Memory of Chirality in the Enantioselective Synthesis of β-Lactams Derived from Amino Acids. Influence of the Reaction Conditions

Abstract

The asymmetric induction observed during cyclisation of N-benzyl-N-chloroacetyl-l-Phe derivatives to the corresponding S-enriched 2-azetidinones, ascribed to chirality memory, can be controlled by the appropriate choice of the base and solvent. Using the organic base BTPP, the ee values obtained in different solvents showed a good correlation with the AN solvent parameter, except for NMP. It seems that a combination of the solvent properties, rather than individual parameters, and the presence of enolate aggregates are decisive for final enantiomer distribution.

Key words

amino acids - memory of chirality - β-lactams - enantio­selectivity - AN solvent-depedency

References

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7

Column OL-389. Eluent: hexane/acetone (96:4). Flow rate: 1.5 mL/min. UV detection at 220 nm. Isomer 2a: t _R = 7.77 min. Isomer 2b: t _R = 9.07 min.

8

A general procedure was as follows: Compound 1 (83 mg, 0.19 mmol) was dissolved in the corresponding solvent (0.7 mL) and treated, at r.t. and under Ar atmosphere, with the appropriate base (0.28 mmol). The reaction was monitored by TLC until complete disappearance of the starting material. The solution was evaporated, redissolved in EtOAc, washed with H₂O, and dried over Na₂SO₄. After evaporation, the resulting residue was purified on a silica gel column using a gradient from 20 to 30% of EtOAc in hexane. The obtained compound 2ab was directly evaluated by chiral HPLC, or transformed into dipeptide derivatives 3a and 3b as described (ref. [5] ). For the phase transfer reactions, 3 equiv of NaOH and KOH, and 10 equiv of CsOH were respectively used.

9

BTPP: tert-Butylimino-tri(pyrrolidino)phosphorane. BEMP: 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro1,3,2-diazaphosphorine.

12

Reaction of chloroacetyl derivative 1 with LHMDS afforded pyrrolidinone 5, which was characterized as its methoxy derivative 6 after treatment with diazomethane. The formation of compound 5 could be attributed to the initial generation of the amide enolate and a Dieckmann-type condensation of this enolate with the ester group, followed by enolisation of the resulting ketone (Figure [3] ).
Selected data for compound 6: ¹H NMR (300 MHz, CDCl₃): δ = 7.26 (m, 3 H, Ph), 7.05 (m, 2 H, Ph), 7.00 (d, 2 H, J = 8.6 Hz, Pmb), 6.80 (d, 2 H, J = 8.6 Hz, Pmb), 5.18 (d, 1 H, J = 15.1 Hz, 1-CH₂), 4.16 (s, 3 H, OMe), 3.93 (dd, 1 H, J = 5.4, 4.1 Hz, 5-H), 3.83 (d, 1 H, J = 15.1 Hz, 1-CH₂), 3.78 (s, 3 H, OMe), 3.13 (dd, 1 H, J = 14.3, 4.1 Hz, 5-CH₂), 2.89 (dd, 1 H, J = 14.3, 5.4 Hz, 5-CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 167.4 (2-C), 164.22 (4-C), 159.07, 134.95, 130.05, 129.45, 129.04, 128.74, 127.32, 114.03 (Ar), 97.91 (3-C), 59.05 (OMe), 58.65 (5-C), 55.21 (OMe), 43.88
(5-CH₂), 35.47 (1-CH₂). MS (ES, positive mode): 358.2
(M⁺ + 1).

15

NMP was not included because really poor correlations were found. To the best of our knowledge, the AN value for 2-butanone has not been described.

17

Among all the solvents tested here, NMP has not only the highest donor number (DN) but also the biggest difference between AN and DN parameters. DN is a reasonably good measure of the ability of the solvent to serve as an electron-pair donor to solutes when oxygen bases are considered.