Reversible Diastereoselective Photocyclization of Phenylglyoxylamides of α-Amino Acid Methyl Esters to 3-Hydroxy β-Lactams

Abstract

Phenylglyoxylamides 1a-m were prepared from enantiomerically pure (1b-l) α-amino acid methyl esters in high yields and irradiated in acetonitrile solutions with λ = 300 nm to give the β-lactams 2a-m as photocyclization products in moderate (38 and 40% for 2j and 2k) to excellent yields (85-100%) as racemic mixtures. The photocyclization is completely reversible in the absence of trace amounts of acid and the diastereoselectivity of the lactam formation largely depends on the amount of acid in the reaction medium. The isoleucine and a dipeptide derivative 1f and 5, respectively, enabled NMR-spectral evidence for the zero degree of chirality memory in the photocyclization.

Key words

amino acids - cyclizations - hydrogen transfer - lactams - photochemistry

References

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  Griesbeck, A. G.; Heckroth, H. J. Am. Chem. Soc. in press.

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1

New address: BAYER AG, PH-R CR MC 1, D-42096 Wuppertal.

19

Experimental Procedure: The substrates were synthesized from the amino acid methyl ester HCl salts which were coupled with equimolar amounts of phenyl glyoxylic acid, triethylamine, DCC and 10% of DMAP in CH₂Cl₂ and purified by column chromatography on silica. For photolysis, a 2 mM solution of the substrate in acetonitrile (water cooled) was irradiated at 300 nm (Rayonet photoreactor RPR-208) for 5-8 h at r.t. while purging with nitrogen gas. After evaporation of the solvent, the crude reaction mixture was purified by column chromatography on silica.

20

Selected spectral data for the valine derivatives cis- and trans-2d: ¹H NMR of cis-2d (200 MHz, DMSO-d₆): δ = 0.46 (d, 3 H, J = 6.6 Hz, CH₃), 0.59 (d, 3 H, J = 6.7 Hz, CH₃), 1.83 (dqq, 1 H, J = 0.8, 6.6, 6.7 Hz, CH), 3.72 (s, 3 H), 7.44 (mc, 5 H), 9.11 (d, 1 H, J = 0.8 Hz, NH). ¹³C NMR of cis-2d: δ = 16.9 (CH₃), 18.4 (CH₃), 31.6 (CH), 51.8 (CH₃), 74.3 (C_q), 89.6 (C_q), 125.7 (C_q), 127.2 (CH), 128.1 (CH), 129.4 (CH), 133.1 (C_q), 137.6 (CH), 168.6 (C_q), 171.1 (C_q). ¹H NMR of trans-2d (200 MHz, DMSO-d₆): δ = 0.90 (d, 3 H, J = 6.8 Hz, CH₃), 1.08 (d, 3 H, J = 6.7 Hz, CH₃), 2.29 (dqq, 1 H, J = 0.8, 6.7, 6.8 Hz, CH), 3.04 (s, 3 H), 7.44 (mc, 5 H), 9.20 (d, 1 H, J = 0.8 Hz, NH). ¹³C NMR of trans-2d: δ = 18.3 (CH₃), 18.5 (CH₃), 32.8 (CH), 51.2 (CH₃), 75.3 (C_q), 91.0 (C_q), 125.9 (C_q), 127.0 (CH), 128.6 (CH), 129.0 (CH), 133.1 (C_q), 137.2 (CH), 169.4 (C_q), 170.8 (C_q).

22

Alternatively, subsequent introduction of a MEM group stabilized the β-lactams against retro-aldol processes.