Catalytic Asymmetric Transacetalization

A catalytic enantioselective transacetalization has been developed. The chiral phosphoric acid TRIP was demonstrated to be an efficient and highly enantioselective catalyst for the activation of O,O-acetals. The reaction enables the asymmetric synthesis of acetals with the acetal carbon as the only stereogenic center

N-Phosphinyl Phosphoramide — A Chiral Brønsted Acid Motif for the Direct Asymmetric N,O-Acetalization of Aldehydes

Fine‐tuning the sites: The readily accessible N‐phosphinyl phosphoramide 1 proved to be highly efficient and enantioselective in catalyzing the title reaction. The synthetic utility of this methodology was demonstrated with the first catalytic asymmetric synthesis of the analgesic pharmaceutical (R)‐chlorothenoxazine (see scheme)

Direct Catalytic Asymmetric Synthesis of Cyclic Aminals from Aldehydes

A highly enantioselective Brønsted acid catalyzed direct synthesis of cyclic aminals from aldehydes has been developed. The methodology has been applied to the first asymmetric synthesis of several antihypertensive aminal drugs including (R)-Thiabutazide

The Catalytic Asymmetric Acetalization

In straitened circumstances: In an asymmetric version of the acid‐catalyzed acetalization of aldehydes, a novel member of the chiral confined Brønsted acid family significantly outperformed previously established catalysts, providing cyclic acetals with excellent enantioselectivity (see scheme; Ar=2‐iPr‐5‐MeC6H3)

Developing Catalytic Asymmetric Acetalizations

Acetals are among the most common stereocenters in Nature. They form glycosidic bonds that link together essential molecules of life, carbohydrates, including starch and cellulose, the most abundant organic material on Earth. Stereogenic acetals are also common motifs in other natural products, from small insect pheromones to highly complex spiroacetal polyketides. Although far less common than O,O-acetals, chiral N,N-, N,O-, and N,S-acetals are structural motifs also found in a number of natural products and pharmaceuticals. Here, recent progress towards chiral acetals using asymmetric Bronsted acid catalysis is summarized, with particular emphasis on O,O-acetalizations. In this context the development of novel catalyst classes, namely spirocyclic phosphoric acids and confined Bronsted acids, proved crucial and is also presented

Employing homoenolates generated by NHC catalysis in carbon-carbon bond-forming reactions: state of the art

Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon β to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,β-unsaturated aldehydes via N-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal

Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead.

The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-β-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/β-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic