Ye Zhu 09/02/10 Burgess’s Group Meeting Chiral Ligands On A Spiro Scaffold for Transition-Metal- Catalyzed Asymmetric Reactions Work by Prof. Zhou Qi-Lin

Ubiquitous Spirocyclic Framework in 1900, von Baeyer introduced the name “spirocyclane” for bicyclic hydrocarbons having two rings with a common carbon atom (spiro carbon) the two rings of the spiro compounds lie in perpendicular planes, which not only gives rise to an axial chirality in spiro compounds having substituents on the rings but also increases molecular rigidity racemization of chiral spiro compounds virtually impossible very few applications despite these excellent characteristics the spirocyclic framework is considerably more rigid than that of biaryls, since conformational changes involve distortion of the entire molecule 2

Spiro[4,4]nonane-1,6-diol As Chiral Auxiliaries in the Reduction of Ketones Kumar, A., et al, Chem. Commun. 1992, eq. (+) 1, 2 eq. LAH, -80 °C, 80%, 98% ee 2 eq. (+) 1, 2 eq. LAH, -20 °C, 75%, 89% ee 3

Spiro[4,4]nonane-1,6-diol As Chiral Auxiliaries in the Reduction of Ketones Kumar, A., et al, Chem. Commun. 1992, eq. (+) 1, 2 eq. LAH, -80 °C, 80%, 98% ee 2 eq. (+) 1, 2 eq. LAH, -20 °C, 75%, 89% ee 4

Monodentate Spiro Phosphoramidite Ligand Xumu, Zhang, et al, Org. Lett. 2004,

Synthesis of Chiral Monodentate Spiro Ligand via 9,9’-Spirobixanthene-1,1’-Diol Xumu, Zhang, et al, Org. Lett. 2004,

Synthesis of 1,1’Spirobiindane-7,7’-diol Birman, V.B., et al, Tetrahedron Asymmetry 1999,

Synthesis of 1,1’Spirobiindane-7,7’-diol 8

Highly efficient and practical resolution of 1,1-spirobiindane-7,7-diol by inclusion crystallization with N-benzylcinchonidinium chloride Zhou, Qi-Lin, et al, Tetrahedron Asymmetry 2002, A highly efficient and practical resolution of racemic 1,1-spirobiindane-7,7-diol (±)-1 has been achieved, with the (S)-(−)- and (R)-(+)-forms of 1 obtained with >99% e.e. in 82% yield from the inclusion complex and 75% yield from the mother liquor, respectively 9

Synthesis of 9,9’- Spirobifluorene-1,1’-diol Zhou, Qi- lin, et al, 10

Synthesis of 9,9’- Spirobifluorene-1,1’-diol SBIFOL was conveniently synthesized from 1,2- dibromobenzene and 3-bromoanisole in high yield. Both enantiomers of SBIFOL were obtained in 99% ee by inclusion resolution with 2,3-dimethoxy-N,N,N’,N’ tetracyclohexylsuccinamide 11

Synthesis of SDP Ligands Zhou, Qi-Lin, et al, J. Am.Chem.Soc., 2003,

Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2005, Zhou, Q.-L. et al, Angew. Chem., Int. Ed. 2002, 41, Zhou, Q.-L. et al, Org. Lett. 2006, 8, Zhou, Q.-L. et al, J. Org. Chem. 2004, 69, Zhou, Q.-L. et al, J. Am.Chem. Soc. 2006, 128, Zhou, Q.-L. et al, Org. Lett. 2005, 7,

Crystal Structures of Pd-complexes 14

Synthesis of Chiral Spiro Phosphine-Oxazoline Ligands Zhou, Q.-L. et al, J. Am.Chem. Soc. 2006, 128,

Applications: Asymmetric Hydrogenation ketones a new chiral scaffold and their application in the ruthenium- catalyzed asymmetric hydrogenation of simple ketones with high activity (S/C up to ) and excellent enantioselectivity (ee up to 99.5%) Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128,

Highly Enantioselective and Diastereoselective Synthesis of Chiral Amino Alcohols Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010,

Enantioselective Hydrogenation of α-Arylmethylene Cycloalkanones Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, the asymmetric hydrogenation of exocyclic α,β-unsaturated ketones is a challenge task 18

Applications: Asymmetric Hydrogenation Zhou, Q.-L. et al, J. Am. Chem. Soc. 2007, 129, 1868 aldehydes the first example of asymmetric hydrogenation of aldehyde via DKR 19

Applications: Asymmetric Hydrogenation Zhou, Q.-L. et al, Angew. Chem. Int.Ed. 2005, 1118 α,β-unsaturated carboxylic acid these results are comparable to, or better than, those obtained with [Ru(OAc) 2 (binap)] and other catalysts 20

Applications: Asymmetric Hydrogenation Zhou, Q.-L. et al, Angew. Chem. Int.Ed. 2005, 1118 α,β-unsaturated carboxylic acid these results represents the highest level of enantiocontrol reported to date in the asymmetric hydrogenation of cinnamic acid derivatives 21

Applications: Asymmetric Hydrogenation Zhou, Q.-L. et al, Adv. Synth, Catal. 2006, 1271 α,β-unsaturated carboxylic acid 22

Hydrogenations with Chiral Spiro Phosphine-Oxazoline Ligands Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128, Zhou, Q.-L. et al, J. Am. Chem. Soc. 2008, 130, Zhou, Q.-L. et al, J. Am. Chem. Soc. 2010, 132,

Applications: Asymmetric Hydrogenation enamines 24

Applications: Asymmetric Hydrogenation Other ligands such as the diphosphine ligands BINAP, Josiphos, and SDP (6a) and the monodentate phosphorus ligands Mono- Phos, H-MOP, SIPHOS (9a), and ShiP (10a) provided the hydrogenation product with very low enantioselectivities under the same reaction conditions Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128,

Iridium-Catalyzed Asymmetric Hydrogenation of Cyclic Enamines Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010,

Enantioselective Iron-catalysed O–H Bond Insertions Zhou, Qi-Lin, et al, Natural Chemistry, 2010,

Other Developments Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2007, Enantioselective Insertion of Carbenoids into N−H Bonds Catalyzed by Copper Complexes of Chiral Spiro Bisoxazolines Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2008, 932. Enantioselective Synthesis of a-Hydroxyesters by a Copper–Carbenoid O-H Insertion Reaction 28

Other Developments Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2008, Enantioselective Rhodium-Catalyzed Addition of Arylboronic Acids to β-Ketoesters 29 Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2008, Copper-Catalyzed Highly Enantioselective Carbenoid Insertion into Si-H Bonds

Addition of Arylboronic Acids to Aldehydes and N-Tosylarylimines 30

Ni Catalyzed Reactions Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, Enantioselective Nickel-Catalyzed Reductive Coupling of Alkynes and Imines Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2008, Enantioselective Nickel-Catalyzed Alkylative Coupling of Alkynes and Aldehydes 31

Asymmetric hydrovinylat- ion of Vinylarenes Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128,

Pd Catalyzed Carboamination Reactions John, Wolfe, et al, J. Am. Chem. Soc. 2010,

Possible Works 34

Thanks 35