Asymmetric synthesis

Asymmetric Synthesis
Contents:
Introduction
Types
Partial Asymmetric Synthesis
Absolute Asymmetric Synthesis
Asymmetric induction approaches
Enantioselecrive catalysis
Chiral Auxiliaries
Bio-catalysis
Chiral pool synthesis..

S. Y. B. Pharmacy
Sem -IV

1. levorotatory Dextrorotatory
© Dr. Atul R. Bendale

2. Asymmetricsynthesis,alsoknownasEnantioselectivesynthesis.
ItisdefinedbyIUPACas:achemicalreaction(orreactionsequence)in
whichoneormorenewelementsofchiralityareformedinasubstrate
moleculeandwhichproducesthestereoisomeric(enantiomericor
diastereoisomeric)productsinunequalamounts.
Moresimply:Thesynthesisofanasymmetriccompoundcarriedwiththe
helpofanopticallyactivemoleculeorgroupistermedasymmetric
synthesis.
[Enantiomersarestereoisomersthathaveoppositeconfigurationsatevery
chiralcenter.
Diastereomersarestereoisomersthatdifferatoneormorechiralcenters.]
© Dr. Atul R. Bendale

3. Insuchsynthesisthetwodandlformsarenotproducedinequalquantities.
For example, pyruvic acid on reduction yields a dl mixture of lactic acid
Butifitisesterifiedwithsomeopticallyactivealcohol(ROH*)andthen
reduced,theresultingesteronhydrolysisyieldsanopticallyactivelactic
acid.
© Dr. Atul R. Bendale

4. Theasymmetricsynthesisexplainswhymostasymmetriccompounds
obtainedfromnaturalsourcesareopticallyactive.
Innature,thesynthesesarecarriedoutundertheinfluenceofoptically
activeenzymes.
Theenzymesunitewiththesubstanceandwhenthesynthesisiscomplete,
theyseparatefromtheproductandareagainfreetocombinewithfresh
moleculesoftheoriginalsubstance.
Thusthereexistsaradicaldifferencebetweenthereactionsthatgoonin
theanimalandvegetableworldontheonehandandthoseinthe
laboratoryontheother.
Enantioselectivesynthesisisakeyprocessinmodernchemistryandis
particularlyimportantinthefieldofpharmaceuticals,asthedifferent
enantiomersordiastereomersofamoleculeoftenhavedifferentbiological
activity.
© Dr. Atul R. Bendale

5. Manyofthebuildingblocksofbiologicalsystemssuchassugarsandamino
acidsareproducedexclusivelyasoneenantiomer.
Asaresult,livingsystemspossessahighdegreeofchemicalchiralityand
willoftenreactdifferentlywiththevariousenantiomersofagiven
compound.
Examplesofthisselectivityinclude:
Flavour:theartificialsweeteneraspartamehastwoenantiomers.L-
aspartametastessweetwhereasD-aspartameistasteless.
Odor:R-(–)-carvonesmellslikespearmintwhereasS-(+)-carvonesmellslike
caraway.
Drugeffectiveness:theantidepressantdrugCitalopram,onlythe(S)-(+)
enantiomerisresponsibleforthedrug'sbeneficialeffects
Drugsafety:D-penicillamineisusedinchelationtherapyandforthe
treatmentofrheumatoidarthritiswhereasL-penicillamineistoxic.
Assuchenantioselectivesynthesisisofgreatimportancebutitcanalsobe
difficulttoachieve.
OVERVIEW Of ASYMMETRIC SYNTHESIS
© Dr. Atul R. Bendale

6. Why we always need a chiral component to achieve asymmetric
synthesis?
The answer is if both reactant and reagent are achiral resulting transition
state is enantiomericand results in racemic products.
© Dr. Atul R. Bendale

7. TYPES Of ASYMMETRIC SYNTHESIS
1.Partial asymmetric synthesis
2. Absolute asymmetric synthesis
© Dr. Atul R. Bendale

8. 1.Partialasymmetricsynthesis
Definedasamethodforpreparingopticallyactivecompoundfrom
opticallyinactivesubstancebytheuseofopticallyactivereagentbut
withouttherequirementofresolution(withoutseparation).
Principle
1.Forpreferentialformationofonestereoisomerovertheother,the
reagentmustbeinpureenantiomericform.
2.Thechiralreagentmustplayactiveroleinthereaction(transitionstate)
3.Chiralreagentreactwithenantiomeratdifferentrates.
Sochiralreagentinvolvedinasymmetricsynthesisshouldleadtorapid
completiontoproducepurestereoisomericproduct(pureenantiomer).
© Dr. Atul R. Bendale

9. For Example
Direct reduction of pyruvic acid yield racemic mixture of lactic acid
Here, in this reaction neither pyruvic acid nor hydrogen are chiral but the
product lactic acid is chiral. However it is produced in racemic form i.e.
equimolarmixture of (+) and (–) enantiomer. It becomes stereo-selective
reaction.
So, how one can prepare pure enantiomer that we will see ahead…
© Dr. Atul R. Bendale

10. ModificationinReaction
•Ifpyruvicacidispre-esterifiedwithopticallyactivealcohol(-)menthol
andthereafterreducedandsubsequentlyhydrolysed,theresultant
productformedexclusivelypureenantiomer(-)lacticacid
(enantioselectivereaction)
•Ifreactionleadstoformationofenantiomerproducesmajorityofone
enantiomeroveritsmirrorimage(otherenantiomer)thereactionis
saidtobeEnantioselective.
•Inthischiralreagentmustassertaninfluenceonthecourseofreaction.
•Inthisreactionpreferredenantiomerisformedalongwithsmall
amountofun-preferredenantiomerandhenceitiscalledaspartial
asymmetricsynthesis.
© Dr. Atul R. Bendale

11. © Dr. Atul R. Bendale
For example (-) menthol utilized for asymmetric synthesis of (+) tartaric
acid, (+) maleic acid, (-) nicotine etc.

12. 2. Absolute asymmetric synthesis
Preparationofopticallyactivecompoundfromopticallyinactivesubstance
withouttheuseofchiralreagentbutjustirradiatingitbyrightorleft
circularlypolarisedlightiscalledabsolute(total)asymmetricsynthesis.
Here one of the enantiomer is selectively or preferentially decomposed by
the light irradiated.
© Dr. Atul R. Bendale

13. © Dr. Atul R. Bendale
For Example
Aracemicmixtureof(±)azidopropionicaciddimethylamidewhen
irradiatedseparatelybyrightandleftcircularlypolarizedlightyieldedthe
correspondingun-decomposedproductswithcorresponding(+)and(-)
rotation.

14. Asymmetric induction Approaches
1.Enantioselectivecatalysis
Theyarechiralcoordinationcomplexes.
Catalysisiseffectiveforabroaderrangeoftransformationsthananyother
methodofenantioselectivesynthesis.
Thecatalystsarealmostinvariablyrenderedchiralbyusingchiralligands.
Mostenantioselectivecatalystsareeffectiveatlowsubstrate/catalyst
ratios.
Giventheirhighefficiencies,theyareoftensuitableforindustrialscale
synthesis.
Aversatileexampleofenantioselectivesynthesisisasymmetric
hydrogenation,whichisusedtoreduceawidevarietyoffunctionalgroups
© Dr. Atul R. Bendale

15. 2.Chiralauxiliaries
Achiralauxiliaryisanorganiccompoundwhichcouplestothestarting
materialtoformanewcompoundwhichcanthenundergo
enantioselectivereactionsviaintramolecularasymmetricinduction.
Attheendofthereactiontheauxiliaryisremoved,underconditionsthat
willnotcauseracemizationoftheproduct.Itistypicallythenrecoveredfor
futureuse.
© Dr. Atul R. Bendale

16. AdvantagesofUsingChiralAuxiliaries
(a)highlevelsofdiastereofacialcontrolinthereactions
(b)Thediastereomersgeneratedfromtheuseofchiralauxiliaries
canbeseparatedbytheuseofsimplemethods(suchaschromatography
andcrystallization).
(c)Chiralauxiliariescanberecycled(re-used)
DisadvantagesofUsingChiralAuxiliaries
(a)Bothenantiomersofachiralauxiliaryareusuallynotreadilyavailable.
Moreoften,oneenantiomermaybefarmoreexpensivethantheother.
(b)Chiralauxiliariesneedtobesynthesized.
(c)Aswithprotectinggroups,thereareextrastepsassociatedwiththeuse
ofchiralauxiliaries.Thechiralauxiliaryhastobeintroducedandthen
removedonceitpurposehasbeenaccomplished.
© Dr. Atul R. Bendale

17. QualitiesofaGoodChiralAuxiliary
(a)Needstobeavailableinbothenantiomericforms
(b)Needstobeeasyandquicktosynthesize
(c)Mustbereadilyincorporatedontoanachiralsubstrate
(d)Itshouldprovidegoodlevelsofasymmetricinductionleadingto
highenantiomericexcess.
(e)Needstobeselectivelycleavedfromthesubstrateundermild
conditions
(f)Mustberecoverableandre-useable
© Dr. Atul R. Bendale

18. 3.Biocatalysis
Biocatalysismakesuseofbiologicalcompounds,rangingfromisolated
enzymestolivingcells,toperformchemicaltransformations.
Theadvantagesofthesereagentsincludeveryhighreagentspecificity,as
wellasmildoperatingconditionsandlowenvironmentalimpact.
Biocatalystsaremorecommonlyusedinindustryforexampleinthe
productionofstatins.
© Dr. Atul R. Bendale

19. 4.Chiralpoolsynthesis
Chiralpoolsynthesisisoneofthesimplestandoldestapproachesfor
enantioselectivesynthesis.
Areadilyavailablechiralstartingmaterialismanipulatedthrough
successivereactions,oftenusingachiralreagents,toobtainthedesired
targetmolecule.Thiscanmeetthecriteriaforenantioselectivesynthesis
whenanewchiralspeciesiscreated,suchasinanSN2reaction.
Chiralpoolsynthesisisespeciallyattractivefortargetmoleculeshaving
similarchiralitytoarelativelyinexpensivenaturallyoccurringbuilding-
blocksuchasasugaroraminoacid.
However,thenumberofpossiblereactionsthemoleculecanundergois
restrictedandindirectsyntheticroutesmayberequired(e.g.Oseltamivir
totalsynthesis).
© Dr. Atul R. Bendale

20. followChemistry
blog
www.atulbe
ndale.wordp
ress.com
Chemistry
Presentation
shttps://www.
slideshare.net
/AtulBendale
2/presentatio
ns
Chemistry
YouTube
Channelhttps://www.yo
utube.com/play
list?list=PLEzjdj
OCsRvJAiJ1Elhu
wq_LV1eInfN4-
© Dr. AtulR. Bendale