Palladium(0)-catalyzed regioselective synthesis of α-dehydro-β-amino esters from amines and allyl acetates: Synthesis of a α-dehydro-β-amino acid derived cyclic peptide as a constrained β-turn mimic

Article abstract of DOI:10.1021/jo010981d

Acetates derived from the adducts of the Baylis-Hillman reaction can be reacted in a regioselective manner with amines in the presence of palladium(0) catalyst to afford α-dehydro-β-amino esters (2 and 3) in good yields. The regioselectivity of the reaction can be controlled by temperature and reaction medium leading to the synthesis of regioisomers 2 or 3. The α-dehydro-β-amino acid 3 is a turn inducer, and the dipeptides 6 derived from it show the presence of an eight-membered intramolecular hydrogen bond. Also, cobalt(II) chloride catalyzes the cleavage of epoxy peptides with α-dehydro-β-amino acid derivative 3b to afford the corresponding dipeptide derivatives 8, which exhibit an intramolecular hydrogen bond and thus mimic a β-turn. This intramolecular hydrogen bonding preorganizes the corresponding diallylated peptide 8c for cyclization via ring-closing metathesis to afford the cyclic peptide 9 as a constrained mimic of a β-turn.

Full text of DOI:10.1021/jo010981d

P a lla d iu m (0)-Ca ta lyzed Regioselective Syn th esis of
r-Deh yd r o-â-a m in o Ester s fr om Am in es a n d Allyl Aceta tes:
Syn th esis of a r-Deh yd r o-â-a m in o Acid Der ived Cyclic P ep tid e a s
a Con str a in ed â-Tu r n Mim ic
S. Rajesh, Biswadip Banerji, and J aved Iqbal*,†
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
javediqbaldrf@hotmail.com
Received October 8, 2001
Acetates derived from the adducts of the Baylis-Hillman reaction can be reacted in a regioselective
manner with amines in the presence of palladium(0) catalyst to afford R-dehydro-â-amino esters
(2 and 3) in good yields. The regioselectivity of the reaction can be controlled by temperature and
reaction medium leading to the synthesis of regioisomers 2 or 3. The R-dehydro-â-amino acid 3 is
a turn inducer, and the dipeptides 6 derived from it show the presence of an eight-membered
intramolecular hydrogen bond. Also, cobalt(II) chloride catalyzes the cleavage of epoxy peptides
with R-dehydro-â-amino acid derivative 3b to afford the corresponding dipeptide derivatives 8,
which exhibit an intramolecular hydrogen bond and thus mimic a â-turn. This intramolecular
hydrogen bonding preorganizes the corresponding diallylated peptide 8c for cyclization via ring-
closing metathesis to afford the cyclic peptide 9 as a constrained mimic of a â-turn.
In tr od u ction
using palladium-tetrakis-triphenylphosphine4 as cata-
lyst in different solvent systems.
The ever-increasing demand for the design and syn-
thesis of small molecule peptidomimetics1 as pharma-
ceutical probes and drug leads has led to hectic research
activities in the area of new drug discovery. For example,
constrained amino acid as a mimic for the bioactive
conformation of a drug molecule provides an exciting
opportunity for designing molecules with good pharma-
cokinetics and pharmacodynamics. The dehydro-R-amino
acids have been incorporated in peptides to provide
constrain, which helps such species to bind with the
target in an entropically advantageous way. In view of
the importance of â-amino acids as useful pharmaceutical
probes, we felt that an R-dehydro-â-amino acid would be
a useful residue in rendering a peptide more favorable
to binding to its target.2 In the present study, we
demonstrate an easy synthesis of R-dehydro-â amino
esters through a temperature-dependent regioselective
attack of primary amines to Baylis-Hillman3 acetates
Resu lts a n d Discu ssion
The reaction of acetates derived by Baylis-Hillman
protocol with various amines in the presence of pal-
ladium(0) catalyst has shown interesting reaction profiles
under different conditions. Thus aniline and its para-
substituted derivatives reacted with allyl acetates 1 in
THF medium at ambient temperature (condition A) to
afford R-dehydro-â-amino esters 2 as the major products,
and the reaction mixture contained the other regioisomer
3 in minor amounts only (Table 1). The substituents on
the para position of aniline were found to exert moderate
to good influence on the regiochemical outcome of the
(2) For peptides derived from dehydro amino acids, see: (a) Stam-
mer, C. H. Chemistry and Biochemistry of Amino Acids, Peptides and
Protein; Weinstien, B., Ed.; Marcel Dekker: New York, 1982; Vol. IV,
p 3. (b) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1988, 159.
(c) Nunami, K.; Hirmatsu, K.; Hayashi, K.; Matsumoto, K. Tetrahedron
1988, 44, 5467. (d) Patel, H. C.; Singh, T. P.; Chauhan, V. S.; Kaur, P.
Biopolymer 1990, 29, 509. (e) Ciajolo, M. R.; Tuzi, A.; Pratesi, C. R.;
Fissi, A.; Pieroni, O. Biopolymer 1992, 32, 727. (f) Rajashankar, K. R.;
Ramakumar, S.; Chauhan, V. S. J . Am. Chem. Soc. 1992. 114, 9225.
(g) Pieroni, O.; Fissi, A.; Pratesi, C.; Temussi, P. A. Ciardelli, F.
Biopolymer 1994, 33, 1.
(3) (a) Hoffman, H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl.
1983, 22, 795. (b) For a recent review on Baylis-Hillman reactions,
see: Basavaiah, D.; Rao, D. P.; Hyma, R. S. Tetrahedron 1996, 52,
8001.
(4) For reviews of Pd(0)-catalyzed reactions, see: (a) Trost, B. M.
Acc. Chem. Res. 1980, 13, 385. (b) Tsuji, J .; Minami, I. Acc. Chem. Res.
1987, 20, 147. (c) Heck, R. F. Palladium Reagents in Organic Synthesis;
Academic Press: London, 1985. (d) Godleski, S. A. Nucleophiles with
Allyl-Metal Complex. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4,
Chapter 3.3, pp 585-661.
† Present Address: Director, Regional Research Laboratory, Trivan-
drum 695019, India.
(1) (a) Krauthauser, S.; Christianson, L. A.; Powell, D. R.; Gellman,
S. H. J . Am. Chem. Soc. 1997, 119, 11719. (b) Curran, T. P.; Chandler,
N. M.; Kennedy, R. J .; Keaney, M. T. Tetrahedron Lett. 1996, 37, 1933.
(c) Hermkens, P. H. H.; Dinther, T. G.; J oukema, C. W.; Wagenaars,
G. N.; Ottenheijm, H. C. J . Tetrahedron Lett. 1994, 35, 9271. (d) Ripka,
W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.; Blaney, J . M.
Tetrahedron 1993, 49, 3593 and 3609. (e) Gardner, B.; Nakanishi, H.;
Kahn, M. Tetrahedron 1993, 49, 3433. (f) Nowick, J . S.; Powell, N. A.;
Martinez, E. J .; Smith, E. M.; Noronha, G. J . Org. Chem. 1992, 57,
3763. (g) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J . A. J . Am. Chem.
Soc. 1998, 120, 4334. (h) Li, W.; Burgess, K. Tetrahedron Lett. 1999,
40, 6527. (i) Smith, J . A.; Pease, L. G. CRC Crit. Rev. Biochem. 1980,
8, 315. (j) Haubner, R.; Finsinger, D.; Kessler, H., Angew. Chem., Int.
Ed. Engl. 1997, 36, 1374. (k) J ones, I. G.; J ones, W.; North, M. J . Org.
Chem. 1998, 63, 1505. (l) Kemp, D. S.; Li, Z. Q. Tetrahedron Lett. 1995,
36, 4179.
10.1021/jo010981d CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002
7852
J . Org. Chem. 2002, 67, 7852-7857

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters
TABLE 1. P a lla d iu m (0)-Ca ta lyzed Syn th esis of r-Deh yd r o-â-a m in o Ester s
THF, rt
(condition A)
MeCN, reflux
(condition B)
entry
amine (R)
ratio (2/3)b
yielda (%)
ratiob (2/3)
yielda (%)
1
2
3
4
C6H5
2a /3a (3:1)
2b/3b (6:1)
2c/3c (5:1)
2d /3d (3:1)
65
59
61
56
2a /3a (1:8)
2b/3b (1:10)
2c/3c (1:7)
2d /3d (1:10)
68
61
57
60
p-MeOC6H5
p-MeC6H5
p-ClC6H5
a
b
Yield of the isolated compounds 2 and 3 by column chromatography. Ratio determined by 1H NMR of the crude reaction mixture.
TABLE 2. P a lla d iu m (0)-Ca ta lyzed Syn th esis of r-Deh yd r o-â-a m in o Ester s: Effect of Su bstitu en t in Allyl Aceta te on th e
Regioch em istr y of Am in o Ester s
X
R
compd (ratio, yield, %)a,b
OMe (1b)
Cl (1c)
OMe (1b)
Cl (1c)
p-MeOC6H5
2e/3e (90:10, 76)
2f/3f (15:85, 68)
2g/3g (90:10, 66)
2h /3h (2:98, 78)
CH2C6H5
a
b
Ratio determined by 1H NMR of the crude reaction mixture. Yield of the isolated mixture of 2 and 3.
reaction with the p-methoxy substituent exhibiting a high
selectivity in favor of the kinetic product 2 (Table 1,
condition A, entry 2). On the other hand, the Pd(0)-
catalyzed reaction of allyl acetate 1 in acetonitrile at 80
°C (condition B) resulted in the formation of E-R-dehydro-
â-amino ester as the major product. The product 2 was
found only in minor amounts, and the para substituent
effect of aniline was not observed under these conditions
(Table 1, condition B).
We have also noticed the substituent effect in the
aromatic ring of the allyl acetate 1 on the regiochemistry
of R-dehydro-â-amino ester formation. Thus, the reaction
of acetate 1b (containing a p-methoxyphenyl group) with
p-anisidine under condition A afforded a high ratio of the
product 2e along with the small amount of the corre-
sponding product 3e (Table 2). On the other hand, the
reaction of allyl acetate 1c (having a p-chlorophenyl
substituent) gave the corresponding product 3f as the
major product (Table 2). A similar selectivity was also
observed with benzylamine, which afforded the product
2g as the major product in case of reaction with 1b,
whereas the corresponding product 3h was formed as the
only product on reaction with allyl acetate 1c.
dictated by the structure of the substrate. Interestingly,
the palladium-catalyzed reactions with acetates 1 are
highly chemoselective as only the N-allylated products
are formed on reaction with 4-hydroxy-L-proline methyl
ester.
Thus, the reaction of 4-hydroxy-L-proline methyl ester
with 1a ,b,d -f gave the corresponding R-dehydro-â-amino
ester derivatives 4a -e, respectively, as the only product
in good yields (Table 3, entries 1-5). These products were
obtained predominantly under both (i.e., A and B) reac-
tion conditions. In most of the cases, the geometry of the
double bond was found to be E, which was assigned on
the basis of literature precedence.6 The (E,E) geometry
for 4e was assigned by its single-crystal X-ray structure.7
It is noteworthy that the reaction of 4-hydroxy-L-proline
methyl ester with 1d and 1e afforded 4b and 4d ,
respectively, as a mixture of geometrical isomers (E and
Z) in good yields (Table 3, entries 3 and 4). Similarly,
the reaction of the acetate 1a with L-serine methyl ester
having primary amine and hydroxy groups afforded the
expected product 4f as a single geometrical isomer in good
yields (Table 3, entry 6).
R-Deh yd r o-â-a m in o Acid s a s Tu r n In d u cer s. The
R-dehydro-â-amino ester 3 can be converted by usual
coupling protocols to the corresponding dipeptides 6,
which show interesting hydrogen-bonding properties
Recently, Trost and co-workers5 have shown asym-
metric N-alkylation of amino esters where the new
stereogenic centers at carbon is dictated by the catalyst
and not by the substrate. However, in our case, we find
that the regiochemistry of the amino ester is completely
(6) The (E) and (Z) geometry was assigned on the basis of the
correlation with methyl crotanate as mentioned in: Silverstein, R. M.;
Bassler, G. C.; Morrile, T. C. In Spectoscopic Identification of Organic
Compounds; J ohn Wiley and Sons: New York, 1981.
(7) The single-crystal X-ray structure of these compounds will be
published later.
(5) For Pd(0)-catalyzed allylation of amines, see: Trost, B. M.;
Calkins, T. L.; Oertelt, C.; Zambrano, J . Tetrahedron Lett. 1998, 39,
1713.
J . Org. Chem, Vol. 67, No. 22, 2002 7853

Rajesh et al.
TABLE 3. P a lla d iu m (0)-Ca ta lyzed Rea ction of Am in o Ester s w ith Aceta tes of th e Ba ylis-Hillm a n Ad d u ct
*Only one product is achieved under both reaction conditions.
(Scheme 1). Thus, the amino esters 3 were converted to
N-cinnamoyl esters 5 on reaction with cinnamoyl chloride
and subsequently hydrolyzed to the corresponding acids.
The acids were coupled with L-R-amino esters to afford
the corresponding dipeptides 6 in good yields. The
dipeptides 6a -c showed the presence of an eight-
membered hydrogen bond10,14 in the1H NMR and FT-IR
(Scheme 1). The chemical shifts of the amide protons and
the presence of the intramolecular hydrogen bonds in
6a -c were proved by standard protocols as described in
the literature by FT-IR and by recording the proton NMR
spectra of 6a -c dissolved in various concentrations of
(12) Titanium tetraisopropoxide mediated transesterification with
allyl alcohol was carried out according to the following reference:
Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zuger, M. Synthesis 1982, 138.
(13) (a) Feng, Y.; Wang, Z.; J in, S.; Burgess, K. J . Am. Chem. Soc.
1998, 120, 10768. (b) Kim, K.; Germanas, J . P. J . Org. Chem. 1997,
62, 2853.
(8) For cobalt(II) chloride catalyzed cleavage of epoxy amide with
aniline derivatives, see: (a) Bhatia, B.; J ain, S.; De, A.; Bagchi, I.; Iqbal,
J . Tetrahedron Lett. 1996, 37, 7311. (b) De, A.; Ghosh, S.; Iqbal, J .
Tetrahedron Lett. 1997, 38, 8379.
(9) For polyaniline-supported cobalt-catalyzed epoxidation, see: (a)
Das, B. C.; Iqbal, J . Tetrahedron Lett. 1997, 38, 2903. (b) Punniya-
murthy, T.; Iqbal, J . Tetrahedron Lett. 1997, 38, 4463. (c) De, A.; Basak,
P.; Iqbal, J . Tetrahedron Lett. 1997, 38, 8383.
(14) The presence of intramolecular hydrogen bond was proved by
standard protocol as mentioned in ref 10, by FT-IR and by recording
the proton NMR spectrum of 6a -c, 8b dissolved in various concentra-
tion of DMSO-d6 in CDCl3. The amide protons are generally character-
ized by appearance of signal between 6 and 9 ppm, a region where
hydroxy protons are seldom observed. The chemical shift of the amide
proton did not change appreciably with increasing concentration of
DMSO-d6, thereby indicating the presence of intramolecular hydrogen
bond. A similar protocol was followed for ascertaining the intramo-
lecular hydrogen bond in 8c and 9.
(10) Ravi, A.; Balram, P. Tetrahedron 1984, 2577-83.
(11) The absolute stereochemistry of epoxides 7a and 7b was
assigned on the basis of the following correlation protocol. The
similarity in the sign and magnitude of optical rotation for 7b, prepared
by Sharpless’s as well as by polyaniline-supported cobalt-catalyzed
procedures, helped us to assign the indicated absolute stereochemistry.
7854 J . Org. Chem., Vol. 67, No. 22, 2002

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters
SCHEME 1. In tr a m olecu la r Hyd r ogen Bon d in g in r-Deh yd r o-â-a m in o Acid Der ived Dip ep tid es
SCHEME 2
pearance of the amide proton at 6.94 ppm (J ) 8.8 Hz)
in the 1H NMR spectrum. The presence of such hydrogen
bonding10 suggests that a 10-membered cyclic structure
may be formed by a noncovalent interaction between
amide hydrogen and ester carbonyl. It is thus clear that
the opening of an epoxy peptide with an R-dehydro
â-amino acid derivative leads to an organized ten-
member structure mimicking a â-turn and it appears that
the presence of a double bond may constrain the confor-
mation leading to an intramolecular hydrogen bond. To
demonstrate the role of R-dehydro â-amino acid 3b in
constraining the conformation via hydrogen bond, we
have synthesized the cyclic peptide 9 using a ring-closing
metathesis reaction (Scheme 3).
DMSO-d6 in CDCl3. The amide protons are generally
characterized by the appearance of a signal between 6
and 9 ppm, and for 6a and 6b it was found to be at 8.44
ppm with a coupling constant of >7 Hz.
The chemical shift of the amide proton in 6a -c did
not change appreciably with increasing concentration of
DMSO-d6, thereby indicating the presence of an intramo-
lecular hydrogen bond in these dipeptides (Scheme 1).
The R-dehydro-â-amino acid derivative 3b is a very good
nucleophile as it cleaves epoxides in the presence of
catalytic amount of cobalt(II) chloride.8 To demonstrate
this, we have reacted epoxides9 7a and 7b with 3b in
the presence of a catalytic amount of anhydrous cobalt-
(II) chloride in acetonitrile to afford the corresponding
â-phenylisoserine-derived dipeptides 8a and 8b, respec-
tively (Schemes 2 and 3). The dipeptides 8a ,b were
isolated by column chromatography (silica gel, EtOAc-
hexane) predominantly as the anti diastereomer. The
regio- and stereochemistry of 8a and 8b were unambigu-
ously proved on the basis of the chemical shift and the
coupling constants of the methine proton [-(Ar)N-CH-
(Ph)-] according to our earlier studies.8b
Thus, the epoxy peptide 7b single diastereomer ([R]D
) +61)11 obtained by cobalt-catalyzed aerobic oxidation9
of 7 was reacted with 3b in the presence of a catalytic
amount of cobalt(II) chloride8 to afford 8b after column
chromatography in good yield. The ester groups in 8b
were transesterified with excess allyl alcohol in the
presence of titanium tetraisopropoxide12 to afford the
1
diallylated peptide 8c (55-60%). The H NMR spectrum
of 8c also showed the presence of an intramolecular
hydrogen bond as evidenced by the appearance of signal
due to the amide proton at 7.45 ppm (J ) 8.8 Hz). The
variance in δH with increase in solvent concentration has
also indicated the presence of an intramolecular hydrogen
bond in 8c. The appearance of amide proton signal at
above 7 ppm in both peptides 8b and 8c suggests the
presence of intramolecular hydrogen bond14 as its chemi-
cal shift does not undergo an appreciable shift on chang-
ing the concentration of the solution. The preorganized
The dipeptide 8b derived from L-leucine exhibited an
intramolecular hydrogen bond as indicated by the ap-
J . Org. Chem, Vol. 67, No. 22, 2002 7855

Rajesh et al.
F IGURE 1. Energy-minimized structures of 8c and 9.
SCHEME 3
diallylated peptide 8c was subjected to a ring-closing
metathesis reaction using ruthenium alkylidene15 (Grubbs’
catalyst) to afford the corresponding cyclic peptide 9 (40-
1
45%) as a mixture of E/Z (3:1) isomers based on the H
NMR. The presence of an intramolecular hydrogen bond
was also evident in the cyclic structure 9, whose 1H NMR
spectrum showed the appearance of an amide proton at
8.19 ppm (J ) 8.8 Hz). Such a downfield shift in the
amide NH signal is due to the presence of intramolecular
hydrogen bonding. The FT-IR of 9 also indicated the
presence of intramolecular hydrogen bonding as a broad
signal due to the stretching at 3359 cm-1 (Figure 2).
It is not evident from 1H NMR as to which of the
geometrical isomers (E-9 or Z-9) is responsible for the
intramolecular hydrogen bonding. However, it is conceiv-
able that the formation of cyclic structure 9 may be
favored by the pre-organization, via intramolecular hy-
drogen bond, of the diallylated precursor 8c, which
mimics a â-turn.16
F IGURE 2. Intramolecular hydrogen bonding in 8c and 9.
The minimum energy conformations of 8c and E-9 also
indicate the presence of intramolecular hydrogen bonding
as the length of these bonds lie typically between 2.3 and
(15) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606.
7856 J . Org. Chem., Vol. 67, No. 22, 2002

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters
SCHEME 4
2.4 Å (Figure 1). To demonstrate the role of dehy-
droamino acid residue in intramolecular hydrogen bond-
ing, we have converted the peptide 8b into the corre-
sponding saturated analogue 10a (Pd/H2, 25%) and then
transallylated to afford 10b. It is noteworthy, though not
particularly surprising, that the saturated analogue 10a
and 10b did not show the presence of any intramolecular
hydrogen bonding.
It is also interesting to note that the ring-closing
metathesis reaction on the diallylated saturated analogue
10b did not proceed cleanly as only a small amount (10%)
of the corresponding cyclic product 11 (1:1; E/Z mixture)
was isolated from a complex reaction mixture (Scheme
4). These studies suggest the crucial role of the double
bond in 8b,c in promoting the intramolecular hydrogen
bonding, which may in turn encourage the ring-closing
metathesis leading to the constrained â-turn mimic 9.
In conclusion, we have developed an efficient synthesis
of R-dehydro-â-amino esters by a temperature-dependent
regioselective palladium(0)-catalyzed reaction of primary
amines with acetates derived from Baylis-Hillman ad-
duct. We have demonstrated that dipeptides derived from
R-dehydro-â-amino acid exhibit an eight-member in-
tramolecular hydrogen bond due to the presence of the
double bond, which constrains the peptide to adopt a
conformation facilitating the formation of a cyclic struc-
ture. Also, we have demonstrated that R-dehydro-â-amino
acid derivatives can be used as nucleophile to cleave
epoxy peptides leading to the formation of dipeptide
derivative, which mimics a â-turn by exhibiting intramo-
lecular hydrogen bonding. This intramolecular hydrogen
bonding preorganizes the peptide for cyclization via ring-
closing metathesis to afford a cyclic peptide as a con-
strained mimic of a â-turn.
(16) For â-turn, see: (a) Ball, J . B.; Alewood, P. F. J . Mol. Recog.
1990, 3, 55. (b) Ball, J . B.; Hughes, R. A.; Alewood, P. L.; Andrews, P.
R. Tetrahedron 1993, 49, 3467 and references therein. (c) Rose, G. D.;
Gierasch, L. M.; Smith, J . A. Turns in peptides and proteins. In
Advances in Protein Chemistry; Academic Press: New York, 1985. (d)
Farmer, P. S. In Drug Design; Ariens, E. J ., Ed.; Academic: New York,
1980; Vol. 10, pp 119-143. (e) Feng, Y.; Pattarawarapan, M.; Wang,
Z.; Burgess, K. Org. Lett. 1999, 1, 121. (f) Belvisi, L.; Bernardi, A.;
Manzoni, L.; Potenza, D.; Scolastico, C. Eur. J . Org. Chem. 2000, 2563-
2569. (g) Kaul, R.; Angeles, A. R.; J ager, M.; Powers, E. T.; Kelly, J . J .
Am. Chem. Soc, 2001, 123, 5206-5212.
Ack n ow led gm en t. We thank the DST, New Delhi,
for the financial support of this work.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for the compounds 2a -g, 3a -h , 4a -f, 5, 6a -
c, 8a ,b, 9, and 11 are included here. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010981D
J . Org. Chem, Vol. 67, No. 22, 2002 7857