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11.04.18 M. Sierra: Dead Ends and Detours in Total Synthesis

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Title 11.04.18 M. Sierra: Dead Ends and Detours in Total Synthesis
Title of Series Lecture Competing Reactions
Part Number 2
Number of Parts 9
Author Dyker, Gerald
License CC Attribution 3.0 Germany:
You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal purpose as long as the work is attributed to the author in the manner specified by the author or licensor.
DOI 10.5446/38585
Publisher Ruhr-Universität Bochum (RUB), Fakultät für Chemie und Biochemie
Release Date 2018
Language English

Content Metadata

Subject Area Chemistry
Abstract Detours in Total Synthesis
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so welcome to all who election competing reactions today the already at part 2 about when the total synthesis of complex target molecule is published usually the thing about the published paper everything looks nice and straight forward we love the truth there's usually the initial plan for synthesizing such a complex target molecule it doesn't work thought difficulties the thought maybe some dead ends and some due 2 is on to Professor Sarah from Madrid University may denies review published it in under of von chemistry in year from falls into collecting a few examples the goal was so normally those failures are not published at all OK but there are some prominent really prominent and nice examples so the fan these sciences all of brother talks in the the toxin from the red tide this is not Brevet proxy brother took seen B is arrival of large molecules maybe I should drawl a little bit off the not in every detail but that you have an express their in depression for complex these molecules of its service should be here that's really and now we have 3 six-membered rings here 1 oxygen 1 oxygens Aalam oxygen additional substitutions lots of fur coral centers here there's the CH 3 group there the ch the group the Nile here another 6 membered ring and the number 1 1 think of several membered ring at this position and this this wearing age and if you want more 6 membered ring on a very can't bring cake so within this college vistas our model compound all testing the ring closure it to in various d and the they had the the dear that they could start from the macrocycle in this case that's the 12th member to macrocycle Hamming 1st step walls to increase its reactivity these carbons rig TV to you for being produced and they did that by the fi all nations so the SI Alation reagent normal violation Mugen of Troy's there's usually the so-called Lawson's reagent so if you ever has worked before all science reagent you will never forget that it's quite smelly kiss structure and this readjust exchanges double bound oxygens begins double bond some transforms the key to functionality into the FIDO key toward with the following at reflux temperature and while here is the result it's this 1 Sarah to fight Assche's in close proximity the next step walls treating those of sodium Nafta 1st and 2nd the methyl iodide then T. H. F from minus 78 degrees to roam temperature all that year to inverse case 1st of all 78 per cent of good you and here it is reported to be 80 per cent so question to you does everyone everyone know what is the structure of sodium nationally it is not lists OK now Bernhard it is the radical and I thus the so doing counted CAD line so simply having enough to lean in solution then th f and adding sodium maybe you can also treated the sonication I think the green
solution is formed the fact radical and I am and this red in the trends foods electron it's a single electron transfer prejudice reagent It's similar reacts to something like solvated electrons are K you have reducing agent and solution and not the in all the two-phase system with a solid phase reducing agent for sodium the OK this makes a difference and well if you transfer an added trying to some final bastion you who formed radical online having the radical and I'm here radicals confined their it to form the bond and you have to do fire late which then 1 sub sequently all math for weighted by of wired or so as a result you will have failed muffin groups in Institute of positions chaos as power he said 80 percent unit learning in the final step the radical change process this tree but to attain hydride a very common reducing agent H. and for transfering Grandage co hydrogen here and on the radical chain reaction is started to move further AIB and Toto 110 degrees and this reaction those reported to work excellent from 99 % unit so the a double bond here so this is a model compound for this type of reaction this sequence handed to he then hopped over this should be done the model for indeed this as the model for ring he in inner brought exceeding 80 and when we have the goods transfused here what OK it was not reported how to get to this transfused sister use should be easy simply by a hydrogen nation of palladium Cocke or or something like that what OK that well at least I I didn't find it in the case unique allows book classics in Total Synthesis in their 1st pursue he also all be brought back soon physicians since perfect exceeding be uses the synthesis from from case Inc allows that from the scripts institute but still the model reaction and later on they improved those since they found out that if you take this Compaq and simply the radiating it is that such the di fight die value no not fight I fired cycle EU routine formant up to that exempted wars to 1st example of a stable 1 could be isolated crystal the more than 60 per cent unit after irradiating just half an hour and if you'd be radiated debt for the while more than that so here gray-haired 65 per cent of violent and even more be radiating they achieved up to 90 percent of bad and forming soulful than only S 2 but of calls that react from rock great fault they've arrive up trout having invented this food for getting such of the 2 7 Member at Oxon had dropped cycles and related and then the vendor for the convergence synthesis of brother proxy in 80 and had planned Twitter get this plot and that part to give by the double formation and then psych lies maximum converges it takes a long time to synthesize that of very large group I would estimated if you call everything together how many hours and rooking years should be a couple of years to get to that stage and test that reaction while we've facing the problem having all those rings they're attached on to that and it works but applying Lawson's reagent even under forcing conditions large excess of Lawson's reagent around higher temperature only 1 of those 2 carbon was violated this 1 then there nothing happened Amphitrite lot so I might have something
to do there that bit molecule bird while this methyl group here this additional Knafel methyl group that is missing here in the model compound pursuing you makes a big difference because so therefore they thought OK recalled this 1 the 1st generation strategies they developed this 2nd generation strategy again making use of that dive psych edition I take this black board this time having it blocked this then the macrocycle having the methyl group present also the other muffler group theory and still bold bunch of rings on the right and on and on the left hand side also Ruiping years invested to get to this stage OK it worked just fine also photochemical you psych lies in brought up nicely and then the last but 1 step hydrolysis so hydrolyzing this even all the Serre while others especially group all here that selectively they get the problem my group here and here after hydrolysis having the O H unit finally hoping he meets acid so formation here trapping radical age group and the community there was a lot of pretty precedence sorry indeed this Knuth would appear here at this in this 1 it was a lot of precedents for similar cycle ization reactions but unfortunately would ever be tried it didn't want to work not at all so world that was the reason by then they and decided to not to go to maximum convergence but after having invested years after years in synthesizing that thought and that thought and finally noticing you don't get this done they decided well that us synthesized that central part fruits this is a bit more than it's the but it made sense and they were successful finally there and they have developed some interesting sulfur chemistry on that me self the somewhat more linear but this convergent that was the name though they were given their search plan for the the synthesis yeah that's that 3rd third-generation strategy finally worked out archaic so the let's go to another example also from the famous profits slow who nowadays also works at Scripps Research Institute that's day Bogor and again the natural product they had the following plan having but paper proceed past the central portion Scott questions do it this way under your all our reading here CIS on the same side of the ring never grammatik Polish 1 each group found 1 the Fox Ages they planned to treat that's that where so do you I draw based certainly Deep Throat relating to the funnel having the sodium phenyl late than but what bromide time of full sulfide complex there and indium have time and he did that hoping for this
type of product today bedsitters does anyone know what kind of reaction is about to Coupet catalyzed processes Archer isn't so good catalytic may also up induced processes but it works catalytic and it works catalytic you know it's it will 1 it's a clue might coupling reaction yes that's the and all 4 of the lecture on catalytic organometallics the discussed all rose irony catalyzed coupling reactions which turned out that the only route if the dying needed to that of a poor oxide for instance is present great they finally tuned out IQ by bone and buckboard but he's reported processes are indeed also cop catalyzed when the coupling reactions well looks nice this is then after you get rid of that novel group already an interest in natural product but unfortunately this reaction does not work at all so 1 could say it can't work because this system is already looks rather strained yes it the bit strained but that is also true for the natural product and wall then they meant for an alternative approach but very similar actually more easy to some facades Starting component just more easy to synthesize having those common night hoops the present Gray why is this more easy to synthesize actually this is the condensation product to bone mineral acids and you have ready access to Carol manifests double condensation that Daiki tool the proteins they didn't want to grow for bat-first to use this as a compliment to tribal woman coupling reaction because they feared that with some basic stuff been here in the heating it up usually above 100 degrees the 4 cabin nice here the Carroll centers could that the arise they wanted to avoid any problems with that therefore directly this after it didn't work they tried this at least they reported that they may have the country yet heat heat cost of over here on a of and so and then yes it works in room with directly having an H here they have tried various substituents so the same reaction conditions also do you have and 170 degrees wall therefore you can already judge but this has to be done in the pressure tube traits and so if and have you born important 156 also all 154 so you need to pressure to 0 and the 53 percent you to all of this product OK also and they cheered and then getting to the final product having an OH group there there will afforded more steps well let us 1st see what's the difference to the 4 carbon I groups it it changes the geometry very much somewhat flattened and it's less strained than this 1 so makes the formation of a macrocycle the are they sell the memory of a C H 3 group pdf as carbon groups there from the MIT want to get rid of the or it's I'd carbon ions and want to get rid of a muffled please for a couple
of minutes to I think about how would you the chief that transformation just think about regions you would apply so OK bitch
problem he would prefer to solve the 1st become a problem although the fox approach suggestions we would go
for all the the fox interests 1 would go for overcoming our groups OK most of you some would even but start Mr. option if it did that and batter presumably it's better to go full of a carbon our 1st because you can be sure that the methoxy group does not disturb any reactions you do you after D. protecting here in unit of of of having the OH group you have an acidic functionality and this could just so therefore growing for the might for 1st it's reducing that I might functionality wall how do you do that simply using complex hydrides for instance the symbol of minimum hydride is reactive enough in doing so on in this case they applied the experience exists in th and that st step was done in 73 per cent well I would like to remind you all but interesting reaction having and carboxylic acid AT and treating those of but do reducing agent diet ball page this is i-Sobot to bloom in hydro this was this transfer through is just 1 right for the reduction that that's there 1st this secondly hydrolysis and as the product you will get an nicely the all the hired and or hydrolysis on a slightly acidic conditions and you will have also the ammonium salt where they was is a nice way for synthesizing called its that the next step cleaving of user if a cleavage is not an easy task most read
reliable reagent for achieving this there was try Bromont this MOOCs very well the Bowron try bromide is rather aggressive if you have other lt sensitive groups can might run into problems carry in and pyridinium Hydril bromide dry this is important should be dry and that at high temperatures FIL this can also the Eastern group and here in this case they have not for combination of dry or the acidic acid all I would guess it could walls glassy all acidic acid so water water-free city acid and heating up you're aware of more to the direction all 160 reasons that cleaved then the the theory functionality and the last step is sorry understood writing that down but if our remember it correctly they had about 80 per cent so I should mention these 2 examples all of the firm what not dead and total synthesis but deep truce controlled was infuses our from the 1st chapter of us curl that line all of that chip to walls more is working models by do not work what Soccer so in the 1 more example but this time under the patent law and troublesome protecting groups nice example from burial mounds groups in the context of alkaloids and fuses with the phaser cold money reaction actually in the preceding semester in rich rule since the 2 on others lecturer is on organic synthesis the hat exactly those power cope Munashe reactions discussed in detail but but ro focusing all the other COBE money steps not on finishing the synthesis OK so let's see here's the example some of you might remember that's title holiday day so maybe I should draw what and as a code to manage is on this let abortion so once again this is a globe reaction this isn't oxic cope rearrangement discussed yesterday if he put in the books are cute oxygen instead of a C H 2 group we have an ox soccer open of optical book socalled prearrangement this is called normally Claeson rearrangement you don't need to work that out further and now foot in the nitrogen here preferrable asked and 2 million can I the during this aid is a cold rearrangement would give this you know all those that the minute you cut on and present OK
and the reaction often in the come on as an electoral few electrophile move and rule as the crew far out this called knowledge reaction this is the nucleophilic center here we have the electrophilic center that's count all those another 1 2 3 4 5 the five-membered ring is formed so that pyrrolidine that govern our group and such we have 1 olefin he had the alkyl you have the mean but not the million could I soviet Union could iron is formed under the appropriate reaction conditions before form out souls and catalytic H. plus in buffered solutions AP sorry stupid mistake by mark mark it this is not the olefin this this reaction we elected to react thing here the immunity and cut on 1 double bond here is the other double bond there the cover my group and the Centers carbon there 1 2 3 4 5 6 this is the Hexadite system the need for local privilege if you would figure that out in detail you would sooner or later hopefully come to the result that the outcome of that reaction looks like this here we have the five-membered heterocycle protein the Prodi gene here the cobbler my group here the people of all of you protected I mean this is the product after the oxy coke money's rearrangement developed by on the overlapping group on to this looks very well 88 per cent year so let's draw the natural product they were aiming for this 1 quotes a cool why clone soon it is strongly related to who strychnine so it's from a family of strychnine alkyl it's so that's think about it what do we have to achieve for that transformation OK you have to hydrolyzed all of this p-value you'd protecting the the case we have to introduce the acid moiety finally as the best to defer should be directly as the Esther so they tried to to idolize that all of this the group this case your age 10 from all about 80 degrees and that's abbreviate that quite rose they get to this Carolyn 70 % you and then they tried for instance deprotonated youth LOD D. and all the this chloroform make tested has to so methyl chloroform 8 they get a bunch of products bird that long was not all of my the product mixture they also tried to the food smile formulation but then the form you have was that attached to the nitrogen and
here they got to all of that so nothing looked there then they fault while that's stop with this 1 introducing this functional group already on this stage and again the LDA 1st cause you need a bit more here the most acidic proton will be this 1 archaic need to crawl lands so then they didn't use the muffle chloroform made but they had the cyanidin present this also adds that derivatives of the of oxalic acid and indeed this MOOCs so to broaden 18 year deprotonated inventive is this the nucleophile they had a text that the carbon my group and then the cyanide is eliminated so have an 80 8 % you they get that indeed the desired product of this step this 1 sorry of course not aromatic suffering and now what remains to be done simply hydrolyzing the p-value group undone that should make a conditionally which unfortunately that was not but the easy every conditions that group sufficient to hydrolyze that all of also hydrolyzed this asked you to the carboxylic acid and as you know I asked the vet tech key tool as student after I dollars is the D. carboxylates so whatever all they did this hydrolysis post his Monday only 1 we could isolate and they already
knew their walls despite lots of of fluids no way to get that transformation so they decided that to change the protecting groups of course this should be done the idea of choice so they change to the third-tier Schreber toxic carbon I group the box and block protecting but
some minor difficulties these oxy cope Munashe reactions works but than on the final stage they never could isolate to call the mind always the condensation reaction took place the 3rd rather good G. it and while if you remove the BOC Group you will be again on that stage so that means that the reaction conditions the BOC Group at the end protected the the BOC protected nitrogen all stood to nucleophilic so they decided they are in need of all of the better protecting group prefer ocean the 1 which she units 4 hydrogens of the umbrella group which this table and a basic reaction conditions also surviving that that is never marvelous Vt hydrolyzed under somewhat stronger acidic conditions the event into literature on the phone 1 that should they decided to try it's the so-called try of zones protected protected group having that is a real moiety here connected the that long think to buy a 2 no groups function groups they did so battered worked OK and that's the end of this story just a matter of all of the riot protecting group the end that article about dead ends and detours and total synthesis for their power 5 more chapters in the go through next week the BV and expand tick and expected influence of 2 substitutions problems the side chains especially in introducing the side chain and the later stage of the symphysis that seemingly trivial functional group transformations that don't want to work unpredictable stereochemistry problems and finally reluctant green closures self thanks for listening see you next week on Tuesday
Separation process
Substitutionsreaktion
Solution
Ham
Wursthülle
Chemistry
Reactivity (chemistry)
Molecule
Cupcake
Human body temperature
Addition reaction
Toxin
Algal bloom
Doppelbindung
Methyl iodide
Ene reaction
Walking
Carbon (fiber)
Totalsynthese
Wine tasting descriptors
Electronic cigarette
Oxygen
Chemical reaction
Sodium
Alcohol by volume
Tiermodell
Functional group
Coordination complex
Macrocycle
Chemical compound
Tetrahydrofuran
Chemical structure
Dewar benzene
Chain (unit)
Left-wing politics
Solution
Death
Finings
Chemistry
Molecule
Fire
Addition reaction
Medroxyprogesterone
Crystal
Hydride
Doppelbindung
Ene reaction
Walking
Sulfur
Valine
Death
Wine tasting descriptors
Disease
Chemical reaction
Systemic therapy
Acid
Tiermodell
Azo coupling
Hydroxybuttersäure <gamma->
Chemical compound
Macrocycle
Tetrahydrofuran
Locus (genetics)
Biomolecular structure
Hydrolyse
Deep sea
Sense District
Forkhead-Gen
Natural product
Ageing
Phenyl group
Wursthülle
Food
Methylgruppe
Sulfide
Human body temperature
Elektronentransfer
Faserplatte
Indium
Process (computing)
Palladium
Setzen <Verfahrenstechnik>
Potenz <Homöopathie>
Bromide
Hydrierung
Totalsynthese
Carbon (fiber)
Chemical bond
Muffin
Alcohol by volume
Sodium
Radical (chemistry)
Functional group
Solvated electron
Coordination complex
Wine fault
Rock (geology)
Medical prescription
National Rifle Association
Butcher
Natural product
Mineralization (biology)
Hydroxyl
Carbonate
Memory-Effekt
Portable Document Format
Ring strain
Pressurization
Tube (container)
Kohlenstoffgruppe
Tool steel
Transformation <Genetik>
Metallorganische Verbindungen
Oxide
Process (computing)
Substituent
Setzen <Verfahrenstechnik>
Walking
Carbon (fiber)
Kupplungsreaktion
Disease
Systemic therapy
Chemical reaction
Alcohol by volume
Acid
Functional group
Azo coupling
Macrocycle
Protein
Condensation
Stuffing
Semiotics
Forkhead-Gen
Hydride
Walking
Hydroxyl
Carbon (fiber)
Carbonsäuren
Spaltfläche
Wursthülle
Hydro Tasmania
Methoxygruppe
Ammonium
Disease
Diet food
Reducing agent
Chemical reaction
Functional group
Coordination complex
Hydride
Elektronentransfer
Hydrolyse
Intergranular corrosion
Heterocyclic compound
Gene
Pyrrolidine
Pharmaceutical formulation
Ice
Alkaloid
Stratotyp
Transformation <Genetik>
Nitrogen
Strychnine
Patent
Doppelbindung
Alkylation
Oxycodon
Walking
Wine tasting descriptors
Disease
Chemical reaction
Trocknung
Systemic therapy
Neoteny
Acid
Tiermodell
Tetrahydrofuran
Protein
Thermoforming
Deep sea
Butcher
Natural product
Ageing
Detection limit
Wursthülle
Food
Human body temperature
Alkene
Mixture
Potenz <Homöopathie>
Bromide
Chloroform
Rearrangement reaction
Totalsynthese
Carbon (fiber)
Buffer solution
1,1,1-Trichloroethane
Oxygen
Water
Alcohol by volume
Cope rearrangement
Functional group
French fries
Coke (fuel)
Cyanide
Chloroform
Walking
Carbon (fiber)
Protonation
Derivative (chemistry)
Block (periodic table)
Disease
Toxicity
Functional group
Fluid
Oxalsäure
Orlistat
Tool steel
Transformation <Genetik>
Baryte
Hydrolyse
Potenz <Homöopathie>
Nitrogen
Schutzgruppe
Selenite
Stereochemistry
Oxycodon
Hydrierung
Substitutionsreaktion
Totalsynthese
Electronic cigarette
Death
Disease
Chemical reaction
Cope rearrangement
Functional group
Ocean
Transformation <Genetik>
Base (chemistry)
Condensation reaction
Permaculture
Side chain
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