Synthesis of tripeptides containing α,α-diphenylglycine by the modified Ugi reaction

Article abstract of DOI:10.1055/s-1998-2103

The modified Ugi reaction has been developed to synthesize tripeptides containing α,α-diphenylglycine (Dph) together with bulky amino acids. By the use of diphenylmethanimine, N-benzyloxycarbonyl (Z) amino acids and isocyanides derived from amino acids, very crowded tripeptides such as Z- Aib-Dph-Aib-OMe, Z-Ac₆c-Dph-Aib-OMe, Z-Dph-Dph-Dph-OMe, etc. have been synthesized.

Full text of DOI:10.1055/s-1998-2103

SYNTHESIS
July 1998
991
Synthesis of Tripeptides Containing α,α-Diphenylglycine by the Modified Ugi Reaction
Takashi Yamada,* Yuichiro Omote, Yoshinori Yamanaka, Toshifumi Miyazawa, Shigeru Kuwata
Department of Chemistry, Faculty of Science, Konan University, 8-9-1 Okamoto, Higashinada-ku, Kobe 658-8501, Japan
Tel +81(78)4352503; Fax +81(78)4352539; E-mail: yamada@konan-u.ac.jp
Received 18 August 1997; 30 October 1997
Abstract: The modified Ugi reaction has been developed to syn-
thesize tripeptides containing α,α-diphenylglycine (Dph) together
that some peptides in which Dph combines with bulky
amino acids, such as Val, α-aminoisobutyric acid (Aib),
with bulky amino acids. By the use of diphenylmethanimine, N-
1-aminocyclopentanecarboxylic acid (Ac5c), 1-aminocy-
benzyloxycarbonyl (Z) amino acids and isocyanides derived from
amino acids, very crowded tripeptides such as Z-Aib-Dph-Aib-
OMe, Z-Ac6c-Dph-Aib-OMe, Z-Dph-Dph-Dph-OMe, etc. have
been synthesized.
clohexanecarboxylic acid (Ac6c), and Dph, were obtained
in moderate or lower yields.
Previously we revealed that using high pressure condi-
tions can effectively accelerate sluggish peptide-bond for-
mation on sterically crowded substrates.11 Hence, in this
study the above reactions were also performed at high
pressure, 0.9 GPa (9 kbar), using a stainless steel high
pressure apparatus4. However, the yields at high pressure
did not exceed those at atmospheric pressure (Table 1). In
these cases, high pressure conditions seem to scarcely af-
fect the yield.
Key words: α,α-diphenylglycine (Dph), α,α-disubstituted gly-
cines, diphenylmethanimine, Ugi reaction, tripeptides
Peptides containing α,α-disubstituted glycines (DSGs)
are of increasing interest in structure-activity studies of
drugs based on hormone analogs or enzyme inhibitors,
since DSGs restrict the conformational mobility of the
peptide backbone and enhance resistance to the enzymatic
degradation of peptides.1 The synthesis of peptides con-
taining DSGs, however, still provides challenging prob-
lems because of difficulties arising from steric hindrance
in the conventional synthesis of their peptides.1, 2 In order
to overcome these difficulties, we recently applied high
pressure conditions (9 kbar) to the Ugi reaction,3 particu-
larly to the modified Ugi reaction in which Schiff's bases
prepared from amine and ketone components were used,
and, thereby, we succeeded in synthesizing tripeptides
containing the α,α-diisopropylglycine (Dip) residue.4
α,α-Diphenylglycine (Dph), one of the DSGs, is of inter-
est as a very crowded, aromatic amino acid; α,α-diben-
zylglycine (Dbz) is also of interest.5, 7 Although Dph is
commercially available, the only Dph-containing peptide
so far reported is a Dph-Gly segment.6, 7 Recently we suc-
cessfully synthesized a number of dipeptides in which
Dph was coupled with various amino acids (AA), by
screening a variety of coupling methods.8 However, tri-
peptides, in the middle of which Dph is contained, such as
7, were found to be hardly obtained by these coupling
methods, particularly in the cases when the AAs are
bulky. On the other hand, removal of an N-benzyl group
by catalytic hydrogenolysis from the tripeptide containing
an N-benzyl-Dph residue obtained in the previous study4
gave a sluggish reaction and complicated by-products.
Next, we prepared other isocyanides (4b, 4c and 4d) from
N-formyl-Aib methyl ester (2b), N-formyl-Ac6c methyl
ester (2c), and N-formyl-Dph methyl ester (2d), in order
to synthesize DSG-containing peptides having much
more crowded side chains. The isocyanide 4b reacted fair-
ly well with the N-Z derivative 5 of DSG, such as Aib,
Ac5c and Dph, and 6, affording some tripeptides 7i–m
(AA3 = Aib), in which crowded DSGs are linked succes-
sively (Table 2). When using the isocyanide 4c derived
from Ac6c, the desired tripeptides 7n–r could also be ob-
tained, though mostly in yields lower than those of the
corresponding Aib-containing peptides (Table 2). Inter-
estingly, the yield of 7p was rather better under high pres-
sure conditions than under atmospheric conditions.
In the present paper, we report the synthesis of various
tripeptides containing Dph by employing the modified
Ugi reaction in which diphenylmethanimine9 (6) was well
used as a Schiff's base without an N-benzyl group.
The isocyanide 4d was prepared from Dph through 3 steps
in the good, overall yield of 48%. Further, another Dph-
equivalent isocyanide derivative 11 was also obtained
through the product 10 in the modified Ugi reaction using
6. The modified Ugi reactions using 4d or 11 were carried
out under high pressure, affording the desired tripeptides
7s–u and 14 (AA3 = Dph). This is the first synthesis of ho-
mooligomers of Dph (7v and 14). The tripeptide 14 was
The modified Ugi reactions for synthesis of Dph-peptides
were firstly carried out by using an N-(benzyloxycarbon-
yl)amino acid 5, diphenylmethanimine (6), and methyl
isocyanoacetate10 (4a) in dichloromethane or methanol at
room temperature for 7–14 days. A variety of tripeptides
7 which contain various amino acids (AA1) at the N-ter-
minal of Dph could be obtained (Table 1). It is noteworthy

SYNTHESIS
Papers
Table 1. Synthesis of Z-AA1-Dph-Gly-OMe 7a–h
992
Prod- AA1 AA3 Yield
mp (°C)
[α]D25
Molecular
Formulad
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
uct
(%)a
(Solvent)c (c = 1,
(Solvent)b
MeOH)
7a
Ala Gly 51
44e2
144–145
(EtOAc)
–30.4
C28H29N3O6 1.35 (d, 3H, J = 7.2, Ala-βCH3), 18.5 (Ala-βC), 41.9 (Gly-αC),
(503.6)
3.70 (s, 3H, OCH3), 4.01 (d, 2H, 51.1 (Ala-αC), 52.4 (OCH3),
J = 5.4, Gly-CH2), 4.29 (br, 1H, 66.9 (Z-CH2), 70.5 (Dph-αC),
Ala-αCH), 5.09 (d, 1H, J = 128.0, 128.07, 128.13, 128.2,
12.3, Z-CH2), 5.10 (d, 1H, J = 128.3, 128.4, 128.5, 136.2,
12.3, Z-CH2), 5.30 (br, 1H, Ala- 139.1, 139.3 (arom), 155.9 (Z-
NH), 6.44 (br, 1H, Gly-NH), C=O), 169.6, 170.6, 171.7
7.3Ð7.4 (m, 15H, arom), 7.82 (s, (C=O)
1H, Dph-NH)
7b
7c
7d
Val Gly 53
foamy
solid
–30.0
C30H33N3O6 0.76 (d, 3H, J = 6.9, Val-γCH3), 17.4, 19.1 (Val-γC), 31.1 (Val-
36e1
(531.6)
0.84 (d, 3H, J = 6.9, Val-γCH3), βC), 41.9 (Gly-αC), 52.4
2.07 (o, 1H, J = 6.9, Val-βCH), (OCH3), 60.5 (Val-αC), 67.0 (Z-
3.70 (s, 3H, OCH3), 3.99 (dd, CH2), 70.5 (Dph-αC), 128.0,
1H, J = 18.3, 5.4, Gly-CH2), 128.08, 128.12, 128.17, 128.21,
4.01 (dd, 1H, J = 18.3, 5.4, Gly- 128.3, 128.5, 128.7, 136.3,
CH2), 4.08 (br, 1H, Val-αCH), 138.9, 139.1 (arom), 156.5 (Z-
5.12 (s, 2H, Z-CH2), 5.26 (br, C=O), 169.5 (C=O × 2), 171.8
1H, Val-NH), 6.39 (br, 1H, Gly- (C=O)
(EtOAc/
hexane)1
NH), 7.3Ð7.42 (m, 15H, arom),
7.81 (s, 1H, Dph-NH)
Leu Gly 44
oil
–21.8
C31H35N3O6 0.88 (d, 6H, J = 6.0, Leu-δCH3 21.9, 22.9 (Leu-δC), 24.6 (Leu-
(545.6) × 2), 1.44 (m, 1H, Leu-γCH), γC), 41.2 (Leu-βC), 41.9 (Gly-
43e2
(EtOAc/
1.57 (m, 2H, Leu-βCH2), 3.70 αC), 52.3 (OCH3), 54.1 (Leu-
(s, 3H, OCH3), 4.01 (d, 2H, J = αC), 67.0 (Z-CH2), 70.5 (Dph-
5.4, Gly-CH2), 4.24 (br, 1H, αC), 128.0, 128.09, 128.14,
Leu-αCH), 5.09 (d, 1H, J = 128.20, 128.35, 128.41, 128.44,
12.6, Z-CH2), 5.10 (br, 1H, Leu- 128.5, 136.2, 139.1, 139.2
NH), 5.13 (d, 1H, J = 12.6, Z- (arom), 156.2 (Z-C=O), 169.6,
CH2), 6.47 (br, 1H, Gly-NH), 170.6, 171.7 (C=O)
7.3Ð7.4 (m, 15H, arom), 7.84 (s,
hexane)1
1H, Leu-NH)
Phe Gly 55
oil
–12.5
C34H33N3O6 2.97 (dd, 1H, J = 13.8, 7.3, Phe- 37.9 (Phe-βC), 41.8 (Gly-αC),
43e3
(579.7)
βCH2), 3.04 (dd, 1H, J = 13.8, 52.3 (OCH3), 56.5 (Phe-αC),
7.3, Phe-βCH2), 3.69 (s, 3H, 67.0 (Z-CH2), 70.5 (Dph-αC),
OCH3), 3.97 (d, 2H, J = 5.4, 126.9, 128.0, 128.1, 128.3,
Gly-CH2), 4.50 (br, 1H, Phe- 128.4, 128.48, 128.51, 128.7,
αCH), 5.08 (d, 1H, J = 13.2, Z- 129.4, 136.0, 138.9, 139.1
CH2), 5.10 (d, 1H, J = 13.2, Z- (arom), 156.0 (Z-C=O), 169.0,
CH2), 5.25 (br, 1H, Phe-NH), 169.5, 171.5 (C=O)
6.39 (br, 1H, Gly-NH), 7.00 (br,
(EtOAc/
hexane)1
2H, Phe-orthoH × 2), 7.17 (m,
3H, Phe-metaH × 2, paraH),
7.31 (s, 15H, arom), 7.70 (s, 1H,
Dph-NH)
7e
7f
Aib Gly 46
46e2
176–177
(EtOAc)
C29H31N3O6 1.47 (s, 6H, Aib-βCH3 × 2), 25.1 (Aib-βC × 2), 41.8 (Gly-
(517.6)
3.68 (s, 3H, OCH3), 4.01 (d, 2H, αC), 52.2 (OCH3), 57.3 (Aib-
J = 5.4, Gly-CH2), 5.09 (s, 2H, αC), 66.8 (Z-CH2), 70.1 (Dph-
Z-CH2), 5.43 (s, 1H, Aib-NH), αC), 127.9, 128.1, 128.15,
6.82 (br, 1H, Gly-NH), 7.3–7.4 128.2, 128.3, 128.5, 136.2,
(m, 15H, arom), 7.87 (s, 1H, 139.9 (arom), 155.2 (Z-C=O),
Dph-NH)
169.7, 171.6, 172.3 (C=O)
Ac3c Gly 10
foamy
C29H29N3O6 0.97 (dd, 2H, J = 7.5, 4.8, Ac3c- 17.4 (Ac3c-βC × 2), 36.4 (Ac3c-
(EtOAc/ solid
(515.6)
βCH × 2), 1.48 (dd, 2H, J = 7.5, αC), 41.9 (Gly-αC), 52.3
4.8, Ac3c-βCH × 2), 3.69 (s, 3H, (OCH3), 67.3 (Z-CH2), 70.5
OCH3), 3.99 (d, 2H, J = 5.4, Gly- (Dph-αC), 128.0, 128.2, 128.3,
CH2), 5.15 (s, 2H, Z-CH2), 5.61 128.4, 128.6, 136.0, 139.7
(br, 1H, Ac3c-NH), 6.69 (br, 1H, (arom), 156.4 (Z-C=O), 169.7,
Gly-NH), 7.25Ð7.4 (m, 15H, 170.3, 172.0 (C=O)
arom), 8.31 (s, 1H, Dph-NH)
hexane)2

SYNTHESIS
July 1998
993
Table 1. (continued)
Prod- AA1 AA3 Yield
mp (°C)
[α]D25
Molecular
Formulad
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
uct
(%)a
(Solvent)c (c = 1,
(Solvent)b
MeOH)
7g
Ac5c Gly 13
10e1
164–166
(EtOAc)
C31H33N3O6 1.70 (br, 4H, Ac5c-γCH2 × 2), 24.2, 24.6 (Ac5c-γC), 36.8
(543.6)
1.83 (br, 2H, Ac5c-βCH × 2), (Ac5c-βC × 2), 41.8 (Gly-αC),
2.21 (m, 2H, Ac5c-βCH × 2), 52.2 (OCH3), 67.1 (Z-CH2),
3.68 (s, 3H, OCH3), 4.02 (d, 2H, 67.6 (Ac5c-αC), 70.2 (Dph-αC),
J = 5.1, Gly-CH2), 5.11 (s, 2H, 127.8, 128.0, 128.2, 128.3,
Z-CH2), 5.28 (s, 1H, Ac5c-NH), 128.6, 136.1, 140.2 (arom),
6.99 (br, 1H, Gly-NH), 7.3Ð7.4 155.6 (Z-C=O), 169.8, 171.6,
(m, 15H, arom), 7.95 (s, 1H, 172.2 (C=O)
Dph-NH)
7h
Dph Gly 58
foamy
solid
C39H35N3O6 3.65 (s, 3H, OCH3), 3.88 (d, 2H, 41.8 (Gly-αC), 52.3 (OCH3),
38e1
(641.7)
J = 5.1, Gly-CH2), 4.96 (s, 2H, 66.4 (Z-CH2), 69.6 (Dph-αC),
Z-CH2), 6.27 (br, 1H, Gly-NH), 70.3 (Dph-αC), 127.7, 127.8,
6.87 (s, 1H, Dph1-NH), 7.2–7.3 128.0, 128.1, 128.2, 128.3,
(m, 25H, arom), 7.86 (s, 1H, 128.4, 128.5, 136.5, 138.1,
(EtOAc/
hexane)2
Dph2-NH)
139.5 (arom), 154.1 (Z-C=O),
169.0, 169.4, 171.2 (C=O)
a Isolated yield by chromatography or recrystallization.
d Satisfactory microanalyses obtained: C ± 0.25, H ± 0.21, N ± 0.29.
e Yield in the high pressure reaction at 0.9 GPa (9 kbar) for 14 d (e1),
7d (e2) or 10d (e3).
b For open column chromatography (1) or flash chromatography (2).
c For recrystallization.
Table 2. Synthesis of Z-AA1-Dph-AA3-OMe 7i–r
Prod- AA1
uct
AA3
Yield
mp (°C)
Molecular
Formulad
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
(%)a
(Solvent)c
(Solvent)b
7i
Gly
Aib
16
35
30
141–142
(EtOAc/
hexane)
C29H31N3O6
(517.6)
1.45 (s, 6H, Aib-βCH3 × 2), 24.1 (Aib-βC × 2), 44.9 (Gly-
3.68 (s, 3H, OCH3), 3.88 (d, αC), 52.7 (OCH3), 57.2 (Aib-
2H, J = 5.4, Gly-CH2), 5.11 (s, αC), 67.0 (Z-CH2), 70.2 (Dph-
2H, Z-CH2), 5.41 (br, 1H, Gly- αC), 128.0, 128.08, 128.14,
NH), 6.42 (s, 1H, Aib-NH), 128.3, 128.4, 128.47, 128.53,
7.28–7.46 (m, 15H, arom), 7.90 136.2, 139.3 (arom), 156.4 (Z-
(s, 1H, Dph-NH)
C=O), 167.0, 170.5, 174.3 (C=O)
7j
7k
Aib
Aib
Aib
172–173
(EtOAc/
hexane)
C31H35N3O6
(545.6)
1.47 (s, 6H, Aib-βCH3 × 2), 24.3, 25.1 (Aib-βC × 4), 52.4
1.49 (s, 6H, Aib-βCH3 × 2), (OCH3), 56.9 (Aib-αC), 57.2
3.65 (s, 3H, OCH3), 5.08 (s, 2H, (Aib-αC), 66.7 (Z-CH2), 69.8
Z-CH2), 5.42 (s, 1H, Aib1-NH), (Dph-αC), 127.8, 128.0, 128.1,
6.85 (br, 1H, Aib3-NH), 7.2Ð7.4 128.2, 128.5, 136.2, 140.1
(m, 15H, arom), 7.87 (s, 1H, (arom), 155.1 (Z-C=O), 170.3,
Dph-NH)
172.2, 174.5 (C=O)
Ac3c
183–184
(EtOAc/
hexane)
C31H33N3O6
(543.6)
0.99 (dd, 2H, J = 7.5, 1.8, Ac3c- 17.4 (Ac3c-βC × 2), 24.3 (Aib-
βCH × 2), 1.45 (s, 6H, Aib- βC × 2), 36.4 (Ac3c-αC), 52.5
βCH3 × 2), 1.49 (dd, 2H, J =7.5, (OCH3), 57.0 (Aib-αC), 67.3 (Z-
4.5, Ac3c-βCH × 2), 3.68 (s, CH2), 70.3 (Dph-αC), 127.8,
3H, OCH3), 5.15 (s, 2H, Z- 128.2, 128.3, 128.6, 135.9, 139.9
CH2), 5.45 (s, 1H, Ac3c-NH), (arom), 156.3 (Z-C=O), 170.0,
6.67 (br, 1H, Aib-NH), 7.3Ð7.4 170.7, 174.4 (C=O)
(m, 15H, arom), 8.32 (s, 1H,
Dph-NH)
7l
Ac5c
Aib
56
174–175
(EtOAc)
C33H37N3 O6
(571.7)
1.48 (s, 6H, Aib-βCH3 × 2), 24.3, 24.4 (Aib-βC × 2, Ac5c-
1.71 (br, 4H, Ac5c-γCH2 × 2), γC × 2), 37.0 (Ac5c-βC × 2),
1.84 (br, 2H, Ac5c-βCH × 2), 52.3 (OCH3), 56.8, 67.6 (Aib-αC,
2.22 (br, 2H, Ac5c-βCH × 2), Ac5c-αC), 67.0 (Z-CH2), 70.0
3.64 (s, 3H, OCH3), 5.11 (s, 2H, (Dph-αC), 127.7, 128.1, 128.2,
Z-CH2), 5.25 (s, 1H, Ac5c-NH), 128.6, 136.0, 140.5 (arom), 155.5
7.00 (br, 1H, Aib-NH), 7.2Ð7.4 (Z-C=O), 170.2, 172.0, 174.5
(m, 15H, arom), 7.90 (s, 1H, (C=O)
Dph-NH)

SYNTHESIS
Papers
994
Prod- AA1
uct
AA3
Yield
mp (°C)
Molecular
Formulad
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
(%)a
(Solvent)c
(Solvent)b
7m
Dph
Aib
29
foamy
solid
C41H39N3O6
(669.8)
1.36 (s, 6H, Aib-CH3 × 2), 3.58 24.1 (Aib-βC × 2), 52.5 (OCH3),
(s, 3H, OCH3), 4.95 (s, 2H, Z- 56.9 (Aib-αC), 66.4 (Z-CH2),
CH2), 6.40 (br, 1H, Aib-NH), 69.6 (Dph-αC), 70.2 (Dph-αC),
6.87 (s, 1H, Dph1-NH), 7.1–7.4 127.6, 127.7, 127.9, 128.0, 128.1,
(m, 25H, arom), 7.81 (s, 1H, 128.15, 128.2, 128.3, 128.6,
(EtOAc/
hexane)2
Dph2-NH)
128.8, 138.8, 139.6 (arom), 154.1
(Z-C=O), 169.0, 169.9, 174.3
(C=O)
7n
Gly
Ac6c 18
(EtOAc/
hexane)1
foamy
solid
C32H35N3O6
(557.7)
0.60Ð0.80 (m, 2H, Ac6c-γCH2), 20.9 (Ac6c-γC × 2), 24.7 (Ac6c-
1.02Ð1.18 (m, 1H, Ac6c-δCH2), δC), 31.8 (Ac6c-βC × 2), 44.9
1.31Ð1.50 (m, 3H, Ac6c-γCH2, (Gly-αC), 52.4 (OCH3), 59.3
δCH2), 1.61Ð1.74 (m, 2H, Ac6c- (Ac6c-αC), 67.0 (Z-CH2), 70.2
βCH2), 1.85Ð1.96 (m, 2H, (Dph-αC), 127.7, 127.9, 128.0,
βCH2), 3.72 (s, 3H, OCH3), 3.86 128.03, 128.06, 128.12, 128.2,
(d, J = 5.4, 1H, Gly-αCH2), 5.10 128.3, 128.4, 136.2, 139.4 (Z-,
(s, 2H, Z-CH2), 5.39 (br, 1H, Dph-arom), 156.4 (Z-C=O),
Gly-NH), 5.93 (s, 1H, Ac6c- 166.8, 170.4, 173.8 (C=O)
NH), 7.28Ð7.54 (m, 15H, arom),
7.95 (s, 1H, Dph-NH)
7o
Aib
Ac6c 14
175–176
(EtOAc)
C34H39N3O6
(585.7)
0.84Ð1.05 (m, 2H, Ac6c- 21.0 (Ac6c-γC × 2), 24.9 (Ac6c-
γCH2), 1.05Ð1.22 (m, 1H, δC), 25.1 (Aib-βC × 2), 31.9
Ac6c-δCH2), 1.38Ð1.56 (m, (Ac6c-βC × 2), 52.1 (OCH3),
9H, Ac6c-γ, δCH2, Aib-βCH3 57.2 (Aib-αC), 59.3 (Ac6c-αC),
× 2), 1.62Ð1.78 (m, 2H, Ac6c- 66.6 (Z-CH2), 70.1 (Dph-αC),
βCH2), 1.92Ð2.05 (m, 2H, Ac6c- 127.9, 128.0, 128.1, 128.3, 128.5,
βCH2), 3.67 (s, 3H, OCH3), 5.08 136.2, 140.0 (Z-, Dph-arom),
(s, 2H, Z-CH2), 5.43 (br, 1H, 154.9 (Z-C=O), 170.5, 172.2,
Aib-NH), 6.40 (br, 1H, Ac6c- 174.0 (C=O)
NH), 7.27Ð7.52 (m, 15H, arom),
8.04 (s, 1H, Dph-NH)
7p
Ac3c
Ac6c 39
50e
188–190
(EtOAc)
C34H37N3O6
(583.7)
0.79Ð0.95 (m, 2H, Ac6c- 17.5 (Ac3c-βC × 2), 21.0 (Ac6c-
γCH2), 0.95Ð1.04 (m, 2H, γC × 2), 24.8 (Ac6c-δC), 31.9
Ac3c-βCH2), 1.04Ð1.21 (m, 1H, (Ac6c-βC × 2), 36.4 (Ac3c-αC),
Ac6c-δCH2), 1.36Ð1.53 (m, 5H, 52.1 (OCH3), 59.2 (Ac6c-δC),
Ac3c-βCH2, Ac6c-γCH2, δCH2), 67.3 (Z-CH2), 70.4 (Dph-αC),
1.62Ð1.75 (m, 2H, Ac6c-βCH 127.89, 127.92, 127.95, 128.4,
× 2), 1.89Ð2.01 (m, 2H, Ac6c- 128.53, 128.56, 128.6, 128.7,
βCH2 × 2), 3.70 (s, 3H, OCH3), 135.9, 140.0 (arom), 156.3 (Z-
5.14 (s, 2H, Z-CH2), 5.43 (br, C=O), 170.0, 170.7, 174.1 (C=O)
1H, Ac3c-NH), 6.40 (br, 1H,
Ac6c-NH), 7.25Ð7.53 (m, 15H,
arom), 8.37 (Dph-NH)
7q
Ac6c
Ac6c
8
148–149
(EtOAc/
hexane)
C37H43N3O6
(625.8)
1.00Ð1.65 (m, 12H, Ac6c-γCH2 21.23, 21.28 (Ac6c-γC × 4),
× 4, δCH2 × 2), 1.65Ð1.84 (m, 24.97, 25.01 (Ac6c-δC × 2),
4H, Ac6c-βCH × 4), 1.92Ð2.10 31.83, 31.95 (Ac6c-βC × 4), 51.9
(m, 4H, Ac6c-βCH × 4), 3.64 (OCH3), 59.2, 60.1 (Ac6c-αC
(s, 3H, OCH3), 5.07 (s, 1H, × 2), 67.0 (Z-CH2), 70.1 (Dph-
Ac6c1-NH), 5.12 (s, H, Z-CH2), αC), 127.7, 127.74, 127.8, 128.2,
6.78 (s, 1H, Ac6c3-NH), 7.26Ð 128.47, 128.50, 128.57, 128.6,
7.46 (m, 15H, arom), 8.03 (s, 136.1, 140.5 (arom), 155.0 (Z-
6e
1H, Dph-NH)
C=O), 170.4, 172.5, 174.2 (C=O)
7r
Dph
Ac6c 10
(EtOAc/
hexane)2
oil
C44H43N3O6
(709.8)
0.56Ð0.74 (m, 2H, Ac6c-γCH2), 20.9 (Ac6c-γC × 2), 24.7 (Ac6c-
1.02Ð1.10 (m, 1H, Ac6c-δCH2), δC), 31.7 (Ac6c-βC × 2), 52.2
1.32Ð1.44 (m, 2H, Ac6c-γCH2), (OCH3), 59.2 (Ac6c-αC), 66.3
1.54Ð1.68 (m, 3H, Ac6c-βCH2, (Z-CH2), 69.6, 70.3 (Dph-αC),
-δCH2), 1.74Ð1.84 (m, 2H, 127.0, 127.68, 127.72, 127.9,
Ac6c-βCH2), 3.61 (s, 3H, 128.00, 128.03, 128.1, 128.17,
OCH3), 4.93 (s, 2H, Z-CH2), 128.23, 128.3, 128.4, 128.66,
5.76 (s, 1H, Ac6c-NH), 6.94 (s, 128.72, 138.7, 139.4 (arom),
1H, Dph1-NH), 7.19Ð7.41 (m, 153.9 (Z-C=O), 169.0, 169.9,
25H, arom), 7.85 (s, 1H, Dph2- 173.7 (C=O)
NH)
a Isolated yield by chromatography or recrystallization.
c For recrystallization.
b For open column chromatography (1), flash chromatography (2)
or preparative TLC (3).
d Satisfactory microanalyses obtained: C ± 0.26, H ± 0.16, N ± 0.13.
e Yield in the high pressure reaction at 0.9 GPa (9 kbar) for 14 d.

SYNTHESIS
July 1998
995
was added dropwise over 15 min. After stirring for 30 min at the same
temperature and then for 1 h at r.t., the resulting Et3N·HCl was filtered
off and the filtrate was concentrated under reduced pressure. The res-
idue was dissolved in EtOAc (100 mL), and the solution was washed
with water, dried (MgSO4), and concentrated under reduced pressure.
The crude product was distilled in vacuo to give a colorless oil; yield:
6.57 g (64%); bp 48–51°C/2 Torr.
C6H9NO2 calcd
(127.14) found
C
56.68
56.50
H
7.13
7.09
N
11.02
10.73
IR (neat): ν = 1752 (C=O), 2144 cm–1 (-NC).
1H NMR (CDCl3): δ = 1.63 (s, 6H, βCH3 × 2), 3.79 (s, 3H, OCH3).
13C NMR (CDCl3): δ = 27.5 (βC × 2), 53.5 (OCH3), 59.5 (αC), 157.8
(NC), 170.0 (C=O).
Methyl 1-Isocyanocyclohexane-1-carboxylate (4c):
HCO-Ac6c (2c):
To a solution of Ac6c (14.32 g, 100 mmol) in 98% HCO2H (250 mL) was
added Ac2O (10 mL) drop by drop at 60°C under stirring. After stirring
for 3.5 h, to the mixture was added ice-water (10 mL) and the mixture
was concentrated under reduced pressure, affording white crystals. The
crude product was suspended in Et2O and filtered after vigorous stirring,
to give pure HCO-Dph; yield: 16.1 g (94%); mp 179–184°C (dec).
also obtained under atmospheric pressure, though in a
lower yield.
C8H13NO3 calcd
(171.2) found
C
56.13
56.08
H
7.65
7.89
N
8.18
8.20
In conclusion, we could clarify that the modified Ugi re-
action using the Schiff's base 6, as a key compound is very
useful and potent for synthesis of various crowded pep-
tides containing α,α-diphenylglycine (Dph) together with
very bulky α,α-disubstituted glycines.
1H NMR (DMSO-d6): δ (trans/cis) = 1.10–1.25 (m, 1H, Ac6c-δCH2),
1.29–1.54 (m, 5H, Ac6c-γCH2 × 2, -δCH2), 1.54–1.68 (m, 2H, Ac6c-
βCH2), 1.74–1.96 (m, 2H, Ac6c-βCH2), 7.90/8.11 (d, 1H, J = 1.5/11.7
Hz, HCO), 8.14 (br, 1H, Ac6c-NH) (trans/cis 6:1).
HCO-Ac6c-OMe (3c):
Mps were obtained on a Yamato melting point apparatus and are un-
corrected. 1H and 13C NMR spectra were recorded on a Varian UNI-
TY 300 spectrometer. IR spectra were obtained on a JASCO IR-810
spectrophotometer. Optical rotations were recorded on a JASCO DIP-
4 digital polarimeter. Most of reagents and solvents were purchased
from Wako Pure Chemical Industries, Ltd. and Tokyo Kasei Kogyo
Co. and used without further purification. Dph, Ac5c, Ac6c and tri-
phosgen were purchased from Aldrich Chemical Co. and diphosgen
from Hodogaya Chemical Co. Methyl isocyanoacetate,10 cyclohexyl
isocyanide,10, 12 and Ac3c13 were prepared by the literature method.
TLC analysis was performed on Merck precoated silica gel glass
plates (type G60-F254). Products were isolated by flash column chro-
matography on silica gel (Wakogel FC-40, Wako Pure Chemical In-
dustries, Ltd.) or by open column chromatography (Wakogel C-300,
Wako Pure Chemical Industries, Ltd.). Reactions at high pressure at
9 kbar (0.9 GPa) were carried out by using a stainless steel apparatus
for high pressure reaction made by Hikari Kogyo Ltd.
To a solution of 2c (5.00 g, 29 mmol) in Et2O (20 mL) and CHCl3
(5 mL) was added a solution of freshly prepared diazomethane in
Et2O. After 1 d, to the mixture was added a small amount of AcOH in
order to decompose excess diazomethane and the solution was con-
centrated under reduced pressure, to give a white solid. The crude
product was recrystallized (EtOAc/n-hexane), affording white crys-
tals; yield: 4.72 g (87%); mp 104–105°C.
C9H15NO3 calcd
(185.2) found
C
58.36
58.11
H
8.16
8.19
N
7.56
7.55
1H NMR (CDCl3): δ (trans/cis) = 1.24–1.40 (m, 1H, Ac6c-δCH2),
1.40–1.54 (m, 2H, Ac6c-γCH2), 1.54–1.61 (m, 1H, Ac6c-δCH2),
1.61–1.72 (m, 2H, Ac6c-γCH2), 1.80–1.92 (m, 2H, Ac6c-βCH2), 2.11
(m, 2H, Ac6c-βCH2), 3.72/3.76 (s, 3H, OCH3), 6.37 (br, 1H, Ac6c-
NH), 8.13/8.26 (d, 1H, J = 1.2/12.3 Hz, HCO), (trans/cis 4:1).
13C NMR (CDCl3): δ = 20.88, 21.23 (Ac6c-γC × 2), 24.75, 25.00
(Ac6c-δC), 32.28, 33.74 (Ac6c-βC × 2), 52.4, 52.8 (OCH3), 58.5, 59.1
(Ac6c-αC), 160.8, 164.3 (HCO), 174.0, 174.2 (Ac6c-C=O).
Methyl 2-Isocyano-2-methylpropionate (4b):
Conversion of HCO-Ac6c-OMe (3c) to 4c:
HCO-Aib-OMe (3b):
To a solution of HCO-Aib14 (2b) (13.1 g, 0.1 mol) in EtOH (300 mL)
was added a solution of freshly prepared diazomethane in Et2O. Then
to the mixture was added a small amount of AcOH in order to decom-
pose excess diazomethane and the solution was concentrated under
reduced pressure. The crude product was distilled in vacuo, affording
a colorless oil; yield: 14.2 g (98%); bp 91–93°C/0.6–0.7 Torr.
While a cold solution of 3c (4.83 g, 26 mmol) and Et3N (8.0 g, 79
mmol) in CH2Cl2 (84 mL) was stirred below –10°C using ice-salt
bath, a solution of triphosgen (2.55 g, 8.6 mmol) in CH2Cl2 (25 mL)
was added dropwise over 15 min. After stirring for 5 min at the same
temperature and then for 4 h at r.t., the resulting Et3N•HCl was fil-
tered off and the filtrate was concentrated under reduced pressure.
The residue was dissolved in EtOAc (50 mL), and the solution was
washed with water, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by distillation in vacuo to
give a colorless oil; yield: 3.03 g (69.5%), bp 45–50°C/0.4 Torr.
C6H11NO3 calcd
(145.16) found
1H NMR (CDCl3): δ (trans/cis) = 1.55/1.57 (s, 6H, Aib-CH3 × 2),
3.75/3.74 (s, 3H, OCH3), 6.38 (br, 1H, NH), 8.07/8.24 (d, 1H, J = 1.5/
12.3 Hz, HCO), (trans/cis 6:1).
C
49.65
49.58
H
7.64
7.71
N
9.65
9.60
C9H13NO2 calcd
(167.21) found
C
64.65
64.81
H
7.84
7.77
N
8.38
8.42
IR (neat): ν = 1750 (C=O), 2140 cm–1 (-NC).
Conversion of 3b to 4b:
1H NMR (CDCl3): δ = 1.15–1.35 (m, 1H, Ac6c-δCH2), 1.57–1.77 (m,
5H, Ac6c-γCH2 × 2, -δCH2), 1.77–1.90 (m, 2H, Ac6c-βCH2), 1.95–
2.05 (m, 2H, Ac6c-βCH2), 3.81 (s, 3H, OCH3).
While a cold solution of 3b (11.7 g, 0.08 mol) and Et3N (16.2 g, 0.16
mol) in CH2Cl2 (150 mL) was stirred below –10°C using an ice-salt
bath, a solution of diphosgen (4.5 mL, 0.04 mol) in CH2Cl2 (30 mL)

SYNTHESIS
Papers
Table 3. Synthesis of Z-AA1-Dph-Dph-OMe 7s–v and Z-Dph-Dph-Dph-NHcHex (14)
996
Prod- AA1
uct
AA3
Yield
mp (°C)
Molecular
Formulad
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
(%)a
(Solvent)c
(Solvent)b
7s
Aib
Dph
41e2
181–182
(EtOAc/
hexane)
C41H39N3O6
(669.8)
1.43 (s, 6H, Aib-CH3 × 2), 3.61 25.0 (Aib-βC × 2), 53.4 (OCH3),
(s, 3H, OCH3), 4.99 (s, 2H, Z- 57.1 (Aib-αC), 66.5 (Z-CH2),
CH2), 5.42 (br, 1H, Aib-NH), 69.7, 70.0 (Dph-αC), 127.66,
7.19–7.37 (m, 25H, arom), 7.63 127.72, 127.86, 127.9, 128.0,
(s, 1H, Dph3-NH), 8.07 (s, 1H, 128.1, 128.3, 136.3, 137.4,
Dph2-NH)
137.8, 139.4 (arom), 154.8 (Z-
C=O), 169.4, 171.8, 171.9
(C=O)
7t
Ac3c
Dph
Dph
10e1
188–190
(EtOAc/
hexane)
C41H37N3O6
(667.8)
0.92–0.99, 1.43–1.50 (m, 4H, 17.2 (Ac3c-βC × 2), 36.3, (Ac3c-
Ac3c-βCH2 × 2), 3.64 (s, 3H, αC), 53.5 (OCH3), 66.2 (Z-CH2),
OCH3), 5.06 (s, 2H, Z-CH2), 69.9, 70.0 (Dph-αC), 127.6,
5.29 (br, 1H, Ac3c-NH), 7.17Ð 127.8, 127.86, 127.89, 128.0,
7.37 (m, 25H, arom), 7.61 (s, 128.1, 128.15, 128.3, 128.4,
1H, Dph3-NH), 8.38 (s, 1H, 128.5, 135.8, 137.9, 139.5
Dph2-NH)
(arom), 156.1 (Z-C=O), 169.5,
171.8, 175.6 (C=O)
7u
Ac6c
9e1
(EtOAc/
hexane)
oil
C44H43N3O6
(709.8)
1.14Ð1.22 (m, 1H, Ac6c-δCH2), 21.1 (Ac6c-γC × 2), 25.0 (Ac6c-
1.22Ð1.38 (m, 2H, Ac6c- δC), 31.6 (Ac6c-βC × 2), 53.2
γCH2), 1.50Ð1.62 (m, 3H, (OCH3), 60.0 (Ac6C-αC), 66.9
Ac6c-γ, δCH2), 1.66Ð1.79 (m, (Z-CH2), 69.8, 69.9 (Dph-αC),
2H, Ac6c-βCH2), 1.88Ð2.00 (m, 127.77, 127.82, 127.9, 128.0,
2H, Ac6c-βCH2), 3.61 (s, 3H, 128.2, 128.27, 128.32, 128.4,
OCH3), 4.97 (s, 1H, Ac6c-NH), 128.8, 128.87, 128.9, 129.0,
5.01 (s, 2H, Z-CH2), 7.16Ð7.4 136.1, 138.2, 140.0 (arom),
(m, 25H, arom), 7.82 (br, 1H, 154.9 (Z-C=O), 169.5, 171.8,
Dph3-NH), 8.16 (s, 1H, Dph2- 172.3 (C=O)
NH)
7v
14
Dph
Dph
Dph
Dph
12e3
219–220
(EtOAc)
C51H43N3O6
(793.9)
3.56 (s, 3H, OCH3), 4.90 (s, 2H, 53.4 (OCH3), 66.2 (Z-CH2), 69.5,
Z-CH2), 6.92 (s, 1H, Dph1-NH), 69.8, 70.2 (Dph-αC), 127.76,
7.04–7.09, 7.22–7.30 (m, 36H, 127.83, 128.0, 128.1, 128.2,
arom and Dph-NH), 7.76 (s, 128.3, 128.4, 128.6, 137.6, 138.4,
1H, Dph-NH)
139.2 (arom), 153.8 (Z-C=O),
168.6, 168.9, 171.7 (C=O)
15
188–189
(EtOAc/
PE)
C56H52N4O5
(861.1)
0.8–1.6 (m, 10H, cHex-CH2 × 24.3 (cHex-3,6-C), 25.2 (cHex-
5), 3.56 (m, 1H, cHex-CH), 4-C), 32.1 (cHex-2,5-C), 48.9
4.90 (s, 2H, Z-CH2), 5.42 (br, (cHex-1-C), 66.2 (Z-CH2), 69.6,
1H, cHex-NH), 6.93 (s, 1H, 70.0, 70.2 (Dph-αC), 127.6,
Dph1-NH), 7.0–7.3 (m, 35H, 127.7, 127.8, 128.0, 128.15,
arom), 7.74 (s, 1H, Dph-NH), 128.2, 128.4, 128.5, 128.7,128.8,
43e1
7.83 (s, 1H, Dph-NH)
136.6, 138.5, 139.3 (arom),
153.8 (Z-C=O), 168.3, 169.0,
169.7 (C=O)
a Isolated yield by chromatography or recrystallization.
b preparative TLC.
c For recrystallization.
d Satisfactory microanalyses obtained: C ± 0.26, H ± 0.16, N ± 0.06.
e Yield in the high pressure reaction at 0.9 GPa (9 kbar) for 14 d (e1), 10 d (e2) or 17 d (e3).
13C NMR (CDCl3): δ = 20.8 (Ac6c-γC × 2), 24.3 (Ac6c-δC), 34.3
(Ac6c-βC × 2), 53.3 (OCH3), 64.3 (Ac6c-αC), 158.8 (NC), 170.0
(Ac6c-C=O).
ture was concentrated under reduced pressure, affording a white solid.
The crude product was suspended in 50% aq AcOH and filtered after
vigorous stirring, to give pure HCO-Dph ; yield: 4.41 g (86%); mp
200°C (dec).
C15H13NO3 calcd
(255.3) found
1H NMR (DMSO-d6): δ (trans/cis) = 7.2–7.4 (m, 10H, Dph-arom),
8.15/7.77 (d, 1H, J = 1.5/12.3 Hz, HCO), 9.25 (br, 1H, NH) (trans/cis
95:5).
C
70.58
70.55
H
5.13
5.12
N
5.49
5.53
Methyl 2-Isocyano-2,2-diphenylacetate (4d):
HCO-Dph (2d):
To a solution of Dph (4.54 g, 20 mmol) in 90% HCO2H (50 mL) was
added Ac2O (20 mL) drop by drop at 60°C under stirring. After stir-
ring for 3 h, to the mixture was added ice-water (5 mL) and the mix-

SYNTHESIS
July 1998
997
HCO-Dph-OMe (3d):
product was purified by flash chromatography using the eluents given
in Tables. Results are summarized in Tables 1–3.
To a solution of 2d (4.47 g, 17.5 mmol) in MeOH (100 mL) was add-
ed a solution of freshly prepared diazomethane in Et2O. Then to the
mixture was added a small amount of AcOH in order to decompose
excess diazomethane and the solution was concentrated under re-
duced pressure, to give a white solid. The crude product was recrys-
tallized (EtOAc), affording white crystals; yield: 4.52 g (85%); mp
146–147°C.
Z-Dph-Dph-Dph-NHcHex (12):
HCO-Dph-NHcHex (10):
A solution of HCO2H (1.52 g, 33 mmol), diphenylmethanimine (6)5
(9.80 g, 36 mmol), and cyclohexyl isocyanide (9) (3.28 g, 30 mmol)
in CH2Cl2 (30 mL) was stirred at r.t. for 12 d. A precipitate formed
during the reaction was filtered and the crude product (11.1 g) was re-
crystallized (EtOAc), affording white crystals (7.69 g). The filtrate
was concentrated under reduced pressure and the residue was also re-
crystallized (EtOAc), giving some white crystals (0.85 g). Total yield:
8.54 g (85%); mp 188–190°C.
C16H15NO3 calcd
(269.3) found
C
71.36
71.55
H
5.61
5.76
N
5.20
5.44
1H NMR (CDCl3): δ (trans/cis) = 3.77/3.81 (s, 3H, OCH3), 7.21 (d,
0.6H, J = 12 Hz (cis), NH), 7.25–7.5 (m, 10.4H, Dph-arom and NH),
8.25/7.78 (d, 1H, J = 1.5/12.3 Hz, HCO), (trans/cis 2:3).
1H NMR (DMSO-d6): δ (trans/cis) = 3.66/3.75 (s, 3H, OCH3), 7.2–
7.4 (m, 10H, arom), 8.14/7.77 (d, 1H, J = 1.5/12 Hz, NH), 9.25/8.70
(d, 1H, J = 1.5/12 Hz, HCO), (trans/cis 94:6).
C21H24N2O2calcd
(336.4) found
C
74.97
75.03
H
7.19
7.23
N
8.33
8.30
1H NMR (CDCl3): δ (trans/cis) = 0.9–1.16 (m, 3H, cHex-2,6-Hax and
4-Hax), 1.22–1.4 (m, 2H, cHex-3,5-Hax), 1.45–1.62 (m, 3H, cHex-3,5-
Heq and 4-Heq), 1.7–1.86 (m, 2H, cHex-2,6-Heq), 3.7–3.87 (m, 1H,
cHex-1-H), 5.46/5.31 (d, 1H, J = 8 Hz, -NH-cHex), 7.28–7.53 (m,
10H, arom), 7.79/7.53 (br/d, 1H, J = 12 Hz (cis), Dph-NH), 8.22/7.87
(d, 1H, J = 1.2/12 Hz, HCO), (trans/cis 3:2).
13C NMR (CDCl3): δ (trans/cis) = 53.6/53.7 (OCH3), 69.7/69.9 (Dph-
αC), 128.0/128.3, 128.4/128.7, 138.2/139.3 (Dph-arom), 159.2/164.8
(HCO), 172.3/ 171.9 (Dph-C=O).
Conversion of HCO-Dph-OMe (3d) to 4d:
While a cold solution of 3d (808 mg, 3 mmol) and Et3N (607 mg,
6 mmol) in CH2Cl2 (30 mL) was stirred below –10°C using an ice-
salt bath, a solution of diphosgen (0.16 mL, 1.5 mmol) in CH2Cl2 (5
mL) was added dropwise over 15 min. After stirring for 30 min at the
same temperature and then for 2 h at r.t., the resulting Et3N•HCl was
filtered off and the filtrate was concentrated under reduced pressure.
The residue was dissolved in EtOAc (20 mL), and the solution was
washed with water, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by flash column chromatog-
raphy (Wakogel FC-40, hexane/EtOAc 2:1) to give white solid,
which was recrystallized (EtOAc); yield: 657 mg (65%), mp 66–
68°C.
13C NMR (CDCl3): δ (trans/cis) = 24.3/24.4 (cHex-3,5-C), 25.2
(cHex-4-C), 32.2/32.4 (cHex-2,6-C), 49.1/49.2 (cHex-1-C), 70.0/
69.8 (Dph-αC), 128.1, 128.3, 128.4, 128.8, 129.0, 139.4/139.9
(arom), 159.2/164.4 (HCO), 170.4/169.9 (Dph-C=O).
Conversion of HCO-Dph-NHcHex (10) to N-Cyclohexyl-2-isocyano-
2,2-diphenylacetamide (11):
While a cold solution of 10 (2.02 g, 6 mmol) and Et3N (1.01 g, 12
mmol) in CH2Cl2 (40 mL) was stirred below –10°C using ice-salt
bath, a solution of triphosgen (600 mg, 3 mmol) in CH2Cl2 (15 mL)
was added dropwise over 15 min. After stirring for 30 min at the same
temperature and then for 3 h at r.t., the resulting Et3N•HCl was fil-
tered off and the filtrate was concentrated under reduced pressure.
The residue was dissolved in EtOAc (30 mL), and the solution was
washed with water, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by flash column chromatog-
raphy (Wakogel FC-40, hexane/EtOAc 5:1) to give white crystals;
yield: 782 mg (41%); mp 113–114°C.
C16H13NO2 calcd
(251.3) found
C
76.48
76.70
H
5.21
5.18
N
5.57
5.50
IR (KBr): ν = 1748 (C=O), 2138 cm–1 (-NC).
1H NMR (CDCl3): δ = 3.89 (s, 3H, OCH3), 7.41 (s, 10H, arom).
13C NMR (CDCl3): δ = 54.1 (OCH3), 69.0 (αC), 127.2, 128.7, 129.1,
137.0 (arom), 161.6 (NC), 167.8 (C=O).
C21H22N2O calcd
(318.4) found
C
79.21
79.11
H
6.96
7.04
N
8.80
8.87
IR (KBr): ν = 1665 (C=O), 2128 cm–1 (-NC).
Synthesis of Dph-Containing Peptides:
1H NMR (CDCl3): δ = 1.1–1.5 (m, 5H, cHex-2,6-, 3,5- and 4-Hax),
1.55–1.8 (m, 3H, cHex-3,5- and 4-Heq), 1.9–2.0 (m, 2H, cHex-2,6-
Heq), 3.82 (m, 1H, cHex-1-H), 6.55 (br, 1H, J = 8.4 Hz, NH), 7.3–7.45
(m, 10H, arom).
Z-AA1-Dph-AA3-OMe 7a–w; General Procedure:
Method A (Atmospheric Pressure):
A solution of N-Z-amino acid 5 (11 mmol), diphenylmethanimine
(6)5 (2.00 g, 11 mmol), and isocyanides 4a–d (10 mmol) in CH2Cl2
(10 mL) was stirred at r.t. for 14 d. In the case of the reaction of Z-
Ac5c, MeOH was used as a solvent because Z-Ac5c hardly dissolves
in CH2Cl2. The solvent was removed under vacuum, and the residue
was dissolved in EtOAc (400 mL). This solution was washed with
1 M HCl (2 × 50 mL), 1 M NaHCO3 (2 × 50 mL) and H2O (2 × 50
mL), and dried (Na2SO4). The solvent was evaporated and the crude
product was purified by flash chromatography or open column chro-
matography using the eluents given in Tables, and/or by recrystalliza-
tion. Results are summarized in Tables 1–3.
13C NMR (CDCl3): δ = 24.6, 25.3, 32.6, 49.5, 59.3 (cHex), 74.0 (Dph-
αC), 127.3, 128.5, 128.8, 137.8 (arom), 161.3 (NC), 164.9 (C=O).
Z-Dph-Dph-Dph-NHcHex (12):
Method A (Atmospheric Pressure):
A mixture of N-Z-Dph (5d) (400 mg, 1.1 mmol), 6 (270 mg,
1.5 mmol) and the isocyanide 11 (130 mg, 0.4 mmol) was dissolved
in CH2Cl2 (2 mL), and was stirred for 14 d at r.t. The mixture was con-
centrated under vacuum, and the residue was dissolved in EtOAc
(20 mL). The solution was washed with 1 M HCl (2 × 5 mL), 1 M
NaHCO3 (2 × 5 mL) and H2O (3 × 5 mL), and dried (Na2SO4). Re-
moval of solvent afforded a crude product, which was purified by pre-
parative TLC, affording white crystals. The crude crystals were
recrystallized (EtOAc/petroleum ether); yield: 50 mg (14.5%); mp
188–189°C.
Method B (High Pressure):
A mixture of N-Z-amino acid (4.4 mmol), 6 (797 mg, 4.4 mmol), and
isocyanides 4a, 4c, and 4d (4.04 mmol) was dissolved in CH2Cl2
(2.1–2.5 mL) in a Teflon capsule (4.5 mL capacity). The solution was
compressed at 0.9 GPa (9 kbar) by the use of a stainless steel appara-
tus for 7–14 d. The mixture was concentrated under vacuum, and the
residue was dissolved in EtOAc (200 mL). The solution was washed
with 1 M HCl (2 × 30 mL), 1 M NaHCO3 (2 × 30 mL) and H2O (2 ×
30 mL), and dried (Na2SO4). The solvent was removed and the crude
Method B (High Pressure):
A mixture of N-Z-Dph (5d) (400 mg, 1.1 mmol), 6 (270 mg,
1.5 mmol), and 11 (320 mg, 1.0 mmol) was dissolved in CH2Cl2
(4 mL) in a Teflon capsule (4.5 mL capacity). The solution was com-

SYNTHESIS
Papers
998
pressed at 0.9 GPa (9 kbar) by the use of a stainless steel apparatus for
14 d at r.t. The mixture was concentrated under vacuum, and the res-
idue was dissolved in EtOAc (20 mL). The solution was washed with
1 M HCl (2 × 5 mL), 1 M NaHCO3 (2 × 5 mL), and H2O (3 × 5 mL),
and dried (Na2SO4). The solvent was removed under reduced pres-
sure. The resulting crude product was purified by flash column chro-
matography (Wakogel FC-40, hexane/EtOAc 4:1), affording white
crystals, which were recrystallized (EtOAc/petroleum ether); yield:
421 mg (49%); mp 188–189°C. Spectral data are given in Table 3.
(4) Yamada, T.; Yanagi, T.; Omote, Y.; Miyazawa, T.; Kuwata, S.;
Sugiura, M.; Matsumoto, K. J. Chem. Soc., Chem. Commun.
1990, 1640.
Yamada, T.; Yanagi, T.; Omote, Y.; Miyazawa, T.; Kuwata, S.;
Sugiura, M.; Matsumoto, K. Chem. Express 1991, 6, 575.
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(6) Crisma, M.; Valle, G.; Bonora, G. M.; De Menego, E.; Toniolo,
C.; Lelj, F.; Barone, V.; Fraternali, F. Biopolymers 1990, 30, 1.
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mers 1991, 31, 637.
This work was supported in part by The Hirao Taro Foundation of
the Konan University Association for Academic Research, by The
Science Research Promotion Fund from Japan Private School Pro-
motion Foundation, and by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science and Culture (03640468).
(8) Yamada, T.; Omote, Y.; Nakamura, Y.; Miyazawa, T.; Kuwata,
S. Chem. Lett. 1993, 1583.
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