Novel cyclic tripeptides and substituted aromatic amino acids via ruthenium-activated SNAr reactions

Article abstract of DOI:10.1021/ol991084n

(formula presented) Chlorophenylalanines η⁶-complexed to ruthenium undergo S_NAr reactions with a variety of nucleophiles to form substituted phenylalanines exemplified by 4b. Extension of these reactions to intramolecular ruthenium-a

Full text of DOI:10.1021/ol991084n

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1819-1822
Novel Cyclic Tripeptides and
Substituted Aromatic Amino Acids via
Ruthenium-Activated SNAr Reactions
,†,‡
Christopher W. West† and Daniel H. Rich*
Department of Chemistry and School of Pharmacy, UniVersity of Wisconsin-Madison,
Madison, Wisconsin, 53706
dhrich@facstaff.wisc.edu
Received September 23, 1999
ABSTRACT
Chlorophenylalanines η6-complexed to ruthenium undergo SNAr reactions with a variety of nucleophiles to form substituted phenylalanines
exemplified by 4b. Extension of these reactions to intramolecular ruthenium-activated SNAr cyclizations led to three novel cyclic tripeptide
systems (exemplified by 17 and 20).
Several peptide-derived natural products contain biaryl ether
linkages,1 a functionality that may be important for restricting
conformational freedom.2 While many methods are available
to form biaryl ethers, the ruthenium-activated SNAr reaction
offers access to peptide-derived systems under mild condi-
tions.3,4 Previously, we showed that cyclic biaryl ether-
containing tripeptides K-13 (1) and OF-4949-III (2) can be
synthesized using a ruthenium-activated intramolecular SN-
Ar reaction for the macrocyclization step.4 Here we report
the expansion of this methodology to nucleophiles in amino
acids histidine, cysteine, and lysine in intramolecular reac-
tions and additional simple nucleophiles in intermolecular
reactions.
† Department of Chemistry.
Intermolecular SNAr reaction of various nucleophiles with
simple ruthenium-activated aromatic systems is well
characterized.5 We decided to investigate the utility of these
reactions in more functionalized systems. Boc-3-chloro-
phenylalanine ethyl ester complex 3 in which the aromatic
ring is η6-complexed to cyclopentadienyl ruthenium hexa-
‡ School of Pharmacy.
(1) For reviews see: (a) Evans, D. A.; DeVries, K. M. In Glycopeptide
Antibiotics, Drugs and the Pharmaceutical Sciences; Nagarajan, R., Ed.;
Marcel Decker Inc.: New York, 1994; Vol. 63, p 63. (b) Itokawa, H.;
Takeya, K. Heterocycles 1993, 35, 1467. (c) Zhu, J. Synlett 1997, 133.
(2) (a) Hart, P. A.; Rich, D. H. In The Practice of Medicinal Chemistry;
Wermuth, C. G., Ed.; Academic Press Inc.: San Diego, 1996; p 393. (b)
Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem. 1995, 2,
654. (c) Veber, D.; Holly, F. W.; Nutt, R. F.; Bergstrand, S.; Brady, S. F.;
Hirschmann, R.; Glitzer, M. S.; Saperstein, R. Nature 1979, 280, 512.
(3) Pearson, A. J.; Park, J. G.; Yang, S. Y.; Chuang, Y. J. Chem. Soc.,
Chem. Commun. 1989, 1363.
(5) (a) Moriarty, R. M.; Ku, Y. Y.; Gill, U. S. Organometallics 1988, 7,
660. (b) Moriarty, R. M.; Guo, L.; Ku, Y.; Gilardi, R. J. Chem. Soc., Chem.
Commun. 1990, 1765. (c) Dembek, A. A.; Fagan, P. J. Organometallics
1996, 15, 1319.
(4) Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1997, 119, 6488.
10.1021/ol991084n CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/04/1999

fluorophosphate was used as the model system. Displacement
of chlorine by a variety of nucleophiles, followed by
photolytic removal of the ruthenium complex (Scheme 1),
Scheme 2
Scheme 1
piperidine on 12 gave equal amounts of the 3- and 4-sub-
stituted aniline derivatives (13a + 13b). However, only
monosubstitution was observed, even with an excess of
piperidine.
led to the substituted phenylalanines shown in Table 1. In
this reaction the sodium anions of phenol, benzenethiol,
dimethyl malonate, methanol, and excess neutral piperidine
readily displaced chloride in typical fashion. Additionally,
the sodium thiolate of Boc-Cys-OMe and weakly nucleo-
philic sodium anions of succinimide and hydantoin displaced
chloride from 3, although no attempts were made to optimize
these three reactions.
Displacement of both chlorines from 12 could be ac-
complished with sodium benzenethiolate. Additionally, the
cyclopentadienyl ruthenium complexes of monochloro 13a
and 13b react with sodium benzenethiolate to give the
thioether and piperidine-substituted phenylalanine. Unfor-
tunately, the present irradiation technique did not remove
ruthenium from the complex, a problem previously noted
with highly heteroatom-substituted aromatic rings.5c Further
work on decomplexation is therefore required. The ease of
displacement of chlorine in both mono- and dichlorinated
phenylalanines and the compatibility of the protected amino
acid complex with a variety of nucleophiles indicates that
libraries of substituted peptides could be prepared by use of
combinatorial chemistry.
Table 1. Intermolecular SNAr Reactions
Our results with model intermolecular ruthenium-activated
SNAr reactions led us to see if an intramolecular version
could be used to synthesize novel cyclic systems. Previously,
only phenols3,4 have been used as nucleophiles in the
ruthenium-activated intramolecular SNAr reaction. The nu-
cleophilic heteroatoms sulfur and nitrogen in cysteine,
histidine, and lysine containing tripeptides were chosen to
explore this area of chemistry and provide entry to 14-, 15-,
and 17- member ring systems, respectively.
Formation of the histidine-containing cyclic tripeptide
began with complexation of ruthenium to Boc-(4Cl)Phe-OH7
(14) followed by peptide coupling with Leu-His-OMe to give
the ruthenium-containing linear tripeptide 16 (Scheme 3).
Cyclization under high dilution conditions (c ) 5 mM)
followed by photolytic decomplexation of ruthenium3 led to
the novel heteroaryl cyclized tripeptide 17.
The first attempts to synthesize the analogous cysteine and
lysine cyclic peptides were disappointing due to low yields
obtained in the cyclization step. Our first attempt, outlined
for cysteine (Scheme 4), began with peptide coupling of 15
to the free amine derived from Fmoc-Leu-Cys(Mmt)-OMe
(18) to give ruthenium-containing linear tripeptide 19. Highly
acid-labile protecting groups [4-methyoxytrityl (Mmt) for
cysteine and 4-methyltrityl (Mtt) for lysine] were chosen for
side-chain protection. The trityl group was selectively
a Five equivalents, no NaH for step 1. b Complete transesterification
observed. c DMF as solvent for step 1.
Dichloroaromatic rings are known to undergo stepwise
displacement of halogen.6 However, displacement was not
regioselective with ruthenium complex 3,4-dichlorophenyl-
alanine 12 (Scheme 2). For example, nucleophilic attack by
(6) Pearson, A. J.; Park, J. G.; Zhu, P. Y. J. Org. Chem. 1992, 57, 3583.
(7) Pearson, A. J.; Park, J. G. J. Org. Chem. 1992, 57, 1744.
1820
Org. Lett., Vol. 1, No. 11, 1999

to the S-Teoc group in 22 by use of the hindered guanidinium
base 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]-py-
rimidine (MTBD) (Scheme 5). Selective η6 ruthenium
Scheme 3
Scheme 5
removed in the presence of the Boc group by use of 94/5/1
CH2Cl2/TES/TFA at 0 °C for 30 min.8 After deprotection of
the thiol group, intramolecular SNAr cyclization was ac-
complished by use of 40% KF on Al2O3 in the presence of
18-crown-6. Photolytic decomplexation afforded cyclized
tripeptide 20. When the same strategy and conditions were
repeated with lysine, a very disappointing yield of 2% was
obtained for the deprotection/cyclization/decomplexation
sequence.
complexation provided linear tripeptide 23 in excellent yield.
The one-pot deprotection/cyclization was found to occur
using a variety of fluoride sources, with TBAF giving the
highest yields. Photolytic decomplexation provided 20 in
52% yield for the final deprotection/cyclization/decomplex-
ation sequence.
The same protocol applied to the lysine analogue 24
(Scheme 6) also afforded the cyclic peptide. Reaction of the
Scheme 4
Scheme 6
aromatic peptide 24 with cyclopentadienyltris(acetonitrile)-
ruthenium(II) hexafluorophosphate gave the η6 ruthenium
complex cleanly. Subsequent deprotection and cyclization
with an alternate fluoride source, tris(dimethylamino)sulfur
(trimethylsilyl) difluoride (TASF), followed by photolytic
decomplexation gave the cyclic tripeptide 25.
The overall conformation of compounds 17, 20, and 25
appears by molecular modeling to be â-strand in nature with
differing degrees of conformational flexibility depending on
ring size. The actual crystal structures for these molecules
have not yet been obtained. However, several cyclic biaryl
ether tripeptides previously synthesized have been shown by
this lab9 and by Still10 to be â-strand mimetics. These
mimetics inhibit metalloproteases and upon derivatization
Greater success in the cyclization step for both cysteine
and lysine analogues was achieved by changing the side-
chain protecting group from an acid-labile trityl group to
the fluoride-labile 2-(trimethylsilyl)ethoxycarbonyl (Teoc)
group. The new protecting group strategy allowed two
improvements: (i) selective η6-complexation of ruthenium
to the linear tripeptide, and (ii) one-pot deprotection/
cyclization conditions.
Application of the new strategy began with a protecting
group switch from S-fluorenylmethyl (Fm) in tripeptide 21
(8) Barlos, K.; Gatos, D.; Chatzi, O.; Koutsogianni, S.; Schafer, W. In
Peptides 1992, Proc. 22nd European Peptide Symposium; Schneider, C.
H., Eberle, A. N., Eds.; ESCOM: Leiden, 1993; p 283.
Org. Lett., Vol. 1, No. 11, 1999
1821

with a hydroxyethylamine isostere inhibit HIV-protease.9 The
â-strand conformation is thought to play an important role
in the activity of these compounds. The ability to alter the
conformational flexibility of the tripeptide and thus its
â-strand conformation via side-chain constraint would be an
effective experiment in determining the extent to which the
overall shape influences binding.
The use of the ruthenium-activated SNAr reaction has
provided ready access to several new substituted phenyl-
alanine derivatives and three novel cyclic tripeptide systems
under conditions that do not appear to affect amide bonds,
esters, and epimerizable R-centers. These procedures provide
a mild and general method for the formation of substituted
peptide-derived phenylalanine derivatives containing a wide
range of functionality and the conformationally restricted
tripeptide units may find use in biological studies.
Acknowledgment. This work was supported by a re-
search grant from the National Institutes of Health (GM
50113).
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 3, 4b, 5b,
6b, 7b, 8b, 17, 20, 23, and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Janetka, J. W.; Raman, P.; Satyshur, K.; Rich, D. H. J. Am. Chem.
Soc. 1997, 119, 441.
(10) Hobbs, D. W.; Still, W. C. Tetrahedron Lett. 1989, 30, 5405.
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