Rhodium-Catalyzed Enantioselective Intramolecular Hydroalkoxylation of Allenes and Application in the Total Synthesis of (R,R,R)-α-Tocopherol.

We report herein of a novel, enantioselective and rhodium- catalyzed cyclisation of allenyl alcohols towards chiral α-vinylic, cyclic ethers employing a rhodium/(R,R)-Me-ferrocelane catalyst. The corresponding chiral cyclic products were obtained in general high yields and enantioselectivities. The synthetic value of our obtained products was further exemplified by transformations of the allylic ether function. Furthermore, applying our newly developed method in our previously reported route towards the total synthesis of (R,R,R)-α-tocopherol, we accomplished a significantly improved 2nd generation synthesis of the chromane building providing a total number of 13 steps and an overall total yield of 27 %.

Unprecedented Direct Asymmetric Total Syntheses of 5,8'-Naphthylisoquinoline Alkaloids from their Fully Substituted Precursors Employing a Novel Nickel/N,N-ligand-Catalyzed Atroposelective Cross-Coupling Reaction.

A general and concise synthetic pathway for the preparation of four different 5,8'-coupled naphthylisoquinoline alkaloids, employing a specially developed nickel/N,N-ligand-catalyzed atroposelective Negishi coupling is reported. In the first reported direct atroposelective coupling of the fully substituted precursors, the naturally occurring cross-coupled products were generally obtained directly in reasonable yields and high enantiomeric purities. For the synthesis of the cross-coupling precursors, we employed a modification of Bringmann's known approach to the dihydroisoquinoline compounds and a newly developed route for the naphthalene building blocks. For the latter 1,8-dioxynaphthalene precursors, our strategy utilized Hartwig's borylation/methylation approach and included the efficient installation of orthogonal protecting groups.

Atroposelective NiII -Catalyzed Cross-Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher-Order Zincates.

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3 ]2- Mg(THF)2 2+ . The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions.

Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination of Allenes.

The rhodium-catalyzed asymmetric intramolecular hydroamination of sulfonyl amides with terminal allenes is reported. It provides selective access to 5- and 6-membered N-heterocycles, scaffolds found in a large range of different bioactive compounds. Moreover, gram scale reactions, as well as the application of suitable product transformations to natural products and key intermediates thereof are demonstrated.

Total Synthesis of (-)-Cylindrocyclophane†F: A Yardstick for Probing New Catalytic C-C Bond-Forming Methodologies.

A short and efficient total synthesis of the C2 -symmetric (-)-cylindrocyclophane F is presented, using a cross olefin metathesis dimerization strategy for construction of the [7,7]-paracyclophane macrocycle. The synthesis of the dimerization building block includes a Pd-catalyzed sp3 -sp2 Negishi cross coupling of a sterically hindered Zn-reagent with an aromatic triflate, an enantiospecific Zn-catalyzed sp3 -sp3 cross coupling of an α-hydroxy ester triflate with a Grignard reagent and the application of an enantioselective Rh-catalyzed C-allylation of an electron rich arene.

Stereodivergent and Protecting-Group-Free Synthesis of the Helicascolide Family: A Rhodium-Catalyzed Atom-Economical Lactonization Strategy.

Natural products of polyketide origin, in particular small-sized lactones often possess a very broad range of impressive biological activities. An efficient way to demonstrate the concise access to six-membered lactones was emphasized as part of a stereodivergent and protecting-group-free synthesis of all three representatives of the helicascolide family. This strategy features an atom-economical and highly diastereoselective rhodium-catalyzed "head-to-tail" lactonization by an intramolecular addition of ω-allenyl-substituted carboxylic acids to terminal allenes, including the selective construction of a new stereocenter in the newly formed core structures. The excellent selectivities with which the helicascolide precursors were obtained are remarkable, thus resulting in an expeditious and highly efficient natural product synthesis.

Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity.

We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene-conjugated derivative of SphA by a cross-metathesis reaction involving the phytotoxin's C15,C16-alkene. This derivative's evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5-10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16-alkene cross-metathesis analogues in which the pyrene moiety was replaced with other aromatic or non-aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non-mutagenic, while retaining the high potency of the original pyrene-containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene-containing compounds to overcome intellectual property issues associated with non-patentability of the original pyrene derivative.

Asymmetric Total Syntheses of (-)-Angustureine and (-)-Cuspareine via Rhodium-Catalyzed Hydroamination.

Concise syntheses of the Hancock alkaloids (-)-angustureine and (-)-cuspareine are presented, applying and refining a recently developed rhodium-catalyzed hydroamination for the stereoselective construction of the chiral secondary amine. Furthermore, the syntheses include an allene synthesis via boron-magnesium exchange as well as the construction of the tetrahydroquinoline motive via a hydroboration/Suzuki-Miyaura coupling sequence.

Rhodium-catalyzed asymmetric intramolecular hydroarylation of allenes: access to functionalized benzocycles.

A rhodium-catalyzed regio- and enantioselective cyclization of tethered allenylbenzenes is reported. Employing a RhI/Josiphos catalytic system a diverse set of 6-membered, α-chiral benzocycles were obtained, scaffolds found in many bioactive compounds. Moreover, a gram scale reaction as well as the application of suitable transformations are demonstrated.

Chemo-, Regio-, and Enantioselective Rhodium-Catalyzed Allylation of Triazoles with Internal Alkynes and Terminal Allenes.

The rhodium-catalyzed asymmetric N1-selective and regioselective coupling of triazole derivatives with internal alkynes and terminal allenes gives access to secondary and tertiary allylic triazoles in very good enantioselectivities. For this process, three new members of the JosPOphos ligand family have been prepared and employed in catalysis. The optimized reaction conditions enable the coupling of triazoles with internal alkynes as well as with allenes, displaying a high tolerance for functional groups. A gram scale reaction provided N1-allyltriazole, which was subjected to various transformations highlighting synthetic utility.