chiral drugs & enantioselective additions€¦ · 2/11/2011 · chiral drugs &...

Chiral Drugs & Enantioselective Additions

The Active Site of an Enzyme Can Host Both Enantiomers of aRacemic Ligand Simultaneously

Matthias Mentel, Wulf Blankenfeldt, and Rolf Breinbauer,Angew. Chem. Int. Ed. 2009, 48, 9084-7

Enantioselective Conjugate Silyl Additions to Cyclic and Acyclic Unsaturated Carbonyls Catalyzed by Cu Complexes of Chiral N-Heterocyclic Carbenes

Kang-sang Lee and Amir H. Hoveyda,J. Am. Chem. Soc. 2010, ASAP (DOI: 10.1021/ja910989n)

1995-1998 PhD Thesis at the Max-Planck-Institute of Coal Research, Mülheim, (Prof. M. T. Reetz) 1998-1999 Post-Doc, Harvard University (Prof. E. N. Jacobsen)

2000-2006 Group Leader Max-Planck-Institute for Molecular Physiology, Dortmund

2003-2005 Junior Professor, University of Dortmund

2005-2007 Professor of Organic Chemistry, University of Leipzig

15/09/2007 - Professor of Organic Chemistry and Head of the Institute of Organic Chemistry at the University of Technology, Graz

Prof. Rolf Breinbauer

Three different binding modes - I

selective binding of one enantiomer

Three different binding modes - I

selective binding of one enantiomer

most common case:

only one enantiomer of a racemic mixture binds to a biological receptor

the other enantiomer can be regarded as “isomeric balast”

no effect in in vitro screens

Three different binding modes - II

individual binding of both enantiomers

Nat. Rev. Drug Discovery 2002, 1, 753-68

Three different binding modes - II

individual binding of both enantiomers

second enantiomer shows different binding behavior than the first one

cooperative, side or counterproductive effects

only single-enantiomer drugs may be marketed

racemic mixtures are still preferentially used in primary screens

Nat. Rev. Drug Discovery 2002, 1, 753-68

Three different binding modes - III

simultaneous binding of both enantiomers

this study!

Three different binding modes - III

simultaneous binding of both enantiomers

this study!

first crystal structure of a protein hosting both enantiomers simultaeously

important implications for drug discovery?

Burkholderia cepacia PhzA/B

J. Am. Chem. Soc. 2008, 130, 17053-61

Biosynthesis of Phenazine-1-carboxylic acid

Binding of synthetic ligands to the active center

typical binding mode


typical binding mode simultaneous binding


binding of R enantiomer


binding of R enantiomer binding of S enantiomer

conclusion and question

additional aspect of chiral-drug action at primary drug targets(enzymes, ion channels, etc.)

multiple ligand binding more common than assumed?

interpretation of binding data should therefore be performed with even more caution.

new drug-discovery opportunities?

Prof. Amir Hoveyda

B. A., 1981, Columbia University

Ph. D., 1986, Yale University (Prof. Stuart L. Schreiber)

Postdoctoral Fellow, 1986-1987 and 1988-1990, Harvard University (Prof. David A. Evans)

Assistant Professor, Boston College, June 1990–August 1994

Professor, Boston College, September 1994–August 1998

Vanderslice Millennium Professor, September 1998–present

(Chiral) β-Silylcarbonyls

PhMe2Si∗

R

OR'

OPhMe2Si

R

H

CO2R' cat. PPF-P(t-Bu)2CuH

PMHS, t-BuOH, toluene[PMHS = polymethylhydrosiloxane]

Lipshutz et al., Org. Lett. 2006, 8, 1963-6

Fe PPh2

Me

P(t-Bu)2H

(R,S)-PPF-P(t-Bu)2


PhMe2Si∗

R

OR'

OPhMe2Si

R

H




SiMe Me

NH

O

Ph

O

+ ENC

R

[(salen)Al]2O (10 mol%)

t-BuOH (2 equiv.)cyclohexane, 23 °C

R

E CN

SiMe

Me

NH

O O

Ph

Jacobsen et al., J. Am. Chem. Soc. 2006, 128, 6810-2

O

N

t-Bu

t-Bu

N

O t-Bu

t-Bu

Al

(S,S)-(salen)Al =


PhMe2Si∗

R

OR'

OPhMe2Si

R

H




SiMe Me

NH

O

Ph

O

+ ENC

R

[(salen)Al]2O (10 mol%)

t-BuOH (2 equiv.)cyclohexane, 23 °C

R

E CN

SiMe

Me

NH

O O

Ph

Jacobsen et al., J. Am. Chem. Soc. 2006, 128, 6810-2

KAS et al., J. Am. Chem. Soc. 2004, 126, 84-5

RCO2Me

CO2Me

+ (SiPhMe2)2

2.5-10 mol% Cu(I)X 5-20 mol% n-Bu3P

solventthen TsOH/H2O

R

PhMe2Si

CO2Me

CO2Me

Pd-Catalyzed Asymmetric 1,4-Disilylation

Hayashi et al., J. Am. Chem. Soc. 1988, 110, 5579-81

R1 R2

O

Si-SiPdL*

R1 R2

OSi

R1 R2

OSi

R3R3X

[O]

R1 R2

OOH

R3

PdL* =

P

PPhPh

Pd

Ph PhCl

Cl

Pd-Catalyzed Asymmetric 1,4-Disilylation

Hayashi et al., J. Am. Chem. Soc. 1988, 110, 5579-81

R1 R2

O

Si-SiPdL*

R1 R2

OSi

R1 R2

OSi

R3R3X

[O]

R1 R2

OOH

R3

R1 R2

O

PhCl2SiSiMe3

[Pd], C6H6

R1 R2

OSiMe3PhCl2Si

MeLi R1 R2

OLiPhMe2Si

R3X/THF

orH3O+

R1 R2

OOH

R3

8 examples45-100 % yield

74-92 % e.e

PdL* =

P

PPhPh

Pd

Ph PhCl

Cl

Rh-Catalyzed Conjugate Silyl Transfer

Walter & Oestreich, Angew. Chem Int. Ed. 2006, 45, 5675-77

X

O

n

X

O

n SiMe2PhOB

OSiMe2Ph

MeMe

MeMe

5 mol% [(dppp)Rh(cod)]+ClO4-

5 mol% dppp, 1.0 equiv Et3N

1,4-dioxane/H2O 10:1, 50 °C+


Ph2P PPh2dppp =

Rh-Catalyzed Conjugate Silyl Transfer

Walter & Oestreich, Angew. Chem Int. Ed. 2006, 45, 5675-77

X

O

n

X

O

n SiMe2PhOB

OSiMe2Ph

MeMe

MeMe

5 mol% [((S)-binap)Rh(cod)]+ClO4-

5 mol% (S)-binap, 1.0 equiv base

1,4-dioxane/H2O 10:1, 50 °C+

4 examples22-70 % yield92-97 % e.e.PPh2

PPh2

(S)-binap

X

O

n

X

O

n SiMe2PhOB

OSiMe2Ph

MeMe

MeMe

5 mol% [(dppp)Rh(cod)]+ClO4-

5 mol% dppp, 1.0 equiv Et3N

1,4-dioxane/H2O 10:1, 50 °C+


Ph2P PPh2dppp =

Conjugate Silyl Additions Catalyzed by NHC-Cu

Lee, K.-s.; Hoveyda, A. H., J. Am. Chem. Soc. 2010, 132, ASAP

Catalytic Cycle:

N N

CuOR

ArAr N N

CuSiMe2Ph

ArArPhMe2Si-B(pin)

RO-B(pin)

O

OCu

N N ArAr

PhMe2SiOB(pin)PhMe2Si

PhMe2Si-B(pin)

B(pin) = pinacolatoboron



Optimization

O O

SiMe2Ph

2.5-5.0 mol% NHC-Ag complex5.0 mol % CuCl, 5.0 mol % NaOt-Bu

1.1 equiv PhMe2SiB(pin)THF, -50 °C, 12 h; aq. workup

90-94 % yield74-92 % e.e.



Optimization

more robust(less light sensitive)

R = Me; 1.1 mol%; 95 % e.e.

O O

SiMe2Ph

2.5-5.0 mol% NHC-Ag complex5.0 mol % CuCl, 5.0 mol % NaOt-Bu

1.1 equiv PhMe2SiB(pin)THF, -50 °C, 12 h; aq. workup

90-94 % yield74-92 % e.e.



Substrate Scope

O

SiMe2Phn

n = 1-487-95 yield

80-96 % e.e.

O

SiMe2Phn

Me Me

n = 1-289-94 yield98 % e.e.

O

SiMe2Ph

91 yield93 % e.e.

O

O

SiMe2Ph

91 yield93 % e.e.

Me R

O SiMe2Ph

Ph Me

O SiMe2Ph

MeO R

O SiMe2Ph

NCPh

SiMe2Ph

7 examples88-97 % yield87-97 % e.e.

92 % yield91 % e.e.

R = Me, Ph93-96 % yield91-93 % e.e.

95 % yield80 % e.e.



Enantioselective Additions to Cyclic Dienones:

Further Investigations

O

n

O

SiMe2Phn

1.1 mol% NHC, 1.0 mol % CuCl,2.2 mol % NaOt-Bu

1.1 equiv PhMe2SiB(pin), THF, -78 °C, 1 h;1.5 equiv PhCHO, -78 °C, 10 h

n = 1: 91 % yield, 6:1 d.r. (80 % e.e.)n = 3: 92 % yield, 3:1 d.r. (91 % e.e.)

Ph

OHH


O

n

O

SiMe2Phn




Ph

OHH

O

MeMe

SiMe2Ph

1.1 equiv PhLi

Et2O, -50 °C, 6 hMe

MeSiMe2Ph

HO Ph1.5 equiv Hg(OAc)2

MeCO3H, HOAc22 °C, 6 h Me

MeOH

HO Ph

85 % yield> 98:2 d.r.

84 % yield> 98:2 d.r. (96 % e.e.)

98 % e.e.


O

n

O

SiMe2Phn




Ph

OHH

O

MeMe

SiMe2Ph

1.1 equiv PhLi

Et2O, -50 °C, 6 hMe

MeSiMe2Ph

HO Ph1.5 equiv Hg(OAc)2

MeCO3H, HOAc22 °C, 6 h Me

MeOH

HO Ph

85 % yield> 98:2 d.r.

84 % yield> 98:2 d.r. (96 % e.e.)

98 % e.e.

O1.1 mol% NHC, 1.0 mol % CuCl,

2.2 mol % NaOt-Bu1.1 equiv PhMe2SiB(pin), THF, -78 °C, 1 h;

2.0 equiv n-BuLi, -78 °C, 30 min;5 equiv BrCH2CO2Me, -78 °C, 12 h

O

SiMe2Ph

CO2Me

92 % yield> 98:2 d.r. (95 % e.e.)

Conclusion & Question

Cu-catalyzed silane conjugate additions:

highly efficient and selective method for the synthesis ofβ-silyl carbonyl compounds with large substrate scope

1,6-additions possible (high yields, high selectivity)

β-silyl carbonyl compounds useful for further conversions and stable to common organometallics

useful in complex molecule synthesis?

chiral drugs & enantioselective additions€¦ · 2/11/2011 · chiral drugs &...

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