Olefin Metathesis in the Design and Synthesis of a Globally Constrained Grb2 SH2 Domain Inhibitor

Article abstract of DOI:10.1021/ol0157609

(matrix presented) One drawback frequently associated with olefin metathesis-mediated peptide macrocyclization, the loss of side chain functionality at sites of ring closure, may be circumvented by incorporation of side chain functionality within the ring

Full text of DOI:10.1021/ol0157609

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1617-1620
Olefin Metathesis in the Design and
Synthesis of a Globally Constrained
Grb2 SH2 Domain Inhibitor
Yang Gao, Chang-Qing Wei, and Terrence R. Burke Jr.*
Laboratory of Medicinal Chemistry, DBS, NCI-FCRDC, National Institutes of Health,
Frederick, Maryland 20892-4255
tburke@helix.nih.goV
Received February 26, 2001
ABSTRACT
One drawback frequently associated with olefin metathesis-mediated peptide macrocyclization, the loss of side chain functionality at sites of
ring closure, may be circumvented by incorporation of side chain functionality within the ring-closing olefin segments. This approach is
demonstrated in the preparation of a macrocyclic Grb2 SH2 domain antagonist designed as a conformationally constrained â-bend mimic.
Restriction of conformational flexibility is an important
peptidomimetic design consideration. Global constraint may
be obtained by backbone cyclization either in a head-to-tail
in type-1 â-bend fashion,5a we envisioned that modification
of 4 by incorporation within a macrocyclic structure could
potentially increase affinity by introducing conformational
constraints approximating those needed for binding. Since
the pTyr phenyl phosphate group and the naphthyl ring are
important for high affinity binding, the target macrocycle
must include this side chain functionality at the sites of ring
fashion or through amino acid residue side chains.1
A
modification of this latter approach can be achieved using
the ruthenium-catalyzed ring-closing metathesis reaction of
Grubbs.2 However, one limitation of the use of this method
is that the resulting macrocycle (2) frequently lacks side chain
functionality at the sites of ring closure, originally present
in the open chain parent (1) (Figure 1). Alternatively,
incorporation of the side chain onto ring-closing segments
could potentially allow macrocyclization without this type
of loss (3).
In our ongoing effort to develop tyrosine-kinase dependent
signal transduction inhibitors,3 Grb2 SH2 domain binding
antagonists are being prepared based on the naphthylpropyl-
amide-containing tripeptide 4.4 Because binding of natural
pTyr-containing ligands to Grb2 SH2 domains takes place
(1) (a) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441.
(b) Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945.
(2) (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 9606. (b) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999,
32, 75-103. (c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
Figure 1. Macrocyclization with loss (2) and retention (3) of side
chain functionality at the site of ring closure.
10.1021/ol0157609 This article not subject to U.S. Copyright. Published 2001 by the American Chemical Society
Published on Web 05/09/2001

Heck reaction of known, chiral acrylamide 9 and tert-butyl
protected 4-bromotoluyl phosphonate 10 in a manner similar
to that outlined in our recent disclosure (Scheme 1).6a An
Scheme 1a
Figure 2. Macrocyclization protocol.
closure. Therefore, analogue 5 was designed (Figure 2),
which exemplified the new type of macrocyclization shown
by general structure 3 (Figure 1). (Note: replacement of the
phosphate group in 4 with a phosphonate group in target 5
was done on the basis of the equivalent affinity of the two
moieties in Grb2 SH2 domain assays.)5b
a Conditions: (i) Et3N, Pd(OAc)2, tri-o-tolylphosphine, reflux,
(86% yield); (ii) vinylmagnesium bromide, PhSCu, Et2O/THF, -40
°C (64% de in 67% yield); (iii) H2O2, 2 equiv of LiOH, THF/H2O
(81% yield).
important component of our synthetic approach was the
subsequent introduction of â-vinyl functionality bearing the
(R) configuration. Although 1,4-addition of vinylmagnesium
bromide had been reported in the presence of a strong Lewis
acid such as TMSCl,6b in our hands, solely the 1,2-addition
product was obtained. To effect the desired 1,4-addition, a
variety of reagents were investigated, including vinyl-
magnesium-CuI,7a vinylmagnesium-CuBr‚Me2S,7b and
vinyllithium-CuI-Bu3P7c complexes, as well as vinyllithium7d
itself.
Synthetic Approach. On the basis of a retrosynthetic
analysis leading to 5, dipeptide 6 containing tert-butyl
phosphonate was selected as the penultimate precursor to
metathesis ring closure. The synthesis of 6 in turn required
the synthesis of N- and C-terminal building blocks 7 and 8,
respectively, since the remaining residues were both com-
mercially available in their N-Fmoc forms (Figure 3).
While none of these conditions yielded satisfactory results,
it was found that vinylmagnesium-PhSCu complex8 could
provide desired product 12-(R) with modest diastereo-
selectivity (64% de) in acceptable yield (67%). Separation
of diastereomeric 12-(R) and 12-(S) products was achieved
by silica gel chromatographic purification followed by
crystallization, with hydrolysis of 12-(R) to building block
7 then being achieved in good yield using standard condi-
tions.9
(4) Furet, P.; Gay, B.; Caravatti, G.; GarciaEcheverria, C.; Rahuel, J.;
Schoepfer, J.; Fretz, H. J. Med. Chem. 1998, 41, 3442.
(5) (a) Rahuel, J.; Gay, B.; Erdmann, D.; Strauss, A.; GarciaEcheverria,
C.; Furet, P.; Caravatti, G.; Fretz, H.; Schoepfer, J.; Grutter, M. G. Nat.
Struct. Biol. 1996, 3, 586-589. (b) Burke, T. R., Jr.; Smyth, M. S.; Otaka,
A.; Nomizu, M.; Roller, P. P.; Wolf, G.; Case, R.; Shoelson, S. E.
Biochemistry 1994, 33, 6490-6494.
Figure 3. Synthetic targets for macrocyclization.
(6) (a) Burke, T. R.; Liu, D. G.; Gao, Y. J. Org. Chem. 2000, 65, 6288-
6291. (b) Han, Y.; Hruby, V. J. Tetrahedron Lett. 1997, 38, 7317-7320.
(7) (a) Sanceau, J.-Y.; Brown, R. D. E. Tetrahedron 1994, 50, 3363-
3380, (b) Hon Y. S.; Chen, F. L.; Huang, Y. P.; Lu, T. J. Tetrahedron:
Asymmetry 1991, 9, 879-882, (c) Oppolzer, W. G.; Mills, R. J.; Pachinger,
W.; Stevenson, T. HelV. Chim. Acta 1986, 69, 1542-1545, (d) Bernardi,
A.; Cardani, S.; Pilati, T.; Poli, G.; Scolastico, C.; Villa, R. J. Org. Chem.
1988, 53, 1600-1607.
Preparation of N-terminal pTyr mimetic 7 proceeded from
intermediate 11, which was derived by palladium-catalyzed
(3) (a) Burke, T. R., Jr.; Yao, Z.-J.; Smyth, M. S.; Ye, B. Curr. Pharm.
Des. 1997, 3, 291-304. (b) Burke, T. R., Jr.; Gao, Y.; Yao, Z.-J.
Phosphoryltyrosyl mimetics as signaling modulators and potential antitumor
agents. In Biomedical Chemistry: Applying Chemical Principles to the
Understanding and Treatment of Disease; Torrence, P. R. Ed.; John Wiley
& Sons: New York, 2000; pp 189-210.
(8) Behforouz, M.; Curran, T. T.; Bolan, J. L. Tetrahedron Lett. 1986,
27, 3107-3110.
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Org. Lett., Vol. 3, No. 11, 2001

Similar to the syntheis of N-terminal pTyr mimetic 7,
stereoselective synthesis of C-terminal naphthylpropylamine
8 also utilized Evans’ 4-phenyl-2-oxazolidinone chiral
auxiliary (Scheme 2). Unlike the former synthesis, however,
was deprotected and coupled with commercially available
N-Fmoc 1-aminocyclohexane carboxylic acid to provide
dipeptide amide 18. Removal of Fmoc protection, followed
by HOBt active ester coupling with pTyr mimetic 7, gave
penultimate intermediate 6 in good yield.
Ruthenium-containing catalyst 19 has enjoyed widespread
utility in olefin metathesis, including the formation of peptide
bend mimetics.2,10 Accordingly, by subjecting 6 to olefin
metathesis in the presence of 19 in CH2Cl2 at reflux under
argon, ring-closed product 20 was obtained in good yield
predominantly as the trans isomer (Scheme 4). Although
Scheme 2a
Scheme 4a
a Conditions: (i) (a) LiHMDS, THF; (b) 1-bromomethylnaph-
thalene, (88% yield); (ii) LiAlH4, THF, -78 °C to rt (100% yield);
(iii) DEAD, PPh3, phthalimide, THF (73% yield); (iv) EtOH, H2O,
N2H4‚H2O (91% yield).
the (R)-(-)- rather than (S)-(+)-auxiliary was employed with
a “reversed” addition of aryl functionality to alkenyl side
chain. Therefore, acylation of commercially available Evans’
oxazolidinone provided 13. Subsequent alkylation of the
lithium enolate with 1-(bromomethyl)naphthalene gave 14
in high yield as a single isolated diastereomer. With
stereochemistry established, transformation to amine 8 was
achieved in three steps: reduction to alcohol 15; Mistunobu
addition of phthalimide 16; and finally hydrazine-mediated
cleavage to 8 (66% yield for three steps). With N- and
C-terminal units 7 and 8 in hand, respectively, construction
of metathesis substrate 6 was achieved in straightforward
fashion using standard coupling techniques (Scheme 3).
a Conditions: (i) Grubbs' catalyst (19), CH2Cl2, reflux, 60 h (67%
yield); (ii) TFA/H2O/trimethylsilane, 1 h (60% yield).
Scheme 3a
chromatographic separation of minor amounts of cis con-
tamination proved difficult at this stage, following TFA-
mediated cleavage of tert-butyl phosphonate protection, pure
final product 5 could be obtained in 60% yield using reverse-
phase HPLC chromatography.
As demonstrated herein, olefin metathesis-induced macro-
cyclization of pseudotripeptide precursor can be achieved
with full functionality incorporated into the C- and N-
terminal alkene moieties, so as to afford ring-constrained
peptidomimetics bearing complete side chain functionality
present in the parent open chain peptide. Utilization of
Grubbs’ olefin metathesis reaction in this fashion, may prove
a Conditions: (i) (a) HOBt, DIPCDI (95% yield); (ii) (a) TFA-
CH2Cl2; (b) NaHCO3; (c) Fmoc-1-amino-cyclohexanecarboxylic
acid, HOBt, DIPCDI (70% yield); (iii) (a) piperidine in CH3CN
(86% yield); (b) 7, HOBt, DIPCDI (67% yield).
(10) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(c) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
1998, 120, 4334. (d) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.;
Bonitatebus, P. J.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638. (e)
Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron 1999, 55, 8189. (f)
Ripka, A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chem. Lett. 1998,
8, 357.
N-Boc-protected asparagine amide 17, obtained by conden-
sation of 8 with commercially available N-Boc asparagine,
(9) Pais, G. C. G.; Maier, M. E. J. Org. Chem. 1999, 64, 4551-4554.
Org. Lett., Vol. 3, No. 11, 2001
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useful for the preparation of constrained analogues in a
variety of contexts.
Supporting Information Available: Synthetic procedures
and spectral characterization for compounds 5-20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Appreciation is expressed to Ms. Lynn
Andersen and Dr. James Kelley of the LMC for mass spectral
analysis of synthetic intermediates and final products used
in this study.
OL0157609
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