Convergent approach to (E)-alkene and cyclopropane peptide isosteres

Article abstract of DOI:10.1021/ol0477529

(Chemical Equation Presented) Trisubstituted (E)-alkene isosteres (TEADIs) and novel cyclopropane amide bond isosteres (CPDIs) were synthesized by aldimine addition and three-component aldimine addition-cyclopropanation methodologies, respectively. These

Full text of DOI:10.1021/ol0477529

ORGANIC
LETTERS
2005
Vol. 7, No. 1
103-106
Convergent Approach to (E)-Alkene and
Cyclopropane Peptide Isosteres
Peter Wipf* and Jingbo Xiao
Department of Chemistry and Center for Chemical Methodologies & Library
DeVelopment, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf@pitt.edu
Received November 2, 2004
ABSTRACT
Trisubstituted (E)-alkene isosteres (TEADIs) and novel cyclopropane amide bond isosteres (CPDIs) were synthesized by aldimine addition and
three-component aldimine addition cyclopropanation methodologies, respectively. These new peptide mimetics can serve as -turn promoters.
−
â
Peptide bond isosteres can assist in the investigation of
receptor-ligand and enzyme-substrate interactions.1 In par-
ticular, the replacement of the scissile peptide bond with
nonhydrolyzable isosteric functions is an important design
motif in medicinal chemistry.2-7 In recent years, many
nonhydrolyzable mimetics have been developed, including
(E)-alkene (ψ[(E)-C(R)dCH]) 2,2 ketomethylene (ψ[COCH2])
3,3 hydroxyethylene (ψ[CH(OH)CH2]) 4,1a,4 dihydroxy-
ethylene (ψ[CH(OH)CHOH]) 5,5 hydroxyethylamine
(ψ[CH(OH)CH2NH]) 6,6 and methyleneamine (ψ[CH2NH])-
77 moieties (Figure 1).
The relatively rigid trisubstituted (E)-alkenes
2
(ψ[(E)-C(R)dCH], TEADIs) represent useful, conforma-
tionally preorganized structural mimetics2c-e and have been
used as surrogates of hydrolytically labile amide bonds in a
number of enzyme inhibitors.2a,8 The primary objective of
this strategy is the accurate mimicry of the geometry of the
(1) (a) Kath, J. C.; DiRico, A. P.; Gladue, R. P.; Martin, W. H.; McElroy,
E. B.; Stock, I. A.; Tylaska, L. A.; Zheng, D. Bioorg. Med. Chem. Lett.
2004, 14, 2163. (b) Venkatesan, N.; Kim, B. H. Curr. Med. Chem. 2002,
9, 2243. (c) Hedenstro¨m, M.; Yuan, Z.; Brickmann, K.; Carlsson, J.; Ekholm,
K.; Johansson, B.; Kreutz, E.; Nilsson, A.; Sethson, I.; Kihlberg, J. J. Med.
Chem. 2002, 45, 2501. (d) Peptidomimetics Protocols; Kazmierski, W. M.,
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Walker, D. E.; Davis, D.; Thorsett, E. D.; Jewett, N. E.; Moon, J. B.; John,
V. J. Med. Chem. 2004, 47, 158. (b) Benedetti, F.; Berti, F.; Norbedo, S.
J. Org. Chem. 2002, 67, 8635. (c) Tao, J.; Hoffman, R. V. J. Org. Chem.
1997, 62, 6240.
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D. V.; Patel, M. M.; Schmidt, R. J.; Weller, H. N.; Andahazy, M. L.;
Carboni, J. M.; Gullo-Brown, J. L.; Lee, F. Y. F.; Ricca, C.; Rose, W. C.;
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R.; Manne, V. J. Med. Chem. 1996, 39, 224.
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M.; Maeda, K.; Watai, Y.; Arikuni, H.; Otaka, A.; Mitsuya, H.; Fujii, N. J.
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M.; Ackermann, K.; Garcia, A. M.; Lewis, M. D. J. Org. Chem. 1999, 64,
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10.1021/ol0477529 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/08/2004

Scheme 1. Synthesis of Methyl- and TMS-Substituted
Alkynes
trimethylchlorosilane to afford alkynes 10a and 10b in high
yield.
Figure 1. Peptide bond linkage and isosteric replacements.
Hydrozirconation12 of 10a with Cp2ZrHCl followed by
transmetalation to Me2Zn and addition of N-diphenylphos-
phinoylimine provided the allylic amide 11 in 59% yield
as a 1:1 mixture of diastereomers. Deprotection of 11,
N-acylation with CbzCl, oxidation of alcohol 12 with Dess-
Martin periodinane13 and sodium chlorite,14 and coupling
with 2-naphthylamine led to the methyl-substituted TEADIs
13 and 14, which were easily separated by chromatography
on SiO2 (Scheme 2).15
peptide bond; however, trisubstituted (E)-alkenes like many
other amide bond substitutes lack effective hydrogen bond
donor and acceptor functions and do not provide for the large
dipole moment of the resonance-stabilized amide group. In
addition, alkenes can suffer from potential isomerization,
oxidation, and general chemical lability. On the basis of the
latter considerations, we have designed trisubstituted cyclo-
propane dipeptide isosteres (ψ[RCp], CPDIs) that we expect
to display increased stability compared with the correspond-
ing trisubstituted (E)-alkene dipeptide isosteres (Figure 2).
Scheme 2. Synthesis of Methyl-Substituted (E)-Alkene
Dipeptide Isosteres
Figure 2. Evolution of CPDIs from TEADIs.
Martin and co-workers have developed related side-chain-
rigidifying cyclopropyl peptidomimetics COCpCO and
NHCpNH.9 These moieties also replace the scissile amide
bond in the backbone of peptide sequences. However, our
design of cyclopropane mimetics (CPDIs) represents the first
use of the cyclopropane ring as an exact isosteric replacement
of the labile dipeptide bond linkage.
The preparation of TEADIs and CPDIs was faciliated by
a new Zr/Zn-mediated methodology for the synthesis of
allylic and C-cyclopropylalkylamines.10 For the preparation
of the precursor alkynes, commercially available enantio-
merically pure hydroxy ester 8 was protected with tert-
butylchlorodiphenylsilane (Scheme 1). DIBAL reduction and
Corey-Fuchs reaction gave dibromoolefin 9,11 which was
treated with n-BuLi and quenched with methyl iodide and
TMS-substituted alkene dipeptide isosteres 19 and 20 were
prepared analogously. The diastereomeric products were
separated by chromatography on SiO2 (Scheme 3). The
configuration of 19 and 20 was assigned by X-ray structural
analysis of syn isomer 20 (Figure 3).
The three-component aldimine addition-cyclopropanation
methodology allowed efficient access to the cyclopropyl
(10) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2001, 123, 5122. (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am.
Chem. Soc. 2003, 125, 761.
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(12) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Wipf, P.;
Kendall, C. Top. Organomet. Chem. 2004, 8, 1.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(14) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117,
11106.
(9) (a) Davidson, J. P.; Lubman, O.; Rose, T.; Waksman, G.; Martin, S.
F. J. Am. Chem. Soc. 2002, 124, 205. (b) Reichelt, A.; Gaul, C.; Frey, R.
R.; Kennedy, A.; Martin, S. F. J. Org. Chem. 2002, 67, 4062. (c) Hillier,
M. C.; Davidson, J. P.; Martin, S. F. J. Org. Chem. 2001, 66, 1657. (d)
Martin, S. F.; Dwyer, M. P.; Hartmann, B.; Knight, K. S. J. Org. Chem.
2000, 65, 1305. (e) Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C.;
Kessler, H.; Baur, M.; Matha¨, B.; Erickson, J. W.; Bhat, T. N.; Munshi, S.;
Gulnik, S. V.; Topol, I. A. J. Med. Chem. 1998, 41, 1581.
104
Org. Lett., Vol. 7, No. 1, 2005

Scheme 3. Synthesis of TMS-Substituted Alkene Dipeptide
Scheme 4. Synthesis of Cyclopropane Dipeptide Isosteres
Isosteres
(CPDIs)
23, which were individually converted to cyclopropane
dipeptide isosteres (ψ[MeCp], CPDIs) 24 and 25. The
assembly of pseudotripeptide 26 was easily achieved directly
from alcohol 23.
Relevant information about the differences in the confor-
mational properties of TEADIs and CPDIs could be obtained
by X-ray structural analysis of 14, 20, and 24b (Figure 3).
By comparison to the dihedral angles of typical â-turns,16
we found that TEADI 20 closely mimicked a type II′ â-turn
conformation (ideal dihedral angles are φ2 ) 60°, ψ2 )
-120°, φ3 ) -80°, ψ3 ) 0°), including the ten-membered
hydrogen bonding interaction (N-H‚O hydrogen bond
distance ) 2.52 Å, a typical â-turn hydrogen bond is ∼2.3
Å). This conformation minimized A1,3 allylic strain, which
is particularly severe for compound 20 due to the steric bulk
of the TMS substituent. The type II′ â-turn has been found
in earlier analyses of trisubstituted alkene peptide isosteres.2c
It was interesting to note, however, that the conformation
of the other isosteres differed considerably. TEADI 14 can
be classified as a type V′ â-turn, which is a less common
relative of the type II′ â-turn. The major difference between
types II′ and V′ lies in the ψ-angles, in particular ψ3. Quite
likely, the larger steric bulk of the TMS vs the methyl group
forces a decrease in the value of the ψ3 dihedral angle, which
destabilizes the more open V′-type conformation and facili-
tates the formation of the intramolecular hydrogen bond. In
proteins, type V′ â-turns occur much less frequently than
type II′, and they are often not hydrogen-bonded. However,
for both types, the Di+1Li+2-configuration at the amino acid
R-carbons is preferred, which is the configuration present
in both 14 and 20. In contrast, the Li+1Li+2-configuration
present in 24b would be expected to stabilize turn types I
and III; however, possibly due to the greater flexibility of
Figure 3. Stereoviews of X-ray structures of 14, 20, and 24b.
analogues from the same starting materials (Scheme 4). An
inseparable mixture of N-phosphinoylamino cyclopropanes
21 was obtained in 60% yield with a diastereoselectivity of
3:2 (syn,syn:syn,anti). Global deprotection and N-protection
with CbzCl afforded a separable mixture of alcohols 22 and
(15) Structural assignment of 13 and 14 was based initially on the
ozonolysis product 15, which was compared to the product obtained from
D-phenylglycine. Later, a single-crystal X-ray analysis of 14 confirmed this
assignment (Figure 3). (a) Son, Y.; Park, C.; Koh, J. S.; Choy, N.; Lee, C.
S.; Choi, H.; Kim, S. C.; Yoon, H. Tetrahedron Lett. 1994, 35, 3745. (b)
Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(16) Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467.
Org. Lett., Vol. 7, No. 1, 2005
105

Table 1. Solid-State Dihedral Angles of Dipeptide Isosteres 14, 20, and 24b
distance between
distance between
isostere
C
i+1 and R-Ci+2
R-Ci+1 and R-Ci+2
φ2
ψ2
φ3
ψ3
turn classification
H-bond
14
20
24b
2.546 Å
2.642 Å
2.653 Å
3.904 Å
4.034 Å
3.894 Å
114.4°
65.8°
-122.3°
-117.1°
-121.1°
76.0°
-112.6°
-101.5°
-148.3°
100.1°
-4.2°
153.0°
V′
II′
IV
-
+
-
substituents attached to the cyclopropane group, two angles
(ψ2 and ψ3) differ by >40° from type I, and therefore this
reverse turn should be classified as a type IV â-turn (Table
1). Not unexpectedly, the introduction of the cyclopropane
group slightly increases the conformational freedom of the
peptide backbone vs the corresponding alkene peptide bond
isosteres. This is illustrated by an increase in the distance of
tion but still prefer a reverse turn conformation. We expect
that CPDIs will show greater resistance to oxidative,
CYP450-mediated biological metabolism,18 thus extending
and improving upon the peptidase resistance of TEADIs.
Both dipeptide isostere classes can serve as scaffolds for
structure-activity studies of biologically active peptide
sequences.
the methyl group-bearing C(i+1) and the allylic R-C(i+2)
,
responsible for the A1,3-interaction, from 2.546 to 2.653 Å
in 14 and 24b.
Acknowledgment. This work has been supported by the
NIH P50-GM067082 program. J.X. gratefully acknowledges
an Andrew W. Mellon Predoctoral Fellowship. We thank
Dr. Steven J. Geib (University of Pittsburgh) for X-ray
crystallographic analyses of 14, 20, and 24b.
The distances between R-C(i+1) and R-C(i+2) were found
to be very similar to the parent amide bond (3.8 Å17) for
both TEADIs (14, 3.904 Å; 20, 4.034 Å) and the corre-
sponding CPDI (24b, 3.894 Å). Accordingly, all isosteres
represent sterically relevant replacements for the amide
linkage in peptides (Table 1).
In conclusion, we have developed a general protocol for
the efficient synthesis of trisubstituted (E)-alkene dipeptide
isosteres (ψ[(E)-C(R)dCH], TEADIs) and the novel cyclo-
propane-based dipeptide isosteres (ψ[MeCp], CPDIs) using
our new one-pot aldimine addition methodology. Three
representative X-ray studies provide insight into the potential
of these peptide mimetics to act as â-turn promoters.
Compared to TEADIs, which have a strong preference for
type II turns, CPDIs have a more flexible backbone disposi-
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
1
copies of H and 13C NMR spectra for 10a,b, 13, 14, 19,
20, 24a,b, 25a,b, and 26, and crystal information files (CIF)
for compounds 14, 20, and 24b. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0477529
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Org. Lett., Vol. 7, No. 1, 2005