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.
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.
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.
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 β,β-disubstituted pentanoic acid.
The asymmetric synthesis of tertiary and quaternary stereocentres has been successfully achieved through Cu-catalyzed 1,6-addition of dialkylzinc reagents to 5-(3-aryl-2-propenylidene) Meldrum’s acid ...derivatives in the presence of a phosphoramidite ligand.
The asymmetric synthesis of carboxylic acid derivatives having an all-carbon α-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, γ-butyrolactones, and β-amino acid derivatives.
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 (see scheme). An asymmetric version of this reaction affords enantioenriched pyrrolidines, indolines, and γ‐amino‐α,β‐unsaturated carbonyl compounds.
The modification of sp3-hybridized carbon centers through Pd-catalyzed reductive cleavage of unstrained carbon−carbon σ 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” SN2 pathway.
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.
The modification of benzylic quaternary, tertiary, and secondary carbon centers through palladium‐catalyzed hydrogenolysis of C(sp3)–C(sp3) σ bonds is presented. When benzyl Meldrum's acid ...derivatives bearing quaternary benzylic centers are treated under mild hydrogenolysis conditions – palladium on carbon and atmospheric pressure of hydrogen – aromatics substituted with tertiary benzylic centers and Meldrum's acid are obtained with good to excellent yield. Analogously, substrates containing tertiary or secondary benzylic centers yield aromatics substituted with secondary benzylic centers or toluene derivatives, respectively. Furthermore, this strategy is used for the high yielding synthesis of diarylmethanes. The scope of the reductive dealkylation reaction is explored and the limitations with respect to steric and electronic factors are determined. A mechanistic analysis of the reaction is described that consisted of deuterium labelling experiments and hydrogenolysis of enantioenriched derivatives. The investigation shows that the C(sp3)–C(sp3) σ bond‐cleaving events occur through a hybrid SN1/SN2 mechanism, in which the palladium center displaces a carbon‐based leaving group, namely Meldrum's acid, with inversion of configuration, followed by reductive elimination of palladium to furnish a C−H bond.
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