Introduction to Asymmetry - Medicinal Chemistry Faculty Research | Medicinal Chemistry ... ·...

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

Ault, A. Organic Syntheses, 1969, 49, 93.

•  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

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

Deeter, J.; et al Tetrahedron Le=. 1990, 31, 7101. Fujima, Y.; et al Org. Process Res. Dev. 2006, 10, 905.

•  Resolu)on-‐Racemiza)on-‐Recycle –  Synthesis of Duloxe)ne (Eli Lilly) –  Mandelic acid used as resolving agent

Enzyma)c Resolu)on

Kazlauskas, R. J. Organic Syntheses 1992, 70, 60.

•  Kine)c Resolu)on –  Two enan)omers have different reac)on rates –  Enzyma)c resolu)on

•  Use towards total synthesis –  Amano PS lipase resolves secondary alcohols

Another Enzyma)c Resolu)on

Batwal, R. U. et al. Tetrahedron: Asymmetry 2011, 22, 173.

•  Derived from plants

•  Carbohydrates

•  Amino Acids

Chiral Pool Synthesis

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


Decent scope S)ll limited in scope

No auxiliary cleavage Requires op)miza)on

Enzymes can be cheap Low ee’s

Chiral Pool Synthesis


Enan)omerically pure Extra steps

Cheap source of chirality One ena)omer is available

Precedent

•  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

Chiral Auxiliaries

Corey, E. J. et al J. Am. Chem. Soc. 1975, 97, 6908.

•  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 Aldol Reac)on

Evans, D. A.; et al. J. Am. Chem. Soc. 1981, 103, 2127.

Zimmerman-‐Traxler Transi)on State

•  Auxiliary Removal

•  An)-‐Aldol

–  Open transi)on state under Lewis acid condi)ons –  An) is more thermodynamically stable

Evans aldol Con)nued

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.

•  Crimmins –  Oxazolidinethiones –  Titanium has a higher affinity for S than O

–  Easy to remove

•  Alcohol (NaBH4) •  Weinreb amide (NHCH3OMe) •  Methyl ester (MeOH)

Other Chiral Auxiliaries

Base Equiv Yield Evans:Non-‐Evans

DIPEA 2.5 86 86:14

DIPEA 1.1 75 5:95

Crimmins, M. T.; et al. J. Org. Chem. 2001, 66, 894.

•  Myers –  Both (R,R) and (S,S) pseudoephedrine

Other Chiral Auxiliaries

Myers, A. G.; et al. J. Am. Chem. Soc. 1997, 119, 6496.

Chiral Auxiliaries


Very Selec)ve Adds two steps to synthesis

Mul)ple Auxiliaries Expensive/make

Precedent

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 CO2H HO2C H

Optically pureO

O N

O

O

H

HH

H

N

Marckwald, W. Berichte der deutschen chemischen GesellschaO 1904, 37, 349

•  Metal ligand complexes with chiral ligands •  Chiral organocatalysts •  Biocatalysis •  Chiral Lewis acids

Metal Complex Enantioselective Reactions

E. Erlenmeyer and H. Erlenmeyer, Biochem. Zeitschr. 1922, 233, 52 D. Lipkin and T.D. Stewart, J. Am. Chem. Soc. 1939, 61, 3295

•  First heterogeneous by Erlenmeyer •  ZnO/d-‐Fructose •  Addi)on of Br2 across double bond

OHN

H

N

O

OH

8-9% ee

O

OH

Optically active(+)-!-phenylbutyric acid

PtO2

Metal Complex Enantioselective Reduction

Knowles, S. Chem. Comm. 1968, 1445 Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001

PP

MeOOMe

[RhL,COD]BF4H2MeO

O

CO2H

NHCOMe

MeO

O

CO2H

NHCOMe

L-DOPA

HH

HO2C

(+)-hydratropic acidP

[RhL,COD]BF4H2

HO2C

15% ee

DiPAMP


Knowles, S. Chem. Comm. 1968, 1445

PP

MeOOMe

[RhL,COD]BF4H2MeO

O

CO2H

NHCOMe

MeO

O

CO2H

NHCOMe

L-DOPA

HH

Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001


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

Sharpless, K.B. J. Am. Chem. Soc. 1980, 102, 5979

Allylic Alcohol Epoxide % Yield % ee (Eu)

77 95

79 94

70 >95

87 >95

OH

OH

OAc

OH

OHPh

Ph

OH

OH

OH

OH

O

H

OH

O

HPh

PhOH


Kungl. Vetenskapsakademien. The Royal Swedish Academy of Sciences. Advanced informa)on of the Nobel Prize in Chemistry 2001


Sharpless, K.B. J. Am. Chem. Soc. 1980, 110, 1968

R1

R3 R2 0.2 - 0.4% OsO4, NMO R2

OH

R1

R3 OH

80 - 95% yield20 - 80% ee

N

HR'OAr

N

HR'OAr

R' = p-chlorobenzoyl

OH" OH"

OH"OH"

Metal Complex Enantioselective C-C Bond Formation!•  Formulation

Polymer Supported Pt Catalyst

S)lle. J. Am. Chem. Soc. 1987, 109, 7125

N

O O

PPh2

Ph2P

PtClSnCl3

Metal Complex Enantioselective C-C Bond Formation!•  Grignard Cross-Coupling

SiMe3

Ph MgBrBr

SiMe3

Ph63% 85% ee

Kumada. J. Org. Chem. 1986, 51, 3772

PPh2

Fe

H

NMe2Pd

H

PhSiMe3

Metal Complex Enantioselective C-C Bond Formation!•  Allylic Alkylation

CO2Me

OAc

CO2Me

AcO

CO2Me

CO2Me

Na CO2Me

95% 72% ee

Yoshihiko. Tet. Le=. 1986, 27, 191

PPh2

Fe

HNMe

Pd

R

RNOH

OH

NuR2P

Metal Complex Enantioselective C-C Bond Formation!•  Cyclopropanation

Fritschi. Angew. Chem. 1986, 98, 1028

Ph N2CHCO2EtPh CO2Et

Cu

25-75% 68-97% ee

CN

NH

NHH

HO OH

Metal Complex Enantioselective C-C Bond Formation!•  Diels Alder

39% ee

PhH

O

OtBu

TMSO TMSOH

H

OtBu

PhH

Danishefsky. Tet. Le=. 1983, 24, 3451

Metal Complex Enantioselective C-C Bond Formation!•  Hydrocyanation

HCNCNPdL2

6%40% ee

Hodgson. J. Organomet. Chem. 1987, 325, C27

Metal Complex Enantioselective C-C Bond Formation!•  Cyclization

O

OZn

CHOOH91%

90% ee

Sakane. Tetrahedron 1986, 42, 2203

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

OO

O

NH

O

OH

O

O

OH99%93% ee

OO

OH N

O

OHH

Chiral Lewis Acids

H

OMe3SiCN H OH

CN82% ee

O

OTiCl2

Reetz. Chem. Ind. 1986, 824 Bao. J. Am. Chem. Soc. 1993, 115, 3814

Exploits difference in the energe)cs of the enan)omeric transi)on states

Microorganism Biocatalysis

O O

OCl

79%~ 100% ee

OH O

OCl

Culture of Candida kefyr

Jung. Adv. Biochem. Engin. Biotech. 1993, 50, 21 Schmid. Nature 2001, 409, 258

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