The catalytic enantioselective [1,2]-Wittig rearrangement cascade of allylic ethers

[Pinball1970]

Using a combination of lab experiments and quantum chemistry calculations, researchers have now discovered a new way to control the handedness of a notoriously difficult chemical process, known as the '[1,2]-Wittig rearrangement' that will impact on how scientists design selective chemical reactions, such as those used in pharmaceutical production or advanced materials.

The catalytic enantioselective [1,2]-Wittig rearrangement cascade of allylic ethers - Nature Chemistry

The [1,2]-Wittig rearrangement of allylic ethers is traditionally considered to proceed via formation and recombination of radical pairs. Now it has been shown that an alternative reaction cascade, involving initial enantioselective [2,3]-rearrangement followed by base-promoted anionic...

www.nature.com

exchemist

 

[Pinball1970]

Just to add why this caught my eye, it will be worth reading this.

Chiral Drugs: An Overview - PMC

About more than half of the drugs currently in use are chiral compounds and near 90% of the last ones are marketed as racemates consisting of an equimolar mixture of two enantiomers. Although they have the same chemical structure, most isomers of ...

pmc.ncbi.nlm.nih.gov

 

[Olga]

Я нашла одно знакомое слово в этом вопросе: эфиры. Есть ещё два знакомых, но думаю здесь у них другой смысл: каскад, и перегруппировка.

 

[C C]

Vitamin E comes to mind. It consists of four tocopherols (excluding the four tocotrienols), of which alpha-Tocopherol is the molecule that the body primarily uses. But the synthetic process of making the vitamin yields multiple stereoisomers, which includes the mirror-image enantiomer of alpha-Tocopherol. Accordingly, the synthetic version of vitamin E has less effectiveness.
_

 

[Pinball1970]

Vitamin E comes to mind. It consists of four tocopherols (excluding the four tocotrienols), of which alpha-Tocopherol is the molecule that the body primarily uses. But the synthetic process of making the vitamin yields multiple stereoisomers, which includes the mirror-image enantiomer of alpha-Tocopherol. Accordingly, the synthetic version of vitamin E has less effectiveness.
_

Did not know that. Citation please Ms.

 

[Pinball1970]

Я нашла одно знакомое слово в этом вопросе: эфиры. Есть ещё два знакомых, но думаю здесь у них другой смысл: каскад, и перегруппировка.

"Ether" is just a particular combination. This is talking about the orientation in space about a molecule that gives a different structure.
Chirality come from the Greek for "Handedness."

Your hands are the same but different in the same way. If I found nothing but a hand in a forensic investigation we could tell if it was left or right. Even though all the components are exactly the same, from the same body! Some molecules are the same.EDIT, Some molecules have the same parts, same bonds but a different orientation like a hand.

exchemist feel free to step in and tidy up my clumsy explanation.

 

[Pinball1970]

Vitamin E comes to mind. It consists of four tocopherols (excluding the four tocotrienols), of which alpha-Tocopherol is the molecule that the body primarily uses. But the synthetic process of making the vitamin yields multiple stereoisomers, which includes the mirror-image enantiomer of alpha-Tocopherol. Accordingly, the synthetic version of vitamin E has less effectiveness.
_

Sometimes it doesn't make much of a difference metabolically, sometimes it does.
Thalidomide is the obvious one and the drug is discussed in the article.
I did not know that even if the drug was not racemic so just R, in Vivo metabolism would have converted (at least some) of the R to the S enantiomer.
For observers
R= eliviated morning sickness
S= teratogenic

 

[C C]

Did not know that. Citation please Ms.

Oh, you're instead (or not or ???) specifically inquiring about the effectiveness of natural vitamin E versus synthetic? If the latter, it stems from a common view across source material.

• SciAm: "For the most part, our bodies appear to absorb synthetic forms as well as they do natural forms. The one exception seems to be vitamin E, which in natural form (RRR-alpha tocopherol) is better absorbed than in synthetic form (all-rac-alpha tocopherol)."
  
  Oregon State University: "The body preferentially uses α-tocopherol, and only α-tocopherol supplementation can reverse vitamin E deficiency symptoms..."
  
  Chromatographic Separation of Vitamin E Enantiomers: "Vitamin E is recognized as an essential vitamin since its discovery in 1922. [...] Owing to the three chiral centers in tocopherols, they can appear as eight different stereoisomers. Plant sources of tocopherol are naturally occurring in the form of RRR while synthetic tocopherols are usually in the form of all-racemic mixture..."

Although there are studies exploring if more than just α-tocopherol can have beneficial effects, whether natural occurring stereoisomers or the synthetic output. Some might consider it fringe territory, others not.

• From abstract of paper: Vitamin E comprises eight natural isoforms: tocopherols (α, β, δ, and γ) and tocotrienols (α, β, δ, and γ). While initial research focused on the anticancer properties of α-tocopherol, there is growing interest in other natural forms and modified synthetic analogues of vitamin E due to their unique properties and enhanced anticancer effects...

And here's an old 1997 press release suggesting that there's little difference between natural and synthetic E results (although the whole idea of claims like vitamin E preventing whatever _X_ has been challenged intermittently over the decades): Synthetic vitamin E works as well as natural vitamin E in preventing heart disease
_

 

[TheVat]

One thing I remember from chemistry was the thumb/curled fingers trick for determining R or S chirality. Handier (ha) than the clock method. Your thumb points towards the atom of lowest priority.

I've heard almonds and sunflower seeds are best for vitamin E, due to the RRR-alpha stereoisomer. IIRC canola oil is not as good, usually being refined and having more gamma tocopherol.

Going to take me a while to understand how the enantioselective process works, in the OP. Didn't go that far with chemistry. Stereocontrol seems pretty arcane.

 

[Pinball1970]

Oh, you're instead (or not or ???) specifically inquiring about the effectiveness of natural vitamin E versus synthetic? If the latter, it stems from a common view across source material.

• SciAm: "For the most part, our bodies appear to absorb synthetic forms as well as they do natural forms. The one exception seems to be vitamin E, which in natural form (RRR-alpha tocopherol) is better absorbed than in synthetic form (all-rac-alpha tocopherol)."
  
  Oregon State University: "The body preferentially uses α-tocopherol, and only α-tocopherol supplementation can reverse vitamin E deficiency symptoms..."
  
  Chromatographic Separation of Vitamin E Enantiomers: "Vitamin E is recognized as an essential vitamin since its discovery in 1922. [...] Owing to the three chiral centers in tocopherols, they can appear as eight different stereoisomers. Plant sources of tocopherol are naturally occurring in the form of RRR while synthetic tocopherols are usually in the form of all-racemic mixture..."

Although there are studies exploring if more than just α-tocopherol can have beneficial effects, whether natural occurring stereoisomers or the synthetic output. Some might consider it fringe territory, others not.

• From abstract of paper: Vitamin E comprises eight natural isoforms: tocopherols (α, β, δ, and γ) and tocotrienols (α, β, δ, and γ). While initial research focused on the anticancer properties of α-tocopherol, there is growing interest in other natural forms and modified synthetic analogues of vitamin E due to their unique properties and enhanced anticancer effects...

And here's an old 1997 press release suggesting that there's little difference between natural and synthetic E results (although the whole idea of claims like vitamin E preventing whatever _X_ has been challenged intermittently over the decades): Synthetic vitamin E works as well as natural vitamin E in preventing heart disease
_

Yeah that, I'll check. Thanks

 

[exchemist]

Using a combination of lab experiments and quantum chemistry calculations, researchers have now discovered a new way to control the handedness of a notoriously difficult chemical process, known as the '[1,2]-Wittig rearrangement' that will impact on how scientists design selective chemical reactions, such as those used in pharmaceutical production or advanced materials.

The catalytic enantioselective [1,2]-Wittig rearrangement cascade of allylic ethers - Nature Chemistry

The [1,2]-Wittig rearrangement of allylic ethers is traditionally considered to proceed via formation and recombination of radical pairs. Now it has been shown that an alternative reaction cascade, involving initial enantioselective [2,3]-rearrangement followed by base-promoted anionic...

www.nature.com

exchemist

This seems to be a collaboration between St Andrews and Bath universities. I'm having to revise the Wittig rearrangement - or rather catching up with what modern organic chemistry says about its mechanism. It's quite complicated and my old ROC Norman doesn't go into the mechanistic details.

According to the paper, there is competition between an electrocyclic reaction and a free radical process, leading to different products. They seems to have found a catalyst that allows the equivalent of a forbidden* electrocyclic path to be achieved via the radical route instead, but without the loss of stereospecificity that might be expected by disconnecting the molecule and recombining the fragments in a new configuration. But it's very dense and it will take me more time to understand exactly what they have done.

*In electrocyclic reactions, the symmetry of the interacting orbitals has to be taken into account. The phases have to line up + to + and - to - to create a new bonding orbital rather than + to - and - to + which would be an antibonding orbital. (N.B. This is about wave function phase, not electric charge).

 

[exchemist]

They've finally cracked that. Been a right pain for decades. If you could steer that rearrangement left or right instead of leaving it to chance, you'd save a fortune on purification. Suddenly every enantiomer you make is the useful twin – none of that mirror-image rubbish clogging up the reactor. And in pills? Means half the side-effects might just walk off the map. Bloody useful.

The Witting rearrangement is just one reaction in organic chemisty out of thousands used in drug synthesis. It may be useful but it does not solve the entire issue of selecting for the active enantiomer.