Synthesis and Conformational Studies of Dipeptides Constrained by Disubstituted 3-(Aminoethoxy)propionic Acid Linkers

Article abstract of DOI:10.1021/jo035683q

A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have been prepared as potential β-turn mimics. The desired linkers were prepared from disubstituted pyrones, which were coupled with dipeptides and then subjected

Full text of DOI:10.1021/jo035683q

Syn th esis a n d Con for m a tion a l Stu d ies of Dip ep tid es Con str a in ed
by Disu bstitu ted 3-(Am in oeth oxy)p r op ion ic Acid Lin k er s
D. Srinivasa Reddy, David Vander Velde, and J effrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott Hall, Room 4070,
University of Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received November 15, 2003
A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have
been prepared as potential â-turn mimics. The desired linkers were prepared from disubstituted
pyrones, which were coupled with dipeptides and then subjected to macrocyclization using
diethylcyanophosphonate to furnish cyclic compounds 1-5. Conformational analysis was carried
out using NMR and X-ray crystallography. All of the five cyclic compounds were found to exist in
type I or type II â-turn conformations.
Peptidomimetics based on â-turns are important, as
many peptides are required to adopt such a conformation
while effecting a biological response. A variety of struc-
tural motifs have been utilized as turn mimics, ranging
from substituted heterocycles to scaffolds derived from
steroids or carbohydrates.1,2 More recent work has em-
phasized the generation of libraries for â-turn models
using solid-phase synthesis, in which a linker is attached
to a solid support.3 The use of 6-aminocaproic acid (Aca)
as a dipeptide linker was introduced by Woody and
Scheraga, who showed that such macrocycles adopt a
â-turn around the dipeptide unit.4 They also established
that the type of â-turn formed (type I or type II) depended
on the stereochemistry of the dipeptide used. Our labora-
tory has studied the design and synthesis of dipeptides
constrained by substituted Aca linkers.5 These studies
showed that the position and stereochemistry of Aca
linker substitution had an effect on the conformation of
the macrocycles.
As a part of ongoing research in this area, we were
interested in designing more effective linkers able to
constrain simple dipeptides into particular subtypes of
â-turn conformations. X-ray analysis of cyclic compounds
prepared using a variety of all-carbon Aca linkers showed
that one of the C-H bonds of the C4-methylene group
occupies an inside position in the macrocycle (Figure 1c),
disrupting a potential hydrogen bond between the Aca
carbonyl and its amide nitrogen. We hypothesized that
(1) Selected reviews on â-turn mimics: (a) Rose, G. D.; Gierasch, L.
M.; Smith, J . A. In Advances in Protein Chemistry; Anfinsen, C. B.,
Edsall, J . T., Richards, F. M., Eds.; Academic: Orlando, FL, 1985; Vol.
37, pp 1-109. (b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244-1267. (c) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R.
Tetrahedron 1993, 49, 3577-3592. (d) Olson, G. L.; Bolin, D. R.;
Bonner, M. P.; Bo¨s, M.; Cook, C. M.; Fry, D. C.; Graves, B. J .; Hatada,
M.; Hill, D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.;
Sepinwall, J .; Vincent, G. P.; Voss, M. E. J . Med. Chem. 1993, 36,
3039-3049. (e) Mueller, G. Angew. Chem., Int. Ed. Engl. 1997, 35,
2767-2769. (f) MacDonald, M.; Aube´, J . Curr. Org. Chem. 2001, 5,
417-438. (g) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (h) Burgess, K. Acc.
Chem. Res. 2001, 34, 826-835. (i) Nubbemeyer, U. Top. Curr. Chem.
2001, 216, 125-196. (j) Souers, A. J .; Ellman, J . A. Tetrahedron 2001,
57, 7431-7448. (k) Eguchi, M.; Kahn, M. Mini-Rev. Med. Chem. 2002,
2, 447-462. (l) Hruby, V. J . Nat. Rev. Drug Discovery 2002, 1, 847-
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C.; Ying, J .; Wang, W.; Hruby, V. J . Org. Lett. 2003, 5, 3115-3118. (b)
Lee, H. B.; Pattarawarapan, M.; Roy, S.; Burgess, K. Chem. Commun.
2003, 1674-1675. (c) Xiong, C.; Zhang, J .; Davis, P.; Wang, W.; Ying,
J .; Porreca, F.; Hruby, V. J . Chem. Commun. 2003, 1598-1599. (d)
Baek, B.; Lee, M.; Kim, K.; Cho, U.; Boo, D. W.; Shin, I. Org. Lett.
2003, 5, 971-974. (e) Boruah, A.; Rao, I. N.; Nandy, J . P.; Kumar, S.
K.; Kunwar, A. C.; Iqbal, J . J . Org. Chem. 2003, 68, 5006-5008. (f)
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C. J . Org. Chem. 2003, 68, 1982-1993. (g) Kaul, R.; Deechongkit, S.;
Kelly, J . W. J . Am. Chem. Soc. 2002, 124, 11900-11907. (h) Han, Y.;
Giragossian, C.; Mierke, D. F.; Chorev, M. J . Org. Chem. 2002, 67,
5085-5097. (i) Wels, B.; Kruijtzer, J . A. W.; Liskamp, R. M. J . Org.
Lett. 2002, 4, 2173-2176. (j) Grieco, P.; Campiglia, P.; Gomez-Monter-
rey, I.; Novellino, E. Tetrahedron Lett. 2002, 43, 1197-1199. (k) Gibbs,
A. C.; Bjorndahl, T. C.; Hodges, R. S.; Wishart, D. S. J . Am. Chem.
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Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361-3364. (m) Sukopp,
M.; Marinelli, L.; Heller, M.; Brandl, T.; Goodman, S. L.; Hoffmann,
R. W.; Kessler, H. Helv. Chim. Acta 2002, 85, 4442-4452. (n) Halab,
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arawarapan, M.; Wang, Z.; Burgess, K. Org. Lett. 1999, 1, 121-124.
(c) Feng, Y.; Burgess, K. Chem.sEur. J . 1999, 5, 3261-3272. (d)
Eguchi, M.; Lee, M. S.; Stasiak, M.; Kahn, M. Tetrahedron Lett. 2001,
42, 1237-1239. (e) Virgilio, A. A.; Schurer, S. C.; Ellman, J . A.
Tetrahedron Lett. 1996, 37, 6961-6964. (f) Virgilio, A. A.; Ellman, J .
A. J . Am. Chem. Soc. 1994, 116, 11580-11581. (g) Virgilio, A. A.; Bray,
A. A.; Zhang, W.; Trinh, L.; Snyder, M.; Morrissey, M. M.; Ellman, J .
A. Tetrahedron 1997, 53, 6635-6644.
(4) (a) Bandekar, J .; Evans, D. J .; Krimm, S.; Leach, S. J .; Lee, S.;
McQuie, J . R.; Minasian, E.; Ne´methy, G.; Pottle, M. S.; Scheraga, H.
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187-205. (b) Deslauriers, R.; Evans, D. J .; Leach, S. J .; Meinwald, Y.
C.; Minasian, E.; Ne´methy, G.; Rae, I. D.; Scheraga, H. A.; Somorjai,
R. L.; Stimson, E. R.; Van Nispen, J . W.; Woody, R. W. Macromolecules
1981, 14, 985-996. (c) Ne´methy, G.; McQuie, J . R.; Pottle, M. S.;
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10.1021/jo035683q CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/10/2004
1716
J . Org. Chem. 2004, 69, 1716-1719

Dipeptides Constrained by Oxygen-Containing Linkers
SCHEME 1
F IGURE 1. (a) A generalized â-turn. (b) Dipeptides con-
strained with Aca linkers. (c) Ball-and-stick model showing
the location of the “inside” proton.
SCHEME 2
F IGURE 2. Cyclic compounds with oxa-Aca linkers.
this space might be freed up by replacement of the C4-
methylene group with an oxygen atom or, alternatively,
with an NH group containing an additional hydrogen-
bonding partner. In so doing, it seemed possible that
tighter macrocycles might be obtained, leading to better
conformational control by the hetero-Aca linkers. In this
paper, we describe the synthesis and conformational
analysis of a set of ether-containing â-turn mimics
(Figure 2). In this study, we concentrated on linkers
bearing 1,3-dimethyl substitution as a conformational
controlling feature.6
configuration of (+)-9 was confirmed by comparing its
rotation with the literature value.8 Hydrolysis of the
amide bond of (+)-9 using 6 N HCl followed by esterifi-
cation with SOCl2-MeOH resulted in the desired syn-
dimethyl linker in 95% yield. The crude syn-dimethyl
linker was condensed with commercially available Boc-
Ala-Gly-OH under standard peptide coupling conditions9
to give 10. Ester hydrolysis and deprotection of the Boc
group was followed by macrocyclization under dilute
conditions with diethylcyanophosphonate (DECP)10 to
furnish the target macrocycle 1 in 51% yield. The spectral
data of 1 were consistent with its assigned structure.
For the synthesis of an anti-dimethyl oxa linker, we
prepared trans-2,6-dimethyl tetrahydropyrone (12) from
the known dihydropyrone 1111 via methylcuprate addi-
tion. However, when we subjected 12 to asymmetric
azido-Schmidt conditions, the same mixture of lactams
8a and 8b as obtained above was exclusively isolated.
Control experiments showed that BF3 promoted the
conversion of trans-dimethyl pyrone 12 into the thermo-
dynamically more stable cis-isomer 6 prior to ring expan-
sion (Scheme 3). The use of the more reactive three-
carbon tethered chiral azido alcohol was also unsuccessful
and resulted in several diastereomers resulting from both
cis- and trans-dimethyl groups.
Syn th esis
Retrosynthetically, our target macrocycles 1-5 were
envisioned to arise from the corresponding acyclic pre-
cursors, obtained from coupling the linkers with com-
mercially available dipeptides (Scheme 1).
A synthetic route for the enantiopure syn-dimethyl
linkers was devised on the basis of a ring-expansion
method recently developed in our laboratory. Thus, the
Lewis acid-mediated azido-Schmidt reaction7 of chiral
azido alcohol 7 with ketone 6 furnished a 9:1 diastereo-
meric mixture of ring-expanded lactams 8a and 8b in
75% yield (Scheme 2). The lactams were separated
cleanly using chromatography, and the major product
was converted to lactam (+)-9 by reductive removal of
the phenethyl group using metal ammonia. The absolute
Our inability to secure the trans lactams corresponding
to 8 forced us to pursue an alternative approach. Thus,
(6) (a) Hoffmann, R. W.; Schopfer, U.; Muller, G.; Brandl, T. Helv.
Chim. Acta 2002, 85, 4424-4441. (b) Hoffmann, R. W.; Gottlich, R.;
Schopfer, U. Eur. J . Org. Chem. 2001, 1865-1871. (c) Hoffmann, R.
W. Angew. Chem., Int. Ed. Engl. 2000, 39, 2055-2070. (d) Stenkamp,
D.; Hoffmann, R. W.; Gottlich, R. Eur. J . Org. Chem. 1999, 2929-
2936. (e) Hoffmann, R. W.; Stenkamp, D.; Trieselmann, T.; Gottlich,
R. Eur. J . Org. Chem. 1999, 2915-2927.
(7) (a) Furness, K.; Aube´, J . Org. Lett. 1999, 1, 495-497. (b)
Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.;
Reddy, D. S.; Aube´, J . J . Am. Chem. Soc. 2003, 125, 7914-7922.
(8) Sato, M.; Kuroda, H.; Kaneko, C.; Furuya, T. J . Chem. Soc.,
Chem. Commun. 1994, 687-688.
(9) Sheehan, J . C.; Preston, J .; Cruickshank, P. A. J . Am. Chem.
Soc. 1965, 87, 5468-5469.
(10) Hayashi, K.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1992,
33, 5075-5076.
(11) Danishefsky, S.; Kerwin, J . F. J . J . Org. Chem. 1982, 47, 1597-
1598.
J . Org. Chem, Vol. 69, No. 5, 2004 1717

Reddy et al.
SCHEME 3
F IGURE 3. Characteristic ROEs in predicting type I vs type
II â-turns.
SCHEME 5
SCHEME 4
Aca cyclic compounds are disclosed in the Supporting
Information.
Con for m a tion a l An a lysis
The systematic conformational analysis of the cyclic
peptidomimetics was carried out in solution phase using
nuclear magnetic resonance (NMR) and in the solid state
using X-ray crystallography. All of the protons in the
NMR spectra of each cyclic compound were assigned
1
using H-1H COSY and ROESY experiments. It is well-
established in these systems that a strong rotating-frame
(nuclear) Overhauser enhancement (ROE) between the
glycine NH and the linker NH indicates that a compound
can exist in either a type I or a type II â-turn, and ROE
between the alanine NH and the glycine NH is charac-
teristic for type I turns.5 Similarly, a cross-peak between
the alanine R-hydrogen and the glycine NH indicates a
type II â-turn (Figure 3). On the basis of these charac-
teristics, it appears that compounds 1, 4, and 5 take up
substantial type II conformations. On the other hand,
compound 2 showed significant type I character in the
NMR. We were unable to further analyze compound 3
using NMR because of overlapping proton signals.
In addition, we obtained X-ray crystal structures for
compounds 1 and 2, both of which indicate type I â-turn
conformers (Figure 4). We also note the crystallographic
observation of hydrogen bonding between the linker
carbonyl and Gly-NH units in these structures. We had
anticipated that the oxygen atom present in the linker
would occupy an inside position, and perhaps engage in
hydrogen bonding, but an examination of the two crystal
structures showed that this simplistic situation did not
apply. In fact, neither compound 1 nor 2 took up this
expected conformation; rather, the plane containing the
C-O-C atoms of the ethereal linkage is essentially
perpendicular to the plane approximately defined by the
macrocycle in both cases. Overall, no drastic structural
changes were observed in this series of structures in
crystalline lactams (()-9 and (()-13 were prepared from
6 and 12, respectively, using the standard Beckmann
rearrangement of the corresponding oximes. With lac-
tams in hand, hydrolysis of the amide bond in (()-9
followed by esterification resulted in the desired linker.
The crude linker was reacted with Boc-Ala-Gly-OH under
standard peptide coupling conditions to give the corre-
sponding 1:1 diastereomeric mixture of 14 and 10; no
attempt was made to separate the diastereomers at this
stage (Scheme 4). Removal of the methyl ester and Boc
groups followed by macrocyclization produced the desired
target macrocycles 1 and 2 in an ∼1:1 ratio. Compounds
1 and 2 were separated chromatographically. The spec-
tral data of 1 showed this compound to be identical with
that prepared in Scheme 2 using the asymmetric azido-
Schmidt reaction. Similarly, we prepared the anti series
comprised of 3 and 4 from (()-13 (Scheme 4). Tentatively,
we have assigned the stereochemistry of dimethyl groups
for compounds 3 and 4, as drawn on the basis of high-
field 2D NMR and molecular modeling.
For comparison purposes, we also synthesized the
parent macrocycle 5 (Scheme 5). In this case, linker 18
was obtained by the treatment of Boc-protected ethanol-
amine 17 with ethyl acrylate in the presence of a catalytic
amount of Na in THF.12 After the successful synthesis
of five new cyclic compounds containing an oxygen
heteroatom, we explored several ways of introducing an
NH unit in place of oxygen, but none succeeded. Some of
the unsuccessful routes explored for the synthesis of aza-
(12) Hashimoto, M.; Yang, J .; Holman, G. D. ChemBioChem 2001,
2, 52-59.
(13) X-ray analysis of compound 2 showed the presence of two closely
related conformers in a single unit cell. For clarity, only one of the
conformers is shown in Figure 4; see the Supporting Information for
full details.
1718 J . Org. Chem., Vol. 69, No. 5, 2004

Dipeptides Constrained by Oxygen-Containing Linkers
to control subtype populations. The upside of this is that
these positions can be freed up to accommodate ad-
ditional side chain proxies for potential binding interac-
tions.
Su m m a r y
We have accomplished the synthesis of macrocycles
1-5 constrained with dimethyl-substituted 3-(amino-
ethoxy)propionic acid linkers which were, in turn, gener-
ated from the readily available dimethyl tetrahydro-
pyrones. Conformational analysis showed that com-
pounds 1-5 all adopt â-turn conformations but with
complex results with respect to subtypes. Despite our
original design hypothesis, there appears to be no con-
formational benefit to including the oxygen in the linker
relative to the all-carbon case.
Ack n ow led gm en t. We thank the National Science
Foundation and the National Institutes of Health for
the support of this work and Doug Powell for X-ray
crystallography.
F IGURE 4. Ball-and-stick representations of the X-ray
structures and their dihedral angles of 1 and 2.13
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization of compounds, a summary of unsuc-
cessful routes for the synthesis of the aza cyclic analogues,
and CIF data. This material is available free of charge via the
Internet at http://pubs.acs.org.
comparison to the all-carbon series previously reported.
In part, we attribute the different conformations observed
in solution versus solid state to crystal packing forces.
However, it is also clear that these compounds have a
fair degree of conformational mobility. The bottom line
is that the tether substituents in this series are unlikely
J O035683Q
J . Org. Chem, Vol. 69, No. 5, 2004 1719