Cooperative Asymmetric Catalysis
A Bioinspired Strategy
The major research efforts of our synthetically oriented group are structured around the development of catalytic asymmetric methodologies to provide general solutions for organic reactions of key importance. We are particularly interested in the control of chemical reactivity and stereoselectivity to synthesize high-added-value products with a high level of efficiency. Ideally, the new procedures would proceed quantitatively in an atom economic sense to avoid an unnecessary production of waste. Moreover, these methods should be step economic generating structural complexity from simple starting materials. By that additional step might be avoided again reducing the formation of waste.
The catalyst systems should be readily accessible and the catalytic procedures operationally simple in order to develop practical methods. Today, almost every complex chiral chemical compound can be prepared by synthetic chemists given ample time and resources. However, current catalytic asymmetric methodologies are too often not efficient enough from a practical point of view (e.g., as a result of catalyst and substrate over-engineering and highly sophisticated reaction conditions) and they often suffer from a severe lack of generality and do not match in the least the efficiency achieved by nature.
To achieve a comparable efficiency we incorporate a central strategy in our research program using mother nature as a guide, namely cooperative catalysis: cooperative catalysis means that various functional groups of a catalytic system cooperate to accelerate and control a chemical process.
Nature’s catalysts – namely enzymes – utilize the cooperative action of various enzyme functionalities to simultaneously activate the substrates of a chemical reaction resulting in high reactivity under physiological conditions. A typical example is given by a class-II-aldolase: dihydroxyacetone is coordinated to a Zn ion and thus acidified to allow for deprotonation of the α-position by the weak base glutamate. A Zn-enolate is hence formed under physiological conditions and can attack the aldehyde electrophile which is activated by a Brønsted acid. Both substrates are thus electronically activated in close spatial proximity leading to high catalytic activity under mild conditions. Moreover, interaction of the activating functional groups with the substrates organizes the reactants in space in the chiral environment of the active site allowing for excellent stereoselectivities.
The idea of cooperative catalysis has inspired synthetic chemists to create artificial dual activation catalysts. We develop catalysts that use dual or multiple cooperative activation modes allowing for mild reaction conditions and high turnover numbers. Unlike nature which uses sophisticated enzyme active sites as catalyst, we rely on the subtle electronic and steric interactions between the substrate and the tailormade artificial low molecular weight catalyst. Understanding these interactions through mechanistic studies allows us to predict new results and to discover new applications for the streamlined synthesis of densely functionalized scalemic molecules.
In particular we are interested in 3 concepts of cooperative catalysis:
I) Lewis acid/base catalysis: The Lewis acid serves to activate an electrophile and works in concert with a base generating a nucleophile.
E.g., we have developed a lanthanide/amino alcohol complex, which can catalyze the (formal) hetero Diels-Alder reaction of a diene generated in situ from α,β-unsaturated acid chlorides and various aldehydes:
Our results point to a mechanism in which the reversibly coordinating Lewis basic amino site generates a nucleophilic dienolate which binds to the metal ion, resulting in a highly organized transition state for a vinylogous aldol addition reaction with the Lewis acid activated aldehyde. Turnover is achieved by an intramolecular acylation.
II) Bimetallic catalysis: One metal center serves to activate an electrophile, whereas the second metal can, e.g., be used to generate a nucleophile. Bimetallic catalysis is also frequently used by nature in dinuclear metalloenzymes, e.g., in DNA polymerases, phosphatases, hydrolases or in ureases. In the latter case two Ni centers cooperate to hydrolyze the otherwise unreactive urea. Urea coordinates to one Ni-center thus increasing the electrophilicity whereas water coordinates to the second Ni. It is thus acidified and can be deprotonated by histidine to generate a metal hydroxide as a nucleophile which is now in close spatial proximity to the electrophile and can attack in an intramolecular fashion.
We have developed readily accessible bispalladacycles (4 steps from ferrocene) striving for a similar mode of activation in which an electrophile and a nucleophile would be simultaneously activated. Proof of principle was established by the 1,4-addition of α-cyanoacetates to vinylketones providing functionalized building blocks containing an all-C substituted quaternary stereocenter. The robot-like action of the catalyst unifying both reactands was confirmed by detailed mechanistic studies.
III) Lewis acid / organic ion pair catalysis: combines the concepts of Lewis acid and aprotic organic ion pair catalysis in a single catalyst system. A labile negatively charged nucleophile is stabilized and directed to the electrophile by contact ion pair formation. We have proposed this novel concept in an attempt to develop a general trans-selective catalytic asymmetric β-lactone synthesis by cyclocondensation of acylhalides with aliphatic and aromatic aldehydes.
It is assumed that the pyridinium bromide generates the unstable acyl halide enolate by bromide attack on a ketene substrate. Nucleophilic attack at the ketene carbonyl is known to proceed in the ketene plane trans to the residue R1 generating a geometrically pure enolate. This enolate is now stabilized by ion pair formation with the pyridinium and directed toward the aldehyde which is activated by coordination to the Al central metal triggering C-C bond formation via a staggered open transition state in an anti aldol addition.