The synthesis and conformational analysis of amino acid-tetrahydroanthranilic acid hybrids

Article abstract of DOI:10.1016/j.tetlet.2008.05.148

The optimization of a palladium-catalyzed amidation reaction providing a new class of amino acid-tetrahydroanthranilic acid derivatives has been achieved. The scope of the reaction and preliminary conformational analysis of the resulting series of molecules is discussed.

Full text of DOI:10.1016/j.tetlet.2008.05.148

Tetrahedron Letters 49 (2008) 4897–4900
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis and conformational analysis of amino
acid–tetrahydroanthranilic acid hybrids
*
Jason E. Imbriglio , Daniel DiRocco, Subharekha Raghavan, Richard G. Ball,
Nancy Tsou, Ralph T. Mosley, James R. Tata, Steven L. Colletti
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The optimization of a palladium-catalyzed amidation reaction providing a new class of amino acid–
tetrahydroanthranilic acid derivatives has been achieved. The scope of the reaction and preliminary
conformational analysis of the resulting series of molecules is discussed.
Received 23 May 2008
Accepted 30 May 2008
Available online 5 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
With distinct advantages over peptide-based therapeutics,
anthranilic acid containing peptides (1) have found general utility
as biologically active molecules in a number of drug discovery
programs.1
O
O
H
H
R
R
N
N
N
H
N
H
H
R
H
R
O
N
O
N
O
O
R
R
Despite the broad interest in peptides containing an anthranilic
acid moeity, the functionally similar tetrahydroanthranilic acid
(THA)–peptide hybrids (2) have received no attention. Previously,
we have described the design and discovery of tetrahydroanthrani-
lic acid (THA) as a bioisosteric replacement of anthranilic acid
within a series of GPR109A niacin receptor agonists.2 As part of
an effort to identify new classes of peptidomimetics that might
enable drug discovery, we became interested in exploring the
potential of THA-containing peptides as surrogates to the ubiqui-
tious anthranilic acid embedded peptides. Most notably, we were
interested in determining whether the hydrogen bond central to
the chemical stability and conformational rigidity of anthranilic
acid embedded peptides was also present in the THA-containing
derivatives (Fig. 1).
2
1
Figure 1. Anthranilic acid (1) and THA (2) containing peptides.
reaction of commercially available N-Boc protected alanine 3 with
vinyl triflate 4, in the presence of Pd2(dba)3, xantphos,5 and Cs2CO3
provided the desired tetrahydroanthranilic ester 5 in 63% isolated
yield in 4 h (Table 1, entry 1).
Optimization of the reaction conditions, employing 2 equiv of
triflate and 1 equiv of the amide, provided the desired product 5
in an improved 97% isolated yield (Table 1, entry 3).6 Further inves-
tigations showed that lower catalyst loadings and lower tempera-
tures could be accommodated, albeit with slightly lower yields
(Table 1, entries 4–7). Finally, control experiments showed that
both the palladium catalyst and the xantphos ligand are required
for the reaction to occur (Table 1, entries 8–10).
With this goal in mind, we searched for a proficient synthetic
route toward this class of molecules. Surprisingly, we found that
traditional amide coupling techniques provided low yields of the
desired THA-derived peptide products and required long reaction
time periods.3
Using our optimized reaction conditions, we began exploring
the scope of the reaction by modifying the nitrogen protecting
group on the amino amide coupling partner. As shown in Table
2, synthetically useful yields of the coupled products were
obtained using a variety of traditional N-protected amino amides:
N-Cbz (19, 90%), N-Ac (20, 47%), and N-Fmoc (21, 66%).
The functional group tolerance of the coupling reaction was
investigated by screening a series of Boc-protected amino amides.
The use of phenyl and naphthyl-substituted amino amides 9 and
10 resulted in formation of the desired products in high yields,
90% and 83%, respectively. Whereas the coupling of the more ste-
rically encumbered biphenyl derivative 11 afforded the product
24 in a slightly lower yield (68%). Heteroaromatic amino amides
Recent advances in palladium-catalyzed amidation reactions
have provided alternative methods for the construction of amide
bonds.4 Despite a considerable amount of work in this area, the
use of an amino acid-derived amide as a coupling partner has
not been explored. With only modest success employing tradi-
tional amide coupling methods, we became interested in
constructing our THA–amino acid hybrids using a palladium-cata-
lyzed amidation reaction. Our initial efforts, employing conditions
developed by Klapars and coworkers, were quite promising. The
* Corresponding author. Tel.: +1 732 594 3143; fax: +1 732 594 9473.
E-mail address: jason_imbriglio@merck.com (J. E. Imbriglio).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.148

4898
J. E. Imbriglio et al. / Tetrahedron Letters 49 (2008) 4897–4900
Table 1
12 and 13 were proficient coupling partners under our conditions,
The palladium-catalyzed amidation of amino amides
providing good yields of the desired products, 87% and 78%. In con-
trast, the coupling with tryptophan derivative 14, containing an
unprotected indole moeity, afforded only 31% of the desired prod-
uct 27.7 A free carboxylic acid was also tolerated under the reaction
conditions. The palladium-catalyzed coupling of triflate 4 to glu-
tamic acid derivative 15 provided the desired product 28 in 54%
isolated yield.
Having discovered a general and functional group- tolerant
method for the synthesis of THA-containing amino acid deriva-
tives, we became interested in extending this methodology toward
the synthesis of THA-embedded peptide molecules. With this goal
in mind, we investigated the utility of the palladium-catalyzed
amidation reaction in coupling larger peptide-based amide frag-
ments. The coupling of dipeptide 16 in the presence of vinyl triflate
4 afforded the corresponding peptide–THA hybrid 29 in 77% yield.
Under the same reaction conditions, tripeptide 17 coupled to give
the desired product 30 in 71% yield. We were pleased to see that
neither the size of the peptide nor the dense functionality seemed
Pd2(dba)3
xantphos
H
N
O
H
N
O
+
BOC
NH2
TfO
BOC
N
Cs2CO3
H
CO2Me
CO2Me
Me
temp
Me
4 h
dioxane
3
4
5
a
Entry 3 (equiv) 4 (equiv) Temp (°C) Pd2(dba)3
Xantphosa 5 Yieldb (%)
1
2
3
4
5
6
7
8
9
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
80
80
80
80
80
50
rt
80
80
80
10
10
10
5
20
20
20
10
5
20
20
20
—
63
76
97
83
72
78
65
—
2
10
10
—
10
—
—
—
10
—
a
mol %.
b
Isolated yields after chromatography.
Table 2
Coupling of amino amides and enol-triflatesa
Pd2(dba)3 (10 mol %)
xantphos(20 mol %)
+
TfO
Amide
Amide
CO2Me
CO2Me
4
Entry
1
Amide
Product
Yieldb (%)
90
O
O
N
NH2
Cbz
H
CO2Me
CO2Me
HN
HN
6
Cbz
19
O
O
N
H
NH2
Ac
2
3
4
47
66
90
HN
HN
7
Ac
20
O
N
O
O
O
NH2
H
O HN
CO2Me
O HN
Fmoc
Fmoc
8
21
O
N
O
NH2
BOC
H
HN
CO2Me
HN
9
Cl
Cl
BOC
22
O
O
N
NH2
5
6
83
68
H
CO2Me
BOC
HN
HN
10
BOC
23
Ph O
HN
Ph O
HN
Ph
N
Ph
NH2
H
CO2Me
BOC
BOC
11
24
O
O
N
H
BOC
NH2
7
8
87
78
CO2Me
CO2Me
HN
HN
S
S
BOC
12
25
O
O
N
H
BOC
NH2
BOC
N
BOC
HN
N
BOC
HN
13
26

J. E. Imbriglio et al. / Tetrahedron Letters 49 (2008) 4897–4900
4899
Table 2 (continued)
Entry
Amide
Product
Yieldb (%)
31
O
N
O
NH2
9
10
11
H
CO2Me
CO2Me
HN
HN
HN
O
HN
BOC
BOC
14
27
O
O
O
HO
N
H
HO
NH2
54
77
HN
HN
BOC
BOC
15
28
Ph
Ph
O
O
H
H
BOC
BOC
N
BOC
N
N
N
N
NH2
CO2Me
H
H
H
O
Me
O
Me
16
29
Ph
O
Ph
O
O
O
H
H
H
H
N
N
N
N
BOC
N
H
NH2
N
N
12
71
75
CO2Me
H
H
O
O
Me
Me
30
17
OH
OH
Ph
O
Ph
O
O
H
O
H
H
H
N
N
N
N
N
N
N
N
N
NH2
CO2Me
H
H
H
O
O
O
O
13
BOC
BOC
Me
Me
OH
31
OH
18
a
Reagents and conditions: enol triflate 2.0 equiv, amide 1.0 equiv, Cs2CO3 2 equiv, 1 M in dioxane, at 80 °C for 4 h.
Isolated yields after chromatography.
b
to effect the efficiency of the reaction. Finally, tetrapeptide 18, the
largest and most functionally diverse coupling partner employed in
this reaction, effectively coupled to vinyl triflate 4, affording the
desired product 31 in a 75% isolated yield.
With access to a variety of stereochemically and functionally di-
verse amino acid and peptide-based THA-containing molecules, we
sought to establish whether these compounds pre-organize into
conformations similar to those observed with the corresponding
anthranilic acid derivatives.1 Most importantly, we hoped to verify
that the backbone hydrogen bond observed in peptide anthranilic
acid peptidomimetics was also present in the THA-containing
amino acid derivatives.8
Toward this end, we obtained an X-ray crystal structure of com-
pound 5. As shown in Figure 2, the 1.9 Å bond distance between
O(4) and N(1)H suggests that the preferred conformation of the
amino acid–THA hybrid does indeed conserve this distinct hydro-
gen bond, similar to that observed with the anthranilic acid
moeity.9
Figure 2. X-ray crystal structure of 5.
Further analysis of 5 in solution provided additional support for
the presence of the backbone hydrogen bond. At ambient temper-
ature, the 1H NMR spectrum exists as a sharp set of unique reso-
nances in C6D6. Titrating a solution of alanine derivative 5 in
C6D6 with increasing equivalents of DMSO-d6 causes a characteris-
tic downfield shift of the free BOC NHa proton. In contrast, the
amide NHb resonance is unaffected by increasing DMSO-d6 con-
centrations. These chemical shift data support a solution structure
for 5 in which the amide proton is involved in an intramolecular
hydrogen bond10 (Fig. 3).
cient with respect to a number of protected and unprotected amino
acid-derived amides. In addition, we have showcased the func-
tional group tolerance and convergent nature of the coupling by
employing amide-terminating di-, tri-, and tetrapeptides to pro-
vide direct access to a class of THA-based peptidomimetics. Finally,
preliminary studies have revealed that molecules of type 5, both in
crystalline form and in solution, contain an intramolecular hydro-
gen bond reminiscent of the related anthranilic acid peptidomi-
metics. Future investigations in this effort will continue to focus
on the conformational analysis of both the amino acid and
peptide-based THA hybrid molecules.
In summary, we have developed a palladium-catalyzed amida-
tion reaction employing amino acid-derived amides that allows for
the construction of amino acid THA hybrid molecules. We have
shown that the optimized reaction conditions are generally effi-

4900
J. E. Imbriglio et al. / Tetrahedron Letters 49 (2008) 4897–4900
Nomura, Y. JP Patent 003555, 2005.; (f) Kiso, Y. JP Patent 002438, 2004.; (g)
Mandelkow, E.; Mandelkow, E. M.; Biernat, J.; Bergen, M. V.; Pickhardt, M.; EP
Patent 008031, 2004.
δ(NH) Dependence in C6D6/D6-DMSO
14
12
10
8
2. Raghavan, S.; Tria, G. S.; Shen, H. C.; Ding, Fa-Xiang; Taggart, A. K.; Ren, N.;
Wilsie, L. C.; Krsmanovic, M. L.; Holt, T. G.; Wolff, M. S.; Waters, G.; Hammond,
M. L.; Tata, J. R.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2008, 18, 3163–3167.
3. Standard diimide coupling employing DCC and HOBT in the presence of BOC-
alanine and methyl 2-amino-1-cyclohexen-1-carboxylate provided
a 32%
isloated yield over a 24 h time period. Standard mixed anhydride conditions
of isobutylchloroformate and NMM provided 27% yield of product over a 28 h
time period.
6
4
4. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104; (b) Yin, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 6043–6048; (c) Wallace, D. J.; Klauber, D. J.; Chen,
C.; Volante, R. P. Org. Lett. 2003, 5, 4749–4752; (d) Manley, P. J.; Bilodeau, M. T.
Org. Lett. 2004, 6, 2433–2435; (e) Dallas, A. S.; Gotheif, K. V. J. Org. Chem. 2005,
70, 3321–3323; (f) Klapars, A.; Campos, K. R.; Chen, C.; Volante, R. P. Org. Lett.
2005, 7, 1185–1188; (g) Ganton, M. D.; Kerr, M. Org. Lett. 2005, 7, 4777–4779;
(h) Van den Hoogenband, A.; Lange, J. H. M.; Iwema-Bakker, W.; den Hatrog, J.;
van Schaik, J.; Feenstra, R.; Terpstra, J. W. Tetrahedron Lett. 2006, 47, 4361–
4364.
NH(b)
NH(a)
2
0
0
10
20
30
% DMSO-d6
O
N
5. Kamer, P. C.; van Leeuwen, P. W. N. M.; Reek, J. N. Acc. Chem. Res. 2001, 34, 895–
904.
6. General procedure for the palladium-catalyzed amidation reaction: Synthesis
of THA 5. To a degassed solution of Boc-
D-alanine-amide 3 (0.049 g, 0.26 mmol)
O
N
Hb
in anhydrous dioxane, under nitrogen, was added triflate
4
(0.150 g,
Ha
O
O
0.52 mmol), 9,9-dimethyl-4,5-bis(di-tert-butylphosphino)xanthene (0.030 g,
0.052 mmol), cesium carbonate (0.170 g, 0.52 mmol), and tris(dibenzyl-
ideneacetone)dipalladium (0.024 g, 0.026 mmol) at room temperature. The
reaction mixture was then heated to 80 °C, for 4 h. The reaction was then
allowed to cool to room temperature, filtered through silica gel, and
concentrated in vacuo. The residue was purified by flash chromatography
(Biotage, Horizon) using (20% EtOAc/hexane) to give the desired product 5
(0.083 g, 0.54 mmol, 97%) as a white crystalline solid. 1H NMR (500 MHz,
CDCl3) d 11.97 (s, 1H), 5.08 (s, 1H), 4.25 (s, 1H),3.75 (s, 3H), 2.99 (m, 2H), 2.33
(m, 2H), 1.65 (m, 4H), 1.49 (s, 9H), 1.45 (d, J = 7.0 Hz, 3H);13C (125 MHz,
CDCl3): d 171.8, 170.3, 155.4, 151.8, 150.6, 80.2, 51.8, 51.7, 28.7, 28.6, 24.5,
O
5
Figure 3. Chemical shift data for THA 5 as a function of solvent composition
(% DMSO-d6 in C6D6).
Supplementary data
22.0, 21.8, 19.2. ½ ꢀ +86.2 (c 1.00, HOAc). LCMS [M+Na]: m/z calcd for
a 2D2
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.148.
C16H26N2NaO5 349.17, obsd 349.20.
7. The product resulting from coupling of the triflate to both the amide and the
indole nitrogens was also isolated in 34% yield.
8. (a) Rae, I. D. Can. J. Chem. 1968, 46, 2589–2592; (b) Zanger, M.; Simons, W. W.;
Gennaro, A. R. J. Org. Chem. 1968, 33, 3673–3675; (c) Etter, M. C. J. Am. Chem.
Soc. 1982, 104, 1095–1096; (d) Mascarenhas, Y. P.; DeAlmeida, V. N.; Lechat, J.
R.; Barelli, N. Acta Crystallogr., Sect. B 1980, 502–504; (e) Mascarenhas, Y. P.;
DeAlmeida, V. N.; Lechat, J. R.; Barelli, N. ActaCrystallogr., Sect. B 1980, 502–504.
References and notes
1. (a) Thongtan, J.; Saenboonreung, J.; Rachtawee, P.; Isaka, M. J. Nat. Prod. 2006,
69, 713–714; (b) Komatsu, K.; Shigemori, H.; Kobayashi, J. J. Org. Chem. 2001,
66, 6189–6192; (c) DeLuca, S.; Saviano, M.; Lassiani, L.; Yannakopoulou, K.;
Stefanidou, P.; Aloj, L.; Morelli, G.; Varnavas, A. J. Med. Chem. 2006, 49, 2456–
2462; (d) Varnavas, A.; Lassiani, L.; Valenta, V.; Berti, F.; Tontini, A.; Mennuni,
L.; Makovec, F. Eur. J. Med. Chem. 2004, 39, 85–97; (e) Oka, T.; Ikegashira, K.;
Hirashima, S.; Yamanaka, H.; Noji, S.; Niwa, Y.; Matsumoto, Y.; Sato, T.; Ando, I.;
9. The crystallographic data for compound
Cambridge Crystallographic Data Base.
5 have been deposited in the
10. For a discussion of the interpretation of these titration experiments, see:
Venkatachalapathi, Y. V.; Venkataram Prasad, B. V.; Balaram, P. Biochemistry
1982, 21, 5502–5509.