The named anomer of a glycoside

Given a glycosyl donor supplied as a hemiacetal and an alcohol, and a drawing that names one anomer of the glycoside, a procedure written before any experiment on that pair returns that anomer in quantity. The set includes 1,2-cis glycosides that have no participating group at C2.

The biological activity of an oligosaccharide often sits in which anomer was formed. Neighboring-group participation makes many 1,2-trans linkages reliable and does not make the 1,2-cis linkage. A method that returns whichever anomer the donor and the acceptor happen to prefer still leaves the cis bond as a separate research project. A procedure that hits the named anomer, on pairs it did not choose, is the result that would make oligosaccharide synthesis a planned route rather than a screen.

Park, Harper, Kuhl, Kwan, Liu, and Jacobsen reported a macrocyclic bis-thiourea that catalyzes stereospecific substitution of glycosyl chlorides (doi:10.1126/science.aal1875 (opens in a new tab)). On the model pair, α-mannosyl chloride and benzyl alcohol, catalyst 6 gave 88 percent yield and an α:β ratio of 8:92. The product configuration followed the configuration of the glycosyl chloride: inversion, for both α- and β-chlorides. The paper describes β(1,6) and β(1,3) linkages across several sugars as good to excellent, and states that the more demanding β(1,4) linkage could be produced only when the steric demand of the nucleophile was reduced. The donors in that study were glycosyl chlorides of a chosen anomer, not hemiacetals, and the anomer of the product was the one inversion provides. An 8:92 ratio is about 12 to 1. The main text does not attach a higher numerical ratio to a general pair, and none is invented here.

Lourenço and Ventura, reviewing 1,2-cis glycosylation in 2024, write that construction of the 1,2-cis bond is still a major challenge, that the reactions remain highly dependent on the donor–acceptor pair, and that the donor and the conditions are tuned for the case in hand (doi:10.1039/bk9781837672844-00023 (opens in a new tab)). That is the opposite of one procedure, written before the pairs are known, that returns either named anomer from a hemiacetal.

docs/SELECTION.md describes a Nature Synthesis paper (s44160-025-00846-z (opens in a new tab)) as reporting electrophilic-bromine activation with inversion across a wide set of monosaccharides, and as calling a general method for every linkage unrealized. This problem does not treat that description as a pass. The donor here is the hemiacetal as drawn. The anomer is the one named in advance, including the 1,2-cis pairs with no participating group. The procedure is locked before the pairs are known. Copying a published inversion of a preformed halide for that exact pair fails. No yield or ratio is taken from that paper here, because this draft did not re-open its tables.

The laboratory preregisters 10 donor–acceptor pairs. Each donor is supplied as a hemiacetal. An anomeric mixture is acceptable. The protecting groups are already in the drawing and are not redesigned after disclosure. Each acceptor is a specified alcohol. The product drawing names one anomer, α or β.

At least four pairs are 1,2-cis and have a non-participating substituent at C2: an ether, a benzyl ether, an azide, or a hydrogen, and not an ester, a carbonate, or an amide. At least three pairs are 1,2-trans. The donors include at least three of the following: glucose, galactose, mannose, a glucosamine, and a 2-deoxy sugar. At least three acceptors are secondary alcohols. The pairs are disclosed together.

Within 24 hours, and with no experiment on the test pairs, the attempt submits one procedure per pair, or one general procedure: reagents, catalyst and loading, solvent, temperature, time, and workup. One backup procedure per pair may be submitted at the same time. The laboratory runs the procedure once, on 0.1 to 0.2 mmol of donor.

The anomeric ratio is the proton-NMR integral of the named anomer divided by the integral of the other anomer, measured on the crude mixture before chromatography, against a weighed internal calibrant. The named anomer is then isolated. Its purity is at least 95 percent by absolute quantitative proton NMR. Identity includes a carbon spectrum and a correlation that places the new glycosidic bond. A chemist who did not write the procedure confirms that the isolated material is the named anomer.

At least 8 of the 10 pairs, including at least 3 of the 4 designated 1,2-cis pairs, give the named anomer in an isolated yield of at least 40 percent, with a crude anomeric ratio of at least 19 to 1, at the purity above.

Eight of ten, 3 of 4, 40 percent, 19 to 1, and 95 percent purity are pass marks defined here. Nineteen to one is set above the 8:92 ratio, about 12 to 1, reported for the Jacobsen model pair, and it is not a ratio copied from a best example whose number was not in the text opened here. Forty percent is a floor for an isolable sample. The cis quota, the hemiacetal starting point, and the ban on reprotecting are what keep a stereospecific substitution of a preformed chloride from being scored as a general solution.

For two pairs chosen before the procedures are opened, one of them a 1,2-cis pair, the laboratory runs the reaction with no catalyst and no promoter, otherwise as written. That blank must not itself reach a 19-to-1 ratio in favor of the named anomer. If it does, the donor or the conditions already determine the anomer and the pair is replaced before grading.

The crude spectrum must show both anomeric regions. A single peak is credited only if an independently prepared sample of the other anomer, or a deliberately anomerized sample, resolves from it on the same method and a spike shows which peak is which. Chromatography that enriches the named anomer does not change the crude ratio, which is the number that counts.

Any catalyst, promoter, or leaving-group activation that the written procedure names, including conversion of the hemiacetal into a glycosyl halide or imidate inside that procedure. Enzymes. Computation and literature lookup before the procedures are locked. The one backup procedure submitted with the first procedure.

Redesigning the protecting groups after the pairs are disclosed. Supplying, or buying, a single anomer of a glycosyl chloride or imidate that was not in the preregistered drawing and calling the subsequent inversion a prediction. Separating anomers and discarding the wrong one without the crude ratio meeting the bar. A participating C2 ester added to a pair the laboratory marked as non-participating. Screening promoters on the test pair, or on a close analog made for the purpose, after disclosure. Counting a 1,2-trans outcome on a participating donor toward the cis quota.

At least 6 of the 10 pairs reach a crude anomeric ratio of at least 10 to 1 and an isolated yield of at least 30 percent, including at least 2 of the 4 cis pairs, and the blanks pass. These figures are pass marks for the lesser bar. Partial success is not a solution.

The counts, the 40 percent and 30 percent yields, the 19-to-1 and 10-to-1 ratios, and the cis quota are pass marks defined here.

Cited measurements:

• Park, Harper, Kuhl, Kwan, Liu, and Jacobsen, Science, 2017, 355, 162–166, doi:10.1126/science.aal1875 (opens in a new tab). Catalyst 6, α-mannosyl chloride, benzyl alcohol: 88 percent yield, α:β = 8:92. Stereospecific inversion. The β(1,4) linkage required a less hindered nucleophile. Broader examples are described as good to excellent without a second numerical ratio being taken from the main text.
• Lourenço and Ventura, Carbohydrate Chemistry, 2024, pp. 23–43, doi:10.1039/bk9781837672844-00023 (opens in a new tab). The 1,2-cis linkage is described as still dependent on the donor–acceptor pair and on conditions tuned for that pair. No volume number is cited because the record used here 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).