Design and synthesis of novel conformationally restricted peptide secondary structure mimetics

Article abstract of DOI:10.1021/ol990355r

(matrix presented) A facile synthesis of the novel conformationally restricted reverse turn mimetic is described. The key features are the preparation of the α-keto amide and tandem bicyclic ring formation.

Full text of DOI:10.1021/ol990355r

ORGANIC
LETTERS
2000
Vol. 2, No. 3
301-302
Design and Synthesis of Novel
Conformationally Restricted Peptide
Secondary Structure Mimetics
,†,‡
Hwa-Ok Kim,† Hiroshi Nakanishi,†,‡ Min S. Lee,†,‡ and Michael Kahn*
Molecumetics Ltd., 2023 120th AVenue N.E, BelleVue, Washington 98005-2199, and
UniVersity of Washington, Department of Pathobiology, SC-38,
Seattle, Washington 98195
hkim@molecumetics.com
Received November 12, 1999
ABSTRACT
A facile synthesis of the novel conformationally restricted reverse turn mimetic is described. The key features are the preparation of the
r-keto amide and tandem bicyclic ring formation.
As part of our continuing research program in the area of
peptide secondary structure mimetics,1 we are investigating
the synthesis of new types of â-turn mimetics.2
We envisioned that the general structure 1 would be a good
candidate, based upon molecular modeling (Scheme 1).
for the synthesis (Scheme 2). Acylation of the N-benzyl-
glycine ethyl ester 2 with N-Boc-Ala-OH using EDCI and
HOBt provided the sterically hindered secondary amide 3
in quantitative yield. Hydrolysis of the ethyl ester and
subsequent coupling of the carboxylic acid with cyano-
methylenetriphenylphosphorane using EDCI and DMAP, as
previously described,3 furnished 4 in 71% (from 3) after
purification by flash chromatography. Treatment of 4 with
ozone, followed by coupling with secondary amino ester 2,
afforded the R-keto amide 5 in 40% yield.3
Scheme 1
With R-keto amide 5 in hand, we attempted tandem
cyclization by deprotection of the Boc protecting group with
TFA and subsequent reductive amination (ZnCl2/NaBH3CN,
(1) (a) Kahn, M.; Eguchi, M.; Kim, H.-O. WO98/49168. (b) Peptide
Secondary Structure Mimetics. Tetrahedron (Symposia-in-print; no. 50,
Kahn, M., Ed.) 1993, 49, 3444. (c) Kahn, M. Synlett 1993, 821. (d) Kim,
H.-O.; Kahn, M. Tetrahedron Lett. 1997, 38, 6483. (e) Kim, H.-O.; Lum,
C.; Lee, M. S. Tetrahedron Lett. 1997, 38, 4935. (f). Ogbu, C. O.; Qabar,
M.N.; Boatman, P. D.; Urban, J.; Meara, J. P.; Ferguson, M. D.; Tulinsky,
J.; Lum, C.; Babu, S.; Blaskovich, M. A.; Nakanishi, H.; Ruan, F.; Cao,
B.; Minarik, R.; Little, T.; Nelson, S.; Nguyen, M.; Gall, A.; Kahn, M.
Bioorganic Med. Chem. Lett. 1998, 8, 2321. (g) Eguchi, M.; Lee, M. S.;
Nakanishi, H.; Kahn, M. J. Am. Chem. Soc., in press.
To test the feasibility of the synthesis of 1 from readily
available starting material, we chose 1a as a model compound
(2) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789.
(3) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59, 4364.
† Molecumetics Ltd.
‡ University of Washington.
10.1021/ol990355r CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/11/2000

Scheme 2a
a Reagents and conditions: (a) Boc-Ala-OH, EDCI, HOBt, 100%; (b) (i) LiOH, H2O/THF, 100%; (ii) Ph3PdCHCN, EDCI, DMAP,
CH2Cl2, 71%; (c) (i) O3, CH2Cl2, -78 °C; (ii) N-benzyl-Gly-OEt, 41%; (d) TFA, then workup with saturated NaHCO3, 77%; (e) H2, PtO2,
MeOH, 56%.
In summary, we have demonstrated a facile synthesis of
novel peptide secondary structure mimetics from simple
R-amino acids.
MeOH) in order to form the desired compound 1a. However,
the enamino bicyclic triaza compound 6 was isolated in
77%.4 Presumably, isomerization is faster than reduction of
the imine by ZnCl2/NaBH4CN. When compound 6 was
treated under H2 (20 atm) in the presence of PtO2, the desired
compound 1a was afforded in 56% yield5 along with the
unreacted 6. The diastereomeric ratio of 1a was determined
by HPLC to be 2:1.5 However, the absolute stereochemsitry
was not determined.
Acknowledgment. We thank Dr. Thomas Vaisar and
Richard Shen for obtaining the mass spectra and HPLC
analysis of 1a, respectively.
OL990355R
(4) Spectral data of 6: TLC Rf 0.58 (EtOAc); 1H NMR (CDCl3) δ 1.41
(d, 3H, J ) 6.5 Hz, CHCH3), 3.93 (ABq, 2H, J ) 18 Hz, CH2 in Gly),
4.46 and 4.75 (ABq, 1H each, J ) 14.5 Hz, CH2Ph), 4.76 (ABq, 2H, J )
14 Hz, CH2Ph), 5.22 (q, 1H, J ) 7 Hz, CHCH3), 6.83 (s, 1H, dCH), 7.33
(m, 10H, phenyls); 13C NMR (CDCl3) δ 16.6, 49.6, 49.7, 49.8, 51.0, 111.9,
119.2, 128.1, 128.2, 128.3, 128.5, 128.9, 129.0, 134.8, 134.4, 158.0, 160.7,
165.3; MS ES+ m/z 376.3 (M + H+).
(5) Spectral data of 1a: TLC Rf 0.49 (EtOAc); 1H NMR (CDCl3) δ 1.14
(d, 1.5H, J ) 7 Hz, CHCH3), 1.52 (d, 1.5H, J ) 7 Hz, CHCH3), 3.2-4.8
(set of m, 10H), 7.33 (m, 10H, phenyls); MS ES+ m/z 378 (M + H+);
HPLC (C-18 reverse phase column, 0 to 90% of acetonitrile/H2O gradient,
40 min) analysis 250 nm tR 24.1 and 24.7; 2:1 ratio.
302
Org. Lett., Vol. 2, No. 3, 2000