Download PDF
Synlett 2006(5): 0781-0785  
DOI: 10.1055/s-2006-933125
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereocontrolled Synthesis of 3-Substituted Azetidinic Amino Acids

Mangaleswaran Sivaprakasama, François Couty*a, Gwilherm Evanoa, B. Srinivasb, R. Sridharb, K. Rama Raob
a SIRCOB, UMR 8086, Université de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
e-Mail: couty@chimie.uvsq.fr;
b Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad - 500007, India
Further Information

Publication History

Received 19 October 2005
Publication Date:
09 March 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

A set of enantiomerically pure N-disubstituted β-amino alcohols was chlorinated by treatment with thionyl chloride. This reaction gave a mixture of regioisomeric chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The chlorides thus obtained were engaged in an intramolecular anionic ring-closure and gave access to fully protected enantio- and dia­stereomerically pure 2,3-cis-disubstituted azetidinic amino acids. One of the latter was deprotected and included in a short peptide ­sequence.

Key words

azetidines - amino acids - amino alcohols - asymmetric synthesis

14

All new compounds were characterized by 1H NMR and 13C NMR spectroscopy, mass spectral analysis, and for most relevant compounds, by elemental analysis.
Typical Procedure for the Preparation of Chloride 19.
To a solution of amino alcohol 11 (1.20 g, 4.30 mmol) in CH2Cl2 (30 mL) was added SOCl2 (0.64 mL, 8.81 mmol) at 0 °C and it was then refluxed for 3 h. After the completion of the reaction, the excess SOCl2 was neutralized by a sat. aq solution of NaHCO3 (10 mL). Extraction of the reaction mixture using Et2O followed by usual workup gave a mixture of chlorides (2:1 ratio) that were purified by flash chromatography (EtOAc-PE 1:9, 1.15 g, 90%).The formed chlorides (1.15 g) were then dissolved in DMF (10 mL) and heated at 60 °C for 60 h. DMF was removed under vacuo and the obtained chloride was filtered on silica gel (EtOAc-PE 1:9) and gave pure chloride 22 (1.09 g, 95%) as a thick oil.
R f 0.85 (EtOAc-PE 9:1); [α]D 20 -6.6 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.37 (br s, 12 H), 2.80 (dd, J = 13.7, 6.8 Hz, 1 H), 2.93 (dd, J = 13.7, 6.8 Hz, 1 H), 3.19 (s, 2 H), 3.78 (d, J = 3.4 Hz, 2 H), 3.87-3.94 (m, 1 H), 7.14-7.20 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 23.0, 28.2, 55.7, 56.2, 58.7, 62.5, 81.0, 127.2, 128.7, 128.9, 139.0, 170.7. MS (CI, NH3 gas): m/z (%) = 320 (27) [M + K+], 264 (8), 242 (61).
Typical Procedure for the Azetidine Formation, Starting with Chloride 22.
To a solution of chloride 22 (1.50 g, 5.04 mmol) in THF (20 mL) and HMPA (2 mL) was added dropwise at -90 °C a solution of LiHMDS (1 M solution in THF, 7.56 mL, 7.56 mmol). The reaction was monitored by TLC and then quenched by the addition of an aq sat. solution of NH4Cl (10 mL) at 0 °C. Extraction of the reaction mixture using Et2O gave, after usual workup, a residue that was purified by flash chromatography (EtOAc-PE 1:9) to give cis-azetidine 36 (1.05 g, 80%). R f 0.85 (EtOAc-PE 15:85); [α]D 20 +91.3 (c 0.4, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.23 (d, J = 7.0 Hz, 3 H), 1.40 (s, 9 H), 2.58-2.69 (m, 1 H), 2.90-3.10 (m, 2 H), 3.54 (d, J = 12.5 Hz, 1 H), 3.68 (d, J = 8.0 Hz, 1 H), 3.74 (d, J = 12.5 Hz, 1 H), 7.18-7.39 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 15.5, 28.2, 28.6, 56.8, 61.6, 67.3, 80.6, 127.0, 128.2, 129.2, 137.5, 170.8. MS (CI, NH3 gas): m/z (%) = 300 (10), 284 (74), 262 (28) [M+], 206 (100). Anal. Calcd for C16H23NO2 (%): C, 73.53; H, 8.87; N, 5.36. Found: C, 73.39; H, 9.01; N, 5.42.