Kem-4.450 Asymmetric · PDF fileKem-4.450 Asymmetric Synthesis ... Fraction 4 16.0 58.0 ......

© Helsinki University of Technology, Laboratory of Organic Chemistry© Ari Koskinen, 2007

KemKem--4.450 Asymmetric Synthesis4.450 Asymmetric Synthesis

Prof. Ari KoskinenLaboratory of Organic Chemistry


ChiralityChirality and Differing Propertiesand Differing Properties

O O

HO2CNH2 H

N CO2Me

O

HO2CNH2 H

N CO2Me

O

NH

O O

N

O

ONH

O O

N

O

O

Carvone

Aspartame(Nutrasweet)

Thalidomide

spearmint odor caraway

sweet bitter

sedative, hypnotic teratogenic


PharmaceuticalsPharmaceuticals

Growing need for enantiopure compoundsEnantiomers/diastereomers may have adverse effectsDiastereomers usually easier to separateEnantiomers: FDA required


PharmaceuticalsPharmaceuticals

CO2HSH

NH2

CO2HSH

NH2

NO

NS

N

OOH H

N NO

NS

N

OOH H

N

Penicillamine:

antidote for Pb, Au, Hg can cause optic atrophy => blindness

Timolol:

adrenergic blocker ineffective


Chem. Eng. News 2001, 79 (40), 79-97.

Sales of Enantiomeric Drugs and IntermediatesSales of Enantiomeric Drugs and Intermediates


Asymmetric Induction Asymmetric Induction -- DefinitionsDefinitions

BH

O OH OH

AcO

AcO

AcO

HO

+

A.I. if not 1:1

C2 axis

Asymmetric Induction (A.I.) - process that breaks (local) mirror symmetry

Prostaglandin synthesis intermediateDanishefsky, S.J. JACS 1989, 111, 3456.

Chirality - handednessAsymmetry - lacking all symmetry (except E)Dissymmetry - lacking some element of symmery

NB!!! Molecules can be chiral but not asymmetric! e.g.


Specificity Specificity vsvs SelectivitySelectivity

OOH

H

H OH

H

HO H

H

1) BH3

2) H2O2; HO-

1) BH3

2) H2O2; HO-

Li, NH3, tBuOH

SPECIFICITY - non-statistical outcome of reaction- mechanism based- product determined by thermodynamics (product stability OR rates)

SELECTIVITY

SELECTIVE PROCESS:

SPECIFIC PROCESS:

ALL specific reactions must be selective, but not necessarily vice versaTwo reactions must be carried out to determine if a process is specific


Optically Active SubstancesOptically Active Substances

Chemocatalysis Biocatalysis

Asymmetric synthesis

Prochiral substrates


Optically Active SubstancesOptically Active Substances

Chemical Enzymatic

Kinetic resolution Diastereomer crystallisation

Racemates


Enantioselective SynthesisEnantioselective Synthesis

Purpose:Purpose:to create single enantiomerto control stereochemistry at remote sites

Methods:Methods:resolution

requires separationloss of material

chiral pooladditional operations

asymmetric transformations (rare)Asymmetric induction


Enantioselective SynthesisEnantioselective Synthesis

For A.I. to be practical

> 99% eeAccess both configurationsGeneral transformationsControl agent readily availableNO added stepsCatalysis:

SpeedSelectivityStabilitySafetySustainability

$

+

1


Methods for Obtaining Enantiopure CompoundsMethods for Obtaining Enantiopure Compounds

Purchase directly from a commercial supplierPurchase directly from a commercial supplierIsolate from natural sourcesIsolate from natural sourcesResolutionResolution

direct crystallizationdirect crystallizationdiastereomericdiastereomeric derivativesderivativeschiral chromatographychiral chromatography

Asymmetric TransformationsAsymmetric TransformationsAsymmetric Induction (AI)Asymmetric Induction (AI)

internal a.i. (chiral SM)internal a.i. (chiral SM)relayed a.i. (chiral AUX)relayed a.i. (chiral AUX)external a.i. (chiral RGT)external a.i. (chiral RGT)

Morrison, J.D. Asymmetric Synthesis vol 1, 1983, 1.



Purchase directly from a commercial supplierPurchase directly from a commercial supplier

Problems: Availability, price, purity, ...

A growing number of small companies sell tailor-madespecialty chemicals.

Applicable also in industry: contractors.



Isolate from natural sourcesIsolate from natural sourcesIdeally a nearly unlimited source of new structures.

Tedious!!!

Finding the source!!!

May require vast amounts of purification, structureidentification and labor.

Semisynthetic derivatives (e.g. penicillins).

NB!!! NOT ALL NATURAL PRODUCTS ARE ENANTIOPURE!!!



ResolutionResolutiondirect crystallizationdirect crystallization

Industrial production of Mentholthrough fractional crystallizationof benzoate ester intermediates

Haarmann & Reimer

OHOH OH OH OH

+distil

PhCOCl

benzoate esters

crystallize

OBz OBz+

OH OH


Solubility and melting point diagramsSolubility and melting point diagrams

racemic mixture(conglomerate)

0 50 100%(+)100 50 0%(-)

0 50 100%(+)100 50 0%(-)

racemic solid solution

0 50 100%(+)100 50 0%(-)

racemic compound(racemate)

0 50 100%(+)100 50 0%(-)

0 50 100%(+)100 50 0%(-)


Optical purity during titration with Optical purity during titration with aqaq NaOHNaOH

50

0 50 100%

100 motherliquor

precipitate

N

SN.HCl

starting optical purity


134

122

0100

5050

0 (L)100 (D)

Sample enantiomeric purity % of L-isomer Stg material 20.7 60.3 Fraction 1 37.2 68.6 Fraction 2 31.5 65.7 Fraction 3 25.2 62.6 Fraction 4 16.0 58.0 Fraction 5 4.7 52.3 Stg material 60.2 80.1 Fraction 1 52.5 76.3 Fraction 2 62.0 81.0 Fraction 3 64.1 82.1 Fraction 4 74.3 87.1

CO2H*

OH

S CO2H

H

H

OH

6 %ee 74 %ee 40 %ee 64 %ee racemic non-racemic

Other related examples:

Fractional Sublimation of Fractional Sublimation of LL--Mandelic AcidMandelic Acid



ResolutionResolutiondiastereomericdiastereomeric derivativesderivatives

Corey, E.J. et al. J. Am. Chem. Soc. 1970, 92, 396.

O

OHN

O Ph

MeMe H

H

H

O O O

OHMe H

H

H

O O

hydrolyze

Separate 1:1 mixture of diastereomers by column chromatography

NB! Both enantiomers of this half singleenantiomer



ResolutionResolutionchiral chromatographychiral chromatography

Chiral Stationary Phaseor

Chiral Mobile Phase Additive

Pirkle, W.H.; Finn, J. Asymmetric Synthesis, vol. 1, 1983, 87.

Several applications, both analytical and preparative.

Price!

Columns available ‘on request’.



Asymmetric TransformationsAsymmetric Transformationsfirst orderfirst ordersecond ordersecond order

Thermodynamical control

Equilibrium between enantiomers or epimersis set up to favour one or the other of the products.



Asymmetric TransformationsAsymmetric Transformationsfirst orderfirst order

Classical example: spontaneous crystallisationof NaClO4 from aqueous solution. 844 trials,51.3 % left handed, 48.7 % right handed crystals.

Conditions set up so as to favore.g. crystallisation of one anantiomer.

Soret, C.H. Z. Krystallogr. Mineral. 1901, 34, 630.



Asymmetric TransformationsAsymmetric Transformationssecond ordersecond order

N

N

MeO

NH2

N

N

MeO

NH2

CSA, i-PrOAc/MeCN

CHO

Cl

Cl

Reider, P.J. et al. J. Org. Chem. 1987, 52, 955.



Asymmetric Induction (AI)Asymmetric Induction (AI)internal a.i. (chiral SM)internal a.i. (chiral SM)

Rapoport, H. et al. J. Org. Chem. 1990, 55, 3068.

NN

MeO2CHO

HCO2HH2N

HO2C

Aspartic acid Vincamine


Internal AIInternal AI

O

CO2Me

OHPh

O

CO2MePh

OB

H

OAcAcO

CO2Me

OHPh

OH

Turnbull, M.D. et al. Tetrahedron Lett. 1984, 25, 5449.

Chelation controls selectivity

(Saksena, A.K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273.)



Asymmetric Induction (AI)Asymmetric Induction (AI)relayed a.i. (chiral AUX)relayed a.i. (chiral AUX)

NO

O O

Bn

H

O

NO

O

Bn

O

NCS

OSnL

X*NNCS

OOH

HONHMe

O O

X*N OHN

S

Sn(OTf)2

1) NaHMDS2) MeI

3) LAH4) Swern

1) Me3O+ BF4-

2) H2O

3) KOH4) H3O+



Asymmetric Induction (AI)Asymmetric Induction (AI)external a.i. (chiral RGT)external a.i. (chiral RGT)

H2O

catalyst

NMe2

OH

R' R

HHOR'CHO+R2Zn

Noyori, R. Science 1990, 248, 1194.Angew. Chem., Int. Ed. Engl. 1991, 30, 49.



Asymmetric Induction (AI)Asymmetric Induction (AI)external a.i. (chiral RGT)external a.i. (chiral RGT) N

ZnO

ZnO

N

Me2

Me2

R

R

NZn

OZn

O

N

Me2

Me2

R

R

NZn

OZn

O

N

Me2

Me2

R

R

NZn

O

Me2

R ZnO

NMe2

R+

CHIRALITY MULTIPLICATION

020406080

100120

%ee in DAIB

%ee

in P

rodu

c

OH

H

O


JAMYAX JAMYEB

DAIBDAIB--Zn XZn X--ray structuresray structures


Reagent Control in Double Reagent Control in Double StereodifferentiationStereodifferentiation

S,S-reagent

R,R-reagent

Allyl-MgCl

99.5 %0.5 %

1.9 %98.1 %

44.9 %55.1 %

Reagent

R,R-reagent

+

Ti

OO

OO

PhPh

PhPh

ON

BOC

OH

ON

BOC

OH

ON

BOC

H

O

Duthaler, R.O. et al. J. Am. Chem. Soc. 1992, 114, 2321.


Asymmetric Induction Asymmetric Induction -- Economy?Economy?

•• relayed a.i. (chiral AUX)relayed a.i. (chiral AUX)•• Source of Source of chiralitychirality removedremoved

NO

O O

Bn OH

HONHMe

O

NH2HO

Bn+

•• external a.i. (chiral RGT)external a.i. (chiral RGT)•• Can be catalyticCan be catalytic•• ReRe--usable (?)usable (?)

R' R

HO HOH

NMe2

H2Ocatalyst

R'CHO+R2Zn

•• internal a.i. (chiral SM)internal a.i. (chiral SM)•• ChiralityChirality incorporated (and multiplied) in incorporated (and multiplied) in

productproduct

CO2HH2N

HO2CN N

H

MeO2CHO


Modes of Access to Enantiopure CompoundsModes of Access to Enantiopure Compounds

resolution

transformation

internalasymmetric induction

chiralitymultiplication

chiralityamplification

externalasymmetric induction

relayedasymmetric induction

Noyori, ACIEE 2001, 40.


PolarimetryPolarimetry

Precautions:longest path, large diameterstrained glass (=distorted glass) polarized beam; use center filled tubesparticles; rotate cell, measure againair bubbles - refract lightcolored sample

[α]λ =α

l.c [α]max

[α]obs% o.p. =


EnantiopurityEnantiopurity

%%eeeeee = enantiomeric excess

e.g. mixture 80 % R, 20 % S%ee = |80 - 20| = 60 %ee

100|%%||%%|% ∗

+−

=SRSRee

MeO2COH

CO2MeOH

MeO2COH

CO2MeOH

MeO2COH

CO2MeOH

MeO2COH

CO2MeOH

R SR

RR

S

SS

60 % 20 %

20 %

%ee =60 - 2060 + 20

* 100 = 50 %ee


Enantiomeric ExcessEnantiomeric Excess

Often %e.e. = % o.p., but sources for error[α]max must be knownsolvent, concentration and temperature

reproduction of literature concentratione.g. CHCl3 - how much EtOH?

EtOH - ?rotation not necessarily linear with %ee because of association phenomena[α] not constant for all molecules in solution (impurities with large [α])

R R

R S

S R

S S

R, Senantiomeric

pairs


Optical Rotation Optical Rotation vs.vs. Enantiomeric ExcessEnantiomeric Excess

Achiral impurity can affect optical rotation:

Yamaguchi, S.; Mosher, H.S. J. Org. Chem. 1973, 38, 1870.

O OHLiAlH4, Darvon

*

Increases rotation!!!


Practical Determination: NMRPractical Determination: NMROptically active solvent

use either as sole solvent or more generally as additiveoften requires optimization of mol fractions

NH2

HH3CPh

OH

CF3HPhROH, α-OH acids RNH2,

amino acids


Practical Determination: NMRPractical Determination: NMRDiastereomers

different physical properties− α-methoxy-α-trifluoromethyl phenylacetic acid

(MTPA = Mosher’s acid; Dale Mosher J. Am. Chem. Soc. 1973, 512)

- others: e.g. isocyanates

OMe

CO2HC3FPh MTPA-Cl Ester

Amide

Me

NCO

Me

NCO


Practical Determination: NMRPractical Determination: NMRChiral shift reagent

need not make anythingadd more & more until peaks split

Whitesides, G. J. Am. Chem. Soc. 1974, 1038.Sullivan Top. Stereochem. 1977, 10, 287.

always use dry solventsalways confirm with racemic material! (peak positions)

O

OH

C3F7

hfc = heptafluorocamphorato

Eu(hfc)3


Practical Determination: HPLCPractical Determination: HPLC

Make diastereomeric derivativessame restrictions as in NMR

Chiral columnsBY FAR the most reliable methodcolumns available nearly tailor-made


Creation of StereocentersCreation of StereocentersEnantiotopic differentiation

R1

R1 R2R3

R4

R1 R2R3

R4

R1R2

R3

sp3 sp3

prochiral sp3 center

mirror

Me

PhHHproR

proS

Hanson J. Am. Chem. Soc. 1966, 88, 2731.Tetrahedron 1974, 30, 3649.


EnantiotopicEnantiotopic differentiationdifferentiation

PhO O

O

H

O

OR*

HO

HH

H

SnCl4, -78 C74 %

single diastereomer

Whitesell, J.K. J. Org. Chem. 1985, 50, 3025.

CO2Me CO2Me

OH(+)-Ipc2BH

Uskokovic, M. J. Am.Chem. Soc. 1973, 95, 7171.



O

NPh PhLi

OH31 %o.p.

Whitesell, J.K. J. Org. Chem. 1980, 45, 755.

O OTMSNN

LiN

Ph

Me

TMS-Cl

97 %ee

Koga, K. J. Am. Chem. Soc. 1986, 108, 542.



Natural amino acid => natural steroid configurationamide, ester not as efficient; need bifunctional catalystamino acid can be used catalyticallypolar aprotic solvent => aldol productmineral acid present => enonerather insensitive to temperature (120 °C: 64 %ee)

OR

O

O

O

RO O

O

RO

OH

O

RO

L-Pro

HAJOS-EDER-WIECHERT PROCESS

HClO4

97 %ee

Cohen Accts. Chem. Res. 1976, 412.


Synthetic ConsiderationsSynthetic Considerations

MechanismMolecular structural requirementsRxn limitations (pH, pKa, temp, hν, etc)Rxn conditions compatibilityYieldOperational points


Further ConsiderationsFurther Considerations

Efficiency of overall scheme (Y, %ee)SM’s: price, availabilitySelectivity:

chemoregiostereo

Add to general knowledge of TGTFGI reagents (often serendipitous)


Creation of StereocentersCreation of Stereocenters

Y

X R1R2

Y

XR1

R2

sp2 sp3

prochiral sp 2 center

mirrorXR1

R2

Enantiofacial differentiation

Ph Me

O

Me Ph

O

si re

Hanson J. Am. Chem. Soc. 1966, 88, 2731.Tetrahedron 1974, 30, 3649.


Enantiofacial differentiationEnantiofacial differentiation

OH OH

OH

OH

(S)-BINAP-Ru

(S)-BINAP-Ru

(R)-BINAP-Ru 96-99 %ee

PP

Ru(OCOR)2

Ph2

Ph2

PP

Ru(OCOR)2

Ph2

Ph2

(R)-BINAP-Ru (S)-BINAP-Ru

Noyori, R. Chem. Soc. Rev. 1989, 18, 187.Accts. Chem. Res. 1990, 23, 345.


Methods for Asymmetric InductionMethods for Asymmetric Induction1) Reagent modification

Al-O H

ORO* Li+

OAl-

O

H

OR

Advantages:

Disadvantages:

•no separate reactions on substrate•possibility for catalysis•can be designed (if TS known)

well defined TS for bimolecular rxns rareanalysis of results difficult


Methods for Asymmetric InductionMethods for Asymmetric Induction2) Substrate modification

OH

ON

O

O

O

Ph

N

O

O

O

PhR

OH

O

R

Advantages:

Disadvantages:

•fixed interaction between auxiliary/substrate•products diastereomers: analysis simple

two extra stepscannot be catalytic


Methods for Asymmetric InductionMethods for Asymmetric Induction2) Substrate modification

b) Weak bonda) Strong bond

Advantages:

Disadvantages:

•rxns for attachment/removal easier•possibility for catalysis

combination of rgt modification and strong bond

O N OR


op = ee?op = ee?

Horeau, A. Tetrahedron Lett. 1969, 36, 3121-3124.


NonNon--linear effectslinear effects

Line A: No effectB: Positive non-linear effectC: Negative non-linear effect


NonNon--linear effect in aldollinear effect in aldol

Evans, D.A. et al. J. Am. Chem. Soc. 1999, 121, 669-685.


NLE in DielsNLE in Diels--AlderAlder

Kobayashi, S. et al. Tetrahedron Lett. 1994, 35, 6325-6328.

Kem-4.450 Asymmetric · PDF fileKem-4.450 Asymmetric Synthesis ... Fraction 4 16.0 58.0 ......

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