Scale-Up of a Rh-Catalyzed Asymmetric sp3–sp2 Suzuki–Miyaura-Type Reaction

Csp2–Csp2 Suzuki–Miyaura couplings (SMCs) are ubiquitous in the synthesis of small molecules, but analogous Csp2–Csp3 bond-forming SMCs are rare, especially asymmetric variants. Recently, we developed a series of Rh-catalyzed couplings between racemic sp3-hybridized allyl chlorides and heteroaryl boronic acids. Here, we demonstrate that these catalytic asymmetric reactions can be scaled-up to give over 100 g of a product. The reaction we chose to test couples a heteroaromatic boronic acid derivative and a racemic bicyclic electrophile to give a product with three contiguous stereogenic centers. The SMC product was obtained as a single diastereomer in 90% yield and 98% ee. Kinetic analysis of the reaction reveals two exothermic steps in the reaction setup and revealed the means by which to prevent the generation of heat spikes detrimental to the stability of the catalyst

A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15-C16 bond formation

The esterification of fragment C1-C8 (2) with fragment C16-C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9-C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15-C16 bond formation via Negishi reaction. With simple models, pre-activated Pd-Xantphos and Pd-DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9-C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd-Xantphos and 60 °C

Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(I)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates

Cu-catalyzed asymmetric addition of sp2-hybridized zirconium nucleophiles to racemic allyl bromides

Alkenylzirconium nucleophiles made in situ by the hydrozirconation of terminal alkynes undergo dynamic kinetic asymmetric allylic alkenylation with racemic allyl bromides to give enantioenriched products

Asymmetric remote C-H functionalization: Use of internal olefins in tandem hydrometallation – isomerization – asymmetric conjugate addition sequences

We describe catalytic asymmetric C–C formation using terminal alkyl-metal nucleophiles generated from internal olefins through a ‘chain-walking’ isomerization mechanism. Hydrometallation of internal olefins with the Schwartz reagent gives the least hindered alkyl-zirconocene after thermal (60°C in THF) isomerization. After switching the solvent from THF to dichloromethane, the alkyl-zirconocenes can be used in copper-catalyzed asymmetric conjugate additions. Addition to a variety of cyclic α,β-unsaturated species were achieved in modest (22–50 %) yield with high (84–92 % ee) enantioselectivity. This work demonstrates that remote C–H functionalization coupled with asymmetric C–C bond formation is possible, but the present procedures are limited in terms of yield and olefin scope

Asymmetric remote C-H functionalization: Use of internal olefins in tandem hydrometallation – isomerization – asymmetric conjugate addition sequences

We describe catalytic asymmetric C–C formation using terminal alkyl-metal nucleophiles generated from internal olefins through a ‘chain-walking’ isomerization mechanism. Hydrometallation of internal olefins with the Schwartz reagent gives the least hindered alkyl-zirconocene after thermal (60°C in THF) isomerization. After switching the solvent from THF to dichloromethane, the alkyl-zirconocenes can be used in copper-catalyzed asymmetric conjugate additions. Addition to a variety of cyclic α,β-unsaturated species were achieved in modest (22–50 %) yield with high (84–92 % ee) enantioselectivity. This work demonstrates that remote C–H functionalization coupled with asymmetric C–C bond formation is possible, but the present procedures are limited in terms of yield and olefin scope

Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation

The development of new reactions forming asymmetric carbon–carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy—dynamic kinetic asymmetric transformation—involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield2. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods

Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

A practical solution to the formation of mixtures of E/Z and open/cyclic isomers in the reaction of (2R,4S)-4-hydroxy-2-methylpentanal (as its hemiacetal, a lactol) with conjugated phosphoranes (stabilised Wittig reagents) and Horner-Wadsworth-Emmons reagents is disclosed. The HWE reaction has a strong bias to give oxolanes. On the other hand, stabilised Wittig reagents give unsaturated carboxyl derivatives of configuration E (major) and oxolanes (minor); the latter can be avoided by addition of CF3CH2OH or using morpholine amide phosphorane