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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Weiman on February 22, 2019, 12:27:57 PM

Title: Roast my retrosynthesis
Post by: Weiman on February 22, 2019, 12:27:57 PM
This is a retrosynthesis plan I've been working on for a senior undergraduate organic synthesis class. I would appreciate any criticism/feedback on any of the steps of the proposed plan. My biggest concerns are my use of protecting groups and the general feasibility of isolating/purifying each compound.

Thank you!

Here are the papers for some of the more important reactions:

https://imgur.com/u5xHFeM
Title: Re: Roast my retrosynthesis
Post by: OrganicDan96 on February 22, 2019, 02:08:18 PM
too stepwise, a convergent synthesis would be far better.
it is most likely unnecessary to form that pyridine ring, there must be a way to install that ring in one piece (maybe grignard to an aldehyde or some sort of metal catalysed reaction
I wouldn't use mercury if you can avoid, an acetal would be far better. doing a Jones oxidation at such a late stage of a long synthesis is a bad idea as your molecule may not tolerate the acid. there are many better conditions.

i dont have time to go over this in detail but you should first consider these points.
Title: Re: Roast my retrosynthesis
Post by: Weiman on February 22, 2019, 03:46:50 PM
too stepwise, a convergent synthesis would be far better.
it is most likely unnecessary to form that pyridine ring, there must be a way to install that ring in one piece (maybe grignard to an aldehyde or some sort of metal catalysed reaction
I wouldn't use mercury if you can avoid, an acetal would be far better. doing a Jones oxidation at such a late stage of a long synthesis is a bad idea as your molecule may not tolerate the acid. there are many better conditions.

i dont have time to go over this in detail but you should first consider these points.

These are excellent points! Thank you so much  :)
Title: Re: Roast my retrosynthesis
Post by: AlphaScent on February 22, 2019, 04:03:35 PM
TEMPO oxidation for the late stage oxidation of alcohol to acid.  Also Pinnick oxidation.
Title: Re: Roast my retrosynthesis
Post by: AlphaScent on February 22, 2019, 04:09:18 PM
As OrganicDan said, I would think about the chemistry you can do with the product of the treating pyridine with bromine in the presence of an acid.
Title: Re: Roast my retrosynthesis
Post by: rolnor on February 23, 2019, 06:29:40 AM
Jones and TEMPO will oxidise the ditian i think.
Title: Re: Roast my retrosynthesis
Post by: AlphaScent on February 23, 2019, 10:30:13 AM
Dithiane oxidation is correct, but as OrganicDan says, just use a ketal.
Title: Re: Roast my retrosynthesis
Post by: rolnor on February 23, 2019, 12:01:42 PM
I think it could be some problem with ketal-protection, the TBDPS-group can cleave, at least partially.
Title: Re: Roast my retrosynthesis
Post by: OrganicDan96 on February 23, 2019, 01:29:32 PM
to be honest i'm not sure it even needs to be protected, the only the thing the protecting group is there for is the deprotection of that silyl ether and an oxidation a ketone should tolerate that
Title: Re: Roast my retrosynthesis
Post by: Weiman on February 23, 2019, 01:40:30 PM
As OrganicDan said, I would think about the chemistry you can do with the product of the treating pyridine with bromine in the presence of an acid.

Definitely gonna rethink this pyridine part of my synthesis. Thank you AlphaScent!  :)
Title: Re: Roast my retrosynthesis
Post by: Weiman on February 23, 2019, 01:43:35 PM
to be honest i'm not sure it even needs to be protected, the only the thing the protecting group is there for is the deprotection of that silyl ether and an oxidation a ketone should tolerate that

The dithiane or ketal protection was more to avoid cyclization after deprotection of the silyl ether.
Title: Re: Roast my retrosynthesis
Post by: zarhym on February 25, 2019, 11:11:59 PM
I do find a paper with similar structure of your target molecule.
https://www.nature.com/articles/nchem.2112

You can may consider the naphthalene ring formation method in this paper (compound 17 to 19).
The actual synthesis work of the target molecule is tremendous.

Although you are doing retrosynthesis for this molecule, I do suggest you find some paper with similar skeleton frame for reference.

Besides, I realize that there are many chiral centers in your molecule. Maybe you can bring some of these chiral centers by using chiral starting material which is abundant in nature (such as chiral amino acids).
Title: Re: Roast my retrosynthesis
Post by: Weiman on February 26, 2019, 07:11:41 PM
I do find a paper with similar structure of your target molecule.
https://www.nature.com/articles/nchem.2112

You can may consider the naphthalene ring formation method in this paper (compound 17 to 19).
The actual synthesis work of the target molecule is tremendous.

Although you are doing retrosynthesis for this molecule, I do suggest you find some paper with similar skeleton frame for reference.

Besides, I realize that there are many chiral centers in your molecule. Maybe you can bring some of these chiral centers by using chiral starting material which is abundant in nature (such as chiral amino acids).

Thank you for this! Some of these reactions are very interesting and I may be able to integrate into my retrosynthesis.