Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7.

CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.

Catalytic asymmetric C-N bond formation: phosphine-catalyzed intra- and intermolecular γ-addition of nitrogen nucleophiles to allenoates and alkynoates.

Pin the amine on the gamma: A new method has been developed for the γ-addition of nitrogen nucleophiles to γ-substituted alkynoates or allenoates through intra- and intermolecular processes that are catalyzed by spirophosphine 1. An asymmetric version of this reaction affords enantioenriched pyrrolidines, indolines, and γ-amino-α,ß-unsaturated carbonyl compounds.

New directing groups for metal-catalyzed asymmetric carbon-carbon bond-forming processes: stereoconvergent alkyl-alkyl Suzuki cross-couplings of unactivated electrophiles.

The ability of two common protected forms of amines (carbamates and sulfonamides) to serve as directing groups in Ni-catalyzed Suzuki reactions has been exploited in the development of catalytic asymmetric methods for cross-coupling unactivated alkyl electrophiles. Racemic secondary bromides and chlorides undergo C-C bond formation in a stereoconvergent process in good ee at room temperature in the presence of a commercially available Ni complex and chiral ligand. Structure-enantioselectivity studies designed to elucidate the site of binding to Ni (the oxygen of the carbamate and of the sulfonamide) led to the discovery that sulfones also serve as useful directing groups for asymmetric Suzuki cross-couplings of racemic alkyl halides. To our knowledge, this investigation provides the first examples of the use of sulfonamides or sulfones as effective directing groups in metal-catalyzed asymmetric C-C bond-forming reactions. A mechanistic study established that transmetalation occurs with retention of stereochemistry and that the resulting Ni-C bond does not undergo homolysis in subsequent stages of the catalytic cycle.

Stereoconvergent amine-directed alkyl-alkyl Suzuki reactions of unactivated secondary alkyl chlorides.

A new family of stereoconvergent cross-couplings of unactivated secondary alkyl electrophiles has been developed, specifically, arylamine-directed alkyl-alkyl Suzuki reactions. This represents the first such investigation to be focused on the use of alkyl chlorides as substrates. Structure-enantioselectivity studies are consistent with the nitrogen, not the aromatic ring, serving as the primary site of coordination of the arylamine to the catalyst. The rate law for this asymmetric cross-coupling is compatible with transmetalation being the turnover-limiting step of the catalytic cycle.

Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via conjugate addition to alkylidene and indenylidene Meldrum's acids.

A systematic study outlining the enantioselective 1,4-addition of dialkylzinc reagents to 5-(1-arylalkylidene) and indenylidene Meldrum's acids is presented. Variation of the aryl and alkyl groups present on the alkylidene was thoroughly explored. The 1,4-addition displayed compatibility with a wide range of heteroaromatics and functional groups, and the arene pattern of substitution affected enantioselection, with a para-substituted aryl group consistently leading to high enantioselectivities. The nature of the organozinc reagent on the efficiency and selectivity of the conjugate addition was also investigated. The solid-state conformation was determined for a number of alkylidene Meldrum's acids and correlated with the observed enantioselectivity in relation to the arene pattern of substitution.

Hydrogenolysis of unstrained carbon-carbon sigma bonds: stereoselective entry into benzylic tertiary centers.

The modification of sp(3)-hybridized carbon centers through Pd-catalyzed reductive cleavage of unstrained carbon-carbon sigma bonds is described. From the hydrogenolysis of benzyl Meldrum's acids bearing an all-carbon benzylic quaternary center, Meldrum's acid and aromatics substituted with a tertiary benzylic stereocenter were obtained in good to excellent yields. Mechanistic studies showed that the reductive cleavage of enantioenriched benzylic quaternary centers proceeded with inversion of configuration, supporting a "loose" S(N)2 pathway.

Probing persistent intramolecular C-H...X (X = O, S, Br, Cl, and F) bonding in solution using benzyl Meldrum's acid derivatives.

Persistent intramolecular interactions between acidic C-H hydrogens and a variety of acceptors (X) (X = O, S, Br, Cl, and F) in solution were probed by (1)H NMR experiments, using 5-benzyl Meldrum's acid derivatives. To bring about formation of intramolecular C-H...X bonding, ortho-substituted benzyl Meldrum's acids were designed, for which hydrogen bonding occurred through a six-membered ring. Introduction of substituents on the aromatic moiety and in the tether allowed variation of electronic and steric factors. The superior acidity of Meldrum's acids impacted the ability of the C-H hydrogen to engage in nonclassical C-H...X bonds and drove the conformational properties of benzyl Meldrum's acid, in combination with steric factors, namely A(1,3)-allylic strain. Further understanding of intramolecular C-H...X bonds was gained by characterization of benzyl Meldrum's acids in the solid state, by X-ray analysis, and by the conformation correlated to the observations made in solution.

Asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center through Cu-catalyzed 1,4-addition of dialkylzinc reagents to 2-aryl acetate derivatives.

The asymmetric synthesis of carboxylic acid derivatives having an all-carbon alpha-quaternary center has been achieved via copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives in the presence of phosphoramidite ligand. High isolated yields and enantioselectivities were obtained. It was demonstrated that the Meldrum's acid and ester moieties present on the all-carbon quaternary center allow for a wide variety of subsequent transformations, leading to the expedient preparation of succinimides, succinate esters and succinic acids, gamma-butyrolactones, and beta-amino acid derivatives.

Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via Cu-catalyzed conjugate addition of dialkylzinc reagents to 5-(1-arylalkylidene) Meldrum's acids.

The asymmetric synthesis of all-carbon benzylic quaternary stereocenters has been successfully achieved through copper-catalyzed addition of dialkylzinc reagents to 5-(1-arylalkylidene) and 5-(dihydroindenylidene) Meldrum's acids in the presence of phosphoramidite ligand. The resulting benzyl-substituted Meldrum's acids and 1,1-disubstituted indanes were obtained in good yields and up to 99% ee. The significance of substituting the position para, meta, and ortho to the electrophilic benzylic center was highlighted. A benzyl Meldrum's acid product was further transformed to a 3,3-disubstituted 1-indanone and a beta,beta-disubstituted pentanoic acid.

Meldrum's acids as acylating agents in the catalytic intramolecular Friedel-Crafts reaction.

[reaction: see text] The intramolecular Friedel-Crafts acylation of aromatics with Meldrum's acid derivatives catalyzed by metal trifluoromethanesulfonates is reported. Meldrum's acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, while accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum's acids) and 5-benzyl-5-substituted Meldrum's acids (quaternized Meldrum's acids), forming 1-indanones and 2-substituted-1-indanones, respectively, are delineated. This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments: 1-tetralones form faster than both 1-indanones and 1-benzosuberones, and 1-benzosuberones cyclize faster than 1-indanones.

Potential energy surfaces for gas-phase SN2 reactions involving nitriles and substituted nitriles.

The stationary points on the potential energy surfaces for a number of gas-phase S(N)2 reactions have been determined using a combination of pulsed ionization high-pressure mass spectrometry. MP2/6-311++G**//B3LYP/6-311+G** calculations are shown to provide excellent agreement with the experimentally determined values, providing confidence for the use of this computational method to predict values that are not available experimentally. The binding in the halide/nitrile complexes has been described in the past as either hydrogen bonding or electrostatic bonding. The trends in the binding energies observed here, though, cannot be rationalized in terms of simply hydrogen bonding or ion-dipole bonding but a mixture of the two. The computed structures support the description of binding as a mixture of hydrogen bonding and ion-dipole bonding.