okay good morning
everybody um don't know if you have
noticed but
dogecoin has tripled in the past 24
hours
uh and pure doge also has gone up very
high
there's only a 515 doge in circulation
and um so get ready for lots of prizes
in this class okay so good morning
everybody
at the convergence of the people who
really love organic chemistry
and the people who really want to invent
the medicine
that's heterocyclic chemistry and the
existential question
that every medicinal chemist who starts
off is going to ask when they are
tasked with a particular lead or target
structure
is this question of do you make it or do
you buy it
and then substitute it so for the
remainder of this class we will be
obsessed with this question
and we will be doing retrosynthetic
analyses over and over and over again
from three vantage points of processed
med chem
and radiochemistry now some of the
heterocycles we're going to cover
are not are less medicinally relevant
than others
and today's topic is one of the ones
that is less medicinally relevant
we'll go through some examples probably
the most famous example of a pyrrole and
a medicine
but in general they're frowned upon
because for the reason we talked about
in lecture number one
they're pi excessive they're often
metabolized and they're
usually giving rise to genotoxic red
flag impurities that people want to
avoid
but that doesn't mean you can skip this
lecture or tune out because we will be
covering
bridged and fused heterocycles wherein
if you don't know
pyrrole synthesis logic you will be
handicapped
so when do you make a ring and when do
you buy it
well this is a general rule of thumb uh
as your number of header atoms increases
you're going to want to think more about
making the ring and when your ring size
is smaller like a five member ring most
of those are
you're going to see tending towards uh
making them
whereas pyridines and pyrimidines
you know quinolines often those you can
very often find ways to make them
by buying materials and substituting
but you will have cases where you even
need to make periods and we'll go
through that
i guess next week but for now let's
cover
pyrroles and ring synthesis if you want
to understand the four basic ways of
making any ring system they're sort of
summarized
right here for you that's pretty much it
that's all we're going to really see in
the remaining of this
class and if you want to think about
pyrrole synthesis strategy in general
a sort of cliffs nodes version
of this entire class would be when you
have a pyrrole that looks kind of like
this
where you've got um die alkylation
in the three and four position in
general those are usually better made
from scratch
and in general when you have things that
have halogen atoms and they have
two 3 or 2 5 substitution
in general those will often be easier to
make
by a substitution pathway now
when we think about making pyrroles
there are a number of ways of making
them that
don't involve 1-4 dicarbonyls but
there's a large proportion of syntheses
that do
and so for problem of the day number one
what i need from
you folks is a nice conceptual way
of viewing one four dicarbonyls in terms
of equivalencies so
what precursors can you predict
might be relevant to making pyrroles
perhaps someone can start us
off maybe aaron or camille
can give us there's almost nothing you
can say that will be wrong
could you make it from the 1 4
butane dial right
and you can imagine various
substitutions here and all we need to do
to get that to the one for
carbonyl would be let's say we uh do one
of them with the mitsunobu to put the
amine in there
and then oxidize and it will immediately
cyclize up to the corresponding
pyrrole but that would definitely be a
nice precursor to a 1 4 dicarbonyl
are are there any more ones you can
think of that are perhaps more subtle
are the the alkyne the terminal alkyne
like that oh uh sure
sure you could definitely massage that
into the
right oxidation state if you're on the
alkyne
theme you could take it even further to
something like that
and if you want to think about other
types of unsaturations guess what
alkynes can be used this way too
and if you want other unsaturation you
know even butadiene
through some palladium as of acrotype
chemistry as well you could imagine so
anything any four carbon atoms that can
somehow
be coaxed into making 1-4 dicarbonyls
will be
your own new pyrrole synthesis and if
you sci-finder or google scholar it
it's very likely you'll find a paper
somewhere where someone took an
equivalent of a 1 4 dicarbonyl
and found a way to turn it into a pyrol
so when we think about making pyrroles
there's a great starburst in the book
that goes to this and you'll notice that
the
starburst is divided into two types of
pathways
on the left you see pathways which are
not really one four dicarbonyl logic
and then on the right you see the one
four dicarbonylogic
by which all of those pathways involve
the intermediacy
of something which is basically a 1 4
dicarbonyl that's hiding
so that's how important the 1 4
dicarbonyl recognition is
to the thinking about the synthesis of
how you make a pyrrole
okay so here are some typical examples
that you'll see in the book we've got
the nor
uh we've got the palnor which is the one
i think we covered that already in
lecture number one
one fourth carbonyl is mixed with an
amine you've got the hash type
and you've got the strange one called
trophomob uh trophamove is uh
where one takes an oxime and cooks it up
with
koh and uh some sort of alkyne
usually acetylene gas under high
pressure
and um perhaps uh tim can give us uh
a quick summary of what happens here
yeah sure so
you have a double deprotonation of the
auxin
hydrogen on that alcohol there as well
as the
alpha proton um and then from there
you're generating almost like an
intermediate that undergoes a pericyclic
reaction
let's draw that intermediate one more
time
what did you say let's draw that
intermediate
okay now what do i do uh like you said i
double deprotonate let's double let's
see protonate again
okay now what do you want to do
you said a parasitic rearrangement yeah
i was thinking like a 3-3 of sorts
what do we have here
there's your 1 4 dicarbonyl in hiding
correct
so a trophy mode can be done in a
variety of different ways here's another
example
what do you suspect is the product in
this one we're going to treat this with
koh
heat dmso
and the product is clearly going to be a
pyrrole but the question is
what regiochemical outcome do you get
um maybe we can have uh
simona help us out
yeah so i think it depends on if
so if you had the auxin directly attack
attack and displace your bromide
then you could imagine an elimination
and a tautomerization
which would get you the c3
muscle um
versus uh but i could also see this as
like a
alkyne precursor so if you
right away eliminate the bromides um
then you would attack
um at the position closer to the methyl
um and then you would
have the c2 methyl
oh you could also have the allene lovely
and that
would give that which is actually
the product observed
fantastic thanks simona let's take a
look at some deeper details on the hatch
synthesis
what i like about that question sure of
course um so can you
sort of adjust the conditions so that
instead of forming the alkyne you
induce the other regiochemistry by
having the auxin attack
like displace the bromide first so like
by eliminating heat for example
well i haven't seen that the problem is
the oxime is also easy to eliminate and
so you end up with a
degenerate pathway that leads you back
to the allene
what you bring up is a really good point
and so let's
dive deeper into nora's question in
in terms of how would you get this one
selectively
what i would recommend would be to go to
and i believe
this paper exists
the auxin plus
r where r is equal to a bronic acid
are or is equal to a halide so if you
did that in a controllable way such as a
chan lam in the case of the first
instance
or a simple almond type coupling in the
case of the second one
uh that would be a way of giving you
regiochemically pure product
a sort of modern take on trophomob and
then treat that in the same pot probably
with base you get the same product
now remember trophomo because we will
see it again next week when we start to
talk about indoles it's related to one
of the
probably the most famous indulgences out
there
very similar logic to this one so don't
forget it
great question any other questions okay
let's take a look at hans
hinch is nice because it has some
tunability associated with it
so if i take my amine and i add it to
the pre-incubated solution
of the two starting materials i get a
certain product
and luckily we have stone to guide us
through what might be
happening in that first step so i'm
going to pre-incubate these two
and then i'm going to add the amine to
that mixture what might be the result
of that uh so
um you could have the uh
the right hand um
molecule uh total hormones and then
attack the bromide
and then and then the amine can condense
onto the wonderful dicarbonyl
now stone if you're feeling particularly
daring maybe you can help us with the
next one too
this time we're going to pre-mix the
amine and the beta dicarbonyl
and then we're going to add the alpha
halo ketone
uh so this time the amine
can condense onto the onto the ketone
then and then
the i guess
the nitrogen or the carbon can attack
the chloride
and then uh
so um serving here the i mean it will
just start
attack the cardio
and notice my substituent is here
versus here and all i've done is change
my order of addition
that's the power of hansch that's why i
used time so what do you say nick uh
would you see
a mixture of byproducts from the c
attack from
if not the nitrogen but the the enemy
attacks
the chloride that's a good question and
it normally depends on the r
group here so when the r group is
something small alkyl
you'll get mainly the carbon uh attack
um versus the sorry
mainly nitrogen attack and then when the
r group changes
so can the uh selectivity of
attack here versus at the amine so
one of the issues with hans is that it
often is
a reaction that needs to be optimized
based on solvent temperature and the
substituent so it's not
a uber reliable way of making anything
in the world that you want
on paper you've got to uh
you know you've got a field test at
first
yeah there can be some ambiguity
depending on your substituents is the
answer
okay let's take a look at gewald it's a
super important way of making
heterocycles because of its broad
implications for
everything we're going to talk about in
the rest of this class
so when you take this uh alpha
midoketone
and uh you react it with
melano-dinitrile
what you get is an intermediate adduct
that looks like this
and we need some bass now subsequently
what happens
when you continue to heat this up
is
a cyclization
now those n-acetyl pyrroles are pretty
unstable
and so they will be de-protected
upon workup now the key thing that i
want to drive home and make you remember
because i'm going to ask it to you
so many times that by lecture 19 you're
going to be throwing up
is the recognition that a carbon like
that
is always a retrosynthetic signal
signaling element
for a nitrile so from now on
when you see a nitrogen like that that
is adjacent to another hat or atom
you almost always 99 of the time
are going to be thinking that's a hiding
nitrile
it's one of the little tricks of
heterocyclic chemistry that will save
you a lot of time and misery
hey phil is the requirement of that for
it to be on the same side
as the amine you have there
no often if you see sometimes you can
also use an activated carbon we'll see
later on
and other types of heterocycles like
pure knowns that if there's an activated
carbon
it can also attack into a nitrile to
give you a
um an amino group so but normally you're
going to see
it's a header atom of some sort adding
in
now i taught you in lecture one that
aminopyrols are bad
but i gave you the provision that they
are okay
as long as there's an electron
withdrawing group so this will be fine
because it's more of like a vanilla
amide than an actual amine
questions on gowall we'll see gowald
over and over again
including i think again on friday
so don't forget that
okay let's take a look at uh the next
one which looks like it's a typo
actually but it's not
so we've got one of these which is a
nitrile
and we've got the other one which is an
isonitrile
and when we treat this with base
you can probably guess we're going to
make a pyrol but how
and what luckily uh we've got
nathan who's going to help us out with
this one
um so first you deprotonate
the nitrite ester and then you attack
in a 1-4
fashion
[Music]
and i draw the isonitrile it can be
drawn as a
carbine or it can be drawn with a plus
minus there to aid in your
mechanistic analysis
so what shall i do with that compound
um
cannot attack the carbine
and then what um
you can have some sort of uh
see protonation
and then totalization perfect
great job isonitriles are very very
useful for making
pyrroles and imidazoles the midazoles we
won't cover until
i think after the midterm is that right
yeah so but
remember uh isometrics and we're still
not done with them
they're super useful compounds and
probably
the most useful manifestation of
the isonitrial functional group within
the context
of making pyrroles and as you'll see
later in the future
imidazoles is the famous van loosen
pyrrole synthesis
now the signaling element for a van
leusen
is when you've got functional groups on
a pyro
that have this arrangement an r group
here
and nothing here what you want to do
conceptually in your head
is remove this piece from it that is
your tosmic
unit cosmic is your isonitrile
and it has within it the ability to add
to
all sorts of different uh alphabet
unsaturated compounds by the exact
mechanism that we just saw
instead of losing cyanide however you're
going to lose
the tosal group so the intermediate you
get here
which gives you your pyro
so how do you make these cosmic
derivatives so for instance if i want to
put r3 and r3 is equal to i don't know
benzyl or parabromophenyl
benzyl whatever how do i put an r3 under
this thing
anybody ever deal with toss make anybody
ever use cosmic
no yes somebody said yes who is that oh
yes kelly
i know you've been using todd why don't
you tell us a little bit about cosmic
how would i how would i make the r3
there
so you can install that from the aero
alkyl halide
yes with base and then
that takes you back to the iso
isonitrile which you can
get from the amide or the format
so you can buy this or
you can make it from that and that comes
from
uh
four mana plus some tassel source
so formaldehyde and a
sulfonate salt uh
merged together and that's your
formaldehyde right there
and then you just dehydrate that's how
they make it on scale
but you can buy tosmic
so let's take a look at how this can
work in the real world here's a
real consulting problem from the
archives
what is the first thing you think about
when you see this compound like
all right you're in a consulting session
and the medicinal chemist says
you know i'm thinking of making this
compound uh brennan what are your
thoughts on this compound
[Music]
i guess that bridging ch2 might be a
little bit tricky
okay the bridging ch2 might be tricky
the other thing i would think that is
weird about this compound is
what do you think is the stability of
this compound
yeah not great yeah i wouldn't want to
i mean you know unless it's a pro drug i
think if you took this as an
oral medicine as soon as it gets to the
stomach you can wave goodbye to that ch2
but remember a consultant never says no
so whatever they give you you just sort
of say
yes sir or ma'am and you make it and so
we need to think about a way to make
this despite the fact that it may not
look good
on paper it could be a tool compound
maybe they just want to figure out if
the computational chemists are right
about a binding pose for example
so maybe that's the reason for
suggesting it
so what what ways do you think we can
think about putting this together what
disconnections can we use
drawing on this lecture and the last
lecture
what would be the obvious strategic one
to break first maybe the one that
brendan said right
let's get rid of that first we certainly
don't want to make
ring b and then build out ring a and c
that's probably something we're going to
put in at the very end
and if i had to put a group here
why not make it something that already
has formaldehyde hiding there
like a mom
now how would you make this
let's see how about taway any
suggestions
or ellie
um could you do like a
chiral substitution to get the bromide
um like to do a cross coupling between
the
pyrol that's a good idea that's a good
idea ellie but keep in mind
going from ester to bromide have you
simplified the problem or you just
delayed it to later on
and i also have to worry about the
regiochemistry of my bromination
and i'm carrying through a pyrrole that
is probably not very stable
because it's totally there's no electron
withdrawing groups on it
so try to avoid uh i call them
knee-jerk retrosynthetic disconnections
so they're the first thing that comes to
mind
but then when you look at it you're like
wait a minute uh i didn't get any closer
to so
if the race is over here at the end and
you just move to the right instead of
moving forward
so it's a good disconnection because
everybody makes it as a knee-jerk
response
but then when you take a step back and
think about it for a moment it didn't
really get you closer to the target
so let's think about a disconnection
that gets us that's dramatically
simplifying
that gets us closer to the target you
know we can do the canonical
disconnection
which is you see a by arrow what do you
think of
what whatever you think of when you see
a by arrow oscar playing
yeah suzuki city right everybody loves
suzuki
and this can be any any permutation of
it so you have a pg here that can be
bronic acid
and this can be metal or x
and other polarity you want in the
disconnection
that might be fine there's another way
we just learned the van lewson so what
if we disconnect
imagining right across the ring here
that gets us back to an intermediate
that looks like this
that can be converted into the
corresponding um
van lewson precursor
and we learned in the last lecture how
we would make
an aldehyde like that
and um luckily
we have someone who's going to tell us
what that is maybe sung helen will be
the one
to tell us what the group is that he
would recommend
removing first in a molecule like that
based on monday's lecture
and if how about um
what about debbie
how would aldehyde we can do
uh methylation of the allergen and with
a co2 and reduction yeah you could just
take
oops you could just take this compound
and do directive metallation here quench
with dmf
oh yeah that's true yeah right or you
could do the halogenation followed by
halogen middle exchange and then quench
the cmf
and then making this is pretty simple
uh we can we can buy a substitute or we
can make as you'll learn next week
okay great so that's how van lucen can
help you in that context
hey phil what would you consider is more
of a simplifying disconnection
like if you had to try one of those
which would you try first
well i'm positive that uh
this one would give me my desired
product
and on the bottom the only question i
would have you know the the bottom one
is going to require some protective
group chemistry with regards to the
pyrrole
cross coupling it could be more modular
it really depends on the purpose
uh this is a question which often comes
up
and that is the context of your
modularity
uh if you're basically looking to
explore
the groups on this position it might be
more strategic to make a library of
these
and do a gram scale synthesis of that
intermediate and then condense it with a
bunch of acrylates
if however you really don't know what
your arrow group needs to be it might be
pyrrole it might be imidazole it might
be oxazole then the cross-coupling
approach
probably makes more sense
yeah question from the outside yeah so
um someone wants to know is it possible
to perform the oxidative process between
the question from outside is is it
possible to do some sort of formal
ch functionalization of a pyrrole
let's say like this plus
this type here that is the question max
uh yeah it's just some kind of general
long stick yeah
oxidative coupling between a pyrrole and
a
pyridine is going to be difficult simply
because the pyridine does not want to
cooperate
number one number two oxidative
couplings are often
statistically challenged where you need
to use two equivalents of one
and one equivalent of the other and so
for those two reasons
that's a uh a non-starter however
there is a way of thinking about this
that could get you to a
product sometimes which is to think
about doing direct aerations
for example if this were a halogen and
you said let's try direct heck
onto a pallidated species like that
pyrroles and indoles undergo
electrophilic aromatic substitution with
palladium to give you the pallidated
intermediate
and sometimes that pallidated
intermediate can be engaged in a
cross-coupling like this so
you'll find dozens or maybe hundreds or
maybe more
papers where people take pyrroles and
indoles and do direct validation and
then subsequently
react those pallidated intermediates in
a cross-coupling like mode
but for the reasons i mentioned this is
not one i would suggest
in this case because it's a consulting
problem
so the idea is that you want people to
hire you back when you go there
so this is a very speculative idea it's
a good one for an academician to maybe
explore and see if it might work
but not one that i would suggest just
because i cannot bet my kidney would
work
whereas these other two suggestions are
organ donating level suggestions
okay good question any other questions
okay let's take a look at uh the famous
example of lipitor
i this is one of my favorite stories of
medicinal chemistry because of
all the rule breaking involves and uh
the the anti-reliance on
the modern tools that we know and love
today
uh you know computational chemistry ai
and all those sort of structural biology
all these things that we hold near and
dear
one of the greatest selling drugs in the
history of humankind
uh was not was invented with with none
of those things but rather
just a curious chemist who had an idea
and some plastic molecular models
and went about to try to make
the greatest one of the greatest drugs
of all time
so that person is bruce roth he's
retired now he was at pfizer for many
years and then at genentech for many
years
and um during his phd at rochester he
was working
on this type of chemistry so this
encompasses what we call
problem of the day number three
so for problem of the day number three
we need a
deep thinker to try to figure out what
in the world is going on
we treat this uh amino acid
amino acid sorry with acetic anhydride
and
somehow out from this mixture with an
alkyne
pops a pyrrole product so we have any
volunteers to go through this or should
i call and i can jump in
what do you say alex what do i do so
you'll form the anhydride first
and then
you can push arrows from the nitrogen
and then you'll have the adjacent oxygen
add in um
now what and then if you have
deprotonation
um at the benzylic position yeah that'll
be primed
to do a 3-2 with your alkyne
and then
you'll have loss of co2 and that will
give you your pearl
uh so for some bonus
dogecoin here alex do you know the name
of the
charged intermediate that did the
dipolar cycle edition
it's a german word i think oh that's
close
munchknowns lunch knowns it is
and i think the correct pronunciation is
moonshnown like munich
as it was named after the famous rolf
wieskin
of course uh the inventor of all dipolar
psycho editions
this was one of his many dipoles that he
brought to the forefront and so this
munch known can be used to make
pyrroles and um you may look at this and
say wait a minute phil i thought we're
not allowed to have a pyrol in medicinal
chemistry
back then uh it was still something of a
problem for a couple of reasons because
now we have a
pyrrole and we have a potential
hydrolysis of a
amide to give aniline so this has all
the warning signs that
you know i don't think and if you bruce
roth gives a nice lecture on this topic
in the modern era
this would never be progressed no one
would progress this compound
but it was progressed and uh it
obviously worked brilliantly well you
probably have a lot of
friends family members you know that
take lipitor
cardiologists suggest adding into
drinking water because if it's all of
its
great uh preventative beneficial benef
beneficial effects
okay so lipitor yeah sure
so how to control the visual sensitivity
of the
once integral reactions yeah so the
dipolar cycloaddition is controlled
by this being delta plus and that being
delta minus
normally what i used to teach the
synthesis class
uh shared with dale and we talked all
about dipolar cycloaddition for 90
minutes
and i like to refer to dipolar
cycloaddition as kind of a
schizophrenic paracyclic reaction
because it prefers to react with dipoles
that are either
very electron rich or very electron poor
but it doesn't like the neutral ones so
these munchknowns are charged and they
have the
polarity you see here and so these are
also
primed and the same rules you would use
for a diels alder is what would you
would use for
predicting the regiochemistry of this
does that make sense
i'm not sure if i'm missing something
obvious here but the
uh polarity that you're drawing on the
alkyne is not making sense to me
well this is a good electron withdrawing
group
and so you would imagine as a michael
acceptor for instance it would add in
here
oh okay i'm okay thank you it's not i
mean it may be weird because i put
c-o-n-h-p-h but it's just
that
and so it's an ewg just look at it that
way maybe that's why somehow was also
confused does that make sense
yeah yeah great thank you yup thank you
sorry about that
we should draw it out next time and then
in process chemistry
uh the far easier way to make this uh
you know for the purpose of one
particular target is just to take the
uh one four dicarbonyl and condense it
with the corresponding amine and i think
alex already taught us how to make this
compound in lecture two
when she brought us through the
mechanism of the setter reaction
bond is disconnected remember great
let's look at a couple of examples that
i won't draw through but simply remind
you
of one for dicarbonylogic
so the very interesting little alkaloid
called rosiophilin
a number of very beautiful approaches to
this have appeared over the years
here's one from more than 20 years ago
from the firstner group
where wherein you can see here this is
basically
a 1 4 dicarbonyl
item and the way to unleash it
is simply to use pi alloy chemistry
where that bond
is cleaved you make a pi owl complex the
amine adds in
and subsequently you make your
corresponding pyrrole
which can then be completed by making
the acid chloride here
and then doing pyrrole substitution
chemistry
of the type we talked about in the
previous lectures
again the same thing tsu's approach
one for dicarbonyl simply adding in
ammonia
and the lewis acid gets you to your
desired product
let's take a look at this example from
the boger group um
wherein an interesting heterocycle
called a tetrazine
is coupled with an enol ether somehow
and uh we need help with this product
maybe daniel can help us out with the
product of this reaction
um
so i would think
now tetrazines are all the rage now uh
because of their use
utility in click-like bio-orthogonal
type
chemistries where great things happen
when you have a dienophile
and this tetrazine that's your clue yeah
so i would think it would go through
that that
cycloaddition kind of reaction
[Music]
okay so we're going to draw our initial
cycloaddition here
we've got our r group
got our omethoxy and now what happens
um
so i know nitrogen would definitely be
released
i'm just figuring out how
yes so so yeah go ahead that's number
two step two
what's step one uh
i would think addition of some sort of
base
yeah so when you continue to heat this
up you're just going to lose methanol
okay
so i i think that
proton that you drew suggestively
is deprotonated and
releases the methanol brilliant
awesome that gets us into
thank you daniel that's great that gets
us into problem of the day number four
now we have taken a tetrazine and we
have converted it
into a pyritizine
and the pyridizine is this is a very
electron deficient pyridoxine by the way
we've got these
two esters here electron withdrawing
groups and we treat this with zinc
and tfa and something magical happens
now we didn't cover it in the 2021
lecture but yesterday i
or monday i told you to watch the rest
of the 2019 lecture
and in there was the answer to this
question
hiding
what might happen when you what is what
is zinc really doing
what you know just zinc zero what's
going on here
chun chen any ideas
zing will we do a reduction uh-huh so
what
to
to nitrogen nitrogen bond i guess
well not quite yet
oh okay yeah dude light birch reaction
yes so the zinc is gonna just
dump electrons into that system which
really really wants to
get those electrons
we can draw the tautomeric form of this
compound and then we can do what you
want
chen chen
what did you say you wanted to do oh i
just say
you reduce the nitrogen nutrient bond
and what is that it seems like
some precursor of pyro
so that's the other way of making
pyrroles is to ring contractions from
other heterocycles
we've covered condensation we've covered
van lewson type
and now we've cut we've covered
cycloaddition and finally we've covered
ring contraction now before we move
forward i want to mention to you
again that the book is a treasure trove
of information each chapter has at the
end of it
what we call these report cards it's
modeled uh
around a popular magazine that i grew up
with called consumer reports
probably all of you just showing that
i'm
very old now probably none of you know
this magazine you probably just
i don't know where you get your
information on where to buy a vacuum
cleaner or whatever just go to costco i
guess
but in the old days people wanted to
know what was good or bad and they had
these really cool
rating lists that would be color coded
in a very similar fashion to give you
recommendations
on particular products so we model it
after consumer reports but for
heterocycles and so
you can look at the different
substitution that you've got
for a pyrrole use this handy little
table
and then immediately go to the desired
the transformation that would be best
for
the particular heterocycle so for
example we covered the two three
disubstitution of a pyrrole and we said
hey you know trophomob is good
we click our finger on trophy mode and
we get to that
and we change our mind we can
simply go back to that report card page
so this is a handy way to use the book
to come up with
syntheses of pyrroles when you want to
starting material and just figure out
very quickly
what might be the best disconnection
okay so let's take a look at some case
studies
here's an example of ningaon b an
interesting little pyrol natural product
that's put together by the exact same
way we just talked about
we've got these two aryans here
we've got the nitrile we simply use this
uh conjugate addition pathway with the
isonitrile
loss of cyanide we get out the product
it can then be alkylated
and then uh lactinized with the after d
protection of all the methoxy groups
we're going to spend a little time on
the lamellarams because they have a
number of really cool ways of
approaching them
so let's take a look at firsters classic
synthesis of lamellar and
o which is initiated by uh treatment
with
and this is a mistake this should be ar
here sorry about that
this is initiated by a treatment with
bf3 etherate and then hydroxylamine
so we need somebody to help us out with
this one because i've forgotten what
goes on
so maybe nor can help us with uh
what might happen with bf3 eth right
uh yeah so i guess it would
coordinate to the epoxide
okay
well i guess if there's nothing else in
the pot um
if you let that stir for a while
considering that you generate sort of
like a partially charged
one of the carbons would be partially
charged you can induce a one two one two
shift
brilliant
and that will give us an intermediate
it looks like that which when treated
with hydroxylamine
what do you think that will lead to
um to isola i believe that's called yes
right exactly
so we've made now an isoxazole
um a great sort of prelude to that
lecture
is that isoxazoles are best put together
from one three dicarbonyl compounds
so that's the product you get of that
and then we treat this with um
h2 and palladium followed by an
isolating agent
so what might h2 and palladium
do to an isoxazole
are we going to disrupt the aromaticity
and bring it back to an ice
axel ice oxazoline or is something else
more subtle going to happen
well you okay the next gen oxygen bomb
song has got it fantastic so that brings
us back
to a ring open form
which can then be isolated
and you see this a lot there's a lot of
examples of doing this
stork has done it there's a million
examples and synthesis of taking
ice ox ice oxazoles and using them
as hidden vanilla amides
okay this is a vanilla gasoline
and so once we have that we treat this
with titanium and graphite and it's a
very convenient and safe way
of doing mcmurray couplings so titanium
graphite gives you
wherein that bond has been forged
through the mcmurray
questions okay great
uh i'm just gonna ask so essentially you
also you make um two three four try
substituted
parallel that way so if you compare that
for example to one newton where you can
make a similar magnetic is there any
advantage
of one method over another from the eyes
um for sure and so if we were to
disconnect this via a van loosen
type it would require
uh that correct all right
yeah and so in many cases it just might
be more convenient to start
off with a very simple
intermediate like this chalcone
epoxidize
and get the rearrangement to take place
and
that may be an easier to access material
than
the one shown here in general the reason
we're going to cover
so many ways of making the same thing is
because
if if one method worked for everything
we wouldn't really need more anything
more than the palodi
pyrosynthesis there would be no need for
anything else and the way to vividly
i think the way to vividly demonstrate
just how important that is
is what we'll cover in a few minutes
when we introduce you to radiochemistry
that's where it's essential to know a
hundred
different disconnections for every type
of ring synthesis
actually it's a great question it's a
great question because if i have a good
way to make this
what you said nick yeah i i just said
this i like this because it's not it's
quite a non-obvious route you wouldn't
think of a spiral starting from this
epoxide yes exactly yeah
thanks yeah i also have a question sure
what do you got
in the first step uh it's the original
selectivity
good enough that only the aldehyde group
could conversate with
uh that's a great question we are going
to talk a lot about that when we get to
pyrazoles and isoxazoles
uh it is the hardest problem when you
make those types of azoles with the one
two heteroatoms the question of taking a
one three dicarbonyl
and controlling the regiochemistry we'll
spend a lot of time on that
tons of consulting problems i've gotten
over the years over that exact question
now in this case in this easy case
the aldehyde will always react with the
amine so the regiochemistry is
incontestable in the cases that are
difficult
is when you might have another ar group
here and then it's like uh oh
which one is going to condense first and
we're going to talk about that
in a few weeks but for now the answer to
your question is there's no
regiochemical ambiguity when you have
a 1 3 dicarbonyl and one of them is an
aldehyde the aldehyde is going to react
with the nitrogen atom first
so stay tuned stay tuned for the more
nuanced
versions of this which become
increasingly complicated
great question
all right let's move on to lamellar and
h and d
and for this one we're going to take a
isoquinoline
we haven't learned how to make those yet
but we will soon and
um it's got appended onto it this ketone
and we want to find out somehow this
alkylating agent reacts with the system
and then hcl and then triethylamine so
what
what in the world is going on here
well we learned in lecture i think it
was one
what pyridine like heterocycles like to
do with an electrophile
and so perhaps aaron can tell us what
step
one would be here
and if he's not on the line then perhaps
we can move
to um feng
um
yeah bud
we've got this fantastic electrophile
and hopefully somewhere in this molecule
there's a nucleophile
i need you to tell me where that is
i guess the uh possible quinlan could be
a nucleophile
awesome
then we're going to treat with hcl the
hcl
is going to take the mom and convert it
selectively into the phenol
and then we're going to treat it with
triethylamine so
feng if you want to continue you can
tell us what happens with triple mean we
need to think about
what position might be deprotonated
uh the ch2 between the
isoquantly and the electron withdrawing
ester
i guess awesome that gets us too
can i ask a good question of course
so um would you i guess having the salt
the pure
like isoquinolinium salt in hcl would
you worry that the alkyl group might
fall off considering that it's an
activated
position with the ester
ah so you're worried about chloride ion
coming back
and and displacing it back yeah
oh it's a great question and what i want
you to remember is that that will never
happen
so that the pyridiniums are the
thermodynamic happy
happy compounds and and uh adding
a nucleophile deposition to do kind of
sn2
when the reverse reaction of uh
the compound just alkylating the great
electrophile
that will not happen we will see
examples when we talk about making
pyridines
where we use intermediates that have
pyridiniums that will gracefully depart
in what's known as a chromakey synthesis
so neuro remember that
i'm going to remember you when we get
the chroma key and i'm going to ask you
the mechanism for that one
so chromekey is when something like that
might happen but for
a normal pyridinium it's actually very
difficult to de-alkylate a pyridinium
okay great great question
super all right so uh that gets us to
that product it lactonizes immediately
and you get out
uh the desired product which is lamellar
let's look at problem with amber five
which is kind of a overall summary of
everything you learn
and it's just basically an open forum
for people to earn some peer dose coins
and i'll aid your participation in this
in telling us some possible routes by
labeling
these atoms
now there's probably no wrong answers
are there any wrong answers
probably not yeah the tas tell me
there's no wrong answer so all we need
is some
all we need is some disconnections and
we'll be on our way
um so can we do
can we do like what uh first what we've
learned in the first nerve approach with
the
isoxazole you generate that um
the parole with uh one ch bond and then
you could imagine
um coupling that with like a dihalo
uh phenyl ethyl aryl species
so if you just take the the same
substitution pattern we
generated from the firstner and then you
can brominate the c5 position
and then um perhaps cross-couple that
okay quite a c6 let's take a look at
that in
more depth what you're saying here so
is that what you're suggesting brendan
yeah something like that that seems
that seems simplifying to me
and we just learned if you scroll up
your notes
we just learned how to make that yep
totally reasonable
great what what about that three plus
two cutting
between the the two arrow and the
nitrogen
using a azamethine elite and an alkyne
assuming that the two areas are
different
so there is a control of the
regiochemistry
that sounds very interesting let's look
into what that would
entail
yeah if you put any mean uh there
you form like kind of an admitting elite
and then alkyne
but r2 and r1 should be very different
otherwise the original chemistry is not
going to be good
yeah as long as there's some electron
withdrawing groups or pyridine like
nitrogens in the right spot
you may be able to mimic the case where
you've got
ewg and r if these two are basically
like benzene
it's probably not going to work very
well if they're electron neutral
that probably won't work out so well
but otherwise i love the disconnection
it certainly is reasonable
we can do something very similar to what
you just suggested if we cut a different
bond
so anyone want to take a crack at a
different bond
we've cut 5 4
three two but there's another bond we
have not broken
break one two nick what what is your
disconnection what will that what will
that lead us to
yeah i was thinking of um perhaps
tetrahydro um
[Music]
i just literally adding into some sort
of
electrophile but no i think yeah that
seems like it could be
it wouldn't be advantageous compared to
first and second approach
something like this uh potentially yeah
well but probably you'd still have to
make obviously you'd have to
make maybe let's not give let's not give
up on your disconnection nick
because i said there's no wrong answer
so i don't want to be a liar
could you do the one for dicarbonyl and
condensation hold on hold on save that
thought
we're still working on nick
that would is that pretty much what you
want nick something like this yeah
essentially when you said n1 you really
meant 4-3 um
well yeah that basically yeah you'd have
to keep focusing
on that yeah actually we're going to see
the conceptual version of this in action
in just a moment
so save that thought because we're going
to see something very similar to that
when we get to the next problem of the
day
now what was the suggestion i didn't
hear who that was
um i was thinking the
one four dicarbonyl where do the
condensation
carbon numbers give me the carbon
numbers so uh you could
simultaneously break one nine
uh one two and one five wow
holy cow that's rather
bold
let's try to draw this out in all of its
glory
that's what you want
yeah that's not bad
i mean the only challenge if i see this
is the alpha keto ester here
that may be a bit of a problematic thing
but i bet you could make this
from this compound i bet you could pull
it off
certainly if you put this on a test
you would get full credit
setter and then dump in ammonia that's
brilliant dan you'll love it
well we should give him a fistful of
puritos for that one
all right great any other uh any other
disconnection before i get on to
probably number six
so nick you gave a great suggestion here
and it is conceptually related to
problem of the number six
so uh what do we think is happening here
we can go with you or maybe debbie
because she mentioned something very
related to this a minute ago
yeah in this case you can do
i think one tree dipolar
you will form uh what's the name of this
um
if i'm in the ring but i don't remember
detroit cycle name like
oxazol leading ice oxazoline
yeah uh then
is gonna do undergo a ring opening
like the lone pair on the nitrogen
ah it's gone not really a ring opening
it's a ring closure actually because
it's gonna attack
like uh there yeah
and you form a weird like remembering
yeah
and the and the carbon ion
um yeah you already rode the
open part um
[Music]
yeah you're going too fast for me let me
catch up
oh look at that that's exactly what we
needed in probably number five
and nick do you see how it's kind of
conceptually equivalent to what you were
saying before
yeah yeah i agree i think it's a better
approach because you just do
um just do sort of one part
yeah just oxidize the um
the hardware either
do the rearrangement exactly yeah all
right great
so let's move on to some miscellaneous
uh synthesis
uh we have allotted about five minutes
for these so
the if you search pyrrole synthesis
you're going to find thousands of
entries and the portable chemist
consultant we've tried to amalgamate the
ones that are the most
often seen and we do include include
some random
miscellaneous examples but these are
kind of uh
um you know representative of
of the types of things you might see out
there and they take advantage of one for
dicarbonyl logic in the majority of
cases so
let's take a look at the first one the
palodi which is just taking a ketone and
heating up with hydrazine and a little
cobalt iodide
what do you think might be a key
intermediate here
so you'll get double condensation
onto the ketone or like onto two ketones
i guess
and then and that's primed to do a
uh 3 3 which will break the nitrogen
nitrogen bond
great that's our 1 4 dicarbonyl hiding
not usually not a very popular method of
making pyrroles just because of the
necessity of it being symmetrical
but anyway when when it can be used it
can be quite powerful
now if you take this compound and you
simply treat it with palladium on carbon
there's no hydrogen there triethylamine
and methanol
you get essentially a cycloisomerization
and when you treat this compound under
hydro formulation conditions as you can
imagine
if we label these carbons
are these atoms
you can see very quickly where your
carbon monoxide
came in
and if you treat this butadiene
under azerbacher type conditions you get
out your pyrrole just as we talked about
at the beginning of lecture
and uh there's also this very
interesting iron
octocarbonyl chemistry that you can read
about but
it's not really used very often i can
only think of one example where i ever
use such chemistry in the real world
and that brings us down to a consulting
problem from oh about 12 years ago
where these folks needed to make a
trifluoroethylated pyrrole
so what are some ways that we can think
about putting this together
any suggestions based on all the things
we learned today
you can take advantage of the chemistry
i just talked about or you can come up
with something new
but um
this suggestion could aid in medicinal
chemists out there
could you do the tosmic approach
and then potentially burn off the
electron withdrawing group at the three
or four position
like this tim
yes yeah that looks great
that's a great suggestion any other ones
what about if you replace the cf3 with a
carboxylic acid
and just treat with a dust sulfur
trifluoride
you should get directly cf3 you know
oh i'm so happy you said that one um
the conversion of an acid to a cf3 is
not something that most medicinal
chemists want to ever do
um you can convert these to the thiol
type intermediates the thioester type
intermediates and sometimes a little bit
less um
less harsh but in general when you start
telling people to do deoxyfluoronations
of things like acids which are
much harsher conditions there's a lot of
pushback from the medicinal chemists
they don't want it
so and not only that these conditions
are pretty harsh and that
pyrrole could itself polymerize under
those conditions so
i'm going to say this one is not one
that i would recommend you suggest
you could put it on a test for example
but it's not something you want to
suggest in the real world
it's a great i'm glad you said it thanks
phil
yeah any other thoughts
yeah go ahead go ahead no i was thinking
you could do
just a one fourth carbonyl maybe with
uh like the nor type chemistry and just
do condensation
and how do we make that thing
um maybe you could make it through a
setter
but i'm not sure hm
well if we do stutter here we're gonna
need to use uh
a um very
uh this is you know this acrylate is not
not the most fun one to use and you're
gonna have a problem with controlling
what aldehyde is actually reacting so
you probably need to use
something like that and then reduce it
down and then you'll have selectivity
problem between the reduction of the
ester and the reduction of the ketone
and this is probably going to be a
volatile compound
so i'm glad you suggested it because
part of the challenge of consulting
is giving suggestions that you would
actually do yourself in a hood
right it's not about just providing to
the practitioner here's something that
on paper should work
what i want you to do everyone in this
class when you think about consulting
problems or you think about
how designing a synthesis in your own
life will work
you want to imagine yourself at the hood
and ask yourself the question do i
really want to do this
and if the answer is um i don't really
want to do this stuff
then don't recommend it
can you make it from the uh so the 1 4
dicarbonyl can you make it from the
protected aldehyde like the alpha bromo
of the acetal and then just alkylate it
with the ketone
like this um
no so you'd have the aldehyde protected
as an acetalin i guess yeah it would be
like that
or like the wrong version
like that yeah maybe
um i'm just not sure how probably this
is okay i'm just not sure how good
the deprotonation of this thing is with
the cf3 there
whether yeah it might be fine i need to
look into it i might be fine this is
probably very volatile and nobody
probably wants to deal with that it
probably comes as a hydrate
we can look into it it could be okay but
in general when you start putting
fluorines on
small building blocks you need to put
enough molecular weight the thing
doesn't just evaporate
okay um so but not a bad idea i mean
certainly for a test these things are
just fine but what you folks are
suggesting is just fine
but the sort of at the end of the day i
think
one that you might want to keep in mind
is the case where
in a cycle isomerization might actually
help you
so this one
followed by a copper iodide will give
you the product
and there's a million ways of making
this you can either make it from
the commercial e9
using tony reagent or you can make it
via
a sangashira
and then this is a simple uh closure and
it's
nice and modular so if you need to make
a lot of analogs you can make a hundred
different aryans here
mix it into this compound and you can
make a bunch of uh various compounds
that
retain the trifluoria ethyl group all
right
super we have 11 minutes left and i
really really want to talk about
this topic which is radio labeling we
haven't talked about it yet
it's the third leg of the stool of this
class we've got process chemistry we've
got medicinal chemistry and then
we have radio chemistry there is a team
of radiochemists in this class that
we've assigned
so hopefully they've been reading up on
this topic
radiolabing retrosynthesis is completely
different than the other two because it
is
completely based upon conservation
of steps and costs relative to your
radial label
so the entire goal of a radiochemist we
have some visiting ones we'll give a
guest lecture later on in the class
the entire goal of a radio label chemist
is to
make synthesis happen based upon
the minimum cost of reagent and
availability
and limit the number of steps that one
does with radioactive material
now stable label isotopes are easier to
deal with
but the radioactive isotopes like
especially c14
because those are sometimes difficult to
embed every time you do a step
you have to separately sequester that
waste
and there's a variety of regulations and
difficulties and special labs you need
to go to
to do that chemistry so the idea is
counter to a process or a medicinal
chemistry route these routes are
always going to be starting material
focused
not complexity focus of the compound
many cases you'll see that the best
radio chemical route to a compound
is simply by taking the api or an
intermediate in the synthesis of a
compound
degrading it and then reconstituting it
now for the purposes of this class we
like to do radio labeling a lot
because it forces you into a
retrosynthetic
corner there's only certain type of
disconnections that are possible
by strategically placing the atom in the
right spot
we started doing this a few maybe five
six years ago
because it made it impossible for people
to keep saying the same thing
over and over again you can't do the
same disconnection anymore
if you need to have certain positions
labeled so let's go through this
the labeled building blocks that you
will have available in this class are
here
and they're all really expensive when
you start to go to even more
complicated materials it can be
literally
thousands of dollars for a few
milligrams
so when you're consulting for a
radiochemist this is all you need to
think about
is how do you get back down to the earth
air water and fire the basics the
smallest simplest materials
because only those smallest ones are
going to be cost effective
on scale you can't be proposing to use
very complicated materials just imagine
there's going to be some supplier out
there
that have c14 labeled building blocks
it's not going to happen
okay so let's talk about this first one
based on all the cool disconnections
we've seen today
you should be able to put these together
with some speed and so i started off
with a
very easy one to begin with so this
labeled carbon you can imagine is let's
say c13 or c14
let's go with c14 i need a quick way to
make that radio labeled pyrol
and i have uh six radio chemists on the
call here
tim tiffany aaron camille stone and
weequi
so who is it going to be
maybe yeah go for it okay the one
for dicarbonyl awesome
so if we do that
where does that come from
um
that can come from
i'm not sure that's okay
what do you think about lipitor how do
we make that on process scale
um
what's a nice go-to way to get one for
dicarbonyls
it's the thing i botched earlier
fantastic now which setter do you want
to do we can do a setter here
or we can do a setter here
um the one between three and four or one
three and four okay so if we do the
center between three and four
on paper this is fine but you're a radio
chemist so where do i get this
okay so we wanted to just that would
take more steps involving your
radio light bulb material exactly it's
all about
conservation of time and cost with
regards to the radio label material
now i end up with this now how do we
make this in radio label form really
cheap
and quick
yeah exactly so grignard whatever you
want here
plus uh are we allowed label oh look we
have labeled dmf
nice there we go so plus your label dmf
done how about this next one now we want
to label the nitrogen
and we want n15 there so how do we do
that what's the quick disconnection for
that one
we have six radio chemists hopefully one
of them can help us out
stone uh disconnect a menu
and the one for that carbonyl
and that's fine one can also take
to get to the same intermediate one can
also take
that plus
and when you couple those together
you get that which
loses an acetate
to give you the product now the
advantage
of either approach
is that you can either use ammonia
or to make this compound you can
nitrosylate and reduce
from the corresponding diketone
both are fine and we'll get you there
super how about these two this is sneaky
we've got the same compound but one side
we've got the c13 here
and one side we've got the c13 there how
are you going to do that
i think you can use the vanilla
tiffany says we're gonna use van lewson
so for the first one
how do we do van loosen our electrophile
is going to be that
but what do we do now
um so van lewson requires tonsil
yep cosmic and so in one case i need if
i need my radio label to be
at this position where on the tosmek is
it going to be
that would be the natural equivalent i
think
yeah and if i need it to be at this
position
uh the carbon between the passages and
the isometry
and kelly already taught us how to make
both of those compounds
oh did i reverse it
oh yeah well we've reversed it sorry
so here is our um
in this case remember the michael
addition goes this way so our tozzle was
here
and so that's where c21 was
and that one comes back from
formaldehyde which we know we can get
radio labeled
and here's our c5 that's where the
iso nitrile comes from and that one
comes back
from a formamide
which you can just buy
what's that even outside outside
question let's hear it um the
radio wavelength chemist decide which is
to use oh
okay so often the radio label chemist
needs to make sure that they choose a
position which won't be chewed up but
metabolically so the reason you radio
label something to begin with is to find
out where it goes where it's excreted
you know how much is made and where it's
located
and um so you often first thing you want
to do is find a position
that cannot be excreted so if for
instance you had a
methyl ether on a phenol you don't want
to label the methyl ether because that's
probably just going to be chewed off you
want it to be in the benzene ring
because it's going to retain itself
when it's excreted and then deciding
where to put it
after you know which sites are
metabolically stable
comes down to synthetic ease
great question and we're gonna hear all
about that from the guest lecture
later on in the class all right
how about this one this one should be
pretty easy
suggestions i need a quick way to put
that in
co2 yeah
so for instance the end tips pyro we
brominate it we do
uh halogen metal exchange quench with
co2 which is nice and cheap
in labeled form and then d protect and
we're done
great the final two in the last one
minute of the class
we need a way of making these two
differently labeled compounds
suggestions just for the top of those
two could you use
um deuterated cyanide potassium cyanide
one
and add that into an acyl
chloride to install
well there's no there's no nitrile let's
avoid all nitriles we don't need it
could you just do a van loosen here as
well
well if you do do a van loosen it's
going to require that you've got
then you need to make a labeled acrylic
which you could use i suppose that's
fine
but there's probably even cheaper way of
doing this that gets you to the same two
starting materials
for both products
so that would be the labeled one is
gonna be for that one and then the van
lucen one is going to be
you know you're going to be doing
multiple steps with labeled material
you could use probably the hunch
synthesis okay and that would require
and the label is there and
in the second case we can do the exact
same thing
but instead
the label is here and this one comes
back
it's two very simple materials
does everybody see how that works okay
fantastic we're going to be doing a lot
of radio labeling in this class
and on friday we're going to continue
with the 1-4 dicarbonyl saga but move on
to
furan's and thiophenes so
looking forward to that see you in a
couple days thanks everyone