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A simple procedure for the intermolecular enantioselective palladium-catalyzed decarboxylative allylation of β-ketoacids is described. This method, inspired by a stoichiometric control experiment p...

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a catalytic enantioselective dehydrative lactonization of allylic alcohols using a novel Pd(II)-catalyst containing the imidazole-based P,N -ligand ( S )-StackPhos is reported. The high-yielding reactions are operationally simple to perform with enantioselectivities up to 99% ee. This strategy facilitates the replacement of a poor leaving group with what would ostensibly be a better leaving group in the product avoiding complications arising from racemization by equilibration.

In this work, we report enantioselective orthogonal tandem catalysis for the one pot conversion of Meldrum's acid derivatives and alkynes into δ-lactones. This new transformation, which resembles a formal [4+2] cycloaddition with concomitant decarboxylation and loss of acetone, proceeds in high yields and excellent enantioselectivity (up to 99 % ee) over a broad substrate scope. The products are densely functionalized and ripe for further transformations, as demonstrated here by both ring-opening reactions and reduction to saturated lactones. It was discovered that a new and serendipitously formed AgI -Me-StackPhos complex efficiently catalyzes the highly selective 6-endo-dig cyclization, completely reversing the regiochemistry that has been previously reported in related systems. More generally, in this study we identify a pair of compatible catalysts for alkyne difunctionalization that operate concurrently, which enable the alkyne to act as both a nucleophile and an electrophile in sequential one-pot transformations.

Here we report a strategy for the systematic variation of atropisomeric C1 -symmetric P,N ligands to incrementally change the position of the groups within the chiral pocket without modifying their steric parameters. More specifically, the effects of systematic modification of the nitrogen heterocycle in atropisomeric C1 -symmetric stack ligands have been investigated in this study. The versatility and applicability of this approach has been demonstrated in mechanistically distinct catalytic enantioselective transformations, resulting in the identification of a P,N-ligand for a highly enantioselective synthesis of organoboranes.

A highly versatile enantioselective intermolecular Tsuji allylation that generates alpha-quaternary stereocenters is reported. The methodology utilizes a prochiral enol acetate as a substrate, which is the last class of the original Tsuji substrates to be successfully employed in an enantioselective variant of the venerable reaction. This development enables a highly convergent approach that lends itself to rapid diversification and analogue synthesis by facilitating the incorporation of the allyl moiety from an allylic alkoxide, obviating the need for the preparation of allylic enol carbonates. The reaction is operationally simple and employs the readily available PHOX ligand class. More than 30 examples are reported that proceed with enantiomeric excess (ee) values of up to 96% and a scope that tolerates a wide range of functional groups on the allylic component. The enol acetate substrates are readily prepared from both aryl and aliphatic ketones, where the regioselective preparation has long been known utilizing a variety of methods. The power of this methodology lies in its ability to quickly produce a diverse set of single enantiomer products using different allylic alcohols with a common prochiral enol acetate. This is demonstrated here by two rapid formal syntheses of hamigeran B that utilize a common intermediate to intercept both Clive and Stoltz intermediates, and also to prepare novel intermediate analogues.

By the nature of its structure, the 5-membered chiral biaryl heterocyclic scaffold represents a departure from 6-membered P,N-ligands that facilitates tuning and enables ligand evolution to address issues of selectivity and reactivity. In this vein, the Cu-catalyzed enantioselective conjugate alkynylation of Meldrum's acid acceptors is reported using Me-StackPhos. Enabled by this new ligand, the reaction tolerates a wide range of alkynes furnishing the products in high yields and excellent enantioselectivity. The transformation provides access to highly useful chiral β-alkynyl Meldrum's acid building blocks as demonstrated by an efficient enantioselective synthesis of the preclinical agent OPC 51803.

A complementary strategy for ligand tuning that enables controlling ligand conformation is described here. The concept is demonstrated with new ligands that are employed in the catalytic enantioselective preparation of the highly important C2-aminoalkyl five-membered heterocycle motif. The alkynylation/cyclization sequence developed here is convergent, highly modular, and allows for a complementary scope to the heteroarylation of imines. This new ligand platform should offer new possibilities for expanding the use of PHIM-type ligands in a large variety of new transformations.

The Cu-catalyzed synthesis of nonracemic 3-amino skipped diynes via an enantiodetermining C-C bond formation is described using StackPhos as ligand. Despite challenging issues of reactivity and stereoselectivity inherent to these chiral skipped diynes, the reaction tolerates an extremely broad substrate scope with respect to all components and provides the title compounds in excellent enantiomeric excess. The alkyne moieties are demonstrated here to be useful synthetic handles, and 3-amino skipped diynes are convenient building blocks for enantioselective synthesis.

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu-catalyzed enantioselective alkynylation using the chiral imidazole-based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd-catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional-group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.

A new strategy for increasing the barrier to rotation in biaryls has been developed that allows for the incorporation of 5-membered aromatic heterocycles into chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A(3)-coupling, demonstrating the potential of this new design element.

Mild conditions for the gold-catalyzed dehydrative cyclization of carbamate-protected azaallylic alcohols to form saturated nitrogen heterocycles are reported. The cyclization reactions are high-yielding, operationally easy to perform, and provide heterocycles with a synthetically useful vinyl group, strategically located on the ring system, which can facilitate further transformations for target oriented synthesis. It is also demonstrated through chirality transfer experiments that the mechanism can be either cationic in nature or a Au-catalyzed addition/elimination sequence. The diverging mechanistic scenario is dependent on the nature of the substituents on the allylic alcohol and necessitates judicious substrate design.

The use of a mixture of dl- and meso-divinylethylene carbonate as an electrophile in palladium-catalyzed asymmetric allylic alkylation reactions is reported. From the diastereomeric mixture of meso and chiral racemic starting materials, a single product is obtained in high optical purity employing either oxygen or nitrogen nucleophiles. The resulting dienes have proven to be versatile synthetic intermediates as each carbon is functionalized for further transformation and differentiated by virtue of the reaction. A mechanism for this intriguing transformation is proposed and a concise enantioselective total synthesis of (+)-australine hydrochloride is reported as well as a formal synthesis of isoaltholactone.

A highly enantioselective copper-catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole-based chiral biaryl P,N ligand, and copper bromide to effect a three-component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)-galipinine, (+)-angustureine, and (-)-cuspareine are reported.

Over the past decade and a half, homogenous gold catalysis has emerged as a diverse and rich field of research resulting in the continuous development of new methods for organic synthesis. The activation of alkynes towards nucleophilic attack by Au(I) and Au(III) complexes is a well-established mode of reactivity and the gold-catalyzed hydration and hydroalkoxylation of alkynes are two of the more well-explored reaction pathways. Although these classes of reactions have seen continuous development since their initial reports, achieving regioselectivity persists as one of the most challenging issues for this chemistry. This article aims to draw attention to the general problem of regioselectivity in these reactions. A select set of examples is presented to highlight the challenges and survey some of the strategies employed to address this problem.

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral compounds and the rapid assembly of complex molecular architecture from simple starting materials. While many types of catalyst systems have been successfully employed with certain systems, diphenylphosphino benzoic acid (DPPBA) based ligands have found use over a broad range of substrate classes. This Account highlights the mechanistic aspects considered when designing reactions with DPPBA-based ligands and presents a working model for the a priori prediction of their stereochemical outcome.

The Au(I)-catalyzed intermolecular hydroalkoxylation of alkynes with allylic alcohols to provide allyl vinyl ethers that subsequently undergo Claisen rearrangement is reported. This new cascade reaction strategy facilitates the direct formation of γ,δ-unsaturated ketones from simple starting materials in a single step.

A high-yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl2(MeCN)2] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl-substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted "down-the-chain" and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter.

Density functional calculations and experiment were used to examine the mechanism, reactivity, and origin of chirality transfer in monophosphine Au-catalyzed monoallylic diol cyclization reactions. The lowest energy pathway for cyclization involves a two-step sequence that begins with intramolecular C-O bond formation by anti-addition of the non-allylic hydroxyl group to the Au-coordinated alkene followed by concerted hydrogen transfer/anti-elimination to liberate water. Concerted S(N)2'-type transition states were found to be significantly higher in energy. The two-step cyclization pathway is extremely facile due to hydrogen bonding between diol groups that induces nucleophilic attack on the alkene and then proton transfer between diol groups after C-O bond formation. Importantly, intramolecular proton transfer and elimination provides an extremely efficient avenue for catalyst regeneration from the Au-C σ-bond intermediate, in contrast to other Au-catalyzed cyclization reactions where this intermediate severely restricts catalyst turnover. The origin of chirality transfer and the ensuing alkene stereochemistry is also the result of strong hydrogen-bonding interactions between diol groups. In the C-O bond-forming step, requisite hydrogen bonding biases the tethered nucleophilic moiety to adopt a chair-like conformation with substituents in either axial or equatorial positions, dictating the stereochemical outcome of the reaction. Since this hydrogen bonding is maintained throughout the course of the reaction, establishment of the resultant olefin geometry is also attributed to this templating effect. These computational conclusions are supported by experimental evidence employing bicyclic systems to probe the facial selectivity.

Correction for ‘Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes’ by Justin A. Goodwin et al., Chem. Commun., 2015, 51, 8730–8741.

The palladium-catalyzed asymmetric allylic alkylation of a 1:1 mixture of dl- and meso-1,2-divinylethylene carbonate is reported. For the first time, both the ionization and nucleophilic addition steps of the catalytic cycle act as enantiodiscriminating steps to give a single product in high enantiomeric excess. The reactions proceed in >98% ee to efficiently generate useful chiral building blocks from acrolein. The absolute and relative configurations of iso-cladospolide B and 11-epi-iso-cladospolide B were verified by total synthesis, solving an apparent discrepancy in the literature.

The gold(I)-catalyzed endo-cyclization of o-(1-hydroxyallyl)phenols to form chromenes is reported. The title compounds are prepared in high yield from readily available substrates. The system tolerates both electron rich and deficient aryl rings and a high degree of substitution on the allyl moiety.