Romiti rolls with zirconium in a total synthesis

Citations:

Ramakrishna, G.V.; Latif, Z.; Romiti, F. Enantioselective Total Syntheses of Vallesamidine and Schizozygane Alkaloids. J. Am. Che. Soc. 2025, ASAP.

https://pubs.acs.org/doi/full/10.1021/jacs.4c16900#

Summary Figures:

Background:

There is a philosophical debate to be had about the merits of total synthesis and whether having graduate students spend half a decade making an obscure molecule found in a sea sponge or cactus is worth it. One thing total synthesis is good for is showing trends in reaction development- when a class of reactions starts showing up in total syntheses, it means they're getting common enough to be worth trying, and robust enough to work on materials that have >1 functional group. 

Here's a cross-coupling reaction that was used in a recent total synthesis:

How it works:

Here is a nickel-catalyzed enantioselective cross-coupling of a vinyl zirconium reagent and an alkyl chloride. The original reaction was developed by the Fu group in 2021, but they (and others) have been developing similar chemistry for what has to be at least 20 years now. 

The vinylzirconium reagent is made by taking Schwartz's reagent (HZrCp2Cl), which does a hydrozirconation on an alkyne:

The alkyl chloride is able to be activated by nickel as a radical precursor. The neighboring ester helps stabilize the radical enough to be formed; normally alkyl chlorides make poor targets for single electron transfer. Note that this does not mean they cannot be used in this method, just that it's more difficult. 

The exact mechanism isn't described in this paper nor the original method from the Fu lab, but some educated guesses can be made. After halogen atom abstraction to make the above radical, the nickel catalyst can recombine with the radical to generate the alkyl nickel species (or nickel enolate, whichever you prefer). 

This can either (a) undo the previous step and go back to the alkyl radical (bond homolysis) or isomerize through the enolate to set that alpha stereocenter. Eventually, the chiral ligand bound to nickel will preferentially bias one of the two enantiomers, enriching the stereochemistry. 

Transmetalation with the zirconium reagent gives a species ripe for reductive elimination, which does not change the stereochemistry of the quaternary center (stereoretentive):

Initial Questions and Key findings:

1. How do you make this chiral quaternary center? Chiral quaternary centers are found in many natural products and are notoriously difficult to form, as they are sterically congested and often have to be constructed in a specific order, which may not coincide with the key stereochemistry defining step. 

A: This is one of the places where cross-coupling reactions shine. In this case, there is an obvious alternative in trying to make the enolate and doing some sort of aldol reaction or alkylation:

You might be able to tell I'm not a total synthesis chemist. 

However, you don't need some model to give diasteroselectivity if you can grab an enantioenriched ligand off the shelf. Cross-coupling reactions simplify the bond disconnection, so that any time you see an sp2-sp2 bond or an sp3-sp2 bond (eventually we'll get there with sp3-sp3...eventually...), you can at least consider a coupling reaction of some kind. 

2. Why zirconium?

A: The authors don't explain why they chose to use zirconium reagents, as opposed to any number of organometallic reagents.

In general, the three most prominent cross-coupling methods found in total synthesis are Stille, Negishi, and Kumada couplings. Stille couplings (tin reagents) have the best functional group compatibility, making them the option of choice for total synthesis labs that don't worry about their health. Negishi reactions (zinc reagents) have better functional group compatibility than Kumada reactions, but alkyl and arylzinc reagents are difficult to make and usually quite pyrophoric. I cannot emphasize enough that scaling up these reactions to the 10 gram scale should be avoided. Finally, Kumada reactions (magnesium reagents) are common and by far the easiest to conduct, but have the worst functional group compatibility, and likely would not be compatible with the esters present here. 

Suzuki reactions (boron reagents) with sp3 centers are finicky often enough that they don't show up in as many total syntheses. 

Zirconium is nice here because it has the necessary functional group compatibility (tolerant of esters and nitriles), plus the vinyl zirconium reagent can easily be formed from Schwartz's reagent, with extremely high selectivity for the (E)-alkene. This is because the hydride and the zirconium add to the same side of the alkyne. 

Zirconium has also been featured in a number of reductive coupling reactions developed by Kishi and coworkers which have also been used heavily in total synthesis (mostly by the Kishi lab) (See: https://pubs.acs.org/doi/full/10.1021/jacs.0c07390).

For reference when choosing organometallic reagents, I find Knochel's analysis linking the electronegativity of the metal to the functional group compatibility the best:

https://pubs.acs.org/doi/10.1021/acs.accounts.4c00242

I'll probably do a full writeup on this accounts at some point when I can't find a good paper of the week!