Lecture Catalytic Organometallics 20 - 04.06.14
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| Teil | 20 | |
| Anzahl der Teile | 27 | |
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| Lizenz | CC-Namensnennung 3.0 Deutschland: Sie dürfen das Werk bzw. den Inhalt zu jedem legalen Zweck nutzen, verändern und in unveränderter oder veränderter Form vervielfältigen, verbreiten und öffentlich zugänglich machen, sofern Sie den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen. | |
| Identifikatoren | 10.5446/37047 (DOI) | |
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00:00
GastrinWursthülleFunktionelle GruppeTransformation <Genetik>RutheniumAlkohole <tertiär->WasserAlkeneTachyphylaxieKreuzmetatheseIonenbindungFließgrenzeBiosyntheseEliminierungsreaktionEthylenChemische ReaktionChemische StrukturGangart <Erzlagerstätte>IsobutylgruppeSchutzgruppeGesundheitsstörungZunderbeständigkeitMolybdänBleitetraethylMetallorganische ChemieVorlesung/Konferenz
07:30
TeeBiosyntheseVinylverbindungenTachyphylaxieMolybdänSubstituentCyclische VerbindungenAzokupplungAllylverbindungenWursthülleFunktionelle GruppeDoppelbindungFließgrenzeMultiproteinkomplexCarbeneSulfurHeterocyclische VerbindungenMolekulargewichtsbestimmungTransformation <Genetik>Setzen <Verfahrenstechnik>KatalysatorgiftChemische ReaktionAlkineZunderbeständigkeitPalladiumVorlesung/Konferenz
14:56
CycloadditionFließgrenzeCyclobutanAzokupplungMethylgruppeAllylverbindungenAlkeneAlkineRutheniumChemische ReaktionChemischer ProzessSubstrat <Chemie>Alkohole <tertiär->Proteinogene AminosäurenDoppelbindungMischenCyclobutenAcetateNaturstoffCarbeneIsomerWursthülleBiosyntheseMultiproteinkomplexReaktionsmechanismusIonenbindungGangart <Erzlagerstätte>Vorlesung/Konferenz
22:21
CycloadditionRutheniumHomöostaseSetzen <Verfahrenstechnik>Chemische StrukturChemische ReaktionReaktionsmechanismusSterische HinderungVorlesung/Konferenz
24:50
AlkeneFließgrenzeFülle <Speise>Vorlesung/Konferenz
25:39
Chemische StrukturMultiproteinkomplexKreuzmetatheseCarbeneRutheniumElektron <Legierung>CycloadditionVorlesung/Konferenz
30:33
BiosyntheseMischenAlkineChemische ReaktionWolframChemischer ProzessLithiumResorcinEthylenAktivität <Konzentration>MolybdänHexaneButyraldehydAlkeneKreuzmetatheseDieneReaktionsmechanismusOctaneOxideKörpertemperaturEtomidatEthanIsobutylgruppeExplosionKetoneButanoleWursthülleSiliciumdioxidIonenbindungKonjugierte PolyeneFunktionelle GruppeSekundärstrukturPetroleumVorlesung/Konferenz
39:59
NaturstoffChemische ReaktionKreuzmetatheseCarcinoma in situChlorbenzolFließgrenzeLigandKörpertemperaturParfümChinolinChemische StrukturAlkineReaktivitätBiosyntheseWursthülleAlkeneMischenLactitolIonenbindungKohlenstofffaserWasserstoffPalladiumSetzen <Verfahrenstechnik>MethylenchloridVorlesung/Konferenz
49:25
MolybdänKreuzmetatheseCarcinoma in situBiosyntheseChemische StrukturAlkeneAlkineKrebsforschungChemische ForschungMischenFunktionelle GruppeAktivität <Konzentration>FließgrenzeVorlesung/Konferenz
55:10
Computeranimation
Transkript: Englisch(automatisch erzeugt)
00:05
Welcome to the lecture on catalytic organometallics part 20. In the preceding lesson we learned about the olefin metathesis and one of the first reactive catalysts was this rather complicated in structure catalyst, a molybdenum.
00:31
This is a catalyst invented by the group of professor Schrock and some students
00:40
asked me after the preceding lesson what about the functional group tolerance of this catalyst. And it was said not by me that it absolutely tolerates no functional groups. Well, that's not true.
01:01
So, let's see an example. For instance, let's plan a synthesis which actually has been done with a key step catalyzed by this catalyst.
01:35
So, this is the target molecule, a terpenoid ductulole, synthesized by Alois Furstner in 1996.
02:00
So, let's think about how would we synthesize this structure making use of the olefin metathesis.
02:21
Well, clearly we would like to form that olefin XCC bond by a metathesis reaction. So, and consequently our plan for the synthesis should be to synthesize this substrate suited for the elimination of one equivalent of ethylene.
03:25
This should lead then already to the final product. So, catalyst on the transformation.
03:41
Well, as we heard this catalyst has a limited functional group tolerance. It is sensitive against oxygen or moisture. So, it reacts with water and if the catalyst reacts with water it normally also reacts with alcohols.
04:04
So, we should be careful with an alcohol functionality in our substrate. Well, there might be some examples on certain reaction conditions where also an alcohol might be tolerated by this catalyst.
04:26
I'm not sure about that. But, well, to avoid the presence of an OH group, well, okay, therefore we have protecting groups. Just put on a TMS group.
04:43
And then we need after the first step simply tetra butyl aminofluoride for the deprotection. And, indeed, this synthesis was performed by the first group and this product was then isolated with an astonishing 92% yield.
05:16
Actually, the first NAG group also tried first generation Grubbs ruthenium catalysts in this case and it completely failed.
05:33
Since this one is more active than the first generation ruthenium catalysts in terms of producing olefins with three or even four substituents.
05:54
And this is obviously a three times substituted olefin. Well, the second generation Grubbs catalyst would also presumably get this transformation done.
06:12
Well, the ruthenium catalysts have a higher functional group tolerance. Nevertheless, there might be some cases still where this is preferred.
06:24
However, well, I've looked up how much does this catalyst cost nowadays. Well, for 100 milligrams, best price offer of today was 130 euro.
06:46
Well, let us assume we need typically 3% catalyst and this catalyst was indeed applied in this transformation with 3%.
07:04
And we want to do this reaction on a one millimole scale. For one millimole scale, we need 0.03 millimole of that.
07:32
Unfortunately, it has a molecular mass of 765 gram per mole.
07:43
And if I've calculated correctly, we would need for a one millimole scale reaction of that kind to invest approximately 30 euro of a catalyst.
08:03
Ah, it's relatively expensive. However, if you have worked for one or two years for synthesizing a rather complex system and you are in need for optimum results,
08:23
well, okay, then in this case, 30 euros don't matter at all, of course. So, some other examples which have been done with this catalyst.
09:00
Benzyloxy substituents. Here, an allylic ether, vinyl ether, all is tolerated.
09:19
And a 72% yield was isolated of the cyclization product.
09:32
Two other examples, an acetal cyclization forming a double bond between this carbon and that one under formation of two boutines.
10:32
85% yield of the benzofuran as the cyclization product.
11:00
A far more simple but nevertheless remarkable transformation forming a sulfur heterocycle. And as you know, a lot of catalysts are inhibited by thio regions as well known catalyst poisons.
11:47
But 94% yield of a cyclization product was obtained. So, the Schrock molybdenum catalyst works very nicely in a couple of examples, sometimes far better than other catalysts.
12:11
However, tedious to synthesize or expensive to buy and you have, that's for sure, to apply Schlenk techniques for your synthesis.
12:28
So, next subject, the ene-yne metaphysis.
12:42
This is not the same as the ene-yne cyclization we discussed in details, with details concerning the palladium catalyzed reactions. So, an alkyne plus an olefin, we need a catalyst.
13:14
Essentially the same euthenium carbene complexes as used as in the olefin, the phassases.
13:39
Mainly second generation Grubbs catalyst.
13:49
So, this is general scheme for the intermolecular case and for the intramolecular case.
14:11
So, we could have a number of methylene groups here or there.
14:43
So, these are the general schemes for intermolecular and intramolecular. Ene-yne metaphysis. Let's have a look at the mechanism.
15:03
As I said, we need as active catalyst an euthenium carbene complex.
15:24
Equilibrium steps, a reaction of a catalytic cycle starts with a reaction of the euthenium carbene complex with the alkyne.
15:44
Again, 2 plus 2 cycloaddition reaction, not a methyl cyclobutane, but a methyl cyclobutene is formed.
16:08
And cycloreversion affects the double bond part of this C-C bond and this carbon, euthenium bond.
16:53
Now, the olefin enters the catalytic cycle.
17:11
Again, the 2 plus 2 cycloaddition, then forming a methyl cyclobutane.
17:44
Preferentially getting to this intermediate with the euthenium at a less sterically crowded position as we would have if the regioselectivity
18:04
of the 2 plus 2 cycloaddition process would be the other way around with the R prime sitting at that position. So, this is preferred and in this case it is productive since the cycloreversion
18:23
restores our active catalyst and will produce a final product of the Ene-yne metaphysis.
18:43
Well, please keep in mind, one usually has a mixture of cis-trans isomers or if I remember it correctly, predominantly the trans isomer.
19:05
Some examples, the acetate of propagolic alcohol plus the allylic trimethylsilane, ruthenium
19:42
catalyst, then producing a 90% yield of the Ene-yne metaphysis product.
20:02
Intramolecularly, the next case, 85% yield.
20:33
Here the Hovader-Grubbs catalyst was applied.
20:55
Another example, starting from this amino acid within a couple of steps in context of natural product synthesis.
21:35
This intermediary substrate was synthesized, E is methyl astro-functionality with a ruthenium catalyst, 5%.
21:59
A 73% yield was obtained of this, let me see, this should be 1, 2, 3, 4, 5, 6, 7, yes it's correct.
22:39
So, this product in 73% yield.
22:45
So, ruthenium catalyst for the mechanistic discussion, please just abbreviate like that.
23:03
So, and as an exercise, please try to figure out the mechanism for this example. It should be possible if you compare it with what we have discussed before.
23:23
So, this type of reaction starts with the 2 plus 2 cycloaddition reaction with the alkyne. And, well, I must admit also my first guess was that the cycloaddition takes place with this regioselectivity,
24:10
simply based on more or less considerations of steric crowdedness.
24:23
However, these are all equilibrium reactions and the cycloreversion then would lead to this kind of structure.
24:59
Well, we could go on with studying what would be the result of that.
25:12
However, let's keep in mind we have this 73% yield. So, that means that 27% of some other stuff might have been formed.
25:26
And, well, maybe the regiochemistry is influenced by a pre-coordination with that olefin. And, on the other hand, there is certainly also some electronic influence with this as an electron pool and that as an electron ridge center.
25:55
So, the alternative is, of course, this regioisomeric-ruthena cycle opening to give this intermediary ruthenium carbene complex.
27:00
And now, the 2 plus 2 cycloaddition reaction looks rather familiar.
27:52
So, let me see. Oh, sorry.
29:11
So, 1, 2, 3. So, let's count the centers. At the end, we want to have formed a 7-membered ring. 1, 2, 3, 4, 5, 6, 7. Right.
29:25
1, 2, 3, 4, 5, 6, 7. And cycloreversion setting free the active catalyst and this should be formed then.
29:50
Of course, cis-fused since trans-olefin in a 7-membered ring. Oh, that doesn't work.
30:08
So, I admit the structure is certainly not nice, but one should be able to follow that drawing. One final example for a very interesting, because very useful in ein metathesis.
30:41
Second generation Rebs catalyst, 5%. Applying a double substituted, so not a terminal, but a double substituted alkaline.
31:03
And ethylene as the olefin component. About 10 atmospheres, atmospheres in toluene, 80 degrees, reaction time from 30 minutes to 1 day.
31:29
And also in this case, a diene is formed. This is the structure, dienes which are ready for the Diels-Alder process.
31:55
Very useful in synthesis of course.
32:09
Next subject. The alkyne metathesis. The earliest report claimed that this pentane with about 6% tungsten oxide on silica at 200 to 450 degrees
33:09
gives an equilibrium with butyne and hexyne, 56% of a starting material after a certain reaction time,
33:34
23% of a mixture of that, plus 21% of polymeric products.
33:48
That means this is not a clean equilibrium. If you let the reaction run too
34:02
long, you won't have any more of those products, but exclusively polymer material of course. Nevertheless, this seems to be the earliest report from 1968.
34:35
Then in 1974, again, not again, in this case a molybdenum catalyst was
34:53
applied, molybdenum carbon oil catalyst mixed with resorcinol in the ratio 1 to 6.
35:17
And 10 mole percent of this applied as the catalyst, 160 degrees reaction temperature.
35:33
And then an equilibrium was observed, the equilibrium of 55% of that and well, they found 23.5% of this one.
36:01
And the simple toluene, 21.5%. For quite a while, this was the best catalyst with the name Montreux, catalyst since this was
36:34
a publication by the group of Montreux, Montreux together with the co-worker Blanchard, again from 1974.
36:50
The first alkyne metathesis catalyst with a higher efficiency, higher activity was presented by Schrock in 1982.
37:17
Well, synthesis of that catalyst started from tungsten tetrachloride plus four equivalents
37:33
of this lithium dimethyl amide produces a product with a tungsten-truple bond.
38:14
The alcoholosis with tertiary butanol exchanges all those imide groups and with this tertiary butyl substituted alkyne.
38:44
Finally, the tungsten carbine is produced having three tertiary butyl oxy groups attached and as I said, this is the first rather active catalyst.
39:22
And an early example is this one. So, the equilibrium of this hexane with a butane and an octane.
39:58
The mechanism should be rather clear following essentially the mechanism we know
40:10
from the olefin metathesis except that in this case, the metallacyclobutadiene is involved.
40:39
And well, let's see what applications for this reaction were found.
41:08
I think it's rather interesting that this alkyne metathesis with active, very active catalysts was developed some years earlier than the alkene metathesis with well-defined catalysts.
41:32
And on the first glimpse, it should be far more difficult involving these unusual structures.
41:43
So, alkyne metathesis with this substrate produces this macrocyclic alkyne known with Trox-tungsten catalyst.
43:06
And in toluene, 80 degrees, 65% were obtained or alternatively also well-modified more true catalyst was tested not resorcinol but trifluorophenol as ligand.
43:49
Somewhat higher temperature chlorobenzene as a solvent than with 59% yield. What is it good for?
44:02
So, in the next step, a hydrogenation was performed with the Lindler palladium catalyst with quinoline added to diminish the reactivity in dichloromethane.
44:32
The reaction, the hydrogenation then stops at the stage of the olefin.
44:58
This olefin is obtained, a natural occurring terpenoid, it's a tone important for perfume industry as a flagrant.
45:24
So, one could ask why not using the olefin metathesis. Could be far more easy. Well, the problem is you get a mixture of the cis and the trans olefin and you don't need the trans olefin.
45:48
And if you have in that case the trans olefin, you can't simply isomerize to the cis olefin. That's certainly not easy. So, this is the way to selectively go for the cis macrocyclic, cis olefin.
46:21
Another example which illustrates how complicated structures can be which are targeted with the alkyne metathesis. So, I draw, I will draw the product of the alkyne metathesis which was part of a natural product synthesis.
47:19
So, I skip drawing starting material. You can imagine how it looks like.
48:11
But by that alkyne metathesis, this C-C bond formation from this carbon to that carbon was achieved.
48:43
And the catalyst was, well, 25% of Schrock's tungsten complex.
49:05
Solvent, chloromethane, 80 degrees, 3 hours and remarkable 77% yield of this product.
49:35
From Füstner's group in 2001, a catalyst or pre-catalyst based on molybdenum chemistry was presented.
50:06
This one, which seems to have a nice activity and this one has been applied in the context of the synthesis of epitilone.
51:10
So, maybe I should draw the structure which was targeted with that alkyne metathesis.
52:44
This macrocyclic alkyne was produced with an 80% yield making use of Füstner's catalyst from 2001. Second, why is this important? Well, the final structure, the epitilone A is important in the context of cancer treatment.
53:35
In the first reported synthesis, Dieter Schinze and Casey Nicolau, for instance,
53:52
all made use of the olefin metathesis forming an olefin at this position.
54:02
Unfortunately, you need the cis olefin which then is epoxidised. In this olefin metathesis, they always get a mixture of cis and the trans olefin.
54:26
And this alkyne metathesis again enables to selectively get to the cis olefin and then, of course, to the target epoxide.
54:59
Okay, enough for today. Thank you for listening. We will go on on the 17th of June. See you then.
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