An efficient method for the reduction of N-protected amino acids and peptides to the corresponding alcohols

Article abstract of DOI:10.1039/a902069a

Reduction of pentachlorophenyl esters of Boc protected amino acids and peptides to the corresponding alcohols is described.

Full text of DOI:10.1039/a902069a

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424 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 424^425y
An Efficient Method for the Reduction of
N-Protected Amino Acids and Peptides to the
Corresponding Alcoholsy
T. Naqvi, M. Bhattacharya and W. Haq*
Division of Biopolymers, Central Drug Research Institute, P.O. Box 173, Lucknow, 226001,
India
Reduction of pentachlorophenyl esters of Boc protected amino acids and peptides to the corresponding alcohols
is described.
Na-Protected b-amino alcohols are key intermediates in the
NaBH4–I2
THF, r.t.
R
Pentachlorophenol
DCC
R
R
synthesis of variety of compounds viz. peptide bond
surrogates, as they lead to a-amino aldehydes by various
oxidation procedures1 which can be used in the design of
protease inhibitors2 or in the synthesis of `reduced peptide
bonds'.3 Further, these are important intermediates in
asymmetric synthesis in peptide and pharmaceutical chem-
Boc-NH
CO2H
Boc-NH
CO2PCP
Boc-NH
CH2OH
Scheme 1
6
istry,4 in resolution of racemic mixtures7 and in synthesis
an improvement in the NaBH4 I2 reduction method by
derivatizing the carboxylic group and the same method
can also be applied to protected amino acids with side chain
functionalities and peptides. It has been found in our lab-
oratory that Na-protected amino acids when converted into
their corresponding pentachlorophenyl (OPCP) esters, on
employing NaBH4 I2 are readily reduced to the amino
alcohols at room temperature and are obtained in excellent
yields and optical purity (Scheme 1). We report here the
reduction of some protected amino acids as well as peptide
active esters into their corresponding alcohols. Protected
amino acids and peptides can successfully be converted
to alcohols from their corresponding pentachloraphenyl
esters by this method with excellent yields and retention
of optical purity under very mild conditions (Table 1).
The highlighting features of this study are: (i) the reaction
involves mild reaction conditions and cheap reagents. It is
safe and simple and, therefore, can be used for even large
scale synthesis of chiral amino alcohols. (ii) Reaction is very
fast and proceeds to completion in 4 h. (iii) The side chain
protection of lysine and arginine by Z and NO2 groups,
respectively, remains una¡ected under the described con-
ditions. (iv) The process does not reduce benzyl ester groups
used for the protection of g- and b-carboxylic groups of
of insecticidal compounds.8 Several methods have pre-
viously been reported using LiAlH4,10 NaBH4,11 DIBAL,12
BH3ÁTHF13 etc, for the reduction of free as well as
protected amino acids to their corresponding alcohols.
However, these reagents su¡er from disadvantages of cost,
in£ammability and tedious isolation procedures. As these
amino alcohols are important intermediates, their prep-
aration on a large scale requires cheaper, simpler and safer
processes. Periaswamy and coworkers14 reported the
reduction of various carboxylic acids into their correspond-
ing alcohols under mild conditions using an NaBH4 I2
system. Using the same reagent, McKennon and Mayers15
reported e¤cient reduction of amino acids into their corre-
sponding amino alcohols. However, this method was
reported to be limited to the reduction of hydrophobic
amino acids and could not be applied for the reduction
of amino acids having side chain functionalities. Further,
the reaction conditions used were also quite drastic (re£ux
for 18^24 h) and not suited for amino acids having side
chain functionalities. Kokotos and Noula16 reported
reduction of various carboxylic acid £uorides under very
mild conditions which showed superiority over the method
reported by McKennon et al. The present work describes
Table 1 Physicochemical characteristics of protected amino alcohols and peptide alcohols
Protected amino
alcohol or peptide
FAB-MS (m/z)
Found (Calc)
c
Entry
Yielda(%)
Mp/8C
Rfb
‰aŠ
1
2
3
4
5
6
7
8
Boc-Ala-ol
Boc-Phe-ol
Boc-Trp-ol
Boc-Tyr-ol
Boc-Arg(NO2)-ol
Boc-Leu-ol
Boc-Gly-ol
89
80
83
62
79
83
85
64
75
74
71
78
76^87
88^90
108^110
Oil
128^130
176^180
148^150
148^150
Oil
0.61
0.38
0.55
0.43
0.42
0.58
0.62
0.61
0.64
0.47
0.75
0.50
3:60
21:6
25:6
176(176)
252(251)
290(290)
267(267)
306(305)
217(216)
162(161)
202(201)
353(352)
324(324)
614(613)
365(364)
^
^
7:20
7:27
Boc-Pro-ol
32:7
8:20
9
Boc-Lys(Z)-ol
Boc-D-Glu(OBzl)-ol
Boc-DAGO
10
11
12
Gum
162
Gum
‡8:0
40
Boc-Phe-Leu-ol
^
aIsolated and purified yields. bSolvent system MeOH^CHCl3 (5:95). cValues are in comparison to those reported in the literature and
uncorrected, c ˆ 1, MeOH. dBoc-Tyr-D-Ala-Gly-MePhe-Gly-OPCP reduced to Boc-Tyr-D-Ala-Gly-MePhe-Gly-ol (Boc-DAGO).
glutamic acid and aspartic acid, respectively. (v) The
reaction conditions do not cause racemization and the
amino alcohols are obtained in high optical purity. Thus,
* To receive any correspondence (e-mail: root@cscdri.ren.nic.in).
y This is a Short Paper as de¢ned in the Instructions for Authors,
this method can be successfully applied for the synthesis
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).
of Na-Boc protected amino alcohols as well as protected

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J. CHEM. RESEARCH (S), 1999 425
peptide alcohols. We observed that the reduction of Boc
amino acids without deriviatization did not proceed at
all under similar conditions.
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Experimental
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5
6
General Procedure for the Reduction of Protected Amino Acids and
Peptide^OPCP Esters to their Corresponding Alcohols.öTo a slurry
of NaBH4 (1.2 mm) in dry THF (5 ml), iodine (0.5 mm) dissolved
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Received, 16th March 1999; Accepted, 24th March 1999
Paper E/9/02069A