Martín Fañanás-Mastral

Direct catalytic cross-coupling of organolithium compounds

Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of natural products, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagents and organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivity of common organolithium reagents have largely prohibited their use as a viable partner in direct catalytic cross-coupling. Here we report that in the presence of a Pd-phosphine catalyst, a wide range of alkyl-, aryl- and heteroaryl-lithium reagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mild conditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation of key alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions for medicinal chemistry and material science. A general and selective palladium-catalysed cross-coupling of aryl- and alkenyl-bromides with a wide range of alkyl-, aryl- and heteroaryl-lithium reagents is reported. The process proceeds quickly at room temperature, and avoids the notorious lithium–halogen exchange and homocoupling side-reactions commonly associated with these extremely reactive organometallic compounds.

[1,5]‐Hydride Transfer/Cyclizations on Alkynyl Fischer Carbene Complexes: Synthesis of 1,2‐Dihydroquinolinyl Carbene Complexes and Cascade Reactions

processes the first and rate-limiting step comprises of a hydride migration from the carbon atom, a to the hetero atom, to the electrophilic position of the vinyl group. Thus, suitable systems for the tandem reaction must feature a heteroatom, to stabilize the carbocation that develops upon hydride migration, and a strong electron-withdrawing group on the terminal position of the double bond. More recently, this strategy has been extended to functionalize the a position of ethers and carbamates, and even tertiary benzylic C H bonds in processes promoted by Lewis acid catalysts (Figure 1b). To the best of our knowledge, there is no precedent for analogous hydride-transfer-promoted cyclizations involving triple bonds, despite the synthetic power of this type of cascade isomerization. In contrast, ortho-alkynyl anilines undergo metal-catalyzed 5-endo-dig cycloisomerizations leading to indole derivatives. As a part of our work on the chemistry of alkynyl Fischer carbene complexes, we turned our attention to the study of chromium ortho-aminophenylalkynyl complexes (1; Scheme 1). Alkynyl carbene complex 1a was synthesized by standard procedures, and it was stable at room temperature, however, when a solution of 1a in THF was heated at 90 8C in a sealed tube, new carbene complex 2a was isolated in 98% yield after the workup (Scheme 1).

Catalytic enantioselective synthesis of naturally occurring butenolides via hetero-allylic alkylation and ring closing metathesis.

An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.

Iridium‐Catalyzed Asymmetric Intramolecular Allylic Amidation: Enantioselective Synthesis of Chiral Tetrahydroisoquinolines and Saturated Nitrogen Heterocycles

For the first time iridium catalysis has been used for the synthesis of chiral tetrahydroisoquinolines with excellent yields and high enantioselectivities (see scheme; cod=1,5-cyclooctadiene, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene). These products are important chiral building blocks for the synthesis of biologically active compounds, in particular alkaloids.

Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with organolithium reagents

A highly efficient method is reported for the asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. Using a copper/chiral phosphoramidite complex together with a Lewis acid (BF(3)·OEt(2)), full selectivity for the anti isomer and excellent enantioselectivities were obtained for the ring opened products.

Palladium-catalysed direct cross-coupling of secondary alkyllithium reagents

Palladium-catalysed cross-coupling of secondary C(sp3) organometallic reagents has been a long-standing challenge in organic synthesis, due to the problems associated with undesired isomerisation or the formation of reduction products. Based on our recently developed catalytic C–C bond formation with organolithium reagents, herein we present a Pd-catalysed cross-coupling of secondary alkyllithium reagents with aryl and alkenyl bromides. The reaction proceeds at room temperature and on short timescales with high selectivity and yields. This methodology is also applicable to hindered aryl bromides, which are a major challenge in the field of metal catalysed cross-coupling reactions.

Catalytic Direct Cross-Coupling of Organolithium Compounds with Aryl Chlorides

Palladium-catalyzed direct cross-coupling of aryl chlorides with a wide range of (hetero)aryl lithium compounds is reported. The use of Pd-PEPPSI-IPent or Pd2(dba)3/XPhos as the catalyst allows for the preparation of biaryl and heterobiaryl compounds in high yields under mild conditions (room temperature to 40 °C) with short reaction times.

Copper-Catalyzed Synthesis of Mixed Alkyl Aryl Phosphonates

Copper-catalysis allows the direct oxygen-arylation of dialkyl phosphonates with diaryliodonium salts. This novel methodology proceeds with a wide range of phosphonates and phosphoramidates under mild conditions and gives straightforward access to valuable mixed alkyl aryl phosphonates in very good yields and near perfect selectivity.

Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones

γ-Butenolides, γ-butyrolactones, and derivatives, especially in enantiomerically pure form, constitute the structural core of numerous natural products which display an impressive range of biological activities which are important for the development of novel physiological and therapeutic agents. Furthermore, optically active γ-butenolides and γ-butyrolactones serve also as a prominent class of chiral building blocks for the synthesis of diverse biological active compounds and complex molecules. Taking into account the varying biological activity profiles and wide-ranging structural diversity of the optically active γ-butenolide or γ-butyrolactone structure, the development of asymmetric synthetic strategies for assembling such challenging scaffolds has attracted major attention from synthetic chemists in the past decade. This review offers an overview of the different enantioselective synthesis of γ-butenolides and γ-butyrolactones which employ catalytic amounts of metal complexes or organocatalysts, with emphasis focused on the mechanistic issues that account for the observed stereocontrol of the representative reactions, as well as practical applications and synthetic potentials.

Palladium-catalysed direct cross-coupling of organolithium reagents with aryl and vinyl triflates.

A palladium-catalysed cross-coupling of organolithium reagents with aryl and vinyl triflates is presented. The reaction proceeds at 50 or 70 °C with short reaction times, and the corresponding products are obtained with moderate to high yields, with a variety of alkyl and (hetero)aryl lithium reagents.