Ligand differentiated complementary Rh-catalyst systems for the enantioselective desymmetrization of meso-cyclic anhydrides
Graphical abstract
Introduction
The formation of carbon–carbon bonds through transition metal-catalyzed cross-coupling methodology continues to revolutionize the synthesis of complex organic molecules.1 New combinations of electrophilic and nucleophilic coupling partners present myriad options for bond construction, and mild conditions are tolerant of a wide range of functional groups. Despite the constant advances in this area, significant challenges remain, including the selective construction and definition of stereocenters and the use of sp3 hybridized coupling partners.2, 2(a), 2(b), 2(c)
Although activated acyl species have long been utilized in the formation of ketones,3, 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i) only recently has the use of carboxylic acid anhydrides as acylating agents been investigated in metal mediated reactions.4, 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i) While the process of acylation does not in itself result in the construction of a stereogenic center, acylation utilizing a prochiral anhydride results in desymmetrization and definition of backbone stereocenters. While there are several reports of such efforts with heteroatom nucleophiles,5, 5(a), 5(b), 5(c), 5(d), 5(e) the use of carbon-based nucleophiles in similar efforts is quite limited.6
The power of this methodology lies in the use of organozinc reagents to transform substituted meso-cyclic anhydrides into enantioenriched ketoacid derivatives with stereodefined backbones. Our group has focused on the transition metal-catalyzed desymmetrization of meso-cyclic anhydrides with organozinc nucleophiles. Early efforts with nickel-catalyzed reactions were quite promising, although the development of an enantioselective reaction remained elusive.7, 7(a), 7(b), 7(c), 7(d), 7(e), 7(f), 7(g) More recently, the enantioselective desymmetrization of succinic anhydrides became a reality with the development of a Pd(OAc)2 and Josiphos (1) catalyst system.8 Reaction of meso-cyclic succinic anhydrides with Ph2Zn provides the corresponding ketoacids in excellent yields with enantioselectivities typically above 92% (Scheme 1). Despite this success, efforts to extend this methodology were problematic. Reactions with glutaric anhydrides and dialkylzinc reagents are largely ineffective, and in situ prepared organozinc nucleophiles are incompatible with the palladium-catalyzed methodology, an issue not uncommon in asymmetric catalysis with organozinc reagents.9
In efforts to develop methodology to expand the utility of the enantioselective desymmetrization of cyclic anhydrides, we turned to the use of rhodium. These catalysts promise to be less susceptible to complications from in situ prepared nucleophiles, specifically the presence of halides, as rhodium complexes have demonstrated tolerance to Lewis bases in asymmetric conjugate addition reactions run in water.10 Furthermore, employment of the Rh(I)/Rh(III) redox couple presents the possibility of a mechanism distinct of that observed in the Ni(0)/Ni(II) and Pd(0)/Pd(II) systems. The use of a new metal also provides the opportunity to introduce ligand scaffolds that are ineffective with earlier systems. Herein we describe the development of two complementary Rh-catalyzed systems, utilizing phosphinooxazoline (PHOX) and phosphoramidite ligands, for the enantioselective desymmetrization of succinic and glutaric anhydrides with sp2- and sp3-hybridized in situ prepared nucleophiles.11, 11(a), 11(b)
Section snippets
Rh/tBu-PHOX catalyst system
Early studies into the enantioselective desymmetrization of meso-3,5-dimethylglutaric anhydride 3 focused on the use of dialkylzinc reagents, with the intent of generating syn-deoxypolypropionate synthons, a motif common in natural products. While nickel and palladium catalysts were generally ineffective for the addition of alkyl nucleophiles to glutaric anhydrides, initial success was uncovered with a rhodium(I) catalyst, with bidentate phosphine–nitrogen ligands such as tert
Conclusion
Herein we have described the development and optimization of complementary rhodium-catalyzed reaction manifolds for the enantioselective desymmetrization of meso-cyclic anhydrides. Advances in reaction methodology now allow the general use of glutaric and succinic anhydrides, in situ prepared nucleophiles, and both sp3- and sp2-hybridized organozinc nucleophiles for the formation of ketoacids with multiple stereocenters in high yields and enantioselectivities.
General
All reactions were carried out under an atmosphere of argon in oven-dried glassware with magnetic stirring. Tetrahydrofuran (THF) and dimethylformamide (DMF) were purged with argon and passed through two columns of neutral alumina. Column chromatography was performed using EM Science silica gel 60 (230–400 mesh). Thin layer chromatography was performed using EM Science 0.25 mm silca gel 60-F plates. Visualization was accomplished with UV light, KMnO4, aqueous ceric ammonium molybdate, or
Acknowledgements
Thanks to David Rubush for his invaluable assistance in preparing this manuscript. J.B.J. thanks the National Institute of Health for a postdoctoral fellowship. M.J.C. thanks the American Heart Association for a postdoctoral fellowship. T.R. thanks Johnson and Johnson, Merck, Eli, Lilly and Boehringer-Ingelheim for support. T.R. is a fellow of the A.P. Sloan Foundation and thanks the Monfort Family Foundation for a Monfort Professorship.
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Present address: Department of Chemistry, Hope College, Holland, MI 49423, United States.
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Present address: Chemistry Department, Imperial College, London SW7 2AZ, England.