Synthesis of ω-(hetero)arylalkynylated α-amino acid by sonogashira-type reactions in aqueous media

Article abstract of DOI:10.1021/jo061300n

(Chemical Equation Presented) Mild conditions are described that allow the palladium-catalyzed cross-coupling of C_α-alkynylated glycine with a wide variety of electron-rich and electron-poor aryl and heteroaryl halides in aqueous media.

Full text of DOI:10.1021/jo061300n

the use of simple peptides in sensors requires the incorporation
of high-affinity metal-binding sites into peptides with defined
structures. Nonstandard amino acids can also be used to integrate
additional functionality or allow performance monitoring.4
Moreover, the incorporation of nonproteinogenic R-amino acids
has been found to improve the medical properties of numerous
peptide and peptidomimetic drugs.5 Finally, a number of
nonnatural amino acids are themselves biologically active,6 and
others can act as organocatalysts in chemical synthesis.7 For
all these reasons, the development of new synthetic routes to
enantiopure nonproteinogenic R-amino acids is of great current
chemical interest.8,9 Although they can be obtained by a number
of methods, including biotransformation, the use of chiral
auxiliaries, and asymmetric catalysis, there is a continuing need
for mild procedures that are compatible with a wide range of
functionalities and are well-suited for library synthesis. Perhaps
the most powerful method is the modification of available amino
acids equivalents, such as radical, cationic, and anionic alanine
and homoalanine or bishomoalanine equivalents, by means of
transition metal mediated cross-couplings.10 Specifically, since
Pd(0)-catalyzed cross-couplings are both selective and compat-
ible with a wide range of functional groups, and since the Suzuki
reaction has the drawback of requiring prior preparation of the
appropriate organoborane,11 we decided to employ Sonogashira-
type reactions for the crucial cross-coupling step.12,13
Synthesis of ω-(Hetero)arylalkynylated r-Amino
Acid by Sonogashira-Type Reactions in Aqueous
Media
Roberto J. Brea, M. Pilar Lo´pez-Deber, Luis Castedo, and
Juan R. Granja*
Departamento de Qu´ımica Orga´nica e Unidade Asociada o´
C.S.I.C., Facultade de Qu´ımica, UniVersidade de Santiago,
15782 Santiago de Compostela, Spain
qojuangg@usc.es
ReceiVed June 23, 2006
Mild conditions are described that allow the palladium-
catalyzed cross-coupling of CR-alkynylated glycine with a
wide variety of electron-rich and electron-poor aryl and
heteroaryl halides in aqueous media.
(4) (a) Bark, S. J.; Kent, S. B. H. FEBS Lett. 1999, 460, 67-76. (b)
Duhamel, J.; Kanagalingam, S.; O’Brien, T. J.; Ingratta, M. W. J. Am. Chem.
Soc. 2003, 125, 12810-12822. (c) Gochin, M.; Guy, R. K.; Case, M. A.
Angew. Chem., Int. Ed. 2003, 42, 5325-5328. (d) Enander, K.; Dolphin,
G. T.; Baltzer, L. J. Am. Chem. Soc. 2004, 126, 4464-4465.
(5) (a) Roberts, D. C.; Vellaccio, F. In The Peptides; Gross, E.,
Meienhofer, J., Eds.; Academic Press: New York, 1983; Chapter 6. (b)
Fauche´re, J.-L.; Thurieau, C. AdV. Drug Res. 1992, 23, 127-159.
(6) Barrett, G. C.; Elmore, D. T. Amino Acids and Peptides; University
Press: Cambridge, U.K., 1998. Esposito, A.; Piras, P. P.; Ramazzotti, D.;
Taddei, M. Org. Lett. 2001, 3, 3273-3275.
(7) (a) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-5175.
(8) (a) Belokon, Y. N.; Bespalova, N. B.; Churkina, T. D.; C´ısarova, I.;
Ezernitskaya, M. G.; Haratyunyan, S. R.; Hrdina, R.; Kagan, H. B.;
Kocovsky, P.; Kochetkov, K. A.; Larionov, O. V.; Lyssenko, K. A.; North,
M.; Pola´sek, M.; Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskocil, S. J.
Am. Chem. Soc. 2003, 125 12860-12871. (b) Cativiela, C.; D´ıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645-732. (c) Ryan,
S. J.; Zhang, Y.; Kennan, A. J. Org. Lett. 2005, 7, 4765-4767.
(9) Barrett, G. C.; Davies, J. S. In Amino Acids, Peptides, and Proteins;
The Royal Society of Chemistry: Cambridge, U.K., 2003; Vol. 34.
(10) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Dieder-
ich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2.
(11) (a) Miyaura, N. Top. Curr. Chem. 2002, 219, 11-59. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147-168. (c) Collier, P. N.; Campell,
A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002, 67,
1802-1815.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467-4470. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28,
3313-3315. (c) For a recent review, see: Sonogashira, K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; pp 493-529. (d) Negishi, E.; Anastasia,
L. Chem. ReV. 2003, 103, 1979-2017. (e) Tykwinski, R. R. Angew. Chem.,
Int. Ed. 2003, 42, 1566-1568.
Introduction
The main goal of the de novo design of polypeptides is the
preparation of short synthetic motifs with defined secondary
and tertiary structure that are able to perform functions similar
to those of large natural proteins.1 For small peptides, this
generally requires conformational restriction by either disulfide
bridges or metal binding,2 which in some cases can be achieved
by the introduction of nonnatural amino acids.3 For instance,
(1) For research on the design of peptide sequences with a predictable
three-dimensional structure, see for example: (a) Struthers, M. D.; Cheng,
R. P.; Imperiali, B. Science 1996, 271, 342-345. (b) Zondlo, N. J.;
Schepartz, A. J. Am. Chem. Soc. 1999, 121, 6938-6939. (c) De Alba, E.;
Santoro, J.; Rico, M.; Jime´nez, M. A. Protein Sci. 1999, 8, 854-865. (d)
Baltzer, L.; Nilsson, H.; Nilsson, J. Chem. ReV. 2001, 101, 3153-3163.
(e) Pokala, N.; Handel, T. M. J. Struct. Biol. 2001, 134, 269-281. (f) Yadav,
M. K.; Redman, J. E.; Leman, L. J.; AÄ lvarez-Gutie´rrez, J. M.; Zhang, Y.;
Scout, C. D.; Ghadiri, M. R. Biochemistry 2005, 44, 9723-9732.
(2) (a) Handel, T. M.; Williams, S. A.; DeGrado, W. F. Science 1993,
259, 1288-1293. (b) Ghadiri, M. R.; Case, M. A. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1594-1597. (c) Barthe, P.; Rochette, S.; Vita, C.;
Roumestand, C. Protein Sci. 2000, 9, 942-955. (d) Neidigh, J. W.;
Fesinmeyer, R. M.; Andersen, N. H. Nat. Struct. Biol. 2002, 9, 425-430.
(e) Kelso, M. J.; Beyer, R. L.; Hoang, H. N.; Lakdawala, A. S.; Snyder, J.
P.; Oliver, W. V.; Robertson, T. A.; Appleton, T. G.; Fairlie, D. P. J. Am.
Chem. Soc. 2004, 126, 4828-4842.
(3) (a) Imperiali, B.; Prins, T. J.; Fisher, S. L. J. Org. Chem. 1993, 58,
1613-1616. (b) Rajashankar, K. R.; Ramakumar, S.; Jain, R. M.; Chauhan,
V. S. J. Am. Chem. Soc. 1995, 117, 10129-10130. (c) Nowick, J. S.; Chung,
D. M.; Maitra, K.; Maitra, S.; Stigers, K. D.; Sun, Y. J. Am. Chem. Soc.
2000, 122, 7654-7661. (d) Bilgic¸er, B.; Kumar, K. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 15324-15329.
(13) (a) For a copper-free Sonogashira coupling, see: Soheili, A.;
Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett.
2003, 5, 4191-4194. (b) For Sonogashira cross-coupling of unactivated
alkyl halides using carbene ligands, see: Eckhardt, M.; Fu, G. C. J. Am.
Chem. Soc. 2003, 125, 13642-13643.
10.1021/jo061300n CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
7870
J. Org. Chem. 2006, 71, 7870-7873

SCHEME 1. Synthesis of Propargyl- and
Homopropargylglycines
(a) t-BuOK, dioxane, 100 °C, X-(CH2)nCtCH (n ) 1, X ) OTs, 93%;
n ) 1, X ) Br, 89%; n ) 2, X ) OTs, 70%); (b) NaOH, H2O, ∆; (c) H2O
∆ (n ) 1, 91%; n ) 2, 71%, two steps); (d) HCl, H2O, ∆, 91%; (e) (Boc)2O,
DIEA, dioxane/H2O, 97%.
FIGURE 1. General strategy for synthesis of novel amino acids.
the method originally reported,19 no significant yields were
obtained starting from diethyl N-acetylaminomalonate when the
alkyne was tosylated and the solvent was THF. After trials with
various solvents (THF, dioxane, DMF), bases (NaH, tBuOK,
EtONa, LDA) and alkyne derivatives (tosylates, bromides,
iodides, triflates), reasonable yields of intermediates 3 and 4
were finally obtained using the tosylates in dioxane with
potassium tertbutoxide as base (Scheme 1). Basic hydrolysis
of compounds 3 and 4, followed by decarboxylation, afforded
N-acetyl-CR-alkynyl amino acids 5a and 6a. Then, protecting
group exchange of 5a by hydrolysis and treatment with Boc
anhydride provided the desired propargylglycine 5c. In view to
future work, we also obtained enantiopure products by enanti-
oselective hydrolysis of the N-acetyl-CR-alkynyl amino acids
(ee > 99%) using a Pseudomonas putita aminopeptidase,20
followed by Boc protection as before, but in the remainder of
the present study only the racemates were used.
Compounds 5a and 6a failed to undergo cross-coupling with
3-bromopyridine under conventional Sonogashira conditions
(Table 1, entries 1-5), but with Pd/C, like their N-propargylated
analogues,14 the cross-coupling of 6a proceeded in 58% yield
using PPh3, cesium carbonate, and DME/H2O. Remarkably, the
replacement of the combination PPh3/DME by 4-diphenylphos-
phinebenzoic acid (4-DPPBA) and DMF raised the coupling
yield from 58% to 86% (entries 6 and 7).21 To explore the
generality of the above conditions, we extended these studies
to other aryl halides (Table 1), finding that with both
electron-deficient aryl bromides (entries 7, 8, 10, 13, and
Results and Discussion
Recently we have described a highly efficient Sonogashira-
type cross-coupling reaction of N-propargyl amino acids (1a)
or peptide with different (hetero)aryl halides (Figure 1).14 The
optimized condition used palladium on carbon (10% Pd/C) as
the catalyst and DME/H2O as solvent in the presence of PPh3,
CuI, and K2CO3.15 This was especially pleasing because Pd/C
allows easy recovery and recycling of Pd and causes little Pd
contamination of the product16 and because reactions in aqueous
conditions are both environmentally and economically attrac-
tive.17 Here in this work we improve these conditions and apply
them to the preparation of R-amino acids with CR-side chains
terminating in aryl or heteroaryl units. The strategy would be
based, as before, on equipping the amino acid with an alkyne-
terminated CR-chain (1b) that would then be linked to the
(hetero)aryl unit, after which the triple bond could be reduced
as required (Figure 1). These CR-functionalized amino acids with
potential utility for metal binding or monitoring would retain
all the hydrogen-bonding properties required for formation of
the usual secondary structures by polypeptides containing them
(R-helices, â-sheets, etc.) and complement properties of polypep-
tides containing previously reported N-modified amino acids.18
Application of the previously reported cross-coupling pro-
cedure to the preparation of CR-(ω-aryl)alkynylated glycine was
initially frustrated by the failure of attempts to obtain the
required CR-propargylated and -homopropargylated glycines by
treating N-Boc-glycine methyl ester with propargyl or homopro-
pargyl bromide in the presence of 2 equiv of LDA. Contrary to
(18) N-modified amino acids are known to influence polypeptides
containing them by (a) adopting an extended conformation and ensuring
the adoption of a similar conformation by their N-terminal neighbours, see
Stewart, D. E.; Sarkar, A.; Wampler, J. E. J. Mol. Biol. 1990, 214, 253-
260; (b) promoting the formation of â-turns, see Braun, W.; Kallen, J.;
Mikol, V.; Walkinshaw, M. D.; Wuthrich, K. FASEB J. 1995, 9, 63-72;
Fusetani, N.; Matsunaga, S. Chem. ReV. 1993, 93, 1793-1806; or (c)
promoting the formation of left-handed R-helical structures, see Manavalan,
P.; Momany, F. A. Biopolymers 1980, 19, 1943-1973.
(19) (a) Van Hest, J. C. M.; Kiick, K. L.; Tirrell, D. A. J. Am. Chem.
Soc. 1989, 122, 1282-1288. (b) Baldwin, J. E.; Bradley, M.; Abbott, S.
D.; Adlington, R. M. Tetrahedron 1991, 47, 5309-5328. (c) Leukart, O.;
Caviezel, M.; Eberle, A.; Escher, E.; Tun-Kyi, A.; Schwyzer, R. HelV. Chim.
Acta 1976, 59, 2181-2183. (d) Coulter, A. W.; Talalay, P. J. Biol. Chem.
1968, 243, 3238-3247.
(14) Lo´pez-Deber, M. P.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3,
2823-2826.
(15) (a) De la Rosa, M. A.; Velarde, E.; Guzma´n, A. Synth. Commun.
1990, 20, 2059-2064. (b) Marck, G.; Villiger, A.; Buchecker, R.
Tetrahedron Lett. 1994, 35, 3277-3280. (c) Bleicher, L. S.; Cosford, N.;
Herbaut, A.; McCallum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63,
1109-1118. (d) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr.
Org. Lett. 2001, 3, 1555-1557. (e) For Sonogashira cross-coupling reactions
using water-soluble catalysts, see: Dibowski, H.; Schmidtchen, F. P. Angew.
Chem., Int. Ed. 1998, 37, 476-478. Anderson, K. W.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2005, 44, 6173-6177. Wolf, C.; Lerebours, R.
Org. Biomol. Chem. 2004, 2, 2161-2164. (f) For an example using
diaryliodonium salts, see: Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001,
3, 859-860. (g) For an example of a copper-free coupling reaction in water
see: Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391-
393.
(20) (a) Chenault, H. K.; Dahmer, J.; Whitesides, G. M. J. Am. Chem.
Soc. 1989, 111, 6354-6364. (b) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F.
P. J. T.; Hiemstra, H.; Schoemaker, H. E. Tetrahedron Lett. 1998, 39, 5081-
5084.
(16) Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M. Org. Process
Res. DeV. 1997, 1, 163-164.
(17) (a) Organic Reactions in Aqueous Media; Li, C.-J., Chan, T.-H.,
Eds.; Wiley: New York, 1997. (b) Organic Synthesis in Water; Grieco, P.
A., Ed.; Academic Press: Dordrecht, The Netherlands, 1997. (c) Aqueous-
Phase Organometallic Catalysis, 2nd ed.; Cornils, B., Herrmann, W. A.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004. (d) Shaughnessy, K. H.;
DeVasher, R. B. Curr. Org. Chem. 2005, 9, 585-609.
(21) (a) On the importance of the solvent for the catalytic efficiency of
Pd/C, see: Felpin, F.-X.; Vo-Thanh, G.; Villie´ras, J.; Lebreton, J.
Tetrahedron: Asymmetry 2001, 12, 1121-1124. (b) Recently it has been
shown that DMA-water solvent system reaction rates are comparable to
the analogous homogeneous reactions, see: Nova´k, Z.; Szabo´, A.; Re´pa´si,
J.; Kotschy, A. J. Org. Chem. 2003, 68, 3327-3329.
J. Org. Chem, Vol. 71, No. 20, 2006 7871

TABLE 1. Reactions of Propargyl (5a and 5c) and Homopropargyl (6a) Glycines with Various (Hetero)aryl Halides
a Isolated yields. b Reactions of 3-bromopyridine (1.1 mmol) with 5a/6a (1.0 mmol) were carried out at 80 °C in 10 mL of solvent using 5% Pd catalyst,
1
7.5% CuI, and Et3N (0.6 mL). c nd, not detected in reaction crude by H NMR. d Reactions of X-Ar (1.1 mmol) with 5a, 5c, or 6a (1.0 mmol) carried out
at 80 °C in 9 mL of solvent mixture using 10% Pd/C (0.05 mmol), CuI (0.2 mmol), Cs2CO3 (2.5 mmol), and ligand (0.2 mmol).
SCHEME 2. Alkyne Reduction Studies
16) or electron-rich aryl halides (entries 9, 11, 12, 14, 15, and
17), despite their lesser reactivity, cross-couple to propargyl (5a,
5c) and homopropagyl (6a) glycines in good yields under these
latter conditions. Moreover, similar high yields are also obtained,
regardless of whether the bromide or the iodide was used, or
whether the N-protecting group on the amino acid was Ac or
Boc.
Reduction of the triple bonds of ω-arylalkynylated amino
acids prepared as above encountered no problems. Treatment
of the CR-(ω-arylalkynylated) compounds 7a or 12c with 10%
Pd/C in 5% AcOH/EtOAc under hydrogen afforded the pyridyl-
amino acids 16c in 98% yield and the bishomotyrosine analogue
17c in 96% yield (Scheme 2, route b). Moreover, it was in both
(a) See Table 1; (b) H2, 10% Pd/C, 5% AcOH, MeOH (87% for 16a,
cases possible to carry out the cross-coupling and hydrogenation
reactions in one-pot, albeit in lower yield: When a mixture of
propargylglycine (5a or 5c), 3-bromopyridine, Pd/C, CuI,
4-DPPBA, and Cs2CO3 in DMF/water was heated for 8 h and
then stirred under hydrogen at room temperature, compound
16a and 16c were obtained in 57% and 63% yield, respectively
98% for 16c, and 96% for 17c); (c) 3-BrPy, 10% Pd/C, CuI, 4-DPPBA,
Cs2CO3, DMF/H2O, 80 °C and then H2, rt (57% for 16a, 63% for 16c); (d)
H2, 10% Lindlar, quinoline, MeOH (82% for 18c, 86% for 19c).
(Scheme 2, route c). Semi-hydrogenation was also successful:
Treatment of 7c or 12c with Lindlar catalyst and quinoline in
7872 J. Org. Chem., Vol. 71, No. 20, 2006

215 mg of 7a as a yellow foam [96%, Rf ) 0.61 (50% MeOH in
DCM with 1% AcOH)]. 1H NMR (CD3OD, 250.13 MHz, δ):
8.62-8.30 (m, 2H), 7.79 (dd, J1 ) 1.6 Hz, J2 ) 7.9 Hz, 1H), 7.34
(dd, J1 ) 4.9 Hz, J2 ) 7.8 Hz, 1H), 4.46 (t, J ) 5.7 Hz, 1H), 2.93
(dd, J1 ) 5.8 Hz, J2 ) 8.4 Hz, 2H), 1.99 (s, 3H). 13C NMR (CD3-
OD, 62.90 MHz, δ): 179.4 (CO), 172.8 (CO), 152.6 (CH), 148.6
(CH), 140.7 (CH), 124.9 (CH), 123.0 (C), 92.1 (C), 79.3 (C), 50.0
(CH), 24.3 (CH2), 22.9 (CH3). MS (CI) [m/z (%)]: 233 ([MH]+,
7), 215 (17), 174 (61). HRMS (CI) calculated for C12H13N2O3
([MH]+), 233.092617; found, 233.092474.
methanol under balloon pressure hydrogen afforded 18c and
cis-dehydrobishomotyrosine derivative 19c in yields of 82% and
86%, respectively (Scheme 2, route d).
In conclusion, we have developed a versatile method for the
preparation of CR-(ω-arylalkynyl)glycines by means of Sono-
gashira-type reactions in mixtures of water with an organic
solvent. We envisage that this new method will be widely
applicable to the assembly of modified peptides that are of
pharmacological interest, can be exploited for the manufacture
of metal ion sensors, or can adopt predefined conformations
upon complexation with metals.
Acknowledgment. Financial support from the Spanish
Ministry of Education and Science (Grants SAF2001-3120
and SAF2004-01044) and the Xunta de Galicia (Grants
PGIDIT02PXIC20902PN and PGIDT02BTF20901PR) is grate-
fully acknowledged. Also M.P.L.-D. thanks the Xunta de Galicia
for a postgraduate grant and R.J.B. thanks the Ministry of
Education and Science for the FPU grant.
Experimental Section
Preparation of 7a. Representative Procedure for Sonogashira
Cross-Coupling with Propargylglycine or Homopropargylgly-
cine Derivatives. 3-Bromopyridine (102 µL, 1.06 mmol), Cs2CO3
(788 mg, 2.42 mmol), CuI (37 mg, 0.19 mmol), 4-DPPBA (59 mg,
0.19 mmol), and 10% Pd/C (52 mg, 0.05 mmol) were mixed in 9
mL of 1:1 DMF/H2O. The resulting suspension was degassed and
stirred at room temperature for 30 min, and then amino acid 5a
(150 mg, 0.97 mmol) was added. The mixture was heated at 80 °C
for 4 h, allowed to cool to room temperature, filtered through Celite,
and concentrated, and this crude product was purified by flash
chromatography (0-8% MeOH in EtOAc with 0.5% AcOH), giving
Supporting Information Available: 1H and 13C NMR data and
spectra for some of the products illustrated in Table 1 (7a-15a,
7c). This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061300N
J. Org. Chem, Vol. 71, No. 20, 2006 7873