%; absorption correction; semi-empirical from equivalents; max. and min. transmission: 0.9888 and 0.9762; refinement method: full-matrix least-squares on F ^²; data/restraints/parameters: 2983/0/144; goodness-of-fit on F ^²; 1.067; final R indices [I > 2σ(I)]R1 = 0.0652, wR2 = 0.1952; R indices (all data); R1 = 0.1041, wR2 = 0.2283; largest diff. peak and hole; 0.425 and -0.298 e Å^-³. Details have been deposited with the Cambridge Crystallographic Data Centre, CCDC 764203, and may be obtained at http://www.ccdc.cam.ac.uk.

12

Diethyl methylphosphonate (8.71 g, 57.3 mmole) in THF (30 mL) and added via cannula to a solution of n-BuLi (48 mL of a 1.6 M solution in hexane, 71.6 mmol) in THF (50 mL) at -78 ˚C. A solution of the Weinreb amide of 3-furoic acid (6.64 g, 47.7 mmol) in THF (20 mL) and added via cannula to the mixture. The mixture was stirred for 2 h. 2 M HCl was added to the mixture, and it was extracted twice with Et₂O. The combined organic layers were dried (MgSO₄), and concentrated to give phosphonate 8 as a brown oil (15 g, 1.29 mmol, 72%), which was used without purification. ^¹H NMR (300 MHz, CDCl₃): δ = 1.30 (t, J = 7.05 Hz, 6 H, CH₃), 3.39 (d, J = 22.7 Hz, 2 H, PCH₂), 4.14 (m, 4 H, CH₂), 6.80 (t, J = 1.2 Hz, 1 H, CH), 7.43 (s, 1 H, CH), 8.16 (s, 1 H, CH). ^¹³C NMR (100 MHz, CDCl₃):
δ = 16.2 (d, J = 5.7 Hz), 40.6 (d, J = 127.8 Hz), 62.7, 108.8, 127.7, 144.2, 149.1, 185.6 (d, J = 6.7 Hz).

18

NMR data for piperidine 12: ^¹H NMR (400 MHz, CDCl₃):
δ = 0.89 (d, J = 6.4 Hz, 3 H), 1.10-1.30 (m, 3 H), 1.35-1.50 (1 H, m), 1.55-1.70 (1 H, m), 1.75-1.85 (2 H, m), 1.95-2.05 (1 H, m), 2.25-2.32 (1 H, m), 2.40-2.45 (2 H, m), 3.57 (m, 1 H), 3.65 (s, 3 H), 6.37 (s, 1 H), 7.33 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 18.4, 28.6, 30.2, 33.9, 34.1, 35.5, 51.5, 53.2, 62.3, 109.1, 129.5, 138.3, 142.7, 174.5.

19

Lactam 13 is also obtained if ester 12 is treated directly with methylmagnesium bromide.