Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation

Article abstract of DOI:10.1021/ja0676004

The efficient preparation of the privileged bicyclic bisarylimidazole kinase inhibitor scaffold was accomplished using rhodium-catalyzed C-H activation and intramolecular alkylation. The key C-H activation/alkylation step represents one of the first evalu

Full text of DOI:10.1021/ja0676004

Published on Web 12/23/2006
Synthesis of Potent Bicyclic Bisarylimidazole c-Jun N-Terminal Kinase
Inhibitors by Catalytic C-H Bond Activation
Jason C. Rech,† Michihisa Yato,† Derek Duckett,‡ Brian Ember,‡ Philip V. LoGrasso,‡
Robert G. Bergman,*,§ and Jonathan A. Ellman*,†
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California 94729, and The Scripps
Research Institute, 5353 Parkside DriVe, Jupiter, Florida 33458
Received October 24, 2006; E-mail: bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
The privileged bisarylimidazole framework is found in a variety
of potent kinase inhibitors, some of which have entered clinical
trials. Bicyclic bisarylimidazole derivatives, such as the c-jun
N-terminal kinase 3 (JNK3) inhibitor 1 (Figure 1),1 have recently
been developed to enhance affinity and particularly selectivity,
which remains a key challenge in kinase inhibitor drug discovery
Figure 1. Retrosynthesis of bicyclic bisarylimidazole kinase inhibitors.
efforts.
Bicyclic bisarylimidazole inhibitors, exemplified by inhibitor 1,
represent challenging synthetic targets. Indeed, the synthesis of 1
Scheme 1. Synthesis of Inhibitor 1
required 14 linear steps and was accomplished in less than 6%
overall yield.1 Herein, we report an efficient asymmetric synthesis
of 1 in 11 linear steps and 13% overall yield with the key bicyclic
imidazole core generated through catalytic C-H bond functional-
ization. We also successfully incorporated substituents in the C7
and C8 positions, substitution patterns difficult to access by the
previously reported synthetic route, and in doing so observed the
first examples of diastereocontrol in metal-catalyzed C-H bond
activation. Moreover, evaluation of the compounds synthesized by
this route resulted in the identification of a JNK3 inhibitor even
more potent than 1.
Conditions: (a) (SS)-tert-butanesulfinamide, CuSO4, CH2Cl2, 86%; (b)
vinylmagnesium bromide, CH2Cl2, 0 °C to room temp, 69% (single
diastereomer); (c) 4 N HCl, CH3OH, 99%; (d) 4-fluorophenyl tosylmethyl
isonitrile,3 glyoxylic acid, K2CO3, DMF, 92%; (e) TBDPSCl, iPr2EtN,
DMAP, CH2Cl2, 98%; (f) [RhCl(coe)2]2, PCy3, MgBr2, toluene, 180 °C,
50%, 92% ee; (g) Br2, CH2Cl2, -78 °C, 94%; (h) 2-methylthio-4-
trimethylstannylpyrimidine,6 Pd2(dba)3‚CHCl3, PPh3, LiCl, CuI, dioxane,
170 °C, 85%; (i) OXONE, THF, H2O, 79%; (j) propylamine, 78%; (k)
Bu4NF, THF, 100%.
In our retrosynthetic analysis of the bicyclic bisarylimidazole
framework, we envisioned installing the C5 pyrimidine by a cross-
coupling with 2 (Figure 1). Synthesis of the bicyclic imidazole core
would be accomplished via rhodium-catalyzed C-H activation/
annulation of 3. A van Leusen cycloaddition could be employed
to generate 3 from 4, which can be readily prepared from
commercially available starting material.
The synthesis of inhibitor 1 commenced with the condensation
of (Ss)-tert-butanesulfinamide and commercially available tert-
butyldimethylsiloxyacetaldehyde to provide 5 in 86% yield (Scheme
1).2 The addition of vinylmagnesium bromide to 5 proceeded with
91:9 dr, and after chromatography the major diastereomer was
obtained in 69% yield. Acidic cleavage of the silyl and tert-
butanesulfinyl groups provided 6 in nearly quantitative yield.2
Condensation of 6 with glyoxylic acid followed by treatment with
4-fluorophenyl tosylmethyl isonitrile3 generated the desired enan-
tiomerically pure imidazole in 92% yield.4 Protection of the resulting
primary alcohol as a tert-butyl diphenyl silyl (TBDPS) ether
provided 7 in 98% yield.
Owing to the steric hindrance introduced by the C6 substituent,
forcing conditions were required to achieve good conversion in the
C-H activation/annulation step. Ultimately, cyclization of 7 was
accomplished by using 5% [RhCl(coe)2]2 and 15% PCy3 to generate
the active catalyst with 5% MgBr2 as an additive and toluene as
solvent at 180 °C to provide 8 in 50% yield and with 92% ee
(Scheme 1).5 Olefin isomerization and reduction products were also
isolated in 11% and 6% yield, respectively. Competitive olefin
isomerization has been shown to occur under these conditions and
is likely responsible for the minor erosion of enantiomeric excess
observed during the cyclization.5c
Treatment of 8 with Br2 resulted in bromination of the imidazole
ring at the C5 position in 94% yield. The resulting bromide was
subjected to Stille cross coupling conditions in the presence of
2-methylthio-4-trimethylstannylpyrimidine6 to provide 9 in 85%
yield (Scheme 1).7 The requisite amine was generated by oxidation
of the thioether to the sulfone (79% yield) followed by the addition
of propylamine (78% yield). Quantitative Bu4NF cleavage of the
silyl ether provided 1 in 13% overall yield.
To demonstrate the flexibility of our synthetic approach toward
bicyclic bisarylimidazole systems and to explore diastereocontrol
in the C-H activation/annulation step, we generated derivatives
of 1 containing methyl substituents at the C7 or C8 positions. By
employing isopropenylmagnesium bromide in place of vinylmag-
nesium bromide in the previously described sequence, we were
poised to generate a derivative with a C7 methyl substituent
† Department of Chemistry, University of California.
§ Division of Chemical Sciences, Lawrence Berkeley National Laboratory.
‡ The Scripps Research Institute.
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J. AM. CHEM. SOC. 2007, 129, 490-491
10.1021/ja0676004 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Inhibition of c-Jun N-Terminal Kinase 3
Scheme 2. Synthesis of C7 Methyl Bicyclic Bisarylimidazole
Derivative
inhibitor
IC50 (nM) a,b
inhibitor
IC50 (nM)a,b
1
13
17
5.38 ((1.40)
5.29 ((1.25)
4.85 ((0.54)
ent-13
ent-17
1.63 ((0.34)
8.10 ((1.82)
a Homogeneous time-resolved fluorescence assay performed in quadru-
plicate. b IC50 values confirmed using standard radioactivity assay (see
Supporting Information).
Conditions: (a) isopropenylmagnesium bromide, CH2Cl2, -78 °C to
room temp, 90% (single diastereomer); (b) 4 N HCl, CH3OH, 96%; (c)
4-fluorophenyl tosylmethyl isonitrile,3 glyoxylic acid, K2CO3, DMF; (d)
TBDPSCl, iPr2EtN, DMAP, CH2Cl2, 86% (over two steps); (e) [RhCl(coe)2]2,
PCy3, MgBr2, toluene, 180 °C, 61%, 3:1 dr, 98% ee; (f) Br2, CH2Cl2, -78
°C, 96%; (g) 2-methylthio-4-trimethylstannylpyrimidine,6 Pd2(dba)3‚CHCl3,
PPh3, LiCl, CuI, dioxane, 170 °C, 66%; (h) OXONE, THF, H2O, 77%
(single diastereomer); (i) propylamine, 93%; (j) TBAF, THF, 87%.
coupling7 to install the pyrimidine, oxidation and formal nucleo-
philic displacement of the resulting sulfone, and silyl ether cleavage
to provide 17 (61% from 16). The overall yield for the preparation
of the C8 methyl derivative 17 from the common aldehyde starting
material was 18%.
The ability of compounds 13 and 17, and their enantiomers ent-
13 and ent-178 prepared by employing (RS)-tert-butanesulfinamide
in the previously described synthetic sequences, to inhibit JNK3
were determined (Table 1). While potency comparable to 1 was
observed for 13, 17, and ent-17, a 3- to 4-fold increase in potency
was observed for ent-13.
Scheme 3. Synthesis of C8 Methyl Bicyclic Bisarylimidazole
Derivative
In summary, we have developed an efficient and flexible
synthetic route for the generation of the potent kinase inhibitor 1
with the key transformation being intramolecular alkylation via
rhodium-catalyzed C-H bond activation. By utilizing this intra-
molecular alkylation, our approach easily allows introduction of
substituents at the C7 and C8 positions, derivatives that would be
much more difficult to access by the previously published route to
1. Determination of the selectivity profiles of the synthesized
analogues and preparation of even more potent compounds are in
progress.
Conditions: (a) allylmagnesium bromide, CH2Cl2, -78 °C to room temp,
92% (single diastereomer); (b) 4 N HCl, CH3OH, 94%; (c) 4-fluorophenyl
tosylmethyl isonitrile,3 glyoxylic acid, K2CO3, DMF; (d) TBDPSCl, iPr2NEt,
DMAP, CH2Cl2, 78% (over two steps); (e) [RhCl(coe)2]2, PCy3, MgBr2,
toluene, 180 °C, 52%, 92% ee; (f) Br2, CH2Cl2, -78 °C, 80%; (g)
2-methylthio-4-trimethylstannylpyrimidine,6 Pd2(dba)3‚CHCl3, PPh3, LiCl,
CuI, dioxane, 170 °C, 84%; (h) OXONE, THF, H2O; (i) propylamine, 91%
(over two steps); (j) TBAF, THF, 99%.
(Scheme 2). The sequence proceeded smoothly with excellent yields
and selectivity for the generation of enantiomerically pure 11 (74%
from 5).
Treatment of 11 with the previously described rhodium-catalyzed
C-H activation/annulation conditions resulted in the formation of
12 in 61% yield as a 3:1 mixture of inseparable diastereomers
(Scheme 2).5 The tetrasubstituted olefin isomerization and olefin
reduction products also were isolated in 24% and 3% yields,
respectively. For operational simplicity the diastereomers were
separated at a later stage in the synthesis.
Bromination of 12 proceeded in 96% yield, and subsequent Stille
cross-coupling installed the requisite arene at the C5 position in
66% yield (Scheme 2).7 Oxidative sulfone formation proceeded in
quantitative yield and enabled separation of the diastereomeric
mixture by silica gel chromatography. Sulfone displacement and
silyl ether cleavage then provided the C7 methyl derivative 13 in
15% overall yield from the commercially available tert-butyldi-
methylsiloxy-acetaldehyde.
The C8 methyl derivative was generated in a similar fashion
(Scheme 3). The addition of allylmagnesium bromide to imine 5
proceeded with excellent yield and selectivity. Subsequent trans-
formations generated enantiomerically pure 15 in excellent overall
yield (67% from 5). Treatment of 15 with [RhCl(coe)2]2 in the
presence of PCy3 and MgBr2 at 180 °C provided the bicyclic
imidazole core with 86:14 dr and enabled the isolation of 16 as a
single diastereomer in 52% yield with 92% ee (Scheme 3).5
Consistent with previous studies, olefin isomerization to the internal
disubstituted position occurs prior to annulation.5c Completion of
the synthesis was accomplished by bromination of 16, Stille cross-
Acknowledgment. This work was supported by NIH Grant
GM069559 to J.A.E. and by the Director and Office of Energy
Research, Office of Basic Energy Sciences, Chemical Sciences
Division, U.S. Department of Energy, under Contract DE-AC03-
76SF00098 to R.G.B. Support for M.Y. by Sankyo is also gratefully
acknowledged.
Supporting Information Available: Complete experimental details
and spectral data for all compounds described; complete ref 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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