Scheme 1:Dynamic kinetic resolution of a secondary alcohol.

The reaction was extended to a variety of different alcohols and these studies have attracted a lot of interest on the international level. Since the beginning of this project in 1996, the group has published more than 25 papers on the combination of enzymes and transition metal-catalyzed reactions. A number of groups have used this new technique with combination of a ruthenium catalyst and an enzyme for deracemization of alcohols. In 2002 DSM Fine Chemicals developed a large scale industrial process based on this method for production of enantiomerically pure alcohols in ton scale.

In the original procedure, the Shvo ruthenium racemization catalyst required 60-70 ^oC for racemization. With this ruthenium catalyst, the dynamic kinetic resolution requires 24-48 h at this temperature. Recently, there was a second breakthrough as the group discovered a new ruthenium catalyst, pentaphenylcyclopentadienyl catalyst I, that racemizes alcohols in less than 10 min at room temperature (Scheme 2). In the combined system with enzyme + metal catalyst, the dynamic kinetic resolution reaction is now over in 3 h at room temperature in quantitative yields with >99% ee.

Scheme 2. Improved DKR catalyst. CALB = Candida Antarctica lipase Bm (Novozym 435).

Biomimetic oxidation

A large part of the studies of transition metal-catalyzed reactions in Prof. Bäckvall’s group has involved oxidation reactions. A logic extension of this work was therefore to focus on the development of processes using environmentally friendly oxidants such as molecular oxygen and hydrogen peroxide. Inspired by nature and the oxidations occurring in living organisms (e.g. the respiratory chain), environmentally friendly biomimetic oxidations with specially designed catalytic systems were developed. In these reactions the electron transfer processes occurring in biological oxidations were mimicked. The first example of such a biomimetic system was the palladium-catalyzed aerobic 1,4-diacetoxylation (Scheme 3), where a quinone and a metal-macrocyclic complex were used as electron transfer mediators (ETMs). Low energy barriers for electron transfer are obtained by the use of ETMs, in contrast to the high barrier for direct reoxidation of Pd(0) by molecular oxygen.

Scheme 3. Palladium-catalyzed aerobic 1,4-diacetoxylation.

The principle of this biomimetic oxidation was extended to other systems such as aerobic oxidation of alcohols and H₂O₂-oxidation of alkenes to 1,2-diols. In the former reaction, the ruthenium catalyst mimics the NAD⁺/NADH in alcohol dehydrogenase that is coupled to the respiratory chain for aerobic oxidation of alcohols (Scheme 4). In the respiratory chain the electrons of NADH are transported to ubiquinone and the hydroquinone thus formed is reoxidized to by cytochrome c and O₂. In the biomimetic process of Scheme 4, the electrons taken up by the ruthenium catalyst are also transported to a quinone and the hydroquinone formed is reoxidized by a metal macrocycle/O₂. Recently this cascade electron transfer chain was extended to the aerobic oxidation of amines.

Scheme 4. Biomimeticaerobic oxidation of alcohols.

Recently, the group has also developed novel osmium-catalyzed dihydroxylations using hydrogen peroxide as the oxidant (Scheme 5). In these reactions an electron transfer mediator, e.g. a flavin, was used to catalyze the hydrogen peroxide oxidation of the N-Methyl morpholine (NMM) to the N-oxide (NMO). The latter reacts rapidly with osmium(VI). This leads to a mild and selective oxidation with hydrogen peroxide without formation of effluents. The reaction was used in enantioselective dihydroxy­lation with chiral ligands and this is the first example of asymmetric dihydroxy­lation employing H₂O₂ as the oxidant. It was recently demonstrated that the whole catalytic system can be immobilized in an ionic liquid and this allows recycling of the whole catalytic system (“catalytic soup”). This is of great impor­tance for future large scale applications.

Scheme 5. Osmium-catalyzed dihydroxylations.

Organo-Metallic Transformations

I) Organopalladium chemistry

Some early contributions by the group on transition metal-catalyzed reactions dealed with the mechanism of specific organometallic steps involved in catalytic transformations. One example is the mechanism study of the industrially important Wacker process, a large-scale industrial process for the manufacturing of acetaldehyde from ethylene (Scheme 6).

Scheme 6. The Wacker process with mechanism.

The mechanism of this reaction had been debated for a long time and it was argued that the reaction occurs via cis-hydroxypalladation. In 1979 the Bäckvall group reported a stereochemical study, using deuterated ethane, which showed that the reaction occurs via trans-hydroxypalladation. The paper led to a new understanding of the mechanism of the process and the results have become textbook material.

In a series of papers the group studied the mechanism of important metal-catalyzed reactions. Some studies that can be mentioned include stereochemistry of amine attack on π-allylpalladium complexes, oxidative cleavage of palladium-carbon bonds, the stereochemistry of the nickel-catalyzed hydrocyanation in the adiponitrile process and the stereocontrolled acetate attack on π-allylpalladium complexes (Scheme 7). Later mechanistic work focused on important mechanistic questions in π-allylpalladium chemistry.

Scheme 7. Stereocontrolled acetate attack on π -allylpalladium complexes.

In parallel to the mechanistic studies, the group focused on the development of transition metal-catalyzed organic transformations. An important achievement was the discovery and development of the stereoselective palladium-catalyzed 1,4-oxidations of conjugated dienes (Scheme 8). These reactions were associated with an interesting duality in the stereochemistry. Thus, the two nucleophiles can be added trans or cis by simple ligand control, as exemplified in Scheme 8. The switch in stereochemistry has its origin in the stereocontrolled acetate attack on the π-allylpalladium complex shown above in Scheme 7.

Scheme 8. Pd-catalyzed 1,4-diacetoxylation and 1,4-chlorocetoxylation.

The synthetic use of the chloroacetoxylation reaction is enhanced by the fact that the chloride and acetate can be substituted by various nucleophiles in a sequential manner and with high stereoselectivity (also with dual stereocontrol). In this way a large number of stereodefined 1,4-functionalized conjugated dienes have been prepared and used in natural product synthesis (Figure 1). The group has recently developed novel palladium-catalyzed carbocyclizations involving conjugated dienes, allenes, and alkenes.

Figure 1. Natural products from 1,4-oxidation.

II) Ruthenium-catalyzed reactions

Bäckvall and coworkers have also made important contributions to metal-catalyzed hydrogen transfer reactions. In 1991 the base effect in ruthenium-catalyzed hydrogen transfer leading to a rate acceleration of 10³-10⁴ was reported. This had a significant impact on the development of ruthenium-catalyzed hydrogen transfer reactions. More recently the work has focused on the mechanisms and this work has been very fruitful for the development of biomimetic oxidations and for the combination of metals and enzymes (vide supra).

Directed Evolution

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