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Introduc)on to Asymmetry Aaron Kempema Nick Struntz September 6, 2012 Importance of enan)omerically pure drugs •  Different enan)omers can have different effects on the body •  Ac)ons of “Inac)ve Isomers” 1. One isomer possesses therapeu)c ac)on while the other contributes to side effects –  Ethambutol – one isomer treats TB, other causes blindness –  Naproxen – one isomer treats arthri)s, other causes liver poisoning –  Thalidomide – next slide 2. Isomers have opposite effects –  Picenadol – one isomer is a agonist, other is an antagonist 3. Stereoselec)ve metabolic inversion of one of the stereocenters –  Ibuprofen 4. Stereoselec)vity may be restricted to only one component in the biological ac)on Ariens, E. J. Eur. J. Clin Pharmacol 1984, 663. Thalidomide •  Origin –  Developed in the 1950’s by Grunenthal in Stolberg, German –  Used by the Nazi’s during WWII –  Treated morning sickness, aid sleep and epidemic typhus •  Birth Defects (Racemiza)on) –  10,000 kids were born with birth defects in 1950’s-­‐60’s –  William McBride and Widukind Lenz found the link –  Never approved by the FDA •  A`ermath –  US Congress passed laws requiring drugs be tested for safety during pregnancy –  Lawsuits against Grunenthal (Dark Remedy) –  Leprosy, but strictly controlled –  Cancer? •  Drugs need to be developed as single enan)omers Chiral Resolu)on •  Louis Pasteur seperated tartaric acid isomers in 1849 –  Naturally occurring in plants –  L-­‐(+) is the natural enan)omer •  Types of crystalliza)on – 
– 
– 
– 
Conglomerate – greater affinity for same enan)omer Racemic – greater affini)ty for other enan)omer Psedoracemate – no strong affinity Quasiracemate – slight preference for one ena)omer •  What do you do if your compound does not crystallize in a conglomerate fashion? Classical Chiral Resolu)on •  Enan)omerically pure compound crystallizes with one of the isomers of the racemic compound •  Several crystalliza)ons are required •  Needs a site for protona)on Ault, A. Organic Syntheses, 1969, 49, 93. Resolving Agents Classical Chiral Resolu)on Advantages Disadvantages Scalable Limited scope Cheap (tartaric acid) Mul)ple crystalliza)ons Precedent 1950’s-­‐70’s Maximum 50% yield Modern chiral resolu)on •  Resolu)on-­‐Racemiza)on-­‐Recycle –  Synthesis of Duloxe)ne (Eli Lilly) –  Mandelic acid used as resolving agent Deeter, J.; et al Tetrahedron Le=. 1990, 31, 7101. Fujima, Y.; et al Org. Process Res. Dev. 2006, 10, 905. Enzyma)c Resolu)on •  Kine)c Resolu)on –  Two enan)omers have different reac)on rates –  Enzyma)c resolu)on Kazlauskas, R. J. Organic Syntheses 1992, 70, 60. Another Enzyma)c Resolu)on •  Use towards total synthesis –  Amano PS lipase resolves secondary alcohols Batwal, R. U. et al. Tetrahedron: Asymmetry 2011, 22, 173. Chiral Pool Synthesis •  Derived from plants •  Carbohydrates •  Amino Acids Madabhushi et al. Tetrahedron Le=. In Press Rasmussen, T. S.; Jensen, H. H. Carbohydr. Res. 2011, 2855. Dana, A.; et al. Tetrahedron, 2001, 57, 1169. Advantages/Disadvantages Enzyma)c Resolu)on Advantages Disadvantages Decent scope S)ll limited in scope No auxiliary cleavage Requires op)miza)on Enzymes can be cheap Low ee’s Chiral Pool Synthesis Advantages Disadvantages Enan)omerically pure Extra steps Cheap source of chirality One ena)omer is available Precedent Chiral Auxiliaries •  Chiral Auxilary –  A chiral compound is temporarily incorporated into a molecule –  First reported by Corey: –  Evans oxazolidinone auxiliaries are the most well-­‐known chiral auxiliaries •  Derive from amino acids Corey, E. J. et al J. Am. Chem. Soc. 1975, 97, 6908. Evans Aldol Reac)on •  Evans aldol reac)on –  Forms the (Z)-­‐boron enolates –  High stereoselc)vity is anributed to the rela)vely short boron –oxygen bond length –  Forms a )ght, six-­‐membered chair-­‐like transi)on state, Carbonyl is opposed to the enolate oxygen dipole –  Syn product Evans, D. A.; et al. J. Am. Chem. Soc. 1981, 103, 2127. Zimmerman-­‐Traxler Transi)on State Evans aldol Con)nued •  Auxiliary Removal •  An)-­‐Aldol –  Open transi)on state under Lewis acid condi)ons –  An) is more thermodynamically stable Weinreb, S. W. et al. Tetrahedron Le=. 1977, 18, 4171. Dias, L. C. et al. Org. Le=. 2003, 5, 265. Evans, D. A. et al. J. Am. Chem. Soc. 2002, 124, 392. Other Chiral Auxiliaries •  Crimmins –  Oxazolidinethiones –  Titanium has a higher affinity for S than O Base Equiv Yield Evans:Non-­‐Evans DIPEA 2.5 86 86:14 DIPEA 1.1 75 5:95 –  Easy to remove •  Alcohol (NaBH4) •  Weinreb amide (NHCH3OMe) •  Methyl ester (MeOH) Crimmins, M. T.; et al. J. Org. Chem. 2001, 66, 894. Other Chiral Auxiliaries •  Myers –  Both (R,R) and (S,S) pseudoephedrine Chiral Auxiliaries Advantages Disadvantages Very Selec)ve Adds two steps to synthesis Mul)ple Auxiliaries Expensive/make Precedent Myers, A. G.; et al. J. Am. Chem. Soc. 1997, 119, 6496. Asymmetric Synthesis
•  Creates one or more desired chiral centers •  Enan)omerically pure chiral catalysts lead to the produc)on of enan)omerically enriched products •  2 func)ons: •  Ac)va)ng func)on •  Controlling func)on HO2C
• 
• 
• 
• 
HO2C
CO2H
Metal ligand complexes with chiral ligands N
Chiral organocatalysts H
Biocatalysis O
H
Chiral Lewis acids H
H
O
N
O
O
Marckwald, W. Berichte der deutschen chemischen GesellschaO 1904, 37, 349 H
Optically pure
Metal Complex Enantioselective Reactions
•  First heterogeneous by Erlenmeyer •  ZnO/d-­‐Fructose •  Addi)on of Br2 across double bond O
O
PtO2
OH
OH
N
OH
H
Optically active
(+)-!-phenylbutyric acid
N
8-9% ee
E. Erlenmeyer and H. Erlenmeyer, Biochem. Zeitschr. 1922, 233, 52 D. Lipkin and T.D. Stewart, J. Am. Chem. Soc. 1939, 61, 3295 Metal Complex Enantioselective Reduction
[RhL,COD]BF4
H2
HO2C
HO2C
P
(+)-hydratropic acid
15% ee
MeO
CO2H
[RhL,COD]BF4
H2
H
MeO
NHCOMe
O
H
CO2H
NHCOMe
OMe MeO
P
P
DiPAMP Knowles, S. Chem. Comm. 1968, 1445 Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001 O
L-DOPA
Metal Complex Enantioselective Reduction
MeO
CO2H
[RhL,COD]BF4
H2
H
MeO
NHCOMe
O
H
CO2H
NHCOMe
OMe MeO
P
P
Knowles, S. Chem. Comm. 1968, 1445 Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001 O
L-DOPA
Metal Complex Enantioselective Reduction
Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932 Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001 Metal Complex Enantioselective Reduction
Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932 Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001 Metal Complex Enantioselective Oxidation
Allylic Alcohol OH
Epoxide O
H
% ee (Eu) 77 95 79 94 70 >95 87 >95 OH
O
H
OH
% Yield OH
OAc
H
O
OH
OH
Ph
Ph
Ph
OH
H
O
Ph
Sharpless, K.B. J. Am. Chem. Soc. 1980, 102, 5979 OH
Metal Complex Enantioselective Oxidation
Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001 Metal Complex Enantioselective Oxidation
N
OH"
OH"
R'O
H
Ar
R3 OH
R3
0.2 - 0.4% OsO4, NMO
R2
R' = p-chlorobenzoyl
R1
Ar
OH"
OH"
R'O
Sharpless, K.B. J. Am. Chem. Soc. 1980, 110, 1968 H
N
R2
R1
OH
80 - 95% yield
20 - 80% ee
Metal Complex Enantioselective C-C Bond Formation!
•  Formulation
O
Polymer Supported Pt Catalyst O
N
Ph2P
PPh2
Cl Pt
SnCl3
S)lle. J. Am. Chem. Soc. 1987, 109, 7125 Metal Complex Enantioselective C-C Bond Formation!
•  Grignard Cross-Coupling
SiMe3
SiMe3
Ph
Br
MgBr
Ph
63%
85% ee
H
NMe2
Fe
Kumada. J. Org. Chem. 1986, 51, 3772 P
Ph2
Pd
H
SiMe3
Ph
Metal Complex Enantioselective C-C Bond Formation!
•  Allylic Alkylation
CO2Me
CO2Me
OAc
AcO
Na
CO2Me
CO2Me
CO2Me
95%
72% ee
H
Fe
Yoshihiko. Tet. Le=. 1986, 27, 191 R2 NMe
P
Pd
P
Ph2
N
R
Nu
R
OH
OH
Metal Complex Enantioselective C-C Bond Formation!
•  Cyclopropanation
Cu
Ph
N2CHCO2Et
Ph
CN
N
HO
N
H H
H
25-75%
68-97% ee
Fritschi. Angew. Chem. 1986, 98, 1028 OH
CO2Et
Metal Complex Enantioselective C-C Bond Formation!
•  Diels Alder
OtBu
OtBu
Ph
H
TMSO
O
Danishefsky. Tet. Le=. 1983, 24, 3451 H
39% ee
TMSO
H
H
Ph
Metal Complex Enantioselective C-C Bond Formation!
•  Hydrocyanation
HCN
PdL2
6%
40% ee
Hodgson. J. Organomet. Chem. 1987, 325, C27 CN
Metal Complex Enantioselective C-C Bond Formation!
•  Cyclization
O
Zn
O
CHO
Sakane. Tetrahedron 1986, 42, 2203 91%
90% ee
OH
Chiral Organocatalysts
Advantages: •  No metal based chemistry (“green”) •  Lack of sensi)vity to oxygen and moister •  Readily available with rela)vely low cost •  Low toxicity O
OH
O
O
NH
O
O
99%
93% ee
O
O
O
H O
H N
H
O
O
OH
Chiral Lewis Acids
Exploits difference in the energe)cs of the enan)omeric transi)on states O
H
Me3SiCN
H OH
82% ee
O
TiCl2
O
Reetz. Chem. Ind. 1986, 824 Bao. J. Am. Chem. Soc. 1993, 115, 3814 CN
Microorganism Biocatalysis
O
Cl
Culture of Candida kefyr
O
O
OH O
Cl
79%
~ 100% ee
Jung. Adv. Biochem. Engin. Biotech. 1993, 50, 21 Schmid. Nature 2001, 409, 258 O