Ye Zhu09/02/10

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 ofbiaryls, 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, 493.

2 eq. (+) 1, 2 eq. LAH, -80 °C, 80%, 98% ee2 eq. (+) 1, 2 eq. LAH, -20 °C, 75%, 89% ee

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Spiro[4,4]nonane-1,6-diol As Chiral Auxiliaries in the Reduction of

Ketones

Kumar, A., et al, Chem. Commun. 1992, 493.

2 eq. (+) 1, 2 eq. LAH, -80 °C, 80%, 98% ee2 eq. (+) 1, 2 eq. LAH, -20 °C, 75%, 89% ee

4

Monodentate SpiroPhosphoramidite

Ligand

Xumu, Zhang, et al, Org. Lett. 2004, 3565.

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Synthesis of Chiral Monodentate Spiro Ligand via

9,9’-Spirobixanthene-1,1’-Diol

Xumu, Zhang, et al, Org. Lett. 2004, 3565.

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

Birman, V.B., et al, Tetrahedron Asymmetry 1999, 125.

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Birman, V.B., et al, Tetrahedron Asymmetry 1999, 125.

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

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Highly efficient and practical resolution of1,1-spirobiindane-7,7-diol by inclusion

crystallization withN-benzylcinchonidinium chloride

Zhou, Qi-Lin, et al, Tetrahedron Asymmetry 2002, 1363.

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

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Synthesis of 9,9’-Spirobifluorene-1,1’-diol

Zhou, Qi-lin, et al,

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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, 4404.

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Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2005, 1118.

Zhou, Q.-L. et al, Angew. Chem., Int. Ed. 2002, 41, 2348. Zhou, Q.-L. et al, Org. Lett. 2006, 8, 1479.

Zhou, Q.-L. et al, J. Org. Chem. 2004, 69, 8157.Zhou, Q.-L. et al, J. Am.Chem. Soc. 2006, 128, 11774.

Zhou, Q.-L. et al, Org. Lett. 2005, 7, 2333.

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Crystal Structures of Pd-complexes

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Synthesis of Chiral Spiro Phosphine-Oxazoline Ligands

Zhou, Q.-L. et al, J. Am.Chem. Soc. 2006, 128, 12886. 15

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 100 000) and excellent enantioselectivity(ee up to 99.5%)

Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128, 11774

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Highly Enantioselective and Diastereoselective Synthesis of

Chiral Amino Alcohols

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, 4222.17

Enantioselective Hydrogenation of α-Arylmethylene Cycloalkanones

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, 4538.

the asymmetric hydrogenation of exocyclicα,β-unsaturated ketones is a challenge task

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Applications: Asymmetric Hydrogenation

Zhou, Q.-L. et al, J. Am. Chem. Soc. 2007, 129, 1868aldehydes

the first example of asymmetric hydrogenation of aldehyde via DKR

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Applications: Asymmetric Hydrogenation

Zhou, Q.-L. et al, Angew. Chem. Int.Ed. 2005, 1118α,β-unsaturated carboxylic acid

these results are comparable to, or better than,those obtained with [Ru(OAc)2(binap)] and other catalysts

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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, 1271α,β-unsaturated carboxylic acid

22

Hydrogenations with Chiral Spiro Phosphine-Oxazoline Ligands

Zhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128,

12886.

Zhou, Q.-L. et al, J. Am. Chem. Soc. 2008, 130,

8584.

Zhou, Q.-L. et al, J. Am.

Chem. Soc. 2010, 132, 1172.

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Applications: Asymmetric Hydrogenation

enamines

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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, 11774

25

Iridium-Catalyzed Asymmetric Hydrogenation

of Cyclic Enamines

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, 1366.26

Enantioselective Iron-catalysed O–H Bond Insertions

Zhou, Qi-Lin, et al, Natural Chemistry, 2010, 546.

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Other Developments

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2007, 5834. 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

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Other Developments

Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2008, 4351. Enantioselective Rhodium-Catalyzed Addition of Arylboronic Acids to β-Ketoesters

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Zhou, Qi-Lin, et al, Angew. Chem. Int. Ed., 2008, 8496. Copper-Catalyzed Highly Enantioselective Carbenoid Insertion into Si-H Bonds

Addition of Arylboronic Acids to Aldehydes and N-Tosylarylimines

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Ni Catalyzed Reactions

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2010, 10955.Enantioselective Nickel-Catalyzed Reductive Coupling of Alkynes and Imines

Zhou, Qi-Lin, et al, J. Am. Chem. Soc., 2008, 14052.Enantioselective Nickel-Catalyzed Alkylative Coupling of Alkynes and Aldehydes

31

Asymmetric hydrovinylat-

ion of VinylarenesZhou, Q.-L. et al, J. Am. Chem. Soc. 2006, 128,

2780

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Pd Catalyzed Carboamination Reactions

John, Wolfe, et al, J. Am. Chem. Soc. 2010, 12157. 33

Possible Works

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Thanks

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