OnStereochemistryandChirality

Whatistherela+onshipbetweenR,Sandd,laka(±)?

Thereisn’tany!

Interac+onwithplanepolarizedlight

Nomenclature

AllIsomers(samemolecularformula)

Iden%cal Enan%omers Diastereomers

Superimposable Non-superimposable Non-superimposable

Samespa+alarrangement

Differentspa+alarrangement

Samespa+alarrangement

Sameatomconnec+vity

Sameatomconnec+vity

Sameatomconnec+vity

Stereoisomers

Cons5tu5onal(Structural)Isomers

Samemolecularformula;differentatomconnec+vity

(-)-limonenelemon

(+)-limoneneorange

TheLimonenes

(S) (R)

MesoCompounds

CO2H

CO2HHOHO

CO2H

CO2HOHOH

CO2H

CO2H

OHHO

CO2H

CO2HOH

HO

mesotartaricacidR,S-stereoisomer

S,S-(-)-tartaricacidR,R-(+)-tartaricacid“natural”

Meso–(middleorintermediate)-theachiralmember(s)ofasetofdiastereoisomerswhichalsoincludesoneormorechiralmembers.

MesoTartaricAcid

CO2H

OHHCO2H

HHOH

CO2HHOCO2H

HHOH

OHHO2CCO2H

OHH

Whyismesotartaricacidnotop+callyac+ve?

CO2H

CO2HOHOH

HH

TheFischerprojec+onisunstable;itiseclipsedandonlyamnemonicdevicetotestforamesocompound.

An+staggeredCenterofsymmetry

GauchestaggeredRacemicmixture

Enan5omersandDiastereomers

CO2H

CO2HBrHOHH

CO2H

CO2HHBrHHO

CO2H

CO2HHBrOHH

CO2H

CO2HBrHHHO

1 2

3 4

enantiomers

diastereomers

SR

RR

SS

RS

OtherSourcesofChirality

C C CCO2H

HHO2C

HCCC

HO2C

H CO2H

H

allenedicarboxylicacid

OO

1,7-dioxaspiro[5.5]undecane

trans-cyclooctene

HH

HH

(R) "M" (S) "P"

OOO

O

(R) "M" (S) "P"

atropisomerism

A

BB

AA

BB

A

(R) "M" (S) "P"

Cholesterol–HowManyStereoisomersarePossible?

H3C

CH3

HO

H3C

2

8

16

3264

128

256

4

512conceivablestereoisomersofcholesterol

256centersofchirality(andstereochemistry)2(S),4(S),8(S),16(R),32(R),64(R),128(S),256(R)

512

Onedoublebondstereochemistry;nochirality(Althoughthedoublebondhastwostereogeniccarbons,onlytwodoublebondgeometriesarepossible.)

Allotherdoublebondisomers–namely,(E)--areimpossibletoexist.

2nstereoisomers;2n-1pairsofenan+omers

MoreonAtropisomerism

TheAmbientTemperatureUllmannReac+onandItsApplica+ontotheTotalSynthesisof(±)-Steganacin;FrederickE.Ziegler*,IreneChliwner,KerryW.Fowler,SheldonJ.Kanfer,StephenJ.Kuo,andNandaD.Sinha;J.Am.Chem.Soc.,1980,102,790.

OO

CH3O

CH3OCH3O

O

H

HO

OAc

Steganacin

tworacemiccompounds3:1ra+o

OO

CHO

CH3OCH3O

CH3OS

O

OO

CHO

CH3OCH3O

CH3OS

O

OO

CHO

CH3OCH3O

CH3OS

O

StereogenicAtoms(Stereocenters)

“Anatombearingseveralgroupsofsuchnaturethataninterchangeoftwogroupswillproduceastereoisomer.”Mislow&Siegel-1984

Stereocentersthatarenotchiralcenters.

OH

OH

OH

OH

C CH

Br H

BrC C

Br

H H

Br

CBrHBrCBr

BrH

ChiralAtom(ChiralCenter)

“Anatomholdingasetofligandsinaspa+alarrangementwhichisnotsuperimposableonitsmirrorimage.”

C2andC4chirotopicandstereogenic;C3stereogenicandachirotopic

C2andC4chirotopicandstereogenic;C3chirotopicandnonstereogenic

CH3

CH3OHOHOH

CH3

CH3OH

OHHO

mesostereoisomers

CH3

CH3

OHHOHO

CH3

CH3

HOOHOH

iden+cal

Resolu5on-I

A(+)+A(-) B(+) A(+)B(+) + A(-)B(+)

A(+) + A(-)B(-)

A(+)B(-) + A(-)B(-)

enan+omers

diastereomers

AssumeA(+)B(+)lesssolublethanA(-)B(+)

A(+)B(+)precipitatesfromsolu+on

IsolateA(+)B(+)

A(+)B(+) aq. NaOH A(+)-(CO2Na)+B(+)

watersoluble ethersoluble

aq.HClA(+)-(CO2H)

Cinchonidine

Brucine

Resolu5on-II

ThenA(-)B(-)islesssolublethanA(+)B(-).

A(-)B(-)precipitatesfromsolu+on.

IsolateA(-)B(-)

A(-)B(-) aq. NaOH A(-)-(CO2Na)+B(-)

watersoluble ethersoluble

aq.HClA(-)-(CO2H)

A(+)+A(-) B(+) A(+)B(+) + A(-)B(+)

A(+) + A(-)B(-)

A(+)B(-) + A(-)B(-)

enan+omers

diastereomers

WhatifA(-)-(CO2H)isdesired? ThenuseB(-)astheresolvingagent.

Resolu5on–III(Pasteur1853) NH

N

O

H3CO

NH

N

O

H

(+)-Cinchotoxine (+)-Quinotoxine

CO2H

CO2HH OH

HO HCO2H

CO2HHHOOHH

R,R-(+) S,S-(-)

(+/-)-TartaricAcid

(+)-T/(+)-Qp-saltinsoluble

(-)-T/(+)-Qn-saltsoluble(-)-T/(+)-Cn-saltinsoluble

(+)-T/(+)-Cp-saltsoluble

(+)-A/+)-Bor(-)-A/(-)-B=p(aired)salt(-)-A/(+)-Bor(+)-A/(-)-B=n(on-paired)salt

Resolu5on-IV

N

Na

C2H5OH NH

d,l-coniine

d-tartaricacid

d-tartaricacidd-coniine

d-tartaricacidl-coniine

+

lesssoluble

NH

d-(S)-coniine

AlbertLadenburg(1842–1911)

1886–resolu+onofracemicconiine

Resolu5on–VTheMethodofPope&Peachey-1899

SirWilliamJacksonPope(1870–1939)

Howdoyoumaximizethedifferenceinsolubilityofthetwodiastereomers?

Howdoyouminimizetheuseofresolvingagent?

NH

d,l-Tetrahydroquinaldine[d,l-2-Methyl-1,2,3,4-tetrahydroquinoline]

d,l-B

DextrorotatoryReychler’sAcid[[(1R)-(endo,an+)]-(+)-3-Bromocamphor-8-sulfonicacid]

O

HO3S

Brd-A

d-A,l-B+d-A,d-B+d-BHCl+l-BHCl

Insolu+on

d-A+HCl+2d,l-Bmix,conc.sol’n

d-A,l-B

d-BHCl

Precipitatescool

Insolu+on

Resolu5on–VITheMethodofPope&Peachey-1899

d-BHCll-BHClsamesolubility

d-A,d-Bd-A,l-B

differentsolubili+esbutclose

SolubilityN

H

d,l-B

O

HO3S

Br

d-A

Resolu5on-VII

Isthereadownsidetoresolu+on?

Youbet!

Theyieldwillalwaysbelessthan50%.

Cannotpredictwhichenan+omerwillbeisolated.

Mirrorimageresolvingagentsarenotalwaysavailable.

Trialanderrormayberequired.

AsymmetricReac5ons–ABeSerWay

Pd/CH2H3CO

CO2H

H3CO

CO2H

racemicnaproxenH2chiralcatalyst

H3CO

CO2H

(S)-Naproxen(97%ee)

PP

PhPh

PhPh

RuO

OO

O

(S)-BINAP-Ru(OAc)2

TheEnd

F.E.Ziegler2013,2016