Crystallization-induced asymmetric transformation. Application to conjugate addition of benzylamine to amides of benzoylacrylic acid

Article abstract of DOI:10.1016/j.tetlet.2004.04.066

Adducts of the conjugate addition of benzylamine to enantiopure amides of aroylacrylic acid possess high enantiomeric and diastereomeric purity. A high degree of stereoselectivity has been achieved by means of crystallization- induced asymmetric transform

Full text of DOI:10.1016/j.tetlet.2004.04.066

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4755–4758
Crystallization-induced asymmetric transformation.
Application to conjugate addition of benzylamine
to amides of benzoylacrylic acid
ꢀ
ꢀ*
Pavol Jakubec, Dusan Berkes and Frantisek Povazanec
ꢀ
ꢀ
Department of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology,
Radlinskꢁeho 9, SK-812037 Bratislava, Slovak Republic
Received 27 February 2004; revised 8 April 2004; accepted 13 April 2004
Abstract—Adducts of the conjugate addition of benzylamine to enantiopure amides of aroylacrylic acid possess high enantiomeric
and diastereomeric purity. Ahigh degree of stereoselectivity has been achieved by means of crystallization-induced asymmetric
transformation. Apractical synthesis leading to dipeptides containing homophenylalanine is depicted.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Our attention has been focused on the application of
CIAT to the reversible conjugate addition of chiral
N-nucleophiles to aroylacrylic acids.4;5 It represents a
direct and straightforward way to diverse homophenyl-
alanine (Hfe) derivatives.6;7 Now we would like to pres-
ent an enlargement of this methodology to the direct
preparation of N-substituted dipeptides with a Hfe sub-
unit starting from enantiomerically pure aroylacrylic
amides 6 (Scheme 2) derived from commercial amino
acids.
Crystallization-induced asymmetric transformation
(CIAT) is a promising methodology for the control of
the stereochemical outcome of diverse chemical reac-
tions. There are number of intriguing applications where
CIAT has been used to obtain enantiomerically and
diastereomerically pure molecules simply by crystalli-
zation of one of two equilibrating isomers. Recoveries
can approach 100% based on the mixture regardless of
the equilibrium constant in solution.1 The CIAT
approach has been used for control of the absolute
configuration of stereogenic carbons2 or other hetero-
elements.3
The synthesis of modified oligopeptides has attracted
significant attention (Scheme 1). N-Substituted dipep-
tides 1a,b with
L
-Hfe incorporated represent a new class
OMe
O
O
O
H
O
O
O
H
N
H
N
N
R2
Met
N
H
.HCl
O
N
S
HOOC
N
H
O
O
R1
O
a: R1=Bn, R2=NHPh
b: R1=i-Pr,R2=NHPh
1a-b
2
3
Scheme 1.
Keywords: Crystallization-induced; Asymmetric transformation; Dipeptide; Homophenylalanine.
* Corresponding author. Tel./fax: +421-2-52968560; e-mail: dusan.berkes@stuba.sk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.066

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P. Jakubec et al. / Tetrahedron Letters 45 (2004) 4755–4758
Table 1. Conjugate addition of benzylamine to amides 6a–d
of potent inhibitors of matrix metalloproteinases, a
novel class of drugs for the treatment of arthritis.8;9
Entry Ar
R
Yield Dr
(%)
Configuration
D
-Hfe based dipeptides are useful in the design of a new
class of stable efflux pump inhibitors.10 Tripeptides 2
with oxo-substituted -Hfe incorporated have been
7a
7b
7c
7d
Ph
Ph
Bn
Ph
Bn
72
81
76
>95:5 (2S,20S)
>95:5 (2S,20S)
>95:5 (2S,20S)
>95:5 (2S,20R)
L
synthesized as a structural framework for subsequent
elaboration into anti-inflammatory oligopeptides.11
Already, amino acid based amides of aroylacrylic acids 3
have shown significant activity such as, for example,
nanomolar inhibitors of the cytomegalovirus protease.12
4-MeOPh
4-MeOPh
CH2i-Pr 76
The conjugate addition of an N-nucleophile to chiral
a,b-unsaturated acyclic amides leading to a-amino acids
is not common in the literature and the known examples
have low stereoselectivity.16 On the other hand, the
CIAT process has served well in the synthesis of
a-amino acids using aroylacrylic acids as substrates for
conjugate addition of N-nucleophiles.4;5 We supposed
that the success of previously published CIAT on this
conjugate addition to aroylacrylic acids is based on the
formation of only slightly soluble amino acids at their
isoelectric point. This scenario can be applied to the
reaction of amides of aroylacrylic acids with a free
carboxyl function. The product of such addition has
also to be the slightly soluble zwitterionic structure. Our
anticipation was correct for the phenyl substituted
amides 6a,b.17 Addition of benzylamine to amides 6a,b
were successful with only 1.1 molar equiv of base. The
best results are summarized in Table 1. The same con-
ditions when applied to 4-methoxyphenyl substituted
amides 6c,d led to very low conversion and poor dia-
stereoselectivity.
2. Results and discussion
The synthesis of amides of benzoylacrylic acids 6a–d is
outlined in Scheme 2. (E)-3-Aroylacrylic acid 4 was
treated with DCC and N-hydroxysuccinimide13 at 20 °C
in tetrahydrofuran for 24 h.14
The isolated active ester 5 was then coupled to an amino
acid in dimethoxyethane.15 The amides 6a–d were iso-
lated sufficiently pure for subsequent conjugate addition
and were used directly without crystallization in the next
step.
O
O
i
OSu
OH
Ar
Ar
O
O
a: Ar = Ph
b: Ar = 4-MeO-Ph
a: Ar = Ph
b: Ar = 4-MeO-Ph
5
4
It was necessary to increase the temperature to 40 °C
and to use 2 equiv of amine to achieve sufficient con-
version and dr. The corresponding adducts 7c,d were
obtained as crystalline salts with an excess of benzyl-
amine (Scheme 3).
6a: Ar = Ph, R = Bn (86%)
6b: Ar = Ph, R = Ph (83%)
6c: Ar = 4-MeO-Ph, R = Bn (94%)
ii
6d: Ar = 4-MeO-Ph, R =CH2i-Pr (87%)
O
O
The course of the addition and the CIAT process has
been monitored for the addition of benzylamine to the
amide 6a. As can be seen from Figure 1 the mixture of
both diastereomers was initially formed with a prev-
alence for the (2S,2R0)-7a isomer (dr ¼ 60:40). However,
CIAT changed the sense of stereo induction and as a
result the less soluble (2S,2S0)-7a was finally isolated in
H
N
Ar
OH
O
R
6a-d
Scheme 2. Reagents and conditions: (i) N-Hydroxysuccinimide, DCC,
THF, 24 h, )20 °C; (ii) a-amino acid, NaHCO3, dimethoxyethane, 1 h.
Bn
O
HN
O
X=H
H
N
BnNH (1.1 eq.)
2
OH
H O, 20-25°C, 7 d
2
O
R
O
O
H
N
7a, b
OH
a: R = Bn (72%)
b: R = Ph (81%)
d.r. > 95:5
O
O
R
X
6a-d
Bn
X=OCH
3
O
HN
*
H
N
BnNH (2.0 eq.)
2
H O, 40°C, 2 d
O NH Bn
2
3
O
R
7c, d
MeO
c: R = Bn (76%)
d.r. > 95:5
d: R = CH i-Pr (76%)
2
Scheme 3. Conjugate addition of benzylamine to unsaturated amides 6a–d.

P. Jakubec et al. / Tetrahedron Letters 45 (2004) 4755–4758
4757
100
90
80
70
60
50
40
30
20
10
0
3. Elucidation of absolute configuration
After hydrolysis of dipeptides 8a–d under standard
conditions19 (6 M HCl, reflux, 6 h), it was possible to
confirm the absolute configuration of the newly syn-
thesized stereogenic centre by means of chiral column
chromatography using Crownpak CR(+) and the
appropriate Hfe standard.
1
1.5
2
3
4
18 24 27 45 51 66 72 138 214
Time [hours]
Figure 1. The stereochemical course of addition of benzylamine to
amides 6a, j––(2S,20R)-diastereomer 7a, Ö–(2S,20S)-diastereomer
7a.
4. Summary
The use of reversible conjugate addition of benzylamine
to chiral unsaturated amides and CIAT represents a
straightforward method for the preparation of enan-
tiomerically enriched dipeptides with homophenylala-
nine residues. This chemistry requires no special
precautions and can be run on a multi-gram scale.
Applications to the synthesis of metalloproteinase
inhibitors are in progress.
high excess (dr>95:5) after filtration. The crystallization
of the less soluble diastereomer was successful in all the
examples studied. As can be seen for compound 7d there
is no rule for prediction of the sense of stereo induction.
No specific intramolecular role is required for the aux-
iliary or its proximity to the equilibrating stereogenic
centre. The most important function of the existing
stereogenic centre is to influence the intermolecular
interactions that govern crystal packing.3 The absolute
configuration of C-2 is opposite to the other examples
(7a–c) studied. However in this case also the diastereo-
meric purity of the isolated product is comparable to the
purity of all the other adducts 7a–c.
Acknowledgements
Financial support by the Slovak Grant Agency No 1/
9250/02 is gratefully acknowledged.
Adducts 7a–d are stable in the solid state, but are prone
to slow epimerization in solution, therefore we decided
to use them directly in follow up reactions. Reduction of
the carbonyl group and simultaneous debenzylation was
accomplished by catalytic hydrogenation (Table 2). In
the case of phenyl substituted derivatives 7a,b (X ¼ H)
the stable dipeptides 8a,b were obtained by hydrogena-
tion in EtOH/water/HBr18 (Scheme 4).
References and notes
1. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; John Wiley & Sons: New York,
1994; pp 364–374.
2. Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 447–456.
€
3. Vedejs, E.; Chapman, R. W.; Lin, S.; Muller, M.; Powell,
The same process failed for 7c,d and led only to a
mixture of unidentified products. The best results for the
methoxyphenyl substituted derivatives (X ¼ OMe) with
only negligible racemization were obtained in the EtOH/
H2SO4 system (Scheme 4).
D. R. J. Am. Chem. Soc. 2000, 122, 3047–3052.
4. Yamaha, M.; Nagashima, N.; Hasegawa, J.; Takahashi,
S. Tetrahedron Lett. 1998, 39, 9019–9022.
5. Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F.
Tetrahedron Lett. 2001, 42, 2579–2582.
6. Berkes, D.; Lopuch, J.; Proksa, B.; Povazanec, F. Chem.
Pap. 2003, 57, 349–353.
7. Berkes, D.; Kolarovic, A.; Povazanec, F. Tetrahedron
Lett. 2000, 41, 5257–5260.
Table 2. Preparation of dipeptides 8a–d
Entry Ar
R
Yield Dr
(%)
Configuration
8. Chapman, K. T.; Wales, J.; Sahoo, S. P.; Niedzwiecki, L.
M.; Izqulerdo-Martin, M.; Chang, B. C.; Harrison, R. K.;
Stein, R. L.; Hangmann, W. K. Bioorg. Med. Chem. Lett.
1996, 6, 329–332.
9. Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman,
K.; Decicco, C. P.; DeGrado, W. F. J. Am. Chem. Soc.
1996, 118, 10337–10338.
8a
8b
8c
8d
Ph
Ph
Bn
Ph
Bn
68
62
64
>95:5 (2S,20S)
>95:5 (2S,20S)
>95:5 (2S,20S)
>95:5 (2S,20R)
4-MeOPh
4-MeOPh
CH2i-Pr 77
ꢁ
10. (a) Renau, T. E.; Leger, R.; Filonova, L.; Flamme, E. M.;
Wang, M.; Yen, R.; Madsen, D.; Griffith, D.; Chamber-
land, S.; Dudley, M. N.; Lee, V. J.; Lomovskaya, O.;
Watkins, W. J.; Ohta, T.; Nakayama, K.; Ishida, Y.
Bioorg. Med. Chem. Lett. 2003, 13, 2755–2758; (b) Renau,
NH2
H
i
N
COOH
7a-d
*
O
R
ꢁ
T.; Leger, R.; Flamme, E. M.; She, M. W.; Gannon, C. L.;
X
Mathias, K. M.; Lomovskaya, O.; Chamberland, S.; Lee,
V. J.; Ohta, T.; Nakayama, K.; Ishida, Y. Bioorg. Med.
Chem. Lett. 2001, 11, 663–667.
8a-d
Scheme 4. Reagents and conditions: (i) (for 7a,b): EtOH/water 5:1,
HBr (48%), 10% Pd/C, H2, 40 °C, 30 h; (i) (for 7c,d): EtOH/1 N H2SO4
1:3, 10% Pd/C, H2, 50 °C, 24 h.
ꢁ
11. Berree, F.; Chang, K.; Cobas, A.; Rapoport, H. J. Org.
Chem. 1996, 61, 715–721.

4758
P. Jakubec et al. / Tetrahedron Letters 45 (2004) 4755–4758
12. Pinto, I. L.; Jarvest, R. L.; Clarke, B.; Dabrowski, C. E.;
Fenwick, A.; Gorczyca, M. M.; Jennings, L. J.; Lavery, P.;
Sternberg, E. J.; Tew, D. G.; West, A. Bioorg. Med. Chem.
Lett. 1999, 9, 449–452.
13. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M.
J. Am. Chem. Soc. 1964, 86, 1839–1842.
17. Typical procedure: Amide 6a (2.619 g, 8.1 mmol) was
suspended in water (90 mL). To this suspension benzyl-
amine (0.972 mL, 8.9 mmol) was added. The resulting
mixture was vigorously stirred for 7 days at 20–25 °C. The
precipitated 7a was filtered off, washed with Et2O and
dried. The same result was achieved when the mixture was
stirred for 2 days at 40 °C. (1.918 g, 72%, dr >95:5, 72%, mp
14. Typical procedure: Asolution of the acid 4a (0.192 g,
1 mmol) and N-hydroxysuccinimide (0.115 g, 1 mmol) in
dry THF (10 mL) was cooled in an ice-water bath and
dicyclohexylcarbodiimide (0.217 g, 1.05 mmol) was added
with stirring. The mixture was kept in a refrigerator
()20 °C) for 24 h. The separated N,N0-dicyclohexylurea
was removed by filtration and the solvent evaporated in
vacuo. The crude product was recrystallized from isopro-
panol (yellow solid, 80–91%, mp 105–107 °C, 1H NMR
(300 MHz, DMSO-d6): 2.88 (s, 4 H); 7.02 (d, 1H,
180–182 °C, ½aꢀ +25.5 0.1 (c 1.0, MeOH/1 M HCl ¼ 3:1
D
1
at 20 °C), H NMR (300 MHz, acetone-d6/DCl): 3.03 (dd,
1H, J3A;2 ¼ 10:0, J3A;3B ¼ 14:1, H-3A); 3.29 (dd, 1H, J3B;2
¼
¼
0
0
4:8 Hz, J3B;3A ¼ 14:1 Hz, H-3B); 3.88 (dd, 1H, J3 A;2
6:6 Hz, J3 A;3 B ¼ 18:6, H-30 A); 4.06 (d, 1H, J ¼ 12:9 Hz,
0
0
0
0
0
0
PhCH2NH-A); 4.08 (dd, 1H, J3 B;2 ¼ 5:7 Hz, J3 B;3 A
¼
18:9 Hz, H-30 B); 4.19 (d, 1H, J ¼ 13:2 Hz, PhCH2NH-
B); 4.57 (‘t’, 1H, J2 ;3 B ¼ 6:0 Hz, J2 ;3 A ¼ 6:0 Hz, H-20); 4.79
(dd, 1H, J2;3B ¼ 4:7 Hz, J2;3A ¼ 10:0 Hz, H-2); 7.05–7.94
(m, 15H, H-Arom), 13C NMR acetone-d6/DCl: 37.5 (C-3);
39.7 (C-30); 50.6 (PhCH2NH); 54.7 (C-2); 56.2 (C-20); 127.3;
128.9; 129.0; 129.6; 130.1; 131.1; 131.3; 134.6; 136.3; 137.9
(C-Arom); 167.5 (C-10); 172.5 (C-1); 196.9 (C-40)).
0
0
0
0
J2 ;3 ¼ 15:9 Hz, H-20); 7.57–7.76 (m, 5H, H-Arom); 8.29
0
0
(d, 1H, J3 ;2 ¼ 15:9 Hz, H-3), 13C NMR (75 MHz, DMSO-
d6): 25.41 (C-3, C-4); 124.74; 128.97; 134.30; 135.45 (Ph, C-
20); 142.13 (C-30); 161.06 (C-10); 169.90 (C-2,5); 188.46 (C-
40)).
0
0
18. Typical procedure: Peptide 7a (1.507 g, 3.5 mmol) was
suspended in a mixture of EtOH/water (75 mL/15 mL) and
48% hydrobromic acid (1.174 g, 7.0 mmol) and 10% Pd/C
(0.301 g) were added. The suspension was stirred under H2
(1.1 bar) for 30 h at 40 °C. Thereafter the catalyst was
filtered off and the volume of residue was reduced in vacuo
to about 10 mL and the pH of the solution was adjusted to
about 6. The precipitated 8a was filtered off, washed with
15. Typical procedure: Amixture of phenylalanine (0.661 g,
4 mmol) and sodium hydrogen carbonate (0.339 g,
4 mmol) in water was treated with a solution of ester 5a
(1.011 g, 3.7 mmol) in dimethoxyethane (20 mL). One hour
later water (30 mL) was added and the solution acidified to
pH 2 with 4 M hydrochloric acid. The crude oily product
solidified on cooling. The crystals were washed on the filter
with cold water and dried to afford 6a (1.196 g, 86%, 139–
Et2O and dried (white solid, 68%, mp 276–279 °C ½aꢀ
D
1
142 °C, ½aꢀ )4.4 0.2 (c 1.0, MeOH at 20 °C), H NMR
+19.8 0.1 (c 0.5, MeOH/1 M HCl ¼ 3:1 at 20 °C), 1H
NMR (300 MHz, D2O/DCl): 2.14 (m, 2H, H-40); 2.67 (m,
2H, H-30); 3.08 (dd, 1H, J3A;2 ¼ 9:0 Hz, J3A;3B ¼ 14:1 Hz,
H-3A); 3.25 (dd, 1H, J3B;2 ¼ 5:6 Hz, J3B;3A ¼ 14:1 Hz, H-
D
(300 MHz, CDCl3): 3.14 (dd, 1H, J3A;3B ¼ 13:8,
J3A;2 ¼ 6:6 Hz, H-3A); 3.26 (dd, 1H, J3B;3A ¼ 14:4 Hz,
J3B;2 ¼ 5:1 Hz, H-3B); 5.03 (m, 1H, H-2); 7.03 (d, 1H,
J2 ;3 ¼ 15:0, H-20); 7.14–7.60 (m, 10H, H-Arom); 7.90 (d,
3B); 3.98 (t, 1H, J2 ;3 ¼ 6:4 Hz, H-20); 4.58 (dd, 1H,
J2;3B ¼ 5:6 Hz, J2;3A ¼ 9:0 Hz, H-2); 7.23–7.42 (m, 10H, H-
arom), 13C NMR (DMSO-d6/DCl): 30.4 (C-40); 33.7 (C-3);
36.6 (C-30); 52.2 (C-20); 54.5 (C-2); 126.6, 127.1, 128.7,
128.9, 129.0, 129.6, 137.7, 141.4 (C-Arom); 168.9 (C-10);
172.9 (C-1)).
0
0
0
0
1H, J3 ;2 ¼ 15:0 Hz, H-30); 7.98 (d, 1H, JNH;2 ¼ 6:9 Hz,
NH), 13C NMR (75 MHz, CDCl3): 37.3 (C-3); 53.7 (C-2);
127.3; 128.7; 128.8; 129.0; 129.3; 133.9; 134.0; 134.6; 135.5;
134.5 (C-Arom, C-20, C-30); 164.5 (C-10); 174.2 (C-1); 190.0
(C-40)).
0
0
16. Harada, K.; Matsumoto, K. J. Org. Chem. 1966, 31, 2985–
2990.
19. Bodansky, M.; Bodansky, A. The Practice of Peptide
Synthesis; Springer: Berlin Heidelberg, 1994. p 209.