Synthesis and peptide coupling of protected 2-pyrrolylalanine

Article abstract of DOI:10.1016/j.tetlet.2010.11.089

2-Pyrrolylalanine has been synthesized in two protected forms and applied in the solution-phase synthesis of a dipeptide. (2S)-N-(Boc)-N′- (phenylsulfonyl)- and (2S)-N,N′-bis-(phenylsulfonyl)-3-(2-pyrrolyl) alanines (7 and 9) were obtained, respectively, in 14% and 13% overall yields and six and seven steps from oxazolidine β-methyl ester 1, which was derived from l-aspartic acid. Homoallylic ketone 2 was obtained from a copper-catalyzed cascade addition of vinylmagnesium bromide to 1 and converted into pyrrolylalanines 7 and 9 by a sequence featuring subsequent olefin oxidation and Paal-Knorr condensation. Protected pyrrolylalanine 9 was then introduced into a dipeptide. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2010.11.089

Tetrahedron Letters 52 (2011) 2159–2161
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and peptide coupling of protected 2-pyrrolylalanine
⇑
Aurélie A. Dörr, William D. Lubell
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Canada QC H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 21 November 2010
2-Pyrrolylalanine has been synthesized in two protected forms and applied in the solution-phase synthe-
sis of a dipeptide. (2S)-N-(Boc)-N0-(phenylsulfonyl)- and (2S)-N,N0-bis-(phenylsulfonyl)-3-(2-pyrrolyl)ala-
nines (7 and 9) were obtained, respectively, in 14% and 13% overall yields and six and seven steps from
Keywords:
oxazolidine b-methyl ester 1, which was derived from L-aspartic acid. Homoallylic ketone 2 was obtained
Homoallylic ketone
Copper-catalyzed cascade addition
Pyrrolylalanine
from a copper-catalyzed cascade addition of vinylmagnesium bromide to 1 and converted into pyrrolyl-
alanines 7 and 9 by a sequence featuring subsequent olefin oxidation and Paal-Knorr condensation. Pro-
tected pyrrolylalanine 9 was then introduced into a dipeptide.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
1. Introduction
3-oxo-5-pyrrolyl)alanine analog 15 (Fig. 1).10 Like Wasserman, we
perceived aspartic acid as an ideal enantiopure starting material
Practical methods for the synthesis of structurally complex
amino acid derivatives are of fundamental importance, due to the
widespread use of these building blocks in peptides, proteins, and
other related compounds of interest in the physical and life
sciences.1 For example, amino acids containing side chains pos-
sessing a five member heterocyclic ring are components of natu-
rally occurring peptides, marine organism, natural products,2
peptidomimetics,3 macromolecular scafolds,4 and building blocks
in combinatorial synthesis.5
Histidine surrogates possessing thienyl, furyl, triazolyl, tetrazol-
yl, thiazolyl, imidazolyl, and pyrazolyl rings, all have been used to
study the importance of hydrogen bond acceptor and donator
properties of the imidazole side chain in peptides.6 On the other
hand, few syntheses of pyrrolylalanine analogs have been reported,
for the most part giving racemic product.7–9 To the best of our
knowledge,7–13 there has been only one application of pyrrolylala-
nine in peptide chemistry, in which racemic amino acid 17d (R = H,
R0 = Cbz, R00 = Boc) was introduced into a TRH (pGlu-His-Pro-
NHMe) analog to investigate the role of histidine for activity
(Fig. 1).7b
for the construction of the heterocyclic amino acid. We report now
the use of aspartate derivative 1 in routes to pyrrolylalanine featur-
ing our copper-catalyzed cascade addition of vinyl magnesium bro-
mide to this b-amino ester.16 In addition, sulfonamide protection
has been examined for the preparation of a pyrrolylalaninyl-proline
dipeptide model for studying the influence of the pyrrole moiety on
prolyl amide isomer population.
2. Results and discussion
Following our strategy for the preparation of N-(Boc)-3-(6-
methylpyridazinyl)alanine,17 2-pyrrolylalanine was pursued by a
route starting from oxazolidine b-methyl ester 1, which was read-
ily prepared in four steps and in 47% yield from L-aspartic acid as
chiral educt.17 The Cu-catalyzed cascade addition of excess vinyl-
magnesium bromide to methyl ester 1 in THF at ꢀ45 °C gave
c,d-unsaturated ketone 2 in 63% yield (Scheme 1). Oxidation of ole-
fin 2 using a mixture of OsO4, NaIO4, and 2,6-lutidine in dioxane/
water gave
-ketoaldehyde 3 in 95% yield.18 Pyrrole 4 was isolated
in 72% yield from the Paal-Knorr19 condensation of
-ketoaldehyde
c
c
In the context of our investigations of biologically active peptides
bearing histidine residues,14,15 we became interested in the synthe-
sis of enantiopure (2S)-2-pyrrolylalanine and its suitable protection
for peptide synthesis. In this light, we appreciated the seminal
research of Professor Wasserman featuring the application of vicinal
tricarbonyl precursors for the preparation of various pyrrole prod-
ucts, in particular the synthesis of enantiopure (2S)-3-(2-carboxy-
3 with ammonium formate in acetonitrile containing a mixture of
NaOAc/AcOH (1:1, 1 equiv w/w) at 65 °C.
In considering the oxidation of the primary alcohol to the car-
boxylic acid, concern arose over the potential for competitive pyr-
role oxidation and degradation.20 In earlier experience making
bipyrrole and prodigiosin analogs,21 sulfonamide protection of
the ring nitrogen prevented oxidation of electron rich pyrroles dur-
ing double bond oxidations.22 N0-(Phenysulfonyl)pyrrole 5 was
thus prepared on the treatment of pyrrole 4 with t-BuOK, 18-
crown-6 ether and phenylsulfonyl chloride in THF in 80% yield.
⇑
Corresponding author.
E-mail address: lubell@chimie.umontreal.ca (W.D. Lubell).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.089

2160
A. A. Dörr, W. D. Lubell / Tetrahedron Letters 52 (2011) 2159–2161
OH
CO2Me
NH
CO2Bn
NSO2Ph
OR
N
N
R
Ac
OH
OMe
OMe
15[10]
Boc2HN
CbzHN
CO2Me
Boc2N
11[11]
BocHN
O
O
O
O
R= Me, Et
16[13]
12[8a]
R= PhCH2, (CH2)3OH, (CH2)3Br
NH
NBoc
OR
R
R'
Ac
Ac
Ac
R''
H
H, Boc
Boc
Boc
H
a
b
[7a] : Me
N
OMe
[7b] : Et
R''
OR
CbzHN
CbzHN
c
[7b] : H
O
O
R'HN
17[7]*
d[7b]
:
:
Et, H Cbz
H
R= Me, Et
13[9]
14[8b]
O
e[7c]
H
3-(3-pyrrolyl)alanine analogs
3-(2-pyrrolyl)alanine analogs
Figure 1. Protected pyrrolylalanine analogs. *17e was not isolated.
N
N
i, ii, iii
64%
SO2Ph
SO2Ph
BocHN
iv
PhO2SHN
OH
OH
6
8
N
SO2Ph
CO2H
PhO2SHN
74%
9
Scheme 2. Synthesis of N,N0-bis-(phenylsulfonyl)-3-(2-pyrrolyl)alanine 9. Reagents
and conditions: (i) TFA/DCM; (ii) 0.1 N HCl; (iii) Na2CO3, PhSO2Cl; dioxane/H2O; (iv)
TEMPO, NaClO2, NaOCl, sodium phosphate buffer, MeCN, 35 °C, overnight.
in CCl4/MeCN/H2O.25 Employing the TEMPO oxidation conditions
described above, (2S)-N,N0-bis-(phenylsulfonyl)-3-(2-pyrrolyl)ala-
nine 9 was obtained in 74% yield from alcohol 8.
With the interest of studying the influence of the aromatic den-
sity of the pyrrole moiety on the prolyl amide isomer population,
2-pyrrolylalanine 9 was next introduced into a dipeptide model
and the relative populations of prolyl cis- and trans-amide isomer
were measured by proton NMR spectroscopy. 2-Pyrrolylalanine 9
was coupled to proline N0-methylamide hydrochloride using TBTU,
HOBt, and DIEA in acetonitrile to give N,N0-bis-(phenylsulfonyl)-3-
(2-pyrrolyl)alaninyl-proline N0-methylamide 10 in 77% yield
(Scheme 3). The prolyl major trans- and minor cis-amide isomers
were assigned by NMR spectroscopy in chloroform on the basis
of their characteristic nuclear overhauser effects between the
Scheme 1. Synthesis of N-(Boc)-N0-(phenylsulfonyl)-3-(2-pyrrolyl)alanine 7.
Reagents and conditions: (i) vinylmagnesium bromide, CuCN, THF, ꢀ45 °C; (ii) cat
OsO4, NaIO4, 2,6-lutidine, dioxane/H2O; (iii) NH4CO2H, AcOH/NaOAc, MeCN, 65 °C;
(iv) t-BuOK, 18-c-6, PhSO2Cl, THF, 0 °C; (v) 80% AcOH aq, 50 °C, overnight; (vi)
TEMPO, NaClO2, NaOCl, sodium phosphate buffer, MeCN, 35 °C, overnight.
a-proton of the 3-pyrrolylalanine residue and, respectively, the
d-protons and the -proton of the proline residue in the NOESY
spectrum. A 13:87 ratio of amide cis- and trans-isomers N-terminal
to proline 10 was measured by integration of the isomeric quadru-
a
Oxazolidine 5 was then ring opened using 80% aqueous acetic acid
at 50 °C overnight to afford N-(Boc)amino alcohol 6 in 81% yield.
(2S)-N-(Boc)-N0-(phenylsulfonyl)-3-(2-pyrrolyl)alanine
7
was
plets for the 2-pyrrolylalanine
a-proton in the NMR spectrum in
finally obtained by oxidation using TEMPO (2,2,6,6-tetramethyl-
1-piperidinyloxy) free radical, sodium chlorite, and sodium hypo-
chlorite in a sodium-phosphate-buffered acetonitrile solution,
albeit in low yields (21–50%, Scheme 1).17,23
chloroform. The effect of the phenysulfonyl electron withdrawing
Low yields in the oxidation of primary alcohol 6 to carboxylate
7 inspired a change in the
a-amino protecting group from Boc to
N
SO2Ph
benzenesulfonyl. Treatment of carbamate 6 with 25% trifluoroace-
tic acid (TFA) in dichloromethane, followed by N-sulfonylation of
the resulting amine with phenylsulfonyl chloride and Na2CO3 in
dioxane/water provided (2S)-N,N0-bis-(phenylsulfonyl)-3-(2-pyrr-
olyl)alaninol 8 in 64% overall yield (Scheme 2). An attempt to
oxidize alcohol 8 using O2 in the presence of Pt in a mixture of
H2O/2-propanol/AcOEt24 gave only recovered starting material,
and decomposition occurred using NaIO4 in the presence of RuCl3
N
SO2Ph
CO2H
i
77%
N
PhO2SHN
PhO2SHN
O
O
MeHN
9
10
Scheme 3. Synthesis of N,N0-bis-(phenylsulfonyl)-3-(2-pyrrolyl)alaninyl-proline
N0-methylamide 10. Reagents and conditions: (i) ProNHMeꢁHCl, TBTU, HOBt, DIEA,
0 °C, MeCN, overnight.

A. A. Dörr, W. D. Lubell / Tetrahedron Letters 52 (2011) 2159–2161
2161
1205; (c) Ikeda, Y.; Kawahara, S.-i.; Taki, M.; Kuno, A.; Hasegawa, T.; Taira, K.
Protein Eng. 2003, 16, 699–706.
group on the pyrrolylalanine residue may reduce the amide cis-
isomer population relative to
p-enriched arylalanine ana-
7. (a) de la Hoz, A.; Díaz-Ortiz, A.; Gómez, M. V.; Mayoral, J. A.; Moreno, A.;
Sánchez-Migallón, A. A.; Vásquez, E. Tetrahedron 2002, 57, 5421–5428; (b)
Bladon, C. M. J. Chem. Soc., Perkin Trans. 1 1990, 1151–1158; (c) Herz, W.;
Dittmer, K.; Cristol, S. J. J. Am. Chem. Soc. 1948, 70, 504–507.
8. (a) Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731–2737; (b) Beecher, J.
E.; Tirrell, D. A. Tetrahedron Lett. 1998, 39, 3927–3930.
9. Yamano, K.; Shirahama, H. Tetrahedron 1992, 48, 1457–1464.
10. (a) Wasserman, H. H.; Long, Y. O.; Zhang, R.; Parr, J. Heterocycles 2002, 58, 393–
403; (b) Wasserman, H. H.; Long, Y. O.; Zhang, R.; Parr, J. Tetrahedron Lett. 2002,
43, 3351–3353.
logs.17,26–33
Sulfonamide protection gave access to the desired pyrrolylala-
nine target 9, which could be coupled to the N-terminal of a pep-
tide; however, attempts (TBAF in THF, SmI2 in DMPU/THF, and
Mg in MeOH) were unsuccessful in removing the sulfonyl groups
from dipeptide 10. Alternative protection, such as the pyridine-2-
sulfonyl group, which has been reported to be cleaved under
milder conditions (Mg/MeOH or SmI2/DMPU/THF)34,35 is currently
being explored to enhance the utility of 2-pyrrolylalanine in pep-
tide chemistry and will be described in future.
11. Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron: Asymmetry 2000, 11,
3063–3068.
12. Masquelin, T.; Broger, E.; Müller, K.; Schmid, R.; Obrecht, D. Helv. Chim. Acta
1994, 77, 1395–1411.
In conclusion, methodology has been developed for the synthe-
sis of protected 2-pyrrolylalanine from aspartic acid. Protection of
2-pyrrolylalanine with sulfonyl groups has allowed insertion of
this unnatural amino acid into a dipeptide model. Considering 2-
pyrrolylalanine as an asparagine and histidine mimic, opportunity
exists for employing this surrogate for studying structure–function
relationships in peptide science and medicinal chemistry.
13. Sarkar, K.; Singha, S. K.; Chattopadhyay, S. K. Tetrahedron: Asymmetry 2009, 20,
1719–1721.
14. Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.; Boeglin, D.; Ong, H.; Lubell,
W. D. Org. Lett. 2009, 11, 3650–3653.
15. Goupil, E.; Tassy, D.; Bourguet, C.; Quiniou, C.; Wisehart, V.; Petrin, D.; Le
Gouill, C.; Devost, D.; Zingg, H. H.; Bouvier, M.; Saragovi, H. U.; Chemtob, S.;
Lubell, W. D.; Claing, A.; Hebert, T. E.; Laporte, S. A. J. Biol. Chem. 2010, 285,
25624–25636.
16. (a) Hansford, K. A.; Dettwiler, J. E.; Lubell, W. D. Org. Lett. 2003, 5, 4887–4890;
(b) Dettwiler, J. E.; Lubell, W. D. Can. J. Chem. 2004, 82, 318–324.
17. Dörr, A. A.; Lubell, W. D. Biopolymers 2007, 88, 290–299.
18. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–3219.
19. (a) Hansford, K. A.; Zanzavora, V.; Dorr, A. A.; Lubell, W. D. J. Comb. Chem. 2004,
6, 893–898; (b) Dorr, A. A.; Lubell, W. D. Can. J. Chem. 2007, 85, 1006–1017.
20. Joule, J. A.; Mills, J. K. Heterocyclic Chemistry, 4th ed.; Springer: New York, 2000.
p 246.
21. (a) Tshibaka, T.; Roche, I. U.; Dufresne, S.; Lubell, W. D.; Skene, W. G. J. Org.
Chem. 2009, 74, 9497–9500; (b) Jolicoeur, B.; Lubell, W. D. Can. J. Chem. 2008,
86, 213–218; (c) Jolicoeur, B.; Lubell, W. D. Org. Lett. 2006, 8, 6107–6110.
22. Jolicoeur, B.; Chapman, E. E.; Thompson, A.; Lubell, W. D. Tetrahedron 2006, 62,
11531–11563.
23. (a) Dettwiler, J. E.; Lubell, W. D. J. Org. Chem. 2003, 68, 177–179; (b) Zhao, M.;
Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. J. Org.
Chem. 1999, 64, 2564–2566.
Acknowledgments
The authors would like to thank the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) and Fond Québécois
de la Recherche sur la Nature et les Technologies (FQRNT) for the
financial support. We thank Dr. Alexandra Fürtös of the Université
de Montréal Mass Spectrometry facility for mass spectral analyses
and Dr. Phan viet Minh Tan and Dr. Cédric Malveau of the Regional
High-Field NMR Laboratory for their assistance in running 2D
NOESY/TOCSY experiments.
24. (a) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367–2371; (b)
Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1989, 54, 1866–1875.
25. Carlsen, P. H. J.; Katsuki, K.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936–3938.
26. MacArthur, M. W.; Thornton, J. M. J. Mol. Biol. 1991, 218, 397–412.
27. We have defined the term prolyl amide as ‘a tertiary amide composed of the
pyrrolidine nitrogen of the prolyl residue and the carbonyl of the N-terminal
residue’. Halab, L.; Lubell, W. D. J. Am. Chem. Soc. 2002, 124, 2474–2484.
28. (a) Hetzel, R.; Wüthrich, K. Biopolymers 1979, 18, 2589–2606; (b) Grathwohl,
C.; Wüthrich, K. Biopolymers 1976, 15, 2043–2057.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.089.
References and notes
1. (a)Synthesis of Peptides and Peptidomimetics: Houben-Weyl Methods in Organic
Chemistry; Goodman, M., Felix, A., Morodwe, L., Toniolo, C., Eds.; Thieme:
Stuttgart, D, 2001; (b)Peptidomimetics Protocols; Kazmierski, W. M., Ed.;
Humana Press: Toyota, NJ, USA, 1999.
2. Somogyi, L.; Haberhauer, G.; Rebek, J., Jr. Tetrahedron 2001, 57, 1699–1708.
3. (a) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Dettori, G. Eur. J. Org. Chem. 2000,
3217–3222; (b) Plant, A.; Stieber, F.; Scherkenbeck, J.; Losel, P.; Dyker, H. Org.
Lett. 2001, 3, 3427–3430; (c) Chakraborty, T. K.; Mohan, B. K.; Kumar, S. K.;
Kunwar, A. C. Tetrahedron Lett. 2002, 43, 2589–2592.
29. (a) Yao, J.; Brüschweiler, R.; Dyson, H. J.; Wright, P. E. J. Mol. Biol. 1994, 116,
12051–12052; (b) Yao, J.; Dyson, H. J.; Wright, P. E. J. Mol. Biol. 1994, 243, 754–
766; (c) Yao, J.; Feher, V. A.; Espejo, B. F.; Reymond, M. T.; Wright, P. E.; Dyson,
H. J. J. Mol. Biol. 1994, 243, 736–753; (d) Dyson, H. J.; Rance, M.; Houghten, R. A.;
Lerner, R. A.; Wright, P. E. J. Mol. Biol. 1988, 201, 161–200.
30. Wu, W.-J.; Raleigh, D. P. Biopolymers 1998, 45, 381–394.
31. Stewart, D. E.; Sarkar, A.; Wampler, J. E. J. Mol. Biol. 1990, 214, 253–260.
32. (a) Stimson, E. R.; Montelione, G. T.; Meinwald, Y. C.; Rudolph, R. K. E.;
Scheraga, H. A. Biochemistry 1982, 21, 5252–5262; (b) Juy, M.; Lam-Thanh, H.;
Linter, K.; Fermandjian, S. Int. J. Peptide Protein Res. 1983, 22, 437–449.
33. Thomas, K. M.; Naduthambi, D.; Zondlo, N. J. J. Am. Chem. Soc. 2005, 128, 2216–
2217.
4. Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567–4570.
5. (a) Perrotta, E.; Altamura, M.; Barani, T.; Bindi, S.; Giannotti, D.; Harmat, N. J. S.;
Nannicini, R.; Maggi, A. J. Comb. Chem. 2001, 3, 453–460; (b) Lewis, J. G.;
Bartlett, P. A. J. Comb. Chem. 2003, 5, 278–284; (c) Edwards, A. A.; Ichihara, O.;
Murfin, S.; Wilkes, R.; Whittaker, M.; Watkin, D. J.; Fleet, G. W. J. J. Comb. Chem.
2004, 6, 230–238.
34. Goulaic-Dubois, C.; Guggisberg, A.; Hesse, M. J. Org. Chem. 1995, 60, 5969–
5972.
35. Han, H.; Bae, I.; Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109–4112.
6. (a) Heyl, D. L.; Dandabathula, M.; Kurtz, K. R.; Mousigian, C. J. Med. Chem. 1995,
38, 1242–1246; (b) Hsieh, K.-h.; Jorgensen, E. C. J. Med. Chem. 1979, 22, 1199–