Lecture Designing Organic Syntheses 8 - 31.10.14
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Aspartate transaminaseEnolConjugated systemHydrocarboxylierungElektronenakzeptorReactivity (chemistry)SymptomChemical compoundAlpha particleOrgan donationHuman subject researchAcidKetoneBiosynthesisBase (chemistry)Retrosynthetic analysisTautomerThermoformingCarbon (fiber)Addition reactionFunctional groupTumorActivity (UML)TeaPetroleumDyeingSetzen <Verfahrenstechnik>Lecture/Conference
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AldehydeKetoneEthanolEnolSodiumAldehydeBase (chemistry)EsterAcidDecarboxylationCarbon dioxideActivity (UML)HydrolysatComplication (medicine)GesundheitsstörungChemical reactionOrganokatalyseMethyl vinyl ketoneAnimal trappingReactivity (chemistry)Organ donationChemical structureElektronenakzeptorProlineFunctional groupSet (abstract data type)ProtonationAlpha particleConjugated systemHydroxybuttersäure <gamma->EthylgruppeRetrosynthetic analysisAcetic acidFatty acid methyl esterAmino acidSynthetic oilBrown adipose tissueDyeingChewing gumChemical compoundMichael-AdditionProteinConnective tissueAzo couplingAdenomatous polyposis coliHuman body temperatureTeaSolutionHybridisierung <Chemie>Lecture/Conference
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CyclohexanonChemical structureFormaldehydeBiomolecular structureChemical compoundBase (chemistry)Aqueous solutionMoleculeBiosynthesisPolymerDimethylaminCycloalkaneAnimal trappingWaterfallSolutionLeadProcess (computing)ThermoformingMaterials scienceLecture/Conference
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Chemical reactionConjugated systemKetoneDimethylaminBeta sheetOxygenierungAlpha particleBase (chemistry)AcidProtonationAlkylationEsterElimination reactionCancerEthylgruppeMethyl iodideMannich reactionProlineElectronic cigaretteIodideMixing (process engineering)SolutionWalkingProteinLecture/Conference
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Chemical compoundLevomethadonLecture/Conference
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Chemical reactionFunctional groupProteinChemistrySolutionSchutzgruppeLithiumElimination reactionSpeciesAzo couplingOrganische ChemieMetalMagnesiumAcetateCarbonylverbindungenMethylgruppeHydrocarboxylierungLithiumorganische VerbindungenZinkorganische VerbindungenLecture/Conference
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Functional groupSpaltflächeDoppelbindungCarbanionRetrosynthetic analysisAldehydeKetoneAldolCondensationChemical compoundHydrocarboxylierungAageSynthetic oilDyeingIslandProteinCarbon (fiber)OxideCondensation reactionBET theoryLecture/Conference
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CondensationSpaltflächeCarbonylverbindungenRetrosynthetic analysisAldolCarbon (fiber)Chemical compoundDoppelbindungFunctional groupOxideLecture/Conference
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Chemical reactionChemical compoundIonenbindungEpoxidationAcidChemical structureBiosynthesisIsoprenLactoneCarboxylierungHeteroatomCarbon (fiber)CarboxylateOxidePotassium permanganateOzonolyseFunctional groupOzoneDoppelbindungStereoselectivitySense DistrictWaterfallCaveRedoxTeaIceButcherOrlistatMoleculeSpaltflächeDiet foodExciter (effect)Lecture/Conference
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DyeingChemical reactionCarbon (fiber)Heck-ReaktionCycloalkaneOrlistatOxideAcidChemistryFunctional groupSpaltflächeChemical structureGesundheitsstörungHomöostaseNaturstoffCyclohexenProcess (computing)Potassium permanganateKetoneLecture/Conference
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Chemical reactionLecture/Conference
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Chemical reactionButanoneAcidCondensation reactionChemical structureEsterDerivative (chemistry)OxalsäureFunctional groupLeakLecture/Conference
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Computer animation
Transcript: English(auto-generated)
00:05
Welcome to part eight of the lecture on designing organic synthesis. In the preceding lesson, we talked about dicarbonyl compounds, 1,2,1,3, and 1,4 dicarbonyl compounds.
00:22
Subject of today are 1,5 and 1,6 dicarbonyl compounds. So, 4,1,5 dicarbonyl compounds. We have a favorable situation
00:57
for setting those dicarbonyl compounds up.
01:03
It will soon become clear. Let us disconnect close to the center.
01:26
Then we have these two fragments. We should designate a reactivity.
01:42
And of course, we would like to choose donator reactivity alpha to that carbonyl since this then fits the natural reactivity. And on the other hand then, we of course need acceptor reactivity
02:02
and indeed translating the symptoms into synthetic equivalence is fairly easy since an alpha-beta unsaturated carbonyl has acceptor reactivity in better position
02:25
because of the conjugation of a carbonyl group. And well, an enol or an enol is an enol. Enolate means the tautomer
02:50
or the deprotonated form of that ketone and exhibits nucleophilicity at that carbon, of course.
03:03
So, put those two together, addition of a base for instance, or maybe also acidic catalyzed, acid catalyzed and you will get that Michael type
03:22
conjugate addition reaction. Here an example. And of course, you already know
03:42
that this is a famous example from the Robinson annihilation reaction first disconnecting here.
04:07
Then we have that 1,5-dicarbonyl set up,
04:29
MVK as the electrophile and well, under the right reaction conditions
04:43
you get directly to this bicyclic product. If we choose to apply proline,
05:03
the amino acid proline as a catalyst in this reaction, then this is one of the, well, maybe the most famous example in organocatalysis. We will be able to get to this product
05:24
in better than 95% enantiomeric excess. Let's have a look at this more simple target
05:45
as an exercise. So, disconnecting here, well, let's take that suggestion as a retrosynthetic plan one
06:01
and here retrosynthetic plan two, R1.
06:21
Problem with this structure is, is this really a simplification compared to that one? If one has a nice idea how to simplify this,
06:43
then really make it more simple by disconnection. Okay, one should further work out on this synthetic plan. The other retrosynthetic plan looks more promising,
07:13
acceptor reactivity here, donator reactivity.
07:22
Well, of course we can't simply deprotonate here the presence of the acid functionality. Well, first idea is let us protect the acid,
07:51
acetic acid ethyl ester. Let us think about it. You take acetic acid ethyl ester plus cyclohexanone,
08:05
add a base sodium ethanolate, what would happen? This alpha protons, alpha to the carbonyl, and also the gamma protons are far more acidic
08:24
than the alpha protons of an ester. Well, then we could increase the acidity here if you say, well, let's choose an aldehyde.
08:46
Yes, then put that aldehyde and cyclohexanone, together, add the base sodium ethanolate and ethanol. Yes, this would be preferentially deprotonated,
09:00
but unfortunately, this enolate will preferentially react with other aldehydes because these are more reactive than ketones or of a better unsaturated ketones. We need another way to activate this here.
09:25
Well, okay, we could make the ester enolate and trap the enolate and have a complicated intermediate TMS enolate of an ester, would be possible, but we shouldn't choose that if there is
09:40
a much simpler solution, and there is. The malonate, it's double activated.
10:03
It will give nicely the Michael addition product, E is now the abbreviation for an ester, and hydrolysis under elevated temperature,
10:28
then we will get two equivalents of ethanol as hydrolysis, byproducts, and one equivalent of CO2
10:44
since the decarboxylation would readily take place. Next example, please analyze this target.
11:35
Once again, an example where we could approach the retrosynthetic analysis systematically,
11:43
R1 or R2, both disconnections are in accord with what we have discussed for 1,5-dicarbonyl compounds in general.
12:02
So, R1 cyclohexanone plus this one.
12:26
Well, the problem is this structure might be able to handle that, yes, you can produce that, but it has some tendency for polymerization.
12:40
For instance, imagine adding a base OH minus, attacks as a nucleophile, you have then the malonate there, this attacks the second molecule of that molecule, kind, it's the anionic polymerization, as we know it from certain glues,
13:06
those split-second glues. It work very fast and you have to be rather careful with applying them. R2, well, and of course, this derives from malonate
13:46
and formaldehyde. And one could think that this derives from cyclohexanone plus formaldehyde.
14:06
And that means that either by this route or by that route, we end up by the same starting materials, it's just for the sequence
14:25
with which we apply those. So, as I said, here we have a problem of handling that. On the other hand, here in this route,
14:46
this structure is the troublemaker. At least, well, one synthesis is known for that structure
15:08
are applying the simple idea that this also won't have a long lifetime. We generate that and the malonate
15:24
should already be present, trapping that. And this then works rather nicely. So, the synthesis has been done starting from cyclohexanone plus formaldehyde,
15:51
an aqueous solution, and dimethyl amine
16:15
leading to this structure. All can be regarded as a conjugate addition product
16:28
of dimethyl amine to this alpha beta unsaturated ketone. But the reaction which you see here
16:42
is a Mannich reaction. Typical Mannich reaction. So, the next step, well, this is a bit all expensive
17:09
because of the methyl iodide and you have to be careful with methyl iodide boiling point, 40 degrees, and it's an alkylating agent and cancer suspect agent, of course.
17:24
Well, but it alkylates very well that aminogroup, take this, plus malonic acid,
17:54
diethyl ester as a mixture, and add a base, what will happen?
18:17
The base deprotonates the most acidic proton first.
18:24
It's this. You have the malonate present. So, maybe it already could attack here, but the base is not catalytically there,
18:40
it's in excess, and it will induce an elimination reaction here. Deprotonating here and eliminating that. So, that means you will have that alpha-beta unsaturated ketone
19:02
and this malonate at the same time together in solution, it will react very nicely. There are not very many competing reactions one might think of, and therefore, presumably works very well.
19:24
It will give the target. Let's talk about 1,6-dicarbonyl compounds.
19:52
Unfortunately, it's especially unfavorable
20:05
for setting that up with a disconnection approach like that. Well, the acceptor, no problem.
20:29
But how to get the donator there?
20:40
What you need is something like a metal here, magnesium organolithium. You don't have a stabilized anion at this position. If it is a metallorganic species,
21:01
you normally can't afford having a carbonyl group present. Unless, well, you have the idea of applying organozinc chemistry, which might tolerate the carbonyl groups,
21:21
so might have to apply protective group chemistry. Next problem you have,
21:41
how do you get to this situation here? Well, you would be in need of something like that,
22:03
with a leaving group here for the methylation. You have the problem that if you deprotonate here, the elimination reaction occurs. Also, trying an acetalization of that
22:24
is also a problem because elimination reactions will compete. So that's the reason why I would say it's especially unfavorable. There are a couple of examples known, several examples,
22:44
because quite a few of research groups targeted this problem and tried to develop convincing solutions.
23:00
But there is one rather simple, which often should be preferred. It's this. For instance, an ozonolysis,
23:23
or another oxidative cleavage of the C-C double bond, will lead to a 1,6-dicarbonyl compound.
23:53
Again, as an exercise, we should have a look
24:09
at the retrosynthetic analysis of this aldehyde.
24:22
With an alpha-beta unsaturated carbonyl compound, the double bond always is a strategic bond, and you should think about synthesizing that by an aldol condensation reaction.
24:57
The aldehyde is more CH acidic than that ketone.
25:02
You, with the influence of a base, you would deprotonate here, and the aldol condensation would take place regioselectively. So now we have a one, two, three, four, five, six, one, six, dicarbonyl compound.
25:26
If you then imagine to generate these two carbonyl groups by an oxidative cleavage of a C-C double bond,
25:41
then your retrosynthetic analysis will lead you to this compound, which is known as limonene. Well, of course, you could further analyze that
26:05
and split it into those two identical units of isoprene. To my knowledge, the Diels-Alder reaction of isoprene doesn't work very well.
26:24
You can buy limonene, no problem. And as already one of you noticed, you will have a problem in selectivity when trying the ozonolysis of this molecule,
26:42
since you have two C-C double bonds and ozonolysis, ozone highly reactive, does not very well discriminate between these. But there are oxidation reaction, which preferentially take place
27:03
at the more electron-rich double bond, and that's the one that is trisubstituted here. I think, for instance, an epoxidation with metachloro-perbenzoic acid.
27:24
So MCPBA would preferentially oxidize here.
27:43
Well, and from that epoxide, you can easily get to the dihydroxy compound and then oxidize the pinacol by cleavage, by cleaving that C-C single bond. This is possible.
28:03
Maybe it's already possible to get that reaction done with potassium permanganate. However, I'm in doubt that you can stop that reaction then at the stage of the aldehyde.
28:20
It would be then further oxidized. Okay, this is a problem, right. But in general, this should help to figure out a good synthesis for this compound.
28:40
Last example for today.
29:15
Please try this one. This is certainly the most complex structure
29:21
we were dealing with today. And while analyzing that means first looking for strategic bonds. Carbon heteroatom bonds are strategic bonds. And moreover, it's a good idea
29:41
to look for the most sensitive functional group you have in that molecule. Carboxylic acid is not sensitive, but an acetal is. So if we hydrolyze that acetal,
30:02
especially this is an acetal where carboxylic acid, acids are involved. A double lactone. So hydrolyzing here leads us
30:34
to this tri-carboxylic acid
30:44
and this keto functionality. And now we have, for instance,
31:05
a 1,4-dicarbonyl, another 1,4-dicarbonyl, a 1,5-dicarbonyl situation and a 1,6-dicarbonyl situation.
31:23
Normally, we should now analyze each of them. But since we are currently discussing 1,6-dicarbonyl, let us make that easier. We choose this one.
31:40
So this connection, let us assume that this dicarbonyl situation derives from an oxidative cleavage of the cyclohexene.
32:28
So oxidation of the cyclohexene, for instance, with potassium permanganate under appropriate reaction conditions, will give this structure.
32:43
We shouldn't worry about that last step. Imagine that this could be a natural product, was isolated from nature. Then, for sure,
33:03
some acid-catalyzed process will give this with the correct stereochemistry, because also, in nature, those equilibrium reactions will exist.
33:20
So, and here, the cyclohexene moiety, well, we have the redrawn of the Diels-Alder reaction, butadiene, and this is all we need.
33:55
And, well, if the Diels-Alder reaction
34:01
maybe wouldn't work very well with the free acid, then we could choose to apply the ester derivative of this. Let us analyze this one here. Okay, the structure here is gluoxylic acid,
34:41
and therefore, we need condensation reaction of butanone with gluoxylic acid to get to this Diels-Alder reaction. Okay, should work. Enough for today. Thank you for listening. Have a nice week, and we meet again next Tuesday.
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