SLereochemlsLry of Medlclnal

Compounds
P8M 412
nanLloLoplc Pydrogens
W lf a carbon ls bonded Lo Lwo hydrogens and Lo
Lwo dlfferenL groups Lhe Lwo hydrogens are
called enanLloLoplc hydrogens
nanLloLoplc Pydrogens
W lor example Lhe Lwo hydrogens ( P
a
and P
b
)
ln Lhe group of eLhanol are enanLloLoplc
hydrogens because Lhe oLher Lwo groups
bonded Lo Lhe carbon ( CP
3
and CP) are noL
ldenLlcal
W 8eplaclng an enanLloLoplc hydrogen by a
deuLerlum (or any oLher aLom or group oLher
Lhan CP
3
or CP) forms a chlral molecule
rochlral Carbon
W 1he carbon Lo whlch Lhe enanLloLoplc
hydrogens are aLLached ls called a prochlral
carbon because lL wlll become a chlrallLy
cenLer (an asymmeLrlc carbon) lf one of Lhe
hydrogens ls replaced by a deuLerlum (or any
group oLher Lhan CP
3
or CP)
pro8hydrogen
W lf Lhe P
a
hydrogen ls replaced by a deuLerlum
Lhe asymmeLrlc carbon wlll have Lhe 8
conflguraLlon 1hus Lhe P
a
hydrogen ls called
Lhe pro8hydrogen
proShydrogen
W 1he hydrogen P
b
ls called Lhe proShydrogen
because lf lL ls replaced by a deuLerlum Lhe
asymmeLrlc carbon wlll have Lhe S
conflguraLlon
pro8 and proShydrogens
W 1he pro8 and proShydrogens are
chemlcally equlvalenL so Lhey have Lhe same
chemlcal reacLlvlLy and cannoL be
dlsLlngulshed by achlral reagenLs
W nanLloLoplc hydrogens however are noL
chemlcally equlvalenL Loward chlral reagenLs
lasLereoLoplc Pydrogens
W lf a carbon ls bonded Lo Lwo hydrogens and
replaclng each of Lhem ln Lurn wlLh deuLerlum
(or anoLher group) creaLes a palr of
dlasLereomers Lhe hydrogens are called
dlasLereoLoplc hydrogens
8egloselecLlve 8eacLlons
W A regloselecLlve reacLlon ls one ln whlch Lwo
consLlLuLlonal lsomers can be obLalned as
producLs buL more of one ls obLalned Lhan of
Lhe oLher
W ln oLher words a regloselecLlve reacLlon
selecLs for a parLlcular consLlLuLlonal lsomer
8egloselecLlve 8eacLlons
W 1here are degrees of regloselecLlvlLy A
reacLlon can be moderaLely regloselecLlve
hlghly regloselecLlve or compleLely
regloselecLlve dependlng on Lhe relaLlve
amounLs of Lhe consLlLuLlonal lsomers formed
ln Lhe reacLlon
8egloselecLlve 8eacLlons
W Pydrogen hallde + 2meLhylpropene ls more
hlghly regloselecLlve (3
o
and 1
o
) Lhan Lhe
addlLlon of a hydrogen hallde Lo 2meLhyl2
buLene because Lhe Lwo carbocaLlons formed
from 2meLhyl2buLene are closer ln sLablllLy
(3
o
and 2
o
)
W 1he addlLlon of P8r Lo 2penLene ls noL
regloselecLlve (1
o
and 2
o
) ApproxlmaLely
equal amounLs of Lhe Lwo alkyl halldes wlll be
formed
SLereoselecLlve 8eacLlon
W SLereoselecLlve ls a slmllar Lerm llke
regloselecLlve buL lL refers Lo Lhe preferenLlal
formaLlon of a sLereolsomer raLher Lhan a
consLlLuLlonal lsomer
SLereoselecLlve 8eacLlon
W lf a reacLlon LhaL generaLes a carboncarbon
double bond or an asymmeLrlc carbon ln a
producL forms one sLereolsomer preferenLlally
over anoLher lL ls a sLereoselecLlve reacLlon
W ln oLher words lL selecLs for a parLlcular
sLereolsomer
W ependlng on Lhe degree of preference for a
parLlcular sLereolsomer a reacLlon can be
descrlbed as belng moderaLely
sLereoselecLlve hlghly sLereoselecLlve or
compleLely sLereoselecLlve
SLereospeclflc 8eacLlon
W A reacLlon ls sLereospeclflc lf Lhe reacLanL can
exlsL as sLereolsomers and each
sLereolsomerlc reacLanL leads Lo a dlfferenL
sLereolsomerlc producL or a dlfferenL seL of
sLereolsomerlc producLs under Lhe same
reacLlon condlLlons
SLereospeclflc 8eacLlon
W ln Lhe precedlng reacLlon sLereolsomer A
forms sLereolsomer 8 buL does noL form so
Lhe reacLlon ls sLereoselecLlve ln addlLlon Lo
belng sLereospeclflc
W All sLereospeclflc reacLlons Lherefore are also
sLereoselecLlve All sLereoselecLlve reacLlons
are noL sLereospeclflc however because Lhere
are sLereoselecLlve reacLlons ln whlch Lhe
reacLanL does noL have a carboncarbon
double bond or an asymmeLrlc carbon so lL
cannoL exlsL as sLereolsomers
1wo meLhyl groups
remaln n
(1 Lrans producL
formed)
1wo meLhyl groups
remaln f
(1 cls producL
formed)
SeparaLlng nanLlomers
W SeparaLlon of enanLlomers ls called Lhe
resoluLlon of a racemlc mlxLure
W nanLlomers cannoL be separaLed by Lhe usual
separaLlon Lechnlques such as fracLlonal
dlsLlllaLlon or crysLalllzaLlon because Lhelr
ldenLlcal bolllng polnLs and solublllLles cause
Lhem Lo dlsLlll or crysLalllze slmulLaneously
SeparaLlng nanLlomers
W Louls asLeur was Lhe flrsL Lo separaLe a palr
of enanLlomers successfully
W Pe found LhaL crysLals of sodlum ammonlum
LarLraLe were noL ldenLlcal
Assymetr|c crysta|s
SeparaLlng nanLlomers
W SeparaLed crysLal enanLlomers by hand
W Sodlum ammonlum LarLraLe forms asymmeLrlc
crysLals only under cerLaln condlLlons
preclsely Lhe condlLlons LhaL asLeur had
employed
W noL a unlversally useful meLhod Lo resolve a
racemlc mlxLure because few compounds
form asymmeLrlc crysLals
SeparaLlng nanLlomers
8y converLlng enanLlomers lnLo dlasLereomers
W A racemlc mlxLure of a carboxyllc acld reacLs
wlLh a naLurally occurrlng opLlcally pure (a
slngle enanLlomer) base Lo form Lwo
dlasLereomerlc salLs
SeparaLlng nanLlomers
8y converLlng enanLlomers lnLo dlasLereomers
W Morphlne sLrychnlne and bruclne are
examples of naLurally occurrlng chlral bases
commonly used for Lhls purpose
W 1he chlral base exlsLs as a slngle enanLlomer
because when a chlral compound ls
synLheslzed ln a llvlng sysLem generally only
one enanLlomer ls formed
SeparaLe
PCl
SeparaLlng nanLlomers
ChromaLographlc Lechnlque
eLone
SeparaLlng nanLlomers
nzymaLlc Lechnlque
SLereochemlsLry rug AbsorpLlon
9ass|ve d|ffus|on
W 1he drug moves from a reglon of hlgh
concenLraLlon Lo lower concenLraLlon
W 1he vasL ma[orlLy of Lhe drugs galn access Lo
Lhe body by Lhls mechanlsm
SLereochemlsLry rug AbsorpLlon
9ass|ve d|ffus|on
W lor example AnLlanglnal drug glyceryl
LrlnlLraLe (C1n)
W C1n spray dellvers a hlgh concenLraLlon of Lhls
very llpldsoluble compound of very low
molecular welghL whlch ls absorbed almosL as
fasL as an lnLravenous ln[ecLlon
SLereochemlsLry rug AbsorpLlon
9ass|ve d|ffus|on
W Llpldsoluble drugs blologlcal membrane
W WaLersoluble drugs aqueous channels
@o factors
W LlpophlllclLy of drug and
W egree of lonlzaLlon
llgure asslve and acLlve LransporL
SLereochemlsLry rug AbsorpLlon
W 1here wlll be no dlfference ln elLher of Lhese
parameLers beLween a palr of enanLlomers
W no dlfference ln Lhe exLenL or raLe of
absorpLlon
W asslve dlffuslon can be consldered Lo be
achlral
SLereochemlsLry rug AbsorpLlon
Act|ve transport
W lnvolves speclflc carrler proLelns LhaL span Lhe
membrane and energy
W A few drugs LhaL closely resemble Lhe
sLrucLure of naLurally occurrlng meLabollLes
are acLlvely LransporLed across Lhe cell
membrane
W Capable of movlng drugs agalnsL a
concenLraLlon gradlenL
SLereochemlsLry rug AbsorpLlon
Act|ve transport
W AcLlve LransporL ls noL a very lmporLanL means
of drug absorpLlon alLhough lron salLs
levodopa for arklnson's dlsease Lhe
anLlLhyrold drug propylLhlouracll and Lhe
anLlcancer drug uorouracll are acLlvely
LransporLed across Lhe lnLesLlnal mucosa
SLereochemlsLry rug AbsorpLlon
Act|ve transport
W 8equlres recognlLlon of Lhe enanLlomers by lLs
carrler proLeln
W Llsomer opamlne
W 8lsomer MeLhoLrexaLe
W lsomer Cephalexln
W e|ated to fe no of drugs
9referent|a||y
absorbed
SLereochemlsLry rug lsLrlbuLlon
actor |nf|uences the drug d|str|but|on
1 8lndlng of drugs Lo plasma proLeln
W AL LherapeuLlc concenLraLlons ln plasma many
drugs exlsL malnly ln bound form
Albumln for acldlc drug
globulln and an acld glycoproLeln for baslc drug
W unbound drug (can be as low as 1) ls
pharmacologlcally acLlve
SLereochemlsLry rug lsLrlbuLlon
Jarfar|n
W 8 (+)warfarln had a free fracLlon of 12 ln
human plasma compared Lo 09 for Lhe S (
)enanLlomer
SLereochemlsLry rug lsLrlbuLlon
actor |nf|uences the drug d|str|but|on
2 arLlLlon lnLo body faL and oLher Llssues
W rug molecule pass Lhrough Lhe bloodsLream
Lhen goes Lo Llssue or body faL
W Malnly drug wlLh hlgh llpophlllclLy
sequesLraLes Lo Lhe CnS and adlpose Llssue
and exerL Lhelr acLlon
SLereochemlsLry rug lsLrlbuLlon
@h|openta|
W lL was sLudled LhaL unbound plasma
concenLraLlons of SLhlopenLal were
approxlmaLely 1020 hlgher Lhan Lhose of
8LhlopenLal correspondlng Lo lLs hlgher
clearance
W CnS Llssue concenLraLlons of SLhlopenLal
were approxlmaLely 20 hlgher Lhan Lhose of
8LhlopenLal
SLereochemlsLry rug lsLrlbuLlon
actor |nf|uences the drug d|str|but|on
3 volume of dlsLrlbuLlon
W lL ls deflned as Lhe volume ln whlch Lhe
amounL of drug would need Lo be unlformly
dlsLrlbuLed Lo produce Lhe observed blood
concenLraLlon
SLereochemlsLry rug lsLrlbuLlon
,ethadone
W 1here ls sLrong evldence LhaL Lhe volume of
dlsLrlbuLlon of (8)meLhadone ls double LhaL
of (S)meLhadone due Lo lower plasma blndlng
and lncreased Llssue blndlng
() lsomer enhanced acLlvlLy
(+) lsomer much reduced acLlvlLy
SLereochemlsLry rug MeLabollsm
Drug
Phase
Oxidation,
reduction
and/or
hydrolysis
Phase
Conjugation
products
Following Phase , the drug may
be activated, unchanged,
inactivated.
Conjugated drug is
usually inactive.
Some drugs directly
Enter Phase
metabolism
DirectIy
SLereochemlsLry rug MeLabollsm
Ierapam||
W Cllnlcally avallable formulaLlons of verapamll
are racemlc mlxLures of S and 8enanLlomers
SLereochemlsLry rug MeLabollsm
Ierapam||
W Sverapamll ls preferenLlally ellmlnaLed durlng
flrsLpass meLabollsm and as a consequence
Lhe plasma concenLraLlon raLlo of 8 Lo S
verapamll ls around 31 afLer oral
admlnlsLraLlon and ls approxlmaLely 21 afLer
lnLravenous admlnlsLraLlon
SLereochemlsLry rug MeLabollsm
Jarfar|n
W An examlnaLlon of Lhe meLabollc faLe of Lhe 8
and Lhe S lsomers of warfarln revealed LhaL
Lhe Lwo lsomers were meLabollzed by
dlfferenL rouLes
hydroxywarfarln
(SS) warfarln
alcohol
6hydroxywarfarln
arfar|n ,etabo||tes
6hydroxywarfarln
(8S) warfarln
alcohol
arfar|n ,etabo||tes
1hese observaLlons suggesLed LhaL lnLeracLlons
beLween warfarln and oLher drugs are
sLereospeclflc eghenylbuLazone
8 warfarln
S warfarln
n presence of pheny|butazone p|asma
c|earance of
1he raLe of clearance of racemlc warfarln remaln
unaffecLed by phenylbuLazone
SLereochemlsLry rug xcreLlon
W Cmeprazole was Lhe flrsL commerclally
avallable l
W someprazole Lhe Slsomer of omeprazole (a
racemlc mlxLure of S 8 opLlcal lsomers) ls
Lhe flrsL l Lo be developed as a slngle opLlcal
lsomer
SLereochemlsLry rug xcreLlon
W 8oLh S and 8omeprazole are prodrugs
whlch are converLed wlLhln Lhe parleLal cell Lo
Lhe acLlve proLon pump lnhlblLor whlch lacks
a chlral cenLre
h|ra| 99
Ach|ra|
n|
Ach|ra|
Act|vated
orm
SLereochemlsLry rug xcreLlon
W 8ecause Someprazole ls less suscepLlble Lo
small lnLesLlnal and hepaLlc meLabollsm Lhan
Lhe 8form aL equal doses esomeprazole
achleves 0 Lo 90 hlgher sLeadysLaLe serum
concenLraLlons Lhan racemlc omeprazole
W llmlnaLed 3 Llmes slowly Lhan 8 lsoform Lhus
has prolong half llfe (due Lo slow meLabollsm)
A lone palr of elecLrons resldes on Lhe sulfur aLom
glvlng lL LeLrahedral molecular geomeLry as for sp
carbon When Lhe Lwo organlc resldues are
dlsslmllar Lhe sulfur ls a chlral cenLer for example
meLhylphenylsulfoxlde
Sulflnyl group Sulfoxlde
SLereochemlsLry rug xcreLlon
W SLereoselecLlve renal clearance may be
observed as a resulL of acLlve LransporL or
renal meLabollsm
W (+) LerbuLallne can compleLely lnhlblL Lhe
reupLake of () eneLlomers ln renal Lubular
resulLlng Lhe lncrease ln Lhe laLLer renal
excreLlon
SLereochemlsLry rug xcreLlon
W 8enal excreLlon of SsoLalol was slgnlflcanLly
reduced afLer admlnlsLraLlon of racemaLe due
Lo Lhe renal perfuslon changes caused by Lhe
beLa blocklng effecLs of 8soLalol
SLreochemlsLry rug 1oxlclLy
W When Lhe LoxlclLy produced by a drug lsomer
ls assoclaLed wlLh Lhe SLereochemlsLry or
ChlrallLy Lhe LoxlclLy ls Lermed as Chlral
1oxlclLy
SLreochemlsLry rug 1oxlclLy
@ha||dom|de
W rescrlbed for LreaLlng mornlng slckness ln
pregnanL women
W 1he drug however was dlscovered Lo cause
deformaLlon ln bables
W only one parLlcular opLlcal lsomer of
Lhalldomlde (S lsomer) caused Lhe
LeraLogenlclLy oLher enanLlomer was
consldered as safe
SLreochemlsLry rug 1oxlclLy
@ha||dom|de
W Pumans lnLerconverL (S) and (8)
Lhalldomlde enanLlomers rapldly wlLh boLh
oral and lnLravenous doslng
W 1haL ls lf a human ls glven pure (8)
Lhalldomlde or (S)Lhalldomlde boLh lsomers
wlll laLer be found ln Lhe serum Lherefore
admlnlsLerlng only one enanLlomer wlll noL
prevenL Lhe LeraLogenlc effecL
nanLlomerlc excess
W 1he enanLlomerlc excess of a subsLance ls a
measure of how pure lL ls
W A sample wlLh 0 of 8 lsomer and 30 of S
wlll have an enanLlomerlc excess of 40
W 1hls can also be LhoughL of as a mlxLure of
40 pure 8 wlLh 60 of a racemlc mlxLure
(whlch conLrlbuLes 30 8 and 30 S Lo Lhe
overall composlLlon)
nanLlomerlc excess
W ln pracLlce lL ls mosL ofLen expressed as a
percenL enanLlomerlc excess
nanLlomerlc excess
W ldeally Lhe conLrlbuLlon of each componenL of
Lhe mlxLure Lo Lhe LoLal opLlcal roLaLlon ls
dlrecLly proporLlonal Lo lLs mole fracLlon and
as a resulL Lhe numerlcal value of Lhe opLlcal
purlLy ls ldenLlcal Lo Lhe enanLlomerlc excess
nanLlomerlc excess
W ure (S)(+)2bromobuLane has a speclflc
roLaLlon of +231
o
A sample of 2
bromobuLane has an observed opLlcal roLaLlon
+92
o
? WhaL ls Lhe percenL of 8 and S ln Lhe
mlxLure?