on stereochemistry and chirality - yale...
TRANSCRIPT
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