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

Abstract 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

Cu-Catalyzed Enantioselective Boron Addition to <i>N</i>‑Heteroaryl-Substituted Alkenes

Catalytic enantioselective Cu–B­(pin) (pin = pinacolato) addition to <i>N</i>-heteroaryl-substituted alkenes followed by protonation promoted by phosphine–Cu complexes is presented. The resulting alkylboron products that contain a <i>N</i>-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

N‑heterocyclic Carbene–Cu-Catalyzed Enantioselective Conjugate Additions with Alkenylboronic Esters as Nucleophiles

Catalytic enantioselective conjugate additions with easily accessible alkenylboronic acid pinacol esters as nucleophiles promoted by chiral copper complexes of N-heterocyclic carbenes are presented. These processes constitute an unprecedented instance of conjugate additions of a variety of functionalized alkenyl groups and afford desired products that are otherwise difficult to access in up to 98% yield and 99.5:0.5 enantiomeric ratio. The origins of ligand-controlled enantioselectivity are elucidated with density functional theory (DFT) calculations

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% <i>ee</i>), 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<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b>, in >99% <i>ee</i> and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b> provided straightforward access to chiral monodentate phosphoramidites <b>6a</b>–<b>c</b> and a tridentate phosphorus-amidopyridine <b>11</b>, 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 <b>20</b> and <b>21</b> 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

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% <i>ee</i>), 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<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b>, in >99% <i>ee</i> and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b> provided straightforward access to chiral monodentate phosphoramidites <b>6a</b>–<b>c</b> and a tridentate phosphorus-amidopyridine <b>11</b>, 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 <b>20</b> and <b>21</b> 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

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% <i>ee</i>), 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<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b>, in >99% <i>ee</i> and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b> provided straightforward access to chiral monodentate phosphoramidites <b>6a</b>–<b>c</b> and a tridentate phosphorus-amidopyridine <b>11</b>, 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 <b>20</b> and <b>21</b> 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

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% <i>ee</i>), 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<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b>, in >99% <i>ee</i> and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b> provided straightforward access to chiral monodentate phosphoramidites <b>6a</b>–<b>c</b> and a tridentate phosphorus-amidopyridine <b>11</b>, 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 <b>20</b> and <b>21</b> 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

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% <i>ee</i>), 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<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b>, in >99% <i>ee</i> and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1<i>S</i>,2<i>S</i>,2′<i>S</i>)-<b>5</b> provided straightforward access to chiral monodentate phosphoramidites <b>6a</b>–<b>c</b> and a tridentate phosphorus-amidopyridine <b>11</b>, 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 <b>20</b> and <b>21</b> 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