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Prof: We're talking about facts, ideas and words,
in relation to stereochemistry.
And the words have to be generalized, in the way we
communicate things, to include models;
things like this, right?
Okay, so models, but also what you can draw on a
piece of paper that will convey stereochemical structure to
people.
So the standard we use in drawing is wedges,
to mean they're coming out at you, in the direction that they
expand, and dashes mean they're going
back into the board.
Although if all you draw is dashes, it's not immediately
obvious which end is going back, if it's a dash.
Right?
But if one end has nothing on it, it's clear,
that it's going back from the carbon that's shown.
So you have to use your stereochemical intuition
sometimes to interpret that.
Although if you draw a wedge, it's clear which way it's
coming.
And sometimes people draw wedges with dots,
meaning they're going back in.
But there are many ways that people make mistakes in drawing
this.
So it needs a little practice.
That one's okay, and clearly corresponds to a
tetrahedron with 109° degree bond angles,
shown like this -- right?
-- the blue one's coming out at you, the black- the yellow ones
going back, green and red, up and down.
Okay, so that drawing is fine.
What's wrong with this drawing?
Sherwin?
Student: It couldn't mean like a
>.
The upper bond and the lower bond are --
Prof: I can't hear -- I still can't hear.
Student: Oh, the upper bond and the lower
bond are >.
Prof: What are the bond angles?
How about between the solid lines?
109.5°?
Student: 90°?.
Prof: Between the solid lines, not the wedges?
Student: Oh, 180°.
Prof: 180°.
How about the other angles?
Student: 90°.
Prof: 90°, right?
This is a square plane, drawn that way.
The dash has to go the other way, and the lines that are in
the plane of the board, or the piece of paper,
have to be at 109°.
Okay, so forget that one.
I assure you that we will get these on exams,
because we always have in the past;
but this is warning.
Okay, so that one's planar, forget that.
How about this one?
There I've got the wedges drawn the right way.
Everything else right?
No, the solid lines in the plane are 180°.
That one's bad obviously.
Not many people draw it that way.
Okay?
Ah, there's one that looks pretty good.
Everybody agree?
Any complaints?
Lucas, what's the complaint?
Student: An acute angle there.
Prof: Pardon me?
Student: An acute angle, over there.
Prof: Ah, the angles between the normal
lines and the wedge are all less than 90°.
Well one of them is bigger than 90°, the one to the top.
But the one to the bottom is less than 90°,
if the normal line is in the plane of the screen.
Right?
That's an acute angle.
Right?
So the one on the top left is the one you want to go for.
Okay?
Now how about this?
Do those look good?
See any problems?
Kate, what do you say?
Looks fine to you.
Tell me what the angle is here, between this bond and this one.
Where would this bond point if it were 90°
from this one, which is in the plane of the
board?
Student: Straight out.
Prof: It would point straight out.
Now if at 90° it would be coming straight out
from that point.
How about there?
Is this angle greater than or less than 90°?
Here's the carbon, here's the one that's in the
plane of the board.
Right?
It's going like that.
Here's the one -- that's 90°, right?
Suppose I bend it up like this, which is what the wedge shows,
now what's the angle?
Student: It's acute.
Prof: It's acute, right?
So these are not right, right?
The same is true at the bottom.
But this structure is okay because, by convention,
it doesn't mean to show the exact angle.
It just means to show that it's going relatively out,
right?
But it wouldn't be -- the solid -- these three lines here,
this one, this one, this one, the ones that are not
wedges and not dashes, could not be in the plane of
the board.
They'd be 120° angles, or something like that.
They couldn't be 109°, right?
But in order to draw this, in a finite amount of time,
when you're writing on paper -- people understand what you mean,
in this case -- but if you draw that one,
which means it's planar, people will be very much
offended.
Right?
Okay, so this again, at a certain level,
is lore.
You have to be criticized before you find out where you're
making mistakes.
Okay?
But anyhow, it's important to be sensitive about the fact that
carbon is tetrahedral.
Now, these things are hard to do in three dimensions.
And the Fischer projection was invented for that purpose in
1891.
And the reason for its invention was interesting.
He wrote: "With the help of
Friedländer's convenient rubber models,
one can construct molecules of right-handed tartaric acid,
left-handed tartaric acid, and inactive tartaric acid and
lay them in the plane of the paper so that the four carbon
atoms are in a straight line and the attached hydrogens and
hydroxyls lie above the plane of the paper."
Now, here's the idea, that Friedländer's models
used rubber tubing to connect these things.
Right?
So drawing this in two dimensions and making clear what
you mean in three is not easy.
But he says what you're going to do is take the four carbons
that are in a chain -- this is tartaric acid,
here's CO_2, carbon with an OH,
carbon with an OH and a carbon with O_2 on it,
right?
So what he wants to do is to lay all four carbons in the
plane of the paper, which you can't do.
Right?
But if the bonds are made of rubber, then you can bend the
bonds -- right?
-- and then you can make them all four, in the plane of the
paper.
Right?
But what you have to understand is that in this convention you
draw the four carbons vertical in a line;
not horizontal.
And then you understand that the bonds between them are
severely bent.
Right?
So that the curious thing is that when you draw a Fischer
projection, as is most convenient for
sugars, for discussing the configuration of sugars,
the bond, the four bonds for this carbon are understood that
these two, the horizontal ones,
come out toward you, as if they were wedges,
and the other two from this carbon go back into the board.
Okay?
This is his paper where he originally proposed it.
Nowadays you wouldn't use dots here, which help make it clear
that it's going back, you'd just draw lines.
But understand that vertical lines mean they're going back
into the board, and horizontal lines mean
they're coming out at you.
Okay, so that's the Fischer convention, that he invented in
1891.
So this bond here is a very funny bond,
because in bonding from this carbon to this carbon,
it's going back into the board from this carbon,
but also back into the board from that carbon,
because it's bent.
Okay?
And it was because Friedländer made his models
with rubber tubing that it occurred to Fischer that you
could do this.
And then all you have to do is draw straight lines -- you don't
have to do wedges and so on -- and just put things in the right
place.
So here he could draw right-handed tartaric acid,
left-handed tartaric acid, and inactive or meso,
as we call it now, tartaric acid.
So the attached hydrogens and hydroxyls lie above the plane of
the paper -- right?
-- and the other carbons, vertical bonds,
go back in from both of the atoms that they attach.
Okay, so there are the wedges.
And if you rotated that 90°, it would look like
that.
Very highly distorted, but you can do it with rubber
and be clear about what the configuration is -- unambiguous.
Okay, they go back from both carbons, and it was because you
had rubber models that you could do that.
Okay, so here are those models.
And notice that you can rotate in-plane by 180°,
and it means the same thing.
So if I have this and it's bent like this, and I rotate it like
that, 180°, it obviously means the same
thing.
Right?
I can rotate a Fischer projection by 180°
and it's still the same model.
But I can't rotate it by 180° -- or by 90°
this way.
Why not?
If I write it this way it won't mean the same thing.
Why not?
Shai?
Student: Because a number of horizontal bonds are
going in.
Prof: Yeah, the horizontal bonds are going
back in, and the vertical ones are coming out at you.
You've reflected it in a mirror, each carbon.
So you could rotate it 180°, but you can't rotate
it 90°.
Okay?
So there, we'll rotate that 180°.
That's still fine.
And in fact what do you notice about it, other than the fact
that the symbols are written backwards?
Student: The same thing.
Prof: It's the same thing it was above.
Right?
So rotating it 180° doesn't change it.
Okay?
How about the next one, if you rotate it 180°?
Same as above?
Yes.
How about the last one?
Okay.
That one is now the mirror image.
If you slide it up, like that, you can see that
there would be a mirror there.
Everybody with me?
So that molecule is its own mirror image,
whereas the first two -- and remember you can draw the mirror
any direction and always get the same mirror image;
xy, yz, xz, they all give the
same mirror image, just differently oriented.
Another way to draw the mirror one,
that's easier, is to draw it right through the
middle of the molecule horizontally,
and then the top half is the mirror image of the bottom.
Right?
So it's obviously not a chiral molecule.
It's superimposable on its mirror image,
whereas the -- and that one's called meso, the name then;
that was called meso-tartaric acid and
the name was generalized to mean any molecule which is its own
mirror image is "meso".
Okay?
And notice that these terms name relationships.
They don't name an absolute molecule, these stereochemical
terms, the ones like this.
What's the relationship between those two?
Are they identical, or are they just plain
different, or are they different in the special way that they're
mirror images of one another; the two on the top left?
Student: They're just different.
Prof: Okay?
Can you rotate them and make them be on top of one another?
No.
If you rotate them, they become the same thing they
were originally, right?
That's what we already did.
Are they mirror images of one another?
Right.
There's a vertical mirror between them,
right?
So those are non-superimposable mirror images.
And the name given to things like that is
"enantiomer".
So the one on the left, the top left,
is the enantiomer of the one that's in the middle.
Caitlyn, what's the question?
Student: Okay.
It's just the notation I guess.
If the OOH were on the other side.
Prof: Oh no, but that's -- but all that
means is the grouping C double bond OOH.
That doesn't have any arrangement in space when it's
just written with letters that way.
Okay?
That was just because I wanted to make strictly the rotation.
Right?
It's where the bonds point that makes a difference.
Okay?
Now, how about the relationship between the middle and the
right?
Are those identical; are they superimposable?
Elizabeth, what do you think?
Student: No.
Prof: No you can't move those, or rotate them any way,
and make them on top of one another.
Are they mirror images?
Student: No.
Prof: So what are they?
Student: Diastereomers.
Prof: They're just plain different.
They're diastereomers.
So the one in the middle is the enantiomer of the one on the
left but the diastereomer of the one on the right.
So you don't say it's a diastereomer,
or it's an enantiomer.
You say it's a diastereomer of this and an enantiomer of that.
Right?
So these name relationships.
Okay?
Okay, how about those two, the first and the last?
What's the proper relationship there?
Maria?
Student: Diastereomer.
Prof: Right, diastereomer.
Good, so we got the idea.
Okay now, how many isomers do you have?
Obviously if you have one chiral center you have
right-handed and left-handed, if there are four different
things on it.
So there are two isomers.
But suppose you have several chiral centers.
That's not so obvious then how many you have.
So if you have n stereogenic centers,
as they're called, and each could be right or
left, then you'd imagine the number
of permutations would be 2^n.
Right?
That would be expected.
But that's not true because of meso compounds.
And we'll illustrate that with a quote from van't Hoff's
brochure, in 1877, where he said:
"Next we consider a symmetrical formula"
(where carbon, the first carbon,
has one, two, three;
the next one has two fours, and the last one has one,
two, three, different substituents;
and also the one where the two in the middle are different,
four and five on the middle carbon.)
"As is easily conceived from the foregoing discussion,
they lead to only three isomers."
Because you have this possibility of meso,
that we just were talking about.
Although this is with three centers possibly in the second
one.
Now, Baeyer and Fischer were -- Baeyer, a student of
Kekulé, was the teacher of Fischer.
And they got together at a resort on the shore of the
Mediterranean, in Italy, and were trying to
figure out this particular question of how many isomers you
have here.
And they had read van't Hoff's thing.
So they knew there were supposed to be three isomers.
So they were sitting at breakfast and they had bread
rolls and they had toothpicks.
So they started making models of these and trying to count how
many isomers.
But they ran out of bread rolls, presumably,
and couldn't answer the questions.
They were completely flummoxed by trying to understand what
van't Hoff was saying.
So they gave up on using bread rolls.
And that is what prompted Fischer to go back and figure
out how to make Fischer projections.
Okay?
Now let's look at that particular case using Fischer
projections.
So we have these three carbons that might have four different
things on them.
The one in the middle is a little bit tough to decide,
because the ones on -- as to whether it has four different
things.
Obviously it has H, OH, and a carbon.
But those carbons that are attached are identical
constitutionally.
They have the same nature and sequence of bonds,
things attached to them, but they might or might not be
the same from the point of view of stereochemistry.
So it's not so obvious how this is going to work out.
But it turns out that it's really easy, if you use Fisher
projections.
And we'll try it here.
So here are the five carbons in a row,
the top and the bottom one being COOHs,
and you have the three carbons in the middle,
each of which has an H and an OH on it,
but they could be either way.
So at first glance it looks like 2^3, or eight possible
isomers.
So let's check them out, instead of using bread rolls,
using Fischer projections.
So we'll draw eight Fischer projections, and try to be
systematic and draw all the possibilities,
and then count them.
Okay, so first of all take the bottom carbon,
and we'll put in the top row all the OHs to the right,
and in the bottom row all the OHs to the left.
And then we'll do the analogous thing with the second row,
except we'll make the first two to the right,
the next two to the left, the next two to the right,
the next two the left.
Okay?
And finally what are we going to do on the top row?
Can you see how we're going to -- so that we get all eight?
We'll go right, left, right,
left, right, left, right,
left.
Okay, and now we've got all the possibilities.
So now we have to go through them one by one and see if
they're unique, or how they are related to the
others, if they're related.
Are they diastereomers?
Are they enantiomers?
Are they identical?
And we're going to use these Fischer projections to do it.
Okay, so we've got the first one.
Okay?
And now we look at the second one and compare it to the first
one.
Is it the same?
Student: No.
Prof: No.
Are they superimposable?
Student: No.
Prof: No, that would make them the same.
Are they mirror images?
Student: No.
Prof: No.
So two is different, right?
They're diastereomers.
Okay, now about how the next one, three?
Is it like any of the previous ones, or the mirror image of any
of the previous ones?
Student: No.
Prof: No, three is unique.
Okay, now how about four?
Does it look like any of the preceding ones?
Wilson?
Student: It's a rotation of two.
Prof: Ah, you can rotate it 180°;
which you can allow, right?
That'll keep the bonds pointing back, in the convention,
right?
And it'll look like two.
So that one actually is two.
So we'll blank it out.
Now how about the first one in the bottom row here?
Does it look like one?
No.
Does it look like three?
No.
Does it look like two?
Student: >
Prof: That's not so easy, right?
But it's not superimposable.
If you rotate it 180°, about the axis into the screen,
it still doesn't look like two.
Right?
So it's different.
Four.
How about the next one?
Virginia, you got an idea?
Does this one here look like any of the previous ones,
if we rotate it?
Student: Well, it's the mirror image of three.
Prof: Can't hear.
Student: Yeah, it looks like three.
Prof: Ah ha, it's like three.
If we rotate it 180° it's like three.
So forget that one.
How about the next one?
Does it look like anybody we've already seen?
Student: Four.
Prof: Four.
Right, if you rotate it 180° it's four.
Okay.
And the last one?
Student: One.
Prof: Pardon me?
Lexy, what do you say?
Student: It's the same as one.
Prof: It's one, if you rotate it 180°.
Okay.
So we've got these four that are different.
Now what are the relationships?
Okay, are any of them meso?
Do any of them have mirror planes, so that their own --
they're their own mirror image.
Angela?
Student: One.
Prof: One has a mirror image.
The top is the mirror image of the bottom.
There's the mirror.
Any others?
Student: Three.
Prof: Three.
Okay, but not two or four.
Anything else that you want to note about two and four?
Prof: Sophie?
Student: They're mirror images.
Prof: They're mirror images of one another.
Okay?
So what we have are two meso isomers -- they're diastereomers
of one another, right?
-- and a pair of enantiomers.
Each of those enantiomers is the enantiomer of one another,
and the diastereomer of either of the previous ones,
one and three.
Okay, so with Fischer projections he could easily
settle this question.
And that became very important in the chemistry of sugars,
where Fischer was deeply involved, as we'll see next
semester.
Okay, now here's Halichondrin B, which comes from a marine
sponge; as it says here.
Okay?
Now, you don't get very much of this out of a sponge.
Right?
But it was found that it was useful in anticancer therapy.
So the hope was you could make it and then see if it will work
as a good drug.
So it was found that you don't need the whole molecule.
If you cut it apart, to have only this portion we've
seen here, then that part is just as good,
medically, as the whole molecule.
So that simplifies the synthesis problem quite a bit.
But it's still non-trivial.
So there's the active fragment of Halichondrin B.
And SAR means Structure Activity Relationship.
They take off this, take off that,
trim it here and so on, change one thing to another
thing, and see if you can get better
activity than you get from just this thing itself;
and especially looking to changes that would make it
easier to synthesize.
Okay?
So they found out that this one, which is called E7389,
that model, is about as easy as you can get to synthesize and
still have really good activity.
But it's not easy to synthesize.
And you have the question that you have to get the right
diastereomer because the other diastereomers are different.
Now how big a problem is that going to be?
Well it depends on how many stereogenic centers there are;
how many carbons can generate two isomers, by being right or
left-handed.
So let's start up here at the left,
and I'll go along this chain, like that,
and you stop me when we get to a carbon that's chiral,
that's stereogenic.
Okay?
So I'll start here, at the top left,
and I'm going across.
Stop me when I get to one.
Oh, you didn't tell me.
Student: That one.
Prof: That one looks -- well you say oh that has only
three things on it.
Prof: You have to have four different things,
to be stereogenic.
Does anybody think that one is stereogenic?
Chenyu?
Student: It left the hydrogen out.
Prof: Can't hear.
Student: It doesn't have the hydrogen in it.
Prof: Ah, it doesn't show the hydrogen;
the hydrogens aren't being shown.
So there are, in fact, four different things
on that third atom -- nitrogen, carbon, but the second carbon
is stereogenic.
Okay?
So there's one.
Now let's keep going.
How about here, that one?
No, that one has two hydrogens.
How about this one?
Students: Yes.
Prof: That's stereogenic.
How about this one?
Students: Yes.
Prof: Yeah.
How about this one?
Students: Yes.
Prof: Okay?
How about this one?
Students: Yes.
Prof: Okay, how about this one?
This one?
This one?
Students: Yes.
Prof: Ah, that's got four bonds already,
no hydrogens there.
Okay, that one's not.
There?
Here?
Okay there.
There?
There?
There?
Yeah, that's got four.
There?
Students: Yes.
Prof: Yeah.
There?
Students: Yes.
Prof: Yeah, four different things,
because you have to count the hydrogen.
Here?
Yeah, the hydrogen also.
That one shows the hydrogen.
Okay.
Here?
Yeah.
Here?
Here, no.
Here?
Well you say there are two oxygens.
Right?
Are they the same?
Student: No.
Prof: No, they're attached to different
things.
Right?
So that one too.
Okay, here?
No, no.
Here?
Student: Yes.
Prof: How many think so?
Yeah, right, that one.
The next one?
This one?
Student: No.
Prof: Yes or no here?
Students: No.
Prof: No.
Here?
Students: Yes.
Prof: Yes.
Here?
Students: No.
Prof: Speak up.
Students: No.
Yes.
No.
Yes.
No.
Yes.
Prof: And there's one more carbon here.
Students: No.
Prof: No. Okay.
Well done.
There are nineteen stereogenic centers.
That means there are 2^19^( )possible isomers.
Will any of them be meso?
Are you going to get any mirror images within this molecule?
No, it's completely unsymmetric, right?
It's not like tartaric acid.
So there are going to be something like -- something
greater than half a million configurational isomers.
So it's not just a question of putting the right groups in the
right place to get constitution.
You have to put them stereochemically correct,
to get one out of million, right?
So this is a problem.
But they figured out how to do it.
And this, I just got this, this morning,
off the web -- pardon me.
It's a -- it'll say so at the top -- but this is the current
report on clinical testing of this;
so testing in humans.
Some of them are in -- like if you look at the top one,
it's in phase three.
In phase one they test for toxicity with humans;
obviously if it's toxic, you can't use it as a drug.
The next one they test "does it work?"
And the third they test whether it's better than current things
for doing it, and what the proper dose should
be and so on.
So this is phase three trials, and they're recruiting people
to -- I'm sorry, I got -- pressed the
wrong button -- they're recruiting subjects for
it.
They already have 1100 people in it.
It started in June 2006, and this was updated last May,
and it's to -- it doesn't have a completion date given there.
This one has a completion date of March 2010.
But in fact this is the objective, to see what the
quality of life is; tumor response rate;
duration of response; how many survive one,
two and three years, in this breast cancer test.
And it's being compared with another drug,
as it says there.
So here's what they're comparing in the two different
things.
Some people do this, some people do this.
So the drug, this drug is injected 1.4
mg/m^2, IV infusion over two to five minutes,
on days one and eight, every twenty-one days.
And it's being compared with this drug, which has 2.5
g/m^2/day, administered orally twice daily in two equal doses,
blah, blah, blah.
Okay, so that's the test that's being undergone now.
And the estimated primary completion date is September
2011.
It's been going since June 2006.
So it's going to be five years that they're doing this test,
with 1100 people.
So these are really, really expensive things.
And you notice it says it's being -- maybe it was on a
previous slide -- that it's being funded by industry.
Because they hope that it'll work and then they'll be able to
recoup their costs and make a profit on the basis of selling
the drug afterwards.
Okay.
If you go to this NIH website, clinicaltrials.gov,
you find that they have 64,268 trials in 158 countries going as
of today.
So these are very, very long, expensive things,
to try to get a drug that will work.
But making that stuff was really something.
But if they get a hit, then the company is on easy
street, for a while at least.
Like Lipitor.
So here's a Lipitor pill, which is the world's best
selling drug.
In 2004 it sold almost eleven billion dollars.
Right?
But it raised a 10 billion dollar problem in stereochemical
notation, that I'll show to you here.
So this is a news report from 2005, dateline New York.
"Pfizer Inc.
won a significant victory on Wednesday when a British judge
upheld a key patent covering its blockbuster cholesterol drug
Lipitor in the United Kingdom.
But the medication still faces a similar yet more important
case in the United States."
(And that was decided in 2006, in the same way,
in the U.S. Court of Appeals.)
Okay, so, "Judge Nicholas Pumfrey"
(in the High Court in London) "upheld the patent covering
atorvastatin, Lipitor's active ingredient,
but ruled that another patent was invalid.
Indian pharmaceutical company Ranbaxy Laboratories Ltd."
(a generic chemical company) "had challenged both
patents, and was joined by Britain's Arrow Generics Ltd.
against the second patent that was ruled invalid.
Pfizer said the decision upholding the exclusivity of the
patent covering atorvastatin until November 2011 was an
important victory for scientists."
And perhaps also for stockholders and executives of
Pfizer.
Okay?
Now, what is patented?
Here's the patent that was under discussion.
This is the U.S. version.
There was also a British version.
Okay, so it's patent number 4,681,893, from 1987.
Okay?
So the important part of a patent is the claims at the end,
what's to be protected.
And it said, "I claim a compound of
structural formula 1."
So this compound, okay?
And notice that it has codes in here;
like X can be any of those groups, linking the right and
the left; R_1 can be any of those groups;
R_2 and R_3_ can be any of these groups.
Right?
Still going.
R_4 can be any of these groups.
Or it can be a hydroxyl -- instead of being this kind of
ester, which is called a lactone,
it forms a ring -- it could be the acid that you'd
get from that by hydrolyzing it, or a salt of that acid.
Okay, so all those things are covered in that patent.
How many molecules are covered in the patent?
If you made all the permutations of those groups,
you'd find that it's greater than the number of protons,
neutrons, and electrons in the solar system.
So it's obviously impossible to make all the molecules.
You'd need quite a few solar systems to have enough particles
to do it with.
Okay?
But the patent is supposed to protect that.
Okay, now.
So here -- but what is patented and what was being discussed was
not what those groups are.
That wasn't in contention.
It's known that Lipitor is this stuff: the calcium salt,
and it has those particular R groups on it.
But that wasn't in question, the fact that it covered so
many compounds.
What was in question was what the stereochemistry is.
Because Lipitor, the drug, is a single
enantiomer.
Right?
Not its mirror image and not a mixture, not a racemate.
Okay?
But the question is, did this patent cover the
single enantiomer?
Which is what the picture shows; although it doesn't show it
very well.
Why not?
If you were drawing this structure, on the top right,
would you draw it that way?
How about that carbon?
Does it show its tetrahedron well?
Student: No.
Prof: It certainly doesn't show 109°
angles, but it's -- and this dash should be up here,
to be even close.
How about that carbon?
That's even worse, if you were trying to really
show the angle, because that one's 180°.
But at least it's unambiguous about that versus its mirror
image, even though it's not very good.
Right?
It's not ambiguous.
So the structure drawn in the patent was a single enantiomer,
and it turned out to be the one that is Lipitor.
Okay?
But the text of the patent didn't do anything.
It never resolved it and made it into one enantiomer.
It just talked about it generically.
And what it would be making is the racemate,
not the single enantiomer.
So does the patent cover Lipitor or doesn't it,
was the question for the judge.
Okay, so this is his opinion.
He said: "In the '633 patent,"
(when they talk about patents they just talk about the last
three digits, not the big number) "it is
absolutely clear from context throughout that formula (1) is
being used to denote a racemate."
(So what they talked about and what they prepared,
tested and so on was both enantiomers.
Okay?)
"In my judgment, every time the skilled person
sees formula 1 or formula X,"
Now, skilled person has a very special meaning.
It means someone who is "skilled in the art",
that knows about pharmaceutical chemistry and so on,
knows what these compounds are, how to make them and that kind
of thing, but is not creative.
Because what you can patent is original creation.
So the skilled person knows everything but can't figure
anything out; if you see what I mean,
can't devise anything new.
Okay so the skilled person sees these formulas.
"He will see them with eyes that tell him that in that
racemate," (which is described in the
text) "there is a single enantiomer that is the effective
compound," (So even though what's
described is both, the person that isn't very
swift, but is knowledgeable, knows that within that there'll
be two mirror images, and one of them will do the
trick, and not the other one.
So you don't have to be creative to know that.)
and he will know "that he can resolve the racemate using
conventional techniques."
(He doesn't have to invent something new,
in order to get from that mixture, the one that will be
the active one.
Okay, so that's not creative.
Okay?)
"When one comes to claim 1,
which echoes the purpose of the invention with its conventional
reference to pharmaceutically acceptable salts,
he will, in my judgment, continue to see the formulae in
this light."
(So the salt's the same deal, right?)
"In my view, the claim covers the racemate
and the individual enantiomers."
So the person without any creativity knows that yes,
the patent described the racemate, but there'll be one in
there that I can get, and that'll be the useful drug.
And it doesn't take anything great to get there.
We'll talk about that soon, how you would do that;
why it's well-known.
Okay?
So this is good news for Pfizer, right?
Their patent holds.
They put out a press release saying this is a victory for
science.
Okay?
But it's in a sense a pyrrhic victory, because they had a
later patent, on the single enantiomer.
Right?
And now that patent is invalid.
Because if the first patent covers it,
you can't just every three years come up and say,
"I patent this again," "I patent this
again," I patent this again," and keep getting
another fifteen years of exclusivity.
Right?
So once they were covered by the first patent,
the second patent is invalid.
Why do they care, if they're already covered by
the first patent?
Isn't that good news?
Dana?
Student: Their fifteen years of exclusivity will run
out.
Prof: Ah, they're going to run out.
So this means that three years earlier their patent is going to
run out -- right?
-- at four or five billion dollars a year.
That adds up.
Okay?
Now, so drug -- so there are conventions for how you name
things, including stereochemistry.
In fact, there was a stamp issued in Switzerland in 1992
commemorating the 100th year of the Geneva Convention,
where chemists got together, once they knew stuff about how
things were connected.
Then they had to agree on how to describe it,
on what the nomenclature and the notation should be.
So the International Union of Pure & Applied Chemistry
continues this.
And you can go to these websites and learn about what
the rules are for notation.
So they had to devise rules for what you want to do when you
make a name for a compound.
So what is maybe the first thing you want to do?
Nate?
Student: You need to -- Prof: No, not you.
Student: The other Nate?
Prof: Well let's see.
Let's try somebody else.
Andrew?
No, no.
Kate?
Kate?
Student: >.
Prof: Kate, what was the first rule?
Student: They want the name to discuss composition,
like which atoms are in it.
Prof: Well -- I didn't mean you anyhow.
So what's the first rule about names?
Prof: John?
Not you.
>
Other Kate?
Student: They should describe only one.
Prof: Ah, they should be unique.
There should only be one compound that has that name.
You shouldn't say, "Take this,"
and they take the wrong John or the wrong Kate or the wrong
Andrew.
Right?
So the very first thing should -- well it should be -- Kate,
you were right first.
It has to be clearly descriptive of what the compound
is.
And so it has to tell composition, constitution,
configuration and conformation maybe, if you care,
i.e., stereochemistry.
And it can be like this.
E7389 was the name of that compound.
Forget trying to name it systematically,
according to rules.
Right?
E is for Eisai, the name of the pharmaceutical
company, and this is their 7,389th compound.
Right?
But at least everybody knows what that means.
Right?
Or you can look it up.
But this is what we were just talking about.
It has to be unambiguous.
Right?
One name must mean one structure, not some other
structure as well.
Okay, so unfortunately "amide"
doesn't fit that bill, because it means the anion of
an amine, but it also means that
functional group we're talking about.
It's the same name.
You have to figure out from context which one you're talking
about.
It also has to be unique.
One structure is one name.
So everybody will have the same name for the compound.
Right?
Which is more important, that it be unambiguous or that
it be unique?
Like you could have two names for the same compound;
like bromobutane and butyl bromide.
Right?
And if you put a number in, you would know which -- where
the bromine was.
Okay?
Or bromoethane and ethyl bromide.
Two different names, right?
So the names aren't unique.
Right?
But they're unambiguous.
You know what compounds you're talking about.
Why would you care whether you have just one agreed-on name by
the people who get together in the International Union of Pure
& Applied Chemistry?
Why would care?
What's wrong with having two names?
Anybody see any disadvantage to having different names for the
same compound?
Sam?
I could've called Sam too.
Yeah, go ahead.
Student: It's hard to communicate about the stuff.
Prof: Not if everybody knows what you're talking about.
Shai?
Student: Well like if something has a lot of names,
eventually you're going to get to a point where someone doesn't
know.
You can say -- you're going to say a name and they're not going
to know what you're referring to.
Prof: Or if you have to look it up, you have to choose
the right name to look it up.
So this was more important, when you didn't have computers
to do the work for you, when you had to look in an
index and get -- and be looking for the right
name that everyone agreed, and the person who made up the
index entered it there.
Nowadays you can draw a structure often on a screen,
and the computer will figure out what the official name is
and then look it up.
But anyhow, that -- so it's not as important that it be unique
as that it be unambiguous.
But if you're looking things up, it's very nice if you know
that everybody will have named it a certain way.
So you can also index things according to their composition,
CHN, or using computer graphics, as we say.
And, if possible, the name should be manageable.
Right?
It should be possible to write it fairly quickly.
It should be easy to figure out; short, if possible,
and pronounceable, if possible,
so that you can talk about it.
Now let's look at systematic constitutional nomenclature,
for this sort of intermediately complex compound.
Compared to these others we've looked it's not much.
Okay, so the first thing you do, these people decided,
when you get together, is decide what the main chain
of carbons is.
Because that will provide the root with a Greek designation
that says what the number of things is.
So we have to find a carbon chain, and we'll find the
longest carbon chain.
We could take this one, or we could take that one.
Which one is longer?
The one, it could be an octane or it could be a nonane.
Which one should we choose?
Students: Nonane.
Prof: Well we could've decided you take the shortest
one.
But that's sort of silly.
There'd be a zillion shortest ones;
or short ones, right?
Or even shortest.
The shortest is one carbon I guess.
But there's only one longest one, right?
Wrong.
Because there's also that one.
Same length.
So now we have to decide when we're going to take the longest;
how are we going to choose, if there are two of them?
Well what you choose by is the number of substituents.
Okay?
Because that one has one, one, three, four,
five substituents, and this one has four
substituents.
Which will you choose, the one with four or the one
with five?
You have to make the rule up.
five or four?
Student: Five.
Student: Four.
Prof: Somebody said four.
Why?
Sophie you said four?
Student: Less naming to do.
Prof: There'd be less naming to do.
Ah ha.
But in fact they chose the most substituents,
and you'll see why shortly.
Okay, so you choose the most substituents.
So you choose the one on the top, not the one in the middle.
Now why?
Sophie's not happy with this.
But you'll see soon.
Now you have to number the carbon atoms,
to say where the substituents are.
Now, we can start from either end.
Right?
If we start one, we could go one,
two, three with green and continue;
or one, two, three with red,
from the other end, and continue.
Now how are we going to decide which way to go?
Kevin?
Student: Right.
So you want in this case the Cl and the Br to have the lowest --
to be associated with the lowest number of carbons on the chain.
Prof: Okay, there are two ways to do it.
You could make it so the overall sum of the numbers
you're going to get -- because you'll get different
numbers, according to which end you
start from.
You could sum them all up and see which one gives the lowest
sum and choose that one; or the highest sum you could do.
Or you could see which one gives the lowest number at the
first number.
So this, if you chose the red, you'd have 2-chloro.
If you chose the green, you'd have 3-bromo.
Right?
And the other numbers would all be higher.
Which one do you want to do, use the lowest sum of all the
numbers, or the lowest number at the first difference?
Lucas?
Student: Lowest number at the first difference.
Prof: Why?
Student: So you can actually build it as you go,
instead of just saying -- Prof: Yeah,
so you don't have to do all the work of going through the whole
thing and adding them all up and so on.
You just go 'til you get a difference and when you get a
difference that's it.
That's much quicker.
Okay?
So we'll go to the first difference, lowest number at the
first difference.
And now we have to say -- now we know we have the chain and
its numbers, and now we say where the various substituents
are.
But first we have to name the substitutents.
Now in the top you can see we have methyl, bromo,
methyl, ethyl and chloro.
Now had we followed Sophie, we would have to name that one,
and that's not as easy to name.
So the fewer substituents you have, the harder they are to
name, because they get more complicated.
Right?
So that's why you choose to have the most substituents,
so they'll be the easiest to name.
You have to do more but it's easier.
That particular one is called 1-chloroethyl.
But why have to name complicated things if you can
name simple things?
Okay?
So you choose the most substituents in order to get
simpler names.
Then you alphabetize them.
You don't put them on by order of their number,
you alphabetize the names of the groups, and you count.
So that compound is 7-bromo- (b is first) 2-chloro- (c)
3-ethyl-6,7-dimethylnonane.
Now you might say dimethyl should be alphabetized by
d, not by m.
But that's not the way it's done.
It's done by the group name and then the prefix that tells the
number doesn't enter into the alphabetizing,
usually; although some people do it the
other way.
Okay, so that's the question about the d.
Okay.
Now, if you go to this website you can get help with
nomenclature.
Here's a compound that it goes through.
And the minute you look at this and see the name at the bottom,
the compound name, 4,5-dichloro-2,4
-chloro-2-hydrox ymethyl-5-oxo-he
xyl-cyclohexane-1-carboxylic acid,
you say "Wow!"
And aren't you glad there are computers that can do this for
you?
But you can go through it and figure out why they did it that
way.
But that's sort of a parlor game.
It's not fundamental chemistry.
Okay?
But there's some very useful non-systematic names for simple
groups: isobutane, isopentane, neopentane.
So you can have an isobutyl group or an isopentyl group or a
neopentyl group, isopropyl, secondary-butyl,
tertiary-butyl, neopentyl.
So these names you just have to learn.
Right?
They're not systematic.
And there's a nomenclature drill available on the course
website.
So it's good to know these so we can talk to one another.
But in principle the systematic name is the way to go.
Okay, that's it.
But we haven't gotten to stereochemistry yet.
That'll be tomorrow, or Monday.