Stereoselective sodium borohydride reduction, catalyzed by manganese(II) chloride, of γ-oxo-α-amino acids. A practical approach to syn-γ-hydroxy- α-amino acids

Article abstract of DOI:10.1016/S0040-4039(00)00800-5

A highly stereoselective reduction of γ-oxo-α-amino acids by sodium borohydride in the presence of a catalytic amount of manganese(II) chloride gives syn-γ-hydroxy-α-amino acids. Enantiomerically pure syn(2S,4R,1'S)-4- aryl-4-hydroxy-2-(1'-phenylethylamin

Full text of DOI:10.1016/S0040-4039(00)00800-5

Tetrahedron Letters 41 (2000) 5257±5260
Stereoselective sodium borohydride reduction, catalyzed by
manganese(II) chloride, of g-oxo-a-amino acids. A practical
approach to syn-g-hydroxy-a-amino acids
Dusan Berkes,* Andrej Kolarovic and Frantisek Povazanec
Â
Department of Organic Chemistry, Slovak Technical University, Radlinskeho 9, SK-812 37 Bratislava, Slovak Republic
Received 9 March 2000; accepted 16 May 2000
Abstract
A highly stereoselective reduction of g-oxo-a-amino acids by sodium borohydride in the presence of a
catalytic amount of manganese(II) chloride gives syn-g-hydroxy-a-amino acids. Enantiomerically pure syn-
(2S,4R,10S)-4-aryl-4-hydroxy-2-(10-phenylethylamino)butanoic acids form stable gels in methanol. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: amino acid derivatives; asymmetric induction; reduction; stereocontrol.
4-Hydroxylated a-amino acids and their lactones are relatively common building blocks of a
vast array of bioactive compounds such as nikkomycins,1 cymbimycins,2 and funebrine,3 that
have been isolated from natural materials.4 The widespread occurrence of this structural unit has
led to the development of a number of stereoselective syntheses, such as the isoxazoline route,5,6
enzymatic methods,7,8 and photolysis of chiral chromium complexes.9
The wide scale of readily accessible enantiomerically pure g-aryl-g-oxo-a-amino acids10 12 has
allowed their usage as starting materials in the preparation of substituted g-aryl-g-hydroxy-a-
amino acid derivatives. The e€ect of an existing stereogenic center on the diastereoselectivity
of the reduction has been extensively studied. The reduction of esters13,14 or amides15 using
hydride reagents proceeds with low selectivity. Jackson16 obtained the best results by using the
.
Et3SiH:Et2O BF3 system (9:1 in favor of a cis-lactone). Little attention has been paid so far to a
direct reduction of g-oxo-a-amino acids. The straightforward access17 to both enantiomers of these
acids by conjugate addition of chiral amines to b-aroylacrylic acids makes this approach attractive.
In our previous paper18 we published the reduction, using NaBH4 at low temperature, of some
4-aryl-4-oxo-a-amino acids with a d.r. of up to 11:1. Here we describe the application of
.
MnCl2 4H2O as a catalyst of such reductions, a process that allowed us to reach a d.r. of up to
97:3 with syn-g-hydroxy-a-amino acids being the major products (Scheme 1).
* Corresponding author. E-mail: dberkes@mtf.stuba.sk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00800-5

5258
Scheme 1.
The starting g-oxo-a-amino acids Ia±n were prepared by conjugate addition of benzylamine,
furfurylamine or 1-phenylethylamine, respectively, to suitable b-aroyl or b-acetyl acrylic acids.
The reduction was carried out in methanol. In reductions without catalyst a large excess of
NaBH4 had to be used because of the insolubility of the starting oxoamino acids (Ia±m) in the
reaction media. The best results under such conditions were achieved in the case of the more
soluble furfurylamino adducts IIc,f at low temperature; in the case of 1-phenylethylamino derivatives
Iig±m, however, the diastereoselectivity was low and independent of the reaction temperature (d.r
ꢀ2:1).
The application of MnCl2 as a chelating agent not only increased the solubility of starting
materials, but also accelerated the reduction and increased the selectivity. This approach has been
used recently19 in the reduction of 2-alkyl-3-oxoesters by a 1,2-asymmetric induction process.
However, metal-chelation control in 1,3-induction is not so conclusive.20 The selective formation
of the syn-isomer can be rationalized by a six-membered metal chelate in a similar fashion as
shown in a previous report20 on the reduction of b-aminoketones with Zn(BH4)2 (Scheme 2).
Scheme 2.
The in¯uence of various factors on the selectivity of oxoamino acid (Id) reduction has been
studied (Scheme 3). The most signi®cant e€ects were observed when varying the amount of catalyst
and the temperature (Table 1). The rate of addition of NaBH4 is also very important. Thus, if it was
too fast with regard to the complexation rate, NaBH4 to some extent attacked the non-complexed
Scheme 3.

5259
carbonyl group to give rise to the anti-isomer. A slightly diminished d.r. in the case of the much
more soluble g-oxo-a-(N-benzylamino)pentanoic acid In can also be attributed to this factor. In
this case, the product was isolated as the corresponding trans-a-benzylaminovalerolactone
hydrochloride IIIn.
Table 1
E€ect of the reaction conditions on the stereochemical outcome of the reduction of Id
Table 2
Reduction of 4-oxo-2-aminoacids (Ia±n) with NaBH4/cat. MnCl2 4H2O in methanol
y
.
y
A typical procedure for the preparation of syn-IId is as follows: To a presonꢁicated (1 min) stirred suspension of Id
.
(655 mg, 2 mmol) and MnCl2 4H2O (80 mg, 0.4 mmol) in MeOH (30 ml) at 20 C NaBH4 (2Â74 mg, 2Â2 mmol) was
slowly added (during 2Â10 min). The resulting solution was stirred additionally for 30 min and water (20 ml) was
added. Methanol was removed under reduced pressure and the pH of the remaining solution was adjusted to 6.0 with
1N HCl. A precipitate was ®ltered o€, washed with EtOH, ether and dried to a€ord 460 mg (70 %) of syn-IId (d.r.
>97:3) as a white solid. An analytical sample was obtained by recrystallization from 70 % EtOH: mp 207±209ꢁC, H
1
NMR (0.2N NaOD/D2O, 300 MHz) ꢀ 7.30±7.42 (m, 3H, Ph), 7.22±7.27 (m, 2H, Ph), 7.11 (bs, 1H, H-20), 7.10 (d, 1H,
J=8.1 Hz, H-60), 6.92 (d, 1H, J=8.1 Hz, H-50), 4.69 (t, 1H, J=6.9 Hz, H-4), 3.75 (d, 1H, J=12.9 Hz, CH2Ph), 3.48 (d,
1H, J=12.9 Hz, CH2Ph), 3.23 (s, 3H, OCH3), 3.02 (t, 1H, J=6.8 Hz, H-2), 2.17 (s, 3H, CH3), 1.98 (t, 2H, J=6.9 Hz,
H-3). 13C NMR (0.2N NaOD/D2O, 75 MHz) 184.4 (C-1), 159.5 (C-40), 141.6 (C-1Ph), 138.2 (C-10), 131.6 (C-20), 131.5,
131.4 (C-Ph), 130.2 (C-4Ph), 129.5 (C-30), 127.9 (C-60), 113.9 (C-50), 74.7 (C-4), 63.3 (C-2), 58.5 (OCH3), 53.9 (CH2Ph),
43.8 (C-3), 18.3 (CH3).

5260
.
A 20 mol% of MnCl2 4H2O was enough to achieve high control of the diastereoselectivity in
favor of the syn-isomer (Table 2). The stereoselectivity was independent of both the R and Ar
substituents and nearly identical results were obtained using protic solvents or their aqueous
mixtures. The reaction represents an inexpensive and simple approach to N-substituted syn-g-
hydroxy-a-amino acids in which the N-benzyl group can be removed easily by catalytic hydro-
genolysis in bu€ered aqueous methanol.
All racemic syn-hydroxy amino acids have been puri®ed by crystallization. The chiral ones
(IIg,i,k), however, underwent extensive gelation. The gelation ability in methanol has been measured
by the method of Hanabusa21 and it was found that 7 mg/ml for IIi stabilized a gel for several
months. Thus, syn-(2S,4R,10S)-4-aryl-4-hydroxy-2-(10-phenylethylamino)butanoic acids provide
another example which ®ts the close gelation±chiral structure relationship.22
In summary, the highly stereoselective reduction described in conjunction with diastereo-
selective conjugate addition of chiral amines a€ords a simple and inexpensive access to the both
enantiomers of a wide variety of syn-g-hydroxy-a-amino acids.
Acknowledgements
The authors are grateful to the Slovak Grant Agency for ®nancial support No. 1/6269/99.
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