Sharpless Asymmetric Epoxidation (SAE), Enantioselective Catalysis - Organic Chemistry Mechanism

An introduction to both transition metal catalysis and enantioselective catalysis in organic chemistry using the Sharpless Asymmetric Epoxidation. This reaction is one of the most reliable highly enantioselective transformations in organic chemistry and uses allylic alcohols as the substrate. There is generally high catalyst turnover and high yields for this reaction in many circumstances. This video will also introduce how the catalytic system can be used to perform a kinetic resolution of a racemic starting material and also to do desymmetrisation of achiral substrates with divinyl carbinols.
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The Sharpless Asymmetric Epoxidation (SAE) extends the idea of pre-coordinating a peroxide type electrophile to molecules to impart facial selectivity for reaction. mCPBA can hydrogen bond to the hydroxyl groups of allylic alcohols to direct the reagent to one face in preference, which sets the stage for a diastereoselective transformation. A higher level of diastereoselectivity can be achieved using a vanadium complex, specifically vanadyl bis(acetylacetonoate), which can pre-coordinate and activate tert-butyl hydrogen peroxide as an oxidant. This system can also achieve limited levels of diastereoselectivity in the epoxidation of homoallylic alcohols. Hydroxamic acid chiral ligands were investigated extensively to attempt to boost this transition metal system from a diastereoselective set of conditions to an enantioselective set, but with only limited success on a restricted substrate scope.
The breakthrough by the Sharpless Group came by switching the transition metal catalyst from vanadium to titanium. A rigid, dimeric, C2-symmetric pre-catalyst assembles with the bidendate dialkyltartrate ligands, both enantiomers of which are readily available and cheap. Hence, a reagent-controlled set of conditions was worked out for a reliable asymmetric epoxidation on a wide substrate scope of allylic alcohols. The epoxides formed in very high enantiomeric excess (e.e.) and are very versatile in synthesis as they can be further manipulated in many ways, a common one being to use a Payne rearrangement to shuttle the epoxide to a different location if required. The high levels of enantioselectivity observed when using the Sharpless Asymmetric Epoxidation means that it is often crowbarred into the early stages of complex, enantioselective synthesis even if epoxides and even oxygenation are not actually intended in the end. Setting initial stereocentres on custom molecules which are not directly from the chiral pool can be challenging to the organic chemist, but there are a large number of stereospecific reactions that can be used subsequently to faithfully install other functionality at stereogenic centres.
If you use a chiral allylic alcohol (stereogenic centre at the hydroxyl group), you can use the Sharpless Asymmetric Epoxidation to do a kinetic resolution of a racemic starting material. This is when one enatiomer of allylic alcohol reacts faster than the other, so you can end up with a mixture of both an allylic alcohol and an epoxy alcohol in very high enantiomeric excess. These products are then separable by standard chromatography.
The Sharpless Asymmetric Epoxidation is also very good at performing desymmetrisation reactions, where an achiral divinyl carbinol can be transformed into an epoxy alcohol in both very high enantiomeric excess and diastereomeric ratio. In the video, I explain how thinking through the kinetic factors involved here means that any formation of an undesired diastereomer is largely eliminated as itself is a great substrate for fast epoxidation, and so quickly reacts away to a bis-epoxide.

[@ProfessorWaltherKotz]

Outstanding explanation of the transition state. I could not find a better drawing of it in any other book!

[@CasualChemistry]

Thanks - glad you enjoyed the video 🙂 I got a lot of practice with drawing 3D transition states from my PhD and teaching so I’m very happy to be competing on clarity with textbooks

[@asmakhurshid6333]

Excellent demonstration with a blend of both theoretical and experimental aspects on the topic!

[@CasualChemistry]

Glad you enjoyed the video! It was very deliberately to present this topic more coherently than you normally see in textbooks etc

[@asmakhurshid6333]

True and that's what depicted in the content!@@CasualChemistry

[@harishsuryadevara3736]

This is a wonderful explanation of a really complicated concept - hats off to you !

[@CasualChemistry]

😀 Thanks! These are topics that I like doing teaching on so glad it works in video format. Please do share around if you know people who might be interested in the video as I know this topic (for example) is often tricky when just reading from a textbook.

[@thayhuongchuyenhoalekhietq6803]

Excellent! Thanks so much!

[@CasualChemistry]

You’re welcome 🙂

[@andrew2237]

Enjoying the high quality content. Keep up the great work. Greetings from Germany

[@CasualChemistry]

Thanks 😀 Will do - it's becoming a nice hobby for me making these videos.

[@amitkumarde9239]

Great video Casual chemistry, I couldn't understand this mechanism before how actually it functions, only knows about product. Now everything is cleared. I have a small request can you bring a video about chemoselectivity (BVO vs epoxidation) by using m-CPBA in different systems like alpha beta unsaturated ketone, non conjugated unsaturated ketone, and a system where two types of double bond is present one alpha beta unsaturated ketonic double bond and another non conjugated double bond.

[@CasualChemistry]

:) Glad you found the video helpful. I'll have a think on Baeyer-Villiger stuff as I don't think I've touched on it yet anywhere - I'd probably try a retrosynthesis that has competing C=C bonds or something. I think the correct answer is not to design a synthesis where that competition exists to avoid the issue. I think there is some dependence also on the pH of the reaction conditions too (e.g. strongly acidic or weakly acidic).

[@ThatChemistOld]

if you isolate your 50% pure allylic alcohol, you can invert it to the desired enantiomer with a mitsunobu inversion

[@CasualChemistry]

Indeed you can - personal preference I guess and how advanced your intermediate is. I’ve always found the Mitsunobu reaction in practice a bit unreliable on the yield front though

[@copycat2508]

How did you know that water would react with the titanium tetraisopropoxide to form titatium dioxide? What kind of organometallic mechanism does that proceed through?

[@CasualChemistry]

Probably not a well defined mechanism and not really an organometallic compound (no metal-carbon bond). There’s just a mega enthalpic driving for forming the strong TiO2 lattice. If you use the reagent, it reacts with atmospheric moisture too if you’re not careful and makes wispy white smoke clouds.

[@siobhanwilkins3251]

Great explanation thank you! My professor has asked for a mechanism in our report of our experiment (epoxidation of geraniol), what would he be expecting us to draw? Would it just be the transition state as shown in the video?

[@CasualChemistry]

Yes - if specifically asking for mechanism the 3D titanium scaffold if probably what you need. If asked just for predict the stereochemistry of product or a retrosynthesis, the mnemonic sketch is more appropriate

[@siobhanwilkins3251]

@@CasualChemistry amazing thank you! Would there be any further arrow pushing involved?

[@CasualChemistry]

Nope, the arrows themselves are quite simple even if the scaffold isn’t

[@gelato3607]

6:30 shouldn't the Product be the other enantiomere with (+)-DET?

[@CasualChemistry]

I think it’s the correct product at this time-stamp using the using model - it’s a rotation rather than a flip into the parallelogram picture, and so the (+)-DET delivers from below

[@rohanodonnell8618]

At 16:47 would the top substrate force the methyl to be down if you want the OH bond to be flat? Or am I looking at the configuration wrong lol😆

[@CasualChemistry]

The -OH does need to be flat in the plane - but the pic in the video is correct. Might be easier to look at the molecule before - the hydroxyl is forwards and the H back; the methyl in the plane. So it’s a bit like a turnstile in a train station: you need to push the hydroxyl down into the plane (30 degree rotation) which pulls the Me to the front and the H is still below the plane. Tricky to visualise for sure

[@rohanodonnell8618]

@@CasualChemistry Ah yes I see thank you, I understand what I was doing wrong now. Thank you for all your videos btw, saving my Chemistry degree!

[@CasualChemistry]

@rohanodonnell8618 You’re welcome 🙂Glad to know that they’re helpful

[@李奕皓-q3b]

I really like your explainer videos, but I always have a lot of questions that I want to ask, if you can, can you please provide a reference, I want to study it myself.😖

[@CasualChemistry]

This link would be a good place to start, though any textbook on Advanced Organic Chemistry (specifically on asymmetric synthesis) will be helpful. doi.org/10.1016/B978-0-08-052349-1.00196-7