End-to-End Automated Synthesis of C(sp3)-Enriched Drug-like Molecules via Negishi Coupling and Novel, Automated Liquid-Liquid Extraction.

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid-liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.

Gold- or platinum-catalyzed cascade processes of alkynol derivatives involving hydroalkoxylation reactions followed by Prins-type cyclizations.

An efficient method for the synthesis of [3.3.1]bicyclic compounds from easily available alkynol derivatives has been developed. The reaction is based on a gold- or platinum-catalyzed tandem process that involves an intramolecular hydroalkoxylation of a triple bond followed by a Prins-type cyclization. The reaction has been carried out with differently substituted alkynol derivatives and oxygen-, nitrogen-, and carbon-centered nucleophiles. The incorporation of halogen atoms as nucleophiles and elimination reactions has also been studied. Enantiomerically pure [3.3.1]bicyclic systems were easily synthesized from the chiral pool.

[W(CO)5]-catalyzed endo- or exo-cycloisomerization reactions of 1,1-disubstituted 4-pentyn-1-ols: experimental and theoretical studies.

The [W(CO)5]-catalyzed cycloisomerization reaction of 1,1-disubstituted 4-pentyn-1-ol derivatives has been studied from both, an experimental and theoretical point of view. Three different catalytic systems have been evaluated {preformed [(thf)W(CO)5], [W(CO)6]/excess Et3N, and [W(CO)6]/2 mol % Et3N]. We have found that the reaction proceeds to give the formal endo- or exo-cycloisomerization products depending on the amount of Et3N used and on the substitution along the alkyl chain of the starting alkynol. The theoretical study allowed us to find the mechanisms of the reactions which explain the formation of the formal endo- or exo-cycloisomerization products.

Solvent-assisted new reaction pathways for the (THF)W(CO)5-promoted endo- and exo-cycloisomerization of 4-pentyn-1-ol: a theoretical investigation.

New solvent-assisted mechanistic routes were located for the (THF)W(CO)5-promoted endo- and exo-cycloisomerization of 4-pentyn-1-ol using the B3LYP/6-31G (with the LANL2DZ relativistic pseudopotential for W) theory level. A mixed model was used by explicitly including a THF molecule as a component of the reactive system and taking into account the effect of bulk solvent by means of the PCM-UAHF method. This THF molecule plays a crucial role by making the endo route leading to the cyclic carbene complex the most favorable one because of an important catalytic effect. These new mechanisms allow a satisfactory rationalization of experimental facts.

One-pot enantioselective formation of eight-membered rings from alkenyl Fischer carbene complexes and ketone enolates.

Eight-membered carbocycles with up to five new stereogenic centers are enantioselectively obtained following a one-pot procedure that involves the coupling of three components: an alkenyl Fischer carbene complex, a ketone enolate, and allyl lithium.