WEBVTT

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J. MICHAEL MCBRIDE: Well, from
the happy hubbub, I gather

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you're as eager as I am
to get this over.

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So the last lecture is a review
of what we've done

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before, actually.

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But it's focused on synthetic
chemistry.

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In particular, the synthesis
of cortisone, which is a

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natural product.

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Cortisone looks like this.

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It's one of these steroids
which, remember, have three

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six-membered rings, then a
five-membered ring, and

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various alcohols and
ketones and so on.

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And in fact, this lecture
originated with a book called

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Advanced Organic Chemistry,
although I've used it so much

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that you can't tell it from the
spine anymore, that was

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written in 1961 when I was
taking organic chemistry by

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Louis Fieser at Harvard, who was
the person I was having at

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that time for this course.

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He was a very good synthetic
organic chemist, and he worked

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a lot on steroids.

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In fact, in 1936, he wrote this
book, which is called

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Chemistry of Natural Products
Related to Phenanthrene.

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Phenanthrene three is a thing
like three benzene rings.

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Bing, bing, bing.

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So you see, steroids are related
to phenanthrene, so

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that's what this
book was about.

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He also was a stylish guy.

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Before I got there, it was
reported that he walked around

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with a gold headed cane.

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He had dropped that affectation

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by the time I arrived.

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But he's still smoked like a
chimney, although at that

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time, he was on the Surgeon
General's committee about

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smoking and health, and he
absolutely quit then, and but

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he ultimately succumbed
to lung cancer.

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So this is a way of
homage to him.

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These are some of the steroids,
the ones that are

01:49.800 --> 01:51.130
sex hormones.

01:51.133 --> 01:54.133
So very small amounts of them
go around and make various

01:54.133 --> 01:55.603
things happen in your body.

01:55.600 --> 01:58.400
And they begin up at the top
left with cholesterol, and you

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can see how various enzymes
oxidize and put a ketone here,

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an alcohol here, making
unsaturation and so on to make

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all these important compounds.

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In fact, they were recognized
as so important that work on

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steroids awarded four Nobel
Prizes between 1927 and 1950,

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and another three between 1965
and 1975, which were, at least

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in part, due to work
on steroids.

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The awards in 1927 and '28
were determining the

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structure, and the one in
1965 recognized the

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synthesis of it.

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You have to know the structure
before you can

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synthesize it, obviously.

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In fact, the ones in 1927 and
'28 were for determining the

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wrong structure.

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The thing they got the Nobel
Prize for was this structure,

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which doesn't have three
six-membered rings, bing,

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bing, bing, like that.

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But it got settled
in the 1930s.

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So by 1950, the Nobel Prize in
Physiology or Medicine was

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awarded to Kendall, Reichsten,
and Showalter Hench "for their

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discoveries relating to the
hormones of the adrenal

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cortex, their structure and
biological effects." So

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Kendall and Reichstein were
organic chemists, and

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Showalter Hench was a
physiologist.

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And Hench's Nobel address
said "This air of pessimism

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regarding the rheumatic disease
in general and rheumatoid

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arthritis in particular still
finds expression in some of

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the modern writings
and texts."

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But then he goes on to describe
how he had a patient

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at the Mayo Clinic, a
65 year old patient,

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with an unusual story.

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A few days before he came, he
was "painfully affected with

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rheumatoid arthritis, and
had been for four years.

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Then jaundice suddenly
developed, and within a week,

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most of his arthritic
manifestations had

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disappeared.

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The jaundice lasted five weeks,
and the rheumatic arthritis

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did not relapse until several
weeks after the jaundice had

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disappeared.

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"The thought occurred instead
of being relentlessly

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progressive, this disease,
rheumatoid arthritis, may be

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potentially reversible, more
so than we believed.

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Perhaps rapidly so."

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"So during the next five years,
from '29 to '34, while

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the organic chemists were
determining the true

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structure, observations were
made on sixteen patients with

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chronic arthritis or fibrositis,
in whom jaundice

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of different types and
degrees developed.

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If the jaundice was deep
enough, it was characterized

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by bilirubinemia of the
'direct-reacting' type, the

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rheumatic symptoms quickly
diminished or disappeared for

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varying lengths of time...
and then gradually returned."

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And furthermore, it was
noted that during

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pregnancy, people lost that.

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So there was thought
to be some hormone

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that would do this.

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So they figured that out.

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You can read that yourself.

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OK.

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So Reichstein then, the Swiss
chemist, took 1000 kilograms

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of adrenal glands from cattle,
and was able to get a 1

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kilogram of dry residue from
that and follow the activity

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as he parcelled it out,
including using Girard's

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ketone reagent T.

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Remember, we talked about that's
the thing that makes a

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hydrazone, and that it has a
permanent cationic charge, so

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it will take a ketone into
water, then you can take it

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off and it'll go back
into the organics?

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That was a powerful way of
separating these ketones.

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And so there we go.

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So they got 7 to 8 grams of
a ketone out of that.

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So this was this fishhook
to extract ketones.

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We've talked about that before,
so I'm just going to

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click through it very rapidly
to show how it was

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synthesized.

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And now we know what it did.

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"Only when pure crystalline
homogeneous substances were

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produced were they tested as far
as possible biologically.

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So accurate determination
of chemical

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structure was given priority.

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In nearly all cases, this could
be elucidated in all its

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details."

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So now by the mid-1930s, they
had what the structures were.

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And here were some of these
steroids from the adrenal

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cortex, 29 of them, of which
these five were particularly

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important as active.

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Now those two, you notice,
are on the top cortisol.

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It has an OH group on
the top left here.

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And below it is cortisone,
the ketone.

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So that position 11 and the
position 17 were particularly

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important then.

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You have to have that ketone
at 11 to get cortisone.

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"The introduction of an oxygen
atom in position 11 of the

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steroid skeleton is one of the
major difficulties in the

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synthetic

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production cortisone." Why?

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Because it's so far away from
any other functional group.

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It's not alpha to something, or
the beta position, where an

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alpha beta unsaturation
could be used.

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Right?

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"The preparation of the
substance from deoxycholic

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acid still remains a long and
laborious way, even when so

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many improvements to it
have been discovered.

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If it is wished to obtain
cortisone more simply, there

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remain two ways.

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Either total synthesis or the
discovery of a better

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qualified raw material that's
close in structure to this,

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that then you could
convert into

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this for medical purposes.

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Both will be tried.

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The prospects of a total
synthesis are difficult to

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assess."

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So it's going to be
tough to do this.

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Either total synthesis
or you've got find

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a better raw material.

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And there's a footnote there.

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"R.B. Woodward referred to the
partial synthesis of an acid

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which is already very closely
related to cortisone...

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9 April 1951 in Boston, Mass."
And it gives a reference here.

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OK.

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So this book that I talked about
uses as an example of a

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total synthesis Woodward's

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synthesis in 1951 of cortisone.

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And this is it, but we're going
to go through it slowly.

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So this is the thing
he wanted to make.

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It's got these four rings, A,
B, C, and D. And obviously

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it's going to take a lot
of steps to get there.

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So the first goal is to make
rings C and D. Why did I put a

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question mark on D?

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STUDENT: It's a
six-membered ring

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PROFESSOR: It's a
six-membered ring, not a

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five-membered ring.

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So he's got something clever in
the back of his mind when

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he thinks of that as the first
thing he wants to make.

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And that will be a handle, that
double bond on the far

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right, a handle to allow
modification, to make the ring

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a smaller size and put
the functionality

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that you need on there.

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OK.

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And this double bond at the
top left of ring C is the

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thing that's going to allow us
to get access to put the

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ketone on there.

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And down at the bottom, this
ketone is a handle.

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It's at this position
down here.

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This is going to be a handle to
build the rings A and B. So

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we'll see how that works.

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So this compound was known and
readily available and cheap.

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So you could get a lot
of it to start with.

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So the first reaction he did was
to build ring D onto that.

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How did he do that?

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What kind of reaction could
build ring D, make these bonds

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that are highlighted
in blue, here?

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Anybody got an idea?

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STUDENT: The Diels-Alder
reaction.

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PROFESSOR: The
Diels-Alder reaction, Right?

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So he did that, the standard old
Diels-Alder reaction, and

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he put that ring on.

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But notice when the diene sits
down on top of that double

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bond, the methyl and the
hydrogen are going to be on

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the same side.

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Whereas over here, they want
to be on opposite sides.

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So we better get that fixed up
so that they won't have the

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wrong stereoisomer when
we get to the end.

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Can you see any way to change it
so that this hydrogen is no

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longer pointing down,
but pointing up?

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Yeah, Amy?

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STUDENT: Can you use the

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Mitsunobu reaction?

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PROFESSOR: Ah.

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Mitsunobu inverts an alcohol.

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If you have an alcohol, you can
go from right-handed to

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left-handed.

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But there's
no alcohol here.

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What functionality is
handy? Rahul?

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What's special about the
position of that H?

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STUDENT: It's... I want to say
it's...

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PROFESSOR: We want to
pull that hydrogen off and put

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it back on the other side.

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There are a zillion
hydrogens in here.

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Ayesha?

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STUDENT: Is it because it's next
to a carbonyl group?

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PROFESSOR: Aha!

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Enol, enolate.

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OK.

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So we want to go to that,
and you do it with base.

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It's an enolate, and the trans
isomer is more stable, so it

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goes all over there
via the enolate.

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And now we're going to make
the ketones into alcohols.

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Can you think of a reagent
that could do that?

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This is review.

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What kind of reagent
is necessary?

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STUDENT: Reducing agent.

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PROFESSOR: A
reducing agent.

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Something that will add hydride
to the carbonyl.

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Any ideas?

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STUDENT: Hydrogen peroxide?

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PROFESSOR:
Hydrogen peroxide.

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Good idea, everyone?

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STUDENT: No.

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PROFESSOR: Why?

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It's an oxidizing agent,
not a reducing agent.

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Lithium aluminum hydride does
the trick, so you do that.

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Now, what they want to do is
get from this diol now over

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here to a ketone and
an unsaturation.

11:48.567 --> 11:52.197
You already have an
unsaturation here.

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So let's think about
how we do that.

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The oxidation levels turn
out to be the same.

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So you just use acid to
eliminate...acid in water, so

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you can protonate and
get that cation.

12:09.767 --> 12:11.597
But why get that cation?

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Why not protonate here and get
the cation on the bottom, or

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protonate here, and
lose methanol, and

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get the cation there?

12:18.600 --> 12:21.730
Well, the cation here is no
good, because it's a sigma--

12:21.733 --> 12:22.833
it's in the sigma system.

12:22.833 --> 12:25.303
It's not conjugated with
the double bond.

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This one is allylic, but that
would be allylic too.

12:30.367 --> 12:33.867
But if you make that one,
then the resonance

12:33.867 --> 12:34.867
structure is here.

12:34.867 --> 12:40.227
There's the vacant orbital, the
low LUMO is here and here,

12:40.233 --> 12:42.873
And it's adjacent to the
unshared pair on oxygen.

12:42.867 --> 12:44.827
So that's the one
you want to do.

12:44.833 --> 12:47.733
So it takes off the one they
want to take off, at the top,

12:47.733 --> 12:48.973
you get that.

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Now you do an allylic
rearrangement of OH.

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Or you complete the allylic
arrangement.

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You took it off here, and
you put it on here.

13:05.333 --> 13:07.133
Now, what functional group
do you have now,

13:10.833 --> 13:13.933
when you have OH an OR
on the same carbon? Ruoyi?

13:18.133 --> 13:19.273
STUDENT: Hemiketal.

13:19.267 --> 13:23.967
PROFESSOR: What does it
do, what does a hemiketal do?

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Loses alcohol.

13:25.600 --> 13:26.900
Right?

13:26.900 --> 13:31.370
So the hemiacetal here, treat it
with acid, protonate, lose

13:31.367 --> 13:33.267
that, and you've got
the ketone now.

13:33.267 --> 13:33.527
Right?

13:33.533 --> 13:35.403
So we've got it to here.

13:35.400 --> 13:39.170
But we need to get this OH off
to get down to what he wants

13:39.167 --> 13:40.527
to build this over here.

13:40.533 --> 13:44.203
So he treats it with
acetic anhydride.

13:44.200 --> 13:47.900
What does an alcohol do with
the acetic anhyride?

13:47.900 --> 13:51.700
The O attacks the carbonyl,
acetate leaves.

13:51.700 --> 13:56.200
It's a substitution reaction
at an acyl carbon.

13:56.200 --> 13:59.500
So you put acetate on here.

13:59.500 --> 14:03.500
And now to get from here to
here, we have to change an O

14:03.500 --> 14:06.530
on the ring into an
H on the ring.

14:06.533 --> 14:09.703
What kind of reagent
do we need?

14:09.700 --> 14:10.400
STUDENT: Reducing.

14:10.400 --> 14:12.100
PROFESSOR: We need a
reducing agent, right?

14:12.100 --> 14:13.570
So like a metal.

14:13.567 --> 14:19.127
So we use the zinc. So zinc
comes in, gives electrons.

14:19.133 --> 14:22.873
The acetate leaves.

14:22.867 --> 14:27.327
So we generate this anion and
that double bond and enolate.

14:27.333 --> 14:29.733
But of course, this is a
resonance structure of it, and

14:29.733 --> 14:32.273
you put a proton on the
anion down there.

14:32.267 --> 14:34.127
So he's got to that.

14:34.133 --> 14:36.603
So now we're ready for
the next step.

14:36.600 --> 14:43.870
And the next step is to build
ring B, and also, to protect

14:43.867 --> 14:46.597
the double bond here so it won't
react when other double

14:46.600 --> 14:49.500
bonds react.

14:49.500 --> 14:54.270
And this thing here on B,
building this thing on B, will

14:54.267 --> 15:03.527
be a handle to construct ring
A. And that double bond here

15:03.533 --> 15:06.273
gives you access to that place,
which is, remember,

15:06.267 --> 15:08.197
where we need to put a
ketone, which is sort

15:08.200 --> 15:11.200
of off in left field.

15:11.200 --> 15:11.470
OK.

15:11.467 --> 15:15.167
So the first thing is to build
ring B. Did you ever see a

15:15.167 --> 15:21.227
thing like that, where from
the ketone here we build a

15:21.233 --> 15:23.233
whole six-membered
ring down here?

15:26.767 --> 15:28.567
We saw it two lectures ago.

15:28.567 --> 15:29.367
STUDENT: The Robinson
annulation.

15:29.367 --> 15:31.997
PROFESSOR: The
Robinson annulation.

15:32.000 --> 15:35.900
So what we need is ethyl vinyl
ketone, not methyl vinyl

15:35.900 --> 15:38.570
ketone, but ethyl, in order
to get this extra

15:38.567 --> 15:39.497
methyl group in here.

15:39.500 --> 15:42.670
So this thing, which normally
would be methyl vinyl ketone,

15:42.667 --> 15:45.427
is now ethyl vinyl ketone,
so we'll have that

15:45.433 --> 15:46.503
methyl group on here.

15:46.500 --> 15:46.800
OK.

15:46.800 --> 15:52.170
So ethyl vinyl ketone generates
the enolate, does a

15:52.167 --> 15:53.997
conjugate addition,
or sometimes

15:54.000 --> 15:56.430
called a Michael addition.

15:56.433 --> 16:00.903
Make that enolate anion,
protonate it, and now make the

16:00.900 --> 16:04.770
other enolate anion and have it
attack the carbonyl to make

16:04.767 --> 16:06.097
the beginning of that
double bond.

16:06.100 --> 16:08.270
What would you call that
kind of reaction?

16:08.267 --> 16:12.167
If you make this enolate react
with this, and end up with an

16:12.167 --> 16:15.797
alpha, beta unsaturated ketone?

16:15.800 --> 16:19.030
So you have a ketone attack
another ketone to give an

16:19.033 --> 16:20.903
alpha-beta unsaturated ketone.

16:20.900 --> 16:22.930
Remember what you call that?

16:22.933 --> 16:24.233
Aldol.

16:24.233 --> 16:25.633
You still have a week,
don't panic.

16:29.233 --> 16:31.433
So we're going to do an
aldol reaction, and

16:31.433 --> 16:35.073
then get over here.

16:35.067 --> 16:37.667
Now, what we do there, in order
to make this protecting

16:37.667 --> 16:40.367
group, is treat with
osmium tetroxyde.

16:40.367 --> 16:41.997
We know that that
makes a diol.

16:42.000 --> 16:43.570
We talked about that when
we were talking

16:43.567 --> 16:46.767
about paracyclic reactions.

16:46.767 --> 16:48.767
OK, so you can get the diol.

16:48.767 --> 16:51.827
Then you make the diol into
this carbon with two more

16:51.833 --> 16:52.833
methyls on it.

16:52.833 --> 16:57.503
What kind of functional
group is this?

16:57.500 --> 17:00.370
Two ORs on the same carbon.

17:03.433 --> 17:05.533
That's a full acetal, right?

17:05.533 --> 17:12.733
And you make it by reacting a
ketone acetone with a diol.

17:12.733 --> 17:15.603
So we're going to get this
ketal, or acetal.

17:15.600 --> 17:15.870
OK.

17:15.867 --> 17:19.867
Now we need to go across
from here to here.

17:19.867 --> 17:23.067
And what we're doing is removing
this double bond.

17:27.000 --> 17:31.030
So that's done with catalytic
hydrogenation.

17:31.033 --> 17:33.233
And notice, that's why
we had to protect

17:33.233 --> 17:34.903
this double bond here.

17:34.900 --> 17:37.270
Because it would have
been destroyed.

17:37.267 --> 17:40.627
And if it was destroyed, then
you'd have no functionality

17:40.633 --> 17:43.533
out here in order to change
the six ring into

17:43.533 --> 17:46.073
five-membered ring and put
the other stuff on.

17:46.067 --> 17:49.227
So you had to first
protect this, then

17:49.233 --> 17:52.233
get rid of this one.

17:52.233 --> 17:55.403
So now he's got this compound.

17:55.400 --> 18:01.730
And now we're going to knock
ring D off while we work on

18:01.733 --> 18:04.573
ring A so the whole slide
won't fill up.

18:04.567 --> 18:08.697
So we'll just take that thing
up there and work on ring A.

18:08.700 --> 18:12.500
Now, what kind of reaction might
make ring A an alpha

18:12.500 --> 18:14.600
beta unsaturated ketone here?

18:17.100 --> 18:20.370
Any reactions that give alpha,
beta unsaturated ketones?

18:20.367 --> 18:20.997
STUDENT: Robinson?

18:21.000 --> 18:22.170
PROFESSOR: Aldol
reactions.

18:22.167 --> 18:24.067
So that's what we're going to be
looking for, but there are

18:24.067 --> 18:26.367
some problems, as you'll see.

18:26.367 --> 18:27.497
So we're going to do that.

18:27.500 --> 18:31.800
We're going to get this, and
then an aldol reaction on that

18:31.800 --> 18:36.530
will make this, and we can get
this by adding the anion here

18:36.533 --> 18:40.933
conjugate to an alpha, beta
unsaturated ketone here.

18:40.933 --> 18:45.533
What do we call it? What do you
call that kind of reaction?

18:45.533 --> 18:47.473
STUDENT: Robinson annulation.

18:47.467 --> 18:49.827
PROFESSOR: The whole
thing, to start from

18:49.833 --> 18:55.373
here and build this ring. Build
a ring? You said it before.

18:55.367 --> 18:56.127
STUDENT: Robinson annulation

18:56.133 --> 18:57.403
PROFESSOR: Robinson
annulation,

18:57.400 --> 18:59.570
we're going to do again.

18:59.567 --> 19:01.967
So that would be ready
for the aldol.

19:01.967 --> 19:05.827
And now this double bond here
is even closer to where we

19:05.833 --> 19:08.373
needed in order to
make that ketone.

19:08.367 --> 19:08.627
OK.

19:08.633 --> 19:09.433
Now how do you do that?

19:09.433 --> 19:10.673
Now there's a problem.

19:10.667 --> 19:14.427
You have to make the enolate to
do the Robinson annulation.

19:14.433 --> 19:18.873
But this is where you form
the enolate, down there.

19:18.867 --> 19:21.767
You could remove one of these
hydrogens and make an enolate,

19:21.767 --> 19:25.097
or you could remove one of those
hydrogens and make an

19:25.100 --> 19:30.100
anion there, which would be
allylic with an anion there,

19:30.100 --> 19:32.530
which is an enolate.

19:32.533 --> 19:35.273
So this one is called a
vinylogous enolate.

19:35.267 --> 19:38.867
It's got an extra double bond
in between, but still, it

19:38.867 --> 19:40.927
would behave as an enolate.

19:40.933 --> 19:44.373
But the problem is that this
one is more reactive.

19:44.367 --> 19:47.927
You want to make the enolate
here, which you can do by

19:47.933 --> 19:52.973
removing one of those purple
H's, and then having the anion

19:52.967 --> 19:54.427
be there as a resonance
structure.

19:54.433 --> 19:55.173
That's fine.

19:55.167 --> 20:00.327
Except that these are the ones
that get pulled off easier.

20:00.333 --> 20:02.703
So what do you do?

20:02.700 --> 20:04.930
You go ahead, pull these off.

20:04.933 --> 20:07.473
Tie them up somehow with
something else.

20:07.467 --> 20:10.597
Then get the other one, and then
come back and take off

20:10.600 --> 20:11.630
what you had put on there.

20:11.633 --> 20:15.303
Use a protecting group.

20:15.300 --> 20:18.130
And notice, incidentally, that
there's another H here that

20:18.133 --> 20:20.733
could also be pulled off that
would have a resonance

20:20.733 --> 20:22.203
structure with the anion here.

20:22.200 --> 20:25.370
So there are lots of
possibilities.

20:25.367 --> 20:30.227
You want to get that anion,
which is like that anion.

20:30.233 --> 20:32.503
So first you have to
protect the more

20:32.500 --> 20:34.870
reactive alpha position.

20:34.867 --> 20:37.797
And they do that by--

20:37.800 --> 20:40.000
that's just abbreviating
what's above.

20:40.000 --> 20:44.030
Makes the enolate, attack that
carbonyl, which has a leaving

20:44.033 --> 20:50.573
group on it, so the OCH3
will leave, and

20:50.567 --> 20:53.927
generate this diketone.

20:53.933 --> 20:57.073
That's like a Claisen reaction
that we talked about last

20:57.067 --> 21:00.227
time, where an enolate
attacks an ester,

21:00.233 --> 21:03.303
and the alcohol leaves.

21:03.300 --> 21:07.370
And then that gets attacked
by an amine to give this.

21:10.500 --> 21:12.430
And that dehydrates.

21:12.433 --> 21:15.503
It's like making an alpha,
beta-unsaturated ketone,

21:15.500 --> 21:17.370
except it has this nitrogen
on it now.

21:17.367 --> 21:18.667
Which helps out.

21:18.667 --> 21:20.297
The unshared pair on
the nitrogen is

21:20.300 --> 21:21.670
stabilized by this.

21:21.667 --> 21:23.997
You can draw resonance
structures that put charge on

21:24.000 --> 21:25.470
the oxygen.

21:25.467 --> 21:25.797
OK.

21:25.800 --> 21:28.830
So this is like an aldol, an
alpha, beta-unsaturated ketone.

21:28.833 --> 21:32.373
And also notice it's
an enamine.

21:32.367 --> 21:35.427
So that's tied up the
downstairs part.

21:35.433 --> 21:39.273
And now you can proceed with
making the anion you want,

21:39.267 --> 21:42.467
which is going to add to
there, and hopefully by

21:42.467 --> 21:44.497
Robinson methyl vinyl
ketone, or--

21:44.500 --> 21:46.100
pardon me.

21:46.100 --> 21:48.330
Yeah, methyl vinyl
ketone this time.

21:48.333 --> 21:51.873
Because the first time, we had
to put the CH3 in there, when

21:51.867 --> 21:56.467
we used this enolate
over here.

21:56.467 --> 22:01.567
Now we don't need a CH3 here,
so we don't need it.

22:01.567 --> 22:02.667
We can use methyl.

22:02.667 --> 22:05.167
Except it doesn't work.

22:05.167 --> 22:06.627
The reaction doesn't work.

22:06.633 --> 22:10.473
So you have to do something
a little more roundabout.

22:10.467 --> 22:12.897
So that doesn't work.

22:12.900 --> 22:19.770
But if you can't add it to
methyl vinyl ketone, you can

22:19.767 --> 22:21.427
add it to the double
bond here.

22:21.433 --> 22:24.203
Do a conjugate addition
to this sort of like a

22:24.200 --> 22:26.870
ketone, to that nitrile.

22:26.867 --> 22:30.267
So the enolate adds to this
carbon, generate the anion

22:30.267 --> 22:32.967
next to the nitrile.Then
protonate it, and you've got

22:32.967 --> 22:33.667
that.

22:33.667 --> 22:35.027
Conjugate addition again.

22:39.833 --> 22:44.003
But the problem is, the
CH3 here could be

22:44.000 --> 22:46.000
either up or down.

22:46.000 --> 22:49.500
You could have added to either
face of that anion.

22:49.500 --> 22:54.200
So here's what they said in
the paper about that.

22:54.200 --> 22:56.100
"The protected ketone
was condensed with

22:56.100 --> 22:57.170
acrylonitrile"--

22:57.167 --> 23:00.067
that's that compound with
cyanide up at the top--

23:00.067 --> 23:02.597
"in the presence of aqueous
Triton B in

23:02.600 --> 23:16.270
t-butanol-benzine, solvent,

23:16.267 --> 23:19.297
and the product on basic
hydrolysis yielded [this long

23:19.300 --> 23:22.300
name thing], as a mixture
of two isomers."

23:22.300 --> 23:23.330
That's the problem.

23:23.333 --> 23:25.173
That's a mixture
of two isomers.

23:25.167 --> 23:27.197
And that's just lore, whether
you're going to get

23:27.200 --> 23:28.000
something like that.

23:28.000 --> 23:31.830
And sometimes you just have to
suck it up, because there's no

23:31.833 --> 23:34.673
hydrogen you can pull off
here to make it come

23:34.667 --> 23:35.527
on the other side.

23:35.533 --> 23:36.573
That's just the way it is.

23:36.567 --> 23:39.567
So you've got to throw away a
certain amount of your stuff.

23:39.567 --> 23:41.797
OK, so that's tough.

23:41.800 --> 23:42.770
Right?

23:42.767 --> 23:49.827
So then they used a strong base
and water, which removed

23:49.833 --> 23:52.303
this protecting group.

23:52.300 --> 23:56.400
Made it back into
the CH2 here.

23:56.400 --> 24:00.130
And at the same time, it was
strong enough that it

24:00.133 --> 24:05.703
hydrolyzed the nitrile to make
a carboxylic acid there

24:05.700 --> 24:09.730
So now, treat that with acid,
protonate there. Then

24:09.733 --> 24:13.673
protonate here, making
that cation.

24:13.667 --> 24:18.767
But that can attack the carbonyl
to get that, which

24:18.767 --> 24:21.267
can then lose a proton,
so you've got a

24:21.267 --> 24:23.827
six-membered ring.

24:23.833 --> 24:26.673
So have we made it?

24:26.667 --> 24:27.327
Not quite.

24:27.333 --> 24:29.803
We got the wrong element there,
oxygen instead of

24:29.800 --> 24:31.900
carbon at the bottom.

24:31.900 --> 24:36.100
So we need another carbon
in the system.

24:36.100 --> 24:41.970
So protonate there, cation,
eliminate, we've got that

24:41.967 --> 24:43.627
double bond.

24:43.633 --> 24:44.573
OK.

24:44.567 --> 24:47.727
But now we need to convert that
into ring A. We need to

24:47.733 --> 24:51.133
put that extra blue methyl
group on there.

24:51.133 --> 24:54.933
So the way to do it is to
use methyl Grignard.

24:54.933 --> 24:58.603
So the methyl minus adds to the
carbonyl, and that is a

24:58.600 --> 24:59.830
leaving group.

25:05.000 --> 25:09.530
And that's an enolate, so
it becomes a ketone.

25:09.533 --> 25:11.973
And we've got this thing here.

25:11.967 --> 25:14.567
So we're getting closer now.

25:14.567 --> 25:19.067
You do an aldol and
you have ring A.

25:19.067 --> 25:22.397
So this is a typical
thing that happens.

25:22.400 --> 25:24.900
It looked like a Robinson
annulation might go directly

25:24.900 --> 25:27.700
there, but it didn't work,
so they do a work-around.

25:30.500 --> 25:34.570
So now A is all set, and now
we need to work on ring D.

25:34.567 --> 25:36.197
Which is, remember, a
six-membered ring, and it

25:36.200 --> 25:38.830
needs to be a five-membered
ring.

25:38.833 --> 25:40.203
So we'll put it up
in the corner and

25:40.200 --> 25:43.430
start working on that.

25:43.433 --> 25:45.873
So the first thing--what they're
going to go for is to

25:45.867 --> 25:48.997
make it a five-membered ring
that has an ester group coming

25:49.000 --> 25:50.830
off, so you have that
carbonyl groups that

25:50.833 --> 25:53.273
we're going to want.

25:53.267 --> 25:55.427
The first thing they do is treat
it with acid and water.

25:55.433 --> 25:56.703
What do they do that for?

26:02.167 --> 26:03.067
PROFESSOR: What's
that going to

26:03.067 --> 26:04.297
do with that compound? Ayesha?

26:06.267 --> 26:08.597
STUDENT: It's going to remove
the acetal and give the diol.

26:08.600 --> 26:09.000
PROFESSOR: Right.

26:09.000 --> 26:10.370
Now you can get rid of
the protecting group.

26:10.367 --> 26:13.097
You want to be able to work on
that double bond now, so you

26:13.100 --> 26:15.270
take the protecting group off
that you had on there when you

26:15.267 --> 26:16.527
were doing the catalytic
hydrogenation.

26:19.300 --> 26:25.770
And now we've got the diol.

26:25.767 --> 26:29.497
And now treat it with
periodic acid.

26:29.500 --> 26:30.730
You remember what that does?

26:32.533 --> 26:33.303
STUDENT: Oxidizes.

26:33.300 --> 26:37.630
J.MICHAEL MCBRIDE: It oxidizes a
diol to cleave the carbon-carbon

26:37.633 --> 26:42.603
bond in between and make two
carbonyl groups.

26:42.600 --> 26:47.500
So at first it adds, and then
that's just an intermediate, a

26:47.500 --> 26:48.570
transient intermediate.

26:48.567 --> 26:51.197
It comes apart to give
two aldehydes.

26:51.200 --> 26:52.200
And now, how are you going
to make a

26:52.200 --> 26:53.470
five-membered ring?

26:56.300 --> 27:01.730
STUDENT: Decarboxylation.

27:01.733 --> 27:04.503
PROFESSOR: You can make
an enolate here, attack

27:04.500 --> 27:07.570
that carbonyl, or
make an enolate

27:07.567 --> 27:10.367
here, attack this carbonyl.

27:10.367 --> 27:11.867
Those are going to give
different products.

27:15.367 --> 27:20.297
What you need to do is to have
this enolate attack this

27:20.300 --> 27:22.700
carbonyl if you want to make
that compound, rather than

27:22.700 --> 27:32.330
have this enolate react with
that one, and get the

27:32.333 --> 27:35.973
carboxylic acid down here.

27:35.967 --> 27:41.427
It turns out that base with
aldol could be either that way

27:41.433 --> 27:45.533
or that way, and luck made it
go the right way this time.

27:45.533 --> 27:48.033
Robinson annulation didn't
work before, but this one

27:48.033 --> 27:50.703
worked the right way.

27:50.700 --> 27:52.430
And then we've got
an aldehyde.

27:52.433 --> 27:54.373
We need the carboxylic acid.

27:54.367 --> 27:57.467
So you use dichromate oxidation,
which we talked

27:57.467 --> 27:58.967
about, to oxidize an alcohol.

27:58.967 --> 28:01.397
And of course, you don't stop
at the aldehyde, you

28:01.400 --> 28:03.070
go on to the acid.

28:03.067 --> 28:04.727
But you need the ester.

28:04.733 --> 28:06.133
So now they're going
to make the ester.

28:06.133 --> 28:08.703
You could do Fischer
esterification, but that's an

28:08.700 --> 28:11.730
equilibrium, and this stuff
is becoming very precious,

28:11.733 --> 28:14.273
because of all the work
that you put into it.

28:14.267 --> 28:17.827
So you want to do this in the
highest possible yield.

28:17.833 --> 28:22.273
So they use diazomethane,
remember, which is the way of

28:22.267 --> 28:28.267
doing it really to change the
acid into methyl ester in

28:28.267 --> 28:29.967
really high yield.

28:29.967 --> 28:32.697
So that's a dangerous compound
to work with.

28:32.700 --> 28:38.630
It's much more expensive and
cumbersome than doing a

28:38.633 --> 28:40.403
Fischer esterification.

28:40.400 --> 28:42.670
But it gives a really
high yield, so

28:42.667 --> 28:45.727
that's what they did.

28:45.733 --> 28:49.803
So now they had the
ketone here.

28:49.800 --> 28:52.170
And now they made
into an alcohol.

28:52.167 --> 28:54.627
Now, this looks nuts, right?

28:54.633 --> 28:56.703
they already had the
ketone there, which

28:56.700 --> 28:59.030
is what they want.

28:59.033 --> 29:02.373
And the double bond here,
they've got it.

29:02.367 --> 29:05.027
Why do they backtrack?

29:05.033 --> 29:09.673
They backtracked because it was
already known from 1918--

29:09.667 --> 29:14.927
so they used borohydride this
time to reduce the ketone to

29:14.933 --> 29:16.503
an alcohol.

29:16.500 --> 29:19.070
If they'd used lithium aluminum
hydride, it would

29:19.067 --> 29:21.227
have reduced the ester to an
alcohol, and they didn't want

29:21.233 --> 29:22.703
to do that.

29:22.700 --> 29:24.770
So you have to choose the
reagents carefully when

29:24.767 --> 29:27.367
there's possible competition
like that.

29:27.367 --> 29:32.127
Now, it was 1909 it was found
out that this alcohol could be

29:32.133 --> 29:35.603
separated, the two enantiomers,
easily.

29:35.600 --> 29:38.900
That was already known 50
years before, right?

29:38.900 --> 29:42.200
So they backtracked in order--

29:42.200 --> 29:44.730
see, all this stuff they've
been doing started with

29:44.733 --> 29:46.373
achiral material.

29:46.367 --> 29:49.267
So they've got both right and
left-handed stuff there, and

29:49.267 --> 29:52.027
they want only the one
enantiomer, ultimately.

29:52.033 --> 29:54.503
And someplace, they're going
to have to separate it, and

29:54.500 --> 29:56.630
this is where they do
the separation.

29:56.633 --> 30:00.273
Because it turns out, if you put
this in together with this

30:00.267 --> 30:04.427
digitonin stuff, which itself,
notice, has a six, six, six,

30:04.433 --> 30:07.903
five steroid inside it--
this complicated

30:07.900 --> 30:10.170
sapogenin, as it's called.

30:10.167 --> 30:14.997
Then those things come
together, and what

30:15.000 --> 30:17.630
precipitates is just one hand.

30:17.633 --> 30:20.133
The other one stays
in solution.

30:20.133 --> 30:22.073
So this was obviously lore.

30:22.067 --> 30:23.327
But anyhow, they got that.

30:23.333 --> 30:27.903
And now, having made this, it
turned out that previous

30:27.900 --> 30:32.030
studies of cortisone had shown
that if you had this, you

30:32.033 --> 30:35.673
could make this from it.

30:35.667 --> 30:38.967
So this in this is called
a total synthesis.

30:38.967 --> 30:41.697
But in fact, it's
a formal total

30:41.700 --> 30:44.330
synthesis, or a relay synthesis.

30:44.333 --> 30:46.603
Because by the time they got
here, they had very little

30:46.600 --> 30:49.530
material, so they couldn't
do a bunch more steps.

30:49.533 --> 30:52.233
But it was known that those
steps could be done, because

30:52.233 --> 30:54.603
people had already done them.

30:54.600 --> 30:57.400
So they could, then, start with
material which had been

30:57.400 --> 31:00.770
made from cortisone or
some other sterol and

31:00.767 --> 31:01.697
then carry it through.

31:01.700 --> 31:03.870
But there was no point in doing
it, because people had

31:03.867 --> 31:06.327
already done those reactions.

31:06.333 --> 31:07.833
So this is the paper.

31:07.833 --> 31:11.873
This is the whole paper that
described the total synthesis

31:11.867 --> 31:13.367
of cortisone.

31:13.367 --> 31:16.567
Woodward was not a man
of many words.

31:16.567 --> 31:17.227
Right?

31:17.233 --> 31:19.603
There had actually been a
previous paper of about two

31:19.600 --> 31:23.770
pages about making the precursor
that we showed.

31:23.767 --> 31:26.197
So he then had this.

31:26.200 --> 31:31.370
He reduced this double bond.

31:31.367 --> 31:37.067
But notice, it did reduce this
one and this one, but didn't

31:37.067 --> 31:38.127
reduce this one.

31:38.133 --> 31:43.403
So again, this is testing the
various methods you're using

31:43.400 --> 31:45.900
to make sure what's going
to react and what isn't.

31:45.900 --> 31:49.930
Why didn't they want to get
rid of that double bond?

31:49.933 --> 31:51.973
Because that's the one that's
going to give them the handle

31:51.967 --> 31:54.297
to get that ketone in up
there, which is a very

31:54.300 --> 31:55.570
difficult position.

31:57.900 --> 32:00.300
And then they could do sodium
borohydride that made the

32:00.300 --> 32:03.600
alcohol that we showed
you before.

32:03.600 --> 32:05.130
But notice that the borohydride

32:05.133 --> 32:06.373
didn't attack here.

32:06.367 --> 32:08.927
It only attacked down here.

32:08.933 --> 32:11.933
Then they made the acetate
from that alcohol.

32:11.933 --> 32:17.473
And now they've got to convert
this to cortisone.

32:17.467 --> 32:21.667
At this point, our synthetic
work intersects the lines

32:21.667 --> 32:25.427
previously laid down in the
extensive prior investigations

32:25.433 --> 32:26.403
by many groups.

32:26.400 --> 32:28.170
So he goes through some
of these groups.

32:28.167 --> 32:29.597
"Heymann and Fieser"--

32:29.600 --> 32:32.330
that's the guy that wrote
this story, right--

32:32.333 --> 32:36.603
"have recently converted the
acetoxy-ester (III) into [this

32:36.600 --> 32:39.670
compound] V." So here's the
reference to that.

32:39.667 --> 32:41.667
It was worked in 1951.

32:41.667 --> 32:45.567
So what they did was to--

32:45.567 --> 32:52.797
let's see, whoa, whoa, whoa, we
have a lot of stuff here--

32:52.800 --> 32:55.630
reaction four, oh, reference
four, reference five, then

32:55.633 --> 32:59.673
reference six puts that thing
on up there, and then

32:59.667 --> 33:05.627
reference seven puts the
alcohol in or whatever.

33:05.633 --> 33:09.433
And finally the double bond
by Mattox and Kendall.

33:09.433 --> 33:11.733
Kendall, remember, is the guy
that got the Nobel Prize, the

33:11.733 --> 33:13.033
chemist at the Mayo Institute.

33:15.967 --> 33:17.127
So that did it.

33:17.133 --> 33:17.673
They had it.

33:17.667 --> 33:21.667
They'd solve the intellectual
artistic problem of how you

33:21.667 --> 33:23.227
can start with simple,
available

33:23.233 --> 33:24.873
compounds and make cortisone.

33:27.400 --> 33:30.870
But what was the yield?

33:30.867 --> 33:33.397
Think a minute about yield.

33:33.400 --> 33:37.900
Suppose you do 39 steps, and
each step has an 80% yield,

33:37.900 --> 33:40.530
which isn't so bad, as
you've found in lab.

33:40.533 --> 33:42.473
Right?

33:42.467 --> 33:47.967
Then the overall yield is 0.01%
if you take 0.8 to the

33:47.967 --> 33:49.867
39th power.

33:49.867 --> 33:52.267
But there's a different
way to go about it,

33:52.267 --> 33:55.067
what's called a convergence
synthesis, where

33:55.067 --> 33:58.667
you make several big pieces,
and then link the pieces

33:58.667 --> 34:02.497
together, so the distance in
number of steps from any one

34:02.500 --> 34:05.270
starting material to the product
is smaller than having

34:05.267 --> 34:07.927
all 39 in a row.

34:07.933 --> 34:09.973
So you could start with
something that does nine

34:09.967 --> 34:13.397
steps, say, that makes A.
Another nine step sequence

34:13.400 --> 34:16.700
makes B. Another makes C, and
another makes D. And now you

34:16.700 --> 34:20.630
put A and B together, and C and
D together, to make E and F,

34:20.633 --> 34:22.203
and then you put
them together.

34:22.200 --> 34:26.570
And now the distance is only
nine steps plus two steps for

34:26.567 --> 34:30.597
any given starting material,
and you get a 9% yield.

34:30.600 --> 34:34.500
So convergent synthesis
has real advantages.

34:34.500 --> 34:38.000
Now, how about a practical
cortisone synthesis that could

34:38.000 --> 34:40.330
make something that people
could afford to use?

34:40.333 --> 34:41.673
Well, there's cortisone.

34:41.667 --> 34:45.727
Remember, that's what the
Nobel laureate said.

34:45.733 --> 34:46.833
There are two things
you can do.

34:46.833 --> 34:49.833
Either do a total synthesis,
or get a better starting

34:49.833 --> 34:52.203
material than was
then available.

34:52.200 --> 34:54.030
So choose an appropriate,
readily

34:54.033 --> 34:55.903
available starting material.

34:55.900 --> 34:56.500
OK.

34:56.500 --> 34:59.600
Desoxycholic acid, a bile acid
that you can get from

34:59.600 --> 35:02.730
slaughterhouses, or get the
glands from which to make it

35:02.733 --> 35:04.273
from slaughterhouses.

35:04.267 --> 35:06.197
It comes from ox bile.

35:06.200 --> 35:11.670
So in 1946, '49, Merck made a
kilogram of cortisone from 600

35:11.667 --> 35:15.167
kilograms of that bile acid
which came from an enormous

35:15.167 --> 35:18.327
amount of stuff from
the slaughterhouse.

35:18.333 --> 35:20.633
But notice why that was a
good starting material.

35:20.633 --> 35:25.233
It has all the rings in place
of the right size,

35:25.233 --> 35:27.333
and it's properly methylated.

35:27.333 --> 35:29.833
So it's got the skeleton,
the carbon skeleton.

35:29.833 --> 35:33.003
It's got all those things in
the right stereochemistry.

35:36.633 --> 35:42.873
It's got, here, functional
groups at or near at least

35:42.867 --> 35:46.027
some of the proper positions.

35:46.033 --> 35:50.033
You're going to have to fiddle
around out here somehow.

35:50.033 --> 35:54.803
But how are you going
to do that?

35:54.800 --> 35:57.970
Well, you could imagine, they
were able to go in twelve

35:57.967 --> 35:58.867
steps to that.

35:58.867 --> 36:01.027
And we're not going to go
through what those next 20

36:01.033 --> 36:03.033
steps are that allow you
to get the red thing.

36:03.033 --> 36:07.503
But you could imagine things
like, do a bromination at a

36:07.500 --> 36:08.430
tertiary position.

36:08.433 --> 36:10.603
Maybe you could do that.

36:10.600 --> 36:13.500
Then eliminate HBr, maybe.

36:13.500 --> 36:15.200
It could go the wrong way.

36:15.200 --> 36:17.300
Then maybe you could cleave the
double bond and make the

36:17.300 --> 36:21.530
ketone, then maybe you could do
alpha-bromination adjacent

36:21.533 --> 36:24.333
to the ketone, and then make
alcohols from that.

36:24.333 --> 36:25.103
Something like that.

36:25.100 --> 36:25.800
You can imagine.

36:25.800 --> 36:26.770
That's not what was done.

36:26.767 --> 36:28.627
That wouldn't be twenty steps.

36:28.633 --> 36:29.903
It didn't work that way.

36:29.900 --> 36:33.530
But you can imagine ways that
you could get at it.

36:33.533 --> 36:37.003
So they did it in 20 steps.

36:37.000 --> 36:38.800
So then they got cortisone.

36:38.800 --> 36:43.100
And they could sell it in 1949
for $200 a gram, having made

36:43.100 --> 36:47.430
it by a 32 step sequence.

36:47.433 --> 36:51.573
But there's another compound
called diosgenin.

36:51.567 --> 36:55.467
And diosgenin also has the right
set of rings and the

36:55.467 --> 37:00.727
right stereochemistry, and
functionality in a good place.

37:00.733 --> 37:04.233
And it's abundant in
a Mexican yam.

37:04.233 --> 37:08.533
And Russell Marker, who was an
organic chemist at Penn State

37:08.533 --> 37:11.103
University, went exploring.

37:11.100 --> 37:14.770
He sort of quit and went down to
Mexico and looked around to

37:14.767 --> 37:18.327
see if he could find
natural things that

37:18.333 --> 37:19.473
contained a lot of this.

37:19.467 --> 37:22.397
And the roots of this yam--

37:22.400 --> 37:27.700
some of them are 20 or 50
kilograms, and a fair

37:27.700 --> 37:30.330
percentage of it
is this stuff.

37:30.333 --> 37:33.933
So he was able to find a
good source of this.

37:33.933 --> 37:37.573
And it could be converted in
five steps into progesterone,

37:37.567 --> 37:40.267
a female hormone.

37:40.267 --> 37:45.497
And so in 1943, he got ten tons
of that yam and from it,

37:45.500 --> 37:49.070
made three kilograms of
progesterone, which was then

37:49.067 --> 37:50.767
worth a quarter million
dollars,

37:50.767 --> 37:54.497
which is-- in 1943, which
is like, I don't

37:54.500 --> 37:56.600
know, $5 million now.

37:56.600 --> 37:58.130
He had the world's supply
of progesterone,

38:01.933 --> 38:03.573
which is a pregnancy hormone.

38:03.567 --> 38:08.497
And so it was selling in 1955
for 48¢ a gram, instead of

38:08.500 --> 38:11.230
this $200/gram stuff.

38:11.233 --> 38:13.503
But there's a problem if you
want to get cortisone this

38:13.500 --> 38:16.270
way, because there's no foothold
to get at that

38:16.267 --> 38:18.567
position, rather than that one
or that one or that one or

38:18.567 --> 38:21.097
that one or that one or
that one or that one.

38:21.100 --> 38:23.730
How are you going to
put the ketone in?

38:23.733 --> 38:27.703
And this is where it was found,
actually, by this guy

38:27.700 --> 38:29.900
here, or by his research
group.

38:29.900 --> 38:32.370
Frederick Heyl, who was an
undergraduate and graduate

38:32.367 --> 38:34.797
student here, was the director
of research at Upjohn.

38:34.800 --> 38:38.970
And at Upjohn research in
Kalamazoo, they found out that

38:38.967 --> 38:43.627
they had some of this-- a mold
started growing on a dish that

38:43.633 --> 38:45.303
was in a windowsill.

38:45.300 --> 38:46.870
And when you put it
on here, it put a

38:46.867 --> 38:48.097
ketone in that position.

38:52.867 --> 38:53.197
Pardon me.

38:53.200 --> 38:55.000
Put the alcohol in
that position.

38:55.000 --> 38:57.130
But then once you've got the
alcohol here, you're home

38:57.133 --> 38:58.373
free, right?

38:58.367 --> 38:59.727
OK.

38:59.733 --> 39:03.073
So Woodward had done the total
synthesis of cortisone, and he

39:03.067 --> 39:05.127
did a lot of total syntheses.

39:05.133 --> 39:08.373
Like the strychnine
synthesis here.

39:08.367 --> 39:11.227
I thank Professor Saunders,
who took these pictures.

39:11.233 --> 39:14.303
He was still a graduate student
at this time in 1954

39:14.300 --> 39:16.700
when strychnine was
synthesized.

39:16.700 --> 39:20.370
And the interesting thing
about Woodward--

39:20.367 --> 39:23.297
there was real cult of
personality, still is, among

39:23.300 --> 39:24.030
older people.

39:24.033 --> 39:26.233
Because young people don't
know who he was anymore.

39:30.600 --> 39:34.970
Because he was such an artist. I
mean, designing these things

39:34.967 --> 39:37.527
is an art, but you have to
really know a lot to

39:37.533 --> 39:38.773
see the art in it.

39:38.767 --> 39:41.397
And his Nobel citation actually,
said "for his

39:41.400 --> 39:45.330
outstanding achievements in the
art of organic synthesis."

39:45.333 --> 39:47.773
I don't think there's never been
another Nobel citation

39:47.767 --> 39:50.027
that said art in it.

39:50.033 --> 39:51.303
So he made a lot of
these things.

39:51.300 --> 39:54.530
Here was strychnine, a very
challenging thing.

39:54.533 --> 39:58.603
And so when they got it done,
they drew it very carefully on

39:58.600 --> 39:59.630
the blackboard.

39:59.633 --> 40:02.173
And the postdocs who
had worked on it--

40:02.167 --> 40:04.567
Ollis was a faculty member
from the University of

40:04.567 --> 40:05.897
Bristol, in England.

40:05.900 --> 40:07.470
Hunger was a German.

40:07.467 --> 40:10.927
Daeniker and Schenker were
from Switzerland.

40:10.933 --> 40:14.303
And Cava was an American
who went to be a

40:14.300 --> 40:18.470
professor at Penn.

40:18.467 --> 40:24.367
But you'll notice, when Woodward
got the Nobel prize,

40:24.367 --> 40:27.667
his colleagues wrote this
in Science magazine.

40:27.667 --> 40:31.297
"Woodward's style is polished,
showing an insight and sense

40:31.300 --> 40:34.930
of proportion that afford him
strong convictions and a

40:34.933 --> 40:37.703
well-developed dramatic
sense."

40:37.700 --> 40:41.070
So you can see, just the way
he's lighting his cigarette

40:41.067 --> 40:43.427
there looks sort of
dramatic to me.

40:43.433 --> 40:45.603
And look at his signature!

40:45.600 --> 40:49.700
He always signed minuscule
signatures.

40:49.700 --> 40:52.170
R. B. Woodward.

40:52.167 --> 40:56.427
And they also put a check mark
on it when they finished the

40:56.433 --> 41:01.033
synthesis, and down in the
bottom wrote, "fecunt."

41:01.033 --> 41:03.573
So you know Latin.

41:03.567 --> 41:05.967
I talked to Victor Bers in
the classics department.

41:05.967 --> 41:08.327
That's not a proper
Latin word.

41:08.333 --> 41:12.133
But fecerunt means,
they made it.

41:12.133 --> 41:12.873
Right?

41:12.867 --> 41:15.727
So that's what-- they almost
got it right, evidently,

41:15.733 --> 41:17.273
writing that on the
blackboard.

41:17.267 --> 41:22.197
But one of the hallmarks of
Woodward's style was that he

41:22.200 --> 41:25.970
always wore the same color
blue suit and blue tie.

41:25.967 --> 41:29.467
So that's a Woodward blue tie.

41:29.467 --> 41:34.397
And in fact, students, one
Halloween, painted his parking

41:34.400 --> 41:36.900
place that light blue.

41:36.900 --> 41:40.730
And I know where they got the
paint, because I got it.

41:45.067 --> 41:45.467
OK.

41:45.467 --> 41:50.697
So then in 1973, they did this
real pinnacle of synthesis.

41:50.700 --> 41:52.970
They synthesized vitamin B12.

41:52.967 --> 41:54.927
You can't imagine all
the problems that

41:54.933 --> 41:55.733
were faced by this.

41:55.733 --> 41:58.703
And it was a collaborative
work between Woodward and

41:58.700 --> 42:02.030
Eschenmoser's laboratory at
the ETH in Zurich, in

42:02.033 --> 42:03.473
Switzerland.

42:03.467 --> 42:06.867
And in connection with this
work is where Woodward

42:06.867 --> 42:11.267
discovered stereochemical
control by orbital symmetry.

42:11.267 --> 42:13.197
Those are called the
Woodward-Hoffmann rules.

42:13.200 --> 42:15.370
You know, conrotation,
disrotation.

42:15.367 --> 42:19.497
And it was while working on this
that he discovered that.

42:19.500 --> 42:21.970
They had 100 coworkers
at these two

42:21.967 --> 42:23.697
labs, working on this.

42:23.700 --> 42:25.800
All of them very,
very talented.

42:25.800 --> 42:29.370
Including this guy, Yoshito
Kishi, who was a faculty

42:29.367 --> 42:33.197
member from Nagoya University
who had come to work on this

42:33.200 --> 42:36.200
project with Woodward.

42:36.200 --> 42:39.030
And this is what Woodward wrote
about him when, in Pure

42:39.033 --> 42:42.973
and Applied Chemistry in 1971,
he wrote about working on the

42:42.967 --> 42:44.427
B12 synthesis.

42:44.433 --> 42:47.573
"The first preparation of
corrigenolide afforded

42:47.567 --> 42:50.067
striking testimony of the
experimental skill of its

42:50.067 --> 42:52.397
discoverer, Dr. Yoshito Kishi.

42:52.400 --> 42:54.700
All the operations had to
be conducted with every

42:54.700 --> 42:57.670
conceivable precaution in
respect to purity of reagents,

42:57.667 --> 43:00.267
exclusion of oxygen and
moisture, and with the

43:00.267 --> 43:01.867
greatest possible speed."

43:01.867 --> 43:04.427
So he was a real wizard
in the laboratory.

43:04.433 --> 43:07.833
And he then joined the Harvard
faculty after that, and then

43:07.833 --> 43:10.333
succeeded Woodward as professor
at Harvard after

43:10.333 --> 43:12.303
Woodward's untimely death.

43:12.300 --> 43:14.430
And we've seen his
name before.

43:14.433 --> 43:15.033
Not for this.

43:15.033 --> 43:19.333
He ultimately synthesized
palytoxin, this compound,

43:19.333 --> 43:26.033
which has C-123, H-213, NO-53.

43:26.033 --> 43:30.073
It's got 42 functional groups
which were protected in eight

43:30.067 --> 43:30.967
different ways.

43:30.967 --> 43:32.897
So you could remove
some of them, put

43:32.900 --> 43:34.900
others on, and so on.

43:34.900 --> 43:38.100
It has 62 stereogenic centers.

43:38.100 --> 43:42.500
It has seven double bonds that
could be either E or Z, so

43:42.500 --> 43:46.930
there are 10 to the 20th
stereoisomers possible.

43:46.933 --> 43:48.503
And it was done convergently.

43:48.500 --> 43:52.300
So they made eight different
pieces and then put those

43:52.300 --> 43:53.170
pieces together.

43:53.167 --> 43:56.167
So you'd get no yield at all
if you did this in a

43:56.167 --> 43:58.027
sequential synthesis, right?

43:58.033 --> 44:00.473
But they actually made it.

44:00.467 --> 44:04.697
And it was not-- although that
was just a tour de force, it's

44:04.700 --> 44:06.200
related to practical stuff.

44:06.200 --> 44:11.500
Because we talked last fall
about this Eisai drug, which

44:11.500 --> 44:14.070
has a lot of similarity
to that.

44:14.067 --> 44:17.827
And the week after we spoke
about it in class, the FDA

44:17.833 --> 44:20.933
approved it for treating
metastatic breast cancer.

44:20.933 --> 44:22.673
Remember we talked about
whether that was

44:22.667 --> 44:24.167
pending at the time.

44:24.167 --> 44:26.227
And you'll notice that
the leader of

44:26.233 --> 44:28.333
this group was Kishi.

44:28.333 --> 44:32.173
So he had cut his teeth on
palytoxin for synthesizing

44:32.167 --> 44:35.667
things like this, so that this
drug can now be made

44:35.667 --> 44:39.727
synthetically, practically, and
sold as a drug that way.

44:39.733 --> 44:42.573
It's just incredible.

44:42.567 --> 44:46.167
So organic synthesis has come
a long way from urea.

44:46.167 --> 44:49.997
Remember what Woehler wrote to
Berzelius in 1828 about the

44:50.000 --> 44:53.400
experiment when he reacted
"cyanic acid with ammonia and

44:53.400 --> 44:55.400
a crystalline substance appears
which is inert,

44:55.400 --> 44:59.400
behaving neither like cyanate
nor like ammonia."

44:59.400 --> 45:02.330
So that's the story.

45:02.333 --> 45:06.233
But first, that a little bit
of thanks and credit.

45:06.233 --> 45:08.703
First to George Maxfield,
who was my high

45:08.700 --> 45:10.030
school chemistry teacher.

45:13.900 --> 45:17.300
I remember his doing--

45:17.300 --> 45:18.970
we'd be working on something,
and he wouldn't be doing

45:18.967 --> 45:19.527
anything at all.

45:19.533 --> 45:20.803
He'd go like this.

45:24.533 --> 45:27.933
And the other thing he did was
he said, "You make something,

45:27.933 --> 45:31.933
you put it in a bottle and sell
it to your neighbor." So

45:31.933 --> 45:34.273
I'm quoting him.

45:34.267 --> 45:37.997
And there's Theodore Roosevelt
Williams, who was my first

45:38.000 --> 45:41.070
college professor at the College
of Worcester.

45:41.067 --> 45:45.827
And then Fieser we talked
about, and Bartlett, and

45:45.833 --> 45:51.173
Conant was his boss, who had two
PhD advisors, a physical

45:51.167 --> 45:53.797
chemist, T.W. Richards, who got
the Nobel Prize, and an

45:53.800 --> 45:56.630
organic chemist, E. P. Kohler,
who was very--

45:56.633 --> 45:59.503
these three pictures were
all taken at Yale.

45:59.500 --> 46:02.200
That was when Sterling
was dedicated.

46:02.200 --> 46:09.130
This was at a meeting in 1931
when Bartlett was just 24 years

46:09.133 --> 46:13.803
old. But Kohler never went
to meetings.

46:13.800 --> 46:15.370
He never left Harvard.

46:15.367 --> 46:18.167
People would come there to talk
to him, but he wasn't

46:18.167 --> 46:18.627
interested in that.

46:18.633 --> 46:21.233
He just taught all the time.

46:21.233 --> 46:26.203
And Kohler's the one that
finally resolved aline.

46:26.200 --> 46:30.270
Remember, we talked about that
van 't Hoff had predicted it.

46:30.267 --> 46:32.227
But Kohler's the one
that made it.

46:32.233 --> 46:34.403
So Kohler was a student
of Remson, who

46:34.400 --> 46:35.930
was at Johns Hopkins.

46:35.933 --> 46:37.833
And Richards studied
with Ostwald.

46:37.833 --> 46:41.033
Remember, the guy that didn't
believe in atoms?

46:41.033 --> 46:44.973
And then the next generation
back was Fittig, who

46:44.967 --> 46:48.697
discovered the pinacol
reaction.

46:48.700 --> 46:52.970
And the one person I couldn't
find a picture of was Carl

46:52.967 --> 46:56.167
Schmidt, who was at
Riga in Latvia.

46:56.167 --> 46:59.067
But he was described by Ostwald
as a "tall, thin man

46:59.067 --> 47:02.067
with a small head, a strong
nose, ice gray hair, and a

47:02.067 --> 47:05.467
thin beard." And a very
nice person, right?

47:05.467 --> 47:08.967
And Schimdt had worked both
with Liebig and Woehler.

47:08.967 --> 47:10.667
He was first a student
of Woehler, who

47:10.667 --> 47:12.267
recommended him to Liebig.

47:12.267 --> 47:14.227
Fittig had worked
with Woehler.

47:14.233 --> 47:16.203
So we're back to those guys.

47:16.200 --> 47:19.070
And then to Gay-Lussac
and Berzelius.

47:19.067 --> 47:23.797
And then to Bertole, who was a
colleague of Lavoisier, and

47:23.800 --> 47:27.670
wrote how to name compounds.

47:27.667 --> 47:30.327
But there are some other heroes
to whom we should pay

47:30.333 --> 47:33.473
homage, even if they weren't
our ancestors.

47:33.467 --> 47:34.997
You know who this is?

47:35.000 --> 47:35.800
STUDENT: Moses Gomberg

47:35.800 --> 47:37.070
PROFESSOR: Right.

47:39.100 --> 47:41.130
Who's this?

47:41.133 --> 47:43.203
Emil Fischer.

47:43.200 --> 47:45.400
The last lecture.

47:45.400 --> 47:46.530
Koerner.

47:46.533 --> 47:51.133
The other guy who did a real
proof in the 19th century.

47:51.133 --> 47:52.403
James Clark Maxwell.

47:55.300 --> 47:58.300
Remember him?

47:58.300 --> 47:59.500
Couper.

47:59.500 --> 48:02.430
The tetravalence of carbon.

48:02.433 --> 48:04.833
Lavoisier.

48:04.833 --> 48:07.173
And Robert Hooke.

48:07.167 --> 48:11.467
There's no known picture of
Hooke, because Newton probably

48:11.467 --> 48:12.727
destroyed it.

48:15.100 --> 48:17.670
I think that's true!

48:17.667 --> 48:20.367
But this is a picture
of somebody

48:20.367 --> 48:22.397
using Hooke's apparatus.

48:22.400 --> 48:25.030
And Hooke was a hunchback,
and he drew that picture.

48:25.033 --> 48:27.933
And I like to think that might
be a self-portrait, although I

48:27.933 --> 48:29.803
sort of doubt it.

48:29.800 --> 48:31.370
But Hooke was certainly
a great guy.

48:31.367 --> 48:34.097
And then of course we have a lot
of people we have to pay

48:34.100 --> 48:36.130
homage to at Yale, too.

48:36.133 --> 48:39.403
Like Silliman, with his T-shirts
that says, "How do

48:39.400 --> 48:41.630
you know?"

48:41.633 --> 48:43.503
Or a giant.

48:43.500 --> 48:44.570
Who's this?

48:44.567 --> 48:44.867
STUDENT: Gibbs

48:44.867 --> 48:47.227
PROFESSOR: Gibbs.

48:47.233 --> 48:48.633
And Onsager.

48:48.633 --> 48:49.673
Those two--

48:49.667 --> 48:54.967
Gibbs was arguably the smartest
guy in the 19th

48:54.967 --> 48:58.027
century, or certainly among
the top half dozen or so.

48:58.033 --> 49:01.473
And Onsager was the same
in this century.

49:01.467 --> 49:03.697
And I actually had Onsager
as a colleague.

49:03.700 --> 49:06.770
We overlapped for a few years.

49:06.767 --> 49:12.197
I mean, he's-- like, Feynman
was in awe of Onsager.

49:12.200 --> 49:15.000
And when Onsager got the Nobel
Prize, when they called to

49:15.000 --> 49:18.200
inform him, he asked, "What
for?" Because he had done so

49:18.200 --> 49:22.130
many things that could have
gotten the Nobel Prize.

49:22.133 --> 49:25.803
And then, you know this is?

49:25.800 --> 49:26.470
Chupka.

49:26.467 --> 49:28.667
These are the colleagues
I've enjoyed having

49:28.667 --> 49:29.497
around for a while.

49:29.500 --> 49:32.070
And he came in and told people
how he determined the heat of

49:32.067 --> 49:34.727
vaporization of carbon.

49:34.733 --> 49:36.573
And that one, you know.

49:36.567 --> 49:38.567
Wiberg.

49:38.567 --> 49:41.927
And here's Professors Ziegler.

49:41.933 --> 49:45.373
These are people who gave
lectures in the course, right?

49:45.367 --> 49:47.167
And of course, you
know who's next.

49:47.167 --> 49:49.997
Not a faculty member, but a
graduate student from Yale.

49:53.967 --> 49:55.767
And then someone who's
almost from Yale.

49:55.767 --> 49:56.927
Leslie Leiserowitz

49:56.933 --> 49:58.303
who spoke to you
last semester.

49:58.300 --> 50:01.800
He's from Israel, but he comes
so often to visit that we'll

50:01.800 --> 50:04.970
call him an honorary Yalie.

50:04.967 --> 50:09.297
And then these people
we quoted.

50:09.300 --> 50:11.100
Remember, he's the guy
that originated "How

50:11.100 --> 50:14.130
do you know" hourly?

50:14.133 --> 50:17.533
And she's the one that
does it now.

50:17.533 --> 50:21.273
And this is my wife, and
that's John's wife.

50:21.267 --> 50:25.397
And here's-- this was night
before last over across the

50:25.400 --> 50:28.830
street here, at a meeting of
the Connecticut Science

50:28.833 --> 50:32.103
Teachers Association,
when this plaque was

50:32.100 --> 50:35.300
awarded to my wife.

50:35.300 --> 50:36.770
And she's sitting back here.

50:45.400 --> 50:49.500
And next to her is the Biology
professor from Bowdoin whom

50:49.500 --> 50:50.670
I've quoted.

50:50.667 --> 50:52.267
And she's sitting
back there, too.

50:59.267 --> 51:01.367
And then these are the kids--

51:01.367 --> 51:03.367
it's the next generation,
right?

51:03.367 --> 51:05.367
And they're here with
Caroline Doty.

51:05.367 --> 51:09.697
You know who Caroline Doty is,
a basketball player at UConn.

51:09.700 --> 51:10.700
So we'd gone to a UConn game.

51:10.700 --> 51:12.700
So I don't know what they're
going to do.

51:12.700 --> 51:14.370
They might be scientists.

51:14.367 --> 51:16.697
They might be basketball
players.

51:16.700 --> 51:20.000
They might be lawyers,
doctors.

51:20.000 --> 51:21.700
But you guys are going
to be that, too.

51:21.700 --> 51:27.130
And you're going to be their
teachers, or their healers, or

51:27.133 --> 51:29.903
Lord forbid, defend them in
court, or something like that.

51:32.600 --> 51:33.200
OK.

51:33.200 --> 51:34.770
So there you are.

51:34.767 --> 51:36.567
So I want to thank
all the students.

51:36.567 --> 51:38.397
Not only you guys,
but many years.

51:44.200 --> 51:44.830
So thanks.

51:44.833 --> 51:47.773
We'll have a review on
Monday in room 110.

51:47.767 --> 51:49.497
There's going to be
a symposium here.

51:49.500 --> 51:51.270
So at class time on Monday,
we'll have a

51:51.267 --> 51:52.797
review down the hall.

51:52.800 --> 51:55.530
And good luck on the final,
and that's it.

52:26.400 --> 52:27.630
Thank you.