Practical, Highly Enantioselective Chemoenzymatic One-Pot Synthesis of Short-Chain Aliphatic β-Amino Acid Esters

Abstract

A practical, highly enantioselective method for the synthesis of short-chain aliphatic β-amino acid esters was developed starting from prochiral and easily accessible substrates. This chemoenzymatic approach is based on a nonenzymatic aza-Michael addition of benzylamine to enoates and subsequent lipase-catalyzed resolution via enantioselective aminolysis. The two reactions are carried out as a one-pot synthesis under solvent free-conditions affording the β-amino esters in satisfying to good yields and with excellent enantioselectivities of up to 99% ee.

Key words

aminolysis - amino acids - asymmetric catalysis - enzyme catalysis - stereoselective synthesis

References and Notes

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• 5b

  PenG acylase-catalyzed hydrolysis, see ref. 4b.

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• 15 During completion of our manuscript we became aware of the following publication, describing processes related to our synthesis shown in Scheme 2: Priego J. Ortiz-Nava C. Carillo-Morales M. Lopez-Munguia A. Escalante J. Castillo E. Tetrahedron  2009,  65:  536 

6

The term ‘solvent-free synthesis’ refers to the composition of the reaction mixture (excluding workup), thus enabling a high space-time yield and free choice of solvent at the downstream-processing stage.

9

The yields given in Scheme  [²] are ‘crude yields’ since the products have not been isolated.

10

This result is in accordance with previous reports by Berglund et al. showing a nonenenatioselective course of another type of CAL-B-catalyzed Michael addition, see
ref. 8.

11

General Procedure for the One-Pot Synthesis of 3 (According to Table 1, Entries 1, 3-6)
In a 5 mL round-bottom flask a mixture of enoate 1 (1.0 mmol) and benzylamine (2, 241.5 µL, 2.2 mmol) was stirred for 3-96 h at 60 ˚C. After adding 50 mg (entries 1, 3, 5, and 6) or 60 mg (entry 4) of a lipase from Candida antarctica B (lipase CAL-B, Novozym 435), the reaction mixture was stirred for further 18-48 h. The crude product was dissolved in MTBE. After filtration from the solid enzyme, the organic phase was concentrated to dryness under vacuo. The resulting oily product was purified by means of column chromatography [entries 1-4: EtOAc-2-PrOH (95:5, v/v), 0.2% Et₂NH; R _f = 3a (0.62), 4a (0.22), 3b (0.66), 4b (0.22), 3c (0.50), 4c (0.16); entry 6: cyclohexane-EtOAc (3:1, v/v); R _f = 3e (0.60), 4e (0.13)]. The ee was determined by chiral HPLC chromatography (compounds 3a,b,e, and 4c: Chiracel OJ-H column; compounds 4a,e: Chiracel AD-H column) with hexane-2-PrOH-diethylamine in a ratio of 95:5:0.1 or 99:1:0.1 as eluent or NMR spectroscopy with Eu(hfc)₃ (compounds 3c, 4b). The absolute configuration of 3a was assigned according to the direction of optical rotation of the product 6 after derivatization (see Scheme 3) and its comparison with the literature value given in ref. 12. The absolute configuration of the other esters 3b,c,e has been assigned in analogy to the result in case of 3a. The spectral data of the ester products (S)-3a-c, (R)-3e were in accordance with literature data. The amides 4a-c, e have been fully characterized (data will be published elsewhere).

13

For the enzymatic resolution of rac-3a with benzylamine as amine and lipase CAL-B as biocatalyst under solvent free conditions at 60 ˚C, an E value of 27 has been obtained for this aminolysis reaction (data not shown).

14

Procedure for the Synthesis of ( S )-β-Amino Butyric Acid, ( S )-6 (According to Scheme 3) In a 10 mL round-bottom flask 4.32 mmol of (S)-ethyl 3-(benzylamino)butanoate [(S)-3a, 955 mg, >99% ee] was dissolved in 25 mL of 6 N HCl and heated to reflux overnight for 18 h. After completion of the reaction remaining solvent was evaporated under reduced pressure at 60 ˚C. The resulting crude product was dissolved in 15 mL AcOH-H₂O (1:1, v/v) and transferred to a ‘Fischer-Porter bottle’. After addition of Pd(OH)₂/C (450 mg), the bottle was evacuated and flushed with inert gas for three times. After evacuation of the inert gas, the bottle was filled with hydrogen (60 psi corresponding to 0.41 MPa) and heated to 65-70 ˚C for 22 h. The reaction mixture was filtered through a thin plug of SiO₂. The resulting hydrochloride of (S)-6 was obtained as a white solid after evaporation of the solvent at reduced pressure at 60 ˚C. The desired product (S)-amino butanoic acid, (S)-6, was obtained in isolated form after Dowex^® ion-exchange chromatography. The spectral data of (S)-6 were in accordance with literature data. Optical rotation data: [α]_D ^²5 +32.1 (c 0.6, H₂O); for comparison, see ref. 12b: [α]_D ^²5 +32.0 (c 0.6, H₂O).