Methyl- and (Trifluoromethyl)alkene Peptide Isosteres: Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide Mimetics

Full text of DOI:10.1021/jo981057v

6088
J . Org. Chem. 1998, 63, 6088-6089
remains within 15 kJ /mol of the energy minimum. Methyl-
alkene moieties are abundant in terpenes and polypropi-
onate natural products and have indeed been shown to serve
as surrogates of backbone amide functions in enzyme-
inhibitor complexes.6
Meth yl- a n d (Tr iflu or om eth yl)a lk en e P ep tid e
Isoster es: Syn th esis a n d Eva lu a tion of Th eir
P oten tia l a s â-Tu r n P r om oter s a n d P ep tid e
Mim etics
Peter Wipf,* Todd C. Henninger, and Steven J . Geib
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received J une 3, 1998
Despite the promise of amide bond isosteres for improving
the resistance toward degradation by exoproteases by sev-
eral orders of magnitude, the use of nonhydrolyzable sub-
stitutes for the amide group has often led to disappointing
decreases in biological activity.1 The frequent lack of success
with ground-state amide bond mimetics stands in contrast
to the very promising use of hydroxyethylene protease
inhibitors as mimics of the tetrahedral intermediate in
amide bond hydrolysis.2 Nonetheless, the development of
effective amide bond isosteres holds considerable promise
as a stepping stone toward the rational design of small
molecule analogues of bioactive oligo- and polypeptides.
Analogues such as thiomethylene and aminomethylene
isosteres, however, exchange the conformationally restricted
amide function with highly flexible single bonds. Disubsti-
tuted (E)-alkene isosteres 1 provide a better fit for the Ci-
(R)-Ci+1(R) distance (3.8 Å) but are inadequate mimetics of
the electrostatic potential surface as well as the backbone
φ,ψ-dihedral angles. Gellman and co-workers designed the
tetrasubstituted (E)-alkene Gly-Gly dipeptide mimetic 2 to
induce conformational rigidification and promote â-hairpin
formation.3 More recently, Hoffman and co-workers re-
ported the use of gauche pentane interactions for the design
of â-hairpin analogue 3.4 We were interested in exploring
the use of trisubstituted (E)-alkene isosteres such as 4 as
â-turn mimetics. A combination of A1,3- and A1,2-strain leads
to considerable restrictions in φ,ψ-dihedral angles in these
substrates, and the Ramachandran plot of the methylalkene
isostere of alanine is closely related to the parent amino
acid.5 In contrast, the disubstituted (E)-alkene analogue is
conformationally much more flexible. Even greater steric
restrictions are observed for a trifluoromethylated derivative
5 where only ca. 15% of the Ramachandran plot area
The mimicry of the electronic properties of the amide bond
represents perhaps the most challenging parameter for
effective isostere design. Electrostatically, the (trifluoro-
methyl)alkene represents a better match of the amide bond
than any other common alkene isostere (Figure 1).
Efficient synthetic approaches toward diastereomerically
and enantiomerically pure alkene peptide isosteres are
under intense investigation.8 A particularly promising
convergent pathway utilizes the SN2′-addition of cuprate
reagents to alkenyl aziridines and allylic mesylates.9 The
former approach has also been applied to solid-phase
synthesis.10 We have now extended these methods toward
a general synthesis of methyl- and (trifluoromethyl)alkene
isosteres and, for the first time, systematically compared the
solid state conformations of these peptide mimetics.
Swern oxidation of the epoxy alcohol 6, obtained in 92%
ee by Sharpless epoxidation,11 followed by Wittig chain
extension and epoxide-aziridine conversion,12 provided alk-
enyl aziridine 7 in 13% overall yield (Scheme 1). N-
Acylation, copper(I)-catalyzed SN2′-addition,9 and aminoly-
sis13 gave the D-Ala-L-Ala isostere 9 in 28% yield.
A modified strategy was necessary for the preparation of
(trifluoromethyl)alkene 14 (Scheme 2). Carboxylation14 of
trifluorotrichloroethane 10, esterification with benzyl alco-
hol, and Reformatzky addition-elimination15 with acetal-
dehyde yielded the trifluoroalkene 11 as a 2:3 mixture of
(E)- and (Z)-isomers. The (Z)-isomer was isolated by column
chromatography on SiO2 and subjected to a Sharpless
asymmetric dihydroxylation.16 The resulting diol was ob-
tained in 73% ee and converted to the epoxide under
Mitsunobu conditions. Reduction to the aldehyde and Wittig
chain extension provided alkenyl oxirane 12. After sodium
azide opening, the resulting azido alcohol could not be
(1) See, for example: (a) Fincham, C. I.; Higginbottom, M.; Hill, D. R.;
Horwell, D. C.; O’Toole, J . C.; Ratcliffe, G. S.; Rees, D. C.; Roberts, E. J .
Med. Chem. 1992, 35, 1472. (b) Kaltenbronn, J . S.; Hudspeth, J . P.; Lunney,
E. A.; Michniewicz, B. M.; Nicolaides, E. D.; Repine, J . T.; Roark, W. H.;
Stier, M. A.; Tinney, F. J .; Woo, P. K. W.; Essenburg, A. D. J . Med. Chem.
1990, 33, 838. (c) Wai, J . S.; Bamberger, D. L.; Fisher, T. E.; Graham, S.
L.; Smith, R. L.; Gibbs, J . B.; Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.;
Rands, E.; Kohl, N. E. Bioorg. Med. Chem. 1994, 2, 939.
(2) Vacca, J . P.; Condra, J . H. Drug Discov. 1997, 2, 261.
(3) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J . Am. Chem. Soc. 1995,
117, 3280.
(4) Schopfer, U.; Stahl, M.; Brandl, T.; Hoffmann, R. W. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1745.
(5) Ramachandran plots were obtained with Macromodel 5.5 using the
MM2 force field. See the Supporting Information.
(9) (a) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875. (b) Ibuka, T.;
Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 652. (c) Ibuka, T.;
Habashita, H.; Funakoshi, S.; Fuji, N.; Oguchi, Y.; Uyehara, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. Engl. 1990, 29, 801.
(10) Wipf, P.; Henninger, T. J . Org. Chem. 1997, 62, 1586.
(11) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(6) See, for example: Ikeda, Y.; Schultz, L. W.; Clardy, J .; Schreiber, S.
L. J . Am. Chem. Soc. 1994, 116, 4143.
(7) Calculated dipole moments were obtained with Spartan 5.0.1 (Wave-
function, Inc.) and AM1 semiempirical parametrization.
(12) (a) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J . J . Org.
Chem. 1978, 43, 4271. (b) Wipf, P.; Venkatraman, S.; Miller, C. P.
Tetrahedron Lett. 1995, 36, 3639.
(13) Hoegberg, T.; Stroem, P.; Ebner, M.; Raemsby, S. J . Org. Chem.
1987, 52, 2033.
(14) A modification of the procedure used by Fujita and Kiyama (Fujita,
M.; Hiyama, T. Bull. Chem. Soc. J pn. 1987, 60, 4377) was used. The yield
was improved from 18% to 50%.
(15) Allmendinger, T.; Lang, R. W. Tetrahedron Lett. 1991, 32, 339.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(8) For some recent examples, see: (a) Kranz, M.; Kessler, H. Tetrahedron
Lett. 1996, 37, 5359. (b) Devadder, S.; Verheyden, P.; J aspers, H. C. M.;
Van Binst, G.; Tourwe´, D. Tetrahedron Lett. 1996, 37, 703. (c) Welch, J . T.;
Lin, J . Tetrahedron 1996, 52, 291. (d) Ibuka, T.; Akaji, M.; Mimura, N.;
Habashita, H.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. Tetra-
hedron Lett. 1996, 37, 2849. (e) Daly, M. J .; Ward, R. A.; Thompson, D. F.;
Procter, G. Tetrahedron Lett. 1995, 36, 7545. (f) Wai, J . S.; Fisher, T. E.;
Embrey, M. W. Tetrahedron Lett. 1995, 36, 3461. (g) Bartlett, P. A.; Otake,
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S0022-3263(98)01057-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/14/1998

Communications
J . Org. Chem., Vol. 63, No. 18, 1998 6089
F igu r e 1. AM1-calculated dipole moments of the amide bond and
selected alkene isosteres.7
Sch em e 1
F igu r e 2. X-ray structures of alkene peptide isosteres 9,22 14,
and 18.23
Sch em e 2
Sch em e 3
In conclusion, we have been able to devise enantioselective
synthetic approaches for L-Ala-D-Ala (or enantiomeric) dipep-
tide alkene isostere sequences that, for the first time,
included the preparation of a (trifluoromethyl)alkene iso-
stere. Our X-ray study has established that methyl- and
trifluoromethyl-substituted alkenes provide conformation-
ally considerably more highly preorganized backbone-rigidi-
fied peptide mimetics than the parent disubstituted alkenes.
The D-L methyl-(E)-alkene isostere sequence 9 prefers an
intramolecularly hydrogen bonded type-II′ â-turn in the solid
state. The corresponding trifluoromethyl analogue 14 rep-
resenting an L-D sequence shows a preference for a type-II
â-turn and folds almost perfectly pseudoenantiomeric to 9.
The conformational properties of 9 and 14 follow closely
those of regular peptides, since a type II â-turn is generally
preferred by an L-Ala-D-Ala sequence and a type-II′ by the
corresponding D-L dipeptide.21 Glycine often replaces the
nonproteinogenic D-amino acid in these turns. Our current
investigations are directed toward comparing the solution
conformations and the biological profiles of methyl- and
(trifluoromethyl)alkene peptide isosteres as well as toward
the synthesis and conformational analysis of L-L (and D-D)
dipeptide analogues.
converted to the aziridine by treatment with triphenylphos-
phine due to the resistance toward SN2-displacement at the
carbon R to the powerful electron-withdrawing CF3 sub-
stituent. Instead, Staudinger reduction of the azide led to
the amino alcohol which was converted to the carbamate and
mesylated to give 13. In contrast to the lack of success of
effecting an SN2 reaction R to the CF3 group, allylic SN2′
displacement of the mesylate occurred readily and, after
transamidation of the methyl ester,17 provided the desired
trifluoromethyl L-Ala-D-Ala alkene isostere 14 in 9% overall
yield from (Z)-11.
For direct experimental comparison with 9 and 14, the
disubstituted alkene isostere 18 was prepared by conversion
of diol 1518 to the cyclic sulfate,19 selective azide displace-
ment at the R-carbon, aziridine formation, and SN2′-cuprate
opening of N-nosylated amide 17 (Scheme 3).10 After
conversion of the nosyl group to the Boc-carbamate, L-Ala-
D-Ala mimic 18 was isolated in 3% overall yield.
X-ray structural analyses of isosteres 9, 14, and 18
revealed an ideal type-II (or -II′) â-turn structure20 for the
trisubstituted alkenes, whereas the disubstituted alkene 18
assumed a much more opened bend (Figure 2). Only 9 and
14 were intramolecularly hydrogen bonded with O-HN
distances of 2.11 and 2.19 Å, respectively. In agreement
with the modeling data, these solid-state structures dem-
onstrate that the A1,3 strain across the double bond is
primarily responsible for the restriction in φ2 and ψ2 dihedral
angles.
Ack n ow led gm en t . This work was supported by the
National Institutes of Health and Merck Research Labo-
ratories.
Su p p or tin g In for m a tion Ava ila ble: Ramachandran plots,
experimental procedures, and compound characterization data (33
pages).
J O981057V
(17) Solladie-Cavallo, A.; Bencheqroun, M. J . Org. Chem. 1992, 57, 5831.
(18) Derived from L-threonine: Servi, S. J . Org. Chem. 1985, 50, 5865.
(19) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(20) Bend types are classified according to the dihedral angles of the two
central residues. An ideal type II â-turn has backbone dihedral angles of
-60° (φ1) and 120° (ψ1), and 80° (φ2) and 0° (ψ2): Chou, P. Y.; Fasman, G.
D. J . Mol. Biol. 1977, 115, 135. Type II′ is enantiomeric to type II. Due to
its D-Ala-L-Ala-derived chirality, 9 actually has dihedral angles typical for
a type II′ â-turn, the mirror image of the L-Ala-D-Ala-derived 14.
(21) Smith, J . A.; Pease, L. G. CRC Crit. Rev. Biochem. 1980, 8, 315.
(22) To simplify comparisons across the series, the mirror image of 9 is
used in this figure.
(23) The atomic coordinates for this work are available on request from
the Director of the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K. Any request should be accompanied by the full
literature citation for this paper.