Sciencemadness Discussion Board

stepwise synthesis of alkane macrocycle

andre178 - 23-4-2010 at 13:09

hello everybody, I have a few questions, and possibly a validity check on the following reactions that I am trying to do in order to synthesize a octomalonyl based macrocycle. I postulated using a template ligand but I don't think that's a viable solution. This is all in dry dichloromethane (under Argon).

I begin with monobenzyl malonate (purchased from Aldrich, I would love to be able to make this for cheaper-but asymmetric yield isn't good.) this has the benzyl ether protecting group (colored in purple).

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My first question: does anyone see any theoretical problems with what I am trying to achieve?

Second question: how can I remove the protecting groups without reducing/hydrogenating the carbonyls/esters. I was thinking about lithium based catalysis but I am not sure. [I have never used P.G.'s before.]



Thanks for any input, even if its not right, I need more second opinions on this.

Andre

12AX7 - 23-4-2010 at 13:29

I'm curious how you're preventing the 2,2 adduct. Purification? Excess of the alkyl chloride? And there might be something about kinetics or availability preventing significant amounts of higher polymers (including polyester per se), like conducting the condensation in dilute solution.

I guess pyridine doesn't react with the alkyl chloride? Seems funny as the alkyl chloride feels acidic, but I realize that's only when it's got a protic solvent around to misbehave. Now, it'll certainly do a great job sucking away the HCl formed in condensation.

I'm afraid I can't be of much more help. I do look forward to seeing the results. (MP, TLC, IR and NMR I hope?)

Tim

andre178 - 23-4-2010 at 14:48

I don't see which 2,2 adduct you're referring to, please specify, you could be right.

The pyridine acts as a base catalyst, it seems to do a fine job esterifying; all this is done in dry methylene chloride

.... and yes I might end up doing it in high dilution in order to get it to not run out of control.

purification wise I'm thinking at the end run through a column with CH2Cl to flush out pyridine salts etc, then do 90:10 CH2Cl2/EtOAc


JohnWW - 23-4-2010 at 15:45

That would not, strictly speaking, be classed as a true "macrocyclic alkane", because of the 6 lactone ( -C-O-C(=O)-C- ) linkages which occur in 3 pairs, instead of the ring consisting only of C atoms. A compound like that is likely to have properties similar to the macrocyclic "crown ethers", used to chelate the cations of highly electropositive metals (which favor oxy-ligands) so as to enable them to be dissolved in non-polar organic solvents.

True macrocyclic alkanes or alkenes, containing more than 6 C atoms in a ring, are very difficult to obtain, especially pure and free from polymers (produced by intermolecular condensation), because of the difficulty in obtaining intramolecular ring closure involving carbons that are large molecular distances apart on the same molecule, and this also applies to macrocyclic ethers and lactones and lactams etc. However, several macrocyclic natural products are known. The most well-known such ones are atropine and cocaine, containing 7-membered all-C rings. Another one is civetone, or cis-9-Cycloheptadecen-1-one, with a 17-carbon ring containing one double bond and having a keto group, in the "musk" obtained from the scent glands of the African civet cat for perfumery, although thankfully the stuff can now be made synthetically from a fatty acid found in oil-palm oil.

Attempts to obtain macrocyclic alkanes or alkenes or ethers or lactones sometimes result in the production of small amounts of catenanes, i.e. supramolecular dimers or polymers in which large macrocyclic rings are linked as in a chain. It appears that rings containing at least about 19 atoms are needed to obtain any of this chain-linking.

[Edited on 23-4-10 by JohnWW]

smuv - 24-4-2010 at 16:19

I see a problem, the synthesis is completely unselective for your final product, you will get everything, namely polymers and even larger cycles.

The step in question will likely go just fine with hydrogenation using a Pd/C catalyst. Of note, platinum catalysts will not work well for this. The benzyl moiety will be reduced to toluene.

chemoleo - 24-4-2010 at 17:37

What smuv says is not only true for the last step (reaction of the dichloro-derivative with malonic acid), but also from compound 3 to 4 - you'd have to use a very large excess of 1,8 dichlorooctane to prevent cyclisation with 1 molecule of 1,8 dichlorooctane rather than producing the compound 4 which you desire (reaction with 2 molecules of 1,8 dichlorooctane). Likewise, you'd have to use less than an equivalent of malonic acid to get from 4 to 5, and dropwise addition, to prevent polymer formation or larger cycles.

Out of curiosity, how readily does the reaction proceed with a chloroalkane and a carboxylic acid, forming ester and HCl (or Pyridine-HCl)? What are the condiitions for this?


UnintentionalChaos - 25-4-2010 at 04:23

That's not a benzyl ether protecting group, it's an ester. There's nothing much to differentiate it from the alkyl chain when you attempt to cleave it off. The use of such long chains is going to seriously inhibit proper cyclicization. Using short diols that can later be functionalized and ring opened are much better bets.

Why so big? That size ring is extremely hard to close, whereas smaller rings (11-15 membered for example) are vastly easier to make (>50% yield by some methods).

Are you dead set on the malonic acid? The acidity of it's alpha hydrogens would make the diol synthons I mentioned earlier harder to functionalize after ring-closure.

DJF90 - 25-4-2010 at 04:46

If you can redesign your molecule so that the open chain form has an alcohol at one end and an acid at the other, lactonisation of said molecule can be had very easily using Yamaguchi conditions. Ring size isn't really an issue as I recall it being used to selectively form a 42 member ring, as opposed to the 41 membered one that could have formed (obviously a case of stereoelectronics but still very impressive!)

smuv - 25-4-2010 at 08:54

@UC - benzyl esters undergo hydrogenolysis with pd/c preferentially to benzyl ethers. This deprotection strategy is widely known for both esters and ethers.

ex. http://pubs.acs.org/doi/abs/10.1021/jo01105a031

UnintentionalChaos - 25-4-2010 at 14:12

Quote: Originally posted by smuv  
@UC - benzyl esters undergo hydrogenolysis with pd/c preferentially to benzyl ethers. This deprotection strategy is widely known for both esters and ethers.

ex. http://pubs.acs.org/doi/abs/10.1021/jo01105a031


Interesting, thanks.

A good move to use might be to utilize heterocyclics incorporating a sulfur to bridge two carbons and pinch off 6 or 7 carbons, significantly shrinking the ring that needs to be closed. Sulfur can be reductively stripped from molecules by rayney nickel afterward.

[Edited on 4-25-10 by UnintentionalChaos]

andre178 - 26-4-2010 at 11:54

good information to keep me from pulling my hair out.

The rate of R-CO-X/R'-OH is slow, but it is decent using milimolar quantities. I am indeed performing this under high dilution, dropwise addition (8 hours for 500 ml solvent). It helps to prevent too many secondary by products.

This is all done in CH2Cl2 for a reason using non protic components besides the reactants. The deprotection step is done in an alcohol from what I've seen.
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Pd-C deprotection on Organic Chemistry Online

I am looking into the Yamaguchi esterification procedure, it looks very mild and a sure way to cyclize the straight chain. The problem now is the stepwise addition to make a straight chain. The difficulty remains because of the repeating malonic acid+octanol units.
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The sulphur containing heterocycle could also be an interesting alternative, I'm just thinking that it might react with the carbonyl groups from the rest of the molecule.


Also, JohnWW, you are abs correct, it's not an alkane macrocycle, however it is pretty non polar compared to most heterocycles out there, which is why I chose that title; but I will change that. I've been scanning through a few select books on the subject and it's rare to find more non polar chains.



UnintentionalChaos - 26-4-2010 at 18:24

What I meant by sulfur-containing cycles is to use something like 2,7-bis(hydroxymethyl)thiepane or 2-(2-hydroxyethyl)-6-hydroxymethyltetrahydrothiopyran as a 1,8-octanediol synthon. The resulting primary chain is then 5 or 6 units long respectively versus 8 when using the unfunctionalized diol.

andre178 - 27-4-2010 at 14:14


I like the heterocycle idea very much, hypothetically using a triphenylmethane template, followed by malonyl chloride reaction and then raney nickel hydrogenation.

The heterocycle with the bis methanols would be difficult to synthesize, (2,7-dibromooctane-1,8-diol).

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