[Weiman]

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:

• Pyridine in 5: Xiong, X.; Bagley, M. C.; Chapaneri, K. Tetrahedron Lett., 2004, 45, 6121-6124.
• Reduction in 10: Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc., 1990, 112(19), 7050-7051.
• IMDA in 11: (a) Burke, L. T.; Dixon, D. J.; Ley, S. V.; Rodríguez, F. Org. Lett. 2000, 2, 3611. (b) Burke, L. T.; Dixon, D. J.; Ley, S. V.; Rodríguez, F. Org. Biomol. Chem. 2005, 3, 274.
  

https://imgur.com/u5xHFeM

[OrganicDan96]

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.

[Weiman]

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 

[AlphaScent]

TEMPO oxidation for the late stage oxidation of alcohol to acid.  Also Pinnick oxidation.

[AlphaScent]

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.

[rolnor]

Jones and TEMPO will oxidise the ditian i think.

[AlphaScent]

Dithiane oxidation is correct, but as OrganicDan says, just use a ketal.

[rolnor]

I think it could be some problem with ketal-protection, the TBDPS-group can cleave, at least partially.

[OrganicDan96]

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

[Weiman]

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! 

[Weiman]

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.

[zarhym]

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).

[Weiman]

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.