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.

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

References

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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.

<A NAME="RG05003ST-8">8</A>

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.

<A NAME="RG05003ST-9">9</A>

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<A NAME="RG05003ST-11">11</A> Attempts to cyclize N-benzyl-N-chloroacetyl-l-Phe-O-t-Bu with DMAP resulted in the nucleophilic attack of the reactive to the chloroacetyl derivative (compound 4, 90%, Figure 2), as previously found for the cyclization of Trp analogues with DBU, see: Gerona-Navarro G. Bonache MA. Herranz R. García-López MT. González-Muñiz R. Synlett  2000,  1249 .Selected data for compound 4: HPLC: t _R = 10.74 min [50:50, H₂O/MeCN (0.05%TFA)]. ¹H NMR (300 MHz, CDCl₃): major rotamer δ = 8.09 (d, 2 H, J = 7.8 Hz, pyridine), 7.32-7.12 (m, 10 H, Ph), 6.68 (d, 2 H, J = 7.8 Hz, pyridine), 5.46 (d, 1 H, J = 16.8 Hz, CH₂N⁺), 5.33 (d, 1 H, J = 16.8 Hz, CH₂N⁺), 4.72 (d, 1 H, J = 17.2 Hz, N-CH₂), 4.39 (dd, 1 H, J = 8.8, 6.2 Hz, α-H), 4.25 (d, 1 H, J = 17.2 Hz, N-CH₂), 3.25 (dd, 1 H, J = 14.9, 6.2 Hz, β-H), 3.17 (s, 6 H, NMe₂), 3.07 (dd, 1 H, J = 14.9, 8.8 Hz, β-H), 1.31 (s, 9 H, t-Bu). ¹³C NMR (75 MHz, CDCl₃): major rotamer δ = 168.29 (COO), 166.07 (CON), 156.34 (4-C, pyridine), 143.68 (2-C, 6-C, pyridine), 137.35, 135.32, 129.29, 128.91, 128.86, 127.91, 127.59, 126,79 (Ph), 107.14 (3-C, 4-C, pyridine), 82.22 (C, t-Bu), 63.09 (α-C), 58.71 (CH₂N⁺), 51.41 (N-CH₂), 40.48 (CH₃N), 35.53 (β-C), 27.92 (CH₃, t-Bu). MS (ES, positive mode): 475.6 (M⁺ + 1)

<A NAME="RG05003ST-12">12</A>

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).

<A NAME="RG05003ST-13">13</A> These results are atypical with respect to other alkylation reactions for which the use of polar solvents, like MeCN, resulted in almost racemic products: Belokon YN. Kochetkov KA. Churkina TD. Ikonnikov NS. Chesnokov AA. Larionov OV. Singh I. Parmar VS. Vyskocil S. Kagan HB. J. Org. Chem.  2000,  65:  7041 

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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.

<A NAME="RG05003ST-16A">16a</A> Taft RW. Pienta NJ. Kamlet MJ. Arnett EM. J. Org. Chem.  1981,  46:  661 

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<A NAME="RG05003ST-17">17</A>

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.

It has been described that the enantioselectivity of the alkylation of Phe derivatives can be controlled by regulating the aggregate structure of chiral enolate intermediates:

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<A NAME="RG05003ST-20">20</A> No memeory of chriality was observed in the photochmically-induced cyclization of phenylglyoxylamide to 3-hydroxy-β-lactams: Griesbeck AG. Heckroth H. Synlett  2002,  131