The Chemical Design and Synthesis of Linkers Used in Antibody Drug Conjugates.

Antibody Drug Conjugates (ADCs) use targeting ability of monoclonal antibodies to deliver potent cytototoxic payloads to their intended target. The linker encompasses a conjugating functionality suitable for attachment to the antibody, a spacer unit that typically incorporates a hydrophilic element and a trigger which releases the potent cytototoxic warhead. Understanding the conflicting requirements of ADC design, providing stability in systemic circulation but efficient payload release once the ADC reaches its intended target, is crucial to effective linker development.

Efficient and selective formation of macrocyclic disubstituted Z alkenes by ring-closing metathesis (RCM) reactions catalyzed by Mo- or W-based monoaryloxide pyrrolide (MAP) complexes: applications to total syntheses of epilachnene, yuzu lactone, ambrettolide, epothilone C, and nakadomarin A.

The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.

Catalytic asymmetric alkylation reactions for the construction of protected ethylene-amino and propylene-amino motifs attached to quaternary stereocentres.

An efficient catalytic and stereoselective method for the direct construction of protected ethylene-amino and propylene-amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N-sulfonyl aziridines using the commercially available phosphazene base 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97% ee) by employing phase-transfer catalysis to control stereoinduction.

Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations.

Total synthesis of (-)-nakadomarin A.

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.