Three-step synthesis of cyclopropyl peptidomimetics

Article abstract of DOI:10.1021/ol201828u

An efficient approach to novel cyclopropyl peptidomimetics has been developed. The synthetic route involves a cyclopropanation using ethyl (dimethylsulfuranylidene)acetate (EDSA) as the key step and affords a cyclopropyl peptidomimetic core in three steps

Full text of DOI:10.1021/ol201828u

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4879–4881
Three-Step Synthesis of Cyclopropyl
Peptidomimetics
Norma Dunlap,*,† Kevin R. Lankford,† Anuradha Liyana Pathiranage,†
Jessica Taylor,† Nikhil Reddy,† Daniel Gouger,† Phillip Singer,†
Kent Griffin,† and Joseph Reibenspies‡
Middle Tennessee State University, Department of Chemistry, Murfreesboro,
Tennessee 37132, United States, and Texas A&M University, Department of Chemistry,
College Station, Texas 77842, United States
ndunlap@mtsu.edu
Received July 27, 2011
ABSTRACT
An efficient approach to novel cyclopropyl peptidomimetics has been developed. The synthetic route involves a cyclopropanation using ethyl
(dimethylsulfuranylidene)acetate (EDSA) as the key step and affords a cyclopropyl peptidomimetic core in three steps from protected amino acid
Weinreb amides.
The hydroxyethylene peptidomimetic core structure is
central to numerous drugs both on the market and in
development for a diverse number of conditions. Some
examples include HIV protease inhibitors, BACE inhibi-
tors, and renin inhibitors.1À3 Cyclopropyl peptidomimetics,
in particular, have been reported to have antitumor, anti-
viral, and antidepressant activity.4À7 Incorporation of the
cyclopropyl ring into the backbone of peptidomimetics has
been shown to increase stability toward degradation, as well
as decreasing conformational flexibility.8,9 Some examples
include Martin’s Ras farnesyltransferase and HIV protease
inhibitors, the natural product belactosin, and Wipf’s cyclo-
propyl tripeptide isosteres (Figure 1).5À7,10
† Middle Tennessee State University.
‡ Texas A&M University.
(1) Abdel-Rahman, H. M.; Al-Karamany, G. S.; El-Koussi, N. A.;
Youssef, A. F.; Kiso, Y. Curr. Med. Chem. 2002, 9, 1905.
(2) (a) Choi, S.; Cho, J.; Im, I.; Lee, S.; Jang, J.; Oh, Y.; Jung, Y.;
Jeon, E.; Kin, Y. Eur. J. Med. Chem. 2010, 45, 2578. (b) Hom, R. K.;
Gailunas, A. F.; Mamo, S.; Yang, L. Y.; Tung, J. S.; Walker, D. E.
J. Med. Chem. 2004, 47, 158.
(3) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.;
Cohen, N.-C.; Stutz, S.; Cumin, F.; Guhrer, W.; Wood, J. M.; Grutter,
M. G. Chem. Biol. 2000, 7, 493.
(4) (a) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.; Mizuka-
mi, T. J. Antibiot. 2000, 53, 81. (b) Vanier, S. F.; Lauroche, G.; Wurz,
R. P.; Charette, A. B. Org. Lett. 2010, 12, 672 and references therein.
(5) (a) Wipf, P.; Xiao, J. Org. Lett. 2005, 7, 103. (b) Wipf, P.; Kendall,
C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122.
(6) (a) Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C. J. Med.
Chem. 1998, 41, 1581. (b) Reichelt, A.; Gaul, C.; Frey, R. R.; Kennedy,
A.; Martin, S. F. J. Org. Chem. 2002, 67, 4062.
Figure 1. Cyclopropyl peptidomimetics and natural products.
Prior approaches to cyclopropyl peptidomimetics in-
clude carbenoid cyclopropanations, as well as ylide addi-
tions to electron-deficient alkenes. As a general target, the
(7) (a) Kazuta, Y.; Tsujita, R.; Yamashita, K.; Uchino, S.; Kohsaka,
S.; Matsuda, A.; Shura, S. Bioorg. Med. Chem. 2002, 10, 3829. (b) Monn,
J. A.; Balli, M. J.; Massey, S. M.; Wright, R. A.; Salhoff, C. R.; Johnson,
B. G.; Howe, T.; Atl, C. A.; Rhodes, G. A.; Robey, R. L.; Griffer, K. R.;
Tizzano, J. P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528.
(8) Burgess, K.; Lim, D.; Ho, K.-K.; Ke, C.-Y. J. Org. Chem. 1994,
59, 2179.
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J. Org. Chem. 1992, 57, 1074.
r
10.1021/ol201828u
2011 American Chemical Society
Published on Web 08/24/2011

peptidomimetic shown in Figure 2, with three variable
positions, would allow access to a variety of potential
medicinal agents starting from the known Weinreb amides
of protected amino acids.11
mildly stereoselective, typically affording a 2:1 mixture of
the 4R and 4S isomers of alcohol 3. Although not pre-
viously reported in peptidomimetic syntheses, EDSA and
chiral sulfur ylides have been used in the synthesis of many
cyclopropyl derivatives.10 The lack of stereocontrol at this
point is not an issue, since eventual conversion of com-
pounds such as 3 to products with potential bioactivity
may benefit from access to multiple stereoisomers.
This procedure allows for very efficient access to a
cyclopropyl peptidomimetic core from a variety of amino
acids. Fiveseries havebeencompleted, asshown inTable1.
Figure 2. Cyclopropyl peptidomimetic core.
A number of carbenoid approaches were investigated, as
well as Corey ylide cyclopropanation of an unsaturated
ester; however all suffered from low yields and numerous
steps.12 The most efficient route was found to be addition
of an enone to the stabilized sulfur ylide EDSA, followed
by ketone reduction, affording the cyclopropyl backbone
in just three steps.
As outlined in Scheme 1, conversion of Cbz-protected
amino acids to the corresponding Weinreb amides, fol-
lowed by addition of vinylmagnesium bromide, afforded
the enones 1. Cyclopropanation using EDSA afforded the
protected cyclopropyl ketones 3 in good yield as a 1:1
mixture of syn and anti isomers. In most cases, the ketones
were separable by HPLC. Reduction of the ketones af-
forded the protected cyclopropyl peptidomimetics.
Table 1. Yields for Conversion of Protected Amino Acids to
Compounds 1À3
enone
ketone
alcohol
amino acid
1aÀe
2aÀe
3aÀe
L-Cbz-
62%
69%
95%
phenyl-
alanine (a)
L-Cbz-
70%
66%
99%
41%
78%
76%
57%
31%
81%
96%
95%
53%
leucine (b)
L-Cbz-
valine (c)
D-Cbz-
alanine (d)
L-Cbz-
proline (e)
Stereochemistry of the phenylalanine series was con-
firmed by conversion of a pure alcohol (syn-4R-3a) to the
corresponding oxazolidinone, as shown in Scheme 2.
Scheme 1. General Synthesis of Cyclopropyl Peptidomimetics 3
Scheme 2. Confirmation of Stereochemistry
Final confirmation by X-ray crystallography (Figure 3)
established the stereochemistry of the cyclopropyl ring
relative to the benzyl group. Assignment of stereochemis-
try in the other series is based on similarities in the HPLC
behavior of the ketone isomers and in the 1H NMR pattern
of the cyclopropyl CH2. In particular, the syn isomers elute
first and show a separation of 0.7 ppm of the methylene
hydrogens, whereas the anti ketone isomers show one
multiplet for both of those hydrogens.13
Asexpectedfor addition tothe terminalmethylene, none
of the cis-cyclopropyl analog of 2 was observed.10b Reduc-
tion of the ketones with sodium borohydride was only
(10) (a) Riches, S. L.;Saha, C.;Filjueira, N. F.; Grange, E.; McGarrigle,
E. M.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 7626 and references
therein. (b) Payne, G. B. J. Org. Chem. 1967, 32, 3351. (c) Curley, R. W.,
Jr.; DeLuca, H. F. J. Org. Chem. 1983, 49, 1944. (d) Collado, I.;
Dominguez, C.; Ezquerra, J.; Pedregal, C.; Monn, J. A. Tetrahedron
Lett. 1997, 38, 2133. (e) Yong, S. R.; Ung, A. T.; Pyne, S. G.; Skelton,
B. W.; White, A. H. Tetrahedron 2007, 63, 1191.
The choice of base for ylide generation was found to be
critical in order to avoid racemization of the cyclopropyl
ketones. Initial conditions involved generation of the ylide
using DBU as base in chloroform, followed by addition of
the enone at room temperature. These conditions resulted
(11) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
€
€
(b) Leucine amide: Kratzel, M.; Hiessbock, R.; Bernkop-Schnurch, A.
J. Med. Chem. 1998, 41, 2339–2344. (c) Phenylalanine amide and enone:
De Lucca, G. V.; Linag, J.; Aldrich, P. E.; Calabrese, J.; Cordova, B.;
Klabe, R. M.; Rayner, M. M.; Chang, C.-H. J. Med. Chem. 1997, 40,
1707. (d) See also: Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10,
4375. (e) Proline amide and enone: De Luca, L.; Giacomelli, G.;
Porcheddu, A. Org. Lett. 2001, 3, 1519. (f) Alanine amide and enone:
Wuts, P. G.; Putt, S. R.; Ritter, A. R. J. Org. Chem. 1988, 53, 4503.
(12) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 83, 417.
(13) See Table 1 in the Supporting Information.
4880
Org. Lett., Vol. 13, No. 18, 2011

In summary, a very efficient synthesis of a series of novel
cyclopropyl peptidomimetics from amino acids has been
developed. The core structures should prove to be useful
intermediates for the synthesis of potential medicinal
agents.
Acknowledgment. We would like to thank the Natio-
nal Science Foundation (NSF-STEP No. 0431652)
for financial support of undergraduates P. Singer,
K. Griffin, and J. Taylor (MTSU). We also would like
to thank Dr. Christopher Denicola for chiral HPLC
analysis (Vanderbilt University, Nashville, TN). Also, we
acknowledge Jacob Basham (MTSU) and Suthaseenee
Jansala (MTSU) for help with preparation of some inter-
mediates.
Figure 3. X-ray crystal structure of oxazolidinone (4R)-4a.
in varying degrees of racemization. However, using either
LDA or sodium hydride as base, and a reduced tempera-
ture and reaction time, led to optically pure materials as
verified by chiral HPLC. The ketones were also found to
racemize upon storage for long periods of time, so sub-
sequent reduction isbestcarried out soon after preparation
of the ketones.
Supporting Information Available. Experimental pro-
cedures, characterization, NMR spectra, X-ray, and
HPLC information are included in the Supporting Iin-
formation. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
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