Pd(0)-catalyzed Heck-type arylation of didehydropeptides

Article abstract of DOI:10.1081/SCC-200054757

Pd(0)-catalyzed Heck-type arylation of several didehydropeptides has been studied and the process has been found to be a viable method for the synthesis of the corresponding arylated products stereoselectively but in moderate yields. Copyright Taylor & Fr

Full text of DOI:10.1081/SCC-200054757

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Pd(0)‐Catalyzed Heck‐Type
Arylation of Didehydropeptides
Shital K. Chattopadhyay a , Benoy K. Pal a & Suman
Biswas a
a Department of Chemistry, University of Kalyani,
Kalyani, West Bengal, India
Version of record first published: 16 Aug 2006.
To cite this article: Shital K. Chattopadhyay, Benoy K. Pal & Suman Biswas
(2005): Pd(0)‐Catalyzed Heck‐Type Arylation of Didehydropeptides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:9, 1167-1175
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Synthetic Communicationsw, 35: 1167–1175, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054757
Pd(0)-Catalyzed Heck-Type Arylation of
Didehydropeptides
Shital K. Chattopadhyay, Benoy K. Pal, and Suman Biswas
Department of Chemistry, University of Kalyani, Kalyani,
West Bengal, India
Abstract: Pd(0)-catalyzed Heck-type arylation of several didehydropeptides has
been studied and the process has been found to be a viable method for the
synthesis of the corresponding arylated products stereoselectively but in moderate
yields.
Keywords: Heck reaction, Pd(0)-catalysis, didehydropeptides, stereoselectivity
INTRODUCTION
Dehydroalanine residues are known[1] to introduce both side-chain and
[2]
backbone conformational constraints within peptides. Their importance
as precursors for various modified peptides are also well documented. For
this and other reasons, the synthesis[3] and synthetic modification[4] of dehy-
dropeptides has proved to be an interesting area of research. Although
Mizoroki–Heck type inter-[5–7] and intra-molecular[8] arylation of didehy-
droalanine derivatives has been extensively studied, to the best of our
knowledge, a similar type of arylation of dehydropeptides has been less docu-
mented.[9] Herein, we report the results of a systematic investigation on the
palladium(0)-catalyzed arylation of dehydropeptides.
Received in India December 20, 2004
Address correspondence to Shital K. Chattopadhyay, Department of Chemistry,
University of Kalyani, Kalyani, 741235, West Bengal, India. E-mail: skchatto@
yahoo.com

1168
S. K. Chattopadhyay, B. K. Pal, and S. Biswas
RESULTS AND DISCUSSION
The N-terminal dehydrodipeptides 1a, b were prepared following literature
[10,11]
procedure
as outlined in Scheme 1. Arylation of the dehydropeptides
1a, b was then examined under a range of conditions.[12] The reaction
[13]
proceeded best under Jeffery’s two-phase protocol
using potassium
acetate as base. The arylated products 2a, b were obtained in geometrically
pure form but in moderate yield. The N-terminal dehydrotripeptide 3
(prepared by condensation of Gly-Gly-OMe.HCl with 1) also underwent
arylation reaction to provide diastereomerically pure 4.
Z-configuration[14] of 2b and 4 were established by their alternate
syntheses. Thus, Pd(0)-catalyzed arylation of methyl 2-(tert-butoxycarbonyl-
amino)acrylate (5) with iodobenzene under reported[15] conditions provided
the cinnamate 6 of known configuration (Scheme 2). Hydrolysis of the
latter followed by coupling of the resulting acid 7 with L-phenylalanine
methyl ester hydrochloride (L-Phe-OMe.HCl) or glycylglycine methyl ester
hydrochloride (Gly-Gly-OMe.HCl) provided products that were identical in
all respects with 2b and 4, respectively.
We next turned our attention on the arylation of C-terminal dehydropep-
tides. Starting from N-Boc-Phe-Ser-OMe (8), the C-terminal dehydrodipep-
tide 9 was prepared by a two-step, one-pot protocol involving mesylation
and elimination sequence (Scheme 3). It was pleasing to observe that the dehy-
drodipeptide 9 underwent smooth arylation with iodobenzene to provide the
arylated product 10. Assignment of Z-configurtion of 10. was based[16] on
3
the JCH-coupling contant of 5.2 Hz between the vinyl proton and ester
carbonyl carbon. Selective decoupling after exchange with D2O allowed
unambiguous determination.
Scheme 1.

Arylation of Didehydropeptides
1169
Scheme 2.
Similarly, the tri-peptide olefin N-Boc-Phe-Phe-D.-Ala-OMe (11) was
prepared from the dipeptide 9 (Scheme 4). The tri-peptide olefin 11, upon
coupling with methyl 4-iodobenzoate, provided the diastereomerically pure
arylated product 12. Assignment of the configuration of the newly formed
double bond in 12 proved to be difficult in view of the fact that
the required signals were not sufficiently separated in the 13C-NMR. We
have tentatively assigned Z-configuration to it based on the trend we have
observed.
In short, we have demonstrated that Pd(0)-catalyzed Mizoroki–Heck-type
arylation of both N-terminal and C-terminal dehydropeptides stereoselectively
leads to the corresponding thermodynamically more stable Z-olefins. The
process appears to be racemization-free and therefore may find application in
the synthesis of modified peptides.
EXPERIMENTAL
Melting points were determined in a sulphuric acid bath and are uncorrected.
IR spectra were recorded on a Perkin Elmer 1330 apparatus purchased in a
DST-FIST grant. 1H-NMR and 13C-NMR spectra were recorded on a
Bruker 300 MHz instrument at the Indian Institute of Chemical Biology,
Kolkata. Mass spectra and elemental analyses were obtained as a paid
service from CDRI, Lucknow and I. I. C. B., Kolkata. Silica gel (60–120
mesh) was obtained from Spectrochem, India. Peteroleum ether refers to the
fraction boiling in the range 60–808C.
Scheme 3.

1170
S. K. Chattopadhyay, B. K. Pal, and S. Biswas
Scheme 4.
General Procedure for the Preparation of N-Terminal
Dehydropeptides
4-Methylmorpholine (270 mg, 2.67 mmol) was added dropwise to a stirred
solution of appropriate amino acid methyl ester hydrochloride (2.67 mmol)
in dry dichloromethane (3 ml) at 0 8C under nitrogen and the mixture was
stirred for 15 min. Then, a solution of 2-(tert-butoxycarbonylamino)acrylic
acid (500 mg, 2.67 mmol) in dry dichloromethane (1.5 ml) and solid
1-hydroxybenzotriazole (361 mg, 2.67 mmol) were added sequentially. After
stirring for another 15 min, dicyclohexyl carbodiimide (DCC) (579 mg,
2.8 mmol) was added in one portion and the resulting mixture was stirred
for 1 h. It was then allowed to come to room temperature and stirred for
18 h. The precipitated urea was filtered off and the filtrate was concentrated
under reduced pressure. It was then diluted with ethyl acetate (25 ml) and
washed sequentially with saturated sodium bicarbonate solutuion
(2 ꢀ 20 ml), HCl (2%, 1 ꢀ 20 ml), and water (20 ml) and then dried
(Na2SO4). It was then filtered and the filtrate was concentrated under
reduced pressure to leave the crude product, which was purified by chromato-
graphy using an appropriate eluent.
Methyl 2-f[2-(f2-[tert-butoxycarbonyl)amino]acryloyl)aminogacetyl]
aminogacetate (3): Eluted with a mixture of 20% ethyl acetate in
petroleum ether and the product was obtained as a colorless viscous
liquid. Yield: 56%. IR (neat, cm21): 3391, 2980, 1729, 1666, 1629, 1439,
1
1394, 1245, 1109. H-NMR (300 MHz, CDCl3): d 7.41 (1H, br s), 7.07 (1H,
br s), 6.85 (1H, br s), 6.08 (1H, s), 5.16 (1H, s), 4.09 (2H, d, J ¼ 5.6 Hz),
3.79 (3H, s), 3.77 (2 H, d, J ¼ 5.8 Hz), 1.46 (9H, s). Anal. found: C,
49.68%; H, 6.94%; N, 13.11%; C13H21N3O6 requires C, 49.52%: H, 6.71%;
N, 13.33%.
(S)-Methyl 2-((2S)-2-[(tert-butoxycarbonyl)-3-phenylpropanamido)-
3-hydroxy-propanoate (8): 4-Methylmorpholine (0.2 ml, 1.84 mmol) was
added dropwise to
a stirred solution of L-Ser-OMe.HCl (286 mg,
1.84 mmol) in dry dichloromethane (3 ml) at 0 8C under nitrogen. Then,

Arylation of Didehydropeptides
1171
Boc-Phe-OH (487 mg, 1.84 mmol), HOBt (284 mg), and DCC (398 mg,
1.92 mmol) were sequentially added and stirring continued for 1.5 h. It was
then allowed to come to room temperature and stirred for 6 h. The precipitated
urea was filtered and the filtrate was diluted with ethyl acetate (30 ml). The
organic extract was washed sequentially with saturated NaHCO3 solution
(2 ꢀ 20 ml), HCl (2%, 2 ꢀ 20 ml), water (2 ꢀ 20 ml), and brine (20 ml). It
was then dried (Na2SO4) and filtered, and the filtrate was concentrated
under reduced pressure to leave the crude product as a pale yellow viscous
liquid, which was purified by chromatography (SiO2) (petroleum ether–
ethyl acetate 3:2) to give the product as a colorless viscous liquid. Yield:
552 mg (82 %). [a]D þ5.0 (c, 0.09 in MeOH). IR (neat, cm21): 3344, 3291,
1
1740, 1689, 1647, 1521, 1367, 1242, 1168. H-NMR (300 MHz, CDCl3): d
7.27–7.16 (6H, m), 5.35 (1H, d, J ¼ 6.9 Hz), 4.64–4.61 (1H, m), 4.43 (1H,
d, J ¼ 5.8 Hz), 3.90 (2H, s), 3.74 (3H, s), 3.20 (1H, br s), 3.14 (1H, dd,
J ¼ 13.6, 5.3 Hz), 3.02–2.95 (1H, m), 1.37 (9H, s). 13C-NMR (75 MHz,
CDCl3): d 171.9, 170.6, 155.8, 136.4, 129.3, 128.4, 126.8, 80.3, 62.5, 55.7,
54.7, 52.6, 38.3, 28.1. Anal. found: C, 59.33%; H, 7.31%; N, 7.42%;
C18H26N2O6 requires C, 59.00%: H, 7.15%; N, 7.65%.
Methyl 2-(f(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylg
-amino)-acrylate (9): Methanesulfonyl chloride (940 mg, 1.96 mmol) was
added in one portion to a stirred solution of Boc-Phe-Ser-OMe (8) (240 mg,
0.66 mmol) in dry dichloromethane (5 ml) at 08C under nitrogen. Then, a
solution of triethylamine (198 mg, 1.96 mmol) in dry dichloromethane (3 ml)
was added dropwise over 10 min and the resulting solution was allowed to
come to room temperature over 3 h. It was then diluted with dichloromethane
(25 ml) and washed sequentially with HCl (5%, 2 ꢀ 20 ml), water (2 ꢀ 20 ml),
and brine (20 ml). The organic phase was dried (Na2SO4) and filtered, and the
filtrate was concentrated under reduced presuure to leave the crude product as a
pale yellow viscous liquid, which was purified by chromatography (SiO2)
(petroleum ether–ethyl acetate 5:1) to give the product as a colorless
viscous liquid. Yield: 180 mg (78%). [a]D 2 6.3 (c, 0.19 in MeOH). IR
1
(neat, cm21): 3390, 3355, 2983, 1720, 1699, 1508, 1440, 1329, 1166. H-
NMR (300 MHz, CDCl3): d 8.15 (1H, br s), 7.31–7.19 (5H, m), 6.61 (1H,
s), 5.90 (1H, s), 5.02–4.96 (1H, m), 4.41 (1H, br s), 3.79 (3H, s), 3.17–3.10
(2H, m), 1.41 (9H, s). 13C-NMR (75 MHz, CDCl3): d 170.2, 163.9, 155.3,
136.2, 130.5, 129.1, 128.7, 127.0, 109.3, 80.4, 56.4, 52.8, 38.1, 28.1. Anal.
found: C, 62.24%; H, 7.13%; N, 8.21%; C18H24N2O5 requires C, 62.05%;
H, 6.94% N, 8.04%.
Methyl 2-((S)-2-((S)-2-(tert-butoxycarbonyl)-3-phenylpropanamido)-
3-phenylpropanamido) acrylate: Trifluoroacetic acid (0.8 ml) was added
in one portion to a stirred solution of the peptide 9 (174 mg, 0.5 mmol) in
dry dichloromethane (4 ml) under nitrogen and the resulting solution was
stirred for 2 h at room temperature. It was then concentrated in vacuo to
leave the crude product as a foam, which was used as such in the next step.

1172
S. K. Chattopadhyay, B. K. Pal, and S. Biswas
4-Methylmorpholine (51 mg, 0.5 mmol), 1-hydroxybenzotriazole (68 mg,
0.5 mmol), and Boc-Phe-OH (132 mg, 0.52 mmol) were added sequentially to
a solution of the amine salt in dichloromethane (2 ml) at 0 8C under nitrogen
and the resulting mixture was stirred at the same temperature for 15 min. Solid
DCC (110 mg, 0.55 mmol) was added in one portion and the mixture was
stirred for 1 h. It was then allowed to come to room temperature and stirred
for 18 h. It was then filtered to remove the precipitated urea and the filtrate
was diluted with ethyl acetate (25 ml). The organic extract was washed
sequentially with saturated sodium bicarbonate (2 ꢀ 25 ml), HCl (2%,
20 ml), water (20 ml) and brine (20 ml), and then dried (Na2SO4). It was
then filtered and the filtrate was concentrated in vacuo to leave the crude
product as a viscous liquid, which was purified by chromatography over
silica gel using a mixture of petroleum ether–ethyl acetate (3:2) as eluent.
Yield: 186 mg (76%). [a]Dþ19 (c 0.29 in CHCl3). IR (neat, cm21): 3399,
3339, 1721, 1673, 1526, 1441, 1368, 1318, 1227, 1251. 1H-NMR
(300 MHz, CDCl3): d 7.98 (1H, brs), 7.45–7.38 (10H, m), 6.51 (2H, br s,
olefinic þ NH), 5.88 (1H, s), 4.93 (1H, br s), 4.69–4.62 (1H, m), 4.35–4.33
(1H, m), 3.79 (3H, s), 3.02 (4H, d, J ¼ 6.5 Hz), 1.38 (9H, s). 13C-NMR
(75 MHz, CDCl3): d 171.5, 169.3, 163.7, 155.3, 136.4, 135.9, 130.7, 129.2,
129.1, 128.5, 128.4, 126.9, 126.8, 109.8, 80.0, 55.5, 55.0, 52.8, 38.3, 37.9,
28.1. Anal. found: C, 65.67%; H, 6.88%; N, 8.57%; C27H33N3O6 requires
C, 65.44%; H, 6.71%; N, 8.48%.
General Procedure for the Heck-Type Arylation of the
Didehydropeptides
To a mixture of appropriate iodobenzene (0.225 mmol), appropriate dehydro-
peptide (0.34 mmol), n-Bu4NþBr2(73 mg, 0.225 mmol), and KOAc (53 mg,
0.54 mmol) in dry and degassed N,N-DMF (3 ml) in a screw-cap-sealed
tube was added Pd(OAc)2 (3 mg, 6 mol%) under argon and the sealed tube
was placed in a preheated oil bath at 958C. The mixture was heated with
stirring for 18 h and then allowed to come to room temperature. It was then
diluted with water (30 ml) and extracted with ethyl acetate (2 ꢀ 30 ml). The
organic extract was washed with hydrochloric acid (1 N, 10 ml), water
(20 ml), and brine (20 ml). It was then dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo. The residual brownish mass was chromato-
graphed over silica using an appropriate eluent.
Methyl 2-(f(Z)-2-[(tert-butoxycarbonyl)amino]-3-phenyl-2-propanoylg
amino)acetate (2a): Eluted with 30% ethyl acetate in petroleum ether.
Yield: 52%. Mp 1438C. IR (KBr, cm21): 3291, 2979, 2929, 1740, 1708,
1
1665, 1527, 1368, 1205, 1164. H-NMR (300 MHz, CDCl3): d 7.40–7.26
(5H, m), 7.15 (1H, s), 6.90 (1H, br s), 6.16 (1H, s), 4.18 (2H, d,
J ¼ 5.1 Hz), 3.78 (3H, s), 1.42 (9H, s). 13C-NMR (75 MHz, CDCl3): d

Arylation of Didehydropeptides
1173
170.3, 165.7, 153.7, 133.8, 129.3, 128.9, 128.7, 128.4, 128.1, 81.4, 52.3, 41.6,
28.1. Anal. found: C, 61.22%; H, 6.69%; N, 8.49%; C17H22N2O5 requires C,
61.07%; H, 6.63%; N, 8.38%.
Methyl (2S)-2-(f(Z)-2-[(tert-butoxycarbonyl)amino]-3-phenyl-2-pro-
penoylg-amino)-3-phenylpropanoate (2b): Eluted with 20% ethyl acetate
in petroleum ether. Yield: 61%. Mp 1188C. [a]D þ 52 (c 0.14 in CHCl3). IR
1
(KBr, cm21): 3316, 2913, 1721, 1668, 1512, 1367, 1246, 1163. H-NMR
(300 MHz, CDCl3): d 7.45–7.14 (10H, m), 7.10 (1H, s), 6.80 (1H, d,
J ¼ 7.5 Hz), 5.99 (1H, br s), 5.01–4.95 (1H, m), 3.72 (3H, s), 3.20 (2H, d,
J ¼ 5.6 Hz), 1.40 (9H, s). 13C-NMR (75 MHz, CDCl3): d 171.7, 165.0,
153.5, 135.8, 133.7, 129.3, 129.0, 128.9, 128.7, 128.5, 128.2, 127.0, 81.3,
53.6, 52.2, 37.9, 28.0. m/z (FAB): 446 (Mþ þ Na). Anal. found: C,
68.11%; H, 6.74%; N, 6.48%; C24H28N2O5 requires C, 67.91%; H, 6.65%;
N, 6.60%.
Methyl 2-f[2-(f(Z)-2-[(tert-butoxycarbonyl)amino]-3-phenyl-2-pro-
penoylg-aminogacetyl]aminogacetate (4): Eluted with 40% ethyl acetate
in petroleum ether. Yield: 49%. Mp 1428C. IR (KBr, cm21): 3323, 2979,
1744, 1665, 1527, 1368, 1248, 1162.1H-NMR (300 MHz, CDCl3): d 7.41–
7.33 (5H, m), 7.27 (1H, br s), 7.10 (1H, br s), 6.90 (1H, br s), 6.37 (1H, s),
4.14 (2H, d, J ¼ 5.9 Hz), 4.04 (2H, d, J ¼ 5.7 Hz), 3.72 (3H, s), 1.44 (9H,
s). 13C-NMR (75 MHz, CDCl3): d 170.1, 169.6, 165.9, 154.2, 133.5, 129.1,
128.9, 82.0, 52.2, 43.3, 41.0, 28.1. m/z (FAB): 414 (Mþ þ Na). Anal.
found: C, 58.56%; H, 6.52%; N, 10.71%; C19H25N3O6 requires C, 58.30%;
H, 6.44%; N, 10.74%.
Methyl (Z)-2-(f(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropa-
noylg-amino)-3-phenyl-2-propenoate (10): Eluted with 30% ethyl acetate
in petroleum ether. Yield: 58%. Mp 1108C. [a]D 2 50 (c 0.27 in CHCl3).
IR (KBr, cm21): 3293, 2928, 2850, 1716, 1675, 1497, 1437, 1267, 1169.
1H-NMR (300 MHz, CDCl3): d 7.69 (1H, s), 7.36–7.12 (11H, m), 4.99 (1H,
d, J ¼ 6.6 Hz), 4.51–4.49 (1H, m), 3.81 (3H, s), 3.20 (1H, dd, J ¼ 13.9, 7.1
Hz), 3.06 (1H, dd, J ¼ 14.0, 7.3 Hz), 1.39 (9H, s). 13C-NMR (75 MHz,
CDCl3): d 170.2, 165.3, 155.6, 136.4, 133.4, 132.6, 129.7, 129.4, 129.3,
128.6, 128.5, 126.9, 123.8, 80.5, 55.9, 52.6, 37.4, 28.2. m/z (EI, 70 eV):
424 (Mþ, 10.8%), 368 (16.7%), 177 (100%). Anal. found: C, 68.06%; H,
6.72%; N, 6.56%; C24H28N2O5 requires C, 67.91%; H, 6.65%; N, 6.60%.
Methyl 4- ((Z)-2-f[(2S)-2- (f(2S)-2-[(tert-butoxycarbonyl)amino]-3-
phenylpropanoylg-amino)-3-phenylpropanoyl]aminog-3-methoxy-3-oxo-
1-propenyl)benzoate (12): Eluted with 30% ethyl acetate in petroleum
ether. Yield: 55%. [a]D þ36 (c, 0.04 in CHCl3). IR (neat, cm21): 3278,
2984, 1663, 1649, 1523, 1497, 1438, 1367, 1283, 1164. 1H-NMR
(300 MHz, CDCl3): d 8.00 (2H, d, J ¼ 8.1Hz), 7.90 (1H, br s), 7.45 (2H, d,
J ¼ 8.0 Hz), 7.37 (1H, s), 7.30–7.26 (6H, m), 7.14–7.11 (4H, m), 6.33 (1H,
d, J ¼ 7.8 Hz), 4.82–4.79 (2H, m), 4.21–4.19 (1H, m), 3.91 (3H, s), 3.82
(3H, s), 3.08–2.93 (4H, m), 1.27 (9H, s). 13C-NMR (75 MHz, CDCl3):

1174
S. K. Chattopadhyay, B. K. Pal, and S. Biswas
d 170.9, 170.6, 169.6, 155.1, 136.3, 136.0, 134.1, 130.5, 130.0, 129.7, 129.6,
129.3, 128.9, 128.8, 128.2, 127.3, 80.6, 59.9, 52.9, 52.6, 38.3, 28.3. m/z
(FAB): 652 (Mþ þ Na). Anal. found: C, 66.81%; H, 6.28%; N, 6.67%;
C35H39N3O8 requires C, 66.76%; H, 6.24%; N, 6.67%.
ACKNOWLEDGMENT
The authors are thankful to C. S. I. R., New Delhi for grants and fellowship.
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