Trifluoromethyl-substituted imidazolines: Novel precursors of trifluoromethyl ketones amenable to peptide synthesis

Full text of DOI:10.1021/ja9614833

J. Am. Chem. Soc. 1996, 118, 8485-8486
8485
Communications to the Editor
Scheme 1
Trifluoromethyl-Substituted Imidazolines: Novel
Precursors of Trifluoromethyl Ketones Amenable to
Peptide Synthesis
Christopher W. Derstine, David N. Smith,† and
John A. Katzenellenbogen*
Department of Chemistry, UniVersity of Illinois
Urbana, Illinois 61801
ReceiVed May 3, 1996
Trifluoromethyl ketones (TFMKs) have been shown to be
potent inhibitors of a variety of esterases and proteases,1 and
peptidyl TFMKs have found specific applications as inhibitors
of serine,2 aspartic,3 metallo,4 and cysteine proteases.5 Current
approaches to synthesizing peptidyl TFMKs involve the oxida-
tion of a trifluoromethyl alcohol precursor to the TFMK, which
limits their use with amino acids having oxidizable residues.6
In this communication we report a new approach to peptidyl
TFMKs through a 1,3-dipolar cycloaddition reaction which
produces trifluoromethyl-substituted ∆3-imidazolines. These
imidazolines, which act as latent forms of the TFMKs, can be
manipulated by standard Fmoc-peptide synthesis methods and
then hydrolyzed to peptidyl TFMKs under mild (nonoxidizing)
acidic conditions.
Our approach to preparing the ∆3-imidazoline heterocycle
was modeled after a 1,3-dipolar cycloaddition reaction between
an azomethine ylide (generated from an acyl chloride and an
R-silylimine) and a dipolarophile,7 a reaction which has been
used for the preparation of related heterocycles.8,9 The specific
heterocycle we required as the TFMK precursor, a 4-trifluo-
romethyl-∆3-imidazoline, is conveniently prepared by 1,3-
dipolar cycloaddition between the azomethine ylide and tri-
fluoroacetonitrile.10 Scheme 1 demonstrates our initial cycload-
dition and hydrolysis studies with the simple R-silylimine 1.
Compound 111 was prepared from N-benzylidinebenzylamine
by benzylic deprotonation and silation with chlorotrimethylsi-
lane. The reaction of 1 with either benzoyl chloride or benzyl
chloroformate produced the N-protected ∆3-imidazolines 2 and
3.12 These ∆3-imidazolines were then cleaved by mild acid
hydrolysis to yield the amino-protected phenylglycine TFMKs
4 and 5 in good yield.
To demonstrate the usefulness of the ∆3-imidazoline as a
protected form of the TFMK, we incorporated it into a larger
peptide. This was done conveniently using Carpino’s carba-
mate-protected amino acid fluorides.13 The amino acid fluorides
required somewhat higher temperatures (75-80 °C) to initiate
the cycloaddition, but they gave cleaner reactions and higher
yields of the corresponding imidazolines. As shown in Scheme
2, the cycloaddition reaction involving Fmoc-Phe-F, benzyli-
dinetrimethylsilylmethylamine,7b and trifluoroacetonitrile pro-
duced imidazoline 6 regioselectively in 70-77% yield. In one
step, this approach produces the imidazoline as part of a pseudo
dipeptide, which can then be readily hydrolyzed to the dipeptide
TFMK 7. More importantly, under standard Fmoc deprotection
and peptide coupling conditions, imidazoline 6 could be
converted to a pseudo tripeptide 8 and then hydrolyzed to give
the tripeptide TFMK 9, in 30% overall yield from the acid
fluoride. Using the Fmoc protecting strategy in conjunction
with the imidazoline as a protecting group for the ketone, one
should be able to access peptidyl TFMKs of any size.14
* Address correspondence to: John A. Katzenellenbogen, Department
of Chemistry, University of Illinois, 461 Roger Adams Laboratory Box
37, 600 S. Mathews Ave., Urbana, IL 61801. Telephone: (217) 333-6310.
FAX: (217) 333-7325. Email: jkatzene@uiuc.edu.
† Current position: Glaxo Wellcome, Hertfordshire, U.K.
(1) For a review of uses and preparation of trifluoromethyl ketones,
see: Be´gue´, J.; Bonnet-Delpon, D. Tetrahedron 1991, 47, 3207-3258.
(2) Representative serine proteases. (a) Human neutrophil elastase:
Edwards, P. D.; Bernstein, P. R. Med. Res. ReV. 1994, 14, 127-194. (b)
R-Chymotrypsin: Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25, 3760-
3767.
(8) For references on 1,3-dipolar cycloadditions, see: (a) Lown, J. W.
In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984. (b) Vedejs, E. In AdVances in Cycloaddition; Curran, D. P., Ed; JAI:
Greenwich, CT, 1988. (c) Carruthers, W. Cycloaddition Reactions in
Organic Synthesis; Pergamon: Oxford, 1990; Chapter 6, pp 269-331. (d)
Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 4.9, pp 1069-1109. (e)
Wade, P. A. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 4.10, pp 1111-1168.
(9) For reviews of azomethine ylides, see ref 8 and: Terao, Y.; Aono,
M.; Achiwa, K. Heterocycles 1988, 27, 981-1008.
(3) Representative aspartic proteases. (a) HIV protease: Hodge, C. N.;
Aldrich, P. E.; Fernandez, C. H.; Otto, M. J.; Rayner, M. M.; Wong, Y.
N.; Erickson-Viitanen S. AntiViral Chem. Chemother. 1994, 5, 257-262.
(b) Pepsin: Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985,
24, 1813-1817. (c) Renin: Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.;
Free, C. A.; Smith, S. A.; Petrillo, E. D. J. Med. Chem. 1993, 36, 2431-
2447.
(4) Representative metallo proteases. (a) Angiotensin-converting en-
zyme: ref 3b. (b) Carboxypeptidase A: ref 3b
(5) Representative cysteine proteases. (a) Cathepsin G: Peet, N. P.;
Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P.; Kolb,
M. Neises, B. Schirlin, D. J. Med. Chem. 1990, 33, 394-407. (b) Cathepsin
B: Smith, R. A.; Copp, L. J.; Donnelly, S. L.; Spencer, R. W.; Krantz, A.
Biochemistry 1988, 27, 6568-6573.
(6) Methods for preparation of peptidyl TFMKs. (a) Stereoselective
synthesis by CF3ZnI addition to an isomerically pure peptidyl aldehyde:
Edwards, P. D. Tetrahedron Lett. 1992, 33, 4279-4282. (b) Modified Dakin-
West procedure: Kolb, M.; Barth, J.; Neises, B. Tetrahedron Lett. 1986,
27, 1579-1582. Kolb, M.; Neises, B. Tetrahedron Lett. 1986, 27, 4437-
4440. (c) Henry reaction: Imperiali, B.; Abeles, R. H. Tetrahedron Lett.
1986, 27, 135-138. (d) Curtius rearrangement: Patel, D. V.; Gauvin, K.
R.; Ryono, D. E. Tetrahedron Lett. 1988, 29, 4665-4668.
(7) (a) Achiwa, K.; Sekiya, M. Chem. Lett. 1981, 1213-1216. (b)
Achiwa, K.; Motoyama, T.; Sekiya, M. Chem. Pharm. Bull. 1983, 31, 3939-
3945.
(10) Trifluoroacetonitrile as a dipolarophile: (a) Kobayashi, Y.; Ku-
madaki, I.; Kobayashi, E. Heterocycles 1981, 15, 1223-1225. (b) Banks,
R. E.; Thompson, J. J. Fluorine Chem. 1983, 22, 589-592.
(11) Popowski, E.; Franz, K. Z. Chem. 1979, 19, 103.
(12) Since trifluoroacetonitrile (bp -65 °C) is a gas, cycloaddition
reactions were carried out in stainless steel sample cylinders which were
sealed and placed in an oven at the appropriate temperature.
(13) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J.
Am. Chem. Soc. 1990, 112, 9651-9652. Carpino, L. A.; Mansour, E. M.
E.; Sadat-Aalaee, D. J. Org. Chem. 1991, 56, 2611-2614.
(14) Although we have not explored peptide synthesis extensively using
the C-terminal trifluoromethyl ketone protected as the ∆3-imidazoline, it
would appear to be generally useful with Fmoc N-terminal protection/acyl
fluoride coupling, using acid labile groups (Boc and trityl) for side chain
protection.
S0002-7863(96)01483-7 CCC: $12.00 © 1996 American Chemical Society

8486 J. Am. Chem. Soc., Vol. 118, No. 35, 1996
Communications to the Editor
Scheme 2
Table 1. Peptidyl TFMKs Prepared with the Structure
stereogenic center does not epimerize significantly during the
formation of the acid fluoride or during the 1,3-dipolar cy-
cloaddition.
R-AA2-AA1-CF3
% overall yield
compound
R
AA2
AA1-CF3
from AA2-F
Thus, we have developed an efficient method to prepare
4-trifluoromethyl-substituted ∆3-imidazolines and incorporate
them into peptides. The imidazoline serves as both a synthetic
precursor to a TFMK and as a protecting group for the ketone
during Fmoc-based peptide synthesis. The imidazolines can be
readily hydrolyzed with mild acid to afford peptidyl TFMKs.
We have also demonstrated that this method is amenable to
oxidizable substrates. The one limitation is with AA1, where
only phenylglycine- and glycine-derived TFMKs are presently
described. This limitation arises from the difficulty of preparing
appropriately substituted R-silylimines and is being addressed
in current studies.16
a
10
11
7
12
9
13
14
15
Cbz
Cbz
Fmoc
Fmoc
Cbz-Ala
Cbz-Ala
Cbz-Ala
Cbz-Ala
Gly
Val
Phe
Phe
Phe
Met
Phe
Met
Phg-CF3
30
29
48
36
30
25
23
26
Phg-CF3
Gly-CF3
Phg-CF3
Gly-CF3
Gly-CF3
Phg-CF3
Phg-CF3
a Phg-CF3 ) -NHCH(Ph)COCF3.
A number of peptidyl TFMKs have been prepared by this
method, some of which are listed in Table 1. Each of these
compounds is composed of at least two amino acids and is
described by the formula R-AA2-AA1-CF3. In this formula, R
is a protecting group or an additional protected amino acid,
which was coupled to the AA2 residue after cycloaddition. AA2
originates as an amino acid fluoride (AA2-F), and AA1 is the
residue formed during the cycloaddition. Numerous amino acids
have been converted to the acid fluoride and used in the
cycloaddition reaction, demonstrating the tolerance of the
cycloaddition reaction to a variety of acid fluoride initiators.
Some examples are glycine (10), alanine (not shown), valine
(11), and phenylalanine (7). Finally, incorporation of methio-
nine (a thioether residue) into peptidyl TFMKs 13 and 15
demonstrates the compatibility of oxidizable moieties with this
synthetic approach to TFMKs.14
It should be noted that in all of the TFMKs prepared, no
attempt was made to control the stereochemistry of AA.1 As a
result, the phenylglycine-derived TFMKs are isolated as a
mixture of two diastereomers. This is not necessarily a serious
drawback, since it is known that the stereogenic center R to the
ketone carbonyl of a TFMK readily epimerizes under very mild
conditions, even in blood.15 It should also be noted that isolating
TFMKs 9 and 13 as single diastereomers indicates that the AA2
Acknowledgment. We are grateful for support of this research
through a grant from the National Institutes of Health (PHS
5R01CA25836). This paper is dedicated to Nelson J. Leonard on the
occasion of his 80th birthday.
Supporting Information Available: Detailed experimental pro-
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JA9614833
(15) P. D. Edwards, Zeneca Pharmaceuticals, personal communication.
(16) In order for this ∆3-imidazoline approach to be generally applicable
to the synthesis of peptidyl trifluoromethyl ketones with any substituent at
the AA1 position, it would be necessary to have a general method for the
synthesis of substituted R-silylimines. Also, if unsymmetrical R-silylimines
and/or azomethine ylides are utilized, it is necessary for the cycloaddition
reaction to operate with appropriate regioselectivity, so that the desired
substituent would become attached to the C-5 vs the C-2 positions. From
our present studies, it appears that the R-silylimine synthesis can be
generalized (C. W. Derstine and J. A. Katzenellenbogen, unpublished
results), and, at least in the one unsymmetrical case we studied (ca. synthesis
of 6), that the cycloaddition can be quite regioselective, although it is not
yet certain how selective the cycloaddition will be with the more complex
unsymmetrical disubstituted R-silylimines.