[jm250]

Hi guys I was wondering what people's ideas might be regarding for a retro-synthesis for the compound cytosporin-D shown in the attachment. (Sorry its in a .doc format, I'm having linux issues!). 

At the moment I'm considering an approach involving an epoxidation (sharpless due to allyl alcohol?) then a payne rearrangement to "migrate" the epoxide and leave an oxygen anion which could perhaps ring close the THP group? Halide displacement?

Any comments on this approach or any alternative routes to these functionalities or others within the compound would be greatly appreciated.

[CaverKat]

Can you show your proposed disconnection for the THP ring closure oxygen anion step?  Just a bit confused...

(Still working on it, though.  Nice challenge)

[jm250]

Hi CaverKat (and all), pleased to see someone is getting involved! I'm not sure the oxygen anion thing is going to work to be fair, i just wondered if sticking a chlorine or something on the end of a previously attached side chain would serve as a good enough leaving group  (as in 2 methyl groups and a halogen on the end of the chain) it was kinda a first thought. At the moment I'm looking at a BF3 catalysed ring closure of the alcohol onto a terminal (methyl substituted) alkene instead. This way, upon addition, the alkene opens up to form the second methyl group. Inspiration came from this paper:

http://www.sciencedirect.com/science/article/pii/S0040403904013644
(Tet Lett, Vol 45, Issue 32, 2 August 2004, Pages 6097-6100)

Still trying to work out how to post images. Will get there soon.
Thanks for your interest. 

[jm250]

Hey, this is the disconnection you asked for (the idea described in the original post). It may well be nonsense, what do you reckon?

[jm250]

Sorry if the attachment above does not work. Try this one ...

[CaverKat]

Nice.  How are you going to control the stereochemistry of the diol?

My brain wants me to go this way with this problem (let me know if you want a picture, but I'm being lazy atm):
Keep your first disconnection.  Instead of Payne rearrangement, go for sharpless epoxidation followed by resolution (got the 2,3 secondary alcohol).

Maybe because I'm unfamiliar with the Payne rearrangement.  Wonder what stops it going aromatic...

[orgopete]

Hey, this is the disconnection you asked for (the idea described in the original post). It may well be nonsense, what do you reckon?

Is this a let me count the ways?

The ether cleavage, tertiary vs allylic? Allylic -> aromatic?
The Payne, okay, but what is going to be the controlling factors here?
Won't it also reverse your original ether cleavage and reform that bond? (Base to from a dimethyl epoxide and open this through a Payne-like epoxide opening.)

Let me also give a disclaimer. I am not an expert in this chemistry. There may well be reagents that can selectively affect one or more of these oxygen atoms. It is just my opinion that a presumed reaction with HCl could hit any oxygen atom as they appear to be of similar basicity and that furthermore, cleavage would be an unimolecular cleavage to form the most stable carbocation intermediate. For all I know, the proposed reaction is a known transformation, but just not to me.

[By the way, if you posted a jpg of your scheme rather than a doc, we could have viewed it within the forum.]

[jm250]

@ CaverKat:

Yeah, this compound does seem to be crying out for a sharpless.

One concern is the presence of other alkene moieties which would also be epoxidised. The cyclohexene alkene (on the left side of the ring) also has a 2,3 alcohol which perhaps could be selectively protected as it is primary. However, this protection would surely only remove the stereoselectivity of a sharpless epoxidation rather than preventing the epoxidation form occuring at all at this position?

While creating a syn diol is relatively easy I'm not sure how I would impart the absolute stereochemistry at these positions, no. Bit of a problem!

Also, I'm not quite sure what you mean about it going aromatic. Could you explain?

Thank you so much for your interest, its really appreciated.

[jm250]

@ orgopete:
I'm a bit confused by your post:

"The Payne, okay, but what is going to be the controlling factors here?
Won't it also reverse your original ether cleavage and reform that bond? (Base to from a dimethyl epoxide and open this through a Payne-like epoxide opening.)"

 I agree that the formation of the dimethyl epoxide on the side chain would occur. However, assuming  the first Payne rearangment (on the cyclohexene ring) would occur, this would result in an oxygen anion which would in turn carry out the second, Payne-like epoxide ring opening (the one you refer too in your post?). This would form the ether link in the THP ring closure. Which is what I want ... formation of the compound on the left of the reaction scheme. (Those are retrosynthetic arrows.)

Or have I completely missed your point? Are you thinking the primary allyl alcohol would be involved in these steps. Perhaps to create a eight membered oxocane ring instead of the THP ring? Would selective protection of this alcohol (silyl ether) not be possible?

[orgopete]

My thinking is as follows. The Payne rearrangement you are showing you wish to have occur is simply an equilibrium. It will give the most stable product. If you had a series of alcohols, you could migrate your epoxide from one end to the other. Since you have two alcohols that can react, what factors are present that indicate it will result in the epoxide you have shown? Could it not react with the bottom OH-group? If the Payne must open at a tertiary center, then why couldn't the oxygen also open at the tertiary center of the new formed epoxide?

Thinking further on this, I've never made an epoxide in which the halide as tertiary. Will they form an epoxide or will it simply eliminate to an allylic alcohol?

Ugh, I just realized you wrote your synthesis backwards. Okay, if success of the Payne requires opening the epoxide at a tertiary center. The newly formed epoxide could react with the bottom OH at a secondary center. I will guess the rate of this reaction will be faster then opening of the epoxide at a tertiary center. Won't this equilibrate to the epoxide at the bottom? What about the other two OH groups? Can either of them react?

If this were me, this is what I would do. I know there are a number of compounds with similar functionality. I would review as much of this chemistry as I could. I would take note of which reactions worked the best and which ones merely succeeded. I would try to use what I learned to propose new chemistry. After a talk with my boss, I used to keep the phrase, "Stick to what you know will work" on the glass doors of my hood. I too had a lot of good ideas, but my boss also wanted to see progress.

Okay, I am going to go one step further and ask you to do some library work. I have written a simple model of your reaction. You are proposing the reaction to go to the center. I think it will go to the right. I think the center compound is a known compound or ought to be. It is the epoxide of the bromination of isoprene and then treated with base. Is this a known reaction and if so, what is the product?

[jm250]

@ orgopete:
 
Thanks for your advice, I hadn't thought of the bottom OH ring closing on the dimethyl epoxide, fair point. Yeah I have been looking through papers where similar functionalities have been synthesised. My boss said he liked the idea of using a payne opening of an epoxide and I was just wondering in which ways this could be applied to the molecule. This probably wasn't what he meant!

Cheers for your help.