Complex Networks of Reactions – a new way to improve the efficiency and capacity of organic synthesis

Artificial metabolism-like multicatalytic networks of reactions create unique opportunities to tackle problems in organic synthesis that are difficult to address with classic approaches. For instance, methods enabling the functionalization of C-H bonds are highly attractive for fine chemical synthesis as they have the potential to create shortcuts in current synthetic routes, thereby increasing the overall yields, lowering the amounts of resources and energy consumed, as well as limiting the generation of waste. However, because of their ubiquity in molecules, selective functionalization of one out of many similar C-H bonds represents a great challenge. Particularly difficult is the functionalization of unactivated aliphatic C(sp3)-H bonds. Due to their low reactivity, harsh conditions or highly reactive reagents are typically required; such conditions result in difficulty controlling the regio- or enantioselectivity of the transformation, and also lead to low functional group tolerance. These deficiencies of many methods of C-H bond functionalization render them rather impractical in synthesis or late-stage functionalization of fine chemicals, which typically bear multiple sensitive functional groups, hence calling for the development of new strategies.

Relay catalysis enabling non-inherent reactivity

With the possibilities of artificial multicatalytic networks in mind, we developed a catalytic method for a direct arylation of aliphatic alcohols at their inherently unreactive β-C(sp3)-H bonds, occurring under mild conditions without the use of highly reactive reagents (Nature Catal. 2019, 2, 114). Given that the catalytic reactions employed in the system occur under mild conditions, the overall transformation of this substrate at its otherwise unreactive strong C(sp3)-H bond occurs also under mild conditions.

Although effective, the products are formed as racemic mixtures, thereby limiting the value of the above-described method in the practical synthesis of fine chemicals, such as pharmaceuticals or agrochemicals, which typically requires the formation of optically pure products. In this case, the development of the enantioselective method is particularly challenging because α-aryl aldehyde intermediates bearing readily enolizable stereocenters undergo facile racemization in the presence of a base. Therefore, no opportunity exists to achieve the stereoselective product formation through the challenging enantioselective Pd-catalyzed arylation of the aldehyde intermediate.

We envision that cooperativity within artificial networks of reactions can also address the above-described challenges. In an ongoing study, we are pursuing dual-catalytic systems to execute the regio- and enantioselective functionalizations of alcohols in a network of cooperative stereoselective catalytic processes.

Complex multicatalytic transformations

Our reported and ongoing studies show that the multicatalytic strategy to functionalize alcohols creates many new opportunities. Several challenging regio- and stereoselective reactions at their strong C(sp3)-H or at their unsaturated bonds (e.g., (homo)allylic alcohols), or their more complex transformations can be executed in the presence of up to 4 catalysts operating in concert to form the target products selectively (see: Org. Lett. 2021, 23, 3502., J. Org. Chem. 2021, 86, 9253). Overall, these studies demonstrate the large capacity of the approach, which we continue exploring for functionalization and valorization of alcohols and other classes of readily available starting materials.

Controlled site-divergent transformations

The ability to precisely modify one complex molecule at its different sites carries the potential to facilitate drug development campaigns, which typically involve studies of the structure-activity relationship, requiring the laborious synthesis of libraries of structural derivatives of a lead molecule. We envision cooperative multicatalysis offering unique opportunities in that regard. We established that, by engaging ‘hydrogen borrowing’ catalysis, C-H functionalization chemistry, and cross-coupling reactions, controlled as needed through the choice of conditions and catalysts, a secondary benzyl amine – a common structural motif of bioactive molecules – can be selectively mono-functionalized at 4 different sites selectively. Further combinations of these reactivities can execute a number of complex transformations, providing access to a broad library of derivatives of the lead structure. We are currently exploring the scope and limitations of these processes. Overall, such diversity-enabling protocols engaging a limited number of catalytic processes underscore the potential of cooperative multicatalysis in the facile build-up of the structural complexity of fine chemicals.