Investigations of the Copper-Catalyzed Oxidative Cross-Coupling of Tetrahydroisoquinolines with Diethylzinc by a Combination of Mass Spectrometric and Electrochemical Methods.

The aerobic oxidative cross-coupling of tetrahydroisoquinolines (THIQs) with diethylzinc catalyzed by CuCl2 has been examined by means of electrospray mass spectrometry (ESI-MS). Substrates, intermediates, and the product were readily detected. Particular emphasis has been placed on the role of CuCl2 . Formation of the intermediate iminium species has been investigated in more detail by ESI-MS, electrochemistry-coupled ESI mass spectrometry (EC-MS), and cyclic voltammetry (CV). Our experiments have consistently revealed strong influences of the N-substituent of the THIQ derivative and its oxidation stability with respect to CuCl2 . The results may help to expand the synthetic scope of the reaction, while also further establishing EC-MS as a valuable technique for linking mass spectrometry with cyclic voltammetry in mechanistic studies of organic redox reactions.

Total Synthesis of Leupyrrins A1 and B1 , Highly Potent Antifungal Agents from the Myxobacterium Sorangium cellulosum.

Full details on the design, elaboration, and application of efficient strategies for the high-yielding total syntheses of leupyrrins A1 and B1 , unique antifungal agents from the myxobacterium Sorangium cellulosum, are reported. A sequential zirconocene-mediated diyne-cyclization, and regioselective opening of the zirconacyclopentadiene intermediate enabled a concise entry into the unique dihydrofuran fragment, whereas another domino reaction was developed for the butyrolactone involving a one-pot lactol opening, stereoselective aldehyde addition and in situ lactonization. Furthermore, an innovative sp2 -sp3 -cross-coupling for pyrrole functionalization and an optimized HATU-mediated amide coupling protocol of two elaborate fragments were established. In addition, an unusual protective group strategy, involving a Teoc-acetonide protected amine in combination with tert-butyl and acetate esters, was successfully elaborated. These tactics and strategies are generally useful and may be also applied in the synthesis of other functionalized compounds. It is expected that the material which was obtained by these total syntheses will enable the further exploration of the biological profile of these potent antifungal agents.

Synthesis of α-Chiral Butyrolactones by Highly Stereoselective Radical Transfer or Sequential Asymmetric Alkylations: Concise Preparation of Leupyrrin Moieties.

Inspired by the bioactive natural metabolites leupyrrin A1 and B1 , two novel stereoselective methods for the highly concise synthesis of densely substituted α-chiral butyrolactones are reported. The first approach relies on an innovative three-step Ti(III) -catalyzed radical reaction that proceeds with excellent chemo-, regio-, and stereoselectivity. The alternative route utilizes sequential asymmetric alkylations and enables asymmetric synthesis of the authentic α-tetrasubstituted butyrolactone motif of the leupyrrins in only four steps from commercially available substrates.

Quaternary Carbon Synthesis by Titanocene Catalyzed Radical Allyl Transfer on Epoxides.

A versatile titanocene-catalyzed radical allyl transfer reaction on epoxides is reported. Epoxide opening occurs regioselectively at the more hindered side, and variously substituted allyl sulfone may be coupled to this position in an efficient manner, enabling a rapid access to quaternary carbon centers with useful functionalities for further elaboration. Furthermore, the procedure can be expanded to stereoselective variants. This new radical allyl transfer expands the scope of allylation in organic synthesis.

Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical Intermediate.

A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl2-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp(3) C-H bond activation allowing for an sp(3)-sp(3) bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.