A practical diastereoselective synthesis of β-amino-α-hydroxy carboxylates

Article abstract of DOI:10.1016/j.tetasy.2003.10.009

Practical synthetic routes to β-amino-α-hydroxy carboxylates (AHC) have been developed from amino acids. Reduction of β-amino-α- keto esters 6 with NaBH₄ was found to give anti-AHCs 7 in high de, which were efficiently converted to the corresponding syn-AHCs 8 via oxazolidine ring 10 formation.

Full text of DOI:10.1016/j.tetasy.2003.10.009

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3639–3641
A practical diastereoselective synthesis of b-amino-a-hydroxy
carboxylates
Jae-Mok Lee, Hyun-Suk Lim, Kyung-Chang Seo and Sung-Kee Chung*
Department of Chemistry, Division of Molecular and Life Sciences, Pohang University of Science and Technology,
Pohang 790-784, Republic of Korea
Received 4 July 2003; revised 1 October 2003; accepted 4 October 2003
Abstract—Practical synthetic routes to b-amino-a-hydroxy carboxylates (AHC) have been developed from amino acids. Reduction
of b-amino-a-keto esters 6 with NaBH4 was found to give anti-AHCs 7 in high de, which were efficiently converted to the
corresponding syn-AHCs 8 via oxazolidine ring 10 formation.
© 2003 Elsevier Ltd. All rights reserved.
b-Amino-a-hydroxy carboxylic acids (AHC) have
received much attention because they are essential
structural components in a variety of biologically
important compounds such as taxol,1 a potent anti-
cancer agent, bestatin,2 an aminopeptidase inhibitor,
amastatin,3 a protease inhibitor, KNI-227 and KNI-
272,4 highly potent HIV protease inhibitors, and
kanamicin A,5 an antibacterial agent (Fig. 1). Much
effort has been devoted to the development of efficient
stereoselective synthetic routes to enantiomerically pure
AHC.6 Recently, we developed a highly practical route
to diastereoselective syntheses of all four sphingosine
stereoisomers via non-chelation controlled and chela-
tion controlled reduction of N-trityl protected amino
enones and free amino enones using NaBH4 and
Zn(BH4)2, respectively.7 We describe herein an exten-
sion of this method to the preparation of optically
active syn/anti AHC derivatives.
Our synthesis procedures are based on commercially
available amino acids and are illustrated with three
representative amino acids;
L-phenylglycine, L-phenyl-
alanine and -leucine (Scheme 1). Esterification of the
L
Scheme 1. Reagents and conditions: (i) (a) AcCl, MeOH,
reflux, (b) TrCl, Et3N, CH2Cl2, rt; (ii) LiCH2PO(OMe)2,
THF, −78°C; (iii) PhCHO, NaH, THF, rt; (iv) conc. HCl,
THF, reflux; (v) O3, NaOH, MeOH–CH2Cl2, −78°C; (vi)
conc. HCl, MeOH, rt.
Figure 1.
* Corresponding author. Tel.: +82-54-279-2764; fax: +82-54-279-3399;
e-mail: skchung@postech.ac.kr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.009

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J.-M. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 3639–3641
amino acids with methanolic hydrogen chloride, fol-
lowed by protection of the amino functionality with
trityl chloride gave the protected amino esters 1a–c in
high yields. The esters 1a–c were quantitatively con-
verted to the b-keto phosphonates 2a–c by treatment
with excess lithium dimethyl methylphosphonate. The
Horner–Wadsworth–Emmons olefination of the b-keto
phosphonates 2a–c with benzaldehyde under the NaH/
THF conditions provided the corresponding enones
3a–c in good yields as previously reported.8 The enones
3a–c were treated with conc. HCl in THF at reflux to
give the deprotected amino enones 4a–c. We first exam-
ined possible diastereoselective reduction of these types
of enones (3 and 4) using the methodology previously
developed in our laboratory,7 on the premise that the
amino alcohol products could be converted to AHCs
by an oxidative cleavage reaction in the next stage. As
expected, reduction of the N-trityl protected enones
3a–c and the unprotected amino enones 4a–c with
NaBH4 and Zn(BH4)2 provided the syn- and anti-
amino alcohols as the major products, respectively.9
However, the observed ratios of the syn/anti-
diastereoselectivity (in the range of 52–85% de) were
not satisfactory for our practical synthetic goal.
hoped that reduction of N-trityl protected a-keto ester
5a would give as the major product the syn-product via
an open Felkin–Anh transition state, whereas the free
amino a-keto ester 6a would yield the anti-product via
a chelation controlled transition state. To our dismay,
however, we obtained the anti-product as the major
product in both cases. With trityl protected compounds
5a–c the observed diastereoselectivities were rather low
with either NaBH4 or Zn(BH4)2 (entries 1–7). The
reduction of compound 5 is supposed to proceed via
the Felkin–Anh transition state model since the R1
group is bulkier than the N-trityl protected amino
group, unlike our previous cases in which the N-trityl
protected amino group is the largest group. The low
selectivities observed with compound 5 are perhaps due
to small differences of bulkiness between the R1 group
and the N-trityl protected amino group.
On the other hand, reduction of the free amino a-keto
esters 6a gave the anti-product in excellent diastereose-
lectivity in accord with the expected cyclic Felkin–Anh
transition state model (entries 8 and 9). Under the same
conditions 6b and c could also be converted to the
corresponding anti-products in good yields and with
equally excellent diastereoselectivities (entries 10–13).11
The stereochemical assignment of 7a were made by
comparison with the literature values,6d and also after
its conversion to the benzoyl derivative 9a.12,13
In an attempt to improve diastereoselectivity, we
wished to subject the b-amino-a-keto esters 5 and 6 to
the reduction conditions. Ozonolysis of the enones 3a-c
in MeOH and CH2Cl2 afforded N-trityl-a-keto esters
5a–c in acceptable yields.10 The N-trityl-a-keto esters
5a–c in THF were treated with conc. HCl to give
deprotected amino-a-keto esters 6a–c as the HCl salt
form. We have then examined diastereoselective reduc-
tion of these a-keto esters and the results are shown in
Table 1.
In order to secure a ready access to the desired syn-
AHC, we had to resort to the inversion of the alcohol
configuration of the anti-products 7a–c (Scheme 2).
Thus, the amino groups of 7 were benzoylated to give
9, and compounds 9 were converted to oxazolidine
derivatives 10 in excellent yields by reaction with SOCl2
in CH2Cl2. Successive treatment of 10a–c with HCl in
methanol, and then aqueous NaHCO3 provided in bet-
ter than 70% overall yields the syn-AHCs 8a–c.14 The
Initially, for direct comparison we examined the syn/
anti selectivity in the reduction of 5a and 6a. It was
Table 1. Reduction of a-keto esters
Entry
Substrate
R1
R2
Conditions
Yield (%)a
Ratio anti:synb
De (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5b
5b
5c
5c
6a
6a
6b
6b
6c
6c
Phenyl
Phenyl
Phenyl
Benzyl
Benzyl
i-Butyl
i-Butyl
Phenyl
Phenyl
Benzyl
Benzyl
i-Butyl
i-Butyl
Trityl
Trityl
Trityl
Trityl
Trityl
Trityl
Trityl
H·HCl
H·HCl
H·HCl
H·HCl
H·HCl
H·HCl
NaBH4/MeOH/−20°C
NaBH4/CeCl3·7H2O/MeOH/0°C
Zn(BH4)2/THF/−78°C
NaBH4/MeOH/−20°C
Zn(BH4)2/THF/−78°C
NaBH4/MeOH/−20°C
Zn(BH4)2/THF/−78°C
NaBH4/MeOH/−20°C
Zn(BH4)2/THF/−78°C
NaBH4/MeOH/−20°C
Zn(BH4)2/THF/−78°C
NaBH4/MeOH/−20°C
Zn(BH4)2/THF/−78°C
77
63
79
55
78
63
72
73
75
77
74
86
75
5.9:1
2.4:1
8.5:1
1.9:1
2.6:1
2.7:1
5.7:1
99:1
49:1
99:1
15.3:1
15.7:1
18.6:1
71
41
79
31
44
46
70
98
96
98
88
88
90
9
10
11
12
13
a Yields of isolated anti products.
b The anti/syn ratio was determined by NMR analysis of the crude mixture.

J.-M. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 3639–3641
3641
37, 2311; (g) Bunnage, M. E.; Davies, S. G.; Goodwin, C.
J. J. Chem. Soc., Perkin Trans. 1 1994, 2385.
7. Lee, J. M.; Lim, H. S.; Chung, S. K. Tetrahedron: Asym-
metry 2002, 13, 343.
8. (a) Chung, S. K.; Kang, K. H. Tetrahedron: Asymmetry
1997, 8, 3027; (b) Abiko, A.; Masamune, S. Tetrahedron
Lett. 1996, 37, 1077.
9. Compounds 3 and 4 were reduced by a variety of condi-
tions employing NaBH4, LiBH4, Zn(BH4)2, L-Selectride,
LiAlH4, NaBH3CN, and DIBAL to give syn/anti prod-
ucts in good chemical yields (68–99%) but moderate
diastereoselectivities (52–85% de).
10. (a) The paucity of examples of the direct preparation of
a-keto esters from enones via oxidative cleavages such as
ozonolysis in the literature may suggest that a further
detailed study of this reaction might be warranted; (b)
Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58,
3675.
11. It is also conceivable that the reduction of a-keto esters 5
and 6 takes place in the H-bonded cyclic structure
between the amino group and the ester group.
Scheme 2. Reagents and conditions: (i) BzCl, NaHCO3,
MeOH, 0°C; (ii) SOCl2, CH2Cl2, reflux; (iii) 1N HCl, MeOH,
reflux, followed by satd NaHCO3, 50°C.
spectroscopic and physical properties of 8a were satis-
factorily compared with the literature data.15
In summary, we have developed practical synthetic
routes to syn/anti b-amino-a-hydroxy carboxylates
from amino acids using highly efficient diastereoselec-
tive reduction of b-amino-a-keto ester derivatives 6 via
a chelation control. This method is expected to be
useful in preparing a variety of biologically important
compounds containing the syn/anti AHC moiety.
12. No racemization during the reduction was confirmed by
converting benzoylated anti-AHC compounds 9a–c to the
corresponding O-(−)-MTPA esters 9a%–9c%.17 1H and 19F
NMR data indicated their homogeneity. Compound 9a%:
1H NMR (CDCl3) l 3.62 (s, 3H), 3.69 (s, 3H), 5.80 (m,
2H), 6.42 (d, J=7.8 Hz, 1H), 7.26–7.60 (m, 15H), 19F
NMR (CDCl3) l 5.00. Compound 9b%: 1H NMR (CDCl3)
l 2.87 (m, 2H), 3.66 (s, 3H), 3.68 (d, J=1.1 Hz, 3H), 5.09
(m, 1H), 5.55 (d, J=3.6 Hz, 1H), 5.85 (d, J=8.5 Hz, 1H),
7.12–7.48 (m, 15H), 19F NMR (CDCl3) l 5.05. Com-
Acknowledgements
1
pound 9c%: H NMR (CDCl3) l 0.89 (d, J=6.4 Hz, 6H),
Financial support from the Ministry of Education/
BSRI Fund is gratefully acknowledged.
0.97 (m, 1H), 1.26 (m, 1H), 1.56 (m, 1H), 3.66 (d, J=1.1
Hz, 3H), 3.86 (s, 1H), 4.86 (m, 1H), 5.50 (d, J=1.9 Hz,
1H), 5.76 (d, J=3.4 Hz, 1H), 7.26–7.62 (m, 10H), 19F
NMR (CDCl3) l 4.92.
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