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

  • 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

  • protonate here, and lose methanol, and

  • get the cation there?

  • Well, the cation here is no good, because it's a sigma--

  • it's in the sigma system.

  • It's not conjugated with the double bond.

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

  • But if you make that one, then the resonance

  • structure is here.

  • There's the vacant orbital, the low LUMO is here and here,

  • And it's adjacent to the unshared pair on oxygen.

  • So that's the one you want to do.

  • So it takes off the one they want to take off, at the top,

  • you get that.

  • Now you do an allylic rearrangement of OH.

  • Or you complete the allylic arrangement.

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

  • Now, what functional group do you have now,

  • when you have OH an OR on the same carbon? Ruoyi?

  • STUDENT: Hemiketal.

  • PROFESSOR: What does it do, what does a hemiketal do?

  • Loses alcohol.

  • Right?

  • So the hemiacetal here, treat it with acid, protonate, lose

  • that, and you've got the ketone now.

  • Right?

  • So we've got it to here.

  • But we need to get this OH off to get down to what he wants

  • to build this over here.

  • So he treats it with acetic anhydride.

  • What does an alcohol do with the acetic anhyride?

  • The O attacks the carbonyl, acetate leaves.

  • It's a substitution reaction at an acyl carbon.

  • So you put acetate on here.

  • And now to get from here to here, we have to change an O

  • on the ring into an H on the ring.

  • What kind of reagent do we need?

  • STUDENT: Reducing.

  • PROFESSOR: We need a reducing agent, right?

  • So like a metal.

  • So we use the zinc. So zinc comes in, gives electrons.

  • The acetate leaves.

  • So we generate this anion and that double bond and enolate.

  • But of course, this is a resonance structure of it, and

  • you put a proton on the anion down there.

  • So he's got to that.

  • So now we're ready for the next step.

  • And the next step is to build ring B, and also, to protect

  • the double bond here so it won't react when other double

  • bonds react.

  • And this thing here on B, building this thing on B, will

  • be a handle to construct ring A. And that double bond here

  • gives you access to that place, which is, remember,

  • where we need to put a ketone, which is sort

  • of off in left field.

  • OK.

  • So the first thing is to build ring B. Did you ever see a

  • thing like that, where from the ketone here we build a

  • whole six-membered ring down here?

  • We saw it two lectures ago.

  • STUDENT: The Robinson annulation.

  • PROFESSOR: The Robinson annulation.

  • So what we need is ethyl vinyl ketone, not methyl vinyl

  • ketone, but ethyl, in order to get this extra

  • methyl group in here.

  • So this thing, which normally would be methyl vinyl ketone,

  • is now ethyl vinyl ketone, so we'll have that

  • methyl group on here.

  • OK.

  • So ethyl vinyl ketone generates the enolate, does a

  • conjugate addition, or sometimes

  • called a Michael addition.

  • Make that enolate anion, protonate it, and now make the

  • other enolate anion and have it attack the carbonyl to make

  • the beginning of that double bond.

  • What would you call that kind of reaction?

  • If you make this enolate react with this, and end up with an

  • alpha, beta unsaturated ketone?

  • So you have a ketone attack another ketone to give an

  • alpha-beta unsaturated ketone.

  • Remember what you call that?

  • Aldol.

  • You still have a week, don't panic.

  • So we're going to do an aldol reaction, and

  • then get over here.

  • Now, what we do there, in order to make this protecting

  • group, is treat with osmium tetroxyde.

  • We know that that makes a diol.

  • We talked about that when we were talking

  • about paracyclic reactions.

  • OK, so you can get the diol.

  • Then you make the diol into this carbon with two more

  • methyls on it.

  • What kind of functional group is this?

  • Two ORs on the same carbon.

  • That's a full acetal, right?

  • And you make it by reacting a ketone acetone with a diol.

  • So we're going to get this ketal, or acetal.

  • OK.

  • Now we need to go across from here to here.

  • And what we're doing is removing this double bond.

  • So that's done with catalytic hydrogenation.

  • And notice, that's why we had to protect

  • this double bond here.

  • Because it would have been destroyed.

  • And if it was destroyed, then you'd have no functionality

  • out here in order to change the six ring into

  • five-membered ring and put the other stuff on.

  • So you had to first protect this, then

  • get rid of this one.

  • So now he's got this compound.

  • And now we're going to knock ring D off while we work on

  • ring A so the whole slide won't fill up.

  • So we'll just take that thing up there and work on ring A.

  • Now, what kind of reaction might make ring A an alpha

  • beta unsaturated ketone here?

  • Any reactions that give alpha, beta unsaturated ketones?

  • STUDENT: Robinson?

  • PROFESSOR: Aldol reactions.

  • So that's what we're going to be looking for, but there are

  • some problems, as you'll see.

  • So we're going to do that.

  • We're going to get this, and then an aldol reaction on that

  • will make this, and we can get this by adding the anion here

  • conjugate to an alpha, beta unsaturated ketone here.

  • What do we call it? What do you call that kind of reaction?

  • STUDENT: Robinson annulation.

  • PROFESSOR: The whole thing, to start from

  • here and build this ring. Build a ring? You said it before.

  • STUDENT: Robinson annulation

  • PROFESSOR: Robinson annulation,

  • we're going to do again.

  • So that would be ready for the aldol.

  • And now this double bond here is even closer to where we

  • needed in order to make that ketone.

  • OK.

  • Now how do you do that?

  • Now there's a problem.

  • You have to make the enolate to do the Robinson annulation.

  • But this is where you form the enolate, down there.

  • You could remove one of these hydrogens and make an enolate,

  • or you could remove one of those hydrogens and make an

  • anion there, which would be allylic with an anion there,

  • which is an enolate.

  • So this one is called a vinylogous enolate.

  • It's got an extra double bond in between, but still, it

  • would behave as an enolate.

  • But the problem is that this one is more reactive.

  • You want to make the enolate here, which you can do by

  • removing one of those purple H's, and then having the anion

  • be there as a resonance structure.

  • That's fine.

  • Except that these are the ones that get pulled off easier.

  • So what do you do?

  • You go ahead, pull these off.

  • Tie them up somehow with something else.

  • Then get the other one, and then come back and take off

  • what you had put on there.

  • Use a protecting group.

  • And notice, incidentally, that there's another H here that

  • could also be pulled off that would have a resonance

  • structure with the anion here.

  • So there are lots of possibilities.

  • You want to get that anion, which is like that anion.

  • So first you have to protect the more

  • reactive alpha position.

  • And they do that by--

  • that's just abbreviating what's above.

  • Makes the enolate, attack that carbonyl, which has a leaving

  • group on it, so the OCH3 will leave, and

  • generate this diketone.

  • That's like a Claisen reaction that we talked about last

  • time, where an enolate attacks an ester,

  • and the alcohol leaves.

  • And then that gets attacked by an amine to give this.

  • And that dehydrates.

  • It's like making an alpha, beta-unsaturated ketone,

  • except it has this nitrogen on it now.

  • Which helps out.

  • The unshared pair on the nitrogen is

  • stabilized by this.

  • You can draw resonance structures that put charge on

  • the oxygen.

  • OK.

  • So this is like an aldol, an alpha, beta-unsaturated ketone.

  • And also notice it's an enamine.

  • So that's tied up the downstairs part.

  • And now you can proceed with making the anion you want,

  • which is going to add to there, and hopefully by

  • Robinson methyl vinyl ketone, or--

  • pardon me.

  • Yeah, methyl vinyl ketone this time.

  • Because the first time, we had to put the CH3 in there, when

  • we used this enolate over here.

  • Now we don't need a CH3 here, so we don't need it.

  • We can use methyl.

  • Except it doesn't work.

  • The reaction doesn't work.

  • So you have to do something a little more roundabout.

  • So that doesn't work.

  • But if you can't add it to methyl vinyl ketone, you can

  • add it to the double bond here.

  • Do a conjugate addition to this sort of like a

  • ketone, to that nitrile.

  • So the enolate adds to this carbon, generate the anion

  • next to the nitrile.Then protonate it, and you've got

  • that.

  • Conjugate addition again.

  • But the problem is, the CH3 here could be

  • either up or down.

  • You could have added to either face of that anion.

  • So here's what they said in the paper about that.

  • "The protected ketone was condensed with

  • acrylonitrile"--

  • that's that compound with cyanide up at the top--

  • "in the presence of aqueous Triton B in

  • t-butanol-benzine, solvent,

  • and the product on basic hydrolysis yielded [this long

  • name thing], as a mixture of two isomers."

  • That's the problem.

  • That's a mixture of two isomers.

  • And that's just lore, whether you're going to get

  • something like that.

  • And sometimes you just have to suck it up, because there's no

  • hydrogen you can pull off here to make it come

  • on the other side.

  • That's just the way it is.

  • So you've got to throw away a certain amount of your stuff.

  • OK, so that's tough.

  • Right?

  • So then they used a strong base and water, which removed

  • this protecting group.

  • Made it back into the CH2 here.

  • And at the same time, it was strong enough that it

  • hydrolyzed the nitrile to make a carboxylic acid there

  • So now, treat that with acid, protonate there. Then

  • protonate here, making that cation.

  • But that can attack the carbonyl to get that, which

  • can then lose a proton, so you've got a

  • six-membered ring.

  • So have we made it?

  • Not quite.

  • We got the wrong element there, oxygen instead of

  • carbon at the bottom.

  • So we need another carbon in the system.

  • So protonate there, cation, eliminate, we've got that

  • double bond.

  • OK.

  • But now we need to convert that into ring A. We need to

  • put that extra blue methyl group on there.

  • So the way to do it is to use methyl Grignard.

  • So the methyl minus adds to the carbonyl, and that is a

  • leaving group.

  • And that's an enolate, so it becomes a ketone.

  • And we've got this thing here.

  • So we're getting closer now.

  • You do an aldol and you have ring A.

  • So this is a typical thing that happens.

  • It looked like a Robinson annulation might go directly

  • there, but it didn't work, so they do a work-around.

  • So now A is all set, and now we need to work on ring D.

  • Which is, remember, a six-membered ring, and it

  • needs to be a five-membered ring.

  • So we'll put it up in the corner and

  • start working on that.

  • So the first thing--what they're going to go for is to

  • make it a five-membered ring that has an ester group coming

  • off, so you have that carbonyl groups that

  • we're going to want.

  • The first thing they do is treat it with acid and water.

  • What do they do that for?

  • PROFESSOR: What's that going to

  • do with that compound? Ayesha?

  • STUDENT: It's going to remove the acetal and give the diol.

  • PROFESSOR: Right.

  • Now you can get rid of the protecting group.

  • You want to be able to work on that double bond now, so you

  • take the protecting group off that you had on there when you

  • were doing the catalytic hydrogenation.

  • And now we've got the diol.

  • And now treat it with periodic acid.

  • You remember what that does?

  • STUDENT: Oxidizes.

  • J.MICHAEL MCBRIDE: It oxidizes a diol to cleave the carbon-carbon

  • bond in between and make two carbonyl groups.

  • So at first it adds, and then that's just an intermediate, a

  • transient intermediate.

  • It comes apart to give two aldehydes.

  • And now, how are you going to make a

  • five-membered ring?

  • STUDENT: Decarboxylation.

  • PROFESSOR: You can make an enolate here, attack

  • that carbonyl, or make an enolate

  • here, attack this carbonyl.

  • Those are going to give different products.

  • What you need to do is to have this enolate attack this

  • carbonyl if you want to make that compound, rather than

  • have this enolate react with that one, and get the

  • carboxylic acid down here.

  • It turns out that base with aldol could be either that way

  • or that way, and luck made it go the right way this time.

  • Robinson annulation didn't work before, but this one

  • worked the right way.

  • And then we've got an aldehyde.

  • We need the carboxylic acid.

  • So you use dichromate oxidation, which we talked

  • about, to oxidize an alcohol.

  • And of course, you don't stop at the aldehyde, you

  • go on to the acid.

  • But you need the ester.

  • So now they're going to make the ester.

  • You could do Fischer esterification, but that's an

  • equilibrium, and this stuff is becoming very precious,

  • because of all the work that you put into it.

  • So you want to do this in the highest possible yield.

  • So they use diazomethane, remember, which is the way of

  • doing it really to change the acid into methyl ester in

  • really high yield.

  • So that's a dangerous compound to work with.

  • It's much more expensive and cumbersome than doing a

  • Fischer esterification.

  • But it gives a really high yield, so

  • that's what they did.

  • So now they had the ketone here.

  • And now they made into an alcohol.

  • Now, this looks nuts, right?

  • they already had the ketone there, which

  • is what they want.

  • And the double bond here, they've got it.

  • Why do they backtrack?

  • They backtracked because it was already known from 1918--

  • so they used borohydride this time to reduce the ketone to

  • an alcohol.

  • If they'd used lithium aluminum hydride, it would

  • have reduced the ester to an alcohol, and they didn't want

  • to do that.

  • So you have to choose the reagents carefully when

  • there's possible competition like that.

  • Now, it was 1909 it was found out that this alcohol could be

  • separated, the two enantiomers, easily.

  • That was already known 50 years before, right?

  • So they backtracked in order--

  • see, all this stuff they've been doing started with

  • achiral material.

  • So they've got both right and left-handed stuff there, and

  • they want only the one enantiomer, ultimately.

  • And someplace, they're going to have to separate it, and

  • this is where they do the separation.

  • Because it turns out, if you put this in together with this

  • digitonin stuff, which itself, notice, has a six, six, six,

  • five steroid inside it-- this complicated

  • sapogenin, as it's called.

  • Then those things come together, and what

  • precipitates is just one hand.

  • The other one stays in solution.

  • So this was obviously lore.

  • But anyhow, they got that.

  • And now, having made this, it turned out that previous

  • studies of cortisone had shown that if you had this, you

  • could make this from it.

  • So this in this is called a total synthesis.

  • But in fact, it's a formal total

  • synthesis, or a relay synthesis.

  • Because by the time they got here, they had very little

  • material, so they couldn't do a bunch more steps.

  • But it was known that those steps could be done, because

  • people had already done them.

  • So they could, then, start with material which had been

  • made from cortisone or some other sterol and

  • then carry it through.

  • But there was no point in doing it, because people had

  • already done those reactions.

  • So this is the paper.

  • This is the whole paper that described the total synthesis

  • of cortisone.

  • Woodward was not a man of many words.

  • Right?

  • There had actually been a previous paper of about two

  • pages about making the precursor that we showed.

  • So he then had this.

  • He reduced this double bond.

  • But notice, it did reduce this one and this one, but didn't

  • reduce this one.

  • So again, this is testing the various methods you're using

  • to make sure what's going to react and what isn't.

  • Why didn't they want to get rid of that double bond?

  • Because that's the one that's going to give them the handle

  • to get that ketone in up there, which is a very

  • difficult position.

  • And then they could do sodium borohydride that made the

  • alcohol that we showed you before.

  • But notice that the borohydride

  • didn't attack here.

  • It only attacked down here.

  • Then they made the acetate from that alcohol.

  • And now they've got to convert this to cortisone.

  • At this point, our synthetic work intersects the lines

  • previously laid down in the extensive prior investigations

  • by many groups.

  • So he goes through some of these groups.

  • "Heymann and Fieser"--

  • that's the guy that wrote this story, right--

  • "have recently converted the acetoxy-ester (III) into [this

  • compound] V." So here's the reference to that.

  • It was worked in 1951.

  • So what they did was to--

  • let's see, whoa, whoa, whoa, we have a lot of stuff here--

  • reaction four, oh, reference four, reference five, then

  • reference six puts that thing on up there, and then

  • reference seven puts the alcohol in or whatever.

  • And finally the double bond by Mattox and Kendall.

  • Kendall, remember, is the guy that got the Nobel Prize, the

  • chemist at the Mayo Institute.

  • So that did it.

  • They had it.

  • They'd solve the intellectual artistic problem of how you

  • can start with simple, available

  • compounds and make cortisone.

  • But what was the yield?

  • Think a minute about yield.

  • Suppose you do 39 steps, and each step has an 80% yield,

  • which isn't so bad, as you've found in lab.

  • Right?

  • Then the overall yield is 0.01% if you take 0.8 to the

  • 39th power.

  • But there's a different way to go about it,

  • what's called a convergence synthesis, where

  • you make several big pieces, and then link the pieces

  • together, so the distance in number of steps from any one

  • starting material to the product is smaller than having

  • all 39 in a row.

  • So you could start with something that does nine

  • steps, say, that makes A. Another nine step sequence

  • makes B. Another makes C, and another makes D. And now you

  • put A and B together, and C and D together, to make E and F,

  • and then you put them together.

  • And now the distance is only nine steps plus two steps for

  • any given starting material, and you get a 9% yield.

  • So convergent synthesis has real advantages.

  • Now, how about a practical cortisone synthesis that could

  • make something that people could afford to use?

  • Well, there's cortisone.

  • Remember, that's what the Nobel laureate said.

  • There are two things you can do.

  • Either do a total synthesis, or get a better starting

  • material than was then available.

  • So choose an appropriate, readily

  • available starting material.

  • OK.

  • Desoxycholic acid, a bile acid that you can get from

  • slaughterhouses, or get the glands from which to make it

  • from slaughterhouses.

  • It comes from ox bile.

  • So in 1946, '49, Merck made a kilogram of cortisone from 600

  • kilograms of that bile acid which came from an enormous

  • amount of stuff from the slaughterhouse.

  • But notice why that was a good starting material.

  • It has all the rings in place of the right size,

  • and it's properly methylated.

  • So it's got the skeleton, the carbon skeleton.

  • It's got all those things in the right stereochemistry.

  • It's got, here, functional groups at or near at least

  • some of the proper positions.

  • You're going to have to fiddle around out here somehow.

  • But how are you going to do that?

  • Well, you could imagine, they were able to go in twelve

  • steps to that.

  • And we're not going to go through what those next 20

  • steps are that allow you to get the red thing.

  • But you could imagine things like, do a bromination at a

  • tertiary position.

  • Maybe you could do that.

  • Then eliminate HBr, maybe.

  • It could go the wrong way.

  • Then maybe you could cleave the double bond and make the

  • ketone, then maybe you could do alpha-bromination adjacent

  • to the ketone, and then make alcohols from that.

  • Something like that.

  • You can imagine.

  • That's not what was done.

  • That wouldn't be twenty steps.

  • It didn't work that way.

  • But you can imagine ways that you could get at it.

  • So they did it in 20 steps.

  • So then they got cortisone.

  • And they could sell it in 1949 for $200 a gram, having made

  • it by a 32 step sequence.

  • But there's another compound called diosgenin.

  • And diosgenin also has the right set of rings and the

  • right stereochemistry, and functionality in a good place.

  • And it's abundant in a Mexican yam.

  • And Russell Marker, who was an organic chemist at Penn State

  • University, went exploring.

  • He sort of quit and went down to Mexico and looked around to

  • see if he could find natural things that

  • contained a lot of this.

  • And the roots of this yam--

  • some of them are 20 or 50 kilograms, and a fair

  • percentage of it is this stuff.

  • So he was able to find a good source of this.

  • And it could be converted in five steps into progesterone,

  • a female hormone.

  • And so in 1943, he got ten tons of that yam and from it,

  • made three kilograms of progesterone, which was then

  • worth a quarter million dollars,

  • which is-- in 1943, which is like, I don't

  • know, $5 million now.

  • He had the world's supply of progesterone,

  • which is a pregnancy hormone.

  • And so it was selling in 1955 for 48¢ a gram, instead of

  • this $200/gram stuff.

  • But there's a problem if you want to get cortisone this

  • way, because there's no foothold to get at that

  • position, rather than that one or that one or that one or

  • that one or that one or that one or that one.

  • How are you going to put the ketone in?

  • And this is where it was found, actually, by this guy

  • here, or by his research group.

  • Frederick Heyl, who was an undergraduate and graduate

  • student here, was the director of research at Upjohn.

  • And at Upjohn research in Kalamazoo, they found out that

  • they had some of this-- a mold started growing on a dish that

  • was in a windowsill.

  • And when you put it on here, it put a

  • ketone in that position.

  • Pardon me.

  • Put the alcohol in that position.

  • But then once you've got the alcohol here, you're home

  • free, right?

  • OK.

  • So Woodward had done the total synthesis of cortisone, and he

  • did a lot of total syntheses.

  • Like the strychnine synthesis here.

  • I thank Professor Saunders, who took these pictures.

  • He was still a graduate student at this time in 1954

  • when strychnine was synthesized.

  • And the interesting thing about Woodward--

  • there was real cult of personality, still is, among

  • older people.

  • Because young people don't know who he was anymore.

  • Because he was such an artist. I mean, designing these things

  • is an art, but you have to really know a lot to

  • see the art in it.

  • And his Nobel citation actually, said "for his

  • outstanding achievements in the art of organic synthesis."

  • I don't think there's never been another Nobel citation

  • that said art in it.

  • So he made a lot of these things.

  • Here was strychnine, a very challenging thing.

  • And so when they got it done, they drew it very carefully on

  • the blackboard.

  • And the postdocs who had worked on it--

  • Ollis was a faculty member from the University of

  • Bristol, in England.

  • Hunger was a German.

  • Daeniker and Schenker were from Switzerland.

  • And Cava was an American who went to be a

  • professor at Penn.

  • But you'll notice, when Woodward got the Nobel prize,

  • his colleagues wrote this in Science magazine.

  • "Woodward's style is polished, showing an insight and sense

  • of proportion that afford him strong convictions and a

  • well-developed dramatic sense."

  • So you can see, just the way he's lighting his cigarette

  • there looks sort of dramatic to me.

  • And look at his signature!

  • He always signed minuscule signatures.

  • R. B. Woodward.

  • And they also put a check mark on it when they finished the

  • synthesis, and down in the bottom wrote, "fecunt."

  • So you know Latin.

  • I talked to Victor Bers in the classics department.

  • That's not a proper Latin word.

  • But fecerunt means, they made it.

  • Right?

  • So that's what-- they almost got it right, evidently,

  • writing that on the blackboard.

  • But one of the hallmarks of Woodward's style was that he

  • always wore the same color blue suit and blue tie.

  • So that's a Woodward blue tie.

  • And in fact, students, one Halloween, painted his parking

  • place that light blue.

  • And I know where they got the paint, because I got it.

  • OK.

  • So then in 1973, they did this real pinnacle of synthesis.

  • They synthesized vitamin B12.

  • You can't imagine all the problems that

  • were faced by this.

  • And it was a collaborative work between Woodward and

  • Eschenmoser's laboratory at the ETH in Zurich, in

  • Switzerland.

  • And in connection with this work is where Woodward

  • discovered stereochemical control by orbital symmetry.

  • Those are called the Woodward-Hoffmann rules.

  • You know, conrotation, disrotation.

  • And it was while working on this that he discovered that.

  • They had 100 coworkers at these two

  • labs, working on this.

  • All of them very, very talented.

  • Including this guy, Yoshito Kishi, who was a faculty

  • member from Nagoya University who had come to work on this

  • project with Woodward.

  • And this is what Woodward wrote about him when, in Pure

  • and Applied Chemistry in 1971, he wrote about working on the

  • B12 synthesis.

  • "The first preparation of corrigenolide afforded

  • striking testimony of the experimental skill of its

  • discoverer, Dr. Yoshito Kishi.

  • All the operations had to be conducted with every

  • conceivable precaution in respect to purity of reagents,

  • exclusion of oxygen and moisture, and with the

  • greatest possible speed."

  • So he was a real wizard in the laboratory.

  • And he then joined the Harvard faculty after that, and then

  • succeeded Woodward as professor at Harvard after

  • Woodward's untimely death.

  • And we've seen his name before.

  • Not for this.

  • He ultimately synthesized palytoxin, this compound,

  • which has C-123, H-213, NO-53.

  • It's got 42 functional groups which were protected in eight

  • different ways.

  • So you could remove some of them, put

  • others on, and so on.

  • It has 62 stereogenic centers.

  • It has seven double bonds that could be either E or Z, so

  • there are 10 to the 20th stereoisomers possible.

  • And it was done convergently.

  • So they made eight different pieces and then put those

  • pieces together.

  • So you'd get no yield at all if you did this in a

  • sequential synthesis, right?

  • But they actually made it.

  • And it was not-- although that was just a tour de force, it's

  • related to practical stuff.

  • Because we talked last fall about this Eisai drug, which

  • has a lot of similarity to that.

  • And the week after we spoke about it in class, the FDA

  • approved it for treating metastatic breast cancer.

  • Remember we talked about whether that was

  • pending at the time.

  • And you'll notice that the leader of

  • this group was Kishi.

  • So he had cut his teeth on palytoxin for synthesizing

  • things like this, so that this drug can now be made

  • synthetically, practically, and sold as a drug that way.

  • It's just incredible.

  • So organic synthesis has come a long way from urea.

  • Remember what Woehler wrote to Berzelius in 1828 about the

  • experiment when he reacted "cyanic acid with ammonia and

  • a crystalline substance appears which is inert,

  • behaving neither like cyanate nor like ammonia."

  • So that's the story.

  • But first, that a little bit of thanks and credit.

  • First to George Maxfield, who was my high

  • school chemistry teacher.

  • I remember his doing--

  • we'd be working on something, and he wouldn't be doing

  • anything at all.

  • He'd go like this.

  • And the other thing he did was he said, "You make something,

  • you put it in a bottle and sell it to your neighbor." So

  • I'm quoting him.

  • And there's Theodore Roosevelt Williams, who was my first

  • college professor at the College of Worcester.

  • And then Fieser we talked about, and Bartlett, and

  • Conant was his boss, who had two PhD advisors, a physical

  • chemist, T.W. Richards, who got the Nobel Prize, and an

  • organic chemist, E. P. Kohler, who was very--

  • these three pictures were all taken at Yale.

  • That was when Sterling was dedicated.

  • This was at a meeting in 1931 when Bartlett was just 24 years

  • old. But Kohler never went to meetings.

  • He never left Harvard.

  • People would come there to talk to him, but he wasn't

  • interested in that.

  • He just taught all the time.

  • And Kohler's the one that finally resolved aline.

  • Remember, we talked about that van 't Hoff had predicted it.

  • But Kohler's the one that made it.

  • So Kohler was a student of Remson, who

  • was at Johns Hopkins.

  • And Richards studied with Ostwald.

  • Remember, the guy that didn't believe in atoms?

  • And then the next generation back was Fittig, who

  • discovered the pinacol reaction.

  • And the one person I couldn't find a picture of was Carl

  • Schmidt, who was at Riga in Latvia.

  • But he was described by Ostwald as a "tall, thin man

  • with a small head, a strong nose, ice gray hair, and a

  • thin beard." And a very nice person, right?

  • And Schimdt had worked both with Liebig and Woehler.

  • He was first a student of Woehler, who

  • recommended him to Liebig.

  • Fittig had worked with Woehler.

  • So we're back to those guys.

  • And then to Gay-Lussac and Berzelius.

  • And then to Bertole, who was a colleague of Lavoisier, and

  • wrote how to name compounds.

  • But there are some other heroes to whom we should pay

  • homage, even if they weren't our ancestors.

  • You know who this is?

  • STUDENT: Moses Gomberg

  • PROFESSOR: Right.

  • Who's this?

  • Emil Fischer.

  • The last lecture.

  • Koerner.

  • The other guy who did a real proof in the 19th century.

  • James Clark Maxwell.

  • Remember him?

  • Couper.

  • The tetravalence of carbon.

  • Lavoisier.

  • And Robert Hooke.

  • There's no known picture of Hooke, because Newton probably

  • destroyed it.

  • I think that's true!

  • But this is a picture of somebody

  • using Hooke's apparatus.

  • And Hooke was a hunchback, and he drew that picture.

  • And I like to think that might be a self-portrait, although I

  • sort of doubt it.

  • But Hooke was certainly a great guy.

  • And then of course we have a lot of people we have to pay

  • homage to at Yale, too.

  • Like Silliman, with his T-shirts that says, "How do

  • you know?"

  • Or a giant.

  • Who's this?

  • STUDENT: Gibbs

  • PROFESSOR: Gibbs.

  • And Onsager.

  • Those two--

  • Gibbs was arguably the smartest guy in the 19th

  • century, or certainly among the top half dozen or so.

  • And Onsager was the same in this century.

  • And I actually had Onsager as a colleague.

  • We overlapped for a few years.

  • I mean, he's-- like, Feynman was in awe of Onsager.

  • And when Onsager got the Nobel Prize, when they called to

  • inform him, he asked, "What for?" Because he had done so

  • many things that could have gotten the Nobel Prize.

  • And then, you know this is?

  • Chupka.

  • These are the colleagues I've enjoyed having

  • around for a while.

  • And he came in and told people how he determined the heat of

  • vaporization of carbon.

  • And that one, you know.

  • Wiberg.

  • And here's Professors Ziegler.

  • These are people who gave lectures in the course, right?

  • And of course, you know who's next.

  • Not a faculty member, but a graduate student from Yale.

  • And then someone who's almost from Yale.

  • Leslie Leiserowitz

  • who spoke to you last semester.

  • He's from Israel, but he comes so often to visit that we'll

  • call him an honorary Yalie.

  • And then these people we quoted.

  • Remember, he's the guy that originated "How

  • do you know" hourly?

  • And she's the one that does it now.

  • And this is my wife, and that's John's wife.

  • And here's-- this was night before last over across the

  • street here, at a meeting of the Connecticut Science

  • Teachers Association, when this plaque was

  • awarded to my wife.

  • And she's sitting back here.

  • And next to her is the Biology professor from Bowdoin whom

  • I've quoted.

  • And she's sitting back there, too.

  • And then these are the kids--

  • it's the next generation, right?

  • And they're here with Caroline Doty.

  • You know who Caroline Doty is, a basketball player at UConn.

  • So we'd gone to a UConn game.

  • So I don't know what they're going to do.

  • They might be scientists.

  • They might be basketball players.

  • They might be lawyers, doctors.

  • But you guys are going to be that, too.

  • And you're going to be their teachers, or their healers, or

  • Lord forbid, defend them in court, or something like that.

  • OK.

  • So there you are.

  • So I want to thank all the students.

  • Not only you guys, but many years.

  • So thanks.

  • We'll have a review on Monday in room 110.

  • There's going to be a symposium here.

  • So at class time on Monday, we'll have a

  • review down the hall.

  • And good luck on the final, and that's it.

  • Thank you.

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

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