Hans-Guenther Schmalz

Enantioselective Cu-Catalyzed 1,4-Addition of Grignard Reagents to Cyclohexenone Using Taddol-Derived Phosphine–Phosphite Ligands and 2-Methyl-THF as a Solvent†

The 1,4-addition (conjugate addition) of C nucleophiles to a,b-unsaturated carbonyl compounds and related activated olefins belongs to the most powerful and reliable tools for C C bond formation. Accordingly, it is frequently exploited in the synthesis of natural products and other complex organic molecules. Three decades of research on asymmetric and, in particular, asymmetric catalytic versions of conjugate addition reactions have resulted in the development of a broad variety of methods. However, the important task of performing the 1,4-addition of simple Grignard reagents, the most common type of organometallic reagents, in an enantioselective fashion still remains a particular challenge. As recently reviewed, several Cu-based catalyst systems have been suggested in the past for the catalytic asymmetric 1,4-addition of Grignard reagents. Nevertheless, high enantioselectivities ( 90% ee) were achieved only in a few special cases, and the reported methods did not find much application owing to limited substrate scope, operational convenience, and accessibility of the chiral ligands required. In 2004, an important advance was made by Feringa and co-workers who, by screening a set of commercially available chiral P,P ligands, identified ferrocene-based diphosphines, in particular Taniaphos (1) and Josiphos (2), as promising ligands for such transformations.

Identification of Suitable Ligands for a Transition Metal-Catalyzed Reaction: Screening of a Modular Ligand Library in the Enantioselective Hydroboration of Styrene

Based on a general modular synthetic scheme, a variety of chiral bidentate P/P-, P/S-, P/N-, and P/Se-ligands is accessible in an efficient divergent manner starting from phenol or naphthol derived backbone systems. A library of 20 selected ligands was tested in the Rh-catalyzed asymmetric hydroboration of styrene to give 1-phenylethanol in up to 91% ee after oxidative work-up. It was demonstrated that small variations of the ligand structures lead to pronounced, unpredictable differences in the performance of the in situ generated rhodium complexes. The modular approach should be applicable for the identification and optimization of suitable ligands for other transition metal-catalyzed transformations with comparably low effort.

Gaining absolute control of the regiochemistry in the cobalt-catalyzed 1,4-hydrovinylation reaction.

The absolute control of the regiochemistry of a cobalt-catalyzed 1,4-hydrovinylation reaction is achieved by alternation of the ligands applied. While the dppe/dppp ligands led to the formation of the branched product, the herein described application of the SchmalzPhos ligand generates the corresponding linear product in both excellent yields and regioselectivities. The catalyst system exhibits a high tolerance toward functional groups, and the very mild reaction conditions allow the synthesis of 1,4-dienes without isomerization into conjugated systems.

Synthesis and biological evaluation of new antimalarial isonitriles related to marine diterpenoids

Abstract By exploiting the chemistry of arene tricarbonylchromium(0) complexes, some analogues of antimalarial marine isonitrile diterpenoids were synthesized in a completely diastereoselective fashion and their activity against the malaria parasite Plasmodium falciparum was assessed in an in vitro assay.

Diallylaluminium-N,N-dimethylaminoethanolate, the first stable allyl-alane suitable for additions to aldehydes, ketones and imines

Abstract The reaction of AlCl 3 with lithium- N , N -dimethylaminoethanolate ( 3 ) in a 1:1 ratio yields the corresponding organo-aluminium chloride [Cl 2 Al(μ-OCH 2 CH 2 NMe 2 )] 2 ( 1 ) from which the diallyl derivative [(CH 2 CHCH 2 ) 2 Al(μ-OCH 2 CH 2 NMe 2 )] 2 ( 4 ) was synthesized by treatment with 2 equiv. of allyl magnesium bromide. The structures of 1 and 4 were deduced from the 1 H, 13 C, 27 Al NMR spectra and confirmed by X-ray structural determination. The allyl aluminium complex 4 was found to be a useful reagent for the transfer of one allyl group to aldehydes, imines and enones. The 1,2-addition products are formed in high yields.

Nucleophile- or Light-Induced Synthesis of 3-Substituted Phthalides from 2-Formylarylketones

The surprisingly facile conversion (isomerization) of 2-formyl-arylketones into 3-substituted phthalides, as observed for the marine natural product pestalone and its per-O-methylated derivative, was investigated using a series of simple 2-acylbenzaldehydes as substrates. The transformation generally proceeds smoothly in DMSO, either in a Cannizarro-Tishchenko-type reaction under nucleophile catalysis (NaCN) or under photochemical conditions (DMSO, 350 nm).

Synthetic analogues of the antibiotic pestalone

Abstract The first synthetic study towards the natural product pestalone ( 1 ) is described culminating in the preparation of selected n −1 analogues. Pestalone is a chlorinated and prenylated benzophenone antibiotic, which is of interest due to a strong activity against methicillin-resistant staphylococcus aureus strains (MRSA). Key step of the synthesis is the nucleophilic addition of a highly functionalized aryllithium building block to a 2-prenylated 3,5-dialkoxy-benzaldehyde followed by oxidation. For the introduction of the prenyl sidechain by aryl-allyl coupling, different procedures were evaluated, among them the Stille reaction and a nickel π-allyl complex coupling.

Asymmetric catalytic arylation of ethyl glyoxylate using organoboron reagents and Rh(I)–phosphane and phosphane–phosphite catalysts

Herein we report the first application of Rh(I)–phosphane and phosphane–phosphite catalysts in the enantioselective catalytic arylation of ethyl glyoxylate with organoboron reagents, providing access to ethyl mandelate derivatives in high yield (up to 99%) and moderate to very good enantioselectivities (up to 75% ee). Commercial phosphane ligands, such as (R)-MonoPhos and (R)-Phanephos were tested, as well as non-commercial (R,R)-TADDOL-derived phosphane–phosphite ligands. Those ligands containing bulky substituents in the ortho-and para-positions of the chiral phosphite moiety were found to be the most selective.

Low‐Pressure Cobalt‐Catalyzed Enantioselective Hydrovinylation of Vinylarenes

An efficient and practical protocol for the enantioselective cobalt-catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L2 CoCl2 ] complexes are employed that are activated in situ with Et2 AlCl. A modular chiral TADDOL-derived phosphine-phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH2 , CN, and CO2 R, are tolerated.

Total Synthesis of (R,R,R)‐α‐Tocopherol Through Asymmetric Cu‐Catalyzed 1,4‐Addition

By introducing a disposable activating substituent at C-3, the asymmetric 1,4-addition to a notoriously unreactive 2-substituted chromenone was achieved with high levels of (2R)-stereoselectivity in the presence of a chiral Cu(I)-phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)-α-tocopherol from readily available starting materials.