Highly diastereoselective synthesis of new, carbostyril-based type of conformationally-constrained β-phenylserines

Article abstract of DOI:10.1016/S0040-4020(03)01172-4

We have demonstrated that the readily available amido-keto compounds 5, with prearranged carbonyl and glycine moieties, under strongly basic conditions easily undergo complete and highly diastereoselective cyclization, affording a generalized and practical access to the conformationally constrained phenylserine derivatives 4. High chemical yields, virtually complete diastereoselectivity combined with the operational convenience of the experimental procedures render this method useful for preparation of these diastereomerically pure derivatives.

Full text of DOI:10.1016/S0040-4020(03)01172-4

Tetrahedron 59 (2003) 7301–7306
Highly diastereoselective synthesis of new, carbostyril-based type
of conformationally-constrained b-phenylserines
*
Hisanori Ueki, Trevor K. Ellis, Masood A. Khan and Vadim A. Soloshonok
Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Room 208, Norman, OK 73019, USA
Received 5 June 2003; revised 22 July 2003; accepted 24 July 2003
Abstract—We have demonstrated that the readily available amido–keto compounds 5, with prearranged carbonyl and glycine moieties,
under strongly basic conditions easily undergo complete and highly diastereoselective cyclization, affording a generalized and practical
access to the conformationally constrained phenylserine derivatives 4. High chemical yields, virtually complete diastereoselectivity
combined with the operational convenience of the experimental procedures render this method useful for preparation of these
diastereomerically pure derivatives.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(dynorphin A,8a deltorphin,8b enkephalins8c,d), peptidic
a-adrenergic agonists8e and enzyme inhibitors,8f as well as
in the study of protein folding.8e Application of the
tetrahydroisoquinoline-based model Tic-2, as a Phe analog
with restricted x 1, x 2 as well as f torsional angles, has been
found to be even more successful. Thus, a systematic study
of Tic-2 for peptide design lead to the development of
potent, yet highly selective angiotensin-converting enzyme
inhibitor ‘Quinapril’,10 a tripeptide currently under clinical
trials, as well as dipeptide Dmt-Tic,11 a potent pharmaco-
phore, representing a conformationally constrained Tyr–
Phe moiety. The most conformationally constrained in this
series, the 3,4-dihydro-1H-quinolin-2-one (carbostyril)-
based model 312 with four restricted torsional angles, x 1,
x 2, c and v, has also been found useful as an analog of Phe
in the design of di-tripeptides. In particular, very promising
results have been reported on the application of model 3 in
the design of HIV-1 reverse transcriptase inhibitors,13a
dopamine D2/D4 receptor antagonists,13b metalloproteinase
inhibitors13c–e as well as other biologically active peptides
and peptidomimetics.13f–h Besides Phe, scaffolds 1–3 have
been used for preparing structurally similar aromatic amino
acid derivatives such as tyrosine and DOPA.8,9,11 On the
other hand the application of models 1–3 as conformation-
ally constrained analogs of other amino acids with
substituents on the aliphatic moiety of 1–3 is not
straightforward and might require the development of new
approaches methodologically different to those applicable
for preparing Phe and its derivatives. Thus, to the best of our
knowledge, no carbostyril-based models of a-hydroxy-
phenylalanine (phenylserine) 4 have been reported to date.
Herein we report the first and highly diastereoselective
(.99/1) synthesis of a new type of conformationally
constrained phenylserine derivatives 4a–e, starting from
The availability of synthetic methods allowing the design
and synthesis of tailor-made amino acids1 and related
compounds is a critical component of any current effort to
understand the proteome and its relation to life, health and
disease.2 For example, application of specially designed
sterically/conformationally constrained amino acids3 for the
rational modification of native peptide secondary structures
has resulted in remarkable progress in understanding of
peptide three-dimensional (3D) structure and its relationship
to biological activity.4 In particular, considerable effort has
been focused on developing conformationally constrained
analogs of aromatic amino acids because of their import-
ance in protein folding and recognition.5 In the case of
phenylalanine (Phe) and structurally related amino acids,
such as tyrosine and DOPA, the design considerations may
include restriction of the torsional angles f (phi), c (psi) and
v (omega), determining the 3D structure of peptide
backbone,6 as well as the x (chi) torsional angles, which
define the position of side-chain functional groups5 (Fig. 1).
Of the various conformationally constrained derivatives of
Phe reported in the literature,5 cyclic models 17,8 and 29–11
were found to be extremely useful conformationally
constrained scaffolds in the de novo peptide design. For
instance, the tetraline-based constrained Phe-model Atc-1,
allowing the restriction of both x 1 and x 2, has been
successfully used in the design of various opioid peptides
Keywords: diastereoselectivity; a-amino acids and derivatives;
conformational and steric constrain.
*
Corresponding author. Tel.: þ1-4053258279; fax: þ1-4053256111;
e-mail: vadim@ou.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01172-4

7302
H. Ueki et al. / Tetrahedron 59 (2003) 7301–7306
Figure 1. Tetraline- (Atc-1), tetrahydroisoquinoline- (Tic-2) and carbostyril-based (3, 4) models of conformationally phenylalanine and its derivatives.
the readily available amides 5a–e (Scheme 1) containing a
glycine moiety and keto group, thus prearranged for the
intramolecular aldol addition reaction.
(entries 3, 4). Continuation of the reaction for up to three
days resulted in the increased conversion of the starting 5a,
also leading to the enhanced amounts of the dehydration
product 9a (entry 5). Further attempts to improve the
reaction outcome by varying solvents did not give
satisfactory results. For instance, the reactions conducted
in ether or acetonitrile, using KO-t-Bu as the base, furnished
4a as the individual product with virtually complete
diastereoselectivity, however, the conversion of the starting
5a was very low. On the other hand we found that the
increased reaction temperature and amount of the base used
had a critical effect on the reaction outcome. Thus, the
reaction conducted in THF at reflux was completed in only
2 h affording the mixture of 5a and 9a in a ratio of 30/70
(entry 6). Continuation of the reaction for two days resulted
in the formation of 9a as the major product isolated in 87%
yield (Table 1).
2. Results and discussion
Starting compounds 5a–e were prepared according to
Scheme 1. Commercially available amino acids 6a–e
were first treated with ethyl chloroformate to form the
intermediate activated mixed anhydrates 7a–e which were
further condensed with o-aminobenzophenone (8) to afford
amides 5a–e in high (.80%) isolated yields.
The cyclization step was studied first using compound 5a
due its high crystallinity and solubility in various organic
solvents. Taking into account the presence of the amide
hydrogen in 5a–e we assumed that the cyclization might
require formation of the corresponding di-anion. Therefore,
we decided to use at least 2 equiv. of relatively strong base
to effect the cyclization.
Further experiments revealed that elevating the temperature
generally accelerated the reaction rates of both desired aldol
addition and undesired dehydration, suggesting that the
room temperature reactions may be a better option. To our
satisfaction we found that increasing the base/substrate ratio
led to the substantial acceleration of the aldol addition
reaction allowing preparation of the target 4a as an
individual reaction product in quantitative chemical yield
(entries 8 and 9). Thus, application of 7 equiv. of the base
for cyclization of 5a resulted in a clean and fast reaction,
giving rise to the product 4a with virtually complete
chemical and stereochemical outcome (entry 9).
The first attempt, using NaOMe as a base and THF as a
solvent, was rather unsuccessful. The sluggish reaction
proceeded overnight at room temperature to afford only
10% conversion giving rise to the target compound 4a
(entry 1). On the other hand the compound 4a was obtained
as a single product in diastereomerically pure form,
encouraging us to search for optimal reaction conditions.
Application of KOH as the base increased the conversion of
starting 5a (entry 2), but the result was still unsatisfactory.
The use of the stronger bases allowed us to substantially
increase the conversion without compromising the
diastereoselectivity of the reaction. However, the target 4a
was obtained along with the product of its dehydration 9a
It should be emphasized that in all reactions studied, using
different bases, solvents, reaction time and temperature, we
always observed formation of a product 4a as a single
diastereomer. This perfect and robust diastereoselectivity
Scheme 1.

H. Ueki et al. / Tetrahedron 59 (2003) 7301–7306
7303
Table 1. Cyclization of amido–ketones 5a–e to 4a–e
Entry Compound
Base
(equiv.)
Time Conver.
(%)a
Products 4, 9
(h)
Yieldb Ratio 4/9a,c
(%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
NaOMe (2)
KOH (2)
NaO-t-Bu (2) 24
24
24
10
25
54
67
nd
nd
nd
nd
nd
nd
87
nd
98
97
89
97
97
.99/1
.99/1
89/11
88/12
53/47
30/70
8/92
86/14
.99/1
.99/1
.99/1
.99/1
.99/1
KO-t-Bu (2)
KO-t-Bu (2)
KO-t-Bu (2)d
KO-t-Bu (2)d
KO-t-Bu (4)
KO-t-Bu (7)
KO-t-Bu (7)
KO-t-Bu (7)
KO-t-Bu (7)
KO-t-Bu (7)
24
72
2
48
12
2
2
2
2
2
Figure 3. Transition states A and B in the intermolecular cyclization of
5a–e.
77
.99
.99
.99
.99
.99
95
of the stereochemical outcome of the cyclization using
compounds 5b–e bearing various substituents of the glycine
moiety. All reactions were conducted under the standard
conditions represented in entry 9. The diethyl derivative 5b
was converted to the cyclized product 4b, isolated as a pure
diastereomer in 97% yield (entry 10). From the point of
view of potential applications of products 4 as confor-
mationally constrained phenylserine derivatives, of particu-
lar interest were the cyclizations of compounds 5c–e, with
potentially removable substituents on the amino group. The
reaction of the dibenzyl 5c occurred at slightly lower rate
allowing about 95% conversion of the starting compound to
the product 4c under the standard conditions (2 h),
presumably due to the substantial steric bulk of two benzyl
groups (entry 11). On the other hand, the reaction of
xylyleneyl derivative 5d occurred with a similar result to the
alkyl series of perfect reaction outcomes (entry 12 vs 9, 10).
Interestingly, the mono-benzyl substituted derivative 5e,
possessing an unprotected N–H group, easily underwent the
cyclization to afford the diastereomerically pure product 4e
in high chemical yield, suggesting a wider than expected
potential generality of this reaction.
9
10
11
12
13
.99
.99
All reactions were run in commercial-grade THF in the presence of the base
indicated at ambient temperature.
a
Determined by NMR (300 MHz) analysis of the crude reaction mixtures.
Isolated yield of crude product.
Compound 4 was isolated as a single diastereomer.
The reaction was conducted at reflux.
b
c
d
was really a remarkable feature of this reaction. The relative
configuration of the diastereomer 4a was found to be
(3R p,4R p) by single crystal X-ray analysis (Fig. 2).14 It is
interesting to note that crystals of compound 4a made of
successive layers of enantiomerically pure (3R,4R) and
(3S,4S) diastereomers.
To account for the diastereoselectivity observed, we
proposed two transition states (TS) A and B, leading to
the (3R p,4R p) and (3R p,4S p) diastereomers, respectively
(Fig. 3). In both TS A and B the enolate and the carbonyl
oxygens are located in close proximity to each other
allowing the reaction to occur with a thermodynamically
advantageous minimum charge separation.15 On the other
hand, considering the steric interactions in the TS A and B,
we can assume that the latter might be less favorable relative
to TS A. Thus, in TS B the substituted amino group
experiences unfavorable repulsive interactions with the two
phenyl rings, while in the TS A these steric interactions are
minimized. Moreover, in the TS A the amino group and the
enolate oxygen are in cis position allowing the nitrogen to
be involved in the stabilizing coordination to the metal.
Since in some experiments (entries 6 and 7) the compound
9a was obtained as the major reaction product, we also
decided to focus on a selective preparation of the derivatives
of this type. 1H-Quinolin-2-one and in particular its amino
derivatives have been used as pharmacophore unit in the
design of various biologically active compounds, for
instance with oxytocin antagonist activity, antidepressant,
antiallergic activity.16 We found that complete dehydration
of 4a to 9a could be easily achieved by simply heating the
former at temperatures above 1808C or application of
classical dehydration methods such as refluxing a toluene
solution of 4a in the presence of an acidic catalyst. Using
these methods compound 4a was cleanly dehydrated to
With these results in hand we decided to study the generality
Figure 2. X-Ray structure of (3R p,4R p)-4a.

7304
H. Ueki et al. / Tetrahedron 59 (2003) 7301–7306
afford 9a in high chemical yields (96–98%) rendering the
cyclization reactions reported here synthetically versatile
and useful for preparing biologically relevant compounds of
types 4 and 9.
4.1.2. N-(2-Benzoyl-phenyl)-2-diethylamino-acetamide
1
(5b). H NMR d 1.07 (6H, t, J¼7.04 Hz), 2.62 (4H, q,
J¼7.04 Hz), 3.17 (2H, s), 7.07 (1H, ddd, J¼7.91, 7.33,
1.17 Hz), 7.40–7.60 (5H, m), 7.70–7.78 (2H, m), 8.66 (1H,
dd, J¼8.35, 1.17 Hz), 11.6 (1H, bs). 13C NMR d 12.1, 48.6,
58.4, 121.3, 121.9, 125.0, 128.0, 129.7, 132.2, 132.2, 133.1,
138.3, 138.8, 171.8, 197.4. HRMS [MþHþ] found m/s
311.1688, calcd for C19H23N2O2 311.1681. Mp 65.58C.
3. Conclusions
In summary, we have demonstrated that the readily
available amido–keto compounds 5a–e, with prearranged
carbonyl and glycine moieties, under strongly basic
conditions easily undergo a complete and highly diastereo-
selective cyclization, affording generalized and practical
access to the conformationally constrained phenylserine
derivatives 4 as well as amino substituted carbostyrils 9.
High chemical yields and robust, virtually complete
diastereoselectivity, combined with the operational con-
venience of the experimental procedures render this method
worth immediate use for multi-gram scale preparation of
these diastereomerically pure derivatives.
4.1.3. N-(2-Benzoyl-phenyl)-2-dibenzylamino-acetamide
1
(5c). H NMR d 3.20 (2H, s), 3.61 (4H, s), 6.93 (1H, t,
J¼8.57 Hz), 7.03–7.16 (6H, m), 7.34–7.44 (4H, m), 7.44–
7.54 (5H, m), 7.76–7.83 (2H, m), 8.67 (1H, d, J¼8.79 Hz)
11.5 (1H, bs). 13C NMR d 58.2, 59.0, 120.9, 121.4, 124.3,
126.7, 127.7, 128.7, 129.6, 131.6, 132.1, 132.6, 136.9,
137.6, 138.5, 170.0, 197.1. HRMS [MþHþ] found m/s
435.1985, calcd for C29H27N2O2 435.1994.
4.1.4. N-(2-Benzoyl-phenyl)-2-benzylamino-acetamide
1
(5d). H NMR d 3.40 (2H, s), 3.80 (2H, s), 7.42 (1H, m),
7.15–7.26 (3H, m), 7.40–7.58 (7H, m), 7.72–7.75 (2H, m),
8.65 (1H, d, J¼8.4 Hz), 11.66 (1H, bs). 13C NMR d 53.1,
54.3, 121.9, 122.5, 125.0, 127.5, 128.5, 128.6, 128.7, 130.4,
132.8, 133.0, 133.9, 138.7, 139.4, 139.4, 171.4, 198.5.
HRMS [MþHþ] found m/s 345.1540, calcd for C22H21N2O2
345.1532. Mp 75.48C.
4. Experimental
4.1. General
Unless otherwise noted, all reagents and solvents were
obtained from commercial suppliers and used without
4.1.5. N-(2-Benzoyl-phenyl)-2-(1,3-dihydro-isoindol-2-
1
yl)-acetamide (5e). H NMR d 3.56 (2H, s), 4.13 (4H, s),
1
further purification. Unless indicated, H, and 13C NMR
7.09 (1H, ddd, J¼7.82, 7.32, 1.22 Hz), 7.12–7.25 (4H, m),
7.35–7.43 (2H, m), 7.46–7.59 (3H, m), 7.62–7.68 (2H, m),
8.61 (1H, dd, J¼8.43, 1.10 Hz), 11.4 (1H, bs). 13C NMR d
59.8, 60.8, 121.6, 122.0, 122.2, 125.0, 126.5, 127.9, 129.6,
132.1, 132.3, 133.1, 138.0, 138.6, 139.2, 169.9, 197.5.
HRMS [MþNaþ] found m/s 379.1431, calcd for
C23H20N2NaO2 379.1423. Mp 152.48C.
spectra, were taken in CDCl3 solutions at 299.95, 282.24
and 75.42 MHz, respectively, on an instrument in the
University of Oklahoma NMR Spectroscopy Laboratory.
Chemical shifts refer to TMS as the internal standards.
Yields refer to isolated yields of products of greater than
95% purity as estimated by 1H and 13C NMR spectrometry.
1
All new compounds were characterized by H, 13C NMR,
and high resolution mass spectrometry (HRMS/ESI).
4.1.6. 4-Hydroxy-4-phenyl-3-piperidin-1-yl-3,4-dihydro-
1
1H-quinolin-2-one (4a). General procedure. H NMR d
1.34–1.44 (2H, m), 1.46–1.60 (4H, m), 2.48–2.60 (2H, m),
2.66–2.78 (2H, m), 3.34 (1H, s), 6.03 (1H, s), 6.76 (1H, dd,
J¼7.77, 1.18 Hz), 7.10 (1H, td, J¼7.62, 1.17 Hz), 7.14–
7.28 (5H, m), 7.60 (1H, dd, J¼7.62, 1.46 Hz), 8.43 (1H, bs).
13C NMR d 23.6, 26.5, 52.1, 72.2, 74.1 114.7, 124.3, 125.2,
127.1, 127.3, 128.3, 128.6, 129.7, 134.5, 145.4, 167.0.
HRMS [MþNaþ] found m/s 345.1571, calcd for
C20H22N2NaO2 345.1579. Mp 188.68C.
Starting amino acids 6a–d were commercially, 6e was
prepared according to the literature procedure.17
4.1.1. N-(2-Benzoyl-phenyl)-2-piperidin-1-yl-acetamide
(5a). General procedure. Triethylamine (1.69 mL,
12 mmol) was added to a flask containing 6a (6 mmol)
and 10 mL of CH2Cl2 and the mixture was stirred at room
temperature for 20 min under N2. Then, ethyl chloroformate
(0.57 mL, 6 mmol) was added at 08C under N2. After
stirring the mixture for 20 min at room temperature,
2-aminobenzophenone (0.99 g, 5 mmol) was added and the
mixture kept stirring at 40–508C overnight. Water was then
added to quench the reaction and the organic phase was
extracted with CH2Cl2 three times and dried over MgSO4
anhydrous. After evaporation of the solvents and silica gel
column chromatograph afforded the target product 5a.
4.1.7. 3-Diethylamino-4-hydroxy-4-phenyl-3,4-dihydro-
1H-quinolin-2-one (4b). 1H NMR
d 1.09 (6H, t,
J¼7.2 Hz), 2.65 (2H, dtq, J¼19.8, 13.5, 6.9 Hz) 2.73 (2H,
dtq, J¼19.8, 13.5, 6.9 Hz) 3.58 (1H, s), 5.94 (1H, s), 6.80
(1H, d, J¼8.1 Hz), 7.11 (1H, t, J¼7.5 Hz), 7.17–7.26 (5H,
m), 7.60 (1H, d, J¼7.8 Hz), 9.10 (1H, bs). 13C NMR d 14.0,
45.6, 69.3, 72.5, 115.0, 124.8, 125.8, 127.8, 127.8, 128.7,
129.1, 130.0, 135.0, 146.0, 168.7. HRMS [MþHþ] found m/
s 311.1680, calcd for C19H23N2O2 311.1688. Mp 174.68C.
1H NMR d 1.40–1.50 (2H, m), 1.72 (4H, m), 2.50 (4H, m),
3.09 (2H, s), 7.09 (1H, dd, J¼7.82, 7.32 Hz), 7.40–7.65
(5H, m), 7.70–7.80 (2H, m), 8.63 (1H, dd, J¼8.31,
1.10 Hz), 11.5 (1H, bs). 13C NMR d 23.8, 25.8, 54.9, 63.1,
121.4, 121.9, 125.0, 127.9, 129.7, 132.1, 132.1, 132.9,
138.1, 138.7, 170.4, 197.1. HRMS [MþNaþ] found m/s
345.1472, calcd for C20H22N2NaO2 345.1479. Mp 111.58C.
4.1.8. 3-Dibenzylamino-4-hydroxy-4-phenyl-3,4-dihydro-
1H-quinolin-2-one (4c). 1H NMR d 3.62 (2H, d,
J¼12.3 Hz), 3.70 (1H, s), 3.83 (2H, d, J¼12.5 Hz), 5.78
(1H, s), 6.52–6.60 (2H, m), 6.82 (1H, d, J¼7.33 Hz), 7.00–
7.40 (15H, m), 7.62 (1H, dd, J¼7.72, 1.17 Hz), 8.46 (1H,

H. Ueki et al. / Tetrahedron 59 (2003) 7301–7306
7305
bs). 13C NMR d 55.3, 65.9, 72.6, 114.5, 124.5, 125.7, 127.3,
127.4, 127.5, 128.0, 128.4, 128.9, 129.5, 134.7, 137.5,
144.9, 167.1. HRMS [MþHþ] found m/s 435.1990, calcd
for C29H27N2O2 435.1994. Mp 241.28C.
7. For synthesis of 2-aminotetralin-2-carboxylic acid (Atc) (1),
see: (a) Liu, W.; Ray, P.; Benezra, S. A. J. Chem. Soc., Perkin
Trans. 5 1995, 553. (b) Obrecht, D.; Spiegler, C.; Schoenholzer,
P.; Mueller, K.; Heimgartner, H.; Stierli, F. Helv. Chim. Acta
1992, 75, 1666.
8. For applications in peptide design of Atc-1, see: (a) Aldrich,
J. V.; Zheng, Q.; Murray, T. F. Chirality 2001, 13, 125. (b)
Darula, Z.; Peter, A.; Toth, G. J. Labelled Compd. Radio-
pharm. 1997, 39, 817. (c) Schiller, P. W.; Weltrowska, G.;
Nguyen, T. M. D.; Lemieux, C.; Chung, N. N.; Marsden, B. J.;
Wilkes, B. C. J. Med. Chem. 1991, 34, 3125. (d) Deeks, T.;
Crooks, P. A.; Waigh, R. D. J. Pharm. Sci. 1984, 73, 457. (e)
Cordi, A. A.; Lacoste, J.-M.; Descombes, J.-J.; Courchay, C.;
Vanhoutte, P. M.; Laubie, M.; Verbeuren, T. J. J. Med. Chem.
1995, 38, 4056. (f) Denyer, C. V.; Turner-Brown, S. J.;
Knowles, R. G.; Dawson, J. Bioorg. Med Chem. Lett. 1992, 2,
1039. (g) Obrecht, D.; Altorfer, M.; Bohdal, U.; Daly, J.;
Huber, W.; Labhardt, A.; Lehmann, C.; Muller, K.; Ruffieux,
R.; Schonholzer, P.; Spiegler, C.; Zumbrunn, C. Biopolymers
1997, 42, 575.
4.1.9. 3-Benzylamino-4-hydroxy-4-phenyl-3,4-dihydro-
1
1H-quinolin-2-one (4d). H NMR d 1.25 (1H, m), 3.10,
3.35 (2H, AB, J¼13.5 Hz), 3.84 (1H, s), 6.83 (1H, d,
J¼7.8 Hz), 6.91 (2H, m), 7.07 (2H, d, J¼6.6 Hz), 7.17–
7.27 (4H, m), 7.30–7.46 (5H, m), 9.35 (1H, s). 13C NMR d
52.7, 65.1, 75.8, 116.0, 124.0, 127.3, 127.4, 127.5, 127.7,
127.9, 128.4, 128.5, 128.6, 128.8, 129.9, 130.2, 136.2,
139.3, 143.3, 170.1. HRMS [MþHþ] found m/s 345.1383,
calcd for C23H23N2O2 345.1532.
4.1.10. 3-(1,3-Dihydro-isoindol-2-yl)-4-hydroxy-4-phenyl-
3,4-dihydro-1H-quinolin-2-one (4e). 1H NMR d 3.87 (1H,
s), 4.06 (2H, d, J¼11.7 Hz), 4.13 (2H, d, J¼11.7 Hz), 5.37
(1H, bs), 6.83 (1H, dd, J¼8.77, 1.17 Hz), 7.0–7.45 (11H,
m), 7.63 (1H, dd, J¼7.62, 1.17 Hz), 9.74 (1H, bs). 13C NMR
d 55.8, 69.4, 73.5, 115.3, 122.1, 124.7, 125.9, 126.9, 126.9,
127.8, 128.4, 129.0, 129.4, 134.6, 138.4, 143.5, 167.9.
HRMS [MþHþ] found m/s 357.1518, calcd for C23H21N2O2
357.1525.
9. For synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid (Tic) (2), see: Majer, P.; Slaninova, J.; Lebl, M. Int.
J. Pept. Protein Res. 1994, 43, 62.
10. For the most recent papers on ‘Quinapril’ and its analogs
(‘Moexipril’), see: (a) Blumer, J. L.; Daniels, S. R.; Dreyer,
W. J.; Batisky, D.; Walson, Ph. D.; Roman, D.; Ouellet, D.
J. Clin. Pharm. 2003, 43, 128. (b) Warnica, J. W.; Van Gilst,
W.; Baillot, R.; Johnstone, D.; Block, P.; Myers, M. G.;
Chocron, S.; Ave, S. D.; Martineau, P.; Rouleau, J.-L. Can.
J. Cardiol. 2002, 18, 1191. (c) Radauceanu, A.; Virion, J.-M.;
Boivin, J.-M.; Zannad, F. Fundam. Clin. Pharm. 2002, 16,
545. (d) Resnick, L. M.; Lester, M. H. Am. J. Hypertens. 2002,
15, 1096. (e) Saran, R.; Dykstra, D. M.; Wolfe, R. A.;
Gillespie, B.; Held, Ph. J.; Young, E. W. Am. J. Kidney Dis.
2002, 40, 1255. (f) Okuguchi, T.; Osanai, T.; Fujiwara, N.;
Kato, T.; Metoki, N.; Konta, Y.; Okumura, K. Am.
J. Hypertens. 2002, 15, 998. (g) Molinaro, G.; Cugno, M.;
Perez, M.; Lepage, Y.; Gervais, N.; Agostoni, A.; Adam, A.
J. Pharm. Exp. Ther. 2002, 303, 232. (h) Sakata, K.; Yoshida,
H.; Obayashi, K.; Ishikawa, J.; Tamekiyo, H.; Nawada, R.;
Doi, O. J. Hypertens. 2002, 20, 103. (i) Hlubocka, Z.;
Umnerova, V.; Heller, S.; Peleska, J.; Jindra, A.; Jachymova,
M.; Kvasnicka, J.; Horky, K.; Aschermann, M. J. Human
Hypertens. 2002, 16, 557. (j) Culy, C. R.; Jarvis, B. Drugs
2002, 62, 339.
11. For examples of application of 20,60-dimethyl-L-tyrosine
(Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic)
pharmacophore, see: (a) Balboni, G.; Salvadori, S.; Guerrini,
R.; Negri, L.; Giannini, E.; Jinsmaa, Y.; Bryant, S. D.;
Lazarus, L. H. J. Med. Chem. 2002, 45, 5556. (b) Bryant, S. D.;
George, C.; Flippen-Anderson, J. L.; Deschamps, J. R.;
Salvadori, S.; Balboni, G.; Guerrini, R.; Lazarus, L. H.
J. Med. Chem. 2002, 45, 5506. (c) Kumar, V.; Murray, T. F.;
Aldrich, J. V. J. Med. Chem. 2002, 45, 3820.
4.1.11. 4-Phenyl-3-piperidin-1-yl-1H-quinolin-2-one
1
(9a). H NMR d 1.41 (6H, bs), 2.90 (4H, bs), 7.03 (1H,
m), 7.18 (1H, ddd, J¼8.21, 1.91, 0.88 Hz), 7.23–7.52 (7H,
m), 11.9 (1H, bs). 13C NMR d 24.2, 26.4, 51.7, 115.2 121.5,
121.7, 125.8, 127.2, 127.7, 127.8, 129.7, 135.5, 136.6,
139.8, 141.5, 163.1. HRMS [MþNaþ] found m/s 327.1374,
calcd for C20H20N2NaO 327.1473. Mp 233.08C (decomp.).
Acknowledgements
The work was supported by the start-up fund provided by
the Department of Chemistry and Biochemistry, University
of Oklahoma.
References
1. See Ref. 2 in Soloshonok, V. A.; Cai, C.; Hruby, V. J.;
Meervelt, L. V. Tetrahedron 1999, 55, 12045.
2. Hruby, V. J. Acc. Chem. Res. 2001, 34, 389–397.
3. For recent collection of papers on stereocontrolled synthesis of
tailor-made amino acids, see: ‘Asymmetric Synthesis of Novel
Sterically Constrained Amino Acids’, Tetrahedron Symposia-
in-Print; # 88; Guest Editors: Hruby, V. J.; Soloshonok, V. A.
Tetrahedron 2001, 57(30), 6329–6650.
4. Hruby, V. J. Nat. Rev. Drug Discov. 2002, 1, 847–858.
5. For recent review on x-(chi)-constrained amino acids, see:
Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55,
585.
12. For synthesis of 3-amino-3,4-dihydro-1H-quinolin-2-one (3),
see: (a) Juarez-Gordiano, C.; Hernandez-Campos, A.; Castillo,
R. Synth. Commun. 2002, 32, 2959. (b) Minin, P. L.; Walton,
J. C. J. Org. Chem. 2002, 68, 2960.
6. (a) In Molecular Conformation and Biological Interactions;
Balaram, P., Ramaseshan, S., Eds.; Indian Academy of
Science: Bangalore, 1991. (b) Ramachandran, G. N.; Sasise-
kharan, V. Adv. Protein Chem. 1968, 23, 283. (c) Scheraga,
H. A. Chem. Rev. 1971, 71, 195. (d) Bloom, S. M.; Fasman,
G. D.; DeLoze, C.; Blout, E. R. J. Am. Chem. Soc. 1961, 84,
458.
13. For application of model 3 in peptide design, see: (a) Patel, M.;
McHugh, R. J.; Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.;
Erickson-Viitanen, S.; Rodgers, J. D. Bioorg. Med. Chem.
Lett. 2001, 11, 1943. (b) Zhao, H.; Thurkauf, A.; Braun, J.;
Brodbeck, R.; Kieltyka, A. Bioorg. Med. Chem. Lett. 2000, 10,

7306
H. Ueki et al. / Tetrahedron 59 (2003) 7301–7306
2119. (c) Shono, T.; Motoyama, M.; Tatsumi, K.; Ulbrich, N.;
Total reflection measured¼18062 (2umax¼53.08), unique
reflections¼6695 [R(int)¼0.0250]. Final R1¼0.0797 for
5795 ‘observed reflections’ [I.2s(I)], wR2¼0.2282 (for
6695 unique reflections), and Goodness-of-fit on F 2¼0.964.
Iwamoto, Y.; Kuwano, M.; Ono, M. Angiogenesis 1999, 2,
319. (d) Iki, K.; Tsutsumi, M.; Kido, A.; Sakitani, H.;
Takahama, M.; Yoshimoto, M.; Motoyama, M.; Tatsumi, K.;
Tsunoda, T.; Konishi, Y. Carcinogenesis 1999, 20, 1323. (e)
Kido, A.; Tsutsumi, M.; Iki, K.; Motoyama, M.; Takahama,
M.; Tsujiuchi, T.; Morishita, T.; Tatsumi, K.; Tamai, S.;
Konishi, Y. Jpn. J. Cancer Res. 1999, 90, 333. (f) Lewis, R. J.;
Francis, C. A.; Lehr, R. E.; LeRoy Blank, C. Tetrahedron
2000, 56, 5345. (g) Masubuchi, K.; Taniguchi, M.; Umeda, I.;
Hattori, K.; Suda, H.; Kohchi, Y.; Isshiki, Y.; Sakai, T.;
Kohchi, M.; Shirai, M.; Okabe, H.; Sudoh, M.; Yamazaki, T.;
Shimma, N. Bioorg. Med. Chem. Lett. 2000, 10, 1459. (h)
Tamura, S. Y.; Goldman, E. A.; Bergum, P. W.; Semple, J. E.
Bioorg. Med. Chem. Lett. 1999, 9, 2573.
23
˚
The largest diff. peak and hole¼1.144 and 20.349 e A
,
respectively. The complete X-ray data were deposited with
Cambridge Crystallographic Data Centre.
15. Suzuki, K.; Seebach, D. Liebigs Ann. Chem. 1992, 51.
16. (a) Beier, N.; Labitzke, E.; Medeski, W. K. R.; Radunz, H.-E.
Heterocycles 1994, 39, 117. (b) Hino, K.; Kawashima, K.;
Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm.
Bull. 1989, 37, 110. (c) Hino, K.; Furukawa, K.; Nagai, Y.;
Uno, H. Chem. Pharm. Bull. 1980, 28, 2618. (d) Buckle, D. R.;
Cantello, B. C. C.; Smith, H.; Spicer, B. A. J. Med. Chem.
1975, 18, 726. (e) Torisawa, Y.; Nishi, T.; Minamikawa, J.
Bioorg. Med. Chem. Lett. 2002, 12, 387. (f) Uray, G.;
Niederreiter, K. S.; Belaj, F.; Fabian, W. M. F. Helv. Chem.
Acta 1999, 82, 1408. (g) Fabian, W. M. F.; Niederreiter, K. S.;
Uray, G.; Stadlbauer, W. J. Mol. Struct. 1999, 477, 209. and
references there in.
14. A colorless crystal (0.22£0.16£0.04 mm) of 4a (C20H22N2O2)
was used for X-ray diffraction measurement. The data were
collected at 120(1) K on a Bruker APEX CCD diffractometer
˚
with Mo Ka radiation (l¼0.71073 A). Crystal system is
triclinic and space group is P-1 with a¼ 10.322(1),
˚
b¼12.265(1), c¼14.336(2) A, a¼73.487(2)8, b¼70.446(2)8,
17. Mancilla, T.; Carrillo, L.; Zamudio-Rivera, L. S.; Beltran,
H. I.; Farfan, N. Org. Prep. Proced. Int. 2001, 33, 341.
3
3
˚
g¼83.155(2)8, V¼1639.0(3) A , Z¼4, D(calc)¼1.307 Mg/m ,