Amino acid and peptide synthesis and functionalization by the reaction of thioacids with 2,4-dinitrobenzenesulfonamides

Article abstract of DOI:10.1021/ol701583t

(Formula Presented) Readily prepared amino thioacids react at room temperature in DMF in the presence of cesium carbonate with 2,4- dinitrobenzenesulfonamides to give amides. When the sulfonamide is derived from an amino acid the method results in peptide bond formation, whereas the use of carbohydrate derived sulfonamides gives neoglycoconjugates.

Full text of DOI:10.1021/ol701583t

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4423-4426
Amino Acid and Peptide Synthesis and
Functionalization by the Reaction of
Thioacids with
2,4-Dinitrobenzenesulfonamides
David Crich,*,†,‡ Kasinath Sana,†,‡ and Songpo Guo‡
Chemistry Department, Wayne State UniVersity, 5101 Cass AVenue,
Detroit, Michigan 48202, and Department of Chemistry, UniVersity of Illinois at
Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@chem.wayne.edu
Received July 5, 2007
ABSTRACT
Readily prepared amino thioacids react at room temperature in DMF in the presence of cesium carbonate with 2,4-dinitrobenzenesulfonamides
to give amides. When the sulfonamide is derived from an amino acid the method results in peptide bond formation, whereas the use of
carbohydrate derived sulfonamides gives neoglycoconjugates.
The development of new methods for amide and peptide
bond formation is an area of considerable current interest.1
Azides have played a prominent role in this burgeoning and
important field,2 as key starting materials in the Staudinger
ligation,3 the traceless Staudinger ligation,4 and in couplings
with thio-5 and selenoacids.6 These excellent azide-based
coupling methods, however, are not without limitations, chief
among which are the need to prepare azides and the obligate
restriction to the formation of secondary amides. In this
respect, as we report here, we have investigated the applica-
tion of the reaction of thioacids with 2,4-dinitrobenzene-
sulfonamides7 to the formation of peptide bonds and
neoglycoconjugates.
As developed and demonstrated by Fukuyama the mono-
and dinitrobenzenesulfonamides are excellent protecting
groups for amines. They are introduced in high yield directly
to the amines themselves, may be alkylated on nitrogen
because of the acidity of the N-H bond, are stable to many
reaction conditions, and are cleaved under very mild condi-
tions by nucleophilic aromatic substitution with a thiol.8
When the nucleophilic thiol is replaced by a thioacid, as
described by Tomkinson and co-workers for simple sub-
strates,7 the product is an amide (Scheme 1). The mild
reaction conditions and high yields observed suggested to
† Wayne State University.
‡ University of Illinois at Chicago.
(1) (a) Bode, J. W. Curr. Opin. Drug DiscoVery DeV. 2006, 9, 765-
775. (b) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467.
(2) Agard, M. J.; Bashkin, J. M.; Prescher, J. A.; Lo, A.; Bertozzi, C. R.
ACS Chem. Biol. 2006, 1, 644-648.
(3) (a) Hang, H. C.; Bertozzi, C. R. Acc. Chem. Res. 2001, 34, 727-
736. (b) Ko¨hn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106-
3116. (c) Kim, H.; Cho, J. K.; Aimoto, S.; Lee, Y.-S. Org. Lett. 2006, 8,
1149-1151. (d) Lin, L. F.; Hoyt, H. M.; van Halbeek, H.; Bergman, R.
G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686-2695.
(4) (a) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2,
2141-2143. (b) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett.
2001, 3, 9-12. (c) Bianchi, A.; Bernardi, A. J. Org. Chem. 2006, 71, 4565-
4577. (d) Soellner, M. B.; Tam, A.; Raines, R. T. J. Org. Chem. 2006, 71,
9824-9830. (e) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Am. Chem.
Soc. 2006, 128, 8820-8828. (f) Grandjean, C.; Boutonnier, A.; Guerreiro,
C.; Fournier, J.-M.; Mulard, L. A. J. Org. Chem. 2005, 70, 7123-7132.
(g) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett. 2004, 6,
4479-4482. (h) Liu, L.; Hong, Z.-Y. ChemBioChem 2006, 7, 429-432.
10.1021/ol701583t CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/27/2007

Scheme 1. Amide Forming Reaction
Figure 1. 2,4-Dinitrobenzenesulfonamides.
us that this protocol could have considerable use in peptide
chemistry provided a suitable method for thioacid synthesis
could be developed.9
Displacement of 9-fluorenylmethyl p-toluenesulfonate with
potassium thioacetate followed by DIBAL reduction gave
9-fluorenylmethanethiol 1, which was then coupled with a
series of N-Boc protected amino acids under standard
carbodiimide conditions to give the thioesters 2-5, each of
which were obtained in excellent yield (Scheme 2).10
Treatment of the 9-fluorenylmethyl thioesters with pip-
eridine in DMF at room temperature gave the corresponding
thioacids, which were immediately coupled to the sulfona-
mides in the presence of cesium carbonate, also in DMF at
room temperature, resulting in the formation of dipeptides
(Table 1). These reactions, which were conducted with
Table 1. Dipeptides from Thioesters and Sulfonamides
Scheme 2. Preparation of 9-Fluorenylmethyl (Fm) Thioesters
no.
thioester sulfonamide
dipeptidea
yield, %
1
2
3
4
5
6
7
8
9
10
11
12b
13c
14d,e
2
2
2
4
4
5
5
5
3
3
3
2
2
2
6
7
9
8
9
8
8
6
9
10
6
6
6
6
Boc-L-V-L-F-OMe
Boc-L-V-D-F-OMe
Boc-L-V-L-W-OMe
Boc-L-P-L-P-OMe
Boc-L-P-L-W-OMe
Boc-L-â-D-L-P-OMe
Boc-L-â-D-Aib-OMe
Boc-L-â-D-L-F-OMe
Boc-Aib-L-W-OMe
Boc-Aib-Aib-OMe
Boc-Aib-L-F-OMe
Boc-L-V-L-F-OMe
Boc-L-V-L-F-OMe
Boc-L-V-L-F-OMe
81
82
82
78
77
75
79
82
80
80
82
51
62
59
Reaction of a set of amino ester hydrochlorides with 2,4-
dinitrobenzenesulfonamide in dichloromethane in the pres-
ence of pyridine gave the sulfonamides 6-10 (Figure 1).
(5) (a) Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1988, 53,
1580-1582. (b) Rakotomanomana, N.; Lacombe, J.-M.; Pavia, A. Carbo-
hydr. Res. 1990, 197, 318-323. (c) Shangguan, N.; Katukojvala, S.;
Greenberg, R.; Williams, L. J. J. Am. Chem. Soc. 2003, 125, 77554-7755.
(d) Merkx, R.; Brouwer, A. R.; Rijkers, D. T. S.; Liskamp, R. M. J. Org.
Lett. 2005, 7, 1125-1128. (e) Kolakowski, R. V.; Shangguan, N.; Williams,
L. J. Tetrahedron Lett. 2006, 47, 1163-1166. (f) Barlett, K. N.; Kolakowski,
R. V.; Katukojvala, S.; Williams, L. J. Org. Lett. 2006, 8, 823-826. (g)
Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am.
Chem. Soc. 2006, 128, 5695-5702. (h) Crich, D.; Dudkin, V. Y.
Tetrahedron Lett. 2003, 44, 1787-1789. (i) Zhu, X. M.; Pachamuthu, K.;
Schmidt, R. R. Org. Lett. 2004, 6, 1083-1085. (j) Merkx, R.; van Haren,
M. J.; Rijkers, D. T. S.; Liskamp, R. M. J. J. Org. Chem. 2007, 72, 4574-
4577.
a V ) valine, F ) phenylalanine, W ) tryptophan, P ) proline, Aib )
R-aminoisobutyrate, D ) γ-aspartic acid R-benzyl ester. b Reaction con-
ducted in methanol as solvent. c Reaction conducted in the presence of an
equimolar amount of Boc-L-Asp-R-O-Bn. d Reaction conducted in the
presence of an equimolar amount of N-R-Cbz-L-Lys-O-Bn. e 23% of the
side chain functionalized lysine derivative 11 was also isolated from this
experiment.
(6) (a) Knapp, S.; Darout, E. Org. Lett. 2005, 7, 203-206. (b) Wu, X.;
Hu, L. J. Org. Chem. 2007, 72, 765-774.
(7) (a) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O. Tetrahedron
Lett. 1998, 39, 1669-1672. (b) Messeri, T.; Sternbach, D. D.; Tomkinson,
N. C. O. Tetrahedron Lett. 1998, 39, 1673-1676.
approximately 1:1 ratios of the thioacid and the sulfonamide,
serve to illustrate the scope of this peptide bond forming
methodology.11 In particular attention is drawn to entries 1
and 2 of Table 1 in which diastereomeric products were
obtained, ruling out the possibility of racemization in the
course of the thioester deprotection or the coupling.12 It is
(8) (a) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831-5834. (b) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353-359.
(9) Previous applications of amino thioacids in peptide synthesis: (a)
Yamashiro, D.; Blake, J. Int. J. Peptide Protein Res. 1981, 18, 383-392.
(b) Mitin, Y. V.; Zapevalova, N. P. Int. J. Peptide Protein Res. 1990, 35,
352-356.
4424
Org. Lett., Vol. 9, No. 22, 2007

Table 2. Neoglycoconjugates from Thioacids and Sulfonamides
a Isolated in the form of a triethylammonium salt and carried forward to the next step without purification
especially noteworthy that the protocol is applicable to
hindered amino acids such as proline and aminoisobutyric
acid, whichever side of the nascent peptide bond they occupy.
Comparison of entries 1 and 12 in Table 1 indicates that
the coupling reaction is compatible with the presence of
alcohols, and that methanol may even be employed as
solvent, albeit with a slight loss of yield. When the reaction
was conducted in the presence of a Boc-L-Asp-R-OBn (Table
1, entry 13) some loss of yield was recorded but no coupling
was observed to the spectator acid. Finally, the inclusion of
N-R-Cbz-L-Lys-O-Bn in the reaction mixture also resulted
in some loss of yield (Table 1, entry 14) accompanied by
some amidation of the free amine group. The interference
of unprotected amines in the peptide bond forming reactions
is, of course, common to most such reactions. In this case it
suggests that the reaction proceeds, at least in part, by
decomposition of the intermediate Meisenheimer complex
(Scheme 1) to a 2,4-dinitrophenyl thioester that subsequently
captures the nucleophilic amine.
As outlined in Scheme 3, we have also applied the method
to the synthesis of a model tetrapeptide by the segment
coupling of two dipeptides.
The method is also adaptable to neoglycoconjugate5i,13
synthesis. Thus, reaction of N-(2,4-dinitrobenzenesulfonyl)-
ethanolamine14 with peracetyl glucopyranose, galactopyra-
(10) Protection of thiols as 9-fluorenylmethyl ethers: (a) Garcia-
Echeverria, C.; Molins, M. A.; Albericio, F.; Pons, M.; Giralt, E. Int. J.
Peptide Protein Res. 1990, 35, 434-440. (b) Gu, X.; Ying, J.; Agnes, R.
S.; Navratilova, E.; Davis, P.; Stahl, G.; Porreca, F.; Yamamura, H. I.;
Hruby, V. J. Org. Lett. 2004, 6, 3285-3288.
(11) Consistent with the early literature9 on the reaction of amino
thioacids with amino acids no coupling was observed when the thioacid
obtained by deprotection of thioester 2 was stirred in DMF at room
temperature with phenylalanine methyl ester in the presence of cesium
carbonate, clearly indicating the need for the sulfonamide in this chemistry.
(12) Within the limits of detection by 500 MHz NMR spectroscopy.
Org. Lett., Vol. 9, No. 22, 2007
4425

conditions at room temperature and is compatible with typical
amino acid protecting groups. The further investigation of
this methodology is currently under investigation in our
laboratory.
Scheme 3. Tetrapeptide Formation
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL701583T
(13) (a) Roy, R. In Carbohydrate Chemistry; Boons, G.-J., Ed.;
Blackie: London, UK, 1998; p 243. (b) Lee, Y. T.; Lee, R. C., Eds.
Neoglycoconjugates: Preparation and Applications; Academic: San Diego,
CA, 1994. (c) Ichikawa, Y.; Matsukawa, Y.; Isobe, M. J. Am. Chem. Soc.
2006, 128, 3934. (d) Ladmiral, V.; Mantovani, G.; Clarkson, G. J.; Cauet,
S.; Irwin, J. L.; Haddleton, D. M. J. Am. Chem. Soc. 2006, 128, 4823. (e)
Hotha, S.; Kashyap, S. J. Org. Chem. 2006, 71, 364. (f) He, Y.; Hinklin,
R. J.; Chang, J.; Kiessling, L. Org. Lett. 2004, 6, 4479. (g) Grandjean, C.;
Boutonnier, A.; Guerreiro, C.; Fournier, J.-M.; Mulard, L. A. J. Org. Chem.
2005, 70, 7123. (h) Wen, S.; Guo, Z. Org. Lett. 2001, 3, 3773. (i) Mizuno,
M.; Goto, K.; Miura, T. Chem. Lett. 2005, 34, 426. (j) Kaneshiro, C. M.;
Michael, K. Angew. Chem., Int. Ed. 2006, 45, 1077. (k) Mandal, M.; Dudkin,
V. Y.; Geng, X.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2004, 43, 2557.
(l) Lin, H.; Walsh, C. T. J. Am. Chem. Soc. 2004, 126, 13998. (m) Tanaka,
H.; Iwata, Y.; Takahashi, D.; Adachi, M.; Takahashi, T. J. Am. Chem. Soc.
2005, 127, 1630. (n) Doores, K. J.; Mimura, Y.; Dwek, R. A.; Rudd, P.
M.; Elliott, T.; Davis, B. G. Chem. Commun. 2006, 1401. (o) Liu, H.; Wang,
L.; Brock, A.; Wong, C.-H.; Schulz, P. G. J. Am. Chem. Soc. 2003, 125,
1702. (p) Brik, A.; Yang, Y.-Y.; Ficht, S.; Wong, C.-H. J. Am. Chem. Soc.
2006, 128, 5626. (q) Hang, H. C.; Bertozzi, C. R. Acc. Chem. Res. 2001,
34, 727. (r) Davis, B. G. Chem. ReV. 2002, 102, 579. (s) Peri, F.; Nicotra,
F. Chem. Commun. 2004, 623. (t) Langenham, J. N.; Thorson, J. S. Curr.
Org. Synth. 2005, 2, 59. (u) Griffith, B. R.; Krepel, C.; Fu, X.; Blanchard,
S.; Ahmed, A.; Edmiston, C. E.; Thorson, J. S. J. Am. Chem. Soc. 2007,
129, 8150.
nose, and cellobiose in the presence of tin(IV) chloride gave
the functionalized sulfonamides 17-19 in good yield as the
â-anomers (Table 2). A further series of amino acid-based
thioacids 20-22 were prepared from the corresponding
N-hydroxysuccinimide esters by reaction with sodium hy-
drogen sulfide (Table 2).15 Coupling of sulfonamides 17-
19 with thioacids 20-22 under the standard conditions then
gave the neoglycoconjugates 24-29 (Table 2).
In summary, we present a facile method for the formation
of peptide bonds and amide-derived neoglycoconjugates that
is based on the reaction of thioacids with readily available
2,4-dinitrobenzenesulfonamides. The precursors are easy to
prepare, and the coupling reaction takes place under mild
(14) Kleb, K. G. Angew. Chem., Int. Ed. Engl. 1968, 7, 291-291.
(15) Goldstein, A. S.; Gelb, M. H. Tetrahedron Lett. 2000, 41, 2797-
2800.
4426
Org. Lett., Vol. 9, No. 22, 2007