Stereoselective Synthesis of a Bicyclic Isoxazolidine Related to the Pyrinodemin Family of Alkaloids via an Intramolecular Asymmetric [2+3] Cycloaddition

Abstract

Bicyclic isoxazolidine 21, a synthetic intermediate for pyrinodemins, was synthesized in six steps using an asymmetric intramolecular [2+3] cycloaddition of a new phenylglycinol-derived oxazoline N-oxide

asymmetric synthesis - alkaloids - pyrinodemin - cyclo­additions - dipolar

References

1 Tsuda M. Hirano K. Kubota T. Kobayashi J. Tetrahedron Lett.  1999,  40:  4819 

2 Hirano K. Kubota T. Tsuda M. Mikami Y. Kobayashi J. Chem. Pharm. Bull.  2000,  48:  974 

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5 For a review, see: Dirat O. Kouklovsky C. Langlois Y. Mauduit M. Pure Appl. Chem.  2000,  72:  1721 

6 Preliminary work on intramolecular cycloaddition of oxazoline N-oxides: Kobayakawa M. Langlois Y. Tetrahedron Lett.  1992,  33:  2353 

7

The crude product consists in essentialy pure orthoester 15 with a trace of pyridine. All attempts to purify the crude product by chromatography resulted in partial hydrolysis of the orthoester to the corresponding methyl ester.

8 Tamura O. Gotanda K. Yoshino J. Morita Y. Terashima R. Kikuchi M. Miyawaki T. Mita N. Yamashita M. Ishibashi H. Sakamoto M. J. Org. Chem.  2000,  65:  8544 

9

Data for compound 18: ¹H NMR (400 MHz, CDCl₃): δ = 7.49-7.14 (5 H, br s), 4.45 (1 H, m, C₂-H), 4.45 (1 H, t, J = 7 Hz), 4.30 (1 H, dd, J = 7 and 2 Hz), 3.73 (3 H, m), 2.75 (1 H, m, C₃-H), 2.18 (1 H, m), 1.85-1.62 (7 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 138.6, 128.4-127.1, 116.0, 77.6, 71.9, 69.7, 60.7, 56.4, 37.0, 31.8, 25.4, 24.6 ppm. IR (liquid film): ν = 3423, 3057, 2959, 1495, 1467, 1452, 1438, 1311, 1266, 1200, 1052 cm^-1. MS (ES): m/z = 298.2 [M + Na], 276.2 [M + 1]. HRMS: m/z calcd for C₁₆H₂₂NO₃ [M + 1]: 276.15997; found: 276.16029. [α]_D ²⁰ -174.4 (c 2, CHCl₃).

10

Condensation of camphor-derived chiral auxiliary 5 with orthoester 15 resulted in the formation of a cycloadduct as a single isomer, albeit in lower yield.

11 Berrien J.-F. Royer J. Husson H.-P. J. Org. Chem.  1994,  59:  3769 

12 Agami C. Couty F. Evano G. Tetrahedron Lett.  1999,  40:  3709 

13

Data for compound 21 (clear oil): ¹H NMR (400 MHz, CDCl₃): δ = 7.25 (2 H, d, J = 9.0 Hz), 6.85 (2 H, d, J = 9.0 Hz), 4.40 (2 H, s), 3.90 (1 H, m), 3.78 (3 H, s), 3.68 (1 H, dd, J = 7.6 and 7.0 Hz), 3.55 (2 H, dt, J = 7.6 and 3.6 Hz), 2.75 (1 H, m), 1.85 (3 H, m), 1.79-1.40 (4 H, m), 1.35 (1 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 130.4, 129.2, 113.7, 83.6, 72.7, 67.7, 66.5, 55.2, 50.1, 34.9, 29.0, 26.9, 26.5 ppm. IR (liquid film): ν = 3428, 2955-2864, 1613, 1513, 1248, 1091 cm^-1. MS (ES): m/z = 300.2 [M + Na], 278.2 [M + 1]. HRMS: m/z calcd for C₁₆H₂₃NaNO₃ [M + Na]: 300.15756; found: 300.15727. [α]_D ²⁰ +36.4 (c 1, CHCl₃).

14

Product arising from elimination of the mesylate was also observed in the crude product. Using microwave activation results in decrease of elimination from 15% to 5%.