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Synlett 2010(6): 917-920  
DOI: 10.1055/s-0029-1219537
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Direct Stereoselective Synthesis of 1-Amino-2,5-diarylcyclohexanecarboxylic Acid Derivatives Based on a [5+1] Annulation of Divinyl Ketone and Isocyanoacetate

Dawei Zhanga,b,c, Xianxiu Xu*a, Jing Tana, Qun Liu*a
a Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax: +86(431)85098966; e-Mail: xuxx677@nenu.edu.cn;
b Department of Agriculture, Jilin University, Changchun 130062, P. R. of China
c Department of Chemistry, Yanbian University, Yanji 133002, P. R. of China
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Publication History

Received 4 December 2009
Publication Date:
18 February 2010 (online)

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Abstract

A 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed stereoselective [5+1] annulation of divinyl ketones and isocyano­acetate was disclosed, which provided a facile and efficient route to 1-amino-2,5-diarylcyclohexanecarboxylic acids as novel constrained cyclohexane analogues of phenylalanine.

Key words

isocyanoacetate - divinyl ketones - [5+1] annulation - 1-amino-2,5-diarylcyclohexanecarboxylic acid - DBU

    References and Notes

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9

General Experimental Procedure for Cyclohexane Analogues of Phenylalanine 3 (3f as an Example)
To the mixture of 1f (392 mg, 1.0 mmol) and ethyl isocyanoacetate 2 (0.132 mL, 1.2 mmol) in DMF (5 mL) was added 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 0.015 mL, 0.1 mmol) in one portion at r.t. The reaction mixture was stirred at r.t., and the reaction mixture was monitored by TLC. After the substrate 1f was consumed, the resulting mixture was poured into ice water (30 mL) under stirring. The precipitated solid was collected by filtration, washed with H2O (3 × 10 mL), and dried in vacuo to afford the crude product 3f, which was purified by flash chromatography (silica gel, PE-Et2O = 3:1, v/v) to give 3f (460 mg, 91%).
Compound 3f: white solid; mp 145-146 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.94 (t, J = 7.5 Hz, 3 H), 2.73 (dd, J = 16.5, 3.5 Hz, 1 H), 2.98-3.09 (m, 2 H), 3.13 (dd, J = 16.5, 12.5 Hz, 1 H), 3.76-3.89 (m, 3 H), 3.94 (dd, J = 12.5, 3.5 Hz, 1 H), 7.04 (d, J = 7.5 Hz, 2 H), 7.15 (d, J = 7.5 Hz, 2 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.48 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl3): δ = 13.4, 41.0, 41.8, 42.7, 50.0, 63.0, 71.3, 122.6, 122.9, 130.1, 130.4, 131.8, 131.9, 135.2, 135.4, 163.9, 166.0, 206.3. MS (ES): m/z = 504.1 [M + 1]+. Anal. Calcd for C22H19Br2NO3: C, 52.30; H, 3.79; N, 2.77. Found: C, 52.42; H, 3.71; N, 2.63.

10

CCDC 753606 (3f) and CCDC 753605 (4d) contain the supplementary crystallographic data for this paper, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centra via www.ccdc.cam.ac.uk/data_request/cif.

11

General Experimental Procedure for N -Formyl Cyclohexane Analogues of Phenylalanine 4 (4d as an Example)
To the mixture of 3j (396 mg, 1.0 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.089 mL, 1.2 mmol) in one portion at r.t. Then the reaction mixture was stirred at r.t. After the substrate 3j was consumed as indicated by TLC, the resulting mixture was poured onto ice water (30 mL) under stirring, following by basification with sat. aq NaHCO3 solution to adjust the pH value of the solution to 7, and extracted with CH2Cl2 (3 × 30 mL), the combined organic phase was washed with brine, dried over anhyd MgSO4, and concentrated in vacuo to give the pure product 4d (406 mg, 98%).
Compound 4d: white solid; mp 136-139 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 7.0 Hz, 3 H), 2.31 (s, 3 H), 2.58-2.70 (m, 2 H), 3.46 (dd, J = 17.5, 15.0 Hz, 1 H), 4.03-4.09 (m, 1 H), 4.13-4.30 (m, 3 H), 4.60 (dd, J = 15.0, 2.5 Hz, 1 H), 6.39 (s, 1 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 7.5 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 7.5 Hz, 2 H), 8.03 (d, J = 1.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 14.0, 21.0, 39.3, 41.0, 42.3, 44.7, 63.2, 69.1, 128.1, 128.6, 129.1, 129.2, 133.4, 134.0, 136.3, 137.7, 160.9, 171.6, 210.5. MS (ES): m/z = 414.1 [M + 1]+. Anal. Calcd for C23H24ClNO4: C, 66.74; H, 5.84; N, 3.38. Found: C, 66.99; H, 5.90; N, 3.20.