Barry Trost

A new bifunctional ligand bearing chiral N‐heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero‐bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto‐homoenolates, leading to the formation of various γ‐vinyl ketones with good regio‐ and enantio‐selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN2’ addition and the ligand‐substrate steric interactions account for the stereoselective outcome.

A novel Pd0‐catalyzed highly regio‐ and enantioselective [3+2] spiroannulation reaction has been developed for rapid assembly of a new class of [5,5] spirocyclic carbo‐ and heterocycles. Notably, the regioselectivity could be dominated by fine‐tuning of the Pd‐π‐allyl intermediate. An array of coupling partners could be well‐tolerated with excellent regio‐, and enantioselectivities. Moreover, the potential application of this reaction was exemplified by several further transformations.

We synthesized a series of phosphine–olefin-type chiral aminophosphines, and we confirmed that these each exists as two rotamers at the C(aryl)–N(amine) bond. We also investigated the ability of these aminophosphines to act as chiral ligands for Pd-catalyzed asymmetric allylic substitution reactions, such as the alkylation of allylic acetates with malonates or indoles, and we found they gave high enantioselectivities (up to 98% ee).

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold. In this step, optimization studies revealed that the stereochemistry of the enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis further highlights an efficient copper-mediated conjugate addition, merged with a gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging the D-ring of the natural product. The synthetic strategy reported herein can provide a general platform to access the skeleton of other members of this family of natural products.

A method for the Brønsted acid promoted desulfination of aryl sulfoxides is presented. In the presence of a thiol, electron-rich sulfoxides undergo C–S bond cleavage to give the corresponding protodesulfinated arenes and disulfides.

The synthesis of the pentacylic core of (+)-citrinadin A is described. Our strategy harnesses the power of palladium-catalyzed trimethylenemethane chemistry (Pd-TMM) to form the key spirooxindole motif in a catalytic, asymmetric fashion. Upon the conversion of this spirooxindole to a vinyl epoxide electrophile, the piperidine ring is directly added via a diastereoselective metalation followed by an SN2′ addition. The final ring of the pentacyclic core is then formed through an intramolecular SN2 displacement of the resulting activated alcohol.

A highly regio-, diastereo-, and enantioselective trimethylenemethane (TMM) cycloaddition reaction for the rapid assembly of 2-acyl-methylenecyclopentane in an atom-economic fashion is described. This intermolecular protocol allows for facile and divergent access to an array of structurally attractive cyclic adducts. The choice of a robust chiral diamidophosphite ligand, developed by our group, proved to be crucial for the success of this transformation.

The palladium-catalyzed [3 + 2] cycloaddition using in situ generated sulfone-TMM species to construct various chiral cyclopentyl sulfones in a highly regio-, diastereo- (dr >15:1), and enantioselective (up to 99% ee) manner is reported. The present strategy can tolerate different types of sulfone-TMM donors and acceptors, and enables the construction of three chiral centers in a single step, specifically with a chiral center bearing the sulfone moiety. The robust chiral diamidophosphite ligand is the key to the reactivity and selectivities of this transformation.