Enantioselective synthesis of ß-aryl-γ-lactam derivatives via Heck-Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles.

We report herein an enantioselective palladium-catalyzed Heck-Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the commercial drug baclofen as hydrochloride.

Effect of Solvents on Proline Modified at the Secondary Sphere: A Multivariate Exploration.

The critical influence of solvent effects on proline-catalyzed aldol reactions has been extensively described. Herein, we apply multivariate regression strategies to probe the influence of different solvents on an aldol reaction catalyzed by proline modified at its secondary sphere with boronic acids. In this system, both in situ binding of the boronic acid to proline and the outcome of the aldol reaction are impacted by the solvent-controlled microenvironment. Thus, with the aim of uncovering mechanistic insight and an ancillary aim of identifying methodological improvements, we designed a set of experiments, spanning 15 boronic acids in five different solvents. Based on hypothesized intermediates or interactions that could be responsible for the selectivity in these reactions, we proposed several structural configurations for the library of boronic acids. Subsequently, we compared the statistical models correlating the outcome of the reaction in different solvents with molecular descriptors produced for each of these proposed configurations. The models allude to the importance of different interactions in controlling selectivity in each of the studied solvents. As a proof-of-concept for the practicality of our approach, the models in chloroform ultimately led to lowering the ketone loading to only two equivalents while retaining excellent yield and enantio- and diastereo-selectivity.

Synthesis of Fulvene Vinyl Ethers by Gold Catalysis.

Gold-catalyzed cyclization of 1,5-diynes with ketones as reagents and solvent provides diversely substituted vinyl ethers under mild conditions. The regioselectivity of such gold-catalyzed cyclizations is usually controlled by the scaffold of the diyne. Herein, we report the first solvent-controlled switching of regioselectivity from a 6-endo-dig- to 5-endo-dig-cyclization in these transformations, providing fulvene derivatives. With respect to the functional-group tolerance, aryl fluorides, chlorides, bromides, and ethers are tolerated. Furthermore, the mechanism and selectivity are put to scrutiny by experimental studies and a thermodynamic analysis of the product. Additionally, 6-(vinyloxy)fulvenes are a hitherto unknown class of compounds. Their reactivity is briefly evaluated, to give insights into their potential applications.

Different Selectivities in the Insertions into C(sp2 )-H Bonds: Benzofulvenes by Dual Gold Catalysis Competition Experiments.

An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp2 )-H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C-H positions. A bidirectional synthesis with two competing ortho-aryl C-H bonds in the selectivity-determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C-H bonds with a benzylic methyl group also showed perfect selectivity.

Secondary-sphere modification in proline catalysis: old friend, new connection.

In this work, we exploit our strategy of in situ secondary-sphere modification of organocatalysts to improve the reactivity and selectivity of amino catalysts. Herein, the carboxylic acid moiety of proline was targeted as a site for modification under catalytic reaction conditions with boronic acids. Intermolecular aldol reactions between aromatic aldehydes and cyclopentanone were selected as a proof-of-concept because cyclopentanone as an aldol donor was often associated with decreased selectivity compared to its 6-membered ring analog, hexanone. Our secondary-sphere modification strategy, using naturally occurring L-proline amino acid, enabled reactions at room temperature with high levels of diastereo- and enantio-selectivity and short reaction times. NMR and HR-MS studies shed light on the nature of the catalyst structure and on the role of water in our reactions.

Experimental and theoretical studies on gold(III) carbonyl complexes: reductive C,H- and C,C bond formation.

The reactivity of cationic (C^C)gold(iii) carbonyl complexes was investigated. While the in situ-formed IPrAu(bph)CO+ complex (bph = biphenyl-2,2'-diyl) does not undergo a migratory insertion of CO into the neighboring gold-carbon bond, nucleophiles can attack the coordinated CO moiety intermolecularly. Water as a nucleophile initiates a CO2 extrusion combined with a reductive C,H bond formation. The rapid formation of a gold(i) species from an intermediary gold(iii) carbonyl has not been observed before and shows a significant difference in reactivity between (C^C) and (C^N^C)gold(iii) carbonyls. The latter have been reported to form stable gold(iii) hydrides via the WGS reaction. In the case of methanol acting as a nucleophile attacking the gold(iii) carbonyl, no extrusion of CO2 is observed. Instead an intermediary gold(iii) carboxyl complex forms an aryl carboxylate via reductive C-C bond elimination. Experimental and theoretical studies on the mechanism explain the observed selectivities and give new insights into the reactivity of elusive gold(iii) carbonyls.