Stereoselective Synthesis of the Conformationally Constrained Glutamate Analogue, (-)-(2R,3S)-cis-2-Carboxyazetidine-3-acetic Acid, from (S)-N-Tosyl-2-phenylglycine

Abstract

The stereoselective synthesis of a novel cis conformationally constrained glutamate analogue containing an azetidine framework was accomplished from (S)-N-tosyl-2-phenylglycine in moderate overall yield. The key steps in the synthesis involved a N-H carbenoid insertion promoted by Cu(acac)₂, a very efficient Wittig olefination of an azetidin-3-one, followed by a highly stereoselective rhodium-catalyzed hydrogenation. Epimerization of the cis to the trans analogue was performed using DBU as base in toluene at reflux.

Key words

azetidin-3-ones - glutamate analogues - N-H insertion - conformationally constrained amino acids - Wittig reaction

References

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12

Inseparable mixture of compounds by column chromatography.

14

The cis compound 6 could not be separated from its trans isomer by column chromatography.

16

Compound 7 was obtained as an inseparable mixture of the cis and trans stereoisomers. The ratio of these compounds was determined by ¹H NMR and GC.

18

Mp 201-202 °C (dec). IR: 3300-2500, 1698, 1437, 1346, 1229, 1161, 943 cm^-1. ¹H NMR (300 MHz, acetone-d ₆): δ = 7.79 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H), 4.62 (d, J = 9.5 Hz, 1 H), 3.90 (t, J = 8.1 Hz, 1 H), 3.50 (dd, J = 8.1, 4.4 Hz, 1 H), 2.97 (m, 1 H), 2.67 (d, J = 8.1 Hz, 2 H), 2.46 (s, 3 H). ¹³C NMR (75 MHz, acetone-d ₆): δ = 172.5, 169.6, 145.1, 134.1, 130.8, 129.0, 63.8, 54.2, 34.5, 28.4, 21.6.

19

IR: 3077, 1679, 1625, 1574, 1421, 1184, 1129, 974, 801, 723 cm^-1. ¹H NMR (300 MHz, D₂O): δ = 4.90 (d, J = 9.5 Hz, 1 H), 4.30 (dd, J = 10.9, 8.8 Hz, 1 H), 3.77 (dd, J = 10.9, 6.6 Hz, 1 H), 3.40 (m, 1 H), 2.60 (dd, J = 16.1, 5.1 Hz, 1 H), 2.44 (dd, J = 16.1, 11.7 Hz, 1 H). ¹³C NMR (75 MHz, D₂O): δ = 176.0, 170.6, 61.8, 48.5, 34.5, 30.5. ESI-MS: m/z = 160 [M + 1], 114, 97, 96, 84, 78, 68. HRMS: m/z calcd for C₆H₉NO₄: 159.05316; found: 159.06178.

21

In some occasions, a small amount of epimerization at C2 was observed.