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Synlett 2010(6): 866-868  
DOI: 10.1055/s-0029-1219554
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Two Nuphar Alkaloids by Allenic Hydroxylamine Cyclisation

Roderick W. Bates*, Chia Juan Lim
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, 637371 Singapore, Singapore
Fax: +6567911961; e-Mail: Roderick@ntu.edu.sg;
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Publication History

Received 6 January 2010
Publication Date:
26 February 2010 (online)

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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

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) ų; Z: 4; density(calcd): 1.124 Mg/m³; absorption coefficient: 0.081 mm-¹; F(000): 472; crystal size: 0.30 × 0.30 × 0.14 mm³; 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.