Welcome back students, so today I will be
ah trying to ah give you ah something different which ah probably we have talked it.
, but not in detail we are trying to discuss ah synthetic equivalents ah synthetic equivalents.
So, synthetic equivalents as I discussed earlier ah sometimes also referred as synthons , now
synthon the term first invented by professor EJ Corey who is also the the principle fellow
who first coined this term retrosynthesis. Now, now professor Corey’s definition for
this synthons says that if you having a particular 2 different unit, as your target molecule
you can simply do a disconnection based on a A minus and B plus just by simply polarite
polarite addition and you may can make a new bond. Now this A minus can be called as a
synthon 1 and B plus can be called as a synthon 2 , now this synthon concept probably is very
well known established earlier, but the terminology synthon nowadays are ah no longer used its
kind of a backdated. Now, synthon probably the you can simply say
that your carbon ion is a synthon ok , your acyl cation in the fedex cup reaction is a
synthon. So, this reactions we already known earlier, but from this view point you probably
have been discussed now you will find that if you having a negative charge on your synthon
this synthons are normally termed as a donor, donor synthon or d .
And if you have a positive charge means that which can act as acceptor which can accept
electron it will be termed as a acceptor. So, donor is basically stands for d and acceptor
stands for a , now depending on the number of carbon this donor part is having it is
abbreviated as d n and this is also a n. So, n could be a integer n could be a integer.
So, d n and a n is usually the terminological definition ah probably the of a very classic
example from. Synthetic equivalent disconnection or synthetic
or synthon concept in terms of retrosynthetic analysis will be visible from this particular
example , where you say that if you having a this particular anion and
this particular acceptor . Now, I am saying this 1 is a synthon 1, so you basically do
a disconnection there and this is your synthon 2, now this 1 is very stable this is basically
a enolate anion and this is your michel acceptor. So, this is normally this is termed as a d
synthon. So, you can call it d 2, so it is 2 carbon
or you can need to and this is basically your acceptor system, just write acceptor the number
of carbon if you can count this 1 2 3 probably this 3 is basically involved remaining part
you can just exclusive it could be a 3 . So, this way you can basically do the a retro
based on donor synthon as well as acceptor synthon, and we have earlier explained that
if you having a electron withdrawing group this 1 this kind of synthons are normal synthons
because this negative charge can easily be stabilized. So, this is called normal synthon
where the polarity remains same. So, now if you having a synthon something
like this where the negative charge decides on carbon, carbon now normally carbon do not
prefer this kind of charge it always prefers a this charge because oxygen is more . So,
this kind of synthons probably you all of you know is referred as umpolung synthon,
or reverse polarity were the polarity has been reverse and this is your acyl cation
which probably you have earlier came across in the reaction. So, in these way you can basically categorize
several synthons normal and umpolung synthon. Now, as you said synthons are usually not
commercially available you know to prepare them in the lab. So, I am saying acyl cation
is a normal synthon, but if you having a acyl anion which is umpolung, now acyl cation is
referred as a 1 and umpolung acyl anion is referred as a d 1 ok .
Now next your enolate, enolate is absolutely known is a normal because a charge can be
stabilized, but if you have a synthon like this which we called enolate cation now enolate
cation is absolutely not stable species. So, is a umpolung there are very few examples
we are not going to talk about this enolate, enolate cation . Now you just change on the
simple polarity you will you can basically create different kind of synthetic equivalents.
So, this is your a 3 and this is a homoenolate cation, so normally, normally carbon prefers
plus minus plus. So, basically charge reverse is in this way plus then minus enolate then
plus then minus. So, in this case it will be a d 3 it is called
homo enolate. So, this is just basically terminological disconnection where ah not going to talk in
detail how these species are generated because this is beyond ah of our scope , now what
I am trying to do I will ah try to ah do some retro based on some target molecule.
then I will find how several synthetic equivalents are basically helpful and how this synthetic
equivalents or synthons can be easily generated. I am giving you a target molecule cis jasmine
cis jasmone I will be doing a very standard retro because we do not have much time . So,
if you do a standard retro through aldol transformation you will find that you basically needing a
this compound this ok. So, just basically need a aldol retro to make
this molecule cis jasmone was used in the perfume industry, next what I am saying that
if you can have a a synthon something like this synthon . So, what I am saying that now
if you, if you visualize that this particular central carbon act as a d 1 umpolung, d 1
umpolung. So, is basically 2 d 1 umpolung and then you react with a alkyl alloy at this
end you get this 1 and here you do a mickel type of reaction with methyl vinyl ketone.
So, this is your acceptor synthon, acceptor synthon this is your donor this is also acceptor
synthon. So, 1 synthon having 2 donor side, so which can react with the 1 acceptor in
the left hand, 1 acceptor with the right hand Now, this kind of 2 d 1 synthon is already
known as a formaldehyde 1 3 diethiane now here we will try to disclose some other synthon
. If you have formaldehyde you react with sodium cyanide and react with E T 2 N H you
basically get a compound named as amino nitrile N E T, N E T how you get you basically react
first, formaldehyde with diethyl amine you basically get this amine then your cyanide
attacks in the ammonium carbon. So, nucleophilic fashions you get this compound .
Now, this amino nitrile this amino nitrile is also acting as a d 1 synthon how the hydrogens
attached to it or extremely acidic because you have a cyano you have electron withdrawn
nitrogen continuing group . So, now, we will now try to visualize how this amino nitrile.
So, N E T E T C H 2 C N first I am reacting with L D A, I am saying that this compound
is acting as your 2 D 1 synthon. So, L D A and the first acceptor synthon I am putting
a bromo here, sorry 1 carbon extra , 1 carbon extra bromo then you see that NET 2 remains
similar , C N similar 1 hydrogen is abstracted and you basically get this compound, fine
next another round of base abstracted this hydrogen and then you react with another acceptor
which is the methyl vinyl ketone. So, you will basically get next you need to generate the carbonyl compound
by simply doing a hydrolysis with copper sulphate , in a acidic medium. Now this hydrolysis
was ah pretty obvious initially actually this copper sulphate and acidic P H first attack
this amine to give you the O H here and then then basically this ah ah is basically converted
to a cyano hydrine, which then which then ah undergoing H in elimination to give you
the parent carbonyl compound , we will get this compound.
So, which is our desired compound you do the aldol and you can end up with the target molecule
cis jasmone . So, what we now formulate in this entire synthesis if you having a diethyl
amino nitrile which can be visualized as a 2 2 d 1 species is a very unique ah reaction
ah to to convert the synthesis. Now, same compound is ah this particular jasmine.
The cis jasmone , now I am saying that this compound you can also make through a or you
can easily synthesize through a another class of starting material. And here what I am saying
that you can make this compound through this starting material as well as this starting
material. Now if you now ah try to analyse this ah retro in earlier sense will have this
starting material now this starting material, if you react with butyl lithium the feuron
basically this acidic hydrogen was first removed and give a lithiarade species.
Now this species this 1 basically react , to give you
a C H 2, C H 2, C H 2 double bond this things. Now feuron compounds can easily be opened
up to a 1 fold dicarbonyl compound, just by acquas hydrolysis and then you will find that
you basically get this 1 4 dicarbonyl compound . Now this this dicarbonyl compound now you
are basically, basically visualizing the entire, entire concept in term of synthetic equivalents
in in this way in this way , so a saying that a properly substituted feuron which is.
basically these methyl can act as a R C double bond O C H 2 C H 2 C double bond O minus.
Now this is also umpolung, but it is a umpolung the number of carbon has been basically intriched
now what we say we said that it this feuron we are reacting with this electrophile whose
electrophile structure we have already given, the feuron initially was reacted with a butyl
lithium and you get this minus and this methyl, now this minus is actually visualized as this
M E C O, M E C O, C H 2, C H 2 C O minus C O minus.
So, once you do this reaction and after hydrolysis you basically get the product which is require
for your jasmone synthesis . Now see the feuron part is basically giving you
M E C O, C H 2, C H 2, C O minus this minus and then you are approaching the electrophile.
Now this 1 by similar way if you do a aldol reaction it will give you cis jasmone , cis
jasmone structure was already ah discussed you in the earlier slide in similar way you
can basically ah basically carry out many synthetic experiences. So, synthetic exercises
let is try to figure it out very simple. synthetic equivalents , so how you can make
this compound , now, if you see this compound can be easily made if you having a this particular
dialdehyde and this as a electrophile. So, what you need to do you basically cut here
cut here and visualize as a C O minus C O minus, now this C O minus basically will be
now reacting with this. So, this is basically donor synthon this donor
synthon will be now reacting with a this acceptor and this acceptor, which you have explained
chorest terminology donor synthon donor acceptor . So, in similar way you can basically ah
basically ah do the couple of ah exercises a similar kind of exercises now I am be doing.
I am saying you are given a target molecule whose structure is this the starting material
is which was given to you is this ok. So, what you basically need you just need a M
E C O minus as a donor species . Now, this donor is a basically umpolung I
remember earlier we have also discussed this kind of umpolung you can also synthesize through
O protected cyanohydrin the chemistry which was a first ah discovered by professor gilbert
stork , O protected cyanohydrin go back to your earlier lecture O protected cyanohydrins
professor gilbert stork was the instrumental for this reaction, where I said that if you
having a O protected cyanohydrin you can easily abstract this hydrogen and that can basically
give you a very nice umpolung species. So, in principle 1 3 diethiane, 1 3 diethiane
definitely you can use 1 3 diethiane chemistry you can also use this O protected cyanohydrin
chemistry as this type of so this is simple things. So, now, how you can basically generated
if you can take this compound as your starting material the reaction is simple in addition
also you can take this compound O T M S cyanide it basically O protected cyanide. So, both
the chemistry you can ah easily do and try to remember in our biological system ah also
this kind of umpolung chemistry was often very much in action.
In our biological system this kind of ah intermediate was very much in action in particularly we
have also discussed a stetter reaction earlier stetter reaction earlier, we say that stetter
reaction is a synthetically very useful reaction , which ah which is basically catalyzed by
N A 2 cycle carbon chemistry or N A cycle carbon and if you now try to do a simple disconnection
of molecule like this 1 4 dicarbonyl compound you can easily do the disconnection followed
by this you can say that this is a your donor this is your acceptor.
So, basically a mickel version of reaction, but where you use a umpolung nucleophile through
a donor species and this is your acceptor synthon . And this is in principle named as
stetter reaction where we use the N A 2 cycle carbon a standard N A 2 cycle carbon structure
I am now drawing it here which is basically ah if you remember the mechanism of benzoin
condensation a similar kind of mechanism and this is 1 heterocycle carbon, where this particular
hydrogen is the key factor of for its main activity stetter reaction mechanism.
We are ah not going to discuss in detail we already ah have it ah we already did discussed
the mechanism earlier. Now what I am trying to do I will I will analyse a similar kind
of ah synthetic equivalents now here I will give a target molecule.
I am saying I am giving you target molecule is alpha beta unsaturated aldehyde , now the
starting material which was given to you a simple propanaldehyde. So, in terms of synthetic
equivalents if you have to do the disconnection what basically you need you need a this kind
of vinylic anion as your donor species, vinylic anion as donor ah its ah definitely difficult
to visualize, but this was first reported by professor Corey in this way if first take
this compound , whose name is epichlorohydin epichlorohydin react with 2 equivalent of
M E S N A methyn thiole its sodium salt. So, initially epoxyte opening will takes place
by M E S minus M E S minus as well as S N 2 with this C l. So, you will basically get
M E S epoxyte opening will give you the alcohol and this S M E, then free hydroxyl was protected
as a sodium hydride and methyl iodide . Now, this reaction was give you this methoxy
protected ether, then L D A was used as a reagent to facilitate 1 equivalent of methanol
elimination from this O M E N H. Now this elimination basically gave you a alyl phenyl
sulphide, alyl phenyl sulphide, now here if you react this alyl phenyl sulphide with 1
equivalent of base then you see how this reaction takes place.
So, you have a alyl this and vinyl you react with a base initially this hydrogen will be
abstracted and will basically getting this carbon ion . Now this carbon ion is stabilised
to give you a canonical structure or symmetrical structure. So, this is ah very much stable
carbonium ion ok symmetrical carbonium ion now this things was reacted with this your
N proponal. So, N propanal reacts and the initially what
you get you get this O H you get this S M E , and S M E fine. Now eventually a water
molecule was reacted here and is found at this nucleophile philic water initially coming
attacking to this vinyl sulphide , ah to undergoing this kind of ah elimination and then after
this elimination you basically get this S M E and O H, now this is what this is basically
a thioacetal this a thiol is there and a O H is there. So, now, you simply deprotect
this thiol with H g 2 plus followed by aquas work up you will get O H O H and this compound
is simple is a acetal which will instantly opened it up and will give you the required
compound. So, in the whole process, so you can basically, basically formulate this initial
compound which have been synthesized. this alyl vinyl sulphide was the equivalent
of this vinylic aldehyde , vinylic aldehyde . So, whole process was basically it was acting
as a d 3 kind of synthon sorry d 3 kind of synthon definitely and this is a donor species,
donor synthon reacting with a acceptor synthon in principle this particular synthon was used
in many ah many synthetic ah synthetic problems probably I will give you the next problem,
which is based on something like this what I am saying that how you can make this compound.
Now if you visualize is a target molecule or you then you do the simple retro if you
have epoxyte as a electrophile you react with this vinylic anion it can open up and will
give you this compound, now this you can easily prepare as mentioned earlier ok . So, this
is ah this is very simple you can ah do it very straight forward way .
We will ah try to conclude by using couple of interesting problems I will just give it
you and lest see how you can analyse or you can solve the first 1 is simple , the second
1 I am giving you a this 1 . So, third 1 a tertiary butyl and the bromide which has been
converted to corresponding t b u c o m e . Now if you analyse all the problem all the problems
are basically based on synthetic equivalents. So, you can simply think of that is in this
case if you have a m e co minus you can do a umpolung type of alkylation in particular
this case the electrophile is here. So, all this case this as this compounds are basically
acceptor acceptor, acceptor. So, this is your donor in this case your donor should be something
like this donor and in this case your donor will be again the same m e c o minus, m e
c o minus. Now in third case you have to look about the stereochemistry the starting compound
is tertiary butyl the cis compound ok. Now, final product which was given is a trans
that is obvious because as a doing S N 2 reaction of this m e c o minus it always attack from
the back side attack S N 2. So, you get this c o m e now what is the source of this m e
c o minus you can ah easily use this ah 1 3 diethiane chemistry, optic this acetaldehyde
thiol protected or even you can ah use this ah as a stork O as O protected cyanohydrin
this also you can use this 1 is ah very useful this 1 you can use the stork ah O protected
cyanohydrin, by using this corresponding o t m s c n, and here tertiary butyl chloride
which is sterically bulky and was used as a electrophile the reaction basically goes
well you have probably need to do a little bit ah refluxing or you need to ah put a thermal
energy. So, all this particular transformation you can easily accomplish easily, easily accomplish
with the help of your synthetic equivalents .
So, synthetic equivalents ah there are there are many things to be discussed, but definitely
as we do not have a enough time we will try to provide you ah few assignments, which you
can ah solve based on this information which you shared in the class and ah in the final
lecture ah which will be ah which will be giving to you next we will ah try to provide
you a complete story or try to basically summarize you.
So, what will I have to do I will ah pick up a natural product and the strategies which
you have discussed till today starting from transformation ah substrate functional group
as well as topology and stereochemistry? If it is possible normally stereochemistry we
tried to avoid because stereo chemical strategies often need a very complex molecule and ah
if you have a ah if you have a relatively complex molecule then explanation of this
stereo chemical strategies will be much more beneficial.
So, eventually ah in the final lecture we will try to ah give you a gist over all gist
by taking as a taking a medium size molecule as a target molecule and we will try to correlate
ah till today ah what we have discussed we will try to basically summarize here, so have
a good time till then good bye.