Palladium(0)-Catalyzed Regioselective Synthesis ofr-Dehydro-â-amino Esters from Amines and Allyl Acetates:

Synthesis of a r-Dehydro-â-amino Acid Derived Cyclic Peptide asa Constrained â-Turn Mimic

S. Rajesh, Biswadip Banerji, and Javed 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 regioselectivemanner 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 andreaction medium leading to the synthesis of regioisomers 2 or 3. The R-dehydro-â-amino acid 3 isa turn inducer, and the dipeptides 6 derived from it show the presence of an eight-memberedintramolecular hydrogen bond. Also, cobalt(II) chloride catalyzes the cleavage of epoxy peptideswith 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 intramolecularhydrogen 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.

Introduction

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 researchactivities in the area of new drug discovery. For example,constrained amino acid as a mimic for the bioactiveconformation of a drug molecule provides an excitingopportunity for designing molecules with good pharma-cokinetics and pharmacodynamics. The dehydro-R-aminoacids have been incorporated in peptides to provideconstrain, which helps such species to bind with thetarget in an entropically advantageous way. In view ofthe importance of â-amino acids as useful pharmaceuticalprobes, we felt that an R-dehydro-â-amino acid would bea useful residue in rendering a peptide more favorableto binding to its target.2 In the present study, wedemonstrate an easy synthesis of R-dehydro-â aminoesters through a temperature-dependent regioselectiveattack of primary amines to Baylis-Hillman3 acetates

using palladium-tetrakis-triphenylphosphine4 as cata-lyst in different solvent systems.

Results and Discussion

The reaction of acetates derived by Baylis-Hillmanprotocol with various amines in the presence of pal-ladium(0) catalyst has shown interesting reaction profilesunder different conditions. Thus aniline and its para-substituted derivatives reacted with allyl acetates 1 inTHF medium at ambient temperature (condition A) toafford R-dehydro-â-amino esters 2 as the major products,and the reaction mixture contained the other regioisomer3 in minor amounts only (Table 1). The substituents onthe para position of aniline were found to exert moderateto good influence on the regiochemical outcome of the

† 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.; 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.

(2) For peptides derived from dehydro amino acids, see: (a) Stam-mer, C. H. Chemistry and Biochemistry of Amino Acids, Peptides andProtein; 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. Tetrahedron1988, 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 withAllyl-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.

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reaction with the p-methoxy substituent exhibiting a highselectivity 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 wasfound only in minor amounts, and the para substituenteffect of aniline was not observed under these conditions(Table 1, condition B).

We have also noticed the substituent effect in thearomatic ring of the allyl acetate 1 on the regiochemistryof R-dehydro-â-amino ester formation. Thus, the reactionof acetate 1b (containing a p-methoxyphenyl group) withp-anisidine under condition A afforded a high ratio of theproduct 2e along with the small amount of the corre-sponding product 3e (Table 2). On the other hand, thereaction of allyl acetate 1c (having a p-chlorophenylsubstituent) gave the corresponding product 3f as themajor product (Table 2). A similar selectivity was alsoobserved with benzylamine, which afforded the product2g as the major product in case of reaction with 1b,whereas the corresponding product 3h was formed as theonly product on reaction with allyl acetate 1c.

Recently, Trost and co-workers5 have shown asym-metric N-alkylation of amino esters where the newstereogenic centers at carbon is dictated by the catalystand not by the substrate. However, in our case, we findthat the regiochemistry of the amino ester is completely

dictated by the structure of the substrate. Interestingly,the palladium-catalyzed reactions with acetates 1 arehighly chemoselective as only the N-allylated productsare formed on reaction with 4-hydroxy-L-proline methylester.

Thus, the reaction of 4-hydroxy-L-proline methyl esterwith 1a,b,d-f gave the corresponding R-dehydro-â-aminoester derivatives 4a-e, respectively, as the only productin good yields (Table 3, entries 1-5). These products wereobtained predominantly under both (i.e., A and B) reac-tion conditions. In most of the cases, the geometry of thedouble bond was found to be E, which was assigned onthe basis of literature precedence.6 The (E,E) geometryfor 4e was assigned by its single-crystal X-ray structure.7It is noteworthy that the reaction of 4-hydroxy-L-prolinemethyl ester with 1d and 1e afforded 4b and 4d,respectively, as a mixture of geometrical isomers (E andZ) in good yields (Table 3, entries 3 and 4). Similarly,the reaction of the acetate 1a with L-serine methyl esterhaving primary amine and hydroxy groups afforded theexpected product 4f as a single geometrical isomer in goodyields (Table 3, entry 6).

R-Dehydro-â-amino Acids as Turn Inducers. TheR-dehydro-â-amino ester 3 can be converted by usualcoupling protocols to the corresponding dipeptides 6,which show interesting hydrogen-bonding properties

(5) For Pd(0)-catalyzed allylation of amines, see: Trost, B. M.;Calkins, T. L.; Oertelt, C.; Zambrano, J. Tetrahedron Lett. 1998, 39,1713.

(6) The (E) and (Z) geometry was assigned on the basis of thecorrelation with methyl crotanate as mentioned in: Silverstein, R. M.;Bassler, G. C.; Morrile, T. C. In Spectoscopic Identification of OrganicCompounds; John Wiley and Sons: New York, 1981.

(7) The single-crystal X-ray structure of these compounds will bepublished later.

TABLE 1. Palladium(0)-Catalyzed Synthesis of r-Dehydro-â-amino Esters

THF, rt(condition A)

MeCN, reflux(condition B)

entry amine (R) ratio (2/3)b yielda (%) ratiob (2/3) yielda (%)

1 C6H5 2a/3a (3:1) 65 2a/3a (1:8) 682 p-MeOC6H5 2b/3b (6:1) 59 2b/3b (1:10) 613 p-MeC6H5 2c/3c (5:1) 61 2c/3c (1:7) 574 p-ClC6H5 2d/3d (3:1) 56 2d/3d (1:10) 60

a 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-â-amino Esters: Effect of Substituent in Allyl Acetate on theRegiochemistry of Amino Esters

X R compd (ratio, yield, %)a,b

OMe (1b) p-MeOC6H5 2e/3e (90:10, 76)Cl (1c) 2f/3f (15:85, 68)OMe (1b) CH2C6H5 2g/3g (90:10, 66)Cl (1c) 2h/3h (2:98, 78)

a Ratio determined by 1H NMR of the crude reaction mixture. b Yield of the isolated mixture of 2 and 3.

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters

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(Scheme 1). Thus, the amino esters 3 were converted toN-cinnamoyl esters 5 on reaction with cinnamoyl chlorideand subsequently hydrolyzed to the corresponding acids.The acids were coupled with L-R-amino esters to affordthe corresponding dipeptides 6 in good yields. Thedipeptides 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 andthe presence of the intramolecular hydrogen bonds in6a-c were proved by standard protocols as described inthe literature by FT-IR and by recording the proton NMRspectra of 6a-c dissolved in various concentrations of

(8) For cobalt(II) chloride catalyzed cleavage of epoxy amide withaniline 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) Punniya-murthy, 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. Thesimilarity in the sign and magnitude of optical rotation for 7b, preparedby Sharpless’s as well as by polyaniline-supported cobalt-catalyzedprocedures, helped us to assign the indicated absolute stereochemistry.

(12) Titanium tetraisopropoxide mediated transesterification withallyl 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 bystandard protocol as mentioned in ref 10, by FT-IR and by recordingthe 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 wherehydroxy protons are seldom observed. The chemical shift of the amideproton did not change appreciably with increasing concentration ofDMSO-d6, thereby indicating the presence of intramolecular hydrogenbond. A similar protocol was followed for ascertaining the intramo-lecular hydrogen bond in 8c and 9.

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.

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DMSO-d6 in CDCl3. The amide protons are generallycharacterized by the appearance of a signal between 6and 9 ppm, and for 6a and 6b it was found to be at 8.44ppm with a coupling constant of >7 Hz.

The chemical shift of the amide proton in 6a-c didnot change appreciably with increasing concentration ofDMSO-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 goodnucleophile as it cleaves epoxides in the presence ofcatalytic amount of cobalt(II) chloride.8 To demonstratethis, we have reacted epoxides9 7a and 7b with 3b inthe presence of a catalytic amount of anhydrous cobalt-(II) chloride in acetonitrile to afford the correspondingâ-phenylisoserine-derived dipeptides 8a and 8b, respec-tively (Schemes 2 and 3). The dipeptides 8a,b wereisolated by column chromatography (silica gel, EtOAc-hexane) predominantly as the anti diastereomer. Theregio- and stereochemistry of 8a and 8b were unambigu-ously proved on the basis of the chemical shift and thecoupling constants of the methine proton [-(Ar)N-CH-(Ph)-] according to our earlier studies.8b

The dipeptide 8b derived from L-leucine exhibited anintramolecular 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 hydrogenbonding10 suggests that a 10-membered cyclic structuremay be formed by a noncovalent interaction betweenamide hydrogen and ester carbonyl. It is thus clear thatthe opening of an epoxy peptide with an R-dehydroâ-amino acid derivative leads to an organized ten-member structure mimicking a â-turn and it appears thatthe presence of a double bond may constrain the confor-mation leading to an intramolecular hydrogen bond. Todemonstrate the role of R-dehydro â-amino acid 3b inconstraining the conformation via hydrogen bond, wehave synthesized the cyclic peptide 9 using a ring-closingmetathesis 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 catalyticamount of cobalt(II) chloride8 to afford 8b after columnchromatography in good yield. The ester groups in 8bwere transesterified with excess allyl alcohol in thepresence of titanium tetraisopropoxide12 to afford thediallylated peptide 8c (55-60%). The 1H NMR spectrumof 8c also showed the presence of an intramolecularhydrogen bond as evidenced by the appearance of signaldue to the amide proton at 7.45 ppm (J ) 8.8 Hz). Thevariance in δH with increase in solvent concentration hasalso indicated the presence of an intramolecular hydrogenbond in 8c. The appearance of amide proton signal atabove 7 ppm in both peptides 8b and 8c suggests thepresence 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

SCHEME 1. Intramolecular Hydrogen Bonding in r-Dehydro-â-amino Acid Derived Dipeptides

SCHEME 2

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters

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diallylated peptide 8c was subjected to a ring-closingmetathesis reaction using ruthenium alkylidene15 (Grubbs’catalyst) to afford the corresponding cyclic peptide 9 (40-45%) as a mixture of E/Z (3:1) isomers based on the 1HNMR. The presence of an intramolecular hydrogen bondwas also evident in the cyclic structure 9, whose 1H NMRspectrum showed the appearance of an amide proton at8.19 ppm (J ) 8.8 Hz). Such a downfield shift in theamide NH signal is due to the presence of intramolecularhydrogen bonding. The FT-IR of 9 also indicated thepresence of intramolecular hydrogen bonding as a broadsignal due to the stretching at 3359 cm-1 (Figure 2).

It is not evident from 1H NMR as to which of thegeometrical isomers (E-9 or Z-9) is responsible for theintramolecular hydrogen bonding. However, it is conceiv-able that the formation of cyclic structure 9 may befavored by the pre-organization, via intramolecular hy-drogen bond, of the diallylated precursor 8c, whichmimics a â-turn.16

The minimum energy conformations of 8c and E-9 alsoindicate the presence of intramolecular hydrogen bondingas 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.

FIGURE 1. Energy-minimized structures of 8c and 9.

SCHEME 3

FIGURE 2. Intramolecular hydrogen bonding in 8c and 9.

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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 thentransallylated to afford 10b. It is noteworthy, though notparticularly surprising, that the saturated analogue 10aand 10b did not show the presence of any intramolecularhydrogen bonding.

It is also interesting to note that the ring-closingmetathesis reaction on the diallylated saturated analogue10b 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 (Scheme4). These studies suggest the crucial role of the doublebond in 8b,c in promoting the intramolecular hydrogenbonding, which may in turn encourage the ring-closingmetathesis leading to the constrained â-turn mimic 9.

In conclusion, we have developed an efficient synthesisof R-dehydro-â-amino esters by a temperature-dependentregioselective palladium(0)-catalyzed reaction of primaryamines 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 thedouble bond, which constrains the peptide to adopt aconformation facilitating the formation of a cyclic struc-ture. Also, we have demonstrated that R-dehydro-â-aminoacid derivatives can be used as nucleophile to cleaveepoxy peptides leading to the formation of dipeptidederivative, which mimics a â-turn by exhibiting intramo-lecular hydrogen bonding. This intramolecular hydrogenbonding preorganizes the peptide for cyclization via ring-closing metathesis to afford a cyclic peptide as a con-strained mimic of a â-turn.

Acknowledgment. We thank the DST, New Delhi,for the financial support of this work.

Supporting Information Available: Spectroscopic andanalytical data for the compounds 2a-g, 3a-h, 4a-f, 5, 6a-c, 8a,b, 9, and 11 are included here. This material is availablefree of charge via the Internet at http://pubs.acs.org.

JO010981D

(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. InAdvances 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.; Jager, M.; Powers, E. T.; Kelly, J. J.Am. Chem. Soc, 2001, 123, 5206-5212.

SCHEME 4

Pd0-Catalyzed Synthesis of R-Dehydro-â-amino Esters

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