[Alwin Kristen]

Here is my suggestion for retrosynthesis. Protection-groups probalby is needed during synthesis.

Ref:

A.R. Surrey, Name Reactions in Organic Chemistry, 1954
E.J. Corey; X. Cheng, The Logic Of Chemical Synthesis, 1989
J. Clayden; N. Greeves; S. Warren, Organic Chemistry, 2 ed., 2015

[Alwin Kristen]

May I ask why you needed this retrosynthesis so badly?

[nayeee1m]

Alwin . I really need it badly..Would you like to help me ?

[nayeee1m]

This is a natural product given by my professor. I gave some retro synthetic analysis. He did not like it and gave more 1 week to analyze. I tried my best . I did very good in more smaller compound but stucked in this big compounds.

[Alwin Kristen]

did you see those attached files at my last post?

[nayeee1m]

Yes I saw thank you very much for your help.. I will analysis those step more.. If  you check my later on comment, I made some correction and changed that terminal isopropyl group to acitamide group. I think the one you showed  will not very different with acitamide group.. Thanks again for your help 

[Alwin Kristen]

For acetamide you can do, as a retrosynthesis, Bechmann rearrangement to get ketone. Then you can do Nenitzescu Reaction to get double bond. With Wittig you can break that to pieces...

Other way around --> wittig to make doublebond, Nenitzescu to make ketone, Bechmann to make acetamide.

[nayeee1m]

You are very good in retrosynthetic. No confusion about it. May I know which school you are going to ?

[Alwin Kristen]

I study chemistry at University of Oulu in Finland.

[Guitarmaniac86]

I've been looking at this compound for a while and I wonder if this could be made with a few ring closing metathesis reactions and/or maybe a radical cascade reaction to make some of these rings, it could save several steps going about it through more traditional chemistry... If I think of any mechanisms I ll draw something out on here.

Alwin Kristen, I like your retrosynthenthesis plan. However, I assume in your Wittig step that the cyclopentane ring requires a halogen to make the ylide, otherwise I do not see this step working.

[Alwin Kristen]

Thanks 

Yes... it does need a halogen. I gave this molecule a second tought with diels-alder as transfer-goal. It gave quite good results. Result of this retrosynthetic pathway is two equally sized molecules. According to E. J. Corey, it is good thing.

Robinson annulation could also do the trick nicely.

[Guitarmaniac86]

Here is my idea. A couple of ring closing metathesis'. I need to think more on how to get to the last product. I was thinking of some radical cascades but I need more time to read up.

Danishefsky has made similar looking natural products using ring closure metathesis and domino or radical cascades.



The first step is a standard ring closure metathesis which closes up the diene. The second step is synthesising the diene components. I have not thought much about how to introduce the allyl alkene and I suspect that converting the tertiary OH to a mesylate or tosylate would preferentially lead to elimination.

The next step introduces the second part of the diene. It would need to be a grignard, lithium cuprate or some other moiety. Next I have another ring closure metathesis. These are good for large rings which is why I thought of them, though efficiency is going to be an issue and the double bond would need to be reduced.

Skip forward we have a friedel crafts reaction and the last step I really have not throught through, but I have a Suzuki coupling to the pyridine ring.

I biased this synthesis to start from pyridine because its cheap. Also, I suspect this will affect yields and the reactivity will be vastly different than if this was benzene.

I looked up radical cascade reactions (dominio reactions) for the synthesis of morphine and tried to apply it to OP's question but I cannot figure out a way to do it without have a lot of double bonds to reduce later, and reducing them specifically whilst leaving the double bond in the SM alone...

Edit: I am aware that the double bonds in some of the compounds are likely to re-arrange into a more stable configuration as well. This retrosynthesis idea is far from perfect.

[Alwin Kristen]

Looks good. Introducing allyl alkene could work with allylic anion (grignard maybe) by Sn1 reaction OTs as leaving group in polar solvent.

How would you activate pyridine against electrophilic substitution?

[Guitarmaniac86]

I'd most likely start from pyridine N-Oxide or similar moiety as it is known that electophilic aromatic substitution does not occur fully due to co-ordination of the reagents to the nitrogen lone pair.

Although saying that, pyridines could undergo nucleophilic substitutions... So there are otherways of introducing elements into pyridine.