Cobalt-Catalyzed Enantioselective Alkenylation of Aldehydes.

Catalytic enantioselective alkenylation of aldehydes with easily accessible alkenyl halides promoted by a chiral cobalt complex derived from a newly developed tridentate bisoxazolinephosphine is presented. Such processes represent an unprecedented reaction pathway for cobalt catalysis and a general approach that enable rapid construction of highly diversified enantioenriched allylic alcohols containing a 1,1-, 1,2-disubstituted and trisubstituted alkene as well as axial stereogenicity in up to 99% yield and 99:1 er without the need of preformation of alkenyl-metal reagents. DFT calculations revealed the origin of enantioselectivity.

Cobalt-Catalyzed Diastereo- and Enantioselective Carbon-Carbon Bond Forming Reactions of Cyclobutenes.

Catalytic enantioselective functionalization of cyclobutenes constitutes a general and modular strategy for construction of enantioenriched complex cyclobutanes bearing multiple stereogenic centers, as chiral four-membered rings are common motifs in biologically active molecules and versatile intermediates in organic synthesis. However, enantioselective synthesis of cyclobutanes through such a strategy remained significantly limited. Herein, we report a series of unprecedented cobalt-catalyzed carbon-carbon bond forming reactions of cyclobutenes that are initiated through enantioselective carbometalation. The protocols feature diastereo- and enantioselective introduction of allyl, alkynyl, and functionalized alkyl groups. Mechanistic studies indicated an unusual 1,3-cobalt migration and subsequent ß-carbon elimination cascade process occurred in the allyl addition. These new discoveries established a new elementary process for cobalt catalysis and an extension of diversity of nucleophiles for enantioselective transformations of cyclobutenes.

Cobalt-Catalyzed Regiodivergent and Enantioselective Intermolecular Coupling of 1,1-Disubstituted Allenes and Aldehydes.

Catalytic enantioselective coupling of 1,1-disubstituted allenes and aldehydes through regiodivergent oxidative cyclization followed by stereoselective protonation or reductive elimination promoted by chiral phosphine-Co complexes is presented. Such processes represent unprecedented and unique reaction pathways for Co catalysis that enable catalytic enantioselective generation of metallacycles with divergent regioselectivity accurately controlled by chiral ligands, affording a wide range of allylic alcohols and homoallylic alcohols that are otherwise difficult to access without the need of pre-formation of stoichiometric amounts of alkenyl- and allyl-metal reagents in up to 92 % yield, >98 : 2 regioselectivity, >98 : 2 dr and >99.5 : 0.5 er.

Cobalt-Catalyzed Regio-, Diastereo- and Enantioselective Intermolecular Hydrosilylation of 1,3-Dienes with Prochiral Silanes.

One of the most straightforward approaches to access chiral silanes is catalytic enantioselective hydrosilylation. Although significant advances have been achieved in enantioselective construction of either a carbon-stereogenic center or a silicon-stereogenic center through enantioselective hydrosilylation, simultaneous establishment of a carbon- and a silicon-stereogenic center in an acyclic molecule through a single intermolecular hydrosilylation remained undeveloped. Herein, an unprecedented cobalt-catalyzed regio-, diastereo- and enantioselective hydrosilylation of 1,3-dienes is presented, enabling construction of a carbon- and a silicon-stereogenic center in a single intermolecular transformation. A wide range of chiral silanes bearing a carbon- and a silicon-stereogenic center were generated in high efficiency and stereoselectivity. Functionalization of the enantioenriched silanes delivered a variety of valuable chiral building blocks that are otherwise difficult to access.

Cobalt-Catalyzed Diastereo- and Enantioselective Reductive Allyl Additions to Aldehydes with Allylic Alcohol Derivatives via Allyl Radical Intermediates.

Catalytic generation of ambiphilic π-allyl-metal complexes and their utility in enantioselective transformations constitutes a powerful approach for introduction of allyl groups to a molecule. Herein an unprecedented cobalt-catalyzed highly site-, diastereo-, and enantioselective protocol for stereoselective formation of nucleophilic allyl-Co(II) complexes followed by addition to aldehydes is presented. The reaction features diastereo- and enantioconvergent conversion of easily accessible allylic alcohol derivatives to diversified enantioenriched homoallylic alcohols with a remarkably broad scope of allyl groups that can be introduced. Mechanistic studies indicated that allyl radical intermediates were involved in this process. These new discoveries establish a new strategy for development of enantioselective transformations through capture of radicals by chiral Co complexes, pushing forward the frontier of Co complexes for enantioselective catalysis.

Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis.

1,1'-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1'-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α'-bis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1 S,2 S,2' S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1 S,2 S,2' S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a-c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.

DABCO-catalyzed synthesis of trifluoromethylated furans from propargyl alcohols and methyl 2-perfluoroalkynoate.

The DABCO-catalyzed reaction of propargyl alcohols with methyl 2-perfluoroalkynoate to give trifluoromethylated furans in up to 98% yield under mild conditions has been developed. The established allene-enol and control experiments indicate that the reaction should proceed through a Michael addition and Claisen rearrangement/cyclization process.

Pathway-divergent coupling of 1,3-enynes with acrylates through cascade cobalt catalysis.

Catalytic cascade transformations of simple starting materials into highly functionalized molecules bearing a stereochemically defined multisubstituted alkene, which are important in medicinal chemistry, natural product synthesis, and material science, are in high demand for organic synthesis. The development of multiple reaction pathways accurately controlled by catalysts derived from different ligands is a critical goal in the field of catalysis. Here we report a cobalt-catalyzed strategy for the direct coupling of inexpensive 1,3-enynes with two molecules of acrylates to construct a high diversity of functionalized 1,3-dienes containing a trisubstituted or tetrasubstituted olefin. Such cascade reactions can proceed through three different pathways initiated by oxidative cyclization to achieve multiple bond formation in high chemo-, regio- and stereoselectivity precisely controlled by ligands, providing a platform for the development of tandem carbon-carbon bond-forming reactions.

Photoredox cobalt-catalyzed regio-, diastereo- and enantioselective propargylation of aldehydes via propargyl radicals.

Catalytic enantioselective introduction of a propargyl group constitutes one of the most important carbon-carbon forming reactions, as it is versatile to be transformed into diverse functional groups and frequently used in the synthesis of natural products and biologically active molecules. Stereoconvergent transformations of racemic propargyl precursors to a single enantiomer of products via propargyl radicals represent a powerful strategy and provide new reactivity. However, only few Cu- or Ni-catalyzed protocols have been developed with limited reaction modes. Herein, a photoredox/cobalt-catalyzed regio-, diastereo- and enantioselective propargyl addition to aldehydes via propargyl radicals is presented, enabling construction of a broad scope of homopropargyl alcohols that are otherwise difficult to access in high efficiency and stereoselectivity from racemic propargyl carbonates. Mechanistic studies and DFT calculations provided evidence for the involvement of propargyl radicals, the origin of the stereoconvergent process and the stereochemical models.

N-Heterocyclic Carbene-Cu-Catalyzed Enantioselective Allenyl Conjugate Addition.

A catalytic enantioselective conjugate addition with commercially available allenylboronic acid pinacol ester as nucleophile promoted by a chiral copper complex of N-heterocyclic carbene (NHC) is disclosed. This process constitutes an unprecedented instance of the conjugate addition that introduces an allenyl group into α,ß-unsaturated carbonyl compounds, affording products that are otherwise difficult to access in up to 92% yield, >98% allenyl addition selectivity and 96:4 enantiomeric ratio. DFT calculations were performed to elucidate the origins of enantioselectivity.

Cu-Catalyzed Enantioselective Boron Addition to N-Heteroaryl-Substituted Alkenes.

Catalytic enantioselective Cu-B(pin) (pin = pinacolato) addition to N-heteroaryl-substituted alkenes followed by protonation promoted by phosphine-Cu complexes is presented. The resulting alkylboron products that contain a N-heteroaryl moiety are afforded in up to 97% yield and 99:1 enantiomeric ratio. The highly versatile C-B(pin) bond can be converted to a range of useful functional groups, delivering a variety of enantiomerically enriched building blocks that are otherwise difficult to access. The utility of this method is further demonstrated by application to a fragment synthesis of biologically active molecule U-75302. Preliminary mechanistic studies revealed that the adjacent N atom of the heterocycles plays a unique role in high reactivity and enantioselectivity.