Convenient synthesis and conversion of a (Z)-α,β-didehydroornithine derivative to α,β-didehydrokyotorphin

Article abstract of DOI:10.1055/s-2000-6219

Hydrogenolysis of the azido group of methyl (Z)-2-(N-Cbz)amino-5- azidopent-2-enoate, derived by selective reduction and azidation of the side chain carboxyl group of N-protected (Z)ΔGlu-OMe, gave (Z)-α,β- didehydroornithine derivative (7). The formed 7 was further converted to the basic (Z)-α,β-didehydroarginine and the acid containing (Z)-α,β- didehydrokyotorphin.

Full text of DOI:10.1055/s-2000-6219

144
PAPER
Convenient Synthesis and Conversion of a (Z)-a,b-Didehydroornithine
Derivative to a,b-Didehydrokyotorphin
Yasuchika Yonezawa, Takako Hirosaki, Takashi Hayashi, Chung-gi Shin*
Laboratory of Organic Chemistry, Faculty of Technology, Kanagawa University, Rokkakubashi, Kanagawa-ku, Yokohama 221-8686,
Japan
Fax +81(45)4917915; E-mail:shin@cc.kanagawa-u.ac.jp
Received 16 June 1999; revised 9 September 1999
4 with NaN3 proceeded smoothly to give 5 almost quanti-
Abstract: Hydrogenolysis of the azido group of methyl (Z)-2-(N-
tatively (Scheme 1).
Cbz)amino-5-azidopent-2-enoate, derived by selective reduction
and azidation of the side chain carboxyl group of N-protected (Z)-
DGlu-OMe, gave (Z)-a,b-didehydroornithine derivative (7). The
formed 7 was further converted to the basic (Z)-a,b-didehydroargi-
nine and the acid containing (Z)-a,b-didehydrokyotorphin.
Attempts to reduce only the azide group of 5 directly by
using reducing agents, such as LiAlH4 and NaBH4, were
unsuccessful, because of further hydrogenation of the
C=C bond and the methyl ester. Therefore, after conver-
sion of the 5-azido group to a 5-triphenylphosphinimino
group, subsequent syntheses of two basic DAA were ef-
fected successfully. Reaction of 5 with Ph3P proceeded
readily to give methyl 5-triphenylphosphiminopent-2-
enoate (6), which was then treated with water in THF7 to
give the expected Cbz-(Z)-DOrn-OMe (7). Since the
formed 7 was slightly unstable, one-pot reaction with
Boc2O was carried out, without complete isolation, to give
Cbz-(Z)-DOrn(Boc)-OMe (8)8,9 in 58% yield in two steps.
On the other hand, the reaction of 7 with CbzCl in the
presence of Et3N gave Cbz-(Z)-DOrn(Cbz)-OMe (9) in
60% yield. Furthermore, guanidylation of 7 with (Boc-
NH)2CS in the presence of HgCl2, according to the report-
ed method,10 gave first the expected Cbz-(Z)-DArg(Boc2)-
OMe (10) in 59% yield, as shown in Scheme 1.
Key words: amines, azides, peptides, condensations, coupling, re-
ductions, didehydroamino acids, didehydroornithine
In previous papers,1-3 we have reported the convenient
synthesis of N-benzyloxycarbonyl-(Z)-a,b-didehydro-
glutamic acids [Cbz-DGlu(OR)-OR (1); a: R = H; b; R =
Me] by the direct condensation of a-oxoglutaric acids
with benzyl carbamate (Cbz-NH2). Meanwhile, the syn-
thesis of Cbz-DGlu-OMe (1c) was reported by Baldwin et
al.4 and we have also reported briefly a useful synthetic
method for 1c by the selective enzymatic hydrolysis of the
g-ethyl ester of 1b using esterase a-chymotrypsin.5 The
structurally unique a,b-didehydroglutamate 1c is thought
to be most applicable to various syntheses of other useful
(Z)-a,b-didehydroamino acids (DAA) and heterocycles.1
Hydrolysis of the methyl ester of 9 with 1 M LiOH, fol-
lowed by cyclization of the resulting Cbz-(Z)-DOrn(Cbz)-
OH (11) with SOCl2 in diethyl ether gave N-carboxy-a,b-
didehydroornithine anhydride [Cbz-(Z)-DOrnNCA] (12)
in 93% yield, according to the method reported previous-
ly.8 Subsequently, facile coupling of 12 with Boc-l-
Tyr(MOM)-OH using dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) in CH2Cl2 gave
the protected Boc-l-Tyr(MOM)-DOrn(Cbz)-OMe (13) in
62% yield. Then, selective deprotection of the Cbz group
of 13 with triethylsilane and PdCl2 in the presence of
Et3N,11 followed by guanidylation of the formed interme-
diate as for 10, gave the desired protected Boc-l-
Tyr(MOM)-(Z)-DArg(Boc2)-OMe (14) in 62% yield. Fi-
nally, deprotection of all the protecting groups of 14 with
1 M LiOH in MeOH and then trifluoroacetic acid (TFA)
in CH2Cl2 were effected successfully to give the expected
H-l-Tyr-(Z)-DArg-OH (15) in 65% yield (Scheme 2).
In this paper, we wish to report the convenient synthesis
of 2-amino-5-hydroxypent-2-enoate derivative 2 from 1c
and the facile conversion of 2 to two kinds of basic DAA,
such as (Z)-a,b-didehydroornithine (DOrn) and (Z)-a,b-
didehydroarginine (DArg). Furthermore, in connection
with the study on the structure-bioactivity relationship of
analgesic dipeptide kyotorphin,6 the synthesis of various
convertible (Z)-a,b-didehydrokyotorphins (Tyr-DArg)
from Tyr-DOrn derivative was first achieved.
Selective reduction of the side chain carboxyl group of 1c
with NaBH4 in the presence of BF3•OEt2 in THF proceed-
ed smoothly to give the expected methyl (Z)-2-(N-
Cbz)amino-5-hydroxypent-2-enoate (2) in 86% yield
(Scheme 1). In order to examine the azidation of the hy-
droxy group, mesylation or tosylation of 2 with methane-
sulfonyl chloride (MsCl) or toluenesulfonyl chloride
(TosCl) in the presence of pyridine was attempted to give
the corresponding 5-mesyloxy 3 and 5-tosyloxy 4 deriva-
tives, respectively. Subsequent azidation of 3 with NaN3
in DMF in the presence of catalytic 15-crown-5 was per-
formed to give the corresponding 5-azidopent-2-enoate
derivative 5. Unfortunately, the yield was found to be
markedly low (44%). On the other hand, the azidation of
In conclusion, a convenient synthetic method for basic
DAA and the acid containing didehydrokyotorphin has
been developed. Further investigation on the various reac-
tions of DOrn and DArg derivatives is currently under way
in our laboratory.
Synthesis 2000, No. 1, 144–148 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conversion of a (Z)-a,b-Didehydroornithine Derivative to a,b-Didehydrokyotorphin
145
OH
COOH
a)
86%
CbzHN
COOMe
CbzHN
COOMe
1c
2
OR
N3
d)
b) , c)
CbzHN
COOMe
CbzHN
COOMe
3 ; R=Ms
4 ; R=Tos
5
N=PPh3
NH2
f)
e)
93%
CbzHN
COOMe
CbzHN
i)
COOMe
59%
7
6
H
N
NHX
NBoc
g) , h)
NHBoc
CbzHN
COOMe
CbzHN
COOMe
10
8 ; X=Boc
9 ; X=Cbz
Reagents and conditions: a) NaBH4/BF3•OEt2, -10°C, 3 min, 86%; b) 3/MsCl/pyridine/CH2Cl2, r.t., 5 h, 74%; c) 4/TosCl/pyridine/CH2Cl2, 6
h, 93%; d) NaN3/15-crown-5/DMF, r.t., 2 h, 44% from 3, 94% from 4; e) Ph3P/THF, r.t. 3 h; f) H2O/THF, r. t., 6 h; g) 8/Boc2O/THF, r.t.. 51%;
h) 9/CbzCl/TEA/THF, r.t., 3 h, 60%; i) (BocNH)2CS/HgCl2/TEA/DMF, r.t. 3 h
Scheme 1
Melting points were determined with Yamato Mp-21 micro melting
points apparatus, and are uncorrected. The IR spectra in KBr were
recorded on a Hitachi 270-30 spectrometer. The H NMR spectra
were measured with a JEOL FX 200 spectrometer in CDCl3 solution
with TMS as the internal standard.
recrystallized from a mixture of Et2O and pentane to give 2 as col-
orless needles; yield: 8.21 g (86%); mp 63-64°C.
IR: n = 3508, 3290, 3004, 2995, 1720, 1689, 1510 cm-1.
1H NMR: d = 2.45 (dt, 2 H, J = 5.9, 7.8 Hz, 4-H), 2.96 (br s, 1 H,
OH), 3.75 (s, 3 H, CO2CH3), 3.78 (t, 2 H, J = 5.9 Hz, 5-H), 5.13 (s,
2 H, CH2Ph), 6.65 (t, 1 H, J = 7.8 Hz, 3-H), 6.81 (br s, 1 H, NH),
7.35 (s, 5 H, C6H5).
1
Methyl (Z)-2-(N-Cbz)Amino-5-hydroxypent-2-enoate (2)
To a stirred solution of NaBH4 (2.10 g, 55.5 mmol) in THF (100
mL) was added 1c (10.00 g, 34.0 mmol) at -10°C. After stirring for
2 min, BF3•OEt2 (9.0 mL, 71.0 mmol) was added slowly over 2 h
and then the mixture was poured into a chilled, satd aq NaHCO3
(150 mL). After removal of THF in vacuo, the aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic extracts
were successively washed with satd aq NH4Cl (3 × 100 mL), satd
aq NaHCO3 (3 × 100 mL), brine (3 × 100 mL), and then dried
(Na2SO4). Concentration in vacuo gave crude crystals, which were
Anal. Calcd for C14H17NO5: C, 60.20; H, 6.14; N, 5.02. Found: C,
59.69; H, 6.18; N, 5.30.
Methyl (Z)-2-(N-Cbz)Amino-5-mesyloxypent-2-enoate (3)
To a stirred solution of 2 (1.50 g, 5.4 mmol) in CH2Cl2 (30 mL) was
added pyridine (0.9 mL, 10.7 mmol) and MsCl (0.60 mL, 7.8 mmol)
at 0°C. After stirring at r.t. for 6 h, the mixture was poured into H2O
(30 mL) and then the resulting solution was extracted with CHCl3
(3 × 10 mL). The organic layer was washed with 1 M HCl (3 × 10
Synthesis 2000, No. 1, 144–148 ISSN 0039-7881 © Thieme Stuttgart · New York

146
Y. Yonezawa et al.
PAPER
NHCbz
a)
b)
9
80%
93%
CbzHN
COOH
11
NHCbz
NHCbz
d)
c)
O
BocHN
O
HN
O
N
H
COOMe
62%
65%
O
13
12
MOMO
H
N
H
N
NH
NBoc
NHBoc
NH2
e)
O
O
H2N
BocHN
65%
N
H
COOH
N
H
COOMe
HO
MOMO
15
14
Reagents and conditions: a) 1 M LiOH/dioxane, r. t., 3 h; b) SOCl2/Et2O, r. t., 1.5 h; c) (i) BocTyr(MOM)-OH/DCC/DMPA/CH2Cl2, -5°C to
r. t., 1.5 h; (ii) MeOH/TEA, r. t., 2 h; d) (i) Et3SiH/PdCl2/TEA/CH2Cl2, r.t., 2 h; (ii) TBAF/(Boc)2CS/HgCl2/TEA/DMF, r.t. 3 h; e) (i) 1 M
LiOH/MeOH, r.t., 2 h, (ii) TFA/CH2Cl2, r. t. 1 h
Scheme 2
mL), satd aq NaHCO3 (3 × 10 mL), brine (3 × 10 mL), and then
dried (Na2SO4). Concentration in vacuo gave crude crystals, which
were recrystallized from a mixture of EtOAc and hexane to give 3
as colorless needles; yield: 1.41 g (74%); mp 66-67°C.
(d, 2 Harom, J = 8.3 Hz), 7.36 (s, 5 H, C6H5), 7.78 (d, 2 Harom, J = 8.3
Hz)
Anal. Calcd for C21H23NO7S: C, 58.19; H, 5.35; N, 3.23. Found: C,
58.53; H, 5.38; N, 3.31.
IR: n = 3454, 3316, 1758, 1725, 1695, 1515 cm-1.
1H NMR: d = 2.68 (dt, 2 H, J = 6.4, 7.3 Hz, 4-H), 3.01 (s, 3 H,
SO3CH3), 3.79 (s, 3 H, CO2CH3), 4.36 (t, 2 H, J = 6.4 Hz, 5-H), 5.14
(s, 2 H, CH2Ph), 6.45 (br s, 1 H, NH), 6.60 (t, 1 H, J = 7.3 Hz, 3-H),
7.37 (s, 5 H, C6H5).
Methyl (Z)-2-(N-Cbz)Amino-5-azidopent-2-enoate (5)
F r o m 3 : To a solution of 3 (1.00 g, 2.8 mmol) in DMF (15 mL)
was added NaN3 (220 mg, 3.4 mmol) and catalytic 15-crown-5
(0.15 mL) at 50°C. After stirring for 2 h, the mixture was poured
into H2O (50 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined organic extracts were washed with 10% citric acid (2 × 10
mL), satd aq NaHCO3 (2 × 10 mL), H2O (2 × 10 mL), and then dried
(Na2SO4). Concentration in vacuo gave a residual syrup, which was
chromatographed on a silica-gel column using a mixture of EtOAc
and hexane (2 : 1 v/v) to give 5 as a colorless syrup; yield: 370 mg
(44%).
Anal. Calcd for C15H19NO7S: C, 50.42; H, 5.36; N, 3.92. Found: C,
50.32; H, 5.40; N, 4.12.
Methyl (Z)-2-(N-Cbz)Amino-5-tosyloxypent-2-enoate (4)
Reaction of 2 (1.51 g, 5.4 mmol) with TosCl (1.30 g, 6.8 mmol) was
carried out analogous to the mesylation of 3 as above and worked
up to give 4 as a colorless syrup; yield: 2.20 g (93%).
IR: n = 3552, 3360, 2960, 2104, 1838, 1716, 1516 cm-1.
IR: n = 3634, 3496, 3354, 3064, 3028, 2950, 2926, 2854, 2254,
1725, 1665, 1599, 1503 cm-1.
1H NMR: d = 2.49 (dt, 2 H, J = 6.8, 7.3 Hz, 4-H), 3.44 (t, 2 H, J =
6.8 Hz, 5-H), 3.78 (s, 3 H, CO2CH3), 5.15 (s, 2 H, CH2Ph), 6.40 (br
s, 1 H, NH), 6.58 (t, 1 H, J = 7.3 Hz, 3-H), 7.28-7.38 (m, 5 H,
C6H5).
1H NMR: d = 2.44 (s, 3 H, ArCH3), 2.57 (dt, 2 H, J = 6.4, 7.3 Hz, 4-
H), 3.77 (s, 3 H, CO2CH3), 4.15 (t, 2 H, J = 6.4 Hz, 5-H), 5.11 (s, 2
H, CH2Ph), 6.39 (br s, 1 H, NH), 6.49 (t, 1 H, J = 7.3 Hz, 3-H), 7.33
Synthesis 2000, No. 1, 144–148 ISSN 0039-7881 © Thieme Stuttgart · New York

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Conversion of a (Z)-a,b-Didehydroornithine Derivative to a,b-Didehydrokyotorphin
147
Anal. Calcd for C14H16N4O4: C, 55.25; H, 5.31; N, 18.41. Found: C,
55.60; H, 5.22; N, 18.62.
Cbz-(Z)-DArg(Boc2)-OMe (10)
A solution of 6 (500 mg, 0.90 mmol) in THF (10 mL) and H2O (1
mL) was stirred at r.t. for 6 h. The mixture was concentrated in vac-
uo to give a residual syrup, which was dissolved in DMF (10 mL).
To the resulting solution was added Et3N (0.43 mL, 3.10 mmol),
(BocNH)2CS (257 mg, 0.90 mmol), and HgCl2 (277 mg, 1.00
mmol) at 0°C and the mixture was continuously stirred at r.t. for 3
h. After removal of insoluble material, the filtrate was diluted with
H2O (30 mL). The aqueous solution was extracted with EtOAc (3
× 5 mL) and the combined extracts were washed with 10% aq citric
acid (3 × 5 mL), satd aq NaHCO3 (3 × 5 mL), brine (3 × 5 mL), and
then dried (Na2SO4). Concentration in vacuo gave residual crystals,
which were recrystallized from a mixture of EtOAc and hexane to
give 10 as colorless needles; yield: 279 mg (59%); mp 128-129°C.
F r o m 4 : A suspension of 4 (1.40 g, 3.20 mmol) and NaN3 (230
mg, 3.54 mmol) in DMF (20 mL) in the presence of catalytic 15-
crown-5 (0.15 mL) was stirred at r.t. for 4 h. The mixture was dilut-
ed with H2O (60 mL) and extracted with EtOAc (3 × 30 mL). The
combined extracts were washed with 10% aq citric acid (3 × 10
mL), satd aq NaHCO3 solution (3 × 10 mL), brine (3 × 10 mL), and
then dried (Na2SO4). Concentration in vacuo gave a residual syrup,
which was purified on a silica gel column using a mixture of EtOAc
and hexane (1:10 v/v) to give 5 as a colorless syrup; yield: 915 mg
(94%).
Methyl (Z)-2-(N-Cbz)Amino-5-triphenylphosphiminopent-2-
enoate (6)
IR: n = 3370, 2974, 1722, 1668, 1596, 1572, 1518 cm-1.
1H NMR: d = 1.45 (s, 18 H, 2 × t-C4H9), 2.51 (dt, 2 H, J = 7.3, 7.8
Hz, 4-H), 3.25-3.76 (m, 2 H, 5-H), 3.70 (s, 3 H, CO2CH3), 5.06 (AB
q, 2 H, J = 12.2, 20.0 Hz, CH2Ph), 6.41 (br s, 1 H, NH), 6.47 (t, 1H,
J = 7.8 Hz, 3-H), 6.95 (br s, 1 H, NH), 7.22-7.44 (m, 5 H, C6H5).
9.45 (br s, 1 H, NH).
A solution of 5 (500 mg, 1.60 mmol) and Ph3P (431 mg, 1.64 mmol)
in benzene (10 mL) was stirred at r.t. for 4 h. Concentration of the
mixture in vacuo gave a residual syrup, which was crystallized from
hexane. The crude crystals were recrystallized from a mixture of
EtOAc and hexane (1:50 v/v) to give 6 as colorless prisms; yield:
800 mg (93 %); mp 69-70°C.
Anal. Calcd for C25H36N4O8: C, 57.68; H, 6.97; N, 10.76. Found: C,
57.95; H, 6.92; N, 11.15.
IR: n = 3052, 2944, 2842, 2818, 2464, 2296, 2248, 2134, 2014,
1965, 1941, 1908, 1887, 1866, 1827, 1719, 1650, 1614, 1590, 1488
cm-1.
1H NMR: d = 2.40-2.56 (m, 2 H, 4-H), 3.16-3.34 (m, 2 H, 5-H),
3.73 (s, 3 H, CO2CH3), 5.08 (s, 2 H, CH2Ph), 6.36 (t, 1 H, J = 7.8
Hz, 3-H), 7.28-7.90 (m, 20 H, 4 × C6H5), 10.00 (br s, 1 H, NH).
Cbz-(Z)-DOrn(Cbz)-OH (11)
A solution of 9 (1.00 g, 2.40 mmol) in dioxane (5 mL) and 1 M
LiOH (3 mL) was stirred at 20°C for 3 h. To the mixture was added
satd aq NaHCO3 solution (30 ml). After removal of dioxane in vac-
uo, the residual aqueous layer was washed with Et2O (3 × 5 mL) and
acidified with 10% aq citric acid to pH 3-4. The aqueous solution
was extracted with EtOAc (3 × 7 mL) and the combined organic ex-
tracts were washed with 10% aq citric acid (3 × 5 mL), brine (3 × 5
mL), and then dried (Na2SO4). Concentration in vacuo gave residual
crystals, which were recrystallized from a mixture of CHCl3 to give
11 as colorless needles; yield: 765 mg (80%), mp 121-123°C.
Anal. Calcd for C32H31N2O4P: C, 71.35; H, 5.81; N, 5.20. Found: C,
71.16; H, 5.78; N, 5.26.
Cbz-(Z)-DOrn(Boc)-OMe (8)
A solution of 6 (500 mg, 0.93 mmol) in THF (10 mL) and H2O (1
mL) was stirred at r.t. for 6 h. To the mixture was added Boc2O (203
mg, 0.93 mmol) and then the resulting solution was continuously
stirred for 6 h. Concentration in vacuo gave a residual syrup, which
was purified on a silica gel column using a mixture of EtOAc and
hexane (1 : 5 v/v) as eluent to give 8 as a colorless syrup; yield: 180
mg (51%).
IR: n = 3424, 1698, 1515, 1404 cm-1.
1H NMR d = 1.46 (s, 9 H), 1.49 (d, 3 H, J = 6.4 Hz), 1.65 (s, 6 H),
1.88 (d, 3 H, J = 7.0 Hz, =CHCH3), 4.05 (d, 1 H, J = 7.5 Hz), 4.38
(dq, 1 H, J = 6.4, 7.5 Hz), 6.57 (q, 1 H, J = 7.5 Hz, =CHCH3), 8.00
(br s, 1 H, NH), 8.11 (s, 1 H, NH at C-5), 8.54 (br s, 1 H, CO2H).
IR: n = 3323, 2928, 1773, 1653, 1508 cm-1.
1H NMR: d = 1.44 (s, 9 H, t-C4H9), 2.42 (dt, 2H, J = 6.4, 7.8 Hz, 4-
H), 3.27 (dt, 2 H, J = 6.4, 7.8 Hz, 5-H), 3.76 (s, 3 H, CO2CH3), 4.90
(br s, 1 H, NH), 5.14 (s, 2 H, CH2Ph), 5.38 (br s, 1 H, NH), 6.63 (t,
1 H, J = 7.8 Hz, 3-H), 7.36 (s, 5 H, C6H5).
Anal. Calcd for C21H22N2O6: C, 63.31; H, 5.57; N, 7.03. Found:
63.45; H, 5.72; N, 7.25.
(Z)-DOrn(Cbz)NCA (12)
To a stirred suspension of 11 (1.00 g, 2.50 mmol) in Et2O (10 mL)
was added SOCl2 (10 mL) at 0°C. After stirring at r. t. for 1 h, the
mixture was thoroughly concentrated in vacuo to give a residual
syrup, which was crystallized from benzene. The crude crystals
were recrystallized from benzene to afford 12 as colorless prisms;
yield: 675 mg (93%); mp 87-89°C.
IR: n = 3342, 1852, 1806, 1694, 1534, 1315 cm-1.
1H NMR: d = 2.48 (q, 2 H, J = 7.0 Hz, 4-H), 3.29 (dt, 2 H, J = 6.0,
7.0 Hz), 5.12 (s, 2 H, CH2Ph), 5.19 (br s, 1 H, CH2NH), 5.94 (t, 1 H,
3-H), 7.31-7.40 (m, 5 H, C6H5), 9.43 (br s, 1H, NH).
Anal. Calcd for C19H26N2O6: C, 60.30; H, 6.93; N, 7.40. Found: C,
60.38; H, 7.15; N, 7.35.
Cbz-(Z)-DOrn(Cbz)-OMe (9)
A solution of 6 (1.08 g, 2.00 mmol) in THF (20 mL) and H2O (2
mL) was stirred at r. t. for 6 h. To the mixture was added CbzCl (375
mg, 2.20 mmol), Et3N (202 mg, 2.00 mmol) and then the resulting
solution was continuously stirred for 3 h. Concentration in vacuo
gave a residual syrup, which was purified on a silica-gel column us-
ing a mixture of EtOAc and hexane (1 : 5 v/v) as eluent to give a
colorless syrup. The obtained syrup was crystallized from hexane.
The crystals were recrystallized from cyclohexane to give 9 as col-
orless needles; yield: 495 mg (60%); mp 80-82°C.
Anal. Calcd for C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C,
57.95; H, 4.92; N, 9.35.
IR: n = 3319, 3303, 1735, 1689, 1553, 1505 cm-1.
Boc-l-Tyr(MOM)-(Z)-DOrn(Cbz)-OMe (13)
1H NMR: d = 2.45 (dt, 2 H, J = 6.5, 7.5 Hz, 4-H), 3.36 (m, 2 H, 5-
H), 3.76 (s, 3 H, CO2CH3), 5.10 (s, 2 H, CH2Ph), 5.13 (s, 2 H,
CH2Ph), 5.24 (br s, 1 H, CH2NH), 6.37 (br s, 1 H, NH), 6.58 (t, 1 H,
J = 7.5 Hz, 3-H), 7.33-7.36 (m, 10 H, 2 × C6H5).
To a stirred solution of Boc-Tyr(MOM)-OH (2.57 g, 7.89 mmol)
and DCC (1.78 g, 8.64 mmol) in CH2Cl2 (40 mL) was added over
30 min at -10°C. After stirring for 30 min, 12 (2.18 g, 1.72 mmol)
and DMAP (3.00 g, 1.50 mmol) were added over 1.5 h at r. t. Final-
ly, after treating further with MeOH (10 mL) and stirring for 2 h,
TEA (1.26 mL, 9.01 mmol) was added to the mixture. After remov-
Anal. Calcd for C22H24N2O6: C, 64.06; H, 5.87; N, 6.79. Found: C,
64.18; H, 5.75; N, 6.55.
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148
Y. Yonezawa et al.
PAPER
al of CH2Cl2 and MeOH in vacuo, the residue was dissolved in
EtOAc (10 mL) and the N,N’-dicyclohexylurea separated out was
filtered. The filtrate was diluted in EtOAc (10 mL) and the resultant
solution was washed successively with 10% aq citric acid (2 x 5
mL), satd aq NaHCO3 (2 x 5 mL), H2O (5 mL) and then dried
(Na2SO4). Concentration in vacuo gave a residual syrup, which was
purified on a silica gel column using a mixture of CHCl3 and ace-
tone (25:1 v/v) to give colorless crystals, which were recrystallized
from a mixture of EtOAc and hexane to give 13 as colorless needles;
yield: 2.85 g (65%); mp 98-99°C; [a]D25 +1.1 (c = 0.97, MeOH).
Anal. Calcd for C33H51N5O11: C, 57.13; H, 7.41; N, 10.09. Found:
C, 57.26; H, 7.60; N, 10.21.
H-l-Tyr-(Z)-DArg-OH (15)
A solution of 14 (105 mg, 0.15 mmol) in dioxane (1 mL) was stirred
with 1 M LiOH (0.20 mL) at r.t. over 3 h. The mixture was washed
with H2O/Et2O (15 mL; 2:1 v/v) and the aqueous layer was acidified
to pH 3 with 3 M HCl and then extracted with EtOAc (3 × 7 mL).
The combined organic layers were concentrated in vacuo. The ob-
tained residue was dissolved in CHCl3/Et3N (1.4 mL; 1:1 v/v) and
the resulting solution was stirred at r.t. for 3 h. After concentration
in vacuo, the crude residue was purified by DOWEX 50W-X18-OH
using EtOH as eluent to give a solid, which was recrystallized from
EtOH/Et2O to give 15 as colorless amorphous material; yield: 33
mg (65%); mp 190-195°C; [a]D25 -5.4 (c = 0.93, MeOH).
IR: n = 3330, 3295, 2951, 1733, 1695, 1684, 1670, 1585, 1525,
1512 cm-1.
1H NMR: d =1.41 (s, 9 H, t-C4H9), 2.27 (dt, 2 H, J = 6.5, 7.5 Hz,
DOrn's 4-H), 3.00 (dd, 1 H, J = 7.0, 14.0 Hz, Tyr's 3-H), 3.10 (dd, J
= 6.5, 14.0 Hz, Tyr's 3-H), 3.32 (dt, 2 H, J = 6.0, 6.5 Hz, DOrn's 5-
H), 3.46 (s, 3 H, OCH3), 3.74 (s, 3 H, CO2CH3), 4.42 (m, 1 H, Tyr's
2-H), 5.01 (br s, 1 H, NH), 5.10 (s, 2 H, CH2Ph), 5.14 (s, 2 H,
OCH2O), 5.47 (t, 1 H, J = 6.0 Hz, CH2NH), 6.63 (t, 1 H, DOrn's 3-
H), 6.96 (d, 2 H, J = 8.5 Hz, Tyr's Harom), 7.13 (d, 2 H, J = 8.5 Hz.
Tyr's Harom), 7.36 (m, 5 H, C6H5), 7.55 (br s, 1 H, NH).
IR: n = 3438, 2979, 2934, 1721, 1680, 1640, 1617, 1511, 1368 cm-1.
1H NMR: d = 2.05 (m, 2 H, DArg's 4-H), 3.04 (dd, 1 H, J = 6.5, 14.0
Hz, Tyr's 3-H), 3.13 (dd, 1 H, J = 7.0, 14.0 Hz, Tyr's 3-H), 3.23 (t,
2 H, J = 6.5 Hz, DArg's 5-H), 4.12 (m, 1 H, Tyr's 2-H), 6.47 (t, 1 H,
J = 7.0 Hz, DArg's 3-H), 6.77 (d, 2 H, J = 8.0 Hz, Tyr's Harom), 7.35
(d, 2 H, J = 8.0 Hz, Tyr's Harom).
Anal. Calcd for C30H39N3O9: C, 61.53; H, 6.71; N, 7.18. Found: C,
61.75; H, 6.87; N, 7.25.
Anal. Calcd for C15H21N5O4: C, 53.72; H, 6.31; N, 20.89. Found: C,
53.45; H, 6.05; N, 21.22.
Boc-l-Tyr(MOM)-(Z)-DArg(Boc2)-OMe (14)
To a solution of 13 (378 mg, 0.64 mmol) in CH2Cl2 (20 mL) was
added Et3SiH (0.4 mL, 3.44 mmol), Et3N (0.17 mL. 0.77 mmol),
and PdCl2 (10 mg, 0.06 mmol). The resultant solution was heated
under reflux for 20 min. The mixture was concentrated in vacuo to
give a residual syrup, to which a solution of Bu4NF (TBAF, 1 M so-
lution in THF, 0.7 mL) in DMF (15 mL) was added with stirring
over 5 min at r. t. To the resulting solution was added Et3N (0.43
mL, 3.1 mmol), (BocNH)2CS (257 mg, 0.90 mmol), and HgCl2 (277
mg, 1.0 mmol) at 0°C and then the mixture was continuously stirred
at r. t. for 3 h. After removal of insoluble material, the filtrate was
diluted with H2O (30 mL). The aqueous solution was extracted with
EtOAc (3 × 15 mL) and the combined extracts were washed with
10% aq citric acid (3 × 5 mL), satd aq NaHCO3 (3 × 5 mL), brine (3
× 5 mL), and then dried (Na2SO4). Concentration in vacuo gave a
residual amorphous, which was recrystallized from a mixture of
EtOAc and hexane to give 14 as a colorless amorphous material;
yield: 279 mg (62%); mp 68-69°C; [a]D25 -3.4 (c = 0.93, MeOH).
References
(1) Shin, C.; Yonezawa, Y.; Watanabe, E. Tetrahedron Lett.
1985, 26, 85.
(2) Shin, C.; Takahashi, N.; Seki, M. Bull. Chem. Soc. Jpn. 1991,
64, 3575.
(3) Shin, C.; Yonezawa, Y.; Unoki, K.; Yoshimura, J.
Tetrahedron Lett. 1979, 1049.
(4) Baldwin, J. E.; Cha, J. K.; Kruse, L. T. Tetrahedron 1985, 41,
5241.
(5) Shin, C.; Seki, M.; Takahashi, N. Chem. Lett. 1990, 2089.
(6) Kirihata, M.; Kawahara, S.; Ichimoto, I.; Ueda, H. Agric.
Biol.Chem. 1990, 54, 753.
(7) Vaultier, M.; Knougi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763.
(8) Shin, C.; Obara, T.; Segami, S.; Yonezawa, Y. Tetrahedron
Lett.1987, 28, 3827.
(9) Shin, C.; Takahashi, N.; Yonezawa, Y. Chem. Pharm. Bull.
1990, 38, 2020.
IR: n = 3438, 2979, 2934, 1721, 1680, 1640, 1617, 1511, 1368 cm-1.
1H NMR: d = 1.42 (s, 9 H, t-C4H9), 1.49 (s, 18 H, 2 t-C4H9), 2.35
(m, 2 H, DArg's 4-H), 3.04 (dd, 1 H, J = 6.0, 14.0 Hz, Tyr's 3-H),
3.11 (dd, 1 H, J = 7.0, 14.0 Hz, Tyr's 3-H), 3.46 (s, 3 H, OCH3), 3.51
(dt, 2 H, J = 7.0, 5.5 Hz, DArg's 5-H), 3.75 (s, 3 H, CO2CH3), 4.43
(m, 1 H, Tyr's 2-H), 5.02 (br s, 1H, NH), 5.14 (s, 2H, OCH2O), 6.65
(t, 1H, J=7.0 Hz, DArg's 3-H), 6.97 (d, 2 H, J = 9.0 Hz, Tyr's Harom),
7.15 (d, 2 H, J = 9.0 Hz, Tyr's Harom), 7.56 (br s, 1 H, NH), 8.31 (t,
1 H, J = 7.0 Hz, CH2NH), 11.5 (br s, 1 H, guanidino group's NH).
(10) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
(11) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
Article Identifier:
1437-210X,E;2000,0,01,0144,0148,ftx,en;F03599SS.pdf
Synthesis 2000, No. 1, 144–148 ISSN 0039-7881 © Thieme Stuttgart · New York