Novel Applications of the Schöllkopf Chiral Auxiliary: A New and Efficient Enantioselective Synthesis of β-Lactams Possessing a C-4 Quaternary Stereocenter

Abstract

A new method for the enantioselective synthesis of substituted β-lactams is described based upon an improved alkylation of substituted Schöllkopf chiral auxiliaries by α-haloacetate esters, employing tert-butyllithium as the deprotonating base, and the efficient conversion of the resulting quaternary 2,5-diketopiperazines to the targeted β-lactams.

Schöllkopf chiral auxiliary - β-lactam - tert-butyllithium - quaternary stereocenter - α-haloacetate ester - enantioselective synthesis

References

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8

The diastereomeric excess of 2 is estimated to be >95% since the minor diastereomer could not be detected by ¹H NMR analysis of the crude reaction mixture.

9 Schöllkopf and coworkers have previously reported the use of tert-BuLi for the deprotonation-alkylation of 1d (Scheme 1) with benzyl bromide in 75% yield, but they stated that use of n-BuLi gave the same result (compare with entry 2, Table 1): Schöllkopf U. Busse U. Lonsky R. Hinrichs R. Liebigs Ann. Chem.  1986,  2150 

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14

Typical Experimental Procedure for the One-Pot Conversion of 2 to 3 (Scheme 1): To a solution of 2 (0.30 g, 0.87 mmol) in MeCN-H₂O (2 mL each), trifluoroacetic acid (0.5mL) was added and the resulting solution was stirred at ambient temperature for 10 h. Then it was evaporated to dryness (azeotrope with toluene) and further dried in a desiccator over phosphorus pentoxide. This crude material was suspended in CH₂Cl₂ (1.5 mL), cooled in an ice bath and 2,2,5,7,8-pentamethyl-chromane-6-sulfonyl chloride (Pmc-Cl) [13] (0.60 g, 2.00 mmol) was added followed by Et₃N (0.52 mL, 3.74 mmol). The resulting solution was stirred at ambient temperature for 2 h and then CH₂Cl₂ (20 mL) was added. The organic phase was successively washed with 0.1 N HCl, 5% NaHCO_3, H₂O, evaporated to dryness and the resulting crude solid was purified by column chromatography using petroleum ether/EtOAc (4:1) as eluent to give 3 as an oil (336 mg, 75% overall yield).
¹H NMR (250 MHz, CDCl₃): δ = 1.25 (s, 6 H), 1.41 (s, 3 H), 1.78 (d, 2 H J = 6.6 Hz), 2.10 (s, 3 H), 2.54 (s, 3 H), 2.56 (s, 3 H), 2.60 (t, 1 H, J = 6.6 Hz), 2.83, 3.20 (AB, 2 H, J _AB = 15 Hz), 3.66 (s, 3 H), 4.95 (AB, 2 H, J _AB = 15 Hz), 6.00 (s, 1 H), 7.32 (bs, 5 H).
¹³C NMR (62.90 MHz, CDCl₃): δ = 12.4, 17.4, 18.3, 21.7, 24.2, 26.9, 32.9, 42.9, 53.3, 60.1, 66.9, 74.1, 118.6, 128.3, 128.4, 128.7, 135.7, 136.1, 170.2, 173.9, 195.6.
MS (EI): 518.65 [M + 1]⁺.

15

Typical Experimental Procedure for the One-Pot Conversion of 3 to 4 (Scheme 1): To a solution of 3 (260 mg, 0.5 mmol) in MeOH (20 mL) containing a few drops of H₂O, 10% Pd/C (40 mg) was added and the suspension was hydrogenated at ambient temperature for 3 h. Filtration over celite and evaporation to dryness afforded the desired β-Pmc-sulfonamide acid as a white solid (210 mg, quant.) which was dissolved in CH₂Cl₂ (5 mL) and stirred at ambient temperature while N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC·HCl, 120 mg, 0.6 mmol) and 4-pyrrolidinopyridine (4-PPY, 5 mg) were added. The resulting solution was stirred for 2 h at ambient temperature and then CH₂Cl₂ (20 mL) was added and the organic phase was washed with 0.1 N HCl and H₂O, dried over Na₂SO_4, and evaporated to dryness. The resulting solid was purified by column chromatography using EtOAc/petroleum ether (9:1) as eluent to furnish 4 as a white solid (186 mg, 91% overall yield).
¹H NMR (250 MHz, CDCl₃): δ = 1.30 (s, 6 H), 1.70 (s, 3 H), 1.82 (d, 2 H J = 6.6 Hz), 2.11 (s, 3 H), 2.52 (s, 3 H), 2.53 (s, 3 H), 2.62 (t, 1 H, J = 6.6 Hz), 2.87, 3.40 (AB, 2 H, J _AB = 15.4 Hz), 3.50 (s, 3 H).
¹³C NMR (62.90 MHz, CDCl₃): δ = 12.4, 14.4, 17.4, 18.4, 20.9, 21.6, 26.8, 26.9, 29.9, 49.6, 53.0, 61.7, 74.7, 118.9, 125.2, 138.7, 138.7, 156.2, 162.5, 170.4.
MS (EI): 410.50 [M + 1]⁺.