Branched allylic amines were prepared by Ir-catalyzed enantioselective allylic aminations with the bulky N-nucleophiles HN(Boc)₂ and HNBn₂. The products were transformed into N-protected amino aldehydes, which were either reduced or coupled diastereoselectively with organometallic compounds to give vicinal amino alcohols. A formal synthesis of the neurokinin receptor antagonist (+)-L-733060 was carried out as an application.

The first immobilized catalyst for Ir-catalyzed asymmetric allylic aminations is described. The catalyst is a cationic (π-allyl)Ir complex bound by cation exchange to an anionic silica gel support. Preparation of the catalyst is facile, and the supported catalyst displayed considerably enhanced activity compared with the parent homogeneous catalyst. Up to 43 consecutive amination runs were possible in recycling experiments.

A sequence of reactions that include an iridium-catalyzed regio- and enantioselective allylic amination, the formation of an amide, a ruthenium-catalyzed ring-closing metathesis, and an intramolecular Heck reaction allows for the preparation of [3,3,1]- and [4,3,1]-bicyclic amides. The target compounds have a nitrogen atom at the bridgehead, a nonplanar amide moiety, and a stereogenic center at the one-carbon bridge.

Stereoselective syntheses of 3-hydroxypiperidines have been developed. Key intermediates are N-protected allylamines that are prepared by an enantioselective iridium-catalyzed allylic amination. A subsequent catch and release procedure that involves an epoxidation and base-mediated elimination yields δ-lactams that are suitably functionalized to prepare biologically active 3-hydroxypiperidines. In addition, applications of this method to the total syntheses of deoxymannojirimycin, D-erythro-sphingosine, and chiral building blocks of interest for medicinal chemistry are described.

Short and concise syntheses of the hexahydroindene cores of the antibiotics indanomycin (X-14547 A) and stawamycin are presented. Key methods used are an asymmetric iridium-catalyzed allylic alkylation, a modified Julia olefination, a Suzuki–Miyaura coupling, and an intramolecular Diels–Alder reaction.

Enantioselective iridium-catalyzed allylic substitutions were used to prepare N-allyl hydroxamic acid derivatives that were suitable for ring-closing metathesis, giving N-methoxylactams. Reactions of these derivatives with Grignard or organolithium compounds gave hemiaminals, which could be reduced diastereoselectively via acyliminium intermediates to give cis-piperidines or cis-pyrrolidines with substituents in the 2,6- or 2,5-positions, respectively. In addition, compounds with a quaternary carbon center could be synthesized by corresponding reactions with potassium cyanide/AcOH. The procedures were applied in the syntheses of alkaloids (−)-209D and (+)-prosophylline.

(π-Allyl)Ir complexes derived from dibenzocyclooctatetraene and phosphoramidites by cyclometalation are effective catalysts for allylic substitution reactions of linear monosubstituted allylic carbonates. These catalysts provide exceptionally high degrees of regioselectivity and allow the reactions to be run under aerobic conditions. A series of (π-allyl)Ir complexes were prepared and characterized by X-ray crystal structure analyses. An allylic amination with aniline displayed different resting states depending on the presence of a strong base. DFT calculations were carried out on the mechanistic aspects of these reactions. The results suggest that for the (π-allyl)Ir complexes, the formation and reactions with nucleophiles proceed with comparable rates.

Total and partial syntheses of brefeldin analogues are described. (6R)-Hydroxy-BFA (5) was obtained through a total synthesis from (1S,2R)-2-[(trityloxy)methyl]cyclopent-3-ene-1-carbonitrile (cis-8) in 13 steps. The BFA lactam analogue 6 was prepared via the key building block 25, which was accessed in four steps from BFA (1). (7S)-Amino-BFC (7) was obtained from 7-dehydro-BFA (3) by reductive amination. The structures of the brefeldin analogues were determined by X-ray analyses. The activities of the brefeldin analogues in blocking protein traffic between the endoplasmatic reticulum and the Golgi apparatus were determined both for mammalian cells and for plant cells. Molecular mechanics calculations and docking into the Arf1-GEF protein complex, an established receptor of BFA, were carried out.

A broadly applicable route to trans-2,5-disubstituted pyrrolidines has been developed. Key steps are an asymmetric iridium-catalyzed allylic amination, a Suzuki–Miyaura coupling, and an intramolecular aza-Michael addition. Enantiomeric excesses in the range of 93–99 % ee have been achieved. Total syntheses of the alkaloids (−)-225 C, (+)- and (−)-223 H (xenovenine), (+)-223 AB, (+)-195 B, and (+)-223 R have been carried out as applications.

Under appropriate reaction conditions, a domino hydroformylation/Wittig olefination can be accomplished with derivatives of allylamines and stabilized Wittig ylides. A further highly diastereoselective aza-Michael reaction yields β-proline derivatives. These are, for example, useful as building blocks for alkaloid syntheses.

Mechanistic aspects of allylic substitutions with iridium catalysts derived from phosphoramidites by cyclometalation were investigated. The determination of resting states by ³¹P NMR spectroscopy led to the conclusion that the cyclometalation process is reversible. A novel, one-pot procedure for the preparation of (π- allyl)Ir complexes was developed, and these complexes were characterised by X-ray crystal structure analyses and spectral data. They are fully active catalysts of the allylic substitution reaction. DFT calculations on the allyl complexes, transition states of the allylic substitution and product olefin complexes gave further mechanistic insight.

A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru-catalyzed cross-metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)-prosopinine, (+)-prosophylline, (+)-prosopine, and of the dendrobate alkaloid (+)-241D and its C6 epimer are described.

A full account of a recently discovered gold(I)-catalyzed reaction, a cycloaddition of carbonyl compounds to enynes yielding 2-oxabicyclo[3.1.0]hexanes with four stereogenic centers, is presented. The reaction proceeds with very high diastereoselectivity. The scope of the reaction has been investigated. In addition, experiments and DFT calculations concerning mechanistic aspects were carried out. The reaction course varies with the substitution pattern of the alkene moiety of the starting enyne. Branched olefins led to 2-oxabicyclo[3.1.0]hexanes; terminally substituted olefins proceeded with the incorporation of two carbonyl components to give hexahydrocyclopenta[d][1,3]dioxines.

The all-cis substituted cyclopentane 3a, an analogue of the Corey lactone, has been prepared from a readily available nortricyclanone derivative by a five-step sequence in an overall yield of 34 %. This chiral building block has been applied in total syntheses of two diastereomeric isoprostanes belonging to the 5-F₂ family: ent-5-F_2c-IsoP (ent-1) and 5-epi-ent-5-F_2c-IsoP (ent-2). Key features of the syntheses are the introduction of the two unsaturated alkyl side chains through an E-selective Horner–Wadsworth–Emmons reaction with the base-sensitive syn-aldehyde 10, along with a Z-selective Wittig olefination.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A broadly applicable synthesis of chiral 2- or 2,4-substituted cyclopent-2-enones has been developed by combining asymmetric iridium-catalyzed allylic alkylation reactions and ruthenium-catalyzed ring-closing metathesis. Enantiomeric excesses (ee values) in the range of 95–99 % ee have been achieved. This method offers a straightforward access to biologically active prostaglandins of the PGA type. As an example, an enantioselective synthesis of the prostaglandin-analogue 13,14-dihydro-15-deoxy-Δ⁷-prostaglandin-A1-methyl ester (TEI-9826) has been carried out. Furthermore, the carbonucleoside 2′-methylcarbovir has been prepared from O-protected 4-hydroxymethyl-2-methyl-cyclopent-2-enone by Pd-catalyzed allylic amination.