This more efficacious addition reaction of aryl nitromethanes to aryl Boc-imines using MAM catalysts has been optimized and applied to the work presented herein, ultimately achieving high enantioselection in the assembly of various masked cis-stilbene diamines.
Superior levels of stereocontrol (up to 99% ee and 200:1 dr) were shown with a host of stereoelectronically-diverse aryl nitromethanes and aryl Boc-imines, thanks to increased tolerance from two novel MAM catalysts. Additionally, this chemistry has allowed for the synthesis of identical, nonsymmetric (4S,5R)-cis-imidazoline analogues from constitutionally
57 Unpublished data courtesy of Kip Guy, Jaeki Min, and Kristin Finch; St. Jude Children’s Research Hospital.
58 Tentative patent titling: “MDMX-p53 cis-imidazoline Inhibitors” Mayasundari, A.; Min, J.K.; Vara, B.A.;
Johnston, J.N.; Guy, R.K. et al. Provisional U.S. Patent Filed 2014
59 For the full report on these compounds prepared by ourselves and collaborators at St. Jude see: Vara, B. A.;
Mayasundari, A.; Tellis, J. C.; Danneman, M. W.; Arredondo, V.; Davis, T. A.; Min, J.; Finch, K.; Guy, R. K.;
Johnston, J. N. J. Org. Chem. 2014, 79, 6913.
isomeric aza-Henry adducts – a phenomenon inherent to masked cis-stilbene diamines. As was exemplified, this chemistry has proven to be robust, scalable, and flexible as applied to the synthesis of more than ten novel, unsymmetric (4S,5R)-Nutlin-3 derivatives. Of these Nutlin derivatives in Chart 2, four proved more efficacious towards the inhibition of MDMX-p53 protein-protein interactions
Many new opportunities in MDM2/MDMX-p53 PPI have been unlocked as a result of our collaboration with Kip Guy and St. Jude collaboration. As is now evident, the chemistry to generate nonsymmetric cis-imidazoline (Nutlin) derivatives via the aza-Henry reaction is truly valuable and additional analogues can be easily examined in the future. At the time this
document was compiled, St. Jude had taken over the medicinal chemistry focus of the project.
The synthesis of a vast library of enantioenriched Nutlin analogues has been prepared using the asymmetric methods developed herein. To our knowledge, a number of lead compounds inhibiting MDMX-p53 have undergone thorough preclinical testing (efficacy, DMPK, animal models, etc.) and may soon be ready for more expansive in vivo testing. For these late stage preclinical trials, potentially tens of grams (or more) of compound may be needed. We hope to have a patent issued on these molecules soon and data to be released in the coming years.
An attractive area to next explore with this chemistry is the synthesis of other, stereochemically-rich MDM2-p53 inhibitors. Upon inspection of Roche’s clinical trial candidate, RG7112, the basic chiral cis-imidazoline scaffold (highlighted in maroon, Scheme 22) is
Scheme 21. New enantioselective methods have driven the development of novel Nutlin derivatives.
novel enantioselective
methods
enantioenriched Nutlin library
lead compound
scale up target
identification
clinical development
analogous to Nutlin-3 and our aza-Henry chemistry may be useful. The reaction needed to be developed would be between two very hindered components, a 2º aryl nitromethanes and an aryl Boc-ketimine. This system has been briefly explored in the group but yielded little promising results, and may require the development of new catalysts to increase reactivity and modulate stereoselectivity in the future. The overarching challenge here of course is setting two adjacent quaternary centers in a highly stereoselective manner.
A small sampling of current, potent MDM2-p53 inhibitors are depicted in Figure 19. As pictured many of the more potent MDM2-p53 inhibitors can be broken down to arrive at a chiral amine intermediate, potentially accessible from aza-Henry -type reactions. True to the class, all molecules contain halogenated arenes strategically positioned to fit the same hydrophobic binding pocket that the Nutlin p-chloro arenes target. This is a truncated list of compounds60 but many small molecules in the field display similar structural design.
60 For a recent review and extensive list of MDM2-p53 inhibitors see the following: Popowicz, G. M.; Domling, A.;
Holak, T. A. Angew. Chem. Int. Ed. 2011, 50, 2680. Millard, M.; Pathania, D.; Grande, F.; Xu, S. L.; Neamati, N.
Curr. Pharm. Design 2011, 17, 536. Rew, Y.; Sun, D. Q.; De Turiso, F. G. L.; Bartberger, M. D.; Beck, H. P.;
Canon, J.; Chen, A.; Chow, D.; Deignan, J.; Fox, B. M.; Gustin, D.; Huang, X.; Jiang, M.; Jiao, X. Y.; Jin, L. X.;
Kayser, F.; Kopecky, D. J.; Li, Y. H.; Lo, M. C.; Long, A. M.; Michelsen, K.; Oliner, J. D.; Osgood, T.; Ragains, M.; Saiki, A. Y.; Schneider, S.; Toteva, M.; Yakowec, P.; Yan, X. L.; Ye, Q. P.; Yu, D. Y.; Zhao, X. N.; Zhou, J.;
Medina, J. C.; Olson, S. H. J. Med. Chem. 2012, 55, 4936. Lucas, B. S.; Fisher, B.; McGee, L. R.; Olson, S. H.;
Medina, J. C.; Cheung, E. J. Am. Chem. Soc. 2012, 134, 12855.
Scheme 22. Retrosynthetic breakdown of RG7112 using the BAM/MAM-catalyzed asymmetric nitro-Mannich reaction.
N N
O N N
EtO
tBu
Cl
Cl
Me
Me
S Me
O O
RG7112 (Hoffmann-La Roche)
NO2
HN Cl
Cl
Me
Me Boc
Me NO2
Me N
Cl chiral BAM Cl
or MAM
catalyst Boc
In the immediate future we plan on opening up new and finishing current collaborations using these novel small molecules. With improved catalysts in hand, we may also examine scaling up the synthesis of (–)-Nutlin-3 or a new derivative for use in in vivo studies. Dual MDM2-p53 and MDMX-p53 inhibition may be a promising therapeutic strategy in the near future, and this developed chemistry may prove very impactful.
Figure 19. Recent potent and selective MDM2-p53 small molecule inhibitors to hit the clinic. All contain halogenated arenes and at least 2 stereocentrers. RG7112 is the most advanced molecule in clinical trials.
Me N
HO Me O
OH O Me
Cl
AM-8553 Cl
N N
Cl Cl
F
Me S Me Me
O
O N
NH F
Daiichi Sankyo IC50 = 1.1± 0.5 nM IC50 = 1.2 nM
NH
NH O HN
OH
tBu
O
Cl Cl F
Wang - Michigan Ki = 0.6 nM
Rew et al.
J. Med. Chem. 2012, 55, 4936
Uoto et al.
WO 2009/151069, 2009
Yu et al.
J. Med. Chem. 2009, 52, 7970
N N
O N N
EtO
tBu
Cl
Cl
Me
Me
S Me
O O
Hoffmann-La Roche RG7112 Ki = 18 nM
Vu et al.
Med. Chem. Lett. 2013, 4, 466 HO
Chapter II