Chiral Drugs & Enantioselective Additions€¦ · 2/11/2011 · Chiral Drugs & Enantioselective...
Transcript of Chiral Drugs & Enantioselective Additions€¦ · 2/11/2011 · Chiral Drugs & Enantioselective...
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?