Palladium(0)-Catalyzed Regioselective Synthesis of r-Dehydro-β-amino Esters from Amines and Allyl Acetates: Synthesis of a r-Dehydro-β-amino Acid Derived Cyclic Peptide as a Constrained β-Turn Mimic S. Rajesh, Biswadip Banerji, and Javed Iqbal*,† Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
[email protected] 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-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 R-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 R-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 ringclosing metathesis to afford the cyclic peptide 9 as a constrained mimic of a β-turn. Introduction The ever-increasing demand for the design and synthesis of small molecule peptidomimetics1 as pharmaceutical 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 pharmacokinetics 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 β-amino acids as useful pharmaceutical probes, we felt that an R-dehydro-β-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-β amino esters through a temperature-dependent regioselective attack of primary amines to Baylis-Hillman3 acetates † Present Address: Director, Regional Research Laboratory, Trivandrum 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.; Joukema, 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) Jones, I. G.; Jones, W.; North, M. J. Org. Chem. 1998, 63, 1505. (l) Kemp, D. S.; Li, Z. Q. Tetrahedron Lett. 1995, 36, 4179.
using palladium-tetrakis-triphenylphosphine4 as catalyst in different solvent systems. Results and Discussion The reaction of acetates derived by Baylis-Hillman protocol with various amines in the presence of palladium(0) catalyst has shown interesting reaction profiles under different conditions. Thus aniline and its parasubstituted derivatives reacted with allyl acetates 1 in THF medium at ambient temperature (condition A) to afford R-dehydro-β-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) Stammer, 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. 10.1021/jo010981d CCC: $22.00 © 2002 American Chemical Society
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Published on Web 10/03/2002
Pd0-Catalyzed Synthesis of R-Dehydro-β-amino Esters TABLE 1. Palladium(0)-Catalyzed Synthesis of r-Dehydro-β-amino Esters
THF, rt (condition A)
a
MeCN, reflux (condition B)
entry
amine (R)
ratio (2/3)b
yielda (%)
ratiob (2/3)
yielda (%)
1 2 3 4
C6H5 p-MeOC6H5 p-MeC6H5 p-ClC6H5
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
Yield of the isolated compounds 2 and 3 by column chromatography. b Ratio determined by 1H NMR of the crude reaction mixture.
TABLE 2. Palladium(0)-Catalyzed Synthesis of r-Dehydro-β-amino Esters: Effect of Substituent in Allyl Acetate on the Regiochemistry of Amino Esters
a
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
Ratio determined by 1H NMR of the crude reaction mixture. b 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-dehydroβ-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-β-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 corresponding 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. Recently, Trost and co-workers5 have shown asymmetric 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 (5) For Pd(0)-catalyzed allylation of amines, see: Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano, J. Tetrahedron Lett. 1998, 39, 1713.
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-β-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) reaction 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-Dehydro-β-amino Acids as Turn Inducers. The R-dehydro-β-amino ester 3 can be converted by usual coupling protocols to the corresponding dipeptides 6, which show interesting hydrogen-bonding properties (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; John Wiley and Sons: New York, 1981. (7) The single-crystal X-ray structure of these compounds will be published later.
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Rajesh et al. TABLE 3. Palladium(0)-Catalyzed Reaction of Amino Esters with Acetates of the Baylis-Hillman Adduct
*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 eightmembered hydrogen bond10,14 in the1H NMR and FT-IR (8) For cobalt(II) chloride catalyzed cleavage of epoxy amide with aniline derivatives, see: (a) Bhatia, B.; Jain, 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) Punniyamurthy, T.; Iqbal, J. Tetrahedron Lett. 1997, 38, 4463. (c) De, A.; Basak, P.; Iqbal, J. Tetrahedron Lett. 1997, 38, 8383. (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.
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(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.; Jin, S.; Burgess, K. J. Am. Chem. Soc. 1998, 120, 10768. (b) Kim, K.; Germanas, J. P. J. Org. Chem. 1997, 62, 2853. (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 concentration of DMSO-d6 in CDCl3. The amide protons are generally characterized 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 intramolecular hydrogen bond in 8c and 9.
Pd0-Catalyzed Synthesis of R-Dehydro-β-amino Esters SCHEME 1.
Intramolecular Hydrogen Bonding in r-Dehydro-β-amino Acid Derived Dipeptides
SCHEME 2
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 intramolecular hydrogen bond in these dipeptides (Scheme 1). The R-dehydro-β-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 β-phenylisoserine-derived dipeptides 8a and 8b, respectively (Schemes 2 and 3). The dipeptides 8a,b were isolated by column chromatography (silica gel, EtOAchexane) predominantly as the anti diastereomer. The regio- and stereochemistry of 8a and 8b were unambiguously 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 The dipeptide 8b derived from L-leucine exhibited an intramolecular hydrogen bond as indicated by the ap-
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 β-amino acid derivative leads to an organized tenmember structure mimicking a β-turn and it appears that the presence of a double bond may constrain the conformation leading to an intramolecular hydrogen bond. To demonstrate the role of R-dehydro β-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). 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 diallylated peptide 8c (55-60%). The 1H 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 chemical shift does not undergo an appreciable shift on changing the concentration of the solution. The preorganized J. Org. Chem, Vol. 67, No. 22, 2002 7855
Rajesh et al.
FIGURE 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 (4045%) as a mixture of E/Z (3:1) isomers based on the 1H 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 conceivable that the formation of cyclic structure 9 may be favored by the pre-organization, via intramolecular hydrogen bond, of the diallylated precursor 8c, which mimics a β-turn.16 (15) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606.
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FIGURE 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
Pd0-Catalyzed Synthesis of R-Dehydro-β-amino Esters
2.4 Å (Figure 1). To demonstrate the role of dehydroamino acid residue in intramolecular hydrogen bonding, we have converted the peptide 8b into the corresponding 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 β-turn mimic 9. In conclusion, we have developed an efficient synthesis of R-dehydro-β-amino esters by a temperature-dependent regioselective palladium(0)-catalyzed reaction of primary amines with acetates derived from Baylis-Hillman adduct. We have demonstrated that dipeptides derived from (16) For β-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, 25632569. (g) Kaul, R.; Angeles, A. R.; Jager, M.; Powers, E. T.; Kelly, J. J. Am. Chem. Soc, 2001, 123, 5206-5212.
SCHEME 4
R-dehydro-β-amino acid exhibit an eight-member intramolecular hydrogen bond due to the presence of the double bond, which constrains the peptide to adopt a conformation facilitating the formation of a cyclic structure. Also, we have demonstrated that R-dehydro-β-amino acid derivatives can be used as nucleophile to cleave epoxy peptides leading to the formation of dipeptide derivative, which mimics a β-turn by exhibiting intramolecular hydrogen bonding. This intramolecular hydrogen bonding preorganizes the peptide for cyclization via ringclosing metathesis to afford a cyclic peptide as a constrained mimic of a β-turn.
Acknowledgment. We thank the DST, New Delhi, for the financial support of this work. Supporting Information Available: Spectroscopic and analytical data for the compounds 2a-g, 3a-h, 4a-f, 5, 6ac, 8a,b, 9, and 11 are included here. This material is available free of charge via the Internet at http://pubs.acs.org. JO010981D
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