[Rutherford]

I thought to practice synthesis, so I've chosen to synthesize a molecules similar to the aflatoxins (I'm not sure whether it has been synthesized yet). I need someone to check the synthesis and find which steps are not so promising and why; propose a better alternative to a step. The target molecules is a racemic mixture.

[Rutherford]

I've noticed that the last step won't be so chemoselective so maybe the less sterically hindered hydroxyl group should be protected first.

[phth]

  I would try this.  The iodine+phosphine ref is DOI: 10.1055/s-2005-918521.  Easier to start from phloroglucinol, IMO.

[Shadow]

Very interesting sequence .  I like the usage of Julia olefination, but how would you carry it out? I have some feeling that the phenol groups will interfere. What is the role of the iodine complex? Is the first reagent (the protected diol) available?

@OP Yes, the chemoselectivity of the esterification is bad.

[phth]

Whoops, yeah Na amalgam would mess with the aromatic group.  It should be pretty easy to use a photocatalyst to remove H· form the benzylic position, so I still think the route is still viable.  The tetrahedral P salt goes to pentavalent P and it gets oxidized.  This method has the atvantage of almost quantitative yield in 30 min for acetonation, lower amounts of acid (it can be removed), and removes water as a latent nucleophile which is good for sensitive molecules.  The intermediate goes through sp2 carbonyl transition state not SN2 I did not include that in the image .

[Rutherford]

An interesting alternative. How would you continue from that? Any feedbacks regarding my scheme?

[phth]

From the beginning we could tether phloroglucinol to a polymer/protect by creating a mono benzyl ether linkage which will erase the problem of chemoselectivity generating the second ring system.  Using MeNO₂ to catalyze FC acylation can be easily controlled to get either kinetic or thermo pdts.  The benzyul ether can be deprotected using a photocatalyst, and it might interfere some with the acetal, but I think the yield will be better than what you proposed. 

[orthoformate]

The Friedel-Crafts to cyclobutanone may be tricky because the two methoxy groups do not direct to the site you proposed.

Also, I think the birch reduction product you gave is unlikely. I would guess the sodium would reduce the phenol OH producing H₂ and 2 5-cyclohexadienone

[yzlou]

my opinion is taht it is not a desirable route to synthsize your targeted molecules.  so you can see https://en.wikipedia.org/wiki/Aflatoxin_total_synthesis

[Rutherford]

The Friedel-Crafts to cyclobutanone may be tricky because the two methoxy groups do not direct to the site you proposed.

Also, I think the birch reduction product you gave is unlikely. I would guess the sodium would reduce the phenol OH producing H₂ and 2 5-cyclohexadienone

It's intramolecular and only that position can possibly react. Yes, I made the same mistake, the phenol needs protection first.

[orgopete]

my opinion is taht it is not a desirable route to synthsize your targeted molecules.  so you can see https://en.wikipedia.org/wiki/Aflatoxin_total_synthesis

I don't see this as helpful. Any synthesis can be done many different ways. If this is about learning, then the published route is simply different.

This is how I see this problem, especially as a learning exercise. I often started out my synthesis planning with trying to learn about what chemistry is known and what reactions work well. In this case, I might have started with phloroglucinol. Introducing a single substituent would still give a symmetrical molecule. A second substituent would make it unsymmetrical. If you were to make the lactone, this would leave the two OH groups open. If doing real chemistry, one could just try the next ring closure. This could go 50:50, preferably the desired or the undesired. If it gave the undesired, then you could try a selective protection reaction. Again, the two OH groups are different, so it wouldn't be unreasonable to expect that one might react faster than the other. If not, then one could start with a protected form of the phloroglucinol and step your way through it.

I guessing the literature may already provide some answers to the chemistry I am speculating about. I also appreciate how your proposed route can be like routes I may have proposed until I developed more skill or knowledge as to what may actually work. I believe the reality is natural product synthesis is strewn with failed routes. That is the price of learning. 

[phth]

my opinion is taht it is not a desirable route to synthsize your targeted molecules.  so you can see https://en.wikipedia.org/wiki/Aflatoxin_total_synthesis

I don't see this as helpful. Any synthesis can be done many different ways. If this is about learning, then the published route is simply different.

This is how I see this problem, especially as a learning exercise. I often started out my synthesis planning with trying to learn about what chemistry is known and what reactions work well. In this case, I might have started with phloroglucinol. Introducing a single substituent would still give a symmetrical molecule. A second substituent would make it unsymmetrical. If you were to make the lactone, this would leave the two OH groups open. If doing real chemistry, one could just try the next ring closure. This could go 50:50, preferably the desired or the undesired. If it gave the undesired, then you could try a selective protection reaction. Again, the two OH groups are different, so it wouldn't be unreasonable to expect that one might react faster than the other. If not, then one could start with a protected form of the phloroglucinol and step your way through it.

I guessing the literature may already provide some answers to the chemistry I am speculating about. I also appreciate how your proposed route can be like routes I may have proposed until I developed more skill or knowledge as to what may actually work. I believe the reality is natural product synthesis is strewn with failed routes. That is the price of learning.

+1

[Rutherford]

my opinion is taht it is not a desirable route to synthsize your targeted molecules.  so you can see https://en.wikipedia.org/wiki/Aflatoxin_total_synthesis

I don't see this as helpful. Any synthesis can be done many different ways. If this is about learning, then the published route is simply different.

This is how I see this problem, especially as a learning exercise. I often started out my synthesis planning with trying to learn about what chemistry is known and what reactions work well. In this case, I might have started with phloroglucinol. Introducing a single substituent would still give a symmetrical molecule. A second substituent would make it unsymmetrical. If you were to make the lactone, this would leave the two OH groups open. If doing real chemistry, one could just try the next ring closure. This could go 50:50, preferably the desired or the undesired. If it gave the undesired, then you could try a selective protection reaction. Again, the two OH groups are different, so it wouldn't be unreasonable to expect that one might react faster than the other. If not, then one could start with a protected form of the phloroglucinol and step your way through it.

I guessing the literature may already provide some answers to the chemistry I am speculating about. I also appreciate how your proposed route can be like routes I may have proposed until I developed more skill or knowledge as to what may actually work. I believe the reality is natural product synthesis is strewn with failed routes. That is the price of learning. 

Thanks for the feedback. I may actually try to devise a route using phloroglucinol as the starting material.

[orgopete]

You might also think more broadly as you work your way through. Phloroglucinol may be commercially available, but it was synthesized from trinitrobenzene (a route shown in Wikipedia). You may consider other possible starting materials or derivatives as you encounter different issues of selectivity or reactivity. For example, I would many times write out routes in which I varied my connections between nucleophiles, electrophiles, or radical connections. You may be able to find examples for all three, but the reactions themselves may be far superior for only one of them.

[Rutherford]

Introducing the double bond in the five membered ring is the major problem for me in the route starting from phloroglucinol. A halide or amine that eliminates have a big issue on reactivity (immine formation, oxygen attacking the halide...). Julia olef. seems like the best option, but removal of the phenolic hydrogens is required first. Any better suggestions about introducing the double bond?