Kem-4.450 Asymmetric Synthesis

Home , Asymmetric induction

KemKem--4.4504.450 AsymmetricAsymmetric SynthesisSynthesis

Prof. Ari Koskinen Laboratory of Organic Chemistry

ChiralityChirality andand DifferingDiffering PropertiesProperties

OO Carvone

spearmint odor caraway

NH NH 2 H 2 H Aspartame HO2C NCO2Me HO2C NCO2Me (Nutrasweet) O O

sweet bitter

O O

Thalidomide N N O O OON OON H H sedative, hypnotic teratogenic

Growing need for enantiopure compounds Enantiomers/diastereomers may have adverse effects Diastereomers usually easier to separate Enantiomers: FDA required

Penicillamine: NH2 NH2

CO2H CO2H SH SH

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

Timolol:

O OH O OH H H N O N N O N

N N N N S S

adrenergic blocker ineffective

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

Chirality - handedness Asymmetry - lacking all symmetry (except E) B Dissymmetry - lacking some element of symmery H NB!!! Molecules can be chiral but not asymmetric! e.g.

C2 axis

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

OOHOH +

A.I. if not 1:1

AcO AcO

Prostaglandin synthesis intermediate Danishefsky, S.J. JACS 1989, 111, 3456. AcO HO

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

SELECTIVE PROCESS: t O Li, NH3, BuOH H OH

SPECIFIC PROCESS: 1) BH3 H 2) H O ; HO- 2 2 HOH

ALL specific reactions must be selective, but not necessarily vice versa Two reactions must be carried out to determine if a process is specific 1) BH3 H 2) H O ; HO- 2 2 HO H

Prochiral substrates

Asymmetric synthesis

Chemocatalysis Biocatalysis

Racemates

Kinetic resolution Diastereomer crystallisation

Chemical Enzymatic

Purpose: to create single enantiomer

to control stereochemistry at remote sites

Methods: resolution z requires separation z loss of material

chiral pool z additional operations

asymmetric transformations (rare)

Asymmetric induction

For A.I. to be practical

> 99% ee Access both configurations General transformations Speed Control agent readily available Selectivity Stability NO added steps Safety Catalysis: + Sustainability 1 $

Purchase directly from a commercial supplier Isolate from natural sources Resolution direct crystallization diastereomeric derivatives chiral chromatography Asymmetric Transformations Asymmetric Induction (AI) internal a.i. (chiral SM) relayed a.i. (chiral AUX) external a.i. (chiral RGT)

Morrison, J.D. Asymmetric Synthesis vol 1, 1983, 1. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds

PurchasePurchase directlydirectly fromfrom aa commercialcommercial suppliersupplier

Problems: Availability, price, purity, ...

A growing number of small companies sell tailor-made specialty chemicals.

Applicable also in industry: contractors.

IsolateIsolate fromfrom naturalnatural sourcessources Ideally a nearly unlimited source of new structures.

Tedious!!!

Finding the source!!!

May require vast amounts of purification, structure identification and labor.

Semisynthetic derivatives (e.g. penicillins).

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

ResolutionResolution

directdirect crystallizationcrystallization

distil + OH OH OH OH OH

PhCOCl Industrial production of Menthol benzoate esters through fractional crystallization of benzoate ester intermediates crystallize

+ OH OH OBz OBz

Haarmann & Reimer © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SolubilitySolubility andand meltingmelting pointpoint diagramsdiagrams

racemic mixture (conglomerate) racemic compound racemic solid solution (racemate)

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

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

100 mother liquor

N 50 .HCl SN

precipitate

0 50 100% starting optical purity

* CO2H

Sample enantiomeric purity % of L-isomer 134 Stg material 20.7 60.3 Fraction 1 37.2 68.6 122 Fraction 2 31.5 65.7 Fraction 3 25.2 62.6 Fraction 4 16.0 58.0 Fraction 5 4.7 52.3 0 50 0 (L) Stg material 60.2 80.1 100 50 100 (D) Fraction 1 52.5 76.3 Fraction 2 62.0 81.0 Fraction 3 64.1 82.1 Fraction 4 74.3 87.1 Other related examples:

H OH

S CO2H H

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

ResolutionResolution

diastereomericdiastereomeric derivativesderivatives

NB! Both enantiomers of this half single enantiomer H H

H H hydrolyze H O N Me OH Me H Me H OPh O O O O O O

Separate 1:1 mixture of diastereomers by column chromatography

Corey, E.J. et al. J. Am. Chem. Soc. 1970, 92, 396. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds

ResolutionResolution

chiralchiral chromatographychromatography

Chiral Stationary Phase or Chiral Mobile Phase Additive

Several applications, both analytical and preparative.

Price!

Columns available ‘on request’.

Pirkle, W.H.; Finn, J. Asymmetric Synthesis, vol. 1, 1983, 87. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds

AsymmetricAsymmetric TransformationsTransformations

firstfirst orderorder

secondsecond orderorder

Thermodynamical control

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

AsymmetricAsymmetric TransformationsTransformations

firstfirst orderorder

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

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

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

AsymmetricAsymmetric TransformationsTransformations

secondsecond orderorder

Me Cl Me O O N CHO N

NH2 Cl NH2 N N CSA, i-PrOAc/MeCN

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

AsymmetricAsymmetric InductionInduction (AI)(AI)

internalinternal a.i.a.i. (chiral(chiral SM)SM)

H H2N CO2H N N MeO C HO2C 2 HO

Aspartic acid Vincamine

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

CO2Me CO2Me Ph CO2Me Ph Ph OH OH O H O B AcO OAc O OH

Chelation controls selectivity

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

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

AsymmetricAsymmetric InductionInduction (AI)(AI)

relayedrelayed a.i.a.i. (chiral(chiral AUX)AUX)

O O 1) NaHMDS 2) MeI O NO 3) LAH H O NCS 4) Swern Bn NO O

Sn(OTf)2

+ - 1) Me3O BF4 S NHMe NCS 2) H2O HN HO X*N X*N O 3) KOH O OH + O OSnL 4) H3O O

AsymmetricAsymmetric InductionInduction (AI)(AI)

externalexternal a.i.a.i. (chiral(chiral RGT)RGT)

NMe2

OH H2O HO H R2Zn + R'CHO R' R catalyst

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

AsymmetricAsymmetric InductionInduction (AI)(AI)

Me2 Me2 N R N R externalexternal a.i.a.i. (chiral(chiral RGT)RGT) Zn Zn O O O O Zn Zn R N R N Me2 Me2

CHIRALITY MULTIPLICATION

120 Me2 N O 100 Zn R + R Zn O N 80 Me2 60 O OH H 40

%ee in Produc in %ee 20 0

Me2 N R Zn %ee in DAIB O O Zn R N Me2

JAMYAX JAMYEB

O OH OH Reagent H + O O O N N N BOC BOC BOC

Allyl-MgCl 55.1 % 44.9 %

Ti Ph R,R-reagent 98.1 % 1.9 % O O Ph S,S-reagent 0.5 % 99.5 % Ph Ph O O

R,R-reagent

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

•• relayedexternalinternalrelayedexternalinternal a.i. a.i. a.i.a.i. (chiral (chiral (chiral(chiral SM) AUX)SM) AUX)RGT)RGT) •• SourceCanChiralitySourceCanChirality bebe ofofcatalyticcatalyticincorporatedincorporated chiralitychirality removedremoved (and(and multiplied)multiplied) inin •• ReproductReproduct--usableusable (?)(?)

NMe2

O O H2N CO2H OH NHMe H HON H HO NH2 HO H O O N R Zn 2 N + 2 + R'CHO Bn HO C MeOO 2COH Bn 2 catalyst R' R HO

resolution

transformation

internal asymmetric induction

external asymmetric induction

relayed asymmetric induction

chirality multiplication

chirality amplification

Noyori, ACIEE 2001, 40. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PolarimetryPolarimetry

α [α]obs [α]λ = . % o.p. = l c [α]max

Precautions: longest path, large diameter strained glass (=distorted glass)  polarized beam; use center filled tubes particles; rotate cell, measure again air bubbles - refract light colored sample

%%eeee

ee = enantiomeric excess − SR |%%| %ee = ∗100 + SR |%%|

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

OH OH R S CO2Me CO2Me MeO2C R MeO2C S OH OH

20 % 60 % 60 - 20 %ee = * 100 = 50 %ee 60 + 20

OH OH

R CO2Me S CO2Me MeO2C S MeO2C R OH OH

20 %

Often %e.e. = % o.p., but sources for error

[α]max must be known solvent, concentration and temperature

reproduction of literature concentration

e.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]) RR RS enantiomeric R, S pairs SR SS

Achiral impurity can affect optical rotation:

OOH LiAlH4, Darvon *

Increases rotation!!!

Yamaguchi, S.; Mosher, H.S. J. Org. Chem. 1973, 38, 1870. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PracticalPractical Determination:Determination: NMRNMR

Optically active solvent

NH2 OH RNH , ROH, α-OH acids 2 Ph Ph amino acids H H3C H CF3

use either as sole solvent or more generally as additive

often requires optimization of mol fractions

Diastereomers

different physical properties

− α-methoxy-α-trifluoromethyl phenylacetic acid (MTPA = Mosher’s acid; Dale Mosher J. Am. Chem. Soc. 1973, 512)

OMe Ester Ph MTPA-Cl Amide CO H C3F 2

- others: e.g. isocyanates NCO NCO Me Me

Chiral shift reagent

need not make anything

add more & more until peaks split z Whitesides, G. J. Am. Chem. Soc. 1974, 1038. z Sullivan Top. Stereochem. 1977, 10, 287.

C3F7

OH Eu(hfc)3

hfc = heptafluorocamphorato always use dry solvents

always confirm with racemic material! (peak positions)

Make diastereomeric derivatives

same restrictions as in NMR

Chiral columns

BY FAR the most reliable method

columns available nearly tailor-made

Enantiotopic differentiation sp3 sp3

R R3 1 R2

R1 mirror R R3 1 R2 R R 2 prochiral sp3 center 1 R3

Me proR Hanson J. Am. Chem. Soc. 1966, 88, 2731. H Tetrahedron 1974, 30, 3649. H Ph proS

O Ph O O H H

H OR* single diastereomer H SnCl4, -78 C 74 % HO O

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

CO2Me CO2Me (+)-Ipc2BH OH

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

PhN Ph Li O 31 %o.p. OH

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

Ph N O N N OTMS Me Li

TMS-Cl

97 %ee

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

HAJOS-EDER-WIECHERT PROCESS

O O O O L-Pro HClO4

O O O O O O OH R R R R 97 %ee Natural amino acid => natural steroid configuration amide, ester not as efficient; need bifunctional catalyst amino acid can be used catalytically polar aprotic solvent => aldol product mineral acid present => enone rather insensitive to temperature (120 °C: 64 %ee)

Cohen Accts. Chem. Res. 1976, 412. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SyntheticSynthetic ConsiderationsConsiderations

¾ Mechanism ¾ Molecular structural requirements

¾ Rxn limitations (pH, pKa, temp, hν, etc) ¾ Rxn conditions compatibility ¾ Yield ¾ Operational points

¾ Efficiency of overall scheme (Y, %ee) ¾ SM’s: price, availability ¾ Selectivity: ¾chemo ¾regio ¾stereo ¾ Add to general knowledge of TGT ¾ FGI reagents (often serendipitous)

sp2 sp3 Enantiofacial differentiation

X R2 R1

R X 2 mirror R1

R X 1 prochiral sp 2 center R2 Y

O O Hanson J. Am. Chem. Soc. 1966, 88, 2731. Ph Me Me Ph Tetrahedron 1974, 30, 3649. si re

Ph2 Ph2 P P Ru(OCOR) Ru(OCOR) P 2 P 2

Ph2 Ph2

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

(S)-BINAP-Ru

OH OH

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

(S)-BINAP-Ru OH OH

Noyori, R. Chem. Soc. Rev. 1989, 18, 187. © Helsinki University of Technology, Laboratory of Organic Chemistry Accts. Chem. Res. 1990, 23, 345. © Ari Koskinen, 2007 MethodsMethods forfor AsymmetricAsymmetric InductionInduction

1) Reagent modification

ORO O OR - - * Al Li+ Al OH O H

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

Disadvantages: ¾well defined TS for bimolecular rxns rare ¾analysis of results difficult

2) Substrate modification

O O O O O O N O N O OH OH R R Ph Ph

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

Disadvantages: ¾two extra steps ¾cannot be catalytic

2) Substrate modification b) Weak bond a) Strong bond

ONO R

Advantages: •rxns for attachment/removal easier •possibility for catalysis

Disadvantages: ¾combination of rgt modification and strong bond

Horeau, A. Tetrahedron Lett. 1969, 36, 3121-3124. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 NonNon--linearlinear effectseffects

Line A: No effect B: Positive non-linear effect C: Negative non-linear effect

Evans, D.A. et al. J. Am. Chem. Soc. 1999, 121, 669-685. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 NLENLE inin DielsDiels--AlderAlder

Kobayashi, S. et al. Tetrahedron Lett. 1994, 35, 6325-6328. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007