Glycine tert butyl ester hydrochloride: Synthesis & Applications

Glycine tert butyl ester hydrochloride is a significant derivative of glycine, at standard temperature and pressure, it exists as a white, fine crystalline powder. Its melting point ranges from 141–143°C, with a density of 0.973 g/cm³. It readily dissolves in water, alcohols, and other highly polar organic solvents, yet exhibits poor solubility in non-polar solvents such as ethers and n-hexane. Storage at −20°C is required. As a critical organic synthesis intermediate, it finds extensive application in fine chemicals and pharmaceuticals, serving in the preparation of peptide drugs and amino acid biochemical reagents. It also exhibits biological activities such as regulating metabolic hormone secretion and supporting sports nutrition supplementation. Glycine tert butyl ester hydrochloride is typically produced by reacting glycine with tert-butyl acetate under specific conditions, followed by neutralisation, extraction, and crystallisation steps. It represents an organic salt compound possessing both industrial value and promising application prospects.

Monoalkylation of p-chlorobenzaldehyde imine of Glycine tert butyl ester hydrochloride

The enantioselective alkylation of the benzophenone imine of glycine tert butyl ester hydrochloride using chiral phase-transfer catalysts has been developed into a powerful method for the synthesis of optically active α-amino acid derivatives. A key feature of this extremely useful asymmetric transformation is the selective monoalkylation of 1 due to the considerable difference in acidity of the α-proton between the starting substrate 1 and the corresponding monoalkylation product 4. This property, imparted by the presence of the benzophenone imine moiety, is essential for securing the configurational stability of the newly created stereogenic center in 4 under the basic reaction conditions. On the other hand, the p-chlorobenzaldehyde imine of α-alkyl-α-amino acid tert-butyl ester 2 has been employed for the preparation of optically active α,α-dialkyl-α-amino acid derivatives by phase-transfer-catalyzed alkylation. This is certainly because the α-proton of 2 is acidic enough to be deprotonated under typical conditions in contrast to its benzophenone imine counterpart 4, and hence aldimine Schiff base 3 derived from glycine tert butyl ester hydrochloride has long been regarded as an unsuitable substrate for the stereoselective monoalkylation. Over the course of our recent studies in this area of research, we became intrigued with the possibility of the enantioselective monoalkylation of 3 under appropriate phase-transfer conditions in view of its practical advantages such as low cost. Herein, we report that the selective monoalkylation of 3 is indeed feasible under mild liquid–liquid phase-transfer conditions, and our binaphthyl-derived chiral quaternary ammonium bromides 7 and 8 act as an efficient catalyst to achieve rigorous stereochemical control.[1]

The requisite aldimine Schiff base 3 can be readily prepared by simple imine formation between glycine tert butyl ester hydrochloride and p-chlorobenzaldehyde in MeOH at room temperature with the aid of MgSO4. Monoalkylation of 3 was then performed by introducing a 50% KOH aqueous solution into a mixture of 3, benzyl bromide (1.2 equiv), and (R,R)-7 in toluene at 0 °C under an argon atmosphere followed by vigorous stirring at that temperature. The reaction was found to go to completion within 2 h and the corresponding α-benzyl-α-amino ester 6a was obtained almost quantitatively without detectable production of the double benzylation product. Interestingly, the enantiomeric excess of 6a was revealed to be 98% ee by HPLC analysis using a chiral column. In conclusion, a highly enantioselective monoalkylation of p-chlorobenzaldehyde imine of glycine tert butyl ester hydrochloride has been accomplished by the utilization of either 7 or 8 as catalysts. The reaction proceeds smoothly at 0 °C in toluene with 50% KOH aqueous solution as a base, and a variety of alkyl halides are employable without fear of substantial racemization. p-Chlorobenzaldehyde, although inexpensive, can be recovered after acidic hydrolysis of the alkylation product, and directly reused for the condensation with glycine tert butyl ester hydrochloride to prepare Schiff base 3; this strengthens the practical aspect of the present methodology for application in the industrial production of various natural and unnatural α-amino acids.

References

[1] Takashi Ooi . (2006). Highly enantioselective monoalkylation of p-chlorobenzaldehyde imine of glycine tert-butyl ester under mild phase-transfer conditions. Tetrahedron, Asymmetry, 17 4, Pages 603-606.

You may like