Synthesis of a conformationally constrained phenylalanine derivative by a strategic combination of ring-closing enyne metathesis and Diels-Alder reaction

Article abstract of DOI:10.1055/s-2008-1067237

An efficient route towards the synthesis of a conformationally constrained phenylalanine derivative is demonstrated using the strategic combination of ring-closing enyne metathesis and Diels-Alder reaction as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067237

PAPER
2925
Synthesis of a Conformationally Constrained Phenylalanine Derivative by a
Strategic Combination of Ring-Closing Enyne Metathesis and Diels–Alder
Reaction
Synthesis of
a
a
Conformat
m
ionally Constrained
b
Phenylalani
a
D
erivativ
s
e
ivarao Kotha,* Priti Khedkar
Department of Chemistry, Indian Institute of Technology – Bombay, Mumbai 400076, India
Fax +91(22)5723480; E-mail: srk@chem.iitb.ac.in
Received 29 April 2008; revised 21 May 2008
CO2R
NR
Abstract: An efficient route towards the synthesis of a conforma-
tionally constrained phenylalanine derivative is demonstrated using
the strategic combination of ring-closing enyne metathesis and
Diels–Alder reaction as key steps.
CO2R
NR
1
2
Key words: constrained amino acid, phenylalanine, ring closure,
metathesis, Diels–Alder
CO2R
NR
CO2R
NR
In the view of increasing demand for peptide-based
drugs,1 conformationally constrained amino acid deriva-
tives have become useful tools in bioorganic chemistry.
There are restrictions in employing peptides as drugs and
these include several factors, such as instability towards
proteolytic degradation, poor absorption after oral inges-
tion, rapid excretion through liver and kidneys, and undes-
ired effects caused by interaction of the conformationally
flexible peptides with various receptors. It has been well
established that incorporation of a constrained amino acid
unit in a peptide chain can modify the physiological as
well as binding properties of the resulting peptide.2 Pep-
tide modifications3 by incorporation of conformationally
constrained amino acids in bioactive peptides and drugs
can result in better substrates for structure–activity rela-
tionship studies.4
3
4
Figure 1 Conformationally constrained phenylalanine analogues
(R = H)
gies based on [2+2+2]-cyclotrimerization reactions10 and
ring-closing enyne metathesis strategies are useful.11
Along similar lines, higher analogues of Tic 1 such as,
2,3,4,5-tetrahydro-1H-3-benzazepine-2-carboxylic acid
(2), 1,2,3,4,5,6-hexahydro-3-benzazocine-2-carboxylic
acid (3), and 2,3,4,5,6,7-hexahydro-1H-3-benzazonine-2-
carboxylic acid (4) seem to be attractive synthetic
targets12 due to their projected utility in peptidomimetics
and pharmacological studies.13 Most of the known meth-
ods available for the preparation of these compounds start
with the preformed benzene derivatives, so they provide
limited opportunity for the introduction of diverse func-
tional groups in the benzene ring.12
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic, 1)
(Figure 1) is a constrained analogue of phenylalanine
(Phe). In Tic 1, the six-membered heterocyclic ring is
formed by incorporation of a methylene unit in between
the amino group and the aromatic ring of the phenylala-
nine. This type of amino acid plays an important role in
designing peptidomimetics.5 It was found that the incor-
poration of Tic 1 in the second position of an opioid recep-
tor exerts conformational restrictions and results in
distinct changes in its activity and selectivity.6 The tet-
rahydroisoquinoline unit is a key element in several pep-
tide-based drugs and forms an integrated part of various
biologically active molecular frameworks.7 Commonly,
Tic 1 and its derivatives are assembled via Pictet–
Spengler reaction and Bischler–Napieralsky reaction or
by alkylation strategies.8 To expand the ‘building block
approach’9 for the synthesis of highly functionalized Tic
derivatives, our group has demonstrated that methodolo-
Herein, we describe our efforts towards the synthesis of
highly functionalized higher analogues of Tic 1 using
ring-closing enyne metathesis14 and Diels–Alder
reactions15 as key steps (Scheme 1). This strategy pro-
vides a unique advantage over the existing methods, as di-
verse substituents in the aromatic ring may be introduced
by the judicious selection of the reacting partners.
Ring-closing enyne metathesis is an attractive process,
which enables the generation of a diene that can easily un-
dergo Diels–Alder reaction with various dienophiles to
deliver intricate polycyclic compounds. The preparation
of the diene, in the presence of reactive functional groups
(-NH2, -CO2Et) is not a trivial task. The commercial avail-
ability of Grubbs first generation catalyst, G-I and Grubbs
second generation catalyst, G-II (Figure 2)16 has provided
access to a wide range of dienes suitable for the construc-
tion of highly functionalized polycycles.
SYNTHESIS 2008, No. 18, pp 2925–2928
x
x.
x
x
.
2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067237; Art ID: Z09908SS
© Georg Thieme Verlag Stuttgart · New York

2926
S. Kotha, P. Khedkar
PAPER
R
R
The first task in our strategy involves the alkylation of the
amide nitrogen of ethyl 2-(tosylamino)pent-4-ynoate (5)
with 4-bromobut-1-ene. The substrate 6 can be subjected
to enyne metathesis to generate diene 7, which in turn may
undergo a [4+2]-cycloaddition reaction with a suitable di-
enophile. Later on, oxidation of 8 may deliver the highly
substituted seven-membered ring analogue of Tic. Thus,
the enyne 6 can be used as a building block to construct
various derivatives of 2,3,4,5-tetrahydro-1H-3-benz-
azepine-2-carboxylic acid by ring-closing enyne meta-
thesis and Diels–Alder reactions as key steps.
R
R
iv
NTs
NTs
EtO2C
EtO2C
9
8
iii
ii
i
NHTs
Towards the realization of this strategy, the alkyne deriv-
ative 5 was treated with 4-bromobut-1-ene and potassium
carbonate in dry acetonitrile at 65 °C to obtain ethyl 2-
[but-3-enyl(tosyl)amino]pent-4-ynoate (6) in 78% yield
(Scheme 2).
NTs
NTs
CO2Et
EtO2C
CO2Et
5
6
7
Scheme 1 A retrosynthetic approach to a conformationally cons-
trained phenylalanine derivative. Reagents and conditions: (i) 4-bro-
mobut-1-ene, base; (ii) Grubbs catalyst; (iii) dienophile; (iv)
aromatization.
The next task in hand was to realize the ring-closing enyne
metathesis strategy as shown Scheme 1. When enyne 6
was subjected to ring-closing enyne metathesis in the
presence of G-I for 24 hours in dry toluene, the complete
conversion of starting material into diene 7 could not be
achieved. However, Grubbs second generation catalyst
G-II delivered the desired diene in 54% yield (Scheme 3).
PCy3
Mes
N
N
Mes
Ph
Ph
H
Cl
Cl
Ru
Cl
Cl
Ru
1
Although, the diene was characterized by H NMR, IR,
PCy3
H
and HRMS data, the 13C NMR spectrum of this material
showed some minor additional peaks that may arise from
decomposition of this sensitive diene. Therefore, the di-
ene 7 was immediately subjected to Diels–Alder reaction
with dimethyl acetylenedicarboxylate to furnish com-
pound 8. Further, functionalized 2,3,4,5-tetrahydro-1H-3-
benzoazepine-2-carboxylic acid derivative 9 was obtained
by the aromatization of 8 using 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (Scheme 4).
PCy3
G-I
G-II
Figure 2
4-bromo-1-butene, K2CO3
MeCN, 65 °C, 14 h, 78%
N
Ts
CO2Et
TsHN
CO2Et
6
5
In conclusion, a building block approach towards the con-
struction of a conformationally constrained phenylalanine
analogue using ring-closing enyne metathesis and Diels–
Alder reactions as key steps has been demonstrated. The
Scheme 2
G-I
G-II
NTs
NTs
CO2Et
6
NTs
toluene, 100 °C,
24 h, 54%
toluene, 100 °C,
24 h, mixture of 6 & 7
EtO2C
EtO2C
7
7
Scheme 3
MeO2C
MeO2C
CO2Me
CO2Me
DDQ
DMAD
NTs
toluene, reflux,
50%
toluene, reflux,
39%
NTs
NTs
EtO2C
EtO2C
EtO2C
7
8
9
Scheme 4
Synthesis 2008, No. 18, 2925–2928 © Thieme Stuttgart · New York

PAPER
Synthesis of a Conformationally Constrained Phenylalanine Derivative
2927
HRMS (Q-Tof): m/z [M + H]+ calcd for C18H24NO4S: 350.1426;
found: 350.1412.
method has several advantages over the existing proce-
dures, as it provides an opportunity to install the desired
substituents in the benzene ring under construction.
2-Ethyl 6,7-Dimethyl 3-Tosyl-2,3,4,5,5a,8-hexahydro-1H-3-
benzazepine-2,6,7-tricarboxylate (8)
To a soln of 7 (27 mg, 0.077 mmol) in dry toluene (20 mL) was add-
ed DMAD (17 mg, 0.118 mmol). The mixture was heated to reflux
for 17 h maintaining the inert atmosphere. At the completion of re-
action (TLC) the mixture was allowed to cool to r.t. and solvent was
removed under reduced pressure. The crude material obtained was
purified by column chromatography (silica gel, 20% EtOAc–hex-
ane) to give 8 (15 mg, 39%) as a colorless liquid; Rf = 0.26 (silica
gel, 30% EtOAc–hexane).
All reactions were monitored by TLC carried out on glass plates
coated with Acme silica gel GF 254 (containing 13% CaSO4 as a
binder). Visualization of the spots on TLC plates was achieved ei-
ther by exposure to I2 vapor or UV light. Flash chromatography was
performed using Acme silica gel (100–200 mesh). Hexane refers to
fraction having boiling point 60–80 °C. All commercial grade re-
agents were used without further purification. IR spectra were re-
corded on a Nicolet Impact 400 FT-IR spectrometer in KBr–
1
CH2Cl2. H NMR (400 MHz) and 13C NMR (75 and 100.6 MHz)
IR (neat): 1966, 1648, 1265, 1157 cm–1.
spectra were determined at r.t. on a Varian VXR 300 in CDCl3 solns
with TMS as internal reference. HRMS were determined on Micro-
mass Q-Tof spectrometer. Starting material 5 was prepared using
literature procedures.11,17
1H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7.2 Hz, 3 H), 1.40–
1.51 (m, 2 H), 1.96 (td, J1 = 14 Hz, J2 = 4 Hz, 1 H), 2.11 (dd,
J1 = 13.6 Hz, J2 = 11.6 Hz, 1 H), 2.40 (s, 3 H), 2.79–3.03 (m, 4 H),
3.36 (dd, J1 = 14 Hz, J2 = 12 Hz, 1 H), 3.76 (s, 6 H), 3.96–4.06 (m,
2 H), 4.50 (dd, J1 = 10 Hz, J2 = 7.2 Hz, 1 H), 5.55–5.59 (m, 1 H),
7.25 (d, J = 8 Hz, 2 H), 7.64 (d, J = 8 Hz, 2 H).
Ethyl 2-[But-3-enyl(tosyl)amino]pent-4-ynoate (6)
To a stirred suspension of finely powdered K2CO3 (100 mg, 0.72
mmol) in anhyd MeCN (15 mL) was added 5 (43 mg, 0.145 mmol)
and 4-bromobut-1-ene (24 mg, 0.17 mmol). The resulting heteroge-
neous mixture was heated at 65 °C for 14 h under N2. The mixture
was cooled and filtered over a short Celite pad. The filtrate was con-
centrated under reduced pressure and diluted with H2O (15 mL).
The aqueous layer was extracted with EtOAc (3 × 25 mL). The
combined organic layers were washed with H2O (25 mL) and brine
(25 mL) and dried (anhyd Na2SO4). Removal of the solvent gave the
crude product that was purified by column chromatography (silica
gel, 5% EtOAc–hexane) to give 6 (40 mg, 78%) as a colorless thick
liquid; Rf = 0.5 (silica gel, 30% EtOAc–hexane).
13C NMR (100.6 MHz, CDCl3): d = 14.1, 21.6, 28.1, 34.9, 37.7,
42.5, 43.7, 52.4, 52.4, 58.8, 61.4, 121.7, 127.3, 127.5, 129.6, 129.6,
131.9, 132.8, 137.2, 137.6, 143.4, 168.0, 168.3, 171.6.
HRMS (Q-Tof): m/z [M + Na]+ calcd for C24H29NNaO8S: 514.1512;
found: 514.1524.
2-Ethyl 6,7-Dimethyl 3-Tosyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine-2,6,7-tricarboxylate (9)
To a soln of 8 (50 mg, 0.10 mmol) in dry toluene (25 mL) was added
DDQ (80 mg, 0.35 mmol) and the mixture was refluxed for 48 h.
The mixture was then allowed to cool to r.t. and solvent was re-
moved under reduced pressure. The crude material obtained was
purified by column chromatography (silica gel, 20% EtOAc–hex-
ane) to give 9 (25 mg, 50%) as a colorless thick liquid; Rf = 0. 27
(silica–gel, 30% EtOAc–hexane).
IR (neat): 1737, 1644, 1343, 1160 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.15 (t, J = 7.2 Hz, 3 H), 2.01 (t,
J = 2.8 Hz, 1 H), 2.42–2.46 (m, 5 H), 2.67–2.88 (m, 2 H), 3.12–3.38
(m, 2 H), 4.05 (q, J = 7.2 Hz, 2 H), 4.66–4.70 (m, 1 H), 5.06–5.08
(m, 2 H), 5.65–5.77 (m, 1 H) 7.28 (d, J = 8.2 Hz, 2 H), 7.75 (d,
J = 8.2 Hz, 2 H).
IR (neat): 1966, 1644, 1266 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 7 Hz, 3 H), 2.38 (s, 3
H), 2.81–2.97 (m, 2 H), 3.27–3.44 (m, 4 H), 3.76–4.07 (m, 8 H),
5.16 (m, 1 H), 7.20–7.27 (m, 3 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.75
(d, J = 8 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 14.0, 21.5, 34.9, 46.0, 59.0,
61.7, 71.6, 79.4, 117.1, 127.7, 128.2, 129.4, 129.5, 130.0 134.7,
137.1, 143.5, 169.4.
HRMS (Q-Tof): m/z [M + Na]+ calcd for C18H23NNaO4S: 372.1245;
found: 372.1244.
13C NMR (100.6 MHz, CDCl3): d = 14.1, 21.5, 32.2, 38.9, 43.4,
52.5, 52.7, 56.0, 61.4, 126.8, 127.3, 128.4, 129.6, 131.5, 135.2,
137.1, 137.9, 142.3, 143.4, 165.9, 169.0, 169.6.
Ethyl 1-Tosyl-4-vinyl-2,3,6,7-tetrahydro-1H-azepine-2-carbox-
ylate (7)
HRMS (Q-Tof): m/z [M + H]+ calcd for C24H28NO4S: 490.1536;
found: 490.1539.
To a soln of 6 (52.2 mg, 0.149 mmol) in dry degassed toluene (20
mL) was added Grubbs’ second generation catalyst G-II (13 mg,
0.015 mmol, 10 mol%). The mixture was heated at 100 °C for 24 h
maintaining the inert atmosphere. The resulting brown soln was al-
lowed to cool to r.t. and solvent was removed under reduced pres-
sure to obtain a crude material that was purified by column
chromatography (silica gel, 10% EtOAc–hexane) gave 7 (28 mg,
54%) as a colorless liquid; Rf = 0.5 (silica gel, 30% EtOAc–hex-
ane).
Acknowledgement
We thank the DST, New Delhi for the financial support and SAIF-
Mumbai for providing spectral facilities. P.K. thanks the CSIR,
New Delhi for the award of research fellowship.
References
IR (neat): 1966, 1651, 1265 cm–1.
(1) (a) Pillai, O.; Panchagnula, R. Drug Discovery Today 2001,
6, 1056. (b) Fletcher, K. Pharm. Sci. Technol. Today 1998,
1, 49. (c) Cochran, A. G. Chem. Biol. 2000, 7, R85. (d) van
Hest, J. C. M.; Tirrell, D. A. Chem. Commun. 2001, 1897.
(2) (a) Wang, W.; Cai, M.; Xiong, C.; Zhang, J.; Trivedi, D.;
Hruby, V. J. Tetrahedron 2002, 58, 7365. (b) Rajesh, B. M.;
Iqbal, J. Curr. Pharm. Biotechnol. 2006, 7, 247.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, J = 7.2 Hz, 3 H), 2.38–
2.62 (m, 6 H), 3.00–3.16 (m, 1 H), 3.43–3.74 (m, 2 H), 3.94–4.08
(m, 2 H), 4.93–5.17 (m, 3 H), 5.75 (t, J = 6 Hz, 1 H), 6.25 (dd,
J1 = 16 Hz, J2 = 10 Hz, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.71 (d, J = 8
Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 14.1, 21.6, 28.7, 29.6, 42.7,
57.2, 61.3, 111.4, 117.1, 127.4, 128.3, 129.6, 130.0, 132.1, 137.1,
139.6, 143.3, 170.5.
Synthesis 2008, No. 18, 2925–2928 © Thieme Stuttgart · New York

2928
S. Kotha, P. Khedkar
PAPER
Carroll, F. I. Synthesis 2008, 856. (l) Wohlgemuth, R.;
(3) (a) Kotha, S.; Lahiri, K. Curr. Med. Chem. 2005, 12, 849.
(b) Liskamp, R. M. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
305.
(4) Griffiths, E. C. In A Text Book of Drug Design and
Development; Krogsgaard, L.; Bundgaard, P., Eds.;
Harwood Academic Publishers: Tokyo, 1992, 487–528.
(5) (a) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999,
55, 585. (b) Kazmierski, W.; Hruby, V. J. Tetrahedron
1988, 44, 697.
(6) (a) Schiller, P. W.; Nguyen, T. M.; Weltrowska, G.; Wilkes,
B. C.; Marsden, B. J.; Lemieux, C.; Chung, N. N. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 11871. (b) Kazmierski, W. M.;
Yamamura, H. I.; Hruby, V. J. J. Am. Chem. Soc. 1991, 113,
2275. (c) Lazarus, L. H.; Bryant, S. D.; Cooper, P. S.;
Guerrini, R.; Balboni, G.; Salvadori, S. Drug Discovery
Today 1998, 3, 284.
(7) (a) Austin, N. E.; Avenell, K. Y.; Boyfield, I.; Branch, C. L.;
Coldwell, M. C.; Hadley, M. S.; Jeffrey, P.; Johns, A.;
Johnson, C. N.; Nash, D. J.; Riley, G. J.; Smith, S. A.;
Stacey, R. C.; Stemp, G.; Thewlis, K. M.; Vong, A. K. K.
Bioorg. Med. Chem. Lett. 1999, 9, 179. (b) Chen, K. X.;
Njoroge, F. G.; Pichardo, J.; Prongay, A.; Butkiewicz, N.;
Yao, N.; Madison, V.; Girijavallabhan, V. J. Med. Chem.
2006, 49, 567.
Benz, P. J. Chem. Technol. Biotechnol. 2007, 82, 1082.
(m) Aubry, S.; Pellet-Rostaing, S.; Faure, R.; Lemaire, M. J.
Heterocycl. Chem. 2006, 43, 139. (n) Ooi, T.; Takeuchi, M.;
Maruoka, K. Synthesis 2001, 1716. (o) Shchetnikov, G. T.;
Osipov, S. N.; Bruneau, C.; Dixneuf, P. H. Synlett 2008, 578.
(9) For the ‘building block approach’ see: (a) Kotha, S. Acc.
Chem. Res. 2003, 36, 342. (b) Corey, E. J.; Cheng, X.-M.
The Logic of Chemical Synthesis; John Wiley: New York,
1989.
(10) Kotha, S.; Sreenivasachary, N. Bioorg. Med. Chem. Lett.
2000, 10, 1413.
(11) (a) Kotha, S.; Sreenivasachary, N. Chem. Commun. 2000,
503. (b) Kotha, S.; Sreenivasachary, N. Eur. J. Org. Chem.
2001, 3375.
(12) (a) Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.;
Tozer, M. J. J. Chem. Soc., Perkin Trans. 1 1997, 447.
(b) Gibson, S. E.; Middleton, R. J. J. Chem. Soc., Chem.
Commun. 1995, 1743.
(13) (a) Gibson, S. E.; Guillo, N.; Jones, J. O.; Buck, I. M.;
Kalindjian, S. B.; Roberts, S.; Tozer, M. J. Eur. J. Med.
Chem. 2002, 37, 379. (b) Gibson, S. E.; Guillo, N.;
Kalindjian, S. B.; Tozer, M. J. Bioorg. Med. Chem. Lett.
1997, 7, 1289.
(8) For selected examples: (a) Manabe, K.; Nobutou, D.;
Kobayashi, S. Bioorg. Med. Chem. 2005, 13, 5154.
(b) Comins, D. L.; Thakker, P. M.; Baevsky, M. F.; Badawi,
M. M. Tetrahedron 1997, 53, 16327. (c) Chen, H. G.; Goel,
O. P. Synth. Commun. 1995, 25, 49. (d) Jansa, P.;
Machacek, V.; Bertolasi, V. Heterocycles 2006, 68, 59.
(e) Liu, Z. Z.; Tang, Y. F.; Chen, S. Z. Chin. Chem. Lett.
2001, 12, 947. (f) Capilla, A. S.; Romero, M.; Pujol, M. D.;
Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297.
(g) Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Chem.
Soc., Perkin Trans. 1 2002, 116. (h) Mash, E. A.; Williams,
L. J.; Pfeiffer, S. S. Tetrahedron Lett. 1997, 38, 6977.
(i) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341. (j) Kotha, S.; Sreenivasachary, N. J. Indian
Inst. Sci. 2001, 81, 277; and references cited therein.
(k) Liu, C.; Thomas, J. B.; Brieaddy, L.; Berrang, B.;
(14) For selected reviews on enyne metathesis, see: (a) Hansen,
E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509. (b) Maifeld,
S. V.; Lee, D. Chem. Eur. J. 2005, 11, 6118. (c) Diver, S.
T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (d) Poulsen,
C. S.; Madsen, R. Synthesis 2003, 1.
(15) Fringuelli, F.; Taticchi, A. The Diels–Alder Reaction:
Selected Practical Methods; John Wiley & Sons: Chichester,
2002.
(16) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100. (b) Schwab, P.; France, M. B.; Ziller, J.
W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039. (c) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W.
J. Am. Chem. Soc. 1995, 117, 5503. (d) Scholl, M.; Ding,
S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(17) Brahmachary, E. PhD Thesis; IIT-Bombay: India, 2000.
Synthesis 2008, No. 18, 2925–2928 © Thieme Stuttgart · New York