An Improved, Convenient Procedure for Reduction of Amino Acids to Aminoalcohols: Use of NaBH4-H2SO4Atsushi Abiko and Satoru Masamune
Institute for Fundamental Research, Kao Corporation, Ichikai-machi. Haga-gun, Tochigi. 321-34, JapanAbstract: The use of NaBH
4-H
2SO
4 for the reduction of
alpha-amino acids to the corresponding aminoalcohols offers definite advantages: 1) operational simplicity, 2) ease of scaling up the reaction without risking explosion. and 3) use of the inexpensive reagents.
During the course of our recent studies of bisoxazoline chemistry
1 we needed to develop a convenient and reliable procedure for the mole-scale synthesis of
alpha,
beta-aminoalcohols from the corresponding
alpha-amino acids. Although there exist several methods
2 including those describe in
Organic Syntheses2a,b (and also some aminoalcohols are commercially available), these methods require the use of rather expensive reagents (e.g., LiBH
4, BH
3-SMe
2) and/or careful control of reaction conditions to minimize the risk of explosion that may occur after the induction period. We recommend herein the use of the two inexpensive reagents, NaBH
4 and H
2SO
4, as exemplified by the reduction of D-phenylglycine.
To a stirred suspension of NaBH
4 (100g, 2.5mol) in THF (1L. reagent grade without further purification) was added D-phenylglycine (151g, 1.0mo1). The flask was immersed in an ice-water bath, and a solution of (fresh) conc. H
2SO
4 (66mL, 1.25mol) in ether (total volume of 200mL) was added dropwise at such a rate as to maintain the reaction mixture blow 20°C (addition time, approximately 3h). Stirring of the reaction mixture was continued at room temperature overnight and MeOH (100mL) was added, carefully to destroy excess BH
3. The mixture was concentrated to ca. 500mL and 5N NaOH (1L) was added. After removing the solvent that distilled below 100°C, the mixture was heated at reflux for 3h. The turbid aqueous mixture was cooled and filtered through a thin pad of Celite
(C) which was washed with water. The filtrate and the washings were combined and diluted with additional water to ca. 1L. The CH
2Cl
2 extraction (4 x 500mL) followed by evaporation of the solvent left solid phenylglycinol, which was recrystallized from ethyl acetate and hexane to yield 115g (84% including the second crop) of the pure product (mp. 74-760 C, >98 %ee by analysis of the
1H-NMR of the bis-MTPA derivative).
The application of the NaBH
4-H
2SO
4: procedure to other amino acids is summarized in Table 1. Protected amino acids were also reduced canine; alanine benzamide was reduced to N-benzylalaninol, while the N-Cbz and N-tosyl groups remained unaffected.
The reduction of the carboxyl group was obviously effected by B
2H
6, generated in situ. Therefore, H
2SO
4 can be replaced by other reagents such as HCI
3a, BF
3-OEt
23a, MeI
3b, Me
2SO
4 3c, MeOTs
3c and MeSO
3H
3d as shown in Table 2. Although the yields of valinol from valine are comparable with that shown in Table 1, the NaBH
4-H
2SO
4 system offers the definite advantages: 1) the reduction can be scaled up without risking explosion, 2) NaBH
4 and H
2SO
4 are inexpensive and 3) the execution of the reduction is simple, and even the rigorous drying of the solvent is unnecessary.
References:
1. a) Lowenthal. R. E.; Abiko, A.; Masamune, S .
Tetrahedron Lett. 31:5005(
1990). b) Lowenthal, R. E.; Masamune, S .
Tetrahedron Lett. 32:7373(
1991).
2. a) Dickman. D. A.; Meyers, A. I.; Smith, G . A.; Gawley, R. E.
Org. Synth. Coll. vol. VlI, 530. b) Gage. J. R.; Evans, D. A.
Org. Synth. 68:77(
1990). c) Bridget, L. N.; Prol, Jr. J.; Alexander, B.; Gillyard, L.
J. Org. Chem. 54:3231(
1989). d) Giannis, A.; Sandhoff, K .
Angew. Chem., Int. Ed. Engl. 28:218(
1989).
3. a) Zweifel, G.; Brown, H . C.
Org. Reactions 13:1(
1963). b) Freeguard, G . F.; Long, L. H.
Chem. lnd. 471(
1965). c) Bell, H . M.; Vanderslice, C. W.; Spehar, A.
J. Org. Chem. 34:3923(
1969). d) Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollmann, T. A.; Kennedy, R. M.; Masamune, S .
J. Am. Chem. Soc. 108:7402(
1986).
