Modular synthesis of cyclic peptidomimetics inspired by γ-turns

Article abstract of DOI:10.1021/ol047323a

(Chemical Equation Presented) A series of peptidomimetics based on a γ-turn motif were synthesized using a modular approach, in which N-protected piperidones were reacted with a selection of 2-hydroxyalkyl azides derived from common L-amino acids. Hydrolysis of the initially formed iminium ethers afforded the targeted series of substituted 1,4-diazepin-5-ones.

Full text of DOI:10.1021/ol047323a

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1059-1062
Modular Synthesis of Cyclic
Peptidomimetics Inspired by
γ
-Turns†
Senthil Kumar Ramanathan, John Keeler, Huey-Lih Lee, D. Srinavasa Reddy,
Gerald Lushington, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Malott Hall,
Room 4070, UniVersity of Kansas, Lawrence, Kansas 66045-7582, and
the KU Chemical Methodologies and Library DeVelopment Center of Excellence,
UniVersity of Kansas, 1501 Wakarusa DriVe, Lawrence, Kansas, 66047
jaube@ku.edu
Received December 28, 2004
ABSTRACT
A series of peptidomimetics based on a
γ-turn motif were synthesized using a modular approach, in which N-protected piperidones were
reacted with a selection of 2-hydroxyalkyl azides derived from common
afforded the targeted series of substituted 1,4-diazepin-5-ones.
L
-amino acids. Hydrolysis of the initially formed iminium ethers
The peptidomimetic concept continues to inspire medicinal
chemists seeking potential drug leads or pharmacological
tools.1 One valuable approach is to synthesize heterocycles
devised to resemble common features of peptide secondary
structures. Although this strategy has been dominated by the
multitudinous approaches to â-turn mimicry,2 there has been
a steady undercurrent of work directed toward γ-turns as
well.3
Scheme 1
A γ-turn features a hydrogen bond between the carbonyl
of a residue i with the amide proton of residue i + 2 (Scheme
† Dedicated to the memory of Professor Murray Goodman, who
epitomized the phrase “a scholar and a gentleman”.
(1) (a) Goodman, M.; Chorev, M. Acc. Chem. Res. 1979, 12, 1-7. (b)
Huffman, W. F.; Callahan, J. F.; Eggleston, D. S.; Newlander, K. A.; Takata,
D. T.; Codd, E. E.; Walker, R. F.; Schiller, P. W.; Lemieux, C.; Wire, W.
S.; Burks, T. F. In Peptides, Chemistry and Biology, Proceedings of the
10th Annual American Peptide Symposium; Marshall, G. R., Ed.; ESCOM:
Leiden, 1988; pp 105-108. (c) Giannis, A.; Kolter, T. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1244-1267. (d) Marshall, G. R. Tetrahedron 1993,
49, 3547-3558. (e) 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. (f) Aube´, J. In AdVances
in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI Press:
Greenwich, CT, 1997; Vol. 1, pp 193-232. (g) Hanessian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-
12854. (h) MacDonald, M.; Aube´, J. Curr. Org. Chem 2001, 5, 417-438.
1). We wanted to synthesize mimics based on a simple,
readily synthesized heterocycle that would accommodate side
(2) For leading reviews on â-turns and their mimics, see: 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, 1985; Vol.
37, pp 1-109. See also ref 1 above.
10.1021/ol047323a CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/11/2005

chains corresponding to residues i through i + 2 at readily
modified positions.
established that the Lewis acid-promoted reaction of a ketone
with a hydroxyalkyl azide permits a ring-expansive route to
lactams.5 To apply this reaction to the present problem, a
sublibrary of hydroxyalkyl azides with side chains corre-
sponding to naturally occurring amino acids 1 were reacted
with N-protected piperidones 2 (Scheme 2). The reaction
The natural amino acid sequence was morphed into a
heterocyclic platform by first changing the directionality of
an amide bond and adding a methylene group into the
backbone.4 Conformational restriction was then carried out
by cyclization into a seven-membered ring. The resulting
1,4-diazepin-5-one ring system was attractive because it
readily accommodated potential side chains/points of diver-
sity R to the carbonyl group, on the lactam nitrogen, and in
the guise of an amino acid attached to N-1. In the last case,
flexibility of the ψ bond of the amino acid permits the side
chain to act as a credible mimic of the parent i substituent.
Ab initio calculations of the proposed turn analogues showed
reasonable overlap of the side chains with those of a standard
γ-turn (see Figure 1).
Scheme 2
proceeds by hemiketal formation followed by azide insertion
into the heterocycle, affording iminium ethers as the primary
product.5a,c Hydrolysis of the latter species was expected to
form the desired 1,4-diazepin-5-ones. The advantage of this
technique is that it permits ready incorporation of enantio-
merically pure, prefabricated amino acid equivalents into
existing ketones. Herein, we demonstrate the concept using
the parent piperidone system. We have previously shown
that the ring expansion reaction readily accommodates
substituted carbocyclic ketones, which bodes well for systems
wherein Ri+1 * H.5e
The desired hydroxyalkyl azides were made from the
corresponding amino acids by reduction and conversion of
the R-amino group to an azide. When necessary, appropriate
protecting groups were incorporated into the products. The
amino acids were reduced using TMSCl/NaBH4 and the
resulting amino alcohols converted to the corresponding
azides via treatment with TfN3.6 In this way, a variety of
azides derived from various amino alcohols were obtained.
Note that 1h was prepared by direct azidation of serine
benzyl ester, resulting in an azidoalkyl alcohol having the
opposite absolute configuration relative to the rest of the
series (Table 1).
Figure 1. Overlay of an idealized γ-turn (grey) with the proposed
mimetic (black), both containing alanine side chains.
Another goal was for the proposed turns to be synthesized
in a modular manner. Recent work in these laboratories has
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Hassan, M.; Goodman, M. J. Am. Chem. Soc. 1985, 107, 4008-4013. (d)
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J. A.; Wong, A.; Huffman, W. F. J. Med. Chem. 1992, 35, 3970-3972. (g)
Peishoff, C. E.; Ali, F. E.; Bean, J. W.; Calro, R.; D’Ambrosio, C. A.;
Eggleston, D. S.; Kline, T. P.; Koster, P. F.; Hwang, S. M. J. Med. Chem.
1992, 35, 3962-3969. (h) d’Ursi, A.; Pegna, M.; Amodeo, P.; Molinari,
H.; Verdini, A.; Zetta, L.; Temussi, P. A. Biochemistry 1992, 31, 9581-
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M.; Wakamiya, T.; Fukase, K.; Horimoto, S.; Kitazawa, M.; Fujita, H.;
Kubo, A.; Shiba, T. J. Am. Chem. Soc. 1992, 114, 5634-5642. (j) Sato,
M.; Lee, J. Y. H.; Nakanishi, H.; Johnson, M. E.; Chrisciel, R. A.; Kahn,
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J. F.; Newlander, K. A.; Burgess, J. L.; Eggleston, D. S.; Nichols, A.; Wong,
A.; Huffman, W. F. Tetrahedron 1993, 49, 3479-3488. (l) Drewes, J. A.;
Rowlen, K. L. Biophys. J. 1993, 65, 985-991. (m) Lisowski, M.;
Pietrzynski, G.; Rzeszotarska, B. Int. J. Pept. Protein Res. 1993, 42, 466-
474. (n) Moroder, L.; D’Ursi, A.; Picone, D.; Amodeo, P.; Temussi, P. A.
Biochem. Biophys. Res. Commun. 1993, 190, 741-746. (o) Newlander, K.
A.; Callahan, J. F.; Moore, M. L.; Tomaszek, T. A., Jr.; Huffman, W. F. J.
Med. Chem. 1993, 36, 2321-2331. (p) Balaji, V. N.; Ramnarayan, K.; Chan,
M. F.; Rao, S. N. Pharm. Res. 1994, 7, 60-71. (q) Hoog, S. S.; Zhao, B.;
Winborne, E.; Fisher, S.; Green, D. W.; DesJarlais, R. L.; Newlander, K.
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(4) This is related to the retro-inverso concept of peptidomimetic
design: (a) Ref 1a. (b) Chorey, M.; Goodman, M. Acc. Chem. Res. 1993,
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Org. Lett., Vol. 7, No. 6, 2005

Functional group compatibility was tested by carrying out
reactions with several of the piperidinones as depicted in
Table 3. In general, excellent yields of products could be
Table 1. Synthesis of Hydroxyalkyl Azides
Table 3. Syntheses of Substituted 1,4-Diazepin-5-ones
overall
yield
(%)
starting
amino acid
azido
alcohol
entry
R
entry azide
R
X
lactam yield (%)
1
2
3
4
5
6
7
8
valine
leucine
-CHMe2
-CH2CHMe2
-CH2Ph
-CH2C6H4OBn
-(CH2)3NHCbz
-(CH2)4NHCbz
-(CH2)2SMe
1a
1b
1c
1d
1e
1f
90
86
93
87
71
93
82
90
1
2
3
4
5
1a
1b
1d
1e
1f
-CHMe2
-CH2CHMe2
Bn
Bn
4
5
89
87
63
84
88
55
62
63
68
52
79
phenylalanine
O-benzyl tyrosine
N-Cbz ornithine
N-Cbz lysine
methionine
-CH2C6H4OBn Bn
-(CH2)3NHCbz Bn
-(CH2)4NHCbz Bn
-(CH2)2SMe
-CO2Bn
6
7
8
9
6
7
8
9
10
11
1g
1h
1a
1b
1b
1b
Bn
Bn
1g
1h
10
11
12
13
14
serine benzyl ester -CH2CO2Bn
-CHMe2
Fmoc
Fmoc
Cbz
-CH2CHMe2
-CH2CHMe2
-CH2CHMe
Hydroxyalkyl azide 1c derived from phenylalanine was
reacted with a series of differently N-protected piperidones
to determine which protecting groups were compatible with
the two-stage sequence involving both acidic and basic
conditions. The results, shown in Table 2, indicate that the
GlyCbz
obtained in this way. Moreover, lactams containing both
hydrophobic side chains as well as those with basic groups
(in protected form) were readily prepared.
Two other synthetic issues were preliminarily investigated
in this work. The direct alkylation of lactam 5 afforded a
dibenzylated derivative that could be converted to give 15
as a mixture of stereoisomers (Scheme 3). For some
Table 2. Reactions of 1c with Piperidinones 2a-c
Scheme 3
entry
ketone
acid
yield (%)
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
BF3‚OEt2
TfOH
BF3‚OEt2
TfOH
BF3‚OEt2
TfOH
52
84
46
51
74
55
applications, this allows entry into a series of mimics in
which the i + 1 residue corresponds to something other than
glycine (here, phenylalanine). More advanced applications
will entail carrying out the ring expansion reaction on a series
of piperidones containing previously installed substitution.
Finally, the applicability of this chemistry to solid-state
synthesis was briefly investigated (Scheme 4). Thus, pip-
eridone itself was attached to Merrifield resin by normal
means and subjected to the ring-expansion protocol using
3-azidopropanol.5a,c Extension into the “C-terminal” direction
transformation is compatible with two of the most important
nitrogen protecting groups in peptide chemistry as well as
an N-benzyl substituent, which is useful for other synthetic
applications and incidentally serves as a useful model for
some kinds of solid-phase attachments. The success of the
reaction with a heterocycle containing a basic nitrogen atom
was not assured at the outset given that such groups have
been problematic with other kinds of acid-promoted azido-
Schmidt reactions.7 It was useful to note that different acidic
conditions, needed to enact the initial ring expansion, were
more compatible with particular functional groups.
(7) Wendt, J. A.; Aube´, J. Tetrahedron Lett. 1996, 37, 1531-1534.
Org. Lett., Vol. 7, No. 6, 2005
1061

also provides one demonstration of the addition of further
diversity to the central core.
Scheme 4
Conformational analysis (Figure 1) suggests that these
heterocycles should be good stand-ins for γ-turns. The main
advantage of the approach is its inherently modular nature.
In addition, it should be possible to diversify the products
through manipulation of the scaffolds and to incorporate these
subunits into growing peptide chains with minor modifica-
tions of the route presented (see especially entry 11, Table
3). Work in these directions, along with the eventual
biological testing of compounds thus obtained, will be
reported in future publications.
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and the National Institutes of Health (PSO-
GM069663) for support of this research.
was accomplished by esterification with N-Boc phenylalanine
on the resin. Compound 16 was obtained in good yield (ca.
80%) by cleavage using a literature method.8 This simple
example suggests that it should be possible to optimize the
overall peptidomimetic sequence in a solid-phase format and
Supporting Information Available: Experimental details
and characterization data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) Conti, P.; Demont, D.; Cals, J.; Ottenheijm, H. C. J.; Leysen, D.
Tetrahedron Lett. 1997, 38, 2915-2918.
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Org. Lett., Vol. 7, No. 6, 2005