August 14, 2020, 04:02:00 PM
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Topic: Help with diastereoselective synthesis  (Read 321 times)

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Offline Rictiovarus

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Help with diastereoselective synthesis
« on: April 01, 2020, 07:04:35 PM »
Hey,

I have been working on this synthesis proposal, and have been stuck at one major diastereoselective transformation:
https://prnt.sc/rr63oy

I have gone through a number of pathways but all have led to some roadblock. Does anyone have any suggestions of a way I could go about achieving this?

Thank you

Offline Babcock_Hall

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Re: Help with diastereoselective synthesis
« Reply #1 on: April 01, 2020, 09:49:11 PM »
Can you show us what you have tried so far?

Online rolnor

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Re: Help with diastereoselective synthesis
« Reply #2 on: April 02, 2020, 12:17:46 PM »
Maybe its possible to brominate to make a tertiary bromide, then react this with lithiated 1,3-dithiane, this must be converted to a copper-derivative first or it will attack the ketone. Then use Tebbes reagent to make the double bond from the ketone and last deprotect the dithiane to the formyl. The 1,3-dithiane reagent should attack from the  side you want because there is so much steric hindrance from the other side snd the tertiary bromide gives SN1.

Online rolnor

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Re: Help with diastereoselective synthesis
« Reply #3 on: April 02, 2020, 04:14:05 PM »
Sorry, I missed your post Babcock-Hall. I guess this is a natural-product synthesis with some really elegant solution.

Offline Rictiovarus

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Re: Help with diastereoselective synthesis
« Reply #4 on: April 02, 2020, 08:41:53 PM »
Can you show us what you have tried so far?

Both of my strategies I have come up with involve an initial epoxidation, whether that be diastereoselective (through coordination with the OBn) or asymmetric, like a shi-epoxidation, followed by some sort of ring-opening and alterations.
Pathway 1. http://prntscr.com/rrxvfd
In pathway 1 I am counting on the relatively labile TMS group to fall off at some point before or during the tosylation, since a fluoride source would also deprotect, at least partially, the TBS group too. The TMS-CN reaction with the zinc iodide catalyst does have high regiochemical selectivity which is an upside to this reaction.
Pathway 2. https://prnt.sc/rrxwls
My main issue with pathway 2 is that I am worried cyanide wouldn't have that great of a diastereoselectivity here, and I am having difficulty finding an alternative. I am also worried about directing the epoxide with. In theory, the Ti(O-I-Pr)4 may coordinate to the OBn group and direct the peroxide (similar to a Sharpless epoxidation), but that peroxide will also want to attack from the other side due to the bulky Bn protecting group itself.

Offline Rictiovarus

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Re: Help with diastereoselective synthesis
« Reply #5 on: April 02, 2020, 08:43:32 PM »
Maybe its possible to brominate to make a tertiary bromide, then react this with lithiated 1,3-dithiane, this must be converted to a copper-derivative first or it will attack the ketone. Then use Tebbes reagent to make the double bond from the ketone and last deprotect the dithiane to the formyl. The 1,3-dithiane reagent should attack from the  side you want because there is so much steric hindrance from the other side snd the tertiary bromide gives SN1.
I really like this idea actually, I'll look into it. Thank you!!!

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