Highly stereoselective iminopinacol coupling of chiral aromatic imines derived from di- and tripeptides

Article abstract of DOI:10.1016/j.tetlet.2008.09.149

The reduction of aromatic imines prepared from (S)-Ile-(S)-Ile-OMe, (S)-Val-(S)-Val-OMe, and (S)-Val-(S)-Val-(S)-Val-OMe with Zn-MsOH in THF gave C₂-symmetric (R,R)-diamines in high yields and stereoselectivities.

Full text of DOI:10.1016/j.tetlet.2008.09.149

Tetrahedron Letters 49 (2008) 7074–7077
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly stereoselective iminopinacol coupling of chiral
aromatic imines derived from di- and tripeptides
*
Naoki Kise , Takashi Iwasaki, Yuko Yasuda, Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reduction of aromatic imines prepared from (S)-Ile-(S)-Ile-OMe, (S)-Val-(S)-Val-OMe, and (S)-Val-(S)-
Val-(S)-Val-OMe with Zn–MsOH in THF gave C2-symmetric (R,R)-diamines in high yields and
stereoselectivities.
Received 28 August 2008
Revised 25 September 2008
Accepted 26 September 2008
Available online 1 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Iminopinacol coupling
1,2-Diamine
Dipeptide
Tripeptide
Zinc
Reductive homocoupling of imines (iminopinacol coupling) is
well known as a useful tool for the synthesis of symmetrical 1,2-
diamines.1 Although a number of methods have been reported
for this purpose, most of them were nondiastereoselective.2
Recently, some studies on the diastereoselective iminopinacol
coupling of chiral imines have been reported.3 We have also
reported the stereoselective inter- and intramolecular coupling of
chiral aromatic imines prepared from (S)-valine (Eqs. 1 and 2).4
The intermolecular coupling of aromatic imine derived from (S)-
valine methyl ester gave the corresponding dimer as a mixture of
three diastereomers (R,R:R,S:S,S = 63:30:7) (Eq. 1). On the other
hand, the reductive intramolecular coupling of bis(imino ester)
gave the macrocyclic diamine in R,R:R,S:S,S = 91:9:0 ratio (Eq. 2).
We report herein the highly diastereoselective intermolecular
iminopinacol coupling of chiral aromatic imines derived from di-
and tripeptide methyl esters with Zn–MsOH (Eq. 3). It was found
that the yield and stereoselectivity of the hydrodimers was
strongly affected by reaction temperature. It is noted that the
reductive coupling of the imine prepared from (S)-Ile-(S)-Ile-OMe
with Zn–MsOH in THF at ꢀ50 °C gave the corresponding R,R-dimer
Ph
NH
NH
Ph
Ph
CO2Me
CO2Me
Zn-MsOH
THF
N
CO2Me
ð1Þ
84% R,R:R,S:S,S = 63:30:7
O
O
N
N
Zn-MsOH
Ph
Ph
O
O
NH
NH
O
O
Ph
Ph
ð2Þ
ð3Þ
THF
O
O
68% R,R:R,S:S,S = 91:9:0
R
R
Ph
CONH
CONH
CO2Me
Ph
Ph
NH
NH
Zn-MsOH
THF
n
N
CONH
CO2Me
n
CO2Me
R
R
n
R
R
R = i-Pr, sec-Bu, i-Bu
n = 1, 2
stereospecifically (99% selectivity). This reaction provides
a
First, we attempted the reductive coupling of chiral aromatic
imine 1a, derived from (S)-Val-(S)-Val-OMe and benzaldehyde,
with zinc powder (5 equiv) as a reducing agent in the presence
of MsOH (5 equiv) in THF or DMF, according to the previously re-
ported method.4 The results are summarized in Table 1. The yield
and diatereoselectivity of hydrodimer 2a increased with a decrease
in temperature accompanying a decrease in the yield of simply
convenient method for the synthesis of a new class of C2-symmetric
chiral 1,2-diamines from readily available di- and tripeptides.
* Corresponding author. Fax: +81 857 31 5636.
E-mail address: kise@bio.tottori-u.ac.jp (N. Kise).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.149

N. Kise et al. / Tetrahedron Letters 49 (2008) 7074–7077
7075
Table 1
Reductive coupling of 1a to 2aa
Ph
Ph
HN
NH CONH
CO2Me
CO2Me
Ph
Ph
Zn-MsOH
N
CONH
CO2Me
CONH
CO2Me
+
NH
CONH
1a
3a
2a
Run
Solvent
Temp (°C)
Time (h)
% Yieldb of 2a
R,R:R,S:S,Sc in 2a
% Yieldb of 3a
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
DMF
DMF
25
0
2
49
63
69
82
85
90
75:18:8
82:12:6
88:12:6
90:7:3
94:4:2
95:3:2
95:3:2
25:47:28
57:28:15
36
23
14
10
5
0
0
0
0
12
24
24
24
48
72
12
24
ꢀ20
ꢀ30
ꢀ40
ꢀ50
ꢀ60
0
<10d
82
83
ꢀ50
a
b
c
Reaction was carried out using 1.0 mmol of la, 5.0 mmol of MsOH, 5.0 mmol of zinc powder, and 10 mL of solvent.
Isolated yields.
Determined by 1H NMR spectra (Ref. 6).
More than 90% of 1a was recovered.
d
reduced amine 3a (runs 1–6). When the reaction was carried out at
ꢀ50 °C for 48 h in THF, the dimer 2a was obtained in 90% yield and
R,R:R,S:S,S = 95:3:2 ratio (run 6).5,6 Of the three diastereomers of
2a, the major isomer could be isolated by column chromatography
and its stereoconfiguration was determined to be R,R by X-ray
crystallographic analysis (Fig. 1).7 The reaction at ꢀ60 °C was very
slow due to low solubility of 1a and afforded a poor yield of 2a
even after 72 h (run 7). As a solvent, THF is much superior to
DMF in the stereoselectivity of 2a (runs 8 and 9).
The reduction of aromatic imines 1b and 1c, derived from (S)-
Ile-(S)-Ile-OMe and (S)-Leu-(S)-Leu-OMe, respectively, was carried
out under the same conditions as those in Table 1 (Table 2). The
reaction of 1b at ꢀ50 °C in THF gave hydrodimer 2b in 94% yield
and R,R:R,S:S,S = 99:1:0 ratio (run 2). The major isomer of 2b was
further purified by recrystallization and its stereochemistry was
confirmed to be R,R-dimer by X-ray crystallography (Fig. 2).7 The
elevation of reaction temperature (run 1) and the use of DMF as
a solvent in place of THF (run 3) brought about a decrease of the
stereoselectivity in 2b. On the other hand, the reduction of 1c gave
dimer 2c in low stereoselectivitity (R,R:R,S:S,S = 62:11:27), even
though the reaction was carried out at ꢀ50 °C in THF (run 5).
Next, we tried the reductive coupling of imines 4a and 4b pre-
pared from tripeptides of (S)-valine and (S)-isoleucine, respectively
(Table 3). In these substrates, the reduction did not proceed below
ꢀ40 °C in THF because of low solubility of 4a,b. The best result for
the hydrocoupling of 4a was obtained by the reduction at ꢀ30 °C in
THF; hydrodimer 5a was formed in 91% yield and R,R:R,S:S,S =
94:5:1 ratio (run 2). However, the stereoselectivities in the reduc-
tive coupling of 4b (runs 4–6) were not so high in comparison to
those of 4a (runs 1–3); the reaction of 4b at ꢀ30 °C in THF gave
hydrodimer 5b in 82% yield and R,R:R,S:S,S = 80:18:2 ratio (run
5). The major dimers of 5a and 5b were isolated by recrystalliza-
tion and confirmed to be R,R by comparison with authentic sam-
ples prepared from (R,R)-2a and (R,R)-2b by usual peptide chain
elongation.
This reaction is conveniently applicable to the gram-scale
synthesis of chiral R,R-dimers. In fact, the reaction of 10 g
(28.9 mmol) of 1b with Zn–MsOH in THF at ꢀ50 °C and subsequent
recrystallization of a crude product gave 8.5 g of pure (R,R)-2b as a
white solid. Similarly, 7.2 g of (R,R)-5a was obtained by the reac-
tion of 10 g (24.0 mmol) of 4a in THF at ꢀ30 °C and following
recrystallization.
Figure 1. X-ray crystal structure (ortep) of (R,R)-2a.

7076
N. Kise et al. / Tetrahedron Letters 49 (2008) 7074–7077
Table 2
Reductive coupling of 1b,c to 2b,ca
R
R
R
R
Ph
Ph
HN
CONH
CONH
CO2Me
CO2Me
Ph
Ph
NH
NH
Zn-MsOH
N
CONH
CO2Me
CONH
CO2Me
+
R
R
R
R
1b (R = sec-Bu)
1c (R = i-Bu)
3b
3c
2b
2c
Run
R
Solvent
Temp (°C)
Time (h)
% Yieldb of 2
R,R:R,S:S,Sc in 2
% Yieldb of 3
1
2
3
4
5
6
sec-Bu
sec-Bu
sec-Bu
i-Bu
i-Bu
i-Bu
THF
THF
DMF
THF
THF
DMF
ꢀ30
ꢀ50
ꢀ50
ꢀ30
ꢀ50
ꢀ50
24
48
24
24
48
24
2b 83
2b 94
2b 87
2c 54
2c 67
2c 76
95:4:1
99:1:0
70:19:11
52:20:28
62:11:27
19:35:46
3b 5
3b 0
3b 0
3c 19
3c 0
3c 0
a
b
c
Reaction was carried out using 1.0 mmol of 1, 5.0 mmol of MsOH, 5.0 mmol of zinc powder, and 10 mL of solvent.
Isolated yields.
Determined by 1H NMR spectra (Ref. 6).
Figure 2. X-ray crystal structure (ortep) of (R,R)-2b.
In summary, the reduction of the aromatic imines prepared
is important to keep the reaction temperature at ꢀ50 °C during
the reaction. The reduction of the imine derived from tripeptide
methyl ester of (S)-valine with Zn–MsOH in THF at ꢀ30 °C also
effectively gave the corresponding R,R-dimer in high stereoselec-
tivity (94%). This reaction provides a practical method for the
from dipeptide methyl esters of (S)-valine and (S)-isoleucine with
Zn–MsOH in THF at ꢀ50 °C efficiently gave the corresponding
R,R-dimers in high stereoselectivities: 95% and 99%, respectively.
To obtain the high yield and stereoselectivity of the R,R-dimers, it
Table 3
Reductive coupling of 4 to 5a
R
R
R
Ph
Ph
CONH
CONH
CO2Me
Ph
NH
NH
Zn-MsOH
2
N
CONH
CO2Me
HN
CONH
CO2Me
+
2
2
Ph
CO2Me
R
R
R
R
2
R
4a (R = i-Pr)
4b (R = sec-Bu)
6a
6b
5a
5b
Run
R
Solvent
Temp (°C)
Time (h)
% Yieldb of 5
R,R:R,S:S,Sc in 5
% Yieldb of 6
1
2
3
4
5
6
i-Pr
i-Pr
i-Pr
sec-Bu
sec-Bu
sec-Bu
THF
THF
DMF
THF
THF
DMF
ꢀ20
ꢀ30
0
ꢀ20
ꢀ30
0
48
72
24
48
72
24
5a 84
5a 91
5a 75
5b 75
5b 82
5b 61
87:9:4
94:5:1
21:48:31
76:15:9
80:18:2
16:48:36
6a 5
6a 0
6a 0
6b 5
6b 0
6b 0
a
b
c
Reaction was carried out using 1.0 mmol of 4, 5.0 mmol of MsOH, 5.0 mmol of zinc powder, and 10 mL of solvent.
Isolated yields.
Determined by 1H NMR spectra (Ref. 6).

N. Kise et al. / Tetrahedron Letters 49 (2008) 7074–7077
7077
NMR (CDCl3) d 11.2 (d), 11.3 (d), 15.6 (d), 15.7 (d), 24.9 (t), 25.2 (t), 37.68 (d),
37.72 (d), 52.1 (q), 55.7 (d), 65.0 (d), 67.0 (d), 126.6 (d), 127.7 (d), 141.1 (s),
174.1 (s), 174.3 (s).
synthesis of C2-symmetric 1,2-diamines promising as new chiral
ligands and catalysts from -amino acids. The investigation of
the scope and limitation for this reaction is in progress.
a
(R,R)-2c: Colorless paste. ½a D22
ꢁ
ꢀ38.7 (c 0.98, CHCl3). 1H NMR (CDCl3) d 0.29 (d,
3H, J = 6.4 Hz), 0.77 (d, 3H, J = 6.4 Hz), 0.97 (d, 3H, J = 6.4 Hz), 1.30–1.79 (m, 6H),
2.77–2.85 (m, 1H), 3.08 (dd, 1H, J = 2.7, 10.9 Hz), 3.72–3.76 (m, 1H), 3.83 (s, 3H),
4.87–4.93 (m, 1H), 7.01–7.14 (m, 5H), 9.07 (d, 1H, J = 10.1 Hz). 13C NMR (CDCl3)
d 19.8 (q), 21.3 (q), 23.0 (q), 23.4 (q), 24.2 (d), 25.0 (d), 41.7 (t), 42.6 (t), 49.6 (d),
52.3 (q), 58.2 (d), 66.6 (d), 126.9 (d), 128.0 (d), 140.6 (s), 175.2 (s), 175.7 (s).
References and notes
1. For a review: Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37,
2580–2627.
2. (a) Machrouhi, F.; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315–1318; (b)
Annunziata, R.; Benaglia, B.; Caporale, M.; Raimondi, L. Tetrahedron: Asymmetry
2002, 13, 2727–2734; (c) Liu, X.; Liu, Y.; Zhang, Y. Tetrahedron Lett. 2002, 43,
6787–6789.
3. (a) Yanada, R.; Okaniwa, M.; Kaieda, A.; Ibuka, T.; Takemoto, Y. J. Org. Chem.
2001, 66, 1283–1286; (b) Sergeeva, E. V.; Rozenberg, V. I.; Antonov, D. Y.;
Vorontsov, E. V.; Starikova, Z. A.; Hopf, H. Tetrahedron: Asymmetry 2002, 13,
1121–1123; (c) Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6,
4747–4750.
(R,R)-5a: White solid. Mp >300 °C (recryst. from MeOH). ½a D21
ꢁ
ꢀ110 (c 1.02,
CHCl3). IR (KBr) 3293, 1749, 1647, 1559, 1522, 1508, 773, 700 cmꢀ1
.
1H NMR
(CDCl3) d 0.88 (d, 3H, J = 6.9 Hz), 0.94 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J = 6.8 Hz),
1.03 (d, 3H, J = 7.0 Hz), 1.05 (d, 3H, J = 6.6 Hz), 1.06 (d, 3H, J = 6.7 Hz), 1.92–2.02
(m, 1H), 2.13–2.23 (m, 1H), 2.25–2.35 (m, 1H), 2.74 (d, 1H, J = 4.9 Hz), 3.30–3.40
(m, 1H), 3.76 (s, 3H), 4.41 (dd, 1H, J = 8.7, 9.8 Hz), 4.72 (dd, 1H, J = 4.6, 8.7 Hz),
6.66 (d, 1H, J = 8.70 Hz), 6.77–7.08 (m, 5H), 8.70 (d, 1H, J = 9.8 Hz). 13C NMR
(CDCl3) d 17.7 (q), 18.5 (q), 18.7 (q), 19.3 (q), 19.4 (q), 19.6 (q), 31.08 (d), 31.10
(d), 31.2 (d), 51.9 (q), 57.5 (d), 58.3 (d), 66.3 (d), 67.3 (d), 126.5 (d), 127.6 (d),
141.4 (s), 172.0 (s), 172.7 (s), 174.8 (s).
4. Kise, N.; Oike, H.; Okazaki, E.; Yoshimoto, M.; Shono, T. J. Org. Chem. 1995, 60,
3980–3992.
(R,R)-5b: White solid. Mp 294–296 °C (recryst. from hexanes–ethyl acetate,
2:1). ½a 2D1
ꢁ
ꢀ84.0 (c 0.86, CHCl3). IR (KBr) 3293, 1749, 1647, 1518, 773, 700 cmꢀ1
.
1H NMR (CDCl3) d 0.71 (t, 6H, J = 7.6 Hz), 0.84 (d, 6H, J = 7.1 Hz), 0.93 (t, 6H,
J = 7.5 Hz), 0.96 (t, 6H, J = 7.6 Hz), 1.01 (d, 6H, J = 6.8 Hz), 1.03 (d, 6H, J = 6.9 Hz),
1.17–1.35 (m, 6H), 1.44–1.56 (m, 4H), 1.62–1.72 (m, 4H), 1.94–2.10 (m, 4H),
2.79 (d, 2H, J = 5.2 Hz), 3.27–3.38 (m, 2H), 3.78 (s, 6H), 4.33 (t, 2H, J = 9.5 Hz),
4.80 (dd, 2H, J = 4.5, 8.8 Hz), 6.52 (d, 2H, J = 8.8 Hz), 6.80–7.09 (m, 10H), 8.71 (d,
2H, J = 10.1 Hz). 13C NMR (CDCl3) d 10.8 (q), 11.3 (q), 11.7 (q), 15.4 (q), 15.9 (q),
16.0 (q), 25.0 (t), 25.20 (t), 25.24 (t), 36.9 (d), 37.7 (d), 37.8 (d), 51.8 (q), 56.6 (d),
57.4 (d), 65.4 (d), 67.3 (d), 126.5(d), 127.6 (d), 141.3 (s), 171.9 (s), 172.6 (s),
174.8 (s).
5. Typical procedure for the reduction of aromatic imines (Table 1, run 6) is as
follows. To a solution of 1a (318 mg, 1 mmol) in THF (10 mL) were added MsOH
(0.48 g, 5 mmol) and zinc powder (0.325 g, 5 mmol) at ꢀ50 °C under nitrogen,
and the suspension was stirred for 48 h at this temperature. After addition of
saturated aqueous NaHCO3 (20 mL), the solution was filtered off. The filtrate
was extracted with ethyl acetate three times, and the organic layer was dried
over MgSO4 and concentrated. The product 2a (288 mg, 90% yield) was isolated
by column chromatography on silica gel (hexanes–ethyl acetate). The
diastereomeric ratio of 2a was determined to be 95:3:2 by 1H NMR analysis.6
Of the three isomers of dimer 2a, the major isomer could be separated by
column chromatography on silica gel (hexanes–ethyl acetate) from the other
two isomers. The major isomer of 2a could be crystallized from hexanes–ethyl
acetate (2:1) and its stereoconfiguration was confirmed to be R,R by X-ray
crystallography.7 The 1H and 13C NMR spectra of the mixture of the other two
isomers showed that major isomer was C1-symmetric (R,S) and minor one was
C2-symmetric (S,S).
6. The chemical shifts (d) of methyne protons adjacent to the ester carbonyl group
in 2 and 5 were as follows: (R,R)-2a 4.89; (R,S)-2a 4.28 and 4.49; (S,S)-2a 4.36;
(R,R)-2b 4.88; (R,S)-2b 4.30 and 4.50; (S,S)-2b 4.38; (R,R)-2c 4.90; (R,S)-2c 4.27
and 4.42; (S,S)-2c 4.40; (R,R)-5a 4.72; (R,S)-5a 4.41 and 4.54; (S,S)-5a 4.47;
(R,R)-5b 4.80; (R,S)-5b 4.45 and 4.57; (S,S)-5b 4.51.
7. All measurements of X-ray crystallographic analysis were made on a Rigaku
RAXIS imaging plate area detector with graphite monochromated Mo
Ka
(R,R)-2a: White solid. Mp 156–157 °C (recryst. from hexanes–ethyl acetate,
radiation. The structure was solved by direct methods with SIR-97 and refined
with SHELXL-97. The non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were refined isotropically. All calculations were performed using the
YADOKARI-XG software package. Crystal data are as follows: CCDC 699821 and
699822 contain the supplementary crystallographic data. These data can be
obtained free of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
2:1). ½a 2D2
ꢁ
ꢀ77.4 (c 1.10, CHCl3). IR (KBr) 3345, 3320, 1730, 1678, 1507, 1497,
773, 702 cmꢀ1
.
1H NMR (CDCl3) d 0.82 (d, 6H, J = 6.9 Hz), 0.87 (d, 6H, J = 6.9 Hz),
0.95 (d, 6H, J = 6.9 Hz), 1.02 (d, 6H, J = 6.9 Hz), 1.89–2.00 (m, 2H), 2.28–2.38 (m,
2H), 2.76 (d, 2H, J = 5.0 Hz), 3.08–3.15 (m, 2H), 3.65 (br d, 2H, J = 7.8 Hz), 3.87 (s,
6H), 4.89 (dd, 2H, J = 4.6, 10.0 Hz), 6.89–7.10 (m, 10H), 8.59, (br d, 2H,
J = 10.0 Hz). 13C NMR (CDCl3) d 17.6 (q), 17.9 (q), 19.28 (q), 19.34 (q), 30.8 (d),
31.0 (d), 52.1 (q), 55.8 (d), 65.7 (d), 66.8 (d), 126.5 (d), 127.5 (d), 140.9 (s), 173.9
(s), 174.2 (s).
(R,R)-2a (CCDC 699821): C36H54N4O6, FW = 638.83, mp 156–157 °C, ortho-
rhombic, P212121 (no. 19), colorless block, a = 11.853(6) Å, b = 11.992(5) Å,
c = 26.363(10) Å, V = 3747(3) Å3, T = 223 K, Z = 4, Dcalcd = 1.132 g/cm3,
l =
(R,R)-2b: White solid. Mp 161–163 °C (recryst. from hexanes–ethyl acetate,
2:1). ½a 2D1
ꢁ
ꢀ62.6 (c 1.01, CHCl3). IR (KBr) 3345, 3331, 1724, 1678, 1506, 1495,
0.77 cmꢀ1, GOF = 0.93.
887, 856, 777, 768, 702, 658 cmꢀ1
.
1H NMR (CDCl3) d 0.70 (t, 6H, J = 7.3 Hz), 0.78
(R,R)-2b (CCDC 699822): C40H62N4O6, FW = 694.94, mp 161–163 °C, ortho-
(d, 6H, J = 7.3 Hz), 0.94 (d, 6H, J = 7.3 Hz), 0.99 (d, 6H, J = 6.4 Hz), 1.04–1.14 (m,
2H), 1.17–1.28 (m, 2H), 1.41–1.52 (m, 4H), 1.60–1.69 (m, 2H), 2.00–2.09 (m, 2H),
2.81 (d, 2H, J = 5.0 Hz), 3.03–3.11 (m, 2H), 3.63 (br d, 2H, J = 8.3 Hz), 3.86 (s, 6H),
4.88 (dd, 2H, J = 5.0, 10.5 Hz), 6.89–7.10 (m, 10H), 8.61 (d, 2H, J = 10.5 Hz). 13C
rhombic, P212121 (no. 19), colorless block, a = 12.1564(9) Å, b = 12.4135(12) Å,
c = 27.409(2) Å, V = 4136.1(6) Å3, T = 298 K, Z = 4, Dcalcd = 1.116 g/cm3,
l =
0.75 cmꢀ1, GOF = 1.015.