A general preparation of (Z)-1-fluorostilbene derivatives for the design of conformationally restricted peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2009.10.099

The preparation of (Z)-1-fluoro-2-bromostyrenes provides a general route for the formation of (Z)-1-fluorostilbene derivatives as configurationally stable spacial linkers for the design of conformationally restricted peptidomimetics. Palladium-catalyzed a

Full text of DOI:10.1016/j.tetlet.2009.10.099

Tetrahedron Letters 51 (2010) 121–124
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A general preparation of (Z)-1-fluorostilbene derivatives for the design
of conformationally restricted peptidomimetics
a
b,
b
David R. Williams a, , Micheal W. Fultz , Thomas E. Christos , Jeffery S. Carter
*
*
a Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
b Icagen, Incorporated, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of (Z)-1-fluoro-2-bromostyrenes provides a general route for the formation of (Z)-1-flu-
orostilbene derivatives as configurationally stable spacial linkers for the design of conformationally
restricted peptidomimetics. Palladium-catalyzed aryl Suzuki and Stille cross-coupling reactions have
been surveyed to proceed with complete retention of fluoroalkene geometry, and permit the direct incor-
poration of a variety of aryl and heteroaromatic substituents.
Received 16 September 2009
Revised 20 October 2009
Accepted 21 October 2009
Available online 27 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The role of fluorine-containing compounds in medicinal chem-
istry is an important area of investigation for drug design and
development.1,2 The electronegativity and the van der Waals
radius of the fluoro-substituent has led to effective replacements
of oxygen as well as hydrogen.3 These aspects may provide for
enhanced binding affinities or may inhibit biological oxidation pro-
cesses which result in improved metabolic stability. The inclusion
of fluorine may also significantly alter the characteristic properties
of potential drug candidates by addressing issues of uptake and
bioavailability.
The design of peptidomimetics has led to the consideration of
alkenyl fluorides as conformationally rigid surrogates for the
amide bond in which the polarity introduced by fluorine in the
olefin linkage would provide an electronic effect analogous to the
carbonyl oxygen.3,4 In fact, vinylic fluorides can participate as
hydrogen bond acceptors within a peptide skeleton as well as with
sequestered solvent molecules.5 Our interest in the preparation of
functionalized trans-stilbenes as configurationally rigid spatial
linkers for the design of peptidomimetic substances as has led to
studies of palladium-catalyzed cross-coupling reactions of (Z)-1-
fluoro-2-bromostyrenes. In this regard, our investigations comple-
ment a previous study by McCarthy and coworkers6 describing
cross-coupling reactions of the regioisomeric E- and Z-b-bromo-
b-fluorostyrenes.
amide 3, the introduction of aryl linker 2 presents two elements
of stereochemical bias which can be harnessed to investigate con-
formational states available to small chains of tethered peptides.
Firstly, the peptide segments may be synclinal, as displayed in 3.
Since the C- and N-terminals of the linker 2 are in close proximity
5
4
F
14
1) Pd(dppf)Cl2
F
9
10
THF; CsCO3
add 4 (64%)
7
2
8
Br
1
O
OCH3
11
2) Pd(dppf)Cl2
THF; CsCO3
add 5 (64%)
1a
I
2
NH2
3) EDCl; DMAP
CH2Cl2, 22 °C
F
O
H
H
HO
6
R1
R2
O
Ph
N
H
N
O
Boc
CH3
CH3
OCH3
4) LiOH; MeOH
N
O
then: EDCl; DMAP
CH2Cl2, 22 °C
NH
H
O
O
Ph
O
H
N
N
CH3
Our studies have defined a general pathway for the preparation
of functionalized stilbenes, such as 2, from readily available
2-bromostyrenes (1) (Scheme 1) which can be sequentially linked
via N- and C-terminal operations for the construction of conform-
ationally restricted peptide derivatives. As exemplified by the
H2N
O
O
O
H3C
7
CH3
3 (R1/R2 = H)
(85%, 2 steps)
HO
B
HO
B
NH2
HO
CH3
O
O
HO
4
5
* Corresponding authors. Tel.: +1 812 855 6629; fax: +1 812 855 8300.
E-mail addresses: williamd@indiana.edu (D.R. Williams), tchristos@icagen.com
(T.E. Christos).
Scheme 1. Formation of (Z)-1-fluorostilbene analogs.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.099

122
D. R. Williams et al. / Tetrahedron Letters 51 (2010) 121–124
(7.06 Å), hydrogen-bonding interactions of the tethered moieties
may be designed to further stabilize the synclinal conformers. On
the other hand, bond rotation (C7–C8) of the stilbene can preorga-
nize the attached peptide chains on opposite sides of the planar
alkenyl fluoride in an anti conformation. Calculations indicate that
synclinal 3 is more stable than the anti conformer by 4.5 kcal/mol.
Secondly, biphenyl atropisomers may be prepared via selected R1
and R2 substituents in 3 as a further refinement of stereochemistry.
A torsional angle of 50° is calculated for the aniline moiety in
Figure 1.
Initial efforts have documented a stepwise assembly of 3 in
Scheme 1 via the Suzuki coupling of boronic acid 4 with the aryl
iodide of 1 followed by a second palladium insertion reaction of
the alkenyl bromide with 5 to yield (Z)-stilbene 2. Subsequent
attachment of the amino acid side chains 6 and 7 yields peptidom-
imetic 3.
An additional feature is illustrated by the sequential Pd(0)
cross-coupling reactions of fully elaborated components (Scheme
2). Thus, the facile Stille coupling of the aryl iodide of 1a selectively
occurs with 8 under neutral conditions followed by the alkenyl
bromide coupling to install the intact dipeptide of stannane 9. In
similar fashion the coupling reactions of 1a with 50-pyrimidyl 10
and stannane 9 have provided a direct route to 11. Thus, readily
available components can be utilized to access focused libraries.
To broaden the flexibility of the approach and accommodate a
general design of probes for biological process, we have explored
the preparation of a variety of substituted (Z)-1-fluoro-2-bromo-
styrenes, and we have surveyed Suzuki and Stille cross-coupling
reactions to access electron-rich and electron-deficient derivatives,
as well as heterocyclic analogs of (Z)-1-fluorostilbenes. Three
methods were examined to prepare substituted 1-bromo-2-aryl-
ethylenes (Scheme 3). Nucleophilic displacement of bromide 12
with lithiodibromomethane at ꢀ78 °C resulted in elimination upon
warming to room temperature to give 13 (E/Z ratio 20:1) in 87%
1) 10 mol% Pd(dppf)Cl2 90 °C
Tol: THF (1:1) 62% yield
F
H
Bu3Sn
N
N
H
H
Boc
O
N
H
O
8
Ph
O
1a
CH3
CH3
OCH3
2) 10 mol% Pd(dppf)Cl2 90 °C
Tol: THF (1:1) 78% yield
H3C
N
O
NH
H
CH3
O
O
O
H
H
N
O
N
Bu3Sn
N
CH3
3
H
O
H
O
O
Ph
9
1) 10 mol% Pd(dppf)Cl2 90 °C
F
Tol: THF (1:1) CsCO 3,64% yield
N
(HO)2B
10
H
N
O
N
1a
Ph
O
2) 10 mol% Pd(dppf)Cl2 90 °C
Tol: THF (1:1) 77% yield
H3C
CH3
CH3
N
N
N
O
H
CH3
O
H
H
N
O
OCH3
Bu3Sn
N
CH3
H
O
H
O
11
Ph
9
Scheme 2. Direct preparation of peptidomimetics.
O
Br
H
CH2Br2 (4 eq.)
+
Y
LHMDS (3 eq.)
Et2O; THF
Y
Ph3PCH2Br
LDA; THF
at –78 °C
X
12 X = I;Y = H
X
(2:3 by volume)
–78 °C → 22 °C
14 X = Y = Cl
Br
Y
1) NBS; Et2O
HF•pyr
X
NBS; CH2Cl2
cat. Et3N
(72–83%)
13 X = I;Y = H (87%)
15 X = Cl;Y = Cl (75%)
18 X = Y = OCH3 (95%)
19 X = H;Y = OPh (75%)
2) KOtBu; THF
F
O
Br
OH
Y
Y
X
X
16 X = Y = OCH3
17 X = H;Y = OPh
1a X = I;Y = H (74%)
1b X = Y = Cl (70%)
1c X = Y = OCH3 (72%)
1d X = H;Y = OPh (76%)
Scheme 3. Preparation of 1-fluorostyrenes 1.
yield.7 On the other hand, benzaldehydes, such as 14, were utilized
in Wittig olefinations to produce 15 as Z/E-mixtures (ꢁ7:1 ratio)
with average yields of approximately 75%.8 The application of the
Hunsdiecker reaction9 proved to be facile in the case of cinnamic
acid derivatives containing aryl electron-donating substituents
such as 16 and 17. In these examples, reactions with recrystallized
N-bromosuccinimide (NBS) in the presence of a catalytic amount of
Et3N led to a rapid decarboxylation at room temperature yielding
the E-alkenyl bromides 18 and 19 with high E-stereoselectivity
(E/Z ratio >25:1). Hunsdiecker reactions of cinnamic acids contain-
ing electron-withdrawing aryl substituents proceeded poorly.
Alkenylbromides 13, 15, 18, and 19 were subsequently reacted
under conditions of Markonikov addition with recrystallized NBS
Figure 1. Energy-minimized conformation of 3 using GMMX in PCModel 9.1 (MMX
employed with p-calculations enabled).

D. R. Williams et al. / Tetrahedron Letters 51 (2010) 121–124
123
Table 1
Formation of (Z)-1-fluorostilbene analogs via cross-coupling reactions
Entry
Alkenyl fluoride
Coupling partnera
Productb
Conditions (yield)c
F
F
F
F
Br
Br
Br
HO
B
OCH3
OCH3
1
B (79%)
C (80%)
B (78%)
HO
Cl
Cl
20
Cl
1b
1b
1c
27
28
Cl
Cl
Cl
Cl
F
F
Bu3Sn
N
N
2
3
Cl
26
HO
B
OCH3
OCH3
HO
H3CO
20
H3CO
29
H3CO
H3CO
F
H3C
HO
H3C
O
N
F
N
Br
O
B
4
A (50%)
CH3
CH3
H3CO
H3CO
HO
1c
H3CO
H3CO
30
22
F
F
HO
HO
F
B
Br
Br
O
O
5
6
7
A (85%)
A (70%)
C (70%)
H3CO
H3CO
23
1c
1c
H3CO
H3CO
31
N
N
F
F
N
N
HO
B
H3CO
H3CO
HO
H3CO
H3CO
10
32
33
F
Br
Bu3Sn
N
N
H3CO
H3CO
H3CO
H3CO
26
1c
F
F
F
F
F
F
Br
Br
Br
HO
OCH3
B
OMe
8
9
B (80%)
B (78%)
C (73%)
HO
PhO
20
21
PhO
PhO
PhO
1d
1d
1d
34
35
36
HO
F
B
F
HO
PhO
PhO
Bu3Sn
N
N
N
10
26
F
O
H3C
F
N
Br
O
HO
B
CH3
HO
CH3
11
A (73%)
1e
22
37
N
N
N
N
(continued on next page)

124
D. R. Williams et al. / Tetrahedron Letters 51 (2010) 121–124
Table 1 (continued)
Entry
Alkenyl fluoride
Coupling partnera
Productb
Conditions (yield)c
F
H3C
F
F
Br
N
HO
N
Boc
B
Boc
12
13
A (71%)
HO
1e
1e
38
39
24
N
N
N
N
N
N
N
N
F
Br
HO
N
H
N
B
H
HO
A (70%)
25
Reaction conditions: (A) Pd(dppf)Cl2 10 mol %; CsCO3; THF, sealed tube at 90 °C/8 h. (B) Pd(PPh3)4 10 mol %; CsCO3; THF, sealed tube at 90 °C/8 h. (C) Pd(PPh3)4 10 mol %;
toluene, sealed tube at 90 °C/10 h. Notes: (a) All coupling partners are commercially available from Frontier Scientific, Inc. (b) Products were purified by flash silica gel
chromatography. (c) Yields are provided for purified products and are based on reactions of 1:1 stoichiometry of coupling reactants.
in the presence of HFꢂpyridine to regioselectively produce b,b-di-
bromo-
-fluorophenyl-ethanes.10 Elimination with potassium
isosteres for the design of peptidomimetics. The differential reac-
tivity of aryl iodide and alkenylbromide moieties in 1a facilitates
an efficient modular synthesis of peptidomimetics allowing for ra-
pid screening of cross-coupling partners.
a
tert-butoxide in THF proceeded smoothly to give the desired (Z)-
1-fluoro-2-bromostyrenes 1a, 1b, 1c, and 1d (yields 70–75%) as
the only observed alkene isomers.11 Substituted (Z)-1-fluoro-2-
bromostyrenes, such as 1e of Table 1, are available from aryl
iodides as illustrated for 1a (see Scheme 2). The trans geometry
of the fluoro and vinylic hydrogen substituents was confirmed
via the characteristically large coupling constants (JHF 38–40 Hz)
apparent in the H NMR spectra of the products.
Acknowledgments
We acknowledge Indiana University and the National Institutes
of Health (GM42897) for generous support. We also thank Nicholas
Chow and Richard Lord for calculations of 3.
Results of the palladium cross-coupling reactions of the (Z)-1-
fluoro-2-bromostyrenes 1b, 1c, 1d, and 1e are compiled in Table
1. Commercially available aryl and heteroaryl boronic acids were
surveyed utilizing Suzuki conditions. Reactions proceeded with
complete retention of olefin geometry to consistently provide
70–80% yields of cross-coupled (Z)-1-fluorostilbenes (Table 1, en-
tries 1–13). Experiments were conducted in resealable Carius tubes
in refluxing THF at 90 °C for 8–12 h in the presence of 10 mol %
Pd(dppf)Cl2. Reactions were monitored for consumption of the
starting alkenyl bromides. Subsequently, we found that 10 mol %
Pd(PPh3)4 could be used in many cases with similar results. The
availability of boronic acids provides convenient access to hetero-
cyclic derivatives, and the inclusion of isoxazole, pyrrole, indole,
and pyrimidine systems offers opportunities for further elabora-
tions. However, sluggish reactions were observed for cross-cou-
pling of the electron-rich styrene 1c and 3-fluorophenyl boronic
acid giving rise to a modest 40% yield of the desired stilbene
product.
Supplementary data
Supplementary information provides a description of general
reaction procedures and a listing of spectral data of products of
Schemes 1, 2 and 3, and Table 1. Supplementary data associated
with this Letter can be found, in the online version, at doi:10.1016/
j.tetlet.2009.10.099.
References and notes
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Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330; (c) Jakobsche, C.
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bromide occurred in refluxing toluene with stereocontrolled gen-
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utilized in Suzuki and Stille cross-coupling reactions to provide
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