[yourdeath01]

Hello all!

We are just about 2 weeks away from wrapping up the semester for ochem 2 at my college and one of our final projects is that we are given a molecule and are tasked with doing a retro synthesis on the molecule and go all the way back to produce the molecule until we can't go back anymore (think benzene or carbon).

Long story short here is the molecule that was personally assigned to me: https://imgur.com/e5S1Tw7

Initially my thoughts is that I see some double bonds which indicates to me Wittig reactions? Is stereochemistry relevant here? Like do I need to worry about the R on the yilde being a phenol or a CH3 and therefore producing the E or Z product?

Other things that jump out at me I see the ether group their so I would assume the last step in my retro synthesis would be to make an ether with alcohol or an alkyl halide?

Also I assume their is a ketone their because of the wittig reaction and so I guess we can do alpha/beta aldol?

My issue with this project is getting started, I am not sure how and where to start, do I attempt to split my molecule in two halves and then start synthesizing each half? Do I not do two halves and instead start off with benzene group which has a methyl group and is therefore going to be o/p director but it can be oxidzed into an ethyl group? I am not sure why I would want to oxidze the methyl group on the benzene to the ethyl group?

I will def be doing some reading here on aromatic substitutions, wittig reactions and aldol reactions but any pointers or things that jump out at you guys when you see this please shoot them my way! For those who love retrosynthesis as well please give me all the tips!

Some things we learned this semester but are not limited to use in this project are: diels-alder, aromatic systems, aldehyde, ketones,carboxylic acid and their synthesis and reactions. Also learned about carbonyl condensations and finally learned about carbohydrates and carbons. Again we don't only have to use those, we can use any information from the internet.

[rolnor]

I think the things you suggest are very good, can you draw your reaction scheme and post it here?

[hollytara]

That is a complex one - did they teach you retrosynthetic analysis?  you will want to try "disconnecting" at a couple of different places and see how easy it is to work your way backwards.

[yourdeath01]

Okay so over the weekend I messed around a bit (still have excess of 2 weeks to work on this)

I did the retrosynthesis in different ways:

Method 1: https://imgur.com/eVlyn7h

Method 2: https://imgur.com/6TUE1Ws

Are both methods wrong? Is either method correct? Any adjustments to make to either method? Which method is more applicable?

[rolnor]

In method 2 you do a aldol with a alkene as nucleophile, how do you think this should work, are protons alpha to alkene double-bond acidic? You are on the right track but needs some adjustments.

[yourdeath01]

Actually I kinda revamped it a little bit, here is how we go all the way back, if you like this then I can show you how we move forward, let me know what the initial retro is missing!

1: https://imgur.com/JDhkZUO

2: https://imgur.com/jqmXgwU

We start off with a bond disconnect next to the ether (guessing that's called alpha carbon?) > then to we have acylation (I think its called) > we move on by disconnecting the alkene and that's asumed their a ketone there > once we disconnected the alkene and have a ketone a simple yilde attached > 3rd disconnect is in the middle between the two molecules > both molecules are hydrated > molecule on the left I am kinda not too sure if that's the final molecule? > molecule on right we perform another aldol to lose OH and make the alkene > which is followed by another aldol to form the molecule initially.

I just did this right now and probably missing some details but what you think so far?

[rolnor]

Actually I kinda revamped it a little bit, here is how we go all the way back, if you like this then I can show you how we move forward, let me know what the initial retro is missing!

1: https://imgur.com/JDhkZUO

2: https://imgur.com/jqmXgwU

We start off with a bond disconnect next to the ether (guessing that's called alpha carbon?) > then to we have acylation (I think its called) > we move on by disconnecting the alkene and that's asumed their a ketone there > once we disconnected the alkene and have a ketone a simple yilde attached > 3rd disconnect is in the middle between the two molecules > both molecules are hydrated > molecule on the left I am kinda not too sure if that's the final molecule? > molecule on right we perform another aldol to lose OH and make the alkene > which is followed by another aldol to form the molecule initially.

I just did this right now and probably missing some details but what you think so far?

I think the first method could be OK, there is risc with the aldol because your product in this step is also a ketone and can react further with nucleophile. This is a common problem in aldol but you will get some of the desired product.

[yourdeath01]

You got a chance to look at this one (2 pages)?

1: https://imgur.com/JDhkZUO

2: https://imgur.com/jqmXgwU

[rolnor]

It looks possible. As I say the aldol with 2 cyclohenanones can bli messy but it will probably give you some product. The target molecule will have som strain because of the isopropyl and the cyclohexyl are a bit stericaly crowded, this could make the synthesis more difficult.

[yourdeath01]

Awesome

I showed the above to some1 else and they suggested the following:

> There’s a reaction called the Vilsmeier-Haack which will add a formal group (-CHO) to anisole. That will make the benzaldehyde starting material you need.

> The homogeneous aldol-dehydration reaction with cyclohexanone will protect one side of the product ketone, so should be done early. That will allow the crossed aldol with p-methoxybenzaldehyde to proceed without complications.

What you think about those suggestions?

[rolnor]

Awesome

I showed the above to some1 else and they suggested the following:

> There’s a reaction called the Vilsmeier-Haack which will add a formal group (-CHO) to anisole. That will make the benzaldehyde starting material you need.

> The homogeneous aldol-dehydration reaction with cyclohexanone will protect one side of the product ketone, so should be done early. That will allow the crossed aldol with p-methoxybenzaldehyde to proceed without complications.

What you think about those suggestions?

I think you need more activated aromatic compounds for Vilsmeyer, like dimethylaniline. A methoxy is not enough but I am no expert on this.
Yes, its good to make the aldol like you suggest. One thing to bear in mind is that the dehydrated compound is a activated alkene that can do Michael-type additions so it can polymerize under basic conditions.

[yourdeath01]

I made another one which is kind of similar to the one I posted above but I was wondering if my starting material is all good?

https://imgur.com/mTGnoGh

Not sure if I should use this one or the ones above, thoughts?

[rolnor]

I made another one which is kind of similar to the one I posted above but I was wondering if my starting material is all good?

https://imgur.com/mTGnoGh

Not sure if I should use this one or the ones above, thoughts?

If you try to alkylate with the ketone present like this you will get alkylation of the alpha-position of the ketone. Also you have acidic alpha-protons on both side of the keton-carbonyl so its hard to do the aldol on just one side.

[yourdeath01]

Never mind then I will stick to my original one.