Retrosynthesis with Hypervalent Iodine

[@CasualChemistry]

1:41 CORRECTION: The Diels-Alder transition state drawn is correct but it should have been labelled as the ENDO TS (not the exo). I don't know what my brain was thinking at the time when recording...

[@anthonytam1803]

I love these kinds of videos where you bring in some really fundamental work from synthetic organic chemistry, keep it up!

[@CasualChemistry]

Thanks :) More on the way for sure. I'm getting some ideas from my in-person teaching that I'm doing a fair bit of for a couple more weeks.

[@That_Chemist]

4:43 this is such a good use of the Stetter

[@CasualChemistry]

Certainly an under-appreciated reaction and am very happy to give it some air-time 🙂

[@ephemeral2552]

Another thanks for showing the Stetter reaction. Ive been using it in a lot of retrosyntheses since seeing it here!

[@CasualChemistry]

Nice 🙂 great reaction to have in your retrosynthesis toolkit

[@antozon5070]

Fantastic video as always! But isn't the reaction product at 8:44 achiral due to the mirror plane that runs from carbon 1 to 4 in the former p-cresol (methyl group and ethylene glycol in plane)? I believe that's not until the Stetter reaction a racemic mixture is generated, because attack can occur on either the "left" or the "right" side of the unsaturated ketone, breaking the mirror plane.

[@CasualChemistry]

Excellent point - that is my bad doing the recording/editing late in the evening... I think I've been able to make a quick snip to fix the video. I'd even been talking about desymmetrisation of that intermediate earlier in the video - whoops!

[@theonearney205]

Amazing as ever!

[@CasualChemistry]

Thanks :)

[@wk5340]

properly short running time of video, and also it's almost accurate. nice

[@CasualChemistry]

Thanks 🙂 I’ve been experimenting with pacing on these videos

[@davide2555]

Wow this was awesome

[@CasualChemistry]

Thanks 🙂

[@keremdiren8590]

great video

[@CasualChemistry]

Thanks 🙂

[@keane6309]

Hi, just came across your channel. Love the videos. Could you do a video on the retrosynthesis of prasugrel?

[@CasualChemistry]

Thanks 🙂 interesting - I’ll have a think about it. I usually pick molecules based on there being some underlying idea that I haven’t done a video on already. I’ll have a think cos I haven’t really done one on thiophenes yet. I’m just finishing up my in-person teaching for a while so I’ll be back on the video production again soon as my calendar is now back in my control.

[@victordonchenko4837]

Very interesting video. At 9:18, why won't the BnCl alkylate the sulfur?

[@CasualChemistry]

Hmm. I’d imagine if that reaction occurred it would be highly reversible - the S plus being a really good leaving group for SN2 of another nucleophile and the N alkylated product is the thermodynamic one because of a stronger C-N bond vs C-S.

[@huutrongphannguyen2908]

Hi, thanks for the video. Just a little confuse at the Diels Alder. I think the product is endo right?

[@CasualChemistry]

Good spot! Sorry that’s my mistake that I’m quite surprised I didn’t spot when doing this. What I’ve drawn is correct and that is the “endo TS” drawn. I’ll pin a correction to the comments

[@dohnjoe5401]

Great video as always! I've seen you mention that you taught chemistry at the graduate level -- what textbooks did students typically use when learning retrosynthetic analysis at this level?

[@CasualChemistry]

A really good set for Masters/early-PhD is to spend some time with all 3 volumes of Classics in Total Synthesis. Though to be honest a lot of this comes from experience with research papers. One of the most effective things to do in a lab setting it to get a group of say 4 people together and set a target to work on and discuss it frequently over the course of a few weeks as you learn what other patterns other people spot, and there’s not really one correct answer. I think practice on bigger problems that initially seem impossible is where I learnt the most.

[@yourfriendlyneighborhoodqu3859]

I’ve finished my orgo book and was wondering if you have any recommendations for books to get cause you seem to know a lot of interesting reactions. Great video as always

[@CasualChemistry]

Thanks for the feedback 🙂Tricky to judge a level that might be appropriate here but assuming forwards the end of an undergraduate chemistry course, a good place to go can be any of the “Classics in Total Synthesis” range and “Named reactions in organic synthesis” can be a good introduction to more advanced techniques.

[@ephemeral2552]

Appreciated the video! Havent seen the Stetter reaction before so that was nice:) You mentioned that you couldve used cyanide for umpolung instead but that itd be toxic. Would there be any downsides to doing the umpolung through the dithiane?

[@CasualChemistry]

Thanks 🙂 Probably would be fine using the dithiane as it’s intramolecular but those things can be a bit hard (as in less soft) so the reactivity pairing isn’t perfect. You’d have to be careful how you’d install a dithiane in this particular molecule as there is scope of other reactions with the S lone pair able to do a Michael addition as well before the dithiane forms.

[@CasualChemistry]

I guess one of my main motivations for this particular video was to raise awareness of the Stetter as I’m aware it often flies under the radar, but it’s more common nowadays in research to see it rather than some of the things that are traditionally found in textbooks.

[@ephemeral2552]

@@CasualChemistry Tysm

[@ephemeral2552]

Or it may be a bit wrong to reason it like that. The enamine prmotes conjugate addition and theres a good site for that intramolecularly thus it is prefered compared to the other intermolecular reactions. Right?

[@CasualChemistry]

Yes, the second comment is correct. The Stetter can also work intermolecularly if that’s an option. It’s probably best seen as a functional group tolerant way of doing umpolung without having to pre-make anything else first. (Note: the enamine that’s made along the way is often referred to as a Bresliw intermediate if you’re looking into these things - I forgot to say that in the video)