An acyclic all-carbon quaternary center

Given an achiral or racemic starting material and a drawing of one enantiomer of a product, a procedure written with no experiment on that substrate forms an acyclic all-carbon quaternary stereocenter as that enantiomer. The set is not ten examples of one privileged reaction.

A carbon that bears four different carbon substituents is a shape that medicinal chemistry and natural-product synthesis both use and both struggle to build, especially when that carbon is not in a ring. Cyclic quaternary centers have a long list of reliable catalytic methods. Acyclic ones are where a route still changes to avoid the stereocenter, or resolves it at the end. A first procedure that returns the named enantiomer, including on constructions that are not the two best-known ones, is the result that would make those centers ordinary intermediates.

The reviews separate cyclic from acyclic, and the best new method occupies one acyclic subclass.

Feng, Holmes, and Krische reviewed enantioselective construction of acyclic quaternary carbon stereocenters and described it as still formidable beside the much larger body of cyclic methods (doi:10.1021/acs.chemrev.7b00385 (opens in a new tab)). Griffiths and Franckevičius, on catalytic allylic alkylation of acyclic enolates, write that the acyclic case is harder because the enolate geometry is not fixed the way it is in a ring (doi:10.1002/chem.202304289 (opens in a new tab)). Xu, Zhou, Zhu, and Zhou reviewed catalytic desymmetrizations that produce all-carbon quaternary centers and still describe the broader construction as a long-term challenge (doi:10.1038/s44160-023-00406-3 (opens in a new tab)).

Chen, Jiang, Yao, Feng, Zhong, Huang, and Shi then reported a nickel-catalyzed enantioselective C(sp³)–H amination that desymmetrizes a gem-dimethyl group and gives β-amino acid derivatives with an acyclic all-carbon quaternary center in high yields and with enantioselectivity up to greater than 99 percent ee (doi:10.1021/jacs.5c16651 (opens in a new tab)). The abstract does not state a single isolated-yield figure for the whole scope, and none is invented here. The transformation is one bond construction, on one substrate pattern. It shows that greater than 99 percent ee is reachable inside that pattern. It does not show a procedure, written before a blinded multi-class set is revealed, that returns the named enantiomer for constructions outside it.

The laboratory preregisters 10 transformations. Each is a single step from a commercial or previously prepared achiral or racemic starting material to one specified enantiomer. The new stereocenter in the product is acyclic and all-carbon: it bears four different carbon substituents, it is not a ring atom, and none of the four bonds is to hydrogen, nitrogen, oxygen, or a halogen.

Before the attempt sees the set, the laboratory marks at least four transformations as unprivileged. A transformation is unprivileged only if the product is not made by either of the following: allylic alkylation, or another enolate alkylation, of a β-ketoester, a β-ketoamide, a malonate, or an α-cyano carbonyl; or C–H functionalization of a gem-dimethyl group. The laboratory records, for each of the four, which bond is formed. The four bonds are not the same bond construction. The other six transformations may be privileged, so that a method cannot pass by declining every case except the one it already knows.

Within 24 hours of disclosure, and with no experiment on a test substrate or on a stand-in made to resemble it, the attempt submits one procedure per transformation: catalyst or reagent, loading, solvent, temperature, time, and workup. Loading of any chiral catalyst or ligand is at most 5 mol percent. One backup procedure per substrate may be submitted at the same time.

The laboratory runs the procedure once. The isolated product is identified by NMR and high-resolution mass spectrometry. The enantiomer ratio is measured by chiral chromatography against a racemic sample of the same constitution, injected on the same method the same day. The specified enantiomer is assigned by a chemical correlation to a compound of known configuration, a vibrational circular-dichroism comparison, or an X-ray structure of a heavy-atom derivative. Optical rotation alone is not sufficient. Purity of the isolated enantiomer is at least 95 percent by absolute quantitative proton NMR.

At least 8 of the 10 transformations, including at least 3 of the 4 unprivileged ones, give the specified enantiomer in an isolated yield of at least 40 percent and an enantiomer ratio of at least 95 to 5, at the purity above.

The count, the unprivileged quota, the 40 percent yield, the 95-to-5 ratio, the 5 mol percent ceiling, and the 95 percent purity are pass marks defined here. Ninety-five to five is 90 percent enantiomeric excess. The Shi result of greater than 99 percent ee shows that a higher ratio is already available inside gem-dimethyl C–H amination, which is why that reaction cannot fill the unprivileged quota. Forty percent is a floor for an isolable sample, not a yield taken from that paper.

The racemic reference must show both enantiomers. A single peak is credited only if the racemate resolves on that method and a spike identifies the named enantiomer. A reaction run without the chiral catalyst, otherwise identical, is performed for two substrates chosen in advance, one of them unprivileged. That control must not itself reach 95 to 5. If it does, the substrate or the assay is contaminated and the batch is invalid.

The laboratory’s assignment of the four unprivileged transformations is checked against the definitions above before the procedures are opened. A transformation that is in fact an enolate alkylation of a β-dicarbonyl, or a gem-dimethyl C–H functionalization, does not count toward the quota.

Any chiral catalyst, ligand, or enzyme named in the procedure, within the loading rule. A different catalyst for each substrate. Computation and literature lookup before the procedures are locked. The one backup procedure submitted with the first procedure.

A stoichiometric chiral auxiliary that is attached and removed. Classical resolution, or separation of enantiomers on a chiral stationary phase presented as a synthesis. A product whose quaternary center is in a ring. Filling the unprivileged quota with four examples of one bond construction, or with the two excluded reaction classes. Changing solvent, catalyst, or temperature after the first experiment. More than 5 mol percent of the chiral catalyst. Quoting enantioselectivity without the absolute-configuration assignment named above.

At least 6 of the 10 transformations reach an enantiomer ratio of at least 90 to 10 and an isolated yield of at least 40 percent, including at least 2 of the 4 unprivileged ones, and the blanks pass. These figures are pass marks for the lesser bar. Partial success is not a solution. Six privileged successes and no unprivileged success are not partial success.

The counts, the yield, the ratios, the loading, and the purity are pass marks defined here.

Cited sources:

• Feng, Holmes, and Krische, Chemical Reviews, 2017, 117, 12564–12580, doi:10.1021/acs.chemrev.7b00385 (opens in a new tab). Acyclic quaternary carbon stereocenters are described as a remaining challenge beside cyclic methods.
• Griffiths and Franckevičius, Chemistry – A European Journal, 2024, 30, e202304289, doi:10.1002/chem.202304289 (opens in a new tab). Acyclic allylic alkylation is harder because the enolate geometry is not fixed.
• Xu, Zhou, Zhu, and Zhou, Nature Synthesis, 2023, 2, 1020–1036, doi:10.1038/s44160-023-00406-3 (opens in a new tab). Desymmetrization routes to all-carbon quaternary centers, with the broader problem still described as open.
• Chen, Jiang, Yao, Feng, Zhong, Huang, and Shi, Journal of the American Chemical Society, 2025, 147, 39060–39066, doi:10.1021/jacs.5c16651 (opens in a new tab). Nickel-catalyzed gem-dimethyl C–H amination, acyclic all-carbon quaternary centers, enantioselectivity up to greater than 99 percent ee. No scope-wide yield is cited because the abstract does not give one.

Purity uses the absolute quantitative proton NMR assay of Pauli and co-workers, Journal of Medicinal Chemistry, 2014, 57, 9220–9231, doi:10.1021/jm500734a (opens in a new tab).