Synthesis and 1,3-Dipolar Cycloadditions of Two New Chiral Geometrically Fixed α-Alkoxycarbonylnitrones from a Single Chiral Source

Peng-Fei Wang; Peng Gao; Peng-Fei Xu

doi:10.1055/s-2006-939691

LETTER

Synthesis and 1,3-Dipolar Cycloadditions of Two New Chiral Geometrically Fixed α-Alkoxycarbonylnitrones from a Single Chiral Source

Peng-Fei Wang, Peng Gao, Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry & Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(931)8625657; e-Mail: xupf@lzu.edu.cn;

Abstract

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Abstract

The synthesis and 1,3-dipolar cycloaddition reactions of two new camphor-derived nitrones are described. These two nitrones reacted with alkenes in high yield and with high stereoselectivity. The chemical transformations of the cycloadducts were also examined.

Key words

1,3-dipolar cycloadditions - chiral nitrone - stereoselectivity - chiral auxiliaries - asymmetric synthesis

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References and Notes

For recent reviews, see:

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Catalytic hydrogenation of 4a in MeOH was also attempted. However, the mixture of compound 5 and a by-product which arised from transesterification of 4a and MeOH were observed.

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Typical Procedure for the Preparation of Nitrone 6.
To a solution of amine 5 (300 mg, 1.43 mmol) in CH₂Cl₂ (12 mL) was added a sat. aq Na₂CO₃ (18 mL). The resulting mixture was stirred at 0 °C. During this period, a solution of MCPBA (767 mg, 4.22 mmol) in CH₂Cl₂ (18 mL) was added dropwise over 1 h. After further stirring at r.t. for 12 h, the layers were separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄) and filtered. Evaporation of the solvents gave a residue which was chromatographed over silica gel to afford the nitrone 6; mp 126 °C (dec.); [α]_D ²³ -280 (c 0.51, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.16 (br s, 1 H), 4.78 (d, J = 8.1 Hz, 1 H), 3.86 (d, J = 8.1 Hz, 1 H), 2.30 (d, J = 4.8 Hz, 1 H), 1.89 (m, 1 H), 1.65 (m, 1 H), 1.30 (m, 1 H), 1.15 (m, 1 H), 1.15 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.15, 124.56, 81.06, 75.48, 52.09, 50.38, 48.38, 36.46, 22.77, 21.82, 19.85, 12.66. MS (EI): m/z (%) = 223 (2) [M⁺], 206 (3) [M - 15], 178 (88), 95 (100). HRMS (ESI): m/z calcd for C₁₂H₁₈NO₃ ⁺ [M + 1]: 224.1281; found: 224.1277.

Representative Experimental Procedure for Cycloaddition Reactions with Nitrone 6. A solution of nitrone 6 (50 mg, 0.224 mmol) and styrene 7a (2.24 mmol) in 7 mL of toluene was heated at 60 °C for 8 h. The mixture was then concentrated under reduced pressure; the ¹H NMR spectrum of the crude product indicated a diastereomeric ratio of >99:1. An analytical sample 8a crystallized from EtOAc-PE (1:1) had a mp of 197-199 °C; [α]_D ¹⁸ +118 (c 1.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.38-7.31 (m, 5 H), 5.41 (dd, J = 9.6, 3.6 Hz, 1 H), 4.53 (d, J = 8.4 Hz, 1 H), 4.34 (dd, J = 8.4, 7.8 Hz, 1 H), 2.93 (d, J = 8.4 Hz, 1 H), 2.69 (m, 1 H), 2.57 (m, 1 H), 2.11 (d, J = 4.8 Hz, 1 H), 1.86 (m, 1 H), 1.63 (m, 1 H), 1.20-1.00 (m, 2 H), 1.14 (s, 3 H), 1.00 (s, 3 H), 0.88 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.11, 139.61, 128.70, 128.38, 126.62, 82.89, 77.52, 67.58, 61.49, 49.97, 49.07, 47.25, 39.82, 34.71, 23.55, 21.26, 20.02, 11.40. MS (EI): m/z (%) = 327 (17) [M⁺], 310 (0.5) [M - 17], 144 (11), 136 (8), 104 (100), 95 (23). HRMS (ESI): m/z calcd for C₂₀H₂₆NO₃ ⁺ [M + 1]: 328.1907; found: 328.1908.
Compound 8b: mp 86-87 °C; [α]_D ¹⁷ +105 (c 0.62, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.43 (d, J = 8.4 Hz, 1 H), 4.40 (m, 1 H), 4.01 (dd, J = 12.3, 8.1 Hz, 1 H), 2.74 (d, J = 8.4 Hz, 1 H), 2.28 (m, 1 H), 2.22 (m, 1 H), 2.03 (d, J = 5.1 Hz, 1 H), 1.79 (m, 1 H), 1.70-1.40 (m, 3 H), 1.40-1.20 (m, 4 H), 1.15-0.95 (m, 2 H), 1.07 (s, 3 H), 0.93 (s, 3 H), 0.88 (m, 3 H), 0.83 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.66, 82.77, 76.08, 67.55, 60.88, 49.92, 48.90, 47.21, 36.37, 34.69, 34.19, 27.97, 23.52, 22.53, 21.23, 19.93, 13.90, 11.35. MS (EI): m/z (%) = 307 (14) [M⁺], 292 (0.5) [M - 15], 250 (13), 222 (17), 136 (68), 95 (100). HRMS (ESI): m/z calcd for C₁₈H₃₀NO₃ ⁺ [M + 1]: 308.2220; found: 308.2215.

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<A NAME="RW00206ST-9B">9b</A> Bonner MP. Thornton ER. J. Am. Chem. Soc. 1991, 113: 1299

Typical Procedure for the Preparation of Nitrone 10. A mixture of an aq solution (50%) of glyoxylic acid (0.728 g, 4.92 mmol), 3-(hydroxyamino) isoborneol hydrochloride (0.990 g, 4.47 mmol) and NaHCO₃ (0.376 g, 4.47 mmol) in CH₂Cl₂ was stirred for 30 min at r.t. The water of the mixture was removed azeotropically for 4.5 h. Anhyd p-TsOH (0.387 g, 2.24 mmol) was added to the mixture, and the mixture was heated at reflux for 14.5 h. After cooling, DCC (0.453 g, 2.24 mmol) was added, and the mixture was stirred for 4 h at r.t. After cooling, the mixture was washed with H₂O, and the aqueous phase was extracted with CH₂Cl₂. The organic phases were combined, dried (Na₂SO₄), and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel to afford nitrone 10 (0.502 g, 50%) as a crystalline solid: mp 117 °C (dec.); [α]_D ¹⁴ +224 (c 1.80, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.16 (br s, 1 H), 4.53 (d, J = 8.8 Hz, 1 H), 3.92 (d, J = 8.8 Hz, 1 H), 2.68 (d, J = 4.4 Hz, 1 H), 1.92 (m, 1 H), 1.70 (m, 1 H), 1.20 (m, 2 H), 1.10 (s, 3 H), 0.91 (s, 3 H), 0.88 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.93, 124.47, 83.91, 72.32, 51.06, 48.63, 47.65, 32.41, 26.12, 21.63, 19.38, 10.81. MS (EI): m/z (%) = 223 (3) [M⁺], 206 (2) [M - 15], 162 (4), 135 (33), 95 (100). HRMS (ESI): m/z calcd for C₁₂H₁₈NO₃ ⁺ [M + 1]: 224.1281; found: 224.1285.

Representative Spectroscopic Data. Compound 15a: mp of 152-154 °C. [α]_D ¹⁵ -156 (c 0.69, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.32 (m, 5 H), 5.42 (dd, J = 10.0, 3.6 Hz, 1 H), 4.28 (m, 1 H), 4.25 (d, J = 8.4 Hz, 1 H), 3.02 (d, J = 8.4 Hz, 1 H), 2.68 (m, 1 H), 2.52 (m, 1 H), 2.16 (d, J = 4.4 Hz, 1 H), 1.80 (m, 1 H), 1.62 (m, 1 H), 1.11 (m, 2 H), 1.04 (s, 6 H), 0.87 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.95, 139.63, 128.67, 128.35, 126.45, 85.97, 77.93, 64.21, 61.37, 49.63, 49.56, 47.44, 39.36, 33.16, 25.63, 21.51, 20.14, 11.02. MS (EI): m/z (%) = 327 (0.9) [M⁺], 283 (0.6), 104 (100), 95 (23). HRMS (ESI): m/z calcd for C₂₀H₂₆NO₃ ⁺ [M + 1]: 328.1907; found: 328.1908.
Compound 15b: oil; [α]_D ¹⁵ -107 (c 2.11, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.45 (m, 1 H), 4.22 (d, J = 8.4 Hz, 1 H), 4.03 (dd, J = 12.0, 8.0 Hz, 1 H), 2.87 (d, J = 8.4 Hz, 1 H), 2.35 (m, 1 H), 2.27 (m, 1 H), 2.12 (d, J = 4.0 Hz, 1 H), 1.80 (m, 1 H), 1.60 (m, 3 H), 1.33 (m, 4 H), 1.09 (m, 2 H), 1.03 (s, 3 H), 0.99 (s, 3 H), 0.90 (t, J = 7.0 Hz, 3 H), 0.87 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.51, 85.81, 64.13, 60.83, 49.48, 49.44, 47.36, 35.96, 34.32, 33.09, 27.86, 25.57, 22.53, 21.47, 20.06, 13.89, 10.99. MS (EI): m/z (%) = 307 (13) [M⁺], 250 (26), 224 (19), 136 (100), 121 (53), 84 (69). HRMS (ESI): m/z calcd for C₁₈H₃₀NO₃ ⁺ [M + 1]: 308.2220; found: 308.2217.

<A NAME="RW00206ST-12A">12a</A> Berranger T. Langlois Y. J. Org. Chem. 1995, 60: 1720

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<A NAME="RW00206ST-12C">12c</A> Ali SkA. Wazeer MIM. Tetrahedron 1993, 49: 4339 ; and references cited therein

Compound 19a: oil, [α]_D ¹⁵ -74 (c 0.53, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 9.38 (br s, 1 H), 7.45 (m, 3 H), 7.35 (m, 2 H), 5.72 (dd, J = 8.4, 6.0 Hz, 1 H), 3.60 (dd, J = 19.6, 8.4 Hz, 1 H), 3.03 (dd, J = 19.6, 6.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.56, 147.41, 138.73, 129.02, 125.44, 78.30, 32.63. MS (EI): m/z (%) = 191 (36) [M], 168 (2), 107 (100), 77 (81), 57 (63). HRMS (ESI): m/z calcd for C₁₀H₁₃N₂O₃ ⁺ [M + NH₄]: 209.0921; found: 209.0925.
Compound 19b: mp 75-77 °C; [α]_D ¹⁵ -58 (c 0.89, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.57 (br s, 1 H), 4.70 (m, 1 H), 3.21 (dd, J = 19.2, 8.1 Hz, 1 H), 2.68 (dd, J = 19.2, 5.1 Hz 1 H), 1.80 (m, 1 H), 1.70 (m, 1 H), 1.40 (m, 4 H), 0.92 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.41, 148.17, 77.87, 36.22, 30.12, 26.62, 22.28, 13.83. MS (EI):
m/z (%) = 154 (9) [M - 17], 126 (10), 114 (100). HRMS (ESI): m/z calcd for C₈H₁₇N₂O₃ ⁺ [M + NH₄]: 189.1234; found: 189.1231.

Compound 17c: mp 243 °C (dec.); [α]_D -9 (c 0.37, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.57 (s, 1 H), 4.46 (d, J = 11.7 Hz, 1 H), 4.22 (br s, 1 H), 3.97 (s, 1 H), 3.22 (d, J = 4.5 Hz 1 H), 2.10-1.30 (m, 12 H), 1.20 (m, 1 H), 1.10 (s, 3 H), 0.98 (s, 3 H), 0.88 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.06, 150.60, 81.47, 75.43, 65.07, 50.60, 50.05, 48.10, 41.42, 34.03, 32.09, 24.97, 24.22, 21.85, 19.81, 19.50, 19.26, 10.32. MS (EI): m/z = 321 (1) [M⁺], 304(3), 276 (7), 260 (3), 248 (4), 223 (77), 55 (99), 41 (100). HRMS (ESI): m/z calcd for C₁₈H₂₈NO₄ ⁺ [M + 1]: 322.2013; found: 322.2009.
Compound 17d: mp 70-72 °C; [α]_D ¹⁵ -31 (c 0.17, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.69 (d, J = 12.3 Hz, 1 H), 4.62 (s, 1 H), 4.60 (br s, 1 H), 4.33 (br s, 1 H), 3.23 (d, J = 4.5 Hz 1 H), 2.20-1.52 (m, 10 H), 1.39 (m, 1 H), 1.12 (s, 3 H), 1.00 (s, 3 H), 0.90 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.79, 150.33, 81.34, 73.17, 72.97, 50.88, 50.09, 48.13, 46.26, 34.08, 32.99, 26.92, 23.03, 21.78, 19.81, 19.25, 10.31. MS (EI): m/z = 307 (0.3) [M⁺], 278 (1), 262 (4), 234 (3), 223 (29), 55 (81), 41 (100). HRMS (ESI): m/z calcd for C₁₇H₂₆NO₄ ⁺ [M + 1]: 308.1856; found: 308.1849.