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Cascading Cross

DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Applications of the Heck Cross Coupling Reaction in the
Synthesis of Pharmaceutical Intermediates
Christopher Raynor
Heck Cross Co!lin" # $har%acetical
Inter%ediate # $alladi% # Intra%oleclar
Richard F. Hecks achievement of chemical magnificence took place
in 1972
when he, bilding pon the fondations of !stom
"i#oroki prodced a new mechanism for prodcing $%$ bonds via
coordination of &alladim to an alkene sbstrate withot need for an
organometallic reagent. 'nitiall( sed for the prposes of preparing
olefinic componds )Heck * +olle(, 1972, this mechanistic feat
frther allowed for intramoleclar -#ipper- reactions. !his involves
a casdcading effect of rapid coordination of the &alladim catal(st to
alkene centres to s(nthethise mltiple $%$ bonds and install several
rings in .ick sccession, perfect for steroid s(nthesis.
!he applications of the Heck reaction in generating intermediates as
bilding blocks for viable pharmaceticals are nmeros. Robinson
and co%workers at /stra0eneca )12,
tilised the intermoleclar
cross copling finesse of the Heck reaction to generate an
intermediate compond on the path to a viable breast cancer
treatment drg )3cheme 1,. !he final prodct acts as active agent to
prevent mitosis in cancer cells and can be taken orall(.
Scheme 1. 'ntemoleclar Heck copling reaction to prodce a standard
bic(clic intermediate for an anti 4 proliferation agent for breast cancer.
!his reaction tilises a 2%chloro%5%nitroben#oate sbstrate and 6%
florost(rene to prodce a critical intermediate via a standard
&alladim catal(sed Heck reaction sing 6 mol 7 &d$l2 and +a2$89
base for the redctive elimination of H$l.
Scheme 2. 'ntramoleclar Heck cross copling reaction as a means of
s(nthesising the comple: fsed ring s(stem on the path to morphine.
!he cross copling power of the Heck reaction is frther evident in
the total s(nthesis of morphine
which emplo(s a ring fsing step in
an as(mmetric reaction as in 3cheme 2. !his intramoleclar reaction
proceeds b( copling the carbon centre bonded to the iodine atom
on the phenol ring to the sp
h(bridised carbon at the decalin
;nction of the bic(clic ring s(stem on the other side of the
molecle, favoring the most sbstitted prodct nder
thermod(namic control. "oreover the (ield is 5<7, high given the
steric strain associated with the tric(clic prodct as well as other
(ield diminishing factors associated with intramoleclar copling
reactions. Hence, this (ield is optimised via se of a dilte soltion
of the reactant that forces the sbstrate to react with itself.
!he ltimate morphine prodct is the most widel( sed pain killer in
the world with an overall potential worth amonting in the tens of
billions. =ithot the intramoleclar versatilit( of the Heck cross
copling mechanism, more comple: and e:pensive alternatives to
generating the comple: c(clic strctre wold be re.ired.
"oreover, the Heck reaction can be tilised to prodce biological
inhibitors in the case of >old
and co%workers at $iba%?eig( /? in
3wit#erlands development of a !(pe 1 H'@ inhibitor via a Heck
cross copled intermediate )3cheme 9,. !he intermediate derived
from a p 4 bromoben#aldeh(de sbstrate being copled with a
thia#ole alkene with <17 (ield is prodced via simple &d)&&h9,6
catal(sis with moderate heating.
Scheme 3. 'ntermoleclar copling reaction to prodce an essential
intermediate for prodction of an H'@ inhibitor.
Frthermore, the se of the cascading effect of the Heck -#ipper
reaction is highl( pertinent to the prodction of steroids
as in
3cheme 6. !he abilit( of the Heck reaction to make mltiple $%$
bonds in a few short steps via the coordination of the &alladim
catal(st to the alkene or alk(ne carbon centres allows the
generation of comple:, strained, mlti ring strctres. !he
-cascading effect of the cross copling reaction can contine as
long as there are no syn- A 4 H(drogens to be eliminated along the
path of the palladims coordination.
!he steroids that are prodced via this mechanism can then
become the sbstrates from which a variet( of mlti ring based
pharmaceticals are prodced inclding anti 4 inflammatories and
immnosppresants sch as de:amethasone and cortisol.
Scheme 4. 'ntramoleclar cascading -#ipper reaction to prodce a mlti
ringed steroid sbstrate
>ristol 4 "(ers 3.ibb
tilised the Heck copling reaction to
prodce a critical alkene intermediate on the path to the total
s(nthesis of a doble #witterion )containing two carbo:(late anions
and two ammonim cations,. !his final prodct has the potential to
be sed as a treatment to methicillin resistant
Staphylococcus Aureus (MSRA), a highly dangerous
strain of bacteria.
!he reaction tilises a 2,6,5 4 tricholoro 4 1 4 iodoben#ene sbstrate
that is copled with acr(lic acid with BC7 (ield via &d)8/c,2
Scheme 5. Heck copling intermediate en rote to an anti "3R/ treatment.
Table 1. &%%ary of Heck 'eaction &che%es
!hs, the -cascading cross copler that is the palladim catal(sed
Heck cross copling reaction is critical in the formation of $ 4 $
bonds for pharmacetical s(nthesis. !he versatilit( of the &d)C, or
&d)'', catal(st in terms of sbstrate, alkene reagent and base make it
an enormosl( powerfl tool for constrcting the comple: carbon
based skeletal strctres essential in commercial drgs. !he Heck
mechanism can be applied in both an intermoleclar and
intramoleclar fashion to generate ni.e ring s(stems withot need
for an organometallic reagent, ideal for the prposes of medicinal
'ecei(ed: ((will be filled in by the editorial staff))
$blished online on ((will be filled in by the editorial staff))
D1E Heck. R , +olle(. F, J. Org. Chem. 1972, 37, 292C%2922
D2E Robinson. ? et al. Org. Process Res. Dev. 2004, 8, 926%927
D9E Hong. $ , 2ado. +, 8verman. G. J. Am. Chem. Soc. 1!, 11,
D6E >old. ? et al. !. J. !e". Chem. 1", #1, 99B7%96C1
D5E $ited inH &a(ne. R. Chem $%1 Assignment, 201!, p 9
D<E 3ingh. F et al. Org. Process Res. Dev. 2000, #, 6B7 % 69C
D7E "agano. F , Inet#. F,. Chem. Rev. 2011, 111, 22C6%2212
Scheme Pharmaceutical
Use of Final
Type of Heck
1 Oral )nti *
$roliferation )"ent
for +reast Cancer
Inter%oleclar ,0
HI1 * 1 Inhibitor
)nti Infla%%atory2
0&') treat%ent
Christo!her 'aynor
&chool of Che%istry
6he 7ni(ersity of &ydney
4&8 201-2 )7&6')9I)
:;%ail: cray-3<