Stereoselective reduction of N-hydroxy-α-iminocarbonyl-oligopeptide methyl esters with Zn-MsOH

Article abstract of DOI:10.1016/S0040-4039(02)01752-5

The reduction of N-hydroxy-α-imino esters with Zn-MsOH in THF afforded α-amino esters in high yields. The reduction of N-hydroxy-α-iminocarbonyl-oligopeptide methyl esters prepared from L-phenylalanine and L-leucine di-, tri-, tetrapeptides gave the corre

Full text of DOI:10.1016/S0040-4039(02)01752-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7297–7300
Stereoselective reduction of
N-hydroxy-a-iminocarbonyl-oligopeptide methyl esters with
Zn–MsOH
Naoki Kise,* Shuji Takaoka, Masahiro Yamauchi and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 7 August 2002; revised 15 August 2002; accepted 22 August 2002
Abstract—The reduction of N-hydroxy-a-imino esters with Zn–MsOH in THF afforded a-amino esters in high yields. The
reduction of N-hydroxy-a-iminocarbonyl-oligopeptide methyl esters prepared from
L-phenylalanine and L-leucine di-, tri-,
tetrapeptides gave the corresponding S-formed oligopeptide methyl esters in moderate diastereoselectivities. © 2002 Elsevier
Science Ltd. All rights reserved.
Reduction of oximes is a useful method for the synthe-
sis of amines from carbonyl compounds.1 Recently, we
have reported the reductive coupling of aromatic
aldoximes and azines to N,N%-unsubstituted 1,2-
diamines with Zn–MsOH or Zn–TiCl4.2,3 We found
that the reduction with Zn–MsOH was also effective
for the conversion of N-hydroxy-a-imino esters to a-
amino esters. We further investigated the reduction of
N-hydroxy-a-imino carbonyl groups bonded to the N-
N-Boc-protection of the resulting a-amino esters, N-
Boc-a-amino esters were obtained in excellent yields
(Eq. (2)). In order to complete the reduction, the addi-
tion of MsOH in amounts equimolar with Zn was
required. These results show that Zn–MsOH is an
effective reducing agent for the reduction of N-
hydroxy-a-imino esters to a-amino esters.
terminus of L-phenylalanine or L-leucine oligopeptides
with Zn–MsOH (Eq. (1)). Herein we report that the
diastereoselectivity in the reduction of N-hydroxy-a-
iminocarbonyl-oligopeptide methyl esters was strongly
affected by the number of amino acid residues of the
oligopeptide moieties. The S-selectivity increased with
increase in the number of amino acid residues (n) in the
(2)
Second,
oligopeptide methyl esters 1a–d (R1=Me) and 1e–h
(R1=Bn) prepared from
-phenylalanine methyl ester
(n=1) and -phenylalanine oligopeptide methyl esters
a
series of N-hydroxy-a-iminocarbonyl-
substrates, N-hydroxy-a-iminocarbonyl-(L-Phe)n-OMe
and N-hydroxy-a-iminocarbonyl-(
L
-Leu)n-OMe (n=1–
L
4).
L
(n=2–4) were reduced with Zn–MsOH in THF or
DMF at 25°C. The results are summarized in Table 1.
In all cases, N-Boc-oligopeptide methyl esters 2 were
obtained as mixtures of two diastereomers ((S)-2 and
(R)-2) in good to excellent yields. The S:R ratios at the
N-terminal residues in 2 were determined by compari-
(1)
1
son of their H NMR spectra with those of authentic
First, the reduction of N-hydroxy-a-imino esters was
carried out with Zn–MsOH in THF at 25°C. After
samples.4 Fig. 1 illustrates the correlation between the
percentage of the S-form in 2 and the number of amino
acid residues (n). In THF, the S-selectivity rose steadily
with an increase of the number of residues. Whereas
slight R-selectivities were found in the reduction of the
Keywords: reduction; zinc; oxime; amino acid; oligopeptide.
* Corresponding author. Fax: +81-857-31-5636; e-mail: kise@
bio.tottori-u.ac.jp
substrates 1a and 1e derived from
L-phenylalanine
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01752-5

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N. Kise et al. / Tetrahedron Letters 43 (2002) 7297–7300
Table 1. Reduction of N-hydroxy-a-iminocarbonyl-oigopeptide methyl esters 1 with Zn–MsOH
In THF
Yielda (%) of 2
In DMF
1
R1
n
S:Rb
1
R1
n
Yielda (%) of 2
S:Rb
1a
1b
1c
1d
Me
Me
Me
Me
1
2
3
4
2a
2b
2c
2d
91
85
77
71
45:55
68:32
75:25
85:15
1a
1b
1c
1d
Me
Me
Me
Me
1
2
3
4
2a
2b
2c
2d
89
87
78
75
41:59
55:45
60:40
60:40
1e
1f
1g
1h
Bn
Bn
Bn
Bn
1
2
3
4
2e
2f
2g
2h
92
89
83
77
48:52
63:37
70:30
82:18
1e
1f
1g
1h
Bn
Bn
Bn
Bn
1
2
3
4
2e
2f
2g
2h
87
88
85
66
42:58
44:56
46:54
42:58
a Isolated yields.
b Determined by 1H NMR spectra.
methyl ester (n=1), S-formed diastereomers of 2 were
obtained preferentially from the substrates 1b–d and
1f–h made of L-phenylalanine di-, tri-, and tetrapeptides
methyl esters (n=2–4). Unfortunately, the substrate
prepared from a pentapeptide methyl ester (n=5) was
sparingly soluble in THF. On the other hand, when the
reduction of 1 was carried out in DMF, the stereoselec-
tivities were relatively low (40–60% of S-2). Especially,
in the cases of R1=Bn (1f–h), the selectivity remained
stable at 40–45% of the S-form. Next, TFA and TiCl4
were used as an additive in place of MsOH. As depicted
in Table 2, the yields of 2 were slightly less than those
obtained with Zn–MsOH. As to the diastereoselectivity
in 2, Zn–TFA gave similar results to those with Zn–
MsOH, while Zn–TiCl4 afforded considerably low S-
stereoselectivities.
Another series of substrates 3a–d (R1=Me) and 3e–h
(R1=i-Bu) derived from
L-leucine methyl ester (n=1)
Figure 1. Correlation between percentage of (S)-2 and num-
ber of residues (n).
and oligopeptide methyl esters (n=2–4) were also
Table 2. Reduction of 1a–d with Zn–TFA or Zn–TiCl4 in THF
With Zn–TFA
With Zn–TiCl4
1
n
Yielda (%) of 2
S:Rb
1
n
Yielda (%) of 2
S:Rb
1a
1b
1c
1d
1
2
3
4
2a
2b
2c
2d
66
63
61
55
40:60
67:33
70:30
76:24
1a
1b
1c
1d
1
2
3
4
2a
2b
2c
2d
71
69
65
48
44:56
40:60
49:51
46:54
a Isolated yields
b Determined by 1H NMR spectra.

N. Kise et al. / Tetrahedron Letters 43 (2002) 7297–7300
Table 4. Reduction of 1 with NaBH4–CoCl2·6H2O
7299
reduced with Zn–MsOH in THF at 25°C as exhibited in
Table 3. Fig. 2 represents the correlation between the %
of the S-form in 4 and n. Similarly to the reduction of
1, the S-forms of 4 were obtained selectively from the
substrates 3b–d and 3f–h (n=2–4). However, the S-selec-
tivity in 4 rose rapidly from n=1 to n=2 and leveled off
practically at n=2.
1
R1
n
Yielda (%) of 2
S:Rb
1a
1b
1c
1d
Me
Me
Me
Me
1
2
3
4
2a
2b
2c
2d
63
80
62
55
53:47
49:51
45:55
45:55
1e
1f
1g
1h
Bn
Bn
Bn
Bn
1
2
3
4
2e
2f
2g
2h
66
77
82
59
46:54
50:50
51:49
46:54
a Isolated yields.
b Determined by 1H NMR spectra.
In conclusion, the reduction of N-hydroxy-a-imino esters
and N-hydroxy-a-iminocarbonyl-oligopeptide methyl
esters with Zn–MsOH in THF gave effectively the
corresponding a-amino esters and oligopeptide methyl
esters, respectively. The diastereoselectivity in the reduc-
tion of N-hydroxy-a-iminocarbonyl-oligopeptide methyl
esters was not influenced largely by the substituents in
N-hydroxy-a-iminocarbonyl groups (R1) and oligopep-
tides (R2), but much affected by the number of residues
in oligopeptides (n). Moderate S-selectivities were
observed in the reduction of the substrates derived from
Figure 2. Correlation between percentage of (S)-4 and num-
ber of residues (n).
As another reducing agent, NaBH4–CoCl2·6H2O5 was
employed for the reduction of 1 (Table 4). In contrast to
the results obtained with Zn–MsOH, the diastereoselec-
tivities in 2 were very low irrespective of the number of
residues.
Table 3. Reduction of N-hydroxy-a-iminocarbonyl-
oligopeptide methyl esters 3 with Zn–MsOH in THF
L
-phenylalanine and
L-leucine di-, tri-, tetrapeptides
(n=2–4).
General procedure is as follows: zinc powder (Wako Pure
Chemical Industries, Ltd.) was washed with 1 M HCl,
water, and ether successively and dried in vacuo. To a
solution of N-hydroxy-a-iminocarbonyl-oligopeptide
methyl ester 1 or 3 (1 mmol) in dry THF (5 mL for n=1
and 2, 10 mL for n=3, 20 mL for n=4) was added freshly
distilled MsOH (0.65 mL, 10 mmol) and zinc powder
(0.65 g, 10 mmol) at 0°C under an atmosphere of
nitrogen. The mixture was allowed to warm to 25°C and
stirred for 8 h. To the mixture was added satd NaHCO3
in water (20 mL) and (Boc)2O (0.44 g, 2 mmol). The
mixture was stirred for 1 h at 25°C, filtered, extracted
with ethyl acetate. After removal of the solvent, N-Boc-
3
R1
n
Yielda (%) of 4
S:Rb
oligopeptide methyl ester
2
was isolated as
a
3a
3b
3c
3d
Me
Me
Me
Me
1
2
3
4
4a
4b
4c
4d
95
85
87
74
46:54
64:36
68:32
71:29
diastereomeric mixture by column chromatography on
silica gel (hexane/ethyl acetate).
3e
3f
3g
3h
i-Bu
i-Bu
i-Bu
i-Bu
1
2
3
4
4e
4f
4g
4h
93
92
82
80
36:64
68:32
69:32
70:30
Acknowledgements
This work was supported by a Grant-in-Aid Scientific
Research (C) (No. 11650896) from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
a Isolated yields.
b Determined by 1H NMR spectra.

7300
N. Kise et al. / Tetrahedron Letters 43 (2002) 7297–7300
1.21; (S)-2c 1.21; (R)-2c 1.18; (S)-2d 1.20; (R)-2d 1.16;
References
(S)-4a 1.355; (R)-4a 1.364; (S)-4b 1.33; (R)-4b 1.35; (S)-4c
1.31; (R)-4c 1.34; (S)-4d 1.32; (R)-4d 1.33. The chemical
shifts (l) of Boc protons (singlet) in 2e–h and 4e–h were as
follows: (S)-2e 1.40; (R)-2e 1.38; (S)-2f 1.37; (R)-2f 1.39;
(S)-2g 1.34; (R)-2g 1.39; (S)-2h 1.30; (R)-2h 1.34; (S)-4e
1.44; (R)-4e 1.45; (S)-4f 1.44; (R)-4f 1.44; (S)-4g 1.45; (R)-4g
1.43; (S)-4h 1.47; (R)-4h 1.43. The chemical shifts (l) of
methoxy protons (singlet) in 4f were as follows: (S)-4f 3.722;
(R)-4f 3.716.
1. Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989; p. 424.
2. Kise, N.; Ueda, N. Tetrahedron Lett. 2001, 42, 2365–2368.
3. We have also reported the reductive coupling of aromatic
imines with Zn–MsOH: Kise, N.; Oike, H.; Okazaki, E.;
Yoshimoto, M.; Shono, T. J. Org. Chem. 1995, 60, 3980–
3992.
4. The chemical shifts (l) of methyl protons (doublet, J=7.0–
7.3 Hz) at the N-terminal alanine residues in 2a–d and 4a–d
were as follows: (S)-2a 1.31; (R)-2a 1.29; (S)-2b 1.25; (R)-2b
5. Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z.
Tetrahedron Lett. 1969, 4555–4558.