molecule synth

Hi, I was wondering how I could potentially make this molecule

Ok ive gotten thus far, ive yet to begin researching the preparation of the 3-hydroxy-2-(2-hydroxyethyl)cyclohexanone.
Your compound is insane, might i add.

The route goes like so.



Step 1
It begins with a wittig reaction, the preparation of the ylide reagent would have to likely start with triphenylphosphine reacting with a alkyl halide followed by addition of a strong base.
From what i understand, both of those hydroxides will not react at all with the phosphonium species or triphenylphosphine however they will be deprotonated by the base.
If i am wrong then one could instead start with both hydroxides oxidized to there corestonding carbonyls (aldehyde and ketone) which could be protected by an ethylene dioxide acetal/ketal dioxolane group.

Step 2
Then the hydroxides can be oxidized or any protecting groups cleaved.

Step 3
The next step is where there is a bit of a problem, it requires an enolation of that ketone in order for the aldol condensation to take place, the major issue is that there is no selectivity for which side the proton is taken from, see below.



Now ive drawn up some other possible side products that could form from this aldol condensation, non of which seem sterically favorable, even if the enol does form on the wrong side, the corresponding aldehyde cannot react with it as the chain is far too short in length.
I also doubt the aldehyde on the other side of the cyclopentene ring will reach over to react with it (sterically unfavorable).
This leaves intermolecular side reactions, for which i might propose a very high dilution within the reaction mixture to attempt to avoid such side reactions.
With that enolation in mind, i suspect the yields for that condensation will be on the low side, although one might be able to recycle any unreacted product.

the easiest way would be to reduce 1,5-pyracenedione (CAS no - 155143-87-6).Sadly I don't know how ,but I think the hydrogenation experts on this forum(ex- nicodem , zed) would be able to help.

@Sigmatropic
You are correct, I like the pinacol coupling elimination idea, so much so that ive included it in this new scheme.
I had a reason for proposing the aldol condensation that would not directly result in hydolosis to the beta alkene by instead picking it up with a stong base such as sodium hydride. It was a late night though so ive decided that idea was far to insane and experimental to work.

I have made some massive modifications, although increased the number of steps quite significantly.
Im still not sure how one would go about preparing the cyclopentanone precursor but im thinking along the lines of a narzarov cyclization.



I have instead chosen to start with primary amines as place holders (protecting groups sorta) for our eventual Ketone/aldehydes.

Step #1
Pinacol coupling, where magnesium donates an electron to the ketone carbon forming a organo magnesium oxide, which proceeds to donate its second electron to another mol of our cyclopentanone species, this organo magnesium species then hydolyses to give the corresponding tertiary vicinal diol.
I know very little about how to perform such a reaction in a practical setting but im hoping the beginning step is not water sensitive as it would be ideal to avoid anhydrous conditions to prevent the formation of any imines.

Step #2
Simply acid calatysed elimination of the vicinal diol resulting in the formation of a diene in concordance with zaitsevs rule.

Step #3
The next step would be a classic sandmeyer reaction with sodium nitrite and HCl followed by hydrolosis of the diazonium cation.
Up to this point i was hoping to avoid anhydrous conditions to prevent the formation of imines, I still have no clear route to the precursor though so this may change.

Step #4
Careful oxidation of the alcohols to yield ketones and aldehydes.
This step may be quite tricky, avoiding over oxidation of the primary alcohols with that many oxidation's taking place on the same molecule would be troublesome.
It may instead be better to attemp using bismuth tribromide to selectively oxidize the alcohols.
I have posted this reference in the acetaldehyde thread but will post here too.
Attachment: lee2015.pdf (143kB)
This file has been downloaded 345 times

Step #5
The aldol Addition reaction where instead of eliminating a molecule of H2O as in a traditional aldol condensation, i would instead propose reducing this alcohol to a saturated alkane.

Step #6
Reduction of the alcohol using red phosphorous and iodine which is self explanitory.
Im not sure how that beta ketone is going to affect the ability of the iodine to leave but i would surmise that the carbonyl carbon with its electrophilic nature would not hinder the oxidation of the iodide by HI, thus this should work fine.

Now, Mr Jackson, as you can see this is no easy compound to prepare and is well beyond my own skills (and i atleast have some comprehension of the undertaking).
You would be hard pressed to convince someone else to carry out such a multi step organic synthesis especially since we are already at 6 steps without even considering preparing the precursor.

With that in mind, i have enjoyed thinking about this and do not want to discourage you from bringing such problems to the forum, even if it is purely theoretical.
If you really are considering a project similar to this though, might i propose something a little less insane.

Quote: Originally posted by Assured Fish

Step #2 Simply acid calatysed elimination of the vicinal diol resulting in the formation of a diene in concordance with zaitsevs rule.

Jackson that was exactly what i was thinking.
The obvious solution would be reacting the diol with HBr followed by elimination using sodium methoxide.

I also completely forgot that this was a thing, meaning the wittig coupling isnt entirely out of the question although i think given that it uses a very strong neucleophile and those amines would be halogenated by any halogen we introduce, it would still be better to opt for the pinacol coupling.

This wont work however, as the halogenation could form on either side of the ketone meaning you would get 2 products, 1-chloro-2-amino-cyclopentanone (undesired product) & 1-chloro-3-amino-cyclopentanone (desired product).
Separation of these 2 products would likely be a pain in the ass.
The second major issue is that halogens will react with the amine forming chloramines or bromoamines or whatever.
The third major issue is that you wont really be able to form an alkyl group from that halide without destroying other funtional groups.
The wurtz fittig reaction might maybe work but that reaction is outdated for the very reason of it being incompatible with alot of functional groups.

Either way it would be better to instead start with the alkyl chain in the right position prior to carrying out the cyclization.
Something like this perhaps:

Another member brought this thread to my attention, and my thought was to try to construct those double bonds by a Hofmann elimination. Retrosynthetically, if you "undo" the Hofmann elimination, you get something that looks like an iminium-driven aldol condensation product. That line of thinking led me to this:

The sulfonation of naphthalene with oleum gives napthalene 1,5-disulfonic acid:

http://en.wikipedia.org/wiki/Armstrong's_acid

Alkaline hydrolysis gives 1,5-dihydroxynaphthalene:

http://en.wikipedia.org/wiki/1,5-dihydroxynaphthalene

According to this paper, acylation of 1,5-dimethoxynaphthalene preferably gives 4,8-disubstitution (when p-methylbenzoyl chloride is used):

https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/200501...

So, without loss of sanity, we hypothesize the production of 4,8-diacetyl-1,5-methoxynaphthalene, at which point I will leave the published literature and start speculating.

First, we protect the acetyl groups as their O-trimethylsilyl enol ethers, then we deprotect the methoxy groups using IBX.

The next step is a Birch reduction, which on phenols produces cyclohexenones. We expect the enol ethers will be left alone because they are electron-rich and so will be less likely to react with e-. The product is compound (2).

Reaction of the product diketone with dimethylamine and acid produces a double directed-aldol condensation, and deprotection of the silyl ethers with HF gives the compound (3).

The central double bond in (3) can be reduced with very high selectivity by diazane:

http://en.wikipedia.org/wiki/Reductions_with_diimide

Reduction of the double bond in (3) and methylation with MeI gives (4), which can then undergo a double Hofmann elimination to give the target compound by Zaitsev's rule.

EDIT: I drew (3) wrong, you'd have to deprotect (3), then diimide.



[Edited on 27-9-2018 by clearly_not_atara]

Let us not forget that the more stable isomer of the title compound is actually a double alpha,beta-unsaturated ketone (see attached scheme).

Several routes I drew up (not shown, because flawed) and the synthesis proposed by clearly_not_atara will preferably end up with an a,b-unsaturated product instead trough virtue of the Ecb1 reaction (https://en.wikipedia.org/wiki/E1cB-elimination_reaction#Aldo...).

I doubt the title compound is accurately represented by the proposed stucture and as such attempts at synthesizing the title compound through hypothetical routes are merely paper chemistry excersizes, which are interesting none the less.





[Edited on 27-9-2018 by Sigmatropic]

clearly_not_atara, the problem is you would end up with a different a,b-unsaturated ketone (see attached file).

Or am I missing something?

The stucture in the OP is defintetively only a kinetic product and most other syntheses will go right on to the stucture described earlier.

That position is blocked. See the picture. Deprotection of the silyl ethers in the final product will not cause rearrangement of the internal double bonds by any mechanism I am aware of.

I came up with a modified version of fish's route ,aka the fureus route
the starting compound is available commercially ( CAS no - 73039-22-2)

1.converted to the lithium enolate followed by reaction with oxirane to give the ethyl alcohol

2.Protection of the alcohol with benzoyl chloride/Pyridine -https://www.synarchive.com/protecting-group/Alcohol_Benzoate

3.pinacol coupling with Mg,followed by double dehydration with POCl₃/Pyridine ,avoiding the subsequent rearrangement -https://www.masterorganicchemistry.com/2015/04/28/eliminatio...

3.Simultaneous deprotection of the alcohol and vinyl ester to give the corresponding cyclopentenone alkyl alcohol

4.Tosylation of the alcohol followed by treatment with LDA to give the target compound via an intramolecular alkylation.

Quote: Originally posted by j_sum1

If we had a name for this molecule it could be put in the thread title.

I made it! I made it!!

Yield is a bit bleak though. I only got one molecule.

On a more serious note...
Some things that may or may not have been noticed by those working on this problem.

1. There are two chiral centres and so two diastereomers. (Labelled in the following photos by the purple bonds.)


2. There seems to be a lot of bond strain. At least if the model kit is anything of an indicator. The structure really wants to fly apart. The trans isomer in particular. I am not predicting that the synthesis will be easy at all.



[Edited on 29-9-2018 by j_sum1]

Throwing it into my phone app...




(Webmo if anyone is interested.)

Quote: Originally posted by Assured Fish

is it possible for an alcohol to react in an aldol condensation with an enol instead of classically reacting an aldehyde with an enol?

Quote: Originally posted by j_sum1

1. There are two chiral centres and so two diastereomers.

actually,there are 5 chiral centres.But since jackson wants to use this molecule as a base for bucky balls,I don't think stereochemistry would matter much.As long as it doesn't have to fit in a particular receptor(like drugs),it should be fine.I may be wrong though

Also,the synthesis is already very hard as it is.Trying to make it asymmetric would be next to impossible.

I suggest we try getting a product first as proof of concept.This could be done by selecting the 2 best routes posted,correcting their flaws and optimising them( like figuring out how many steps could be run in one pot).Then jackson could do a trial run and report back here.

[Edited on 29-9-2018 by CuReUS]

While trying to come up with the route I suggested in the previous page,I faced a dilemma about which protecting group to use.I was torn between converting the primary alcohol and enol to an ester(benzoate) or ether(methyl ether).In the end,I chose benzoate since it was less toxic and the deprotection was a breeze.

But that time I had a nagging doubt - would the Mg used for the pinacol coupling react with the ester ?

I went through greene's book on protective groups,and I am sorry to say, my fellow chemists,but my doubts have been confirmed - https://www.sciencedirect.com/science/article/pii/S004040390...
https://www.sciencedirect.com/science/article/pii/0040403995... (don't know why they published the same thing again after 2 years using different authors)

Although the deprotection condition is Mg/MeOH,rt for 13 h,I don't want to take any chances

So I suggest we proceed via the ether route.The reaction stays the same,the only difference is that the starting material is different ( CAS no: 4683-50-5) and we do a methylation step instead of benzoylation.

the methylation could be done with dimethyl sulphate/Barium hydroxide-https://pubs.acs.org/doi/10.1021/jo00374a020

or methyl iodide/silver oxide-https://pubs.acs.org/doi/10.1021/ja00545a041

deprotection can be done by trimethyl silyl iodide -https://pubs.acs.org/doi/10.1021/jo00443a033

or BBr₃-https://www.jstage.jst.go.jp/article/bbb1961/42/1/42_1_131/_...

Quote: Originally posted by Assured Fish

Ive been researching how one could go about preparing the starting material 3-hydroxy-2-cyclopentenone or an ether thereof.

There is no need to make it,since jackson can directly buy it.

They might be "exotic" from a home chemist's point of view,but they are quite commom in an university setting,where jackson is working.

[Edited on 1-10-2018 by CuReUS]

Quote: Originally posted by Jackson

Just to clear things up im not working at a univeristy

Quote: Originally posted by TGSpecialist1

You will probably enjoy this paper

Im an Idiot.
I forgot to ask a very important question.
This molecule is a segment of a larger molecule. I forgot to ask if the larger molecule could even be made from this molecule.
I will attach a photo of a model of the full molecule.

P.S. the red bonds are single bonds, white bonds are double bonds. The open double bonds on the end are supposed to be where the oxygen it bonded.

I also do not see five chiral centres, havent a clue why Atara stated that, perhaps an oversight on his part.

Anyway, this is route for the preparation of the cyclopentenone species.



Based on the research done in the paper trost2001.

for each of the 3 steps they worked up by way of ethyl ether/petroleum ether over silica gel by way of chromatography.
The last step needs to be done quickly as the geminal diol ether compound is likely unstable, it is also moisture sensitive and chromium 2 chloride is hydroscopic.

This is the ruthenium catalyst used in the first step.
https://www.sigmaaldrich.com/catalog/product/aldrich/667412?...

Yields would likely vary too much to be of much importance but for each step they reported above 60% and the 3rd above 80%.
It would be better if you read the paper yourself.

That first step is somewhat problematic as acetylene is probably not highly soluble in acetone at the reflux temp required for the reaction, a continuous flow of acetylene would likely be required, which would sap energy away from the reaction so a strong heat source would be a necessity.
Thankfully an excess of acetylene would not hinder the reaction or take place in side reactions.

Unfortunately there is nothing easy about this kinda synthesis, non of the materials with exception of the solvents are easily accessible.
Honestly the more i read into it the more i start to learn towards Atara's route starting from naphthalene.

All of this stuff is just madness, well beyond what i would be willing to do, especially with no obvious use for the end product.
A hell of a lot of money would be required to buy reagents, or time required to prepare the more easily prepped ones like PDC and nickel dichloride.
Stannic bromide would be horribly difficult to prepare, buying it would be necessary which would also be challenging.

Attachment: trost2001.pdf (143kB)
This file has been downloaded 408 times

Quote: Originally posted by Assured Fish

I also do not see five chiral centres, havent a clue why Atara stated that, perhaps an oversight on his part.

atara didn't state that,I did
And I was wrong,its 2 only

that's because you have yourself complicated it.
I said so many times that the starting compound is directly available commercially.

Still, you insist on synthesising it,that too via a ridiculously convoluted route,when it can be made in 1 step from 1,3-cyclopentanedione(another commercially available product) -https://pubs.acs.org/doi/10.1021/jo801911s(pg 9 of pdf,compound 74) , which in turn can be made from methyl/ethyl levulinate -https://patents.google.com/patent/US7897802B2/en

ethyl levulinate is available as biofuel - https://en.wikipedia.org/wiki/Ethyl_levulinate, or if you truly wanted to make it from scratch,you could make it from sugar -https://en.wikipedia.org/wiki/Levulinic_acid#Synthesis

Quote: Originally posted by Jackson

Another idea for a route could be: Synthesis of 1,5 dimethyl napthalene as shown here: https://wikivisually.com/wiki/2%2C6-Dimethylnaphthalene (without the final step) Then bromination of both of the methyl groups to form 1,5 dibromomethyl napthalene Then reacting the 1,5 dibromomethyl napthalene with sodium cyanide to form 1,5 diacetonitrile napthalene Then hydrolysis of 1,5 diacetonitrile napthalene to form 1,5 napthalenediacetic acid Then conversion of the OH groups in the acetic acid to H by chlorinating or brominating them and then replace the Chlorine/Bromine with Hydrogen using H2/Pd in the presence of BaSO4.

Quote: Originally posted by Jackson

Then it could be cyclized with H2SO4 to form the molecule