Polarizability matters in enantio-selection.

The prevalence of chirality, or, handedness in biological world is a fundamental phenomenon and a characteristic hallmark of life. Thus, understanding the origin of enantio-selection, i.e., the sense and magnitude of asymmetric induction, has been a long-pursued goal in asymmetric catalysis. Herein, we demonstrated a polarizability-derived electronic effect that was shown to be capable of rationalizing a broad range of stereochemical observations made in the field of asymmetric catalysis. This effect provided a consistent enantio-control model for the prediction of major enantiomers formed in a ruthenium-catalyzed asymmetric transfer hydrogenations of ketones. Direct and quantitative linear free energy relationships between substrates' local polarizabilities and observed enantio-selectivity were also revealed in three widely known asymmetric catalytic systems covering both reductions and oxidations. This broadly applicable polarizability-based electronic effect, in conjunction with conventional wisdom mainly leveraging on steric effect considerations, should aid rational design of enantio-selective processes for better production of chiral substances.

Development of Highly Enantio- and Z-Selective Grubbs Catalysts via Controllable C-H Bond Activation.

Asymmetric olefin metathesis is a powerful strategy for stereocontrolled synthesis that allows the formation of chiral elements in conjunction with carbon-carbon double bonds. Here, we report a new series of cyclometalated stereogenic-at-Ru catalysts that enable highly efficient asymmetric ring opening/cross-metathesis (AROCM) and asymmetric ring-closing metathesis (ARCM) reactions. Single enantiomers of these catalysts with either right-handed or left-handed configurations at the Ru center can be easily accessed via highly stereoselective C-H bond activation-based cyclometalation. Right-handed chiral Ru catalysts enabled the Z- and enantioselective AROCM of a wide range of norbornenes and terminal alkenes, generating densely functionalized cyclopentanes with excellent stereo- and enantioselectivities (99:1 Z/E, up to 99% ee). Left-handed chiral Ru catalysts enabled the facile ARCM of sterically unhindered, all-terminal prochiral trienes, which had not been achieved by previous Ru catalysts, providing simple cyclic ethers and amides with tertiary or quaternary carbon stereocenters with excellent enantioselectivities (up to 99% ee).

Synthesis of Enantioenriched (Z)-Disubstituted Allylic Alcohols via Ru-Catalyzed Selective Dehydrogenation.

A highly efficient kinetic resolution of allylic alcohols with Z/E mixtures was achieved via Ru-catalyzed selective dehydrogenation. Not only allylic alcohols were obtained with pure Z-geometry, but the corresponding selectivity factors rank among the few highest for kinetic resolution reported in the literature.

Developing Ru-Catalysts for Asymmetric Transfer Hydrogenation of Acyclic Imines.

Asymmetric transfer hydrogenation (ATH) of acyclic imines has been rarely reported by using Ru-based catalysts. In this manuscript, employing Ru-catalysts with minimal stereogenicity in combination with formic acid/triethylamine as the hydrogen donor enables a highly efficient ATH of N-diphenylphosphinyl acyclic imines. These substrates that include various aryl alkyl and heteroaryl alkyl substituted imines were all compatible with this catalytic system, and the corresponding reduced amines were obtained with excellent enantiomeric excess (ee's) and yields.

Engineered non-covalent π interactions as key elements for chiral recognition.

Molecular recognition and self-assembly are often mediated by intermolecular forces involving aromatic π-systems. Despite the ubiquity of such interactions in biological systems and in the design of functional materials, the elusive nature of aromatic π interaction results in that they have been seldom used as a design element for promoting challenging chemical reactions. Described here is a well-engineered catalytic system into which non-covalent π interactions are directly incorporated. Enabled by a lone pair-π interaction and a π-π stacking interaction operating collectively, efficient chiral recognition is successfully achieved in the long-pursued dihydroxylation-based kinetic resolution. Density functional theory calculations shed light on the crucial role played by the lone pair-π interaction between the carbonyl oxygen of the cinchona alkaloid ligand and the electron-deficient phthalazine π moiety of the substrate in the stereoselectivity-determining transition states. This discovery serves as a proof-of-principle example showing how the weak non-covalent π interactions, if ingeniously designed, could be a powerful guide in attaining highly enantioselective catalysis.

Simultaneous Kinetic Resolution and Asymmetric Induction within a Borrowing Hydrogen Cascade Mediated by a Single Catalyst.

The mechanistic uniqueness and versatility of borrowing hydrogen catalysis provides an opportunity to investigate the controllability of a cascade reaction, and more importantly, to realize either one or both of chiral recognition and chiral induction simultaneously. Here we report that, in a borrowing hydrogen cascade starting from racemic allylic alcohols, one of the enantiomers could be kinetically resolved, while the other enantiomer could be purposely converted to various targeted products, including α,ß-unsaturated ketones, ß-functionalized ketones and γ-functionalized alcohols. By employing a robust Ru-catalyst, both kinetic resolution and asymmetric induction were achieved with remarkable levels of efficiency and enantioselectivity. Density functional theory (DFT) calculations suggest that corresponding catalyst-substrate π-π interactions are pivotal to realize the observed stereochemical diversity.

Highly Efficient Kinetic Resolution of Aryl-Alkenyl Alcohols by Ru-Catalyzed Hydrogen Transfer.

No matter through asymmetric reduction of ketones or kinetic resolution of secondary alcohols, enantioselective synthesis of the corresponding secondary alcohols is challenging when the two groups attached to the prochiral or chiral centers are spatially or electronically similar. For examples, dialkyl (sp3 vs. sp3), diaryl (sp2 vs. sp2), and aryl-alkenyl (sp2 vs. sp2) alcohols are difficult to produce with high enantioselectivities. By exploiting our recently developed Ru-catalysts of minimal stereogenicity, we reported herein a highly efficient kinetic resolution of aryl-alkenyl alcohols through hydrogen transfer. This method enabled such versatile chiral building blocks for organic synthesis as allylic alcohols, to be readily accessed with excellent enantiomeric excesses at practically useful conversions.

Development of highly efficient platinum catalysts for hydroalkoxylation and hydroamination of unactivated alkenes.

Hydrofunctionalization, the direct addition of an X-H (e.g., X=O, N) bond across an alkene, is a desirable strategy to make heterocycles that are important structural components of naturally occurring molecules. Described here is the design and discovery of "donor-acceptor"-type platinum catalysts that are highly effective in both hydroalkoxylation and hydroamination of unactivated alkenes over a broad range of substrates under mild conditions. A number of alkene substitution patterns are accommodated, including tri-substituted, 1,1-disubstituted, (E)-disubstituted, (Z)-disubstituted and even mono-substituted double bonds. Detailed mechanistic investigations suggest a plausible pathway that includes an unexpected dissociation/re-association of the electron-deficient ligand to form an alkene-bound "donor-acceptor"-type intermediate. These mechanistic studies help understand the origins of the high reactivity exhibited by the catalytic system, and provide a foundation for the rational design of chiral catalysts towards asymmetric hydrofunctionalization reactions.

Asymmetric Transfer Hydrogenation of Densely Functionalized Diheteroaryl and Diaryl Ketones by a Ru-Catalyst of Minimal Stereogenicity.

A highly enantioselective asymmetric transfer hydrogenation (ATH) of densely functionalized diheteroaryl and diaryl ketones was developed using Ru-catalysts of minimal stereogenicity. Various ketone substrates with structurally and electronically similar groups attached to the prochiral centers were reduced successfully in good to excellent enantioselectivities and yields. This protocol provides practical and efficient access to chiral diheteroarylmethanols and benzhydrols, which are key intermediates in pharmaceuticals and biologically active compounds.

Asymmetric Synthesis of γ-Secondary Amino Alcohols via a Borrowing-Hydrogen Cascade.

The borrowing-hydrogen (or hydrogen autotransfer) process, where the catalyst dehydrogenates a substrate and formally transfers the H atom to an unsaturated intermediate, is an atom-efficient and environmentally benign transformation. Described here is an example of an asymmetric borrowing-hydrogen cascade for the formal anti-Markovnikov hydroamination of allyl alcohols to synthesize optically enriched γ-secondary amino alcohols. By exploiting the Ru-(S)-iPrPyme catalyst with minimal stereogenicity, a cascade process including dehydrogenation, conjugate addition, and asymmetric reduction was developed. The mild conditions, functional group tolerance, and broad substrate scope (54 examples) demonstrate the synthetic practicality of the catalytic system.

Highly Active Platinum Catalysts for Nitrile and Cyanohydrin Hydration: Catalyst Design and Ligand Screening via High-Throughput Techniques.

Nitrile hydration provides access to amides that are indispensable to researchers in chemical and pharmaceutical industries. Prohibiting the use of this venerable reaction, however, are (1) the dearth of biphasic catalysts that can effectively hydrate nitriles at ambient temperatures with high turnover numbers and (2) the unsolved challenge of hydrating cyanohydrins. Herein, we report the design of new " donor-acceptor"-type platinum catalysts by precisely arranging electron-rich and electron-deficient ligands trans to one other, thereby enhancing both the nucleophilicity of the hydroxyl group and the electrophilicity of the nitrile group. Leveraging a high-throughput, automated workflow and evaluating a library of bidentate ligands, we have discovered that commercially available, inexpensive DPPF [1,1'-ferrocenendiyl-bis(diphenylphosphine)] provides superior reactivity. The corresponding " donor-acceptor"-type catalyst 2a is readily prepared from (DPPF)PtCl2, PMe2OH, and AgOTf. The enhanced activity of 2a permits the hydration of a wide range of nitriles and cyanohydrins to proceed at 40 °C with excellent turnover numbers. Rational reevaluation of the ligand structure has led to the discovery of modified catalyst 2c, harboring the more electron-rich 1,1'-bis[bis(5-methyl-2-furanyl)phosphino] ferrocene ligand, which demonstrates the highest activity toward hydration of nitriles and cyanohydrins at room temperature. Finally, the correlation between the electron-donating ability of the phosphine ligands with catalyst efficiencies of 2a, 2c, 2d, and 2e in the hydration of nitrile 7 are examined, and the results support the " donor-acceptor" hypothesis.

Palladium(II)-catalyzed allylic C-H oxidation of hindered substrates featuring tunable selectivity over extent of oxidation.

The use of Oxone and a palladium(II) catalyst enables the efficient allylic CH oxidation of sterically hindered α-quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for CH activation allows for unusual tunable selectivity between a two-electron oxidation to the allylic acetates and a four-electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated.

N,N-Dimethylaminobenzoates enable highly enantioselective Sharpless dihydroxylations of 1,1-disubstituted alkenes.

A design scenario aimed at exploring beneficial catalyst-substrate π-π stacking electronic interactions in the classical Sharpless asymmetric dihydroxylations (SAD) leads to the identification of highly polarizable allylic N,N-dimethylaminobenzoate as a remarkably efficient auxiliary for inducing high levels of enantioselectivities (up to 99% ee) in the traditionally challenging substrate class of 1,1-disubstituted aliphatic alkenes.

Ag-carbenoid-initiated catalytic hydration cascades: rapid construction of functionalized bicyclo[3.3.1]nonanes.

Remarkable Ag-carbenoid-initiated enone cyclopropanation-hydrolytic fragmentation-competitive 1,2-vs-1,4 addition reaction cascades were uncovered on a range of propargylic esters tethered to cyclohexadienones, leading to the highly efficient and stereospecific construction of densely functionalized bicyclo[3.3.1]nonanes under mild conditions.

Total synthesis and biological evaluation of grassypeptolide†A.

Herein, we describe in full our investigations into the synthesis of grassypeptolide A (1) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late-stage introduction of sensitive bis(thiazoline) heterocycles and 31-membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose-dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP-ribose) polymerase (PARP) and decreased expression of bcl-2 and bcl-xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21.

Total synthesis of grassypeptolide.

The first total synthesis of grassypeptolide, an anticancer cyclodepsipeptide isolated from marine cyanobacteria, has been achieved in 17 steps and an overall 11.3% yield.