Research

We have established the first catalytic, enantioselective process for the synthesis of 1,4-dicarbonyl compounds with two adjacent stereogenic centers which proceeds with excellent levels of both diastereo- and enantiocontrol. Key to the success was the use of a alpha-acetoxy hydrazone which under silylium ion catalysis forms a resonance-stabilized 1-azaallyl cation and was trapped with a silylketene acetal. With a chiral IDPI-catalyst masked 1,4-hetero dicarbonyl compounds were thus obtained with >90% yield and up to 99:1 e.r. Propionate-based silylketene acetals deliver products with a second stereogenic center and up to >50:1 d.r. and 99:1 e.r.

Mechanistic studies including NMR-, MS-, and kinetic investigations as well as DFT-calculations reveal a detailed picture of the reaction pathway and the transition state of the reaction. First synthetic applications have paved the way towards medicinally relevant agents, such as pregabalin and brivaracetam.

We have recently established the first catalytic, highly stereoselective vinylogous Mannich reactions of acyclic vinylketene silyl-O,O-acetals with imines which furnish valuable unsaturated amino esters with excellent yields, complete regioselectivity and excellent enantio- and diastereoselectivity. As chiral catalyst we employ a BINOL-based phosphoric acid which upon protonation of the imine produces a chiral, highly reactive contact ion pair.

The application of α-silyloxy-substituted silyl dienolates provides vinylogous Mannich products bearing reactive silyl enol ether groups prone for additional modifications. Both the nucleophilic β-position and the electrophilic a-carbonyl group upon hydrolysis can be used to access a variety of multicyclic heterocycles just by modification of the reaction conditions.

An efficient access to functionalized and enantiomerically highly enriched tetrahydrofurans has been developed. The sequential procedure included an an asymmetric Titanium(IV)-BINOLate catalysed aldol reaction of aldehydes with α-silyloxy-substituted silyl dienolates followed by Prins-cyclisation generated products bearing three stereogenic centres in typical good yields, high γ-regioselectivities, very good diastereoselectivities, and excellent enantioselectivities up to 95:5 e.r. With further functionalized aldehydes the sequence could be expanded by a carbonyl-ene reaction to furnish octahydrobenzofuranes bearing two additional stereogenic centres.

For the synthesis of unsymmetrically substituted tetrahydrofurans the complete sequence was conducted to continuous flow process enabling improved stereoselectivities, better yields, and the fast and easy access to multigram quantities of the desired products.

We have established the first catalytic, enantioselective, vinylogous Michael reaction of silyl dienol ethers and enals which proceeds 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 centre can be easily installed with good diastereoselectivity of >10:1.

In the case of using α-silyloxy-substituted silyl dienolates for the catalytic, enantioselective, and vinylogous Michael reaction an additional intramolecular aldol condensation was observed furnishing highly valuable chiral cyclopentenes in good yields and with high enantioselectivities. Furthermore, the α-keto ester moiety of the product can be easily converted with a variety of reagents to obtain highly functionalized chiral cyclopentanes and multicyclic heterocycles. 

Using β-alkyl vinylketene silyl acetals the same process delivers chiral piperidones with superb enantioselectivity in an aza-Diels-Alder reaction. Subsequently, the products are widely manipulated to access substituted piperidines in enantiomerically highly enriched form.

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 cycloaddition or conjugate addition event with excellent enantioselectivity. β-Dicarbonyl compounds, enamides, enolrich aldehydes, indoles, phenols, and diazo esters are among the most suitable reaction partners to furnish benzannulated 5-, 6-, and 7-membered oxygen heterocycles as enantiomerically highly enriched compounds.

Ortho-quinone methide imines are the nitrogen analogues of ortho-quinone methides. They are accessible from the respective amino alcohols by chiral phosphoric acid-catalysis and are converted into hexahydroacridines, dihydroquinolones, and benzannulated quinolizidines with excellent enantioselectivity.

The aforementioned concept of the ortho-quinone methide chemistry can be easily extended to heterocyclic motifs. Thus, hydrogen-bonded, chiral alkylidene 2H-indoles and 2H-pyrroles are produced upon acid-catalysed dehydration from the respective alcohols. They react easily with electronrich π-nucleophiles to produce pyrrolo[1,2-a]indoles, 1H‑pyrrolizines, and cyclopenta[b]pyrroles with defined absolute and relative configuration.

Taking advantage of our enantioselective vinylogous Mannich reaction a range of alkaloids have been prepared in enantiomerically highly enriched form. In particular, bicyclic nitrogen heterocycles such as indolizidines and quinolizidines commonly found as constituents of frog skins have been obtained as single-enantiomer compounds via a straightforward, modular-type strategy. Just recently, the same strategy was applied to the currently shortest enantioselective synthesis of the tricyclic alkaloid (-)-205B. Currently under investigation is a total synthesis of the dimeric nuphar alkaloid thiobinupharidine.

As part of our research into highly reactive ortho-quinone methides, we have established a large number of highly stereoselective synthesis protocols for building complex and optically active heterocycles. Tetrahydrocannabinoids are an interesting class of natural products with a chromane skeleton. Their best-known representative is tetrahydrocannabinol (THC), one of the phytocannabinoids produced in the cannabis plant. These compounds accumulate primarily in the inflorescences of female plants. It has been known since the 1960s that THC is responsible for the characteristic psychoactive effects of cannabis.

Using a mere three-step biomimetic sequence, we have enabled access to several naturally occurring cannabimimetics such as (–)-cis-Δ9-tetrahydrocannabinol and (–)-perrotettine, as well as several unnatural analogues, with the catalytic asymmetric cyclization of 1-arylterpenols serving as the key step. Strongly acidic imidodiphosphorimidates (IDPis) act as optimal chiral catalysts, delivering the products with good yields and excellent enantioselectivity. 

Another class of natural products that we have synthesized recently are polydeoxypropionates. They are produced by bacteria, funghi, 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 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 polydeoxy-propionates. The insect pheromones vittatalactone and norvittatalactone and the lipid components phthioceranic acid and hydroxyphthioceranic acid were assembled as single stereoisomers following this concept.