Retrosynthesis 11 - Organic Chemistry

[@PoppiD93]

Excellent video, thank you!

[@CasualChemistry]

🙂

[@kendalldoer5466]

Very cool!! I haven’t seen that homologation chemistry before really - good use of the Wittig rxn.

[@CasualChemistry]

A favourite sneaky retro trick of mine, particularly useful for cyclohexene disconnections 🙂

[@singularityJoe]

Alkynylation would probably give you a mixture of diastereomers here. You could try cuprate mediated vinylation of the acid chloride then asymmetric reduction to set the alcohol. Maybe if you do the DA afterwards you can use some kind of directing catalyst to render it diastereoselective

[@CasualChemistry]

I think you’re right here. I’d be a bit wary of the vinylation particularly with the Z-cuprate as I’ve not had the best experience with them on scale. I took the direction in the video of ignoring for keeping the pitch a bit less advanced, and I wanted to deliberately raise awareness of the aldehyde homologation. I agree the asymmetric reduction is a good way to set the stereocentre absolutely. To be honest from the point of view to minimising effort and lab time, doing the alkynylation to the mixture and oxidising up to the ketone with something like DMP and then probably a CBS reduction would probably cause the least grief. Notionally an extra step but the reactions are usually quick and the work-ups for both are usually very easy. Using that stereocentre afterwards to direct the DA might be tricky given the distance but but there are lots of catalysts out there so something probably would work as a starting point.

[@oanhtran2784]

Dear Casual Chemistry, The Diels-Alder reaction led to the formation of a mixture of enantiomers. How could we solve this problem?

[@CasualChemistry]

If you need the anti relationship but as one enantiomer of the intermediate, there are a few options. You could try using organocatalysis with MacMillan-type catalysts. I have another video on this topic - Nobel Prize 2021 Part 2 - so you could find out about it there. It might be possible to use an oxazoborolidinone asymmetric Lewis acid catalyst - control coming from activation of the carbonyl by the boron centre and then locking the structure with an internal non-classical formyl hydrogen bond before the intermolecular Diels-Alder. I have another video on similar catalysts as part of the CBS reduction. I have another video on that if you want more details of the catalyst structure. Otherwise you’d probably need to change temporarily away from the aldehyde oxidation state and make say an imide with an oxolidinone ring. Then you’d have a pattern that could work as a bidentate ligand for an asymmetric Lewis acid catalyst - for example a Cu-BOX setup. You’d need to reduce back to the alhdehyde afterwards.

[@JustSomePersonOnline]

Please do more, I love your videos

[@CasualChemistry]

🙂 Thanks for the feedback. Definitely more coming. I have 2 more weeks of intense in-person teaching but I have my next few planned out already.

[@ThatChemistOld]

You could have also made the propargyl chloride and reacted it with sodium acetate or silver acetate to avoid the protection/deprotection

[@CasualChemistry]

Fair point. I’ve just had a lot of positive experience from the silyl ether on and off in practice - usually very high yielding both ways. My background is in total synthesis so I normally lean towards choosing high yield and quick/clean, with minimal purification, even if it means an extra step.

[@ThatChemistOld]

@@CasualChemistry I’ve done a ton of silver chemistry - they usually go to completion in my experience, with bromides anyway; since it’s an alkyne you might need to do the Lindlar reduction first, if you decide to employ the silver salt (p.s. I’m a methods chemist)

[@CasualChemistry]

That’s cool. There are definitely alternative routes to this molecule, including other C-C bonds to choose as disconnections. I went this way also partly for emphasis as I hadn’t covered a similar scenario in previous videos.

[@singularityJoe]

I agree with the silyl ether idea. I'd probably use TBDPS so I could see my intermediates with UV on TLC and have prep TLC as a purification option.

[@CasualChemistry]

This is fair. TBDMS (TBS) is my favourite though as the NMR spectra stay super clean. The TBSO(CH2)2CCH might even be able to be distilled at reduced pressure if you were lucky.

[@Sisi-ns8cd]

👏🏻

[@CasualChemistry]

🙂

[@narogen3431]

could you not just do an aldol followed by luche reduction and monoacetylation?

[@CasualChemistry]

I don't think that would work here I'm afraid. The aldol condensation would form the trans-alkene as it is based on an E1CB elimination on an open chain (not-ring) system - so the thermodynamic product would result. Monoacetylation would be tricky on the more hindered secondary alcohol in the presence of the primary alcohol as the primary hydroxyl group is sterically a much better nucleophile and most esterification reactions depend on that reactivity.

[@oanhtran2784]

Dear Casual Chemistry, The Diels-Alder reaction led to the formation of a mixture of enantiomers. How could we solve this problem?

[@CasualChemistry]

(I’ve replied to the other duplicate comment of this question)