Lecture Designing Organic Syntheses 24 - 21.01.15
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| Teil | 24 | |
| Anzahl der Teile | 29 | |
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| Identifikatoren | 10.5446/37078 (DOI) | |
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00:00
GastrinChemische ReaktionChromosomenkondensationGangart <Erzlagerstätte>GlykoalkaloideKetoneEisenGesundheitsstörungHope <Diamant>SyntheseölAntidotSenseFleischerArzneimittelSetzen <Verfahrenstechnik>Chemischer ProzessSäureThermoformenKonjugateChemische VerbindungenTeeFeuerIonenbindungAdvanced glycosylation end productsOberflächenchemieOrganische ChemieKondensationsreaktionKohlenstofffaserStoffwechselwegEssenz <Lebensmittel>BaseGiftgasDeprotonierungChemische StrukturAdditionsverbindungenAktivität <Konzentration>AmineAtropinHydroxyaldehydeMannich-ReaktionHydrocarboxylierungFormaldehydAldehydeAcetophenonBenzaldehydIminiumsalzeRacemisierungMenschenversuchBiosyntheseCarbonylverbindungenChemieanlageReaktivitätZutatTautomeriePhenylacetatRetrosyntheseVorlesung/Konferenz
08:55
MagnesiumGasphaseProteineChemische ReaktionFormaldehydSäureEisflächeKörpergewichtTieftemperaturtechnikMagnesiumchloridPotenz <Homöopathie>KohlenstofffaserPolymereProlinFunktionelle GruppeDeprotonierungMolekülKörpertemperaturMineralKetoneHydrocarboxylierungSingle electron transferVerrottungFließgrenzeAldolreaktionParaformaldehydBaseEnoleSchönenAlphaspektroskopieAmine <primär->Vorlesung/Konferenz
13:32
OberflächenchemieKarsthöhleChemische ReaktionFunktionelle GruppeGangart <Erzlagerstätte>WursthülleIonenbindungKohlenstofffaserAktivierung <Chemie>Chemische StrukturExtraktSäureAmine <primär->EisenGesundheitsstörungMolekülKohlendioxidFärbenNaturstoffChemischer ProzessFließgrenzeSystemische Therapie <Pharmakologie>UmlagerungTeeGletscherzungeAcetonHydrocarboxylierungAlphaspektroskopieRetrosyntheseBiosyntheseMannich-ReaktionSetzen <Verfahrenstechnik>MethylaminRacemisierungCyclohexenMenschenversuchAldehydeDicarbonsäurenGlykoalkaloideWerkstoffkundeKetoneCarboxylateVorlesung/Konferenz
21:36
Chemische StrukturFunktionelle GruppeChemische ForschungKohlenstofffaserTransformation <Genetik>Bindungstheorie <Chemie>GletscherzungeInitiator <Chemie>Chemische ReaktionAzokupplungMolekülSpaltflächeFließgrenzeChlorideBraunes FettgewebeStickstoffatomSyntheseölWursthülleFormylgruppeOxycodonIonenbindungGesundheitsstörungKlinisches ExperimentSchutzgruppeReduktionsmittelSeitenketteSetzen <Verfahrenstechnik>HydroformylierungNitrideChemischer ProzessSubstitutionsreaktionTranslation <Genetik>SubstituentAcrylnitrilMethylgruppeAlkylierungAlphaspektroskopieCarbonylverbindungenOxalylchloridHydrocarboxylierungAcetonBaseMakrocyclische VerbindungenMannich-ReaktionVorlesung/Konferenz
29:40
MethanolBukett <Wein>Funktionelle GruppeCyanidionReduktionsmittelAlkoholische LösungLithiumGangart <Erzlagerstätte>HydrocarboxylierungKetoneFließgrenzeAcetateAcetonAmine <primär->AdditionsverbindungenEsterSchussverletzungOxobuttersäurenMethylgruppeAluminiumhydridMichael-AdditionChemische ReaktionFalle <Kohlenwasserstofflagerstätte>EtomidatCarbonylverbindungenAzokupplungMethanolFülle <Speise>ZinkCarboxylateSilaneBenzoylchloridSeitenketteBrandsilberSäureAktives ZentrumAktivierung <Chemie>HydrideKohlenstofffaserMähdrescherChemische StrukturTitanchlorideKettenlänge <Makromolekül>Setzen <Verfahrenstechnik>OrlistatOzonChemische ForschungThermoformenOxalateLeckageVorlesung/Konferenz
37:44
AluminiumhydridFunktionelle GruppeLithiumSäureKohlenstofffaserAluminiumAmineHydrocarboxylierungCarboxylateEtomidatCarbonylverbindungenWasserstoffBenzylgruppeAcetateSubstituentChemische ReaktionReduktionsmittelFließgrenzeIminiumsalzeChlorwasserstoffGangart <Erzlagerstätte>PalladiumNucleophile SubstitutionSetzen <Verfahrenstechnik>StereoselektivitätMutationszüchtungFleischerAlkoholische LösungSpaltflächeGesundheitsstörungMenschenversuchKettenlänge <Makromolekül>AlterungSubstrat <Boden>Aktives ZentrumVorlesung/Konferenz
41:08
AcetateGesundheitsstörungChemische VerbindungenGangart <Erzlagerstätte>SäureSubstituentChemische ReaktionAcrylnitrilKohlenstofffaserHydrolysatFunktionelle GruppeBaseBenzylgruppeEthanolChemische StrukturNitrideKlinisches ExperimentKettenlänge <Makromolekül>Aktives ZentrumWasserfallHydroxyethylcellulosenVorlesung/Konferenz
44:06
Funktionelle GruppeAlkohole <tertiär->Setzen <Verfahrenstechnik>EtomidatElektronische ZigaretteSäureMethanolGesundheitsstörungChlorwasserstoffAmine <primär->Chemische ReaktionAlkoholische LösungBiosyntheseCarbonylverbindungenEthanolPalladiumCyclohexanMischenAktivität <Konzentration>BenzylgruppeHydrocarboxylierungAnhydrideDesacetylierungChemischer ProzessEliminierungsreaktionCobaltoxideReduktionsmittelSeitenketteNucleophile AdditionKonjugateAluminiumChemische StrukturChlorideHomöostaseLithiumFließgrenzeKohlenstofffaserWasserstoffAktives ZentrumGangart <Erzlagerstätte>PentapeptideHydridePhysikalische ChemieMolekulardynamikVorlesung/Konferenz
50:25
GraukäseChemische ReaktionPosttranslationale ÄnderungOxidschichtKaliumTEMPO <Organische Chemie>AlkeneHydroxylgruppeInitiator <Chemie>Amine <primär->AldehydeIonenbindungGangart <Erzlagerstätte>Alkohole <tertiär->MolekülChromosomenkondensationGesättigte KohlenwasserstoffeStereochemieWursthülleHydrocarboxylierungChemische StrukturBenzophenonHydroxyaldehydeAlphaspektroskopieFunktionelle GruppeMähdrescherGesundheitsstörungAlkoholateBaseWasserstoffKohlePalladiumPhasengleichgewichtChemische ForschungPegel <Hydrologie>Vorlesung/Konferenz
55:55
CycloalkaneEthanolPhasengleichgewichtFließgrenzeOberflächenbehandlungMeeresströmungFremdstoffBiosyntheseFunktionelle GruppeMolekülChemische StrukturAuxiliarStereoselektivitätVorlesung/Konferenz
58:07
Chemische StrukturTerminations-CodonMagnesiumGangart <Erzlagerstätte>OktanzahlStickstoffatomFunktionelle GruppeTransformation <Genetik>NatriumChemische ForschungWasserfallLithiumchloridGesundheitsstörungAdditionsverbindungenIonenbindungBromideAzokupplungFlussProteineAktivierung <Chemie>FließgrenzeElektronische ZigaretteKonjugateSäureMethanisierungAlterungSetzen <Verfahrenstechnik>Chemische VerbindungenPharmazieAlkoholische LösungTrichterFleischerAktivität <Konzentration>ReduktionsmittelFülle <Speise>UmlagerungBaseBiosyntheseMethanolPhenylgruppeOrganspendeAlphaspektroskopieDeprotonierungAlchemistinAcylgruppeAlkansulfonateImineStereoselektivitätEsterSulfinsäurenOrganische ChemieSulfurSulfoneKupfererzCuprateSulfateVancomycinEtomidatLithiumVorlesung/Konferenz
01:06:09
Chemische StrukturRutheniumFunktionelle GruppeCarbenePropenTransformation <Genetik>AlkeneFließgrenzeStickstoffatomElektronenakzeptorTriphenylphosphinWasserSulfoneChemische ForschungBaseEnoleAdditionsverbindungenSilylierungEthanKreuzmetatheseBiosyntheseKohlenstofffaserMähdrescherChemische ReaktionKonjugateHydrocarboxylierungMutationszüchtungGesundheitsstörungZinkSäureAmine <primär->IsobutylgruppeProteineGangart <Erzlagerstätte>Translation <Genetik>f-ElementAlterungMichael-AdditionReglersubstanzPropionaldehydBukett <Wein>AllmendeBleierzOxideVorlesung/Konferenz
01:15:47
Potenz <Homöopathie>Chemische ReaktionPosttranslationale ÄnderungGangart <Erzlagerstätte>Setzen <Verfahrenstechnik>ProstaglandinsynthaseBaustahlWasserstoffAdvanced glycosylation end productsChromosomenkondensationPropranololBiosyntheseOxidschichtSeitenketteChemischer ProzessFunktionelle GruppeAlkylierungPropylgruppeEnantiomereMannich-ReaktionVorlesung/Konferenz
01:18:50
Computeranimation
Transkript: Englisch(automatisch erzeugt)
00:06
Welcome to part 24 of the lecture on designing organic synthesis. The subjects of today are classical Mannich reactions for alkaloid synthesis.
00:32
Well, you certainly know the Mannich reaction. However, it makes sense that we again have a look at what happens there
00:43
since it is normally a three-component reaction. You have an amino, an amine as one reaction component, maybe a secondary amine,
01:00
and in addition you have two carbonyl compounds that participate. One is the more reactive one in terms of condensation with an amine.
01:21
For instance, an aldehyde, maybe benzaldehyde for instance, and a ketone, for instance acetophenone.
01:41
So, and a Mannich reaction now normally under acid catalysis. What will happen? Since the aldehyde has the higher carbonyl activity, the condensation reaction of the amine will preferentially take place at the aldehyde.
02:08
So, under acid catalysis plus a proton minus H2O, we will get to the formation of an iminium cation.
02:35
On the other hand, under acid catalysis ketoenol tautomerization will take place.
02:54
And now we have the nucleophilic center here.
03:01
So, donate a reactivity, accept a reactivity for the electrophile here. Well, and C-C bond formation will take place and the overall outcome, outcome therefore is then this product.
03:36
So, a one pot reaction, three component one pot reaction, which is called a Mannich reaction.
03:49
Well, you can get to this product by an alternative pathway.
04:01
For instance, make an aldol condensation with a base catalyzed on a basic or acidic conditions.
04:22
Then the aldol condensation product is of course this alpha-beta unsaturated ketone. Whereupon the conjugate addition reaction to the alpha-beta unsaturated ketone will lead to the same final product.
04:55
This is then a two-step process and here, as I said, a one pot reaction.
05:03
Very elegant, a Mannich reaction. So, let's have a look at a very prominent example for a Mannich reaction. And this example has something to do with the synthesis of atropine.
05:30
Here's the structure of this famous alkaloid.
05:55
So, racemic atropine. Racemic atropine is biologically very active.
06:08
It is an ingredients compound that was originally found in that nightshade plant Atropa belladonna.
06:26
And it's used as a medicinal drug for various purposes. It is one of the essential medicines of the WHO list.
06:44
And it is applied, for instance, as a heart medicine and also as an antidote against some of the chemical weapons. Hopefully we will never have to use that for that purpose.
07:02
Well, okay. So, making a retrosynthetic analysis of that atropine.
07:21
The first step is fairly easy. I think every one of you would get the idea to cleave this strategic bond. Then we get to this acid, which is indeed called tropic acid.
07:58
And to the alcohol, which is called tropine.
08:31
So, first of all, how could we synthesize tropic acid?
08:41
Nice idea would be to cleave here. So, phenyl acetic acid should be combined simply with formaldehyde.
09:10
And indeed choosing the right base. Of course, at least two equivalents.
09:22
Because first deprotonation of the highly acidic acid proton. Then the second deprotonation, alpha to the carbonyl group. Then this is the nucleophilic center.
09:41
And this is some kind of aldol addition. So, and the base which has been applied that worked just fine was isopropyl magnesium chloride.
10:08
So, you might ask, how does that work? So, if you give isopropyl magnesium chloride to that aldehyde, you of course get the 1,2 addition product.
10:29
So, the way to perform the reaction was they applied three equivalents of the isopropyl magnesium chloride.
10:42
That was enough for deprotonating twice. But keep that at low temperature. Then you take paraformaldehyde and at temperatures above 200 degrees,
11:03
then the polymer decomposes and sets free this formaldehyde to the gas phase. And this gas formaldehyde, you lead into the reaction flask.
11:24
So, first formaldehyde will of course react with the excess of the isopropyl magnesium chloride. But after a while, all is consumed and then the cheap formaldehyde will react as an electrophile with the deprotonated acid enolate.
11:52
So, this reaction works quite well. 70% yield was published for a new procedure in recent years where they have optimized that.
12:21
So, now we know how to get to the tropic acid. What about the tropine? So, we are talking about the Mannes reaction.
12:42
So, and what we are setting up is an amino group in better position of a carbonyl group. So, here we have the alcohol, but for setting up a Mannes reaction, you need to carbonyl there. So, just let us transform that to the ketone.
13:11
This is then called tropinone.
13:26
And this tropinone was indeed a prominent target molecule at around 1900. And, well, Robinson, the one with the Robinson annihilation and so on, synthesized
13:53
this molecule in his group in the year 1917 with applying the Mannes reaction.
14:06
Well, as in this case some kind of revolutionary example, making a big impression what is possible in natural product synthesis.
14:21
Because he could synthesize that from rather simple starting materials essentially as a one pot reaction with very high yield. So, if we disconnect for the Mannes reaction, we can disconnect here and there.
14:52
Within the Mannes reaction, the C-C bond starting between the alpha and the beta position from the carbonyl is formed and the C-N bonds here.
15:08
So, sutinic aldehyde, methylamine and acetone should in principle be sufficient when treated with acidic conditions.
15:42
Well, to my knowledge, this works was one of the initial examples. However, they improved the synthesis. They kept to the idea, stayed with the idea using this aldehyde of course also the methylamine.
16:06
But this acetone dicarboxylic acid proved to be superior than applied.
16:22
And in this case, as a one step process, you get to this bicyclic ring system with these two acid functionalities still present.
16:50
94% yield, but if you heat that up, then of course two equivalents of
17:08
carbon dioxide will be formed since we have twice the situation of better keto carboxylic acids.
17:24
Well, okay, the last step should work almost quantitatively.
17:40
So, really an impressive achievement by Robinson from the year 1917. Well, let's now have a look at the synthesis of another alkaloid.
18:08
Less important, but somehow an interesting structure, leukopodine.
18:27
So, yes, this is leukopodine.
19:05
Well, I think the first racemic or one of the first racemic synthesis from Clayton Halfcock in 1984.
19:21
As I said, racemic synthesis. Clayton Halfcock is well renowned also for looking for applications for Mannich reactions and Mannich type reactions. Well, okay, this was one of his chosen target molecules.
19:44
And as an exercise, please find out which are the bonds, where are those bonds to be formed by a Mannich reaction.
20:03
And if you find those, you will certainly notice that then the next structure in retrosynthetic analysis will be far more simple. Okay, please have a try.
20:21
So, the subject we were talking about was finding the bonds which could be set up by a Mannich reaction. So, we should go back to the retron concept you all know.
20:44
We discussed cyclohexene, the cyclohexene moiety as the retron of the Diels-Alder reaction, yet also the retron of an oxycope rearrangement. And now we are looking for the retron of a Mannich reaction.
21:02
And this is simply a better amino carbonyl structure. So, that means this moiety having an amino group, a three carbon chain, and the last one with a carbonyl group.
21:24
This is the retron of a Mannich reaction. Let us have a look here. Do we find that? Here is the nitrogen, there is the carbonyl group, and these are the three carbons.
21:43
So, for the Mannich reaction, then this bond and that bond have been formed retro Mannich, which means we have to cleave this one and that one, and that carbon here, there should be originally a carbonyl group there.
22:09
So, but if we do so, cleave this bond, cleave that bond, then we have a macrocyclic structure. This is far more complicated than our initial structure.
22:26
Therefore, we should look for a possibility to simplify that, that we don't have that macrocycle after our initial retro synthetic consideration.
22:44
So, first we want to simplify that. Well, maybe we can easily get rid of one of those cycles.
23:03
And indeed, that should be possible. So, let us cleave this one, having a leaving group here, and let us cleave, in addition, this C-C bond, having a leaving group, well, maybe an Y, X and Y two leaving groups.
23:26
So, alkylation alpha to that carbonyl group and alkylation of an amine here, well, maybe this is the way to do it. So, and now, again, here we have a redrawn of a Mannich reaction. Let us cleave these two positions.
23:53
So, and this is that central position of the carbonyl group there.
24:30
Okay, so this looks relatively complicated.
24:41
But what we should figure out is that we have, essentially, a cyclohexahexanone moiety with one side chain, another side chain and a methyl substituent.
25:00
That's it. So, let us translate that, carbonyl here, nitrogen there. So, here we have the methyl group, then it's in front of a blackboard.
25:33
And here, at this position, we should have that acetone moiety attached.
25:56
This is, indeed, the simplification.
26:01
So, we should keep in mind that we should work with some protective group chemistry in that case. So, what about this having a nitrogen functionality here?
26:27
This should be an electrophilic center. This, a nucleophilic center, shouldn't be a problem in principle. One could think about forming this bond by a Michael type addition process at acrylonitrile.
27:10
Could be an idea, and indeed, that was what the Hevcock group did. So, this now is some kind of principle outline.
27:24
So, let's have a look how the Hevcock group, in reality, synthesized that leukopodine as target molecule. So, they started with this rather simple cyclohexadiene.
27:58
And, indeed, with acrylonitrile, basic conditions, no problem.
28:20
So, next step, transforming one of those equicarbonyl groups in a functionality, which we can get, well, not get rid of, but we need here a situation where we could attack with another nucleophile.
28:55
So, well, anyway, what they did was, first of all, treat this one with oxalyl chloride.
29:08
Turned out as the best way to get the transformation done to this chlorosubstituted alpha-beta-unsaturated carbonyl group.
29:26
All other ways, for instance, using phosphooxychloride were far less efficient. This reaction worked with a 72% yield.
29:40
And then, a reduction was achieved with zinc and methanol with 0.1% silver acetate as a catalyst,
30:32
getting in a very good yield to this alpha-beta-unsaturated ketone. So, now, next step is to find a solution how to get an acetone moiety attached there.
30:52
You can't simply make a Michael addition reaction with acetone.
31:04
Maybe one could use acetoacetic acid, ester, and then hydrolyze the ester functionality, decarboxylate, should be possible. However, we made some tests and decided first step, Sakurai reaction.
31:34
You might know the Sakurai reaction. That is a titanium-induced Michael type addition reaction of an allylic silane.
32:11
So, Sakurai reaction.
32:25
So, and the stereochemical outcome should be this one, and this should be trans to the other one.
33:02
Here you can, of course, equilibrate. So, next step, then, simply an ozonolysis.
33:33
So, okay, overall yield of this combination, Sakurai reaction plus ozonolysis, was an astonishing 90%.
33:56
Okay, this explains why we choose this procedure instead of that Michael type stuff we were already talking about.
34:18
So, let's have a look at a couple of steps more.
34:31
Acetalization, secondly, reduction of lithium aluminum hydride.
34:47
Okay, acetalization to protect those carbonyl groups. Lithium aluminum hydride reduction of the cyano group will give the primary amine, of course.
35:20
Well, to get more close to this structure, we should turn that around.
35:39
And this means, well, that carbonyl group is there, here protected as an acetal.
35:50
And here we have one, two, three carbons, one, two, three carbons, and the amino group after the reduction.
36:07
Here is that methyl group, then the acetone side chain is in, well, better position to this side chain.
36:26
Okay, this one, right. Ah, sorry, we have protected that. Okay.
36:46
So, Hevcock group decided to make a shot as a proof of principle.
37:07
Let's call that intermediate A. They treated intermediate A first with benzoyl chloride.
37:25
And you need an additional base, triethyl amine, to trap the HCl, which will evolve. Forming a carboxylic acid amide to the amino group.
37:47
And then, again, reducing with lithium aluminum hydride. If you reduce a carboxylic acid amide with lithium aluminum hydride, you remove
38:01
the carbonyl group, you reduce the carbonyl group and have simply an amine. Okay, that means, as a result, still having the acetals as protecting groups.
38:31
So, one, two, three. And here you have a benzyl group.
38:41
So, why a benzyl group? You can easily get rid of a benzyl group later on, simply with hydrogenation with palladium oncocoa, as you know. Again, this two-step procedure, with a marvellous yield, 94%.
39:07
And now the proof of principle, 1.5 normal HCl in methanol, 25 degrees 48 hours.
39:29
So, what happens? With acidic reaction conditions, both acetals will be cleaved.
39:43
Iminium cation formation here, as the first step of the Mannich reaction, so iminium cation here. And then, that's this iminium cation as an electrophile, the attack at the enol, you will have here as an intermediate.
40:04
So, and this was obtained in a single proper to step from here to there with 66% yield as proof of principle.
40:42
So, Havecock decided then, instead of cleaving here, or we would need to predict here for the reduction maybe, and then cleaving that and having then nucleophilic substitution here and there to get that sidechain
41:07
and maybe in addition some problems with the stereoselectivity at this position could all happen here. So, they decided to modify it a bit instead of having that benzyl group already a three carbon sidechain there.
41:32
So, and this first step may look a bit strange.
41:48
Okay, let's draw a compound with which they started then.
42:09
We started with the compound they had before structure A that means the nitrile.
42:22
Instead of hydrolyzing this nitrile, sorry, instead of reducing that nitrile they hydrolyzed it with KOH and ethanol.
42:47
As you know, acetals are perfectly stable under basic reaction conditions, they react under acidic reaction conditions. So, hydrolyzation worked nicely in 87% yield.
43:31
Well, you might ask, why did they choose that nitrile, why not having an astral here?
43:46
Instead of using acrylonitrile in that initial step, getting that, getting to the sidechain, they could have used acrylic acid astral. Well, yes, they could. I just assume that they had that in large amounts and just decided, come on, let's hydrolyze this one.
44:13
87%. So, next step, amide formation with this amine, the alcohol protected with a benzyl group.
44:42
Okay, so, for forming an amide you of course have to activate somehow this acid functionality. Well, you could do that with, well, this cyclohexyl carbidimide for instance.
45:08
This standard method we know from Merrifield synthesis of peptides, but another classical method is
45:22
forming an anhydride, forming an anhydride, a mixed anhydride, this acid and this acid chloride.
45:55
Then you have, well, let's draw that here. So, this carbonyl group is by conjugation more stabilized than that.
46:25
Here you have the higher carbonyl activity, therefore the amino group will attack nucleophilic addition elimination process here. So, this is that classical anhydride activation for the amide formation.
46:45
So, and this also works very well. First, amide formation. Secondly, again, as we already have discussed, that lithium aluminum reduction.
47:26
So, and we need three carbons. Then the oxygen and the benzyl group having still an acetyl there.
47:44
And to my knowledge, we had a mixture of diastereoisomers, so this wasn't defined. However, that Mannich type reaction is an equilibrium reaction and here, at this position, you can epimerize under the acidic reaction conditions.
48:15
It turned out that finally you get into the thermodynamic sink.
48:23
So, well, next step, well, again, sorry, again, 87% yield, the same as before, this is not a mistake, 87%.
48:44
Then the next step, well, the same reaction conditions as outlined here, once again, HCl in methanol and so on. And of course, this looks rather similar as the one before with the benzyl group here.
49:16
Essentially the same structure. You are already getting used to draw that.
49:29
So, but now we have this side chain and again a yield within the 60s in percent.
49:58
Okay, so let's have a look how they completed the synthesis.
50:07
So next step, hydrogen, palladium on car coal, but in acidic, ethanolic solution with some HCl in there.
50:24
Well, okay, obviously you don't need to protect that carbonyl group. It works rather nicely having already the alcohol functionality here, the carbonyl functionality here, getting to this structure.
50:54
So how can we go on and get the right stereochemistry here? Well, 96% was isolated of this one.
51:07
And the next step was an oxidation, a highly selective oxidation of this hydroxyl group forming an aldehyde here.
51:47
Some oxidizing agents would cause problems. For instance, the tertiary amine here is also easily oxidized.
52:03
I'm not sure would a tempo oxidation work in that case. Well, in 1984, tempo oxidation wasn't known at all. So they used benzophenone, potassium t-butoxide combination.
52:38
Benzophenone is reduced to the corresponding alcohol where this alcohol is oxidized to the aldehyde.
52:53
This is a special modification of a so-called Oppenauer oxidation and this one is then called the Woodward modification of the Oppenauer oxidation.
53:09
Okay, so I will write that down. Woodward modification of Oppenauer oxidation, very moderate reaction conditions, compatible of course with tertiary amine.
53:47
This wasn't isolated under these strongly basic reaction conditions. You of course can isolate that aldehyde.
54:02
The intramolecular aldol condensation will readily take place.
54:24
72%. So, now what is important?
54:43
And that's the reason why we set that up. How do we get to our final target molecule which indeed has this hydroxyl group while arguably being on the exo phase?
55:21
If this bond would have been formed by the initial idea of nucleophilic substitution, alpha to the carbonyl group, presumably that alkyl group would be exo. But in this case from here to there it's just a hydrogenation again with palladium
55:48
on car coal and then the hydrogen will approach that olefin from the exo phase.
56:00
At least the sterical less hindered phase opposite to this bridge here. So this works just fine in ethanol with an 87% yield.
56:22
Well nevertheless we shouldn't finish today's lesson without another interesting synthesis of the same target molecule. But now a modern synthesis from Rick Carter's group.
56:58
Carter in 2008 with the first Anansio selective synthesis of leucopodine.
57:15
So, he had to decide how to introduce the chiral information and he decided to do that with a chiral auxiliary.
57:47
It's this one. I think you have seen that before.
58:05
This one. So, what is the structure of the chiral pool with which you start? That is comfor, this one.
58:34
And there is some strange miracle type transformation reminding us of those alchemists.
58:52
You indeed can introduce a sulfonic acid group here at this position involving some rearrangements.
59:05
This is not simple CH activation here at that muffled group. It's rather complicated that stuff. But there is an organic synthesis procedure for that transformation getting the sulfonic acid functionality here.
59:28
It's then called comfor sulfonic acid, a chiral sulfonic acid. So, if you form then the sulfonic acid amide, imine formation and then reduction, you end up with this one.
59:46
And this is called, it's the comfor sulfate.
01:00:00
used by, I think it was also Swiss chemist Opolso. And this is similarly used as Evans enolate chemistry in the same context. So what can be done now is getting this acyl group
01:00:44
attached and a cuprate addition, well, allium magnesium bromide with copper bromide
01:01:03
and lithium chloride. And secondly, an alkalosis of this amide bond
01:01:23
with methanol and magnesium methanolate. So what happens, cuprate conjugate addition reaction
01:01:41
in that chiral environment, transforming that to the ester then gave 85% yield of this compound
01:02:10
with that chiral center. Enunciate selectivity all at 98% or so.
01:02:23
A lot of chemistry to get this all medium sized compound. But the enunciate selectivity is the crucial point.
01:02:42
So we were in need of a second component.
01:03:10
This 1,4-dibromobutane was first treated
01:03:22
with this compound. So if you have here an acid functionality, an OH group, then it is the phenyl sulfinic acid.
01:03:42
It's an acid. It's acidic. So you can exchange the sodium here. Then you have the sodium phenyl sulfinite.
01:04:00
So this is sodium phenyl sulfinite. And what's interesting of such a sulfinite, this is a nice nucleophile but reacting with the sulfur
01:04:28
as the nucleophilic center. What you get is van sulfones. So initially we have a bromide here.
01:04:55
But the second step with sodium azide,
01:05:06
we introduced this acido functionality here. We need that later on for that nitrogen, of course. So well, through those two steps, 47% of that was obtained.
01:05:36
Next step, call that within this synthesis
01:05:41
A, this B, A plus B under basic conditions, simple base. You have then here the acidic proton deprotonating here,
01:06:02
more acidic than alpha 2, that ester functionality. Then this is the nucleophilic center. So this is the donator center. This is the acceptor center. And therefore, the combination will lead to this result.
01:06:41
So again, let's count the carbons. If we don't make a mistake, here is already something wrong, I guess. Yeah. So what do we have here?
01:07:02
One, two, three, four centers. So let's stay with one, two, three, four carbons here. Later on we will see is this correct or not.
01:07:20
So, but I think so. OK. So yield of this simple step, 74%.
01:07:41
Next step, a very modern one, not known at the first synthesis at the times of half cock in the late 80s, but hopefully known to everyone of you,
01:08:04
the olefin metathesis. So, and interestingly, there is not only the cyclizing olefin metathesis, which is very well known.
01:08:23
Meanwhile, they've developed reaction conditions where you can achieve an intermolecular cross metathesis. So they used this as the second olefin component
01:08:51
to achieve the transformation propene will involve.
01:09:30
And they used the so-called second generation Grubbs-Hoveyda
01:09:42
catalyst. So what is the structure?
01:10:02
This carbene ligand, mesotube groups here. Well, as you know, ruthenium catalyst
01:10:21
is the preferred one for olefin metathesis. OK. This is the catalyst, and you need 5% of that.
01:10:44
Well, unfortunately, that is a lot for such an expensive and complicated structure. So nevertheless, the yield, OK, moderate, 63%.
01:11:04
Moderate yield, but a modern method. So next step, treating it with a base.
01:11:34
So what will happen with a base? Well, this is, well, basic chemistry deprotonating here
01:11:45
because this is double activated, the sulfon group and the carbonyl group. And well, conjugate addition reaction, Michael addition. It's an intramolecular Michael addition reaction here.
01:12:01
All influenced, of course, by this center for the stereocontrol of the reaction.
01:12:21
Now you will see we are already getting close to the target, or more close to the target. So those 1, 2, 3, 4 carbons are correct.
01:12:44
Here are those still, 1, 2, 3, 4. 89%, next step.
01:13:08
Well, preparing for the Mannich-type reaction, but not as a one-step process, but two steps.
01:13:25
So this we introduced on an enol silyl ether,
01:13:57
tertiary butyl dimethyl silyl enol ether here.
01:14:11
On the other hand, our silylation, the phosphine,
01:14:33
you can cleave that one. Phosphine, triphenylphosphine in THF, bit of water in there.
01:14:46
And you get triphenylphosphine oxide, and nitrogen evolves. And you have the amino group. There, and it will condensate already.
01:15:07
Yes, this intermediate has been isolated with an 82% yield. So now you have here that immune functionality.
01:15:24
There you have the nucleophilic center. You have to increase the electrophilicity of this amine simply by applying a Lewis acid.
01:15:43
Lewis acid was zinc triflate. So then we are again at this stage, 54%.
01:16:22
Well, and four last steps. What did they do? They applied this iodo-propanol, an alkylation,
01:16:51
having that propyl side chain with the alkyl functionality. And the final steps then were the same
01:17:02
as we have already seen in Clayton-Havcox. Synthesis with that Woodward modification of the Oppenauer oxidation.
01:17:21
Had to be careful that I don't say opulser, opulser. So it's the Oppenauer oxidation. And again, condensation and hydrogenation. So same as already seen before. And these last step took another 57%.
01:17:45
Well, I think because that Mannich-type process was not a one-pot reaction as we have seen it with Havcox,
01:18:02
this is less impressive. Nevertheless, it's the first enantioselective. Synthesis of leukopodine. So subject for tomorrow also will be Mannich-type reactions. Mannich reactions with some additional very powerful
01:18:24
transformations. We will call that magic Mannich wall with reference to a lecture given from Clayton-Havcox 30 years before. And you will see that magic Mannich is indeed justified
01:18:43
for the synthesis we will see tomorrow. Thanks for listening. See you tomorrow.