Enantioselective Catalysis and Natural Product Synthesis
The central theme of our research activities is synthetic organic chemistry with a special focus on the development and application of novel stereoselective synthetic methods both for the control of relative and absolute configuration. In this respect we strive to employ chiral catalysts as the stereochemical control element which may be organocatalysts, metal catalysts, or biocatalysts. A good portion of our work is concerned with the application of these methods towards the synthesis of complex natural products and prominent heterocyclic scaffolds with interesting biological and pharmacological properties.
Organocatalytic, Enantioselective, Carbon-Carbon Bond Forming Processes
Small organic molecules have recently been shown to be highly efficient and selective chiral catalysts for a broad range of organic transformations. One class of so-called chiral organocatalysts are sterically demanding BINOL-based phosphoric acids which are capable of protonating imines to furnish highly reactive chiral contact ion pairs in which the chiral counterion controls the stereochemistry of the C-C-bond forming event. One of the reactions currently under investigation in our group is the first vinylogous Mannich reaction of an acyclic vinylketene silyl-O,O-acetal which furnishes valuable δ-amino-α,β-unsaturated carboxylic esters in excellent yields, complete regioselectivity and good diastereo- and excellent enantioselectivity using just 3 mol-% of a BINOL-based phosphoric acid. This protocol can as well be extended to the conversion of vinylketene silyl N,O-acetals from amides which give rise δ-amino α,β-unsaturated amides in excellent yields and enantioselectivities.
Based upon their functional density the Mannich products are ideally suited for further synthetic manipulations in particular in the context of nitrogen heterocycle synthesis. We have thus far synthesized or are currently on the way to various piperidine and pyrrolidine alkaloids, tetrahydroquinolines as well as bicyclic nitrogen heterocycles such quinolizidines and the indolizidines all of which are accessible in just a few steps and high enantiomeric purity.
Vinylogous Michael reactions are even more difficult to control as both reaction components may react at two different sites each resulting in four different regioisomeric combinations. It is therefore mandatory to shut down all pathways other than the desired γ-1,4-selective reaction mode. For this purpose we have developed a reaction protocol for the execution of the first vinylogous Mukaiyama-Michael process of acyclic dienolates proceeding with exceptional regio- as well as enantioselectivity. In the presence of the Jørgensen-Hayashi catalyst the desired products are obtained in typically good yields, complete γ-regioselectivity, and excellent enantioselectivity exceeding 97% ee in all cases studied. Moreover, with γ-substituted nucleophiles a second stereogenic center can be easily installed with good diastereoselectivity of >10:1.
Ortho-quinone methides are highly reactive synthetic intermediates which have only recently been used to a greater extent in organic chemistry. They are easily available from a variety of precursors and react as polarized, electronpoor 1-oxabutadienes mostly with electronrich [2π]-components in hetero-Diels-Alder reactions with inverse electron demand or with nucleophiles in conjugate addition reactions both with reconstitution of the aromatic π-system.
Using chiral phosphoric acids as powerful organocatalysts we have been able to generate hydrogen-bonded ortho-quinone methides in situ to which a variety of electronrich π-nucleophiles can be added in a conjugate addition event with excellent enantioselectivity. With β-dicarbonyl compounds as nucleophiles a broadly applicable and highly selective synthesis of 9H-xanthenones and related heterocycles emerges upon subsequent cyclodehydration. With enamides a formal [4+2]-cycloaddition to generate acetamido-substituted tetrahydroxanthenes has been established with full stereocontrol over the three contiguous chiral centers. Likewise, the ortho-quinone methides can be efficiently trapped with indoles and phenols to generate diarylindolyl methanes and triaryl methanes, respectively, in good yields and excellent enantioselectivity.
Finally, in a synergistic approach using both rhodium and phosphoric acid catalysis the ortho-quinone methides are trapped with oxonium ylides also generated in situ to yield highly substituted and densely functionalized chromanes with three contiguous chiral centers two of which are quaternary. We are currently exploring the full synthetic potential of this exciting chemistry with the intention to extend it to even more π-nucleophiles and related quinone methides as well.
Natural Product Synthesis
We strive to apply our newly developed synthetic methodology in broader context and pursue some natural product syntheses. Taking advantage of our enantioselective vinylogous Mannich reaction piperidine, pyrrolidine, and tetrahydroquinoline alkaloids are easily accessible within a few steps and very high optical purity. Moreover, bicyclic nitrogen heterocycles such as indolizidines and quinolizidines have been obtained as single-enantiomer compounds via a straightforward, modular-type strategy.
Another class currently under investigation are the polydeoxypropionate-based natural products. They are produced by bacteria, fungi, and plants and display potent and diverse biological activities. They are characterized by an alkyl chain substituted with methyl groups at every second carbon atom differing from the related polypropionates in the lack of hydroxyl groups at the other carbon atoms. In the light of their significant biological activity a good amount of work has been directed at their stereoselective assembly worldwide. We have recently developed a novel and conceptually different synthetic access to this product class which for the first time does not rely on an iterative synthesis, but rather provides trideoxypropionate subunits directly which can be coupled in a highly convergent manner to furnish long-chain polydeoxypropionates.
The pheromones vittatalactone and norvittatalactone as well as the lipid component phthioceranic acid have been synthesized according to this strategy and current efforts attempt to extend this methodology towards the first total synthesis of hydroxyphthioceranic acid which is a potential immune stimulator against tuberculosis.
Rapid Assembly of Molecular Complexity
The rapid assembly of novel heterocyclic scaffolds is an important and currently intensely investigated research topic primarily in the light of its relevance to medicinal chemistry. In particular, domino reactions that lead to multiple bond forming events in a one-pot operation are highly attractive processes in this respect on the basis of their flexibility, operational simplicity, and reaction efficiency. Ideally, such processes are accompanied by the generation of new reactive functional groups and full stereochemical control over newly formed stereogenic centers.
As an outgrowth of our vinylogous Mannich reaction we have developed a novel [3+2]-cycloannulation process which furnishes densely functionalized tetrahydropyrrolo[2,1-b] benzoxazoles, pyrrolo[1,2-a]benzoxazinones, and pyrrolo[1,2-a]quinazolinones in excellent yields and as single diastereomers. With a chiral metal catalyst products can be obtained in good enantioselectivity as well. In addition to their unprecedented structure which makes them highly interesting novel heterocyclic scaffolds in their own right these compounds may be further elaborated in various ways on the basis of their reactive N,O-acetal structure to provide valuable unnatural proline derivatives with a quaternary chiral center.
By a slight modification of the reaction conditions and partners a different reaction path is operative and hexahydropyrroloquinolines are accessible in a one-pot domino process in 80-90% yield. Here 6 new sigma-bonds and 4 new stereogenic centers are formed within a single synthetic operation and mainly only diastereomer is obtained in good yield (typically > 95:5 dr). We are currently exploring the full scope of these reactions and expect them to provide a broad range of highly interesting nitrogen heterocycles scaffolds which will certainly be of interest to medicinal chemists. In reactions with other electrophiles (e. g. aldehydes and Michael acceptors) various additional interesting carbo- and heterocyclic scaffolds are accessible in just one step documenting its versatility in synthetic organic chemistry.
The broad applicability of the above mentioned bis-silyl-1,3-dienediolates in [3+2]-cycloannulation reactions was further demonstrated by a highly enantioselective Michael reaction furnishing optically active 1-cyclopentenyl-α-keto esters in excellent enantioselectivities of up to 99% ee. As chiral organocatalyst we employed the Hayashi-Jorgensen chiral diphenylprolinol silylether. The final cyclopentenes were directly obtained through intramolecular Knoevenagel-type condensation of the intermediately formed silyl enol ether toward the intermediate iminium ion resulting both in ring-closure and regeneration of the chiral catalyst. Furthermore, the cyclopentenes proved to be highly versatile synthetic intermediates and were readily converted into various structural motifs.
Ring-Opening of Small-Ring Heterocycles
We are searching for novel and efficient processes towards the catalytic and enantioselective synthesis of a variety of precious fine chemicals, agrochemicals, and pharmaceuticals.
We have succeeded in establishing the first catalytic, enantioselective alcoholysis of meso-epoxides utilizing a novel scandium-bipyridine complex as chiral catalyst. 1,2-Diolmonoethers are accessible in good yields and enantioselectivities of up to 97% ee. The protocol is also applicable ot the aminolysis, thiolysis, and selenolysis of epoxides furnishing valuable 1,2-amino alcohols, 1,2-thio alcohols, and 1,2-seleno alcohols in comparable yields and enantioselectivities. Mechanistic and structural investigations towards a better understanding of the reaction path and a transition state model are currently ongoing.
The asymmetric ring-opening of meso-aziridines holds great potential for the enantioselective synthesis of precious fine chemicals. In particular, the aminolysis of meso-aziridines yields highly valuable chiral 1,2-diamines which may be employed as medicinal agents, chiral ligands or synthetic building blocks.
We have recently identified a simple titanium-binolate-complex as chiral catalyst for the highly enantioselective aminolysis of meso-aziridines. With just 10 mol-% of this readily prepared complex chiral 1,2-diamines are accessible in high yields and up to 99% ee. Investigations concerning the full scope of this reaction as well as further mechanistic studies and synthetic applications are currently underway in our laboratory.
In addition, we have found a number of cationic transition metal complexes to be competent catalysts for the ring-opening of aziridines with anilines. Thus, using just 1-5 mol-% of a dicationic nickel, palladium, or iron complex N-aryl aziridines are readily ring-opened with anilines and deliver trans-1,2-diamines in excellent yields. These protocols provide interesting opportunities for an enantioselective modification of the processes.