The increasing need for structural diversity in the design of bioactive molecules results in the steady appearance of new synthetic challenges. Consequently, the industry regularly faces new synthetic problems that requires the development of innovative approaches. Of particular concern is the synthesis of chiral compounds for the production of agrochemicals and pharmaceuticals. Also, the synthesis of certain functional groups can be particularly challenging when the product itself can over-react, generating an undesired by-product. For these challenging cases, new synthetic methods need to be developed.
In this context, the production of chiral hydroxylamine derivatives still lacks of a selective method of synthesis. In particular, the hydrogenation of oximes into hydroxylamines is a problematic transformation as the latter is directly reduced to the corresponding amine. In this light, a recent article published in Science by the collaboration between Ecole Polytechnique Fédérale de Lausanne and Syngentha AG (DOI: 10.1126/science.abb2559) reports the use of an iridium-based catalyst for the challenging asymmetric hydrogenation of oxime substrates into chiral hydroxylamine with very high enantioselectivity and very high chemoselectivity (see figure below). To the great surprise of the authors, the reaction takes place without formation of the undesired (over-reduced) amine product. The newly developed iridium catalyst is air and moisture-stable and was successfully used in the synthesis of large variety of chiral hydroxylamine products with commercially interesting high turnover numbers (up to 4000) and selectivities (98:2 e.r.).
Chemoselective asymmetric hydrogenation of oximes to chiral hydroxylamines
Initial studies and catalyst optimization
During initial studies, the authors identified an achiral cyclometalated Cp*- iridium [Cp*Ir(C,N)] complex as a very active catalyst for the hydrogenation of an oxime substrate when used in addition to in the presence of a stoichiometric amount of strong Brønsted acid. Furthermore, analysis of the reaction mixture revealed that the formed alkoxy hydroxylamine is completely inactive toward the overreduction and thus no amine product was detected. After these initial findings, the authors elegantly show the different development steps which starts with the introduction of the chiral Cp-ligand to obtain the first chiral catalysis, after which the optimization of the catalyst is performed by alternating rounds of modifications of the Chiral Cp-ligand and the C,N-ligand. Interestingly, the attachment of a methoxyethyl ether improved both the catalyst stability (most probably by temporal ether coordination to the metal center) and the selectivity (by formation of supramolecular H-bond interactions with the protonated oxime substrate). The best catalyst (shown in the figure below) yields full conversion and a high enantiomeric ratio of 96:4 for the oxime model substrate.
Structure of the best chiral iridium catalyst
An initial solvent screening indicated that the reaction performs better in protic solvents. Because the oxime substrate undergoes an E/Z equilibration upon protonation, the selection of the solvent and the acid needs to be carefully tuned. In methanol, a high E/Z isomerization of the substrate is observed, resulting in a lower enantiomeric ratio of the product, while high activity and high selectivity are obtained in tert-amyl alcohol. Performing the reaction in tert-amyl alcohol in the presence of MsOH or TFA provides the product with high conversion and very high selectivity. Afterwards, a sampling experiment shows that the selectivity remains the same at different conversion levels (4h and 20h), thus indicating that the hydrogenation step occurs faster than the isomerization under these conditions.
The optimized conditions were applied to the hydrogenation of a wide variety of oxime substrates, showing that many different varieties of substrate can be converted with very high enantioselectivity. Of particular interests is the functional group tolerance observed toward the hydrogenation of oxime bearing halogen-substituted aryl groups or protection groups, such as acetal and O-benzyl labile groups (both remaining intact after reaction). Interestingly, the presence of chiral groups on the backbone of the oxime does not interfere with the efficiency of the method, which still provides the products with high enantioselectivity (although a small match/mismatch effect is observed). Among the other tested substrates are O-alkyl substituted oximes and free oximes, boronate-substituted oximes, nitrogen- and sulfur-containing substrates (additional examples are given in the supporting material).
The authors noticed that certain substrates benefit from conditions that induce a fast E/Z isomerization of the oxime (instead of a slow E/Z isomerization in the examples above). Detailed experiments show that the Z-isomer reacts faster than the E-isomer and therefore, is the one consumed during the reaction. During hydrogenation of the Z-isomer, the E-isomer isomerizes into the Z-isomer which is subsequently hydrogenated. Interestingly, this phenomenon shows similarities with the classic “lock-and-key” mechanism for the rhodium-catalyzed asymmetric hydrogenation of functionalized alkenes (also called the Halpern mechanism). In the Halpern mechanism, the product of the reaction is also determined by the fast hydrogenation of only one of two substrate-catalyst adducts (major/minor concept).
Proposed outer-sphere mechanism
A plausible mechanism is reported by the authors in which the reaction starts with the activation of the substrate by protonation of the nitrogen of the oxime by the acid. Then, the dissociation of the mesitylate anion from the iridium is followed by coordination of molecular hydrogen. In the next step, the free methanesulfonate anion assists in the heterolytic cleavage of the dihydrogen to form a metal hydride. Addition of the hydride to the C=N bond of the activated substrate via an outer-sphere mechanism results in the formation of the chiral product. Interestingly, the authors point out that the strong Brønsted acid has three different functions. In this mechanism, the acid not only helps in the activation of the substrate but also assists in the splitting of the hydrogen (via the conjugated base) and in the protonotation of the product, preventing from an inhibition of the catalyst by the product.
Finally, the application of the method to the synthesis of industrially-relevant products (including an enzyme inhibitor) and the scale up of the reaction to the production of a 25g-batch of hydroxylamine product certainly establish this new methodology as a new powerful tool for the development of chiral hydroxylamine-containing products (Patent WO2020094527A1).
This paper highlights that the development of new classes of catalysts is of foremost importance in addressing industrial challenges. We hope that this work will encourage other research groups to develop new methodologies for fulfilling the increasing demand for more sustainable methods of production.
About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical and Bulk chemical industry to solve their most challenging projects.
Article: “Iridium-catalyzed acid-assisted asymmetric hydrogenation of oximes to hydroxylamines”
By: Josep Mas-Roselló, Tomas Smejkal and Nicolai Cramer
Science 2020, 368, 1098–1102