Cinchonine-derived catalysts and methods of using same

#Umpolung, or polarity inversion, in organic chemistry refers to the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible under its standard polarity, and thus allows for the development of new reactions of distinct bond connections.

#A classic example of the umpolung reaction is the cyanide-catalyzed condensation of two aromatic aldehydes to provide a benzoin derivative. The successful development of numerous C—C bond-forming umpolung reactions with carbonyls as acyl anion equivalents has greatly expanded the repertoire of organic synthesis. The power of carbonyl umpolung reactions has been tapped for asymmetric synthesis through the successful development of efficient chiral catalysts for enantioselective Stetter reactions (which are 1,4-additions of an aldehyde to an α,β-unsaturated compound, catalyzed by cyanide or a thiazolium salt) and other asymmetric reactions. In contrast, C—C bond-forming umpolung reactions of imines are rarely reported.

#There is a need in the art to identify novel catalysts that can be used to promote asymmetric umpolung reactions. The present invention meets this need.

#The following detailed description of exemplary embodiments of the invention can be better understood when read in conjunction with the appended drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

#FIG. 1 is a schematic illustration of a non-limiting design of a catalytic C—C bond-forming an umpolung reaction of imines.

#FIG. 2 is a set of reactions and table illustrating results from studies with chiral base catalysts. Conditions: room temperature (RT), 10 mol % catalyst, 16 hours.

#The present invention relates to the unexpected discovery of phase-transfer catalysts that can be used to promote carbon-carbon formation using 2-azaallyl anions. Such reactions proceed in a highly chemoselective, regioselective and enantioselective manner. In certain embodiments, the catalysts of the present invention allow for the asymmetric preparation of chiral amines. The present invention further comprises compositions comprising one or more of the catalysts contemplated within the invention, and methods of preparing certain organic compounds using catalysts of the present invention.

#The present disclosure describes the discovery and development of chiral phase-transfer catalysts that promote the highly efficient asymmetric umpolung reactions of imines with the carbon electrophile enals. These catalysts mediate the deprotonation of imines and direct the 2-azaallyl anions thus formed to react with enals in a highly chemoselective, regioselective, diastereoselective and enantioselective fashion. The reaction tolerates a broad range of imines and enals, and can be carried out in high yield with as little as about 0.01 mole percent catalyst with a moisture- and air-tolerant operational protocol. These umpolung reactions provide a practical and efficient approach to chiral amino compounds.

#Modified cinchona alkaloids such as the quinine-derived (Q) catalyst Q-2 can promote highly enantioselective isomerization of trifluoromethyl imines such as 1 (FIG. 1). Without wishing to be limited by any theory, this reaction may proceed through the initial formation of the 2-azaallyl anion 3, and then a highly enantioselective protonation of 3. If the 2-azaallyl anion 3 reacts with carbon electrophiles in a stereoselective manner, novel CC bond-forming asymmetric reactions transforming imines 1 into enantio-enriched amines may be realized (FIG. 1).