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

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

before, actually.

But it's focused on synthetic chemistry.

In particular, the synthesis of cortisone, which is a

natural product.

Cortisone looks like this.

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

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

various alcohols and ketones and so on.

And in fact, this lecture originated with a book called

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

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

written in 1961 when I was taking organic chemistry by

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

that time for this course.

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

a lot on steroids.

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

Chemistry of Natural Products Related to Phenanthrene.

Phenanthrene three is a thing like three benzene rings.

Bing, bing, bing.

So you see, steroids are related to phenanthrene, so

that's what this book was about.

He also was a stylish guy.

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

with a gold headed cane.

He had dropped that affectation

by the time I arrived.

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

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

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

he ultimately succumbed to lung cancer.

So this is a way of homage to him.

These are some of the steroids, the ones that are

sex hormones.

So very small amounts of them go around and make various

things happen in your body.

And they begin up at the top left with cholesterol, and you

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

an alcohol here, making unsaturation and so on to make

all these important compounds.

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

steroids awarded four Nobel Prizes between 1927 and 1950,

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

in part, due to work on steroids.

The awards in 1927 and '28 were determining the

structure, and the one in 1965 recognized the

synthesis of it.

You have to know the structure before you can

synthesize it, obviously.

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

wrong structure.

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

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

bing, bing, like that.

But it got settled in the 1930s.

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

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

discoveries relating to the hormones of the adrenal

cortex, their structure and biological effects." So

Kendall and Reichstein were organic chemists, and

Showalter Hench was a physiologist.

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

regarding the rheumatic disease in general and rheumatoid

arthritis in particular still finds expression in some of

the modern writings and texts."

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

at the Mayo Clinic, a 65 year old patient,

with an unusual story.

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

rheumatoid arthritis, and had been for four years.

Then jaundice suddenly developed, and within a week,

most of his arthritic manifestations had

disappeared.

The jaundice lasted five weeks, and the rheumatic arthritis

did not relapse until several weeks after the jaundice had

disappeared.

"The thought occurred instead of being relentlessly

progressive, this disease, rheumatoid arthritis, may be

potentially reversible, more so than we believed.

Perhaps rapidly so."

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

the organic chemists were determining the true

structure, observations were made on sixteen patients with

chronic arthritis or fibrositis, in whom jaundice

of different types and degrees developed.

If the jaundice was deep enough, it was characterized

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

rheumatic symptoms quickly diminished or disappeared for

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

And furthermore, it was noted that during

pregnancy, people lost that.

So there was thought to be some hormone

that would do this.

So they figured that out.

You can read that yourself.

OK.

So Reichstein then, the Swiss chemist, took 1000 kilograms

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

kilogram of dry residue from that and follow the activity

as he parcelled it out, including using Girard's

ketone reagent T.

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

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

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

off and it'll go back into the organics?

That was a powerful way of separating these ketones.

And so there we go.

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

So this was this fishhook to extract ketones.

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

click through it very rapidly to show how it was

synthesized.

And now we know what it did.

"Only when pure crystalline homogeneous substances were

produced were they tested as far as possible biologically.

So accurate determination of chemical

structure was given priority.

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

details."

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

And here were some of these steroids from the adrenal

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

important as active.

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

It has an OH group on the top left here.

And below it is cortisone, the ketone.

So that position 11 and the position 17 were particularly

important then.

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

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

steroid skeleton is one of the major difficulties in the

synthetic

production cortisone." Why?

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

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

alpha beta unsaturation could be used.

Right?

"The preparation of the substance from deoxycholic

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

many improvements to it have been discovered.

If it is wished to obtain cortisone more simply, there

remain two ways.

Either total synthesis or the discovery of a better

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

that then you could convert into

this for medical purposes.

Both will be tried.

The prospects of a total synthesis are difficult to

assess."

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

Either total synthesis or you've got find

a better raw material.

And there's a footnote there.

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

which is already very closely related to cortisone...

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

OK.

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

total synthesis Woodward's

synthesis in 1951 of cortisone.

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

So this is the thing he wanted to make.

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

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

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

question mark on D?

STUDENT: It's a six-membered ring

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

five-membered ring.

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

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

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

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

a smaller size and put the functionality

that you need on there.

OK.

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

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

ketone on there.

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

It's at this position down here.

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

we'll see how that works.

So this compound was known and readily available and cheap.

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

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

How did he do that?

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

that are highlighted in blue, here?

Anybody got an idea?

STUDENT: The Diels-Alder reaction.

PROFESSOR: The Diels-Alder reaction, Right?

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

he put that ring on.

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

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

the same side.

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

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

wrong stereoisomer when we get to the end.

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

longer pointing down, but pointing up?

Yeah, Amy?

STUDENT: Can you use the

Mitsunobu reaction?

PROFESSOR: Ah.

Mitsunobu inverts an alcohol.

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

left-handed.

But there's no alcohol here.

What functionality is handy? Rahul?

What's special about the position of that H?

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

PROFESSOR: We want to pull that hydrogen off and put

it back on the other side.

There are a zillion hydrogens in here.

Ayesha?

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

PROFESSOR: Aha!

Enol, enolate.

OK.

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

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

goes all over there via the enolate.

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

Can you think of a reagent that could do that?

This is review.

What kind of reagent is necessary?

STUDENT: Reducing agent.

PROFESSOR: A reducing agent.

Something that will add hydride to the carbonyl.

Any ideas?

STUDENT: Hydrogen peroxide?

PROFESSOR: Hydrogen peroxide.

Good idea, everyone?

STUDENT: No.

PROFESSOR: Why?

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

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

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

here to a ketone and an unsaturation.

You already have an unsaturation here.

So let's think about how we do that.

The oxidation levels turn out to be the same.

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

you can protonate and get that cation.

But why get that cation?

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