okay good morning everyone
we have an action-packed lecture for you
today
and um it's all new content
and um i think the interesting
part of this lecture is we're not going
to cover
just as indoles but rather the furano
pyridines and thiano pyridines
and that's where really furions and as i
promised you before that's really where
furans and thiophenes shine
modern medicinal chemists are not making
a lot of benzofurans or
just parent furions they're not making a
lot of thiophenes or benzothiophines it
happens on occasion but
in the modern era they're taking those
five-member ring heterocycles and
they're fusing them
onto pyridine so this lecture combines
everything you already know you already
know how to make furands
you already know how to make thiophenes
and pyrroles and you already know how to
make
pyridines so what happens when these two
are fused together
this is our first example of where we're
systematically going to go through
fused types of heterocycles
and the logic you need to know for this
is very simple all one needs to do
when they have a fuse system such as
this here
is take one of them and pretend
it's a benzene and then take the other
one
and pretend it's a benzene if you do
that
everything is easier now the general
rule of thumb for as in dolls as you see
here
is about 70 percent of the time you're
going to start with a pyridine and
annulate on to that a pyrrole
for thiano pyridines it becomes more
popular to
um annulate the thiophene and finally
for pyridines
almost always you're going to be
annulating the furan onto the pyridine
but
these are kind of the my rule of thumb
over the past
uh many years of consulting it's
definitely not
a guaranteed strategy and we're going to
see today many examples of where those
five percent 20 and 30 cases are really
strategic
so if you take for example a compound
like
a uh thiophene like that
when you think of the retrosynthesis
you're going to be looking at it from
the vantage point of one of them
possible retrosynthetic analyses is that
or
the other possible uh retrosynthetic
analysis
is
that now we haven't learned quinolins
yet so some cases today you're going to
see a sneak preview
of what we talk about next week but
that's conceptually what you're going to
do every time you think about
which one to emulate and you already
know the answers to
many of the problems we're going to be
going through today so hopefully we can
breeze through
a lot of these problems of the day and
case studies in a rapid fashion
i should also mention that there's some
useful reading material for you so
there's a chapter we wrote
a few years ago on the five six fused
heterarians and in those
is a list of all the rules that one
could possibly want to know for all of
these
and the other thing i'll mention to you
is in lecture number one we talked about
aromaticity as a guide
to retrosynthesis and many of you may
have been confused by what in the world
i meant by that
and as you'll see these rules correlate
pretty well to that in terms of
the degree of aromaticity of pyridine
which is
very close to relative the other other
other heterocycles to benzene
and so that's why these rules are almost
always starting with the pyridine and
annulating on because the pyridine
usually looks better
as the benzene ring rather than the
thing that you disconnect
things get very confusing when we start
talking about naphtharians where you've
got two pyridines
attached to each other and then uh
that's when things get kind of complex
and the retrosynthesis kind of become
almost in many cases equally simplifying
so with that little introduction let's
begin with furopyridines and all of the
various isomers of hero pyridines and
we can do this in a rapid fashion i'll
go down the list of people
and um ask for your train of thought so
seonghan maybe you can start us off this
morning in thinking about
what strategy you might very rapidly go
towards
i think i will do something like the
rock
condition awesome
perfect you know that makes a lot of
sense to
start with a and then endulate on b if
we were to do the
b emulate on a gee that would be a
kind of weird thing you want to do there
because you need something like this and
then you need to somehow
append onto their something like that
it could work the only problem is
we learned that these types of amino
furan's are not very stable without an
electron
drawing group so that would be a big
warning sign there and then you have to
actually make that for your end which is
going to be a lot more steps than simply
buying iota purity
or simply making it so that's why this
seems very intuitive and very fast
so with the same logic in mind nathan uh
what are your thoughts on
problem b
do you see any groups in problem b any
particular carbons that
signal something special to you uh
is there a hidden cyanide in there i
love that that is just
great look at that hiding right there
that sneaky little cyanide and what are
we gonna do with that cyanide let's put
it here we need something
oh um so we would need
a uh nucleophile next to the ester
exactly and so that can usually be
made pretty easily from something like
this
treat it with base and all done
brilliant
all right how about brendan for c
um i i think you could probably do a
similar approach uh
to the first one where maybe you have
the
the benzylic alcohol protected and then
you treat that with um
you have the same uh sort of sonagashira
starting material
with just tms acetylene
okay you'll need to come up with a route
to this
um that is sort of going from a to b
can you help me if i do want to do the
b2a
what would that look like
um i'll make your life a little easier
and put as a placeholder here in ester
because we know we can reduce that
and turn it into the benzylic alcohol
so what would that look like so you want
to annulate the period onto the furan
yeah that looks pretty tough
well it would require something like
this
so i predict that if one were to
make this purine a mitofuran
treating an acid and then immediately
dumping this aldehyde that emulation
would work
okay so you end up with two routes that
you're going to be you know going to
scifinder and basically searching for
either your prep of this you'll find out
this is easily available from a
courteous rearrangement
you'll then look up your prep for this
which probably comes back from
something like a nicotinate
and you'll worry about selective
iodination there
but that will be your thought process
and probably what you'll come up with at
the end of the day for this particular
compound is that the annulation route
is pretty decent to start from a amido
furan as long as you liberate it in c2
you don't want to have that amino furan
lying around very long right right
still yeah if you had just a methyl
group there
and you treated that with ncs would you
get chlorination first at c3
uh if you were to take a
it's a good question tim so if you were
to take a compound like this
and treat it under radical halogenation
conditions you have a good chance
of the radical halogenation conditions
going here however in practice you have
to be careful because
this position wants to halogenate really
well so you just have to be really
careful with your conditions to make
sure it's radical based and not
electrophilic based so you don't get
that competing
uh halogenation at the furan side
yep thanks great all right how about
taway for the next one
what would you do and if tawei is not
here
um how about ellie
yeah i would think that you could also
do the tms alkyne
with like a lorac disconnection oh i'm
so happy you said that ellie
oh sorry
okay so that is good
as long as we can find a way
to distinguish you'll need to order or
find a way to
probably will be fine to put a bromo or
an iota there
to make sure you get selectivity between
this halogen
and that halogen but it should be doable
if you wanted to do the b to a
you could imagine this comes this unit
that you see here
is basically an isocyanate hiding
and so you could imagine that if you
were to generate
that compound upon heating
that compound would then cyclize which
after treatment with pocl3 would give
you the product
and this compound simply comes from
a courteous rearrangement
so you would hydrolyze that ester do the
courteous heat it up
and uh out would pop the um
outward pop the desired uh product you
would you would usually treat this with
something like ppa
and you would expect to see some
isomerization if you're worried about
the easy there
so that's another viable route that
people have used to make such systems
you might look at this and say hey phil
i would never do that i want to do the
sangashira that's fine
the lorac is fine but you must have that
disconnection of b to a
as an available one to you if you cannot
execute on the a to b
based on your substituents on the ring
so
great thanks ellie uh how about
this next one which is missing a ester
group here sorry about that
and uh so this next one hopefully alex
can help us out with
would you do a to b or b to a and uh
what would that look like
and if alex is not here how about newer
intuitively i would say a to b
considering that
i want your intuition that's great and
so for your intuition
that would require what
i think an easy way to do it is metal on
type oh
wait
um
yeah okay
now tell me this now that we've drawn
that compound out
do you find it to be simplifying no you
have to put a lot of substituents on the
pyridine
that's right so we tried a to b
and that's where it got us that's great
your intuition was a to b
because it feels better seventy percent
of the time yeah
five percent of the time we taught you
the furo puritans are going to be made
that way so that's great
well now we have to go back and think
about b to a
and if we think about b to a something
magical happens do you see it
um
well i guess i
i don't know if that's right but i'm i
might try to construct
the one five the carbonyl for the
pyridine
that's a great idea because it leads us
to the answer
that is your one carbonyl hiding
and the way to execute this
would be to simply take this compound
stable because it has an electron
withdrawing group on it
plus
that
and under the right conditions we'll
learn about this in quinlan's
you should be able to get the annulated
products so if you have questions about
regiochemistry that's a good reason to
come to
the lecture on monday because when you
see
the compound like this you can basically
view it the same as if the proposed
question
was this
i have a quick question can you um to
act
to make the 2 3 bond can you do sort of
like a michael addition or would that go
to the
ketone like if you do electrophilic
aromatic substitution with the furan
um so if you do electrophilic
oh you're saying it said start with
something like that
and would a nitrogen nucleophile add in
here
uh no so to make the two three bonds so
between um oh oh oh um
so you'd still have the immunogroup
present that's what we're doing
that's exactly what we're doing so that
going here and that is going there so we
are doing it
electrophilic acceptation exactly as you
recommend it right i mean
can you like if you start with the
michael acceptor instead of the diketone
would it would it cause a regio
chemistry problem oh
um it's a that is a viable yeah
you could you could think of this one
instead i see what you're saying
would it have a preference for the
ketone or the four position
uh you'd have to modulate the conditions
and uh
find out but i suspect that this is a
this is a good disconnection
i expect that the region chemistry would
be right in this case
okay thanks either one would be fine to
propose
great awesome all right let's take a
look at a case study this one comes from
a few years ago
from a former postdoc kyle eastman who
was at dms at the time
working on hcv polymerase inhibitors
and the synthesis begins with a very
simple
pyridine starting material and what we
need help with
is guiding us on the various steps
involved
in converting this compound to the
product so
let's get some help from nick wherein
we're going to take this compound and
treat it with nbs
and need some advice on where you think
that bromine is going to go
and if nick is not here we can ask fang
i think uh if you traded it with mbs you
will
get the bromine on five position
a bromide awesome and then that bbr3 is
going to do a good job of
lopping off that methyl group and then
maybe keep going thing so after we treat
that with ncf and
nis what happens now uh so
it will be on the nation on three
positions i guess
awesome and then we know what's going to
happen next
is and then
i want to get ahead of myself
all right we've got the sangashira to
take place we've got our
arrow where it needs to be right there
and then we're going to treat this with
nis
fang you can keep going uh if you treat
it with
a nails i think the few the ferrari will
be on the nation
on the uh what c2 position
well the label would be three oh okay
okay so
position right
and subsequently we'll need to uh
treat this with a set of conditions that
involve palladium
and carbon monoxide uh
so i think based on the reactivity
the carbon ion
bond will be cleaved by platinum and the
uh like a carbonyl insertion
and then
form the mi bound brilliant
these types of intermediates thanks bang
these types of intermediates are
what you see in the real world all the
time med chemists love them
we're going to see an example of this in
a moment when we
circle back to problem of the day number
one which i'll get to in just a second
um this is a kind of intermediate that
you see quite a bit and you take
advantage of the enhanced reactivity of
iodine versus bromine versus the
chlorine
and that's how we get selectivity so
subsequently when we do the suzuki thing
are we going to get suki to take place
at the bromo or the chloro
of course you will get the bromo
displacement
and finally we have one chlorine left
and that's how we get to our product
so using the logic we just saw here
let's circle back to
problem of the day oh number two that we
skipped on purpose
so now problem of the day number two
asks you based on what you have just
seen
to opine on a good strategy
to get us to diversity in the following
order
we want to put r1 in first then r2
and then r3 so we need a good strategy
to think
about how we might do that um
what would be the knee-jerk response
kelly for
a medicinal chemist you think in putting
this together
can we come up with some sort of
trihalogenic intermediate or something
like that
yeah can you also use some shira type
from uh i guess you would also need
maybe like a bromine present in your
pyridine
something like that yeah that's a great
idea
now when we do the uh coupling the cross
coupling this is a typical consulting
problem
where is it going to go here or here
how would you go about answering that
question i think you'd have to do some
hand waving no you don't need hand
waving but it does revolve
involve a hand um
i think it would go at the
four position i think you would go at
the fourth position
so we learned a way that the so-called
handy rules
and uh that was a handout given to you i
think in lecture two
and uh let's look at the handy
prediction so
all we have to do is go to chemdraw
super easy and when we go to chemdraw we
see that oh here's our two positions the
proton
is 8.6 for this one 7.2 for that one
so we know that that one is going to go
first
so you're in deep doo-doo
so this is not a viable you can't
recommend that in the consulting session
you're going to have to do something
different so what would might be a
workaround to this problem
because we could take this compound we
could easily iodinate it
we could do our first coupling there
that's fine but our second coupling is
going to go here and that's not good
we want it to go here so what's the way
around this
can you install a blocking group
first i guess that would be kind of
steppy
that would be kind of sappy how about if
you just use the enable activity
what if we just said you know what let's
scratch that idea
let's just start with something that has
only one of the halogen atoms
we do our first cross coupling here
now kelly we have r1 in there we're good
to go on
r1 we now need to put r2 in
how would you do that and let's say
uh yeah how would you do that would you
have a problem
uh can you brominate instead so then
that would react first in suzuki
okay i love that that is a great idea so
what you're saying is brominate here
and the problem you're going to have is
wait a minute you've got this position
which is super effective
but wait we can fix it
so instead of doing this strategy we're
going to do a lorac
so we're going to take your starting
material
put some big old bulky silo group on
there
we're going to end up with this and now
we have your blocking group that you
mentioned before
but in a little bit different context
now
do you know a way that we can install
something here
from lecture three maybe
um
can you use halogen dance well we don't
need to dance anything yet there's no
other halogen
and you can't can't dance chlorine
chlorines don't want to tango
would bromination just go to that
position directly
that would be probably the not the most
easy thing is there a way to guarantee
you get it
oh oh
i don't know if an oxide would help
that's an interesting idea so if you
wanted to
you could make the anoxide and then put
something there that is a good strategy
might work and it's protected by this
tips group so you might be okay there
is there anything else you can do that
we learned for functionalizing these
um
about just deprotonation
oh okay yeah right so that should be
fine too so you can either use
an oxide or
you can use something like uh bully
or lda something like that this position
is blocked
and that will let you put in your iodide
or bromide
and now we can do suzuki all day
fuckwall whatever you want
that will go selectively here that puts
r2 in and then the final sequence is
just putting your last r3 there's no
other halogens to worry about
and whenever you want to remove this you
can with kf that'll come off or even
some hcl will
will have that silo group come off does
that make sense
everyone that's how a med chemist would
do it
now the process route of course would be
quite a bit different and it would
depend on what r1
r2 and r3 have to play you phil yeah
what do you say though tim
can you just have the bromine in the
four position pre-installed before the
rock or would the you have like the
competitive
the rock would it not favor iodine it
would favor the iodine so another
possible as long as you've got a good
route
to this compound
that's another possible answer as long
as you've got a good coherent route to
that compound
um the only potential issue is you know
um whether
the nbs step works here and yeah you
could sci-finder it probably is known
so you know if you took this compound
and um
you nbs it uh you may you may in fact
get bromine there and that might that
that might be
a a fine solution
in the event the people that did this
work chose to
uh do it in a stepwise fashion but if
you drew that on paper you probably
would be okay we couldn't really take
any points off
phil yep uh going back to the inoxide
formation
if that were if the furan were replaced
with a parole
would you have issues there and like
what kind of factors would you consider
when
when forming the inoxide so
if you're going to make an enoxide with
an azin doll you can do that
um it just depends on what the
substituent is
on the parol part of the as indole
so that you don't get oxidation of that
two three pi bond
but i've seen people make in oxides on
as indoles and it can be done
it just often depends on the
substituents but you should be okay
it's definitely a viable suggestion
okay great any other questions super
quick one for the
no um on the forward route we did right
before this problem
with nis and uh bf3 etherid
what was the eth rate for
uh coordination there and uh
probably also activates the nis to make
it more active
so you can activate xenomides with toxic
acid
lewis acids they make them it makes it
even more potent of a
electrophile
okay great so let's move on to we've
finished
furopuridines let's move on now to
eno pyridians and we're going to do the
same basic
exercise and simona has happily
volunteered to help us with this one
which way are we gonna go i would open
the purity and because
i'm looking at that um hydroxyl group
and wondering if you could tetomorize it
and then use the inherent reactivity at
the c3 position
of the thiophene
so it's very likely
that you may not even need to attend
monday's lecture simona
uh because you have it exactly right
this just comes from an amino thiophene
plus
you know what the answer would have been
identical
if i had drawn this compound
do you see that
yeah so by doing that exercise of
pretending one of them is an aromatic
ring
it was a great idea alternatively if we
went the opposite way and we thought
about
starting with b going to a
look what a mess this would be
does everybody see that which one do you
want to start with
a tetra-substituted pyridine or you know
simple materials dump and stir and heat
and you're done
so the exercise of doing both emulations
is a great one it takes you only 15
seconds to do both of them
and then you immediately know at the
very minimum you're going to get partial
credit on a test if you just show that
retrosynthetic analysis
you don't even don't even need to show
the forward route just show that you
thought about the right disconnection
at the minimum and how much on a job
interview that's all they want to see
it's enough for you to just say oh i
would break up the pyridine and annulate
onto the
diaphragm they're not going to ask you
for reagent conditions i just want to
see how you're thinking
all right great so simona that was so
easy for you maybe we should just keep
harping on it
do you think you can help us with this
one too
sure um can you do snar
to install the phenol um
oh sorry i guess that doesn't really
matter um disconnection
it does you know you simplified it let's
keep it low
um and then i guess
when i see that chlorine i'm thinking
you might have used poco3
from like a pyridone
um and then i'd want to open up that
pyradone
i guess in one of the lectures we used
like a
acyl ketene intermediate
simona knocked you out of the park
as usual
why was that your knee-jerk response
um
let's look at the other way
why do you not like that
sterics well
it's tri-substituted pyridine uh i've
got to worry about how to put these
various groups in in a selective way i
got to get
i'm going to have to do an s and they
are selectively with the two chloros
here
it's just much more complicated it's a
bit of a mess whereas what you did was
very logical there was no no
step that i could catch you and say wait
that how are you going to make that
everything just it felt like a waterfall
it was perfect
brilliant all right let's move on to the
next one
and for this one maybe newen can uh help
us with this
um i would think of
a nitrile group
so you located that immediately didn't
you
yeah and so um why don't we
think for a moment on uh what a good
candidate for a substituent maybe to
remove might be
can we look at this style fiend and just
get rid of it
yeah like i guess we can do crosstalk
and then you notice a
great disconnection
which is that and in practice
this might be surprising to you the x
that they actually used here
was no2 and this comes back
from
that's cheap and easily available from
that by way of first bromination
and then sand miner
and then sorry
uh nitration and then sand mire
will get us to this compound we can then
do a
addition onto that bromonitro compound
cyanation and we get to the product
so what would you go back to scifinder
to look for
you would basically look for a viable
candidate like this
and if you wanted to you could even on
paper
propose something like this it would
certainly be something that i would
search for first
okay and that would bring you down this
road of functionalizations
that's in the literature but certainly
if you were to put on a test that you
wanted to put this compound and you
wanted to add it to a
feistelmann or gowall type donor
that would be fine now let's take a look
at the opposite route
wait uh then like uh
something if the sulfur just add it into
the filling
and kick out the nitrogen pick out the
nitro group correct
yup ipso substitution and loss of the
nitro that can happen
but that's the kind of thing i wouldn't
want you to memorize special case
this is the one you need to know
okay next one worth remembering the
other one that's a bespoke type of
reaction
is one that you would find when you
actually started looking literature but
your logic
the point is you identify the nitrile
you remove the
air through it through a suzuki once you
get there you're
in much simpler land you're in this land
here
it's a lot simpler to think about this
compound than it is to think about
the starting material or alternatively a
lot easier to think about that than
thinking about
you know how you would necessarily
emulate on
the equivalent of something like that
that's not so simple is it right so you
make the two disconnections you see
which one feels right and almost
always the disconnection that brings you
back to a night trial just as you
identified in the first 10 seconds is
the one that's going to get you there
awesome all right how about some radio
late we need a radio chemist
and we have a few of them on this list
uh tim you're a radiochemist so can you
tell us how to make this compound
yeah sure i i actually made this one uh
similar to the one i made up
above um but what i started with is
i had the a ring with chlorines at the
or halides at the c3 and five position
and then what i did is i cross coupled
one
of the or cross coupled the aromatic on
there
that first or the phenol
and then from there what i did was
took the alpha ester
alpha amide and then condensed on
dmf dma or i guess
the dichloro
ketone and my thought was like
if i have those two directing groups
then i should be able to lithiate
at the thermodynamic position uh and
then that would snap close
where is the sulfur coming from oh sorry
i meant the um
uh having an alpha
like the sulfur alpha ester i don't
like it doesn't feel perfect does it
that is what i was trying to do very
close you're very close
um let me ask you this if i just told
you i'm making this compound
just this
would you have had an easier time what
would you have said that came from
just this benzothiophene straight from
lecture whatever it was five
forget about the pyridine what would be
a good disconnection here do we remember
faisalmen
yeah yeah someone tells us we need this
aldehyde
yes but i was i was trying to find a way
to install that aldehyde at the the last
step
which is why for the first route i did
the condensation again
oh well either way you're still it's
still not the last step because then you
need to make a highly volatile
radioactive material don't want to do
that
if i can avoid it i don't want to do
steps to make small molecules that are
volatile
or you know i'd rather just take the
compound you proposed
i don't need any cross coupling at all
i can use we know we can lithiate there
got two directing groups this is super
activated
we can lift the eight there we can
quench with dmf we can add in
no more cross coupling just add in snar
and look what happens it becomes the
same problem as this one
so instead of that intermediate that you
circled if you just took the
thios or the ester um with like a sulfur
at the alpha position
and then put that on the chlorine at c3
would that make it easier to do the
condensation or just not at all
um you're saying add the sulfur
nucleophile before i do the dmf
uh lithiation yes the the problem with
that
is just now i've got two acidic groups
in mind i've got the alpha to the sulfur
and i've
also got the um you know the anapyridine
anion
and i would worry that you would get
actual alkylation at the carbon
in between the sulfur and the ester
rather than the carbon of the pyridine
anion
okay okay so that's why i do it in this
order
i treat this with label dmf i got this
compound which i can then add uh
you know and i by the way i can do it at
this stage or i can save
radio label steps by first doing my snar
and then treating with dmf label to put
this compound get that compound
directly so i have one radial label step
and then i immediately take this crude
material
and uh treat it with my visceramen donor
and i'm done really only have to
traverse through one radial label step
doing it that way
okay thanks great but you captured it
right away that's the intermediate we
want
all right super thanks tim so we've got
this interesting little kinase inhibitor
now
and it is a pareto thiophene and we're
going to need some help putting this
thing together
and perhaps we can lean on daniel to
help us out with
what in the world do we do with this
some disconnections that you think we
can immediately you know
get rid of some complexity get rid of
some functional groups
side handles what do we what can we just
strip the molecule of right away
yeah so my first thought would be the
thiofuran aromatic
group so that could be brought in
through cross-coupling
awesome anything else we can get rid of
really quickly uh the
c4 carbon of the pyridine and that
nitrogen
cross-coupling or snar
it's all gone so let's draw what
intermediate we're left with
and i didn't leave myself in a room
that compound great that should lead us
to the product so how do we make this
what's the first thing we'll get rid of
now based on lecture number three
when we talked about ch
lithiation we had a retrosynthetic
hierarchy tree
of things that go in early and things
that go in late
what was one of the things that you want
to get rid of
at the early stage of retrosynthetic
analysis
iodine chlorine or nitrile
i would say
i got to get rid of something so what am
i going to get rid of
i i guess the chlorine
because that's pretty activated there
well the chlorine will come later but
the first thing i want to get rid of is
that the iodine
because i know i can easily oh oh yeah
yes
i can easily deprotonate there and all
is good for the world
so that's clearable and then i'm going
to do exactly what you said
and i'm going to remove that chlorine
and that brings us back down to that
which
is looking very similar to what simona
just taught us a little while ago
um with that poco3 we can convert that
ester to a nitrile
this is pfcl3 and then we have
a b and daniel based on what simona
taught us
do you see how we can make that pretty
quickly uh she treated
she treated it like an a she she had
started out with the a ring system
he thou furan so she
pretended it was nothing more than a
quinoa
that's it pretty easy
does that feel intuitive to you daniel
now that you see it
feels right right okay good let's move
on to this interesting little protein
kinase inhibitor from gsk
and for this one luckily we have carter
who is going to help us out
in thinking about how we might put this
together
pretty quickly and thinking about it
from a
medicinal chemistry standpoint this is a
bmcl paper
so what groups do we think we can excise
out of here pretty quickly
i think you could remove both extraneous
arrow groups
and that leads us to something like this
now we need to think about
halogenation here and halogenation here
so uh which one do you think
would probably be smarter to put in
retrosynthetically
start with and retrosynthetically put in
later
so i'm gonna i'm gonna give you two
options i'm gonna say
do we start off with something
that will lead us down a path where the
ar is here first and let's say a bromine
is here later
or do we have the ar
here and then let's say
then bromine is
here um
my instinct would say that it's easier
to brominate c3
to the thiophene
so you're saying it's easier yes okay so
that would mean
probably that's the correct answer and
that leads us
down a path of thinking about
this compound now the question for you
is we've got this ar in place we clearly
can't have two bromines there
so what strategy might we use to figure
out
whether we're going to get bromination
here here
or here is there any method we have at
our disposal
a priority that doesn't require breaking
out a supercomputer
uh to tell us where the halogenation
would go
i mean i think it might go here i'm not
sure do you
do you know
um
you're you're in a medcam group right
now let's say carter
and your colleagues are bashing your
ideas saying that's never going to work
because you're never going to get the
halogenation in the right spot what do
you tell them
um i guess i can't pull out my little
handy
oh you can pull out sure you can that's
exactly what you can do you can say hey
but you folks forgot this key paper
um that
we covered in heterocycle class uh
namely this
uh chemdraw trick remember this paper we
covered i don't know lecture two or
something like that
all you need to do is go to chemdraw and
predict the shifts remember that
and so now all we need to do is go to
the chem draw
and let's see what it says okay we've
got
the position here we're worried about
we've got the position here and we've
got the position here
which is the lowest one
uh c2 to the
there's your 113 this is 127 that's 148.
so in while they're complaining about
your idea you open up chem draw you do
the
prediction of c13 and you tell them
i am positive my idea will work and that
means
this is a viable starting material and
so
we can then keep going along this line
with
very high confidence that our nbs step
is going to give us the correct product
now we need to move backwards again and
that leads us down a road
towards this bromide brominated
peritothiophene
much simpler than the starting material
so
thinking about how we might make that
there's a few ways to think about
it but we could use what we did in the
earlier problem of the day which is to
imagine well you know this nh2
it could represent a nitrile but it
might also just represent the product of
a poco3 followed by ammonia
and once we get to something like this
things become kind of simple because now
we can use
what simona taught us before
which is just to pretend it is like a
quinoline in this case an isoquinoline
what do you think of that carter feels
good
great any questions
okay let's take a look at as indoles now
the promised topic of this class
um now in the book there is a
chapter on as indoles and part of that
you'll find this kind of
consumer reports like depiction of what
types of syntheses
might work well for each of these and in
the book you can learn
why certain types of fissures for
instance may not be good
or certain types of bartolius may not be
good but in general
you can basically take all of what we
talked about
in the last lecture or the lecture
before when we talked about indoles
and apply it to as indulge because
you're just going to pretend
that the pyridine is an aromatic ring
so you're just going to pretend you're
dealing with an indole and then in the
other instance you're going to pretend
that you're dealing with a pyrol and you
need to fuse that on and as i said
before at the beginning of the class
roughly 70 percent of the time you're
going to be taking it as
indole and you're going to pretend it's
simply an indole
and then 30 percent of the time it
happens a lot mostly in process
chemistry that's a big clue to you
mostly in process chemistry they will
often go default back to
a pyrrole that then is annulated to give
you a pyridine
and the strategic reason for that will
be clear in the next few minutes
so i encourage you to study that chapter
of the book we include it here in the
notes because i know a lot of the
outside folks don't have access to the
book
so let's take a look at problem today
number four which should
be very much like uh shotgun
answers because you've already learned
all of this already
it's the the only thing that should is
different
is i threw a nitrogen in there but it
shouldn't matter
you'll see it shouldn't matter at all so
we've got a c7 substituted indole
basically
and when you see that that's a good
signaling element for what junction
for larok sure we can think about that
is there another way we can do this
fisher maybe
sure or you might just find when you
check scifinder that
um this compound is cheap as chips
and uh do a bartoli
any of those are fine
questions okay we need a radio chemist
where's tiffany
how do we make b
um can we do official
now if we were going to do first we need
to do something with this benzylic mean
what do you think is a good sort of
placeholder for the benzylic amine
sorry i can't hear you
what do you say tiffany um
i need to put something here i'm not
going to want to carry that benzyl means
the whole sequence am i
no a halide or a
cyano something that you can use is a
good idea
sure well it was reduced off at the end
and then you said you wanted to do
a fissure but keep in mind i've got that
compound
i've got that radio labeled here so
the other issue with a fissure might be
that how do i control the region
selectivity of it going here
versus here that's the tricky little
thing about an as indole
if i were to look at this as a regular
indole your idea tiffany would be
pretty good i couldn't complain about it
if it was just this because i don't have
any regiochemistry problem do i
but here tiffany i've installed that
annoying nitrogen
and now regiochemistry will be
your big problem as a radiochemist
so i need to go back to the indoor
synthesis
chapter and think about a way to ensure
that i'm installing that one carbon
there with the proper regiochemistry
relative to the nitrogen so you have
another idea for us besides fischer
[Music]
madeline
would that give selectivity
something like that treat that with bass
close it off
yeah i think that would work no problem
you could also imagine
a lime grouper type
either one of those is decent sure great
how many steps would it take to make
that the nitro
purity
um i don't think very many you probably
would be able to
just get it back from
perhaps nitration of this is how they
make it
and then conversion of that to the
nitrile and that probable i wouldn't
expect no more than
a couple of steps to make that compound
or it might simply come from
direct nitration of the
pyridine
so because your radiochemistry the
number of steps doesn't matter on the
cold material so you're fine
super how about c and
for this one either tanner or
chuang
and if they're not there on the call how
about debbie
yeah um i think we can disconnect
between the pyridine and the pyrrole
motif um
now i need a good puritan starting
material yeah like
yeah i mean you can use the dimethoxy
and the aldehyde instead of the double
bond like you can disconnect
through the double bond there between
the ester
you know and the pyridine something like
this yeah
and the other one the other motif can be
uh esther ch2 uh
n3 and go through nitrogen
okay so you're saying hemisphere great
lovely
the key folks of as indoles is
don't let the ass intimidate you
okay if you don't forget if you just
pretend it's an indole
you're going to be fine and that's also
why we needed to learn 100 ways of
making indoles
right because when as we saw before and
tiffany's problem
when the nitrogen starts going here you
can't just do fissure for everything
great how about this problem this is an
interesting one
from about a decade ago
and uh we need some key disconnections
for how to think about putting this
thing together
it is a medchem project so we probably
want to put in the diversity in a
stepwise fashion
and um so who would would like to take
us through this one
um either aaron or camille maybe any
thoughts at all on this topic
um i guess i'm thinking
is it possible to buy the the central
uh is it indole
yeah well the first thing that's always
a good first thought the first thing i
really
want to get from you though is what
substituent do you think we can
clear off of here as a med chemist that
you think is fairly straightforward to
just
lop off uh the two amino positions
all right let's get rid of that and then
just make our life a little bit easier
so we don't have to worry about that
and let's just put e for ester there we
can always animate it
right now things are a little bit
simpler slightly simpler
and and and if we're going to buy the
intermediate um
we see here let's think about what we
need to buy so
give me some substituents here uh
camille
for what what are we going to buy or
search inside finder for
um we're not gonna buy this we need
something a little bit simpler before we
start buying
so tell me what to put at the four five
and six position that is to start
searching
can you put it a mino at the four
position
all right now what do i put at five um
[Music]
i guess you could
have a carbonyl there
okay so um okay and then what i put it
six
um
i guess you could have an alcohol
something like that correct yeah
um well the issue with this is
uh let me ask you a question if i told
you to make this compound versus telling
you to make this compound
which would you prefer to make okay yeah
okay that's the question to ask yourself
every time you make a disconnection
i won't be there beside you on the test
or in real life one day
and so that's the question you're going
to be asking yourself after you make the
disconnection
there's no shame to be had about making
a disconnection that is
not strategic in fact that is the best
thing to do
the only way you get better is to show
this is
the logic of what i'm doing and this is
why this is not a good idea
so there's no shame in making the wrong
disconnection
in fact maybe there is a great way to
turn that this connection to reality
but we want to look at both so let's
consider for a moment what both may look
like
um what if we start thinking a little
bit with the
simona like logic on a compound like
that well what she taught us is that
this chlorine atom would look
more like that
so far that feels pretty good
how do we get that compound well one
could imagine this thing could come from
treat this with a little ammonia
and then this thing could come from
now we're back at lecture number four
this is lecture four
put those together this um
will give you very cleanly that one
there's nothing else for it to do
and then treat that with uh trimethyl
orthoformate
and then ammonia should be here
and then pocl3 should be here
feels better doesn't it
so for a job interview what do you need
all you need to do is go in that room
and say well i'm thinking you could
either do this
or you could do this and i think this
looks better i could probably derive
that from pyro
that's it you're done you got the job
they're not going to expect more than
more of you than
in a quick interview like that
this is more seems like a process route
um they didn't use any
uh potentially any cross coupling or any
other diversification oh they did lots
of cross-coupling right here
and right here a mid-bond formation the
two vectors that they want to explore
are here and here
i see okay yeah and but in this case
they want to retain this key active core
and you'll see this a lot when we hear
well the guest talk next week from
aaron sather from merck uh you'll see
that
the reason there is a group that is in
between discovery and process
is precisely for this problem uh a group
in med chem will have a key scaffold
that they know they can't change
anything in the scaffold but they have
two little handles on the side maybe one
is a mine
one is suzuki one is buckle whatever and
so you need a way to get
a kilogram of that key intermediate so
they can make a thousand analogs very
quickly
and that's why you need a group like
errands to bridge the gap
you don't go to process chemistry for
that problem because there's not a final
clinical candidate to give them
but you need an intermediary and that's
why we're having a guest lecture next
week from aaron
great question yeah thanks
so with that here like could could you
you might have explained this but could
you
explain the logic a little bit again
with regards to starting from a pyridine
core versus the parole core
because i feel like if you do the
perioding you can do like uh lorac or
something like that if you
have a halogen or like a heck reaction
let's take it further let's say we're
going to insist upon
this route and that would lead us down
a road of something like this
that's the intermediate we need for
tim's lorac strategy right
and um maybe this can be had from
the corresponding anoxide chemistry here
nitration and then reduction to give the
immunopurity
so if one put this on a test
i don't know what do you think tas would
we mark that off
i don't think you that's what you can
i mean it basically comes down to um
how expensive is this probably pretty
cheap and then
how you know well does the you know you
do the anoxide
nitration reduction iodination
the rock well before you do the rock
you're going to have to throw that
methyl group on there you can't forget
that so you have to do
methylation then the rock
so in terms of scalability
i would personally even as a med chemist
prefer
assuming that i have to keep my core
constant
prefer this dump and stir condensation
chemistry from 1900s
because i can make buckets of this
compound for all my colleagues to give
us lots of sar very quickly
whereas this route might be something
that you would do initially with a cro
just to get a proof of concept but then
when you want buckets and buckets of it
so that's why you need both but it says
you put that on a test tim you wouldn't
be you wouldn't be counted wrong
but in a in an interview you probably
would want to come armed with the
ability to suggest both of these routes
especially if the interviewer says we're
already doing the rock and it's not very
good it's very steppy how do we fix it
great great question other questions
well we have a robust 20 minutes to go
through two of my very favorite case
studies
in the history of as indoles
and we'll start off with a cage match
between process and medchem
on this compound that was reported in
merck by merck
where we're going to talk about the
logical ways of looking at this from the
standpoint of a med chemist versus the
logical ways of looking at this from the
standpoint of a process chemist
so this is very exciting even more
exciting than that movie
all right so for this we need our
designated
medicinal chemist to help us and we've
got a team of medicinal chemists in this
call
uh maybe we can have uh brendan
uh versus simona so brendan you're the
medicinal chemist
uh give us some help on first what
substituents would we want to remove
first that are sort of innately primed
for
action here uh just remove all the uh
sort of extraneous um what's the first
extraneous thing to get rid of
sulfur let's stop there we want to
remove the sulfur
so if we want to remove the sulfur
what kind of chemistry do i need to do
to put that sulfur back
in just tell me that while i'm drawing
so i don't think you can do snar there
uh-huh
okay unless you had an electron
withdrawing group at the
c2 of the uh
indole portion there um
that's a great point you hear
everybody's what he's saying there don't
do that on the test or in real life
please
don't try to do sars snars on that
but you can't but can you do it if like
let's say that that chiral
uh chiral uh methylene ester there comes
from uh
like a ketone perhaps yep so
uh let's take th let's do that first
before we go on let's just draw that
compound because that is a
good way of thinking about how we're
going to install that
exocyclic substituent
and so if we had a halogen here yeah
we can't count that off in a test that
would probably work
with the third nucleophile but is there
a way to do this without all the halogen
stuff
um let's talk about gowald
yeah i don't know if you can do i didn't
let's have a side let's have a sidebar
on gowald
can you remind me what went on with walt
what was the the substituents we needed
for goodwill
so let's see we hiked smile what was
that oh what what
night trial okay so we had um
we had something like that
we had some sort of methyl group and we
added
something into that what did we add you
said what like an ester
um what was the piece of what key adam
we needed to add there i say
aha something special about sulfur
now going back here we need an
electrophilic
if i was to tell you to put an aldehyde
here what would you do
um you'd say bill's meyer right
yeah right i was to tell you to put an x
there what would you do
just nis nbs all right so if i need to
put a software there why can't i do this
that's interesting yes and that's what
they did
so we don't need anything there folks
that's the answer you can put that in a
late stage
do all the interesting uh diversity
explorations you want
just by doing an electrophilic disulfide
that disconnection is so darn good that
even the processed chemists are going to
adopt it
so take note simona when you give your
suggestion
now let's continue on uh with this great
disconnection you got us all the way
to here brendan and so now we just need
a way to complete it
okay sorry so where okay so we're there
here you got here for us
okay um
let me think here for a second um so
what i'm seeing here is
my sort of first thing i would draw
would be cut the arrow
nitrogen bond
um and then you can trace that back then
you can
imagine having an aldehyde on the uh
c3 position of the pyridine and then
that would probably just be dump and
stir chemistry if you were to have like
a chloride
uh
yeah chloride beta to the to the
aldehyde
we're going to do what debbie taught us
before is that what you're saying
oh uh that's not what that's not what i
was saying but
well you have the aldehyde and you want
to put uh and you want to annulate on an
indole the best way to do that is just
hemisphere
okay right and then once we get the
uh product of the hemisphere
we can do a
silly or suzuki with something like that
or negishi and then reduction
now the only thing you haven't told us
is how we're going to put
the key carbon atoms in here to get that
that's the only thing that we're missing
so how do i go from here to here i need
these two carbons to be put in
and there's a nice way to do this
it uses some undergraduate chemistry
i think here um
undergraduate chemistry okay um
so i guess formally yeah you need to add
the carbon into the carbonyl and you
need an electrophile for the nitrogen to
attack so that's
great so a good candidate for that would
probably be this
we're going to get our michael edition
hetero michael to take place we're then
going to get the deacon to take place
with the ester here and then
decarboxylation and you've got your five
ever ring
so that looks like a pretty good med
chem route to me
uh i think they the medcam's probably
pretty happy with that route
but then they tossed it over the fence
to simona who had to clean up the mess
uh obviously process scale is not going
to be so happy with the hemisphere
they're not going to be so happy with
silly coupling or anything like that
followed by hydrogenation
uh there are certain things that they
probably will be okay with
uh for instance i mentioned already that
disulfide hard to beat that
uh you might even think that that
deckman gee that's probably pretty hard
to beat on process scale
so simona what kind of things would you
think about
to revitalize the med chem route to make
it suitable for multi-kilogram scale
well i guess you pointed out that the
hemisperger wasn't going to be such a
good option because of the azide
um so i guess would there be a different
way to disconnect the ring
maybe um the pyridine instead
all right i think that sounds really
good and so what we're going to do
is you still want to stick with this
disconnection though correct
yeah i want to trace back to the ketone
and i want to
do the same cyclization
so
let's redraw let's basically
get all the way to this compound
this is really the crux of it we're
going to use a lot of the medcam logic
just out of curiosity simona how would
you recommend we install that
stereo center here
you're a process chemist uh
can you do a hydrogenate
hydrogenation with like rhodium or
something perfect
great in process chemistry
95 of the time if you want to put
chirality in a molecule you're going to
do it in one of three ways
first resolution and i know resolution
is like a four letter word these days
but
they still do it all the time because
often it's really really inexpensive to
do that
the second one is going to be
hydrogenation
or reduction of some sort and the third
one is going to be biocatalysis
that's pretty much like 90 of it okay um
the other stuff is used on occasion but
90 to 95
of the time it's going to be one of
those three sneaky ways
of getting your chirality in there all
right so simona how are we going to make
this you said you wanted to do
an emulation you wanted to go from b to
a
which is very intriguing how are we
going to pull that off
um can you disconnect through some kind
of uh
one five diaper
dicarbonyl logic let's try
one five die carbonyl and see where it
leaves us
oh well that's one five dicarbonyl but
it should give you a hint as to what we
actually want to do
which of the positions on the pyrrole
simona are innately activated to make a
carbon-carbon bond ready to go we're
ready for you
c2 so the five position so
c2 and c5 we know can come from some
sort of freedom crafts event so
this thought if you continue to
brainstorm on this
thought it's going to lead you naturally
to this intermediate
that and you just told us the answer for
the other one so what do we do now
this thing comes back from
pyro
first step is
friedel crafts that puts the one there
after hydrolysis
with sodium methoxide you get the ester
and then step two
cheap cheap methoxide is cheap
this simple amine here is cheap acid is
cheap
everything to get here is basically
bucket chemistry for free
so great success as a process chemist
look at that
i mean probably they spent 10
human years of work between all the
authors of this paper to come up with
what you folks came up with in
i don't know what was it five minutes
you basically got the answer in five
minutes
of an entire program emerge
so something is working in this class
all right great now yeah i have a
question about the electrophilic sulfur
step
yeah i was i was wondering if if we can
adopt sort of
a sworn type activation of like the
sulfoxide
derivative of that thio arrow
well um if you were to the the problem
with the sulfoxide is there is no
r group here it's just that so if you
wanted to
this kind of compound um
would be the corresponding sulfoxide
equivalent that you would make not so
stable
and we'll probably go straight to the
sulfonate very quickly
which could even run the chance of
getting you all the way to
sulfonic acid which is bad
it's easy easy enough you know it's a
great question but it's easy enough just
to take this thing which
already wants to be the disulfide like
right sulfur you know thiols are
kind of like twins separated at birth
and they always want to be together
yeah i guess i was just thinking that
you're probably losing half of the
molecule
um but it may not matter
um well that is a good point and so
what sometimes people will do is take
the arrow
thiol and add equivalent of something
like
i2 which will generate dimer in c2
and then continue and then you don't
waste all you don't need a full two
equivalents
you see thanks
so if you were to use one equivalent
let's say 0.5 equivalents of this
with a another half an equivalent of
oxidant mild oxidant you wouldn't waste
any newer
yeah great great question other question
i want to make sure that is the threat
of crafts direction more likely to
happen
on the c2 or c5 position
oh c2 you mean c2 or c3 if c5 or c3 on
this compound which which intermediary
i mean the last step the last step so
you're saying
c5 uh here here uh
i mean the the right step
oh c2 goes first and then once as you
know from the pyrol substitution chapter
this is in this
uh pcc book first after the first the
electron withdrawing group is here the
next one to go is going to be
here uh if it is here that why the uh
the last step would happen on c5
position rather than c3 position
because um relative though so the
now you're talking about these two this
this one is adjacent to an electron
withdrawing group
and this one is distal to it so for uh
electronic and steric reasons you're
going to favor going again at c2 and
also in the book you can find that
answer where
if you have a c2 and 5 electron
withdrawing group the next
one that is going to be electrophilic is
at that position but yeah it's a great
question
that's the order of events first here
second here
third here
all right we have not yep
i'm sorry i just wanted to quickly ask
um
it's generally not really true that um
it's easier to build
a purity onto a fire all right it's
it seems like it seems like it generally
could be
the case it well as i said before
seventy percent of the time it's going
to be easier to throw a pyro onto a
purity
and for the purposes of medcam often
that's the way to go but when you know
what your target is already this is an
example of where
it makes sense to build the pyridine
from the pyrrole because we don't need
any diversity
imagine how terrible simona's route
would be
if it was medicinal chemistry every time
i want to put another alkyl group here i
have to go all the way back to the
beginning
that would be horrific you would be
fired right
yeah yeah
all right great we got to move on
because i only have six minutes left and
we have to cover this so
this is sort of the climax of this
lecture the most exciting as indole
in recent history uh the crowning
achievement
by the bms process team led by martin
nisgate and colleagues
reported in 2017 with a lot of fireworks
nine back to back to back to back to
back
oprd papers the entire issue
on this compound i spent many years
in the virtual trenches with these
amazing chemists
uh brainstorming and it was fun because
it started off
back at the wallingford site at bristol
meyers in connecticut
where they were doing med chemists a lot
of really cool chemistry came out of
that as i'll show you in a moment
and then transitioned to new brunswick
where they had to
start completely over again but a lot of
beautiful chemistry was developed by
both the processed chemist and the
medicinal chemist and i'll show you what
that was so
in the remaining five minutes we need
now two
folks who can spar against each other
and maybe we can get ellie from the
medicinal chemistry side
and kelly from the process chemistry
side to
help us decipher what we can do
uh to put this together so ellie can you
give us a quick disconnection let's
remove some
substituents as fast as we can to get to
something good yeah i was thinking of
removing the
um diketone off of the indulge side
awesome let's get rid of that anything
else you can quickly get rid of
um probably would want to get rid of the
triazole
we're going to get rid of that at some
point anything immediately you want to
carry this through the whole synthesis
is pro-drug uh
no yeah you can also get rid of that
really quick
all right now we have to figure out a
way to
put that together and as you mentioned
before it would be
probably a really good idea to get rid
of that
triazole we might worry about the
regio chemistry of the snar but that's a
topic for another time
and now i need a quick way ellie to put
this thing together
um yeah i think you could do like lorac
or maybe madelung even too
right great okay so we can imagine this
kind of thing comes back
from a variety of different precursors
we can imagine
something like this
x is equal to bromo or methoxy
all of these kinds of variations were
used
we'll put them um sorry a chloro goes
there
we can imagine so this would treat with
dmf uh dna and then you would get the
product
we can imagine maybe a bartoli
would work just fine so now we're just
going back to the
essentials handout that you can use on
the test and we look at the name
reactions from making indoles and you
can apply them one by one here
without any problem so all of this would
give you
pretty modular direct access to the as
indulge sample that could be then
interrogated with regards to the alkoxy
substituent with regards to the
heterocycle
and with regards to the friedel crafts
uh amide
eventual oxalate type group that you've
got here all those things can be
systematically done
in a great way thanks to ellie and now
we need to turn to kelly who needs to
fix all the problems associated with
ellie's route
now was there anything good about
ellie's route that we can use from the
very beginning just like we were able to
take some sneak
sneaky things in the previous route and
use them in process
i think the way that she put together
the as indole is
looks pretty good and i think i might
also install the header recycle
by cross-coupling all right so um
you mean you mean uh a frito-crafts type
type reaction
let's first bring it back to an
intermediate that
makes a little bit more sense
yeah i don't want to do the n alkylation
last
so the process chemist recognized that
probably they could use almond
conditions with
ligand control
and somehow optimize for the alkylation
to take place there so that part
would lead us back to the simple bromo
compound
now with that bromo compound in hand you
could imagine doing
cross coupling you could imagine doing
bartoli
there was a period of time where i would
come and there was a
competing sort of internal team at bms
doing
bartoli's and it never made any real
sense for a lot of people because those
yields were never above 50
and it's hard to imagine ever doing
bartoli on large scale and getting a
very good outcome from that
so the cost of goods was also a big
concern because the dose
of this compound was very high it's
about a gram or so per day
so the anticipated cost of good was
extraordinarily high
and necessitated that we start from
almost crude oil
so we've got a and b here and it looked
like at the time
all of the cross coupling and ways of
emulating on a pyrol
had been exhausted and from a cost of
good perspective there simply was
nothing
good to do there so going backwards
they recognize that that bromine here
could probably be installed
through some sort of razor reaction
and we're going to put on here a so2 ph
group for reasons that will become clear
in just a moment
so this could be done by using
methyltrioxarinium
or mctva works fine and uh then
treating that with eyebrow interesting
chemistry that we had worked on with bms
and the very first collaborative paper
we had with them many years ago
uh a nice way of taking those in oxides
and rearranging them to the
two bromo as indole or pyridine or
equinox
okay now the key disconnection here we
need to start thinking like simona again
uh and that is thinking about how we
might annulate
a starting with b so in thinking about
this you can imagine
if we bring it back
if you treat this with methane sulfonic
acid
and trimethyl orthoformate
that's the product you get by way of the
intermediate
being this compound
and loss of tosal to aromatize
that sort of brilliant stroke of logic
there
leads you back to this intermediate
and now all we need to do
start with that which then comes as we
learned in
lecture number two comes from
that frito perhaps taking place
selectively here
with the corresponding acid chloride
gets us to here we then treat this with
a
um nucleophile
followed by deformation of that group
gets you to here
you then treat this with simply with
formaldehyde
or an equivalent of that that does your
frito craft which takes place
here and then upon workup you get your
ketone which can be aromatized so they
get there think about this
their methoxy is coming basically from
methanol rather than using methyl iodide
or using a cross-coupling to put the
methoxy in that's part of the brilliance
of this approach
now this is a very long story and so i
didn't we don't have time to go through
all of it today but
if you want to take a look at a overall
summary we wrote a
a little opening to this nine paper
issue
and it goes to the entire timeline of
how this was discovered
including a lot of really cool as indole
methodologies that we currently learn in
class today that we've covered before
and those things arise from the
medicinal chemistry department
um in wallingford led by the famous
nick meanwhile and uh john cadow and
many of those
pioneers in virology and here is the
medicinal chemistry synthesis very
similar to what we talked about
and then the nine publications that are
shown here
are summarized in a very quick fashion
so if you don't have time to read all
nine papers you can take a look at this
editorial that we wrote
that summarizes this landmark
contribution
to to medicine so with that
we have completed uh on time
all the discussions of our first
exposure to fuse heterocycles and what
remains before the midterm
is a discussion of of course quinlan's
and then maybe the most
difficult part of the first half of the
class will be
a discussion of naphtharity some of the
hardest heterocycles to
figure out how to make so with that have
a great weekend folks and
we will see you on monday