Stereocontrolled Synthesis of 3-Substituted Azetidinic Amino Acids

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.

azetidines - amino acids - amino alcohols - asymmetric synthesis

References and Notes

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For related examples of chlorination of β-amino alcohols, see:

<A NAME="RD32205ST-7A">7a</A> Weber K. Kuklinski S. Gmeiner P. Org. Lett.  2000,  2:  647 

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<A NAME="RD32205ST-14">14</A>

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.