Developing a Practical Chiral Toolbox for
Asymmetric Catalytic Reactions
Molecular chirality plays a very important role in science and technology. Chiral molecules may exist in either "left-handed" or "right-handed" form depending on the absolute configuration of the molecule. The biological activities of many pharmaceuticals are often associated with their absolute molecular configuration. While one "handed" pharmaceutical (enantiomer) gives a desired biological function through interactions with natural binding sites, the other enantiomer usually does not have the same function and often has deleterious side effects. A growing demand in pharmaceutical industries is to make a chiral drug in enantiomerically pure form (> $ 147 billion of chiral drug market).
During the last three decades, chemists have made major progress in discovering man-made catalysts to perform this challenging task: asymmetric catalysis. Nobel Prize in chemistry was awarded in this exciting area to Dr. Knowles, Professors Noyori and Sharpless in 2001. The research in my group addresses fundamental and practical problems in this field by developing a diverse set of chiral ligands (a chiral toolbox approach) that combine with transition metals to form effective catalysts and inventing new metal-catalyzed reactions. Our technology has been licensed to DSM and Chiral Quest for the synthesis of chiral molecules in a highly efficient, cost-effective and environmentally compliant way. Selected chiral ligands developed by us are PennPhos, BICP, Ambox, TunaPhos, PN, DIOP*, KetalPhos, f-KetalPhos, HydroPhos, f-HydroPhos, Binaphane, f-Binaphane, SK-Phos, o-BINAP, o-BIPHEP, FAP, TangPhos and Binaphine. The common features of these novel ligands are that they are conformationally rigid, their steric and electronic properties can be tuned, and they can be prepared from readily available materials. Majority of these ligands are commercially available to pharma and fine chemical companies. We have also explored new metal-catalyzed reactions such as Rh-catalyzed asymmetric ene reaction, Ag-catalyzed [3+2] asymmetric cycloaddition and Pd-catalyzed C-C coupling reactions.
In the first few years of my tenure at Penn State, we have developed a useful set of chiral ligands for asymmetric catalysis (e.g., PennPhos, BICP and Ambox). We have used these catalysts for a highly effective Rh-based hydrogenation of dehydroamino acids (JACS, 1997, 119, 3836). Moreover we has developed a unique asymmetric [3+2] cycloaddition reaction for the synthesis of chiral cyclopentenes using chiral phosphabicylo[2.2.1]heptanes as catalysts (JACS. 1997, 119, 3836) and reported the first asymmetric phosphine-catalyzed nucleophilic g-addition to acetylenes bearing electron-withdrawing groups (JOC,1998, 63, 5631). We also discovered a highly enantioselective Ru-catalyzed transfer hydrogenation catalyst for aromatic ketones (JACS, 1998, 120, 3817); and a breakthrough in base-facilitated Rh-catalyzed hydrogenation of simple ketones, which leads to a highly enantioselective hydrogenation catalyst for both aryl alkyl and dialkyl ketones (ACIEE, 1998, 37, 1100). We have developed a highly enantioselective Rh-based hydrogenation catalyst for E and Z mixtures of enamides (JOC, 1998, 63, 9590) and practical synthesis of chiral amino alcohols from a-hydroxy ketones using a Rh-catalyzed hydrogenation strategy (JOC, 1998, 63, 8100). We have observed high enantioselectivities in Rh-catalyzed hydrogenation of cyclic enamides (JOC. 1999, 64, 1774) and cyclic enol acetates (ACIEE, 1999, 38, 516). We have achieved high enantioselectivity in Rh-catalyzed hydrogenation of 3-aminoacrylic acid derivatives for the practical synthesis of chiral b-aminoacids (JOC, 1999, 64, 6907). We have accomplished highly enantioselective Pd-catalyzed asymmetric cyclocarbonylation of allylic alcohols to g-butyrolactones (up to 97 % ee) (JACS, 1999, 120, 3817) and has made major progress toward Rh-catalyzed [4+2] asymmetric cycloisomerization reactions (up to 99 %ee).
During the last few years, we have accelerated our effort in developing innovative chiral ligands and new reactions. While we have already invented three chiral ligands (PennPhos, BICP and Ambox), our group has developed fourteen new ligands (e. g., Binaphane, ketalPhos, P, N ligands, TunaPhos, DIOP*, FAP and TangPhos). These effective ligands further broaden the scope of many asymmetric reactions and will have many practical applications. The new P, N ligand was used for asymmetric Michael additions of acyclic enones and gave high enantioselectivities (ACIEE, 1999, 38, 3518). Chelating hydroxyl phospholanes (HydroPhos) or DIOP* were prepared from a cheap starting materials (D-mannitol) and these ligands show excellent properties for reduction of enamides (JOC, 2000, 65, 5871). A Rh-binaphane catalyst is highly efficient for hydrogenation of simple enamides (OL, 1999, 1, 1679). In a related study, a Rh-f-binaphane complex is invented as one of the most effective catalysts for hydrogenation of imines (ACIEE, 2001, 40, 3425). Furthermore, Ru-ambox complexes have been developed as effective direct hydrogenation catalysts for reduction of simple ketones and high enantioselectivities have been achieved. A Ru-TunaPhos complex is an excellent catalyst for asymmetric hydrogenation of b-keto esters (JOC, 2000, 65, 6223). Unprecedented highly efficient kinetic resolution (S > 60) has been achieved in a Pd-catalyzed asymmetric allylic alkylation reaction with a FAP ligand (TL, 2000, 41, 5435). Highly diastereoselective and enantioselective cyclopropronation have been achieved with a new Ru catalyst (TL, 2002, 43, 3075). Recently, we have invented o-BINAPO and o-BIPHEP ligands for Ru-catalyzed highly enantioselective hydrogenation of enamides to make b-amino acids (JACS, 2002, 124, 4952) and Rh-catalyzed hydrogenation of cyclic enamides (OL, 2002, 41, 1695). One of the most active Rh-catalysts for hydrogenation of alkenes (up to 10,000 turnovers) has been discovered using the Rh-TangPhos compound (ACIEE, 2002, 41, 1612). The TangPhos can be prepared from PCl3 through three operations and is like to be practical. High enantioselectivities (up to 99.9% ee) have been achieved for hydrogenation of enamides to make chiral amines, a and b-amino acids (OL, 2002, 4, 4159). Finally, simple C2 symmetric chiral phosphines derived from tartrates and D-mannitol are effective for asymmetric hydrogenation (JOC, 2002, 67, 7618).
Developing new transition metal-catalyzed reactions are important missions in organic synthesis. We have found the first Rh-catalyzed enyne isomerization to offer 1,4-dienes exclusively under a mild condition and the first highly enantioselective ene reaction was achieved by us (JACS, 2000, 122, 6490; ACIEE. 2000, 39, 4104). Recently, we have developed second generation of the Rh ene reaction and high enantioselectivities (>99% ee) have been achieved in forming many chiral g-lactones (JACS, 2002, 124, 8198). In a similar manner, a variety of chiral tetrahydrofurans (ACIEE, 2002, 124, 13400), lactams (ACIEE, 2002, 41, 4526) (pyrrolidines, cyclopentanes and cyclopentanones have been formed in over 99% ee with 1000 turnovers. To demonstrate the synthetic utilities of this methodology, (+)-pilocarpine, (+)-pilosine, (+)-kainic acid, jasmonic acid and isocynometrineare are synthesized. A new phospholane-oxozaline ligand is used for hydrogenation of simple alkenes (ACIEE, 2003, 42, 943).
In the area of metal-catalyzed cyclization, we have invented the first highly enantioselective Ag-catalyzed [3+2] cycloaddition for the synthesis of five-membered ring N-containing hetereocyclics. These hetereocyclics can be easily prepared from ready available aldehydes, aminoesters and dipolarphiles. Four stereogenic centers and up to 97% ee have been achieved in this multicomponent coupling reaction (JACS, 2002, 45, 13400). Recently, we have discovered a new metal-catalyzed C-C bond coupling reaction with a goal to tolerate b-hydrogens in both parts of sp3-sp3 C-C bond, which is an extremely challenging problem in organic synthesis. The double transmetallation of RMX with PdX(enolate) is the key step for the new metal-catalyzed reaction. This research has resulted in several publications: coupling reaction for the preparation of biaryls (TL, 2002, 43, 2525), diynes (JOC, 2002, 67, 4952), sp3-sp3 C-C coupling reaction (OL, 2002, 4, 2285). We believe that this research will have a significant impact in metal-catalyzed C-C bond forming field. For example, we have achieved >99% in coupling of all types of diynes and have used this method to prepare polyynes.