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

Binding of synthetic ligands to the active center

typical binding mode simultaneous binding

Binding of synthetic ligands to the active center

binding of R enantiomer

Binding of synthetic ligands to the active center

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

(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

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 =

(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

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+

5 examples76-82 % yield

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+

5 examples76-82 % yield

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

Conjugate Silyl Additions Catalyzed by NHC-Cu

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

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.

Conjugate Silyl Additions Catalyzed by NHC-Cu

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

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.

Conjugate Silyl Additions Catalyzed by NHC-Cu

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

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.

Conjugate Silyl Additions Catalyzed by NHC-Cu

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

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.

Conjugate Silyl Additions Catalyzed by NHC-Cu

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

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

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

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.

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

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?