Professor Dave here let's talk about retrosynthetic analysis
so we know that the task of the synthetic chemist is to build molecules
and oftentimes we may go out into nature, we may find some naturally-occurring
product we find has medicinal properties and we think, wow this is a great compound
but you know it's only found in these tiny amounts in a sponge at the bottom
of the Pacific Ocean, wouldn't it be great if we just had a ton of it? well guess what, we
can build it ourselves. now the thing is we have to find a synthetic pathway to
build that molecule and if it's a very complex molecule it's going to be very
complicated to do but there's a method called retrosynthetic analysis, so it's
basically, it's a lot like starting a maze from the finish and trying to find
the start so instead of starting with some arbitrary molecule and trying to
think, what can I do to this to get to the target molecule. what we do is we
start with the target molecule and then we very selectively break it apart into
smaller pieces in very specific ways. we will only break it apart in such a way
that is feasible because we know that there is some reaction that will put it
back together in the way that we just pulled it apart. and so in order to do
this we need to basically look at the functional groups on the target molecule
and think of what kinds of reactions can generate those functional groups, so
I've drawn three examples here, say we're looking at this compound, let's say the
allowed starting material is alcohols of three carbons or less. ok so we know that
this is an alcohol, we need to build an alcohol from smaller pieces.
what reactions do we know that make alcohol's? well if you're in an organic 1
course the first thing that might come to your head is a Grignard reaction, so
let's say we're gonna make a Grignard, now the kind of analysis that we
need to do here, we're gonna be drawing these retrosynthetic arrows that do not
represent reactions they represent the undoing of reactions, they
mean back in time. and so what we're saying is how can we pull that
molecule apart in a strategic way that represents a disassembling that creates
fragments that when they react will come back together to create that.
well we know that when we do a Grignard reaction it is the carbon attached to
magnesium which is the nucleophilic carbon that makes a new carbon-carbon
bond with what was the carbonyl carbon of a ketone or aldehyde so this must
have been the the carbonyl carbon in the substrate and then either of these can
have been the carbon that attacked it. well let's look at our guidelines we
need alcohols of three carbons or less so let's do ourselves a favor and split
this up here so when we do retrosynthetic analysis we're
either transforming functional groups or we're pulling the parent molecule apart
into smaller pieces in a way that we know that we'll be able to put them back
together in exactly that way so if we pull those apart, this arrow means what
came before that could have been this, this is a valid retrosynthetic
step, these are valid retrosynthetic precursors to this because if this Grignard
reagent and this aldehyde react we will get that molecule, so that's how
retrosynthetic analysis works, we're being very strategic
in the way we pull apart a larger molecule. this is a very simple example
if we have some giant polycyclic structure obviously this gets pretty
complicated by then you're getting into PhD territory so we'll just
settle on these simple ones. now over here we do need alcohols so this
piece can go back to the alcohol, this is a valid retrosynthetic step because we
know that from this alcohol we can get that aldehyde using an oxidizing
agent like PCC. same thing goes right here, we know that with this guy this can
have come from the alkyl bromide which can have come from the alcohol because
we know that in the forward direction PBr3 will give us that and then reacting
with magnesium will get us that so in any retrosynthetic strategy we
should number one
retrosynthesize all the way back to the allowed starting material, these are both
alcohols of three carbons or less so that meets the criteria of what we're
allowed to start with, then we have to go back in the forward direction and make
sure that it's gonna work. well like we said PBr3 will give us that,
magnesium will give us that, PCC will bring us from here to there, and if these
two react we do get our target molecule. that's how retrosynthetic analysis
works. let's take a look at these other two guys here. over here we've got an
alkene and we want to make this from alcohols of four carbons or less, so
again what we need to do is say what kind of molecule is this? what functional
groups are present and what reactions do I know that generate those functional
groups? well we know that this is an alkene, this is an alkene and what
reaction do we know that makes an alkene? well, off top of our heads, in an organic 1
course we might think the Wittig reaction, so let's say we're doing a
Wittig, lets retro-Wittig this thing. and we know that when we do have a
Wittig reaction the negatively charged carbon on the ylide, and the carbonyl carbon end up
having a double bond together so that means one of these must have been the
carbonyl carbon and the other must have been the ylide, so let's arbitrarily
assign one to one and the other to the other, doesn't matter which but we can
say that this came from this, ok so here's the four carbon fragment, here's
the three carbon fragment and this is a valid retrosynthetic step once again
because if we react acetone with this with this Wittig reaction, we will get
this product, so that's why this is a valid back in time
kind of a step, and once again we want to go all the way back to alcohols. this
guy's no problem, this can have come from
isopropanol because in the forward direction we can oxidize. and then over
here we know this can have come from an alkyl bromide which can have come from
an alcohol so we have met the criteria, these are both alcohols of four carbons
or less, and then to double check in the forward direction we know that if we
react with PBr3 we're gonna get the alkyl bromide, we react with
triphenylphosphine and some base, and we're gonna get the Wittig reagent
this has to have a negative charge right there
and we know that if we oxidized that with PCC or KMnO4, we're
gonna get the ketone and then if this if this ketone and this Wittig reagent
react we will get this alkene product. so this is once again a valid
retrosynthetic strategy. now sometimes there is just one step, we oftentimes
maybe in a quiz or something instead of saying here are some reactants what you
get
we might have a product and say what did they come from. so even if it's not a
very large multi-step pathway it might just be one step, we still have to be
able to think retrosynthetically, we have to go to think where did this come
from
so let's say we want to form this from six-membered rings, well what do we know
that makes six-membered rings? Diels Alder reaction. so we want to take a look at
this and say well here's a pi bond right there and where are the two sigma bonds? we
know that any Diels Alder is gonna take three pi bonds and it's going to shuffle
them around to make a pi bond and two sigma, well why don't we undo some sigma
bonds that can have led to the formation of that Diels Alder product, so what
we're saying is if we undo that if we do a retro Diels Alder then that must have
come from these, here's our diene, here's our dienophile, and this works
because we can always check, we can write the mechanism, if we try to combine these
via Diels Alder we are gonna get that product. so the key thing to understand
with retrosynthetic analysis is that we are always looking at a target molecule
and strategically pulling it apart in ways that make sense because for
everything that we undo we know of a way to redo it, and then if you have
some designated starting material you really need to keep going until you get there
but in general these are the basics of any retrosynthetic analysis. thanks for
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