Amgen – UCLA Lectureship

Thu, Feb 2 5:00pm
CS24 Young Hall
Speaker Professor Bradley L. Pentelute
Hosted by
UCLA Department of Chemistry and Biochemistry

The 2017 Amgen – UCLA Lectureship


1:30 PM Lecture

Cram Conference Room – 3440 Molecular Sciences Bldg

Stereoselective Synthesis of a Chiral Lactone Precursor to AMG 232

Dr. Austin G. Smith

Scientist, Drug Substance Technologies

Amgen, Inc.

Abstract.  AMG 232 is a small molecule therapy currently in clinical trials for the treatment of cancer. A stereodefined lactone intermediate, labeled DLAC, was identified as a key synthetic precursor to AMG 232. As such, we required a robust, isolable, and  highly selective synthetic route to DLAC that would enable material for both clinical trials and commercial production. This presentation details process improvements toward the scalable synthesis of DLAC via development of a robust and highly-selective Ru(II)-catalyzed dynamic kinetic resolution. Key features of this work include the discovery of ruthenabicyclic complex RuCl[(S)-diapena][(S)-xylBINAP] ((S)-RUCY-xylBINAP) as a highly effective catalyst for ketone hydrogenation with respect to conversion, yield, selectivity, catalyst loading, and cycle time. This report discusses an important transesterification event to a more sterically hindered isopropyl ester prior to hydrogenation to curb unexpected product erosion during the reaction. Lastly, we detail process control of a deleterious carboxylic acid impurity in the starting material in order to optimize DKR catalyst performance. Comprehensive process improvements led to a 55% yield of DLAC over 7 steps; desired product was obtained in > 90 kg on 3 separate occasions.


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5:00 PM Lecture

CS24 Young Hall

Cysteine Arylation to Engineer Peptides and Proteins

Professor Bradley L. Pentelute

Department of Chemistry

Massachusetts Institute of Technology

Abstract.  Here we report a robust bioconjugation method using cysteine arylation. This chemistry enables site-specific conjugation at cysteine residues within peptides, proteins, and antibodies. Our two developed approaches use either perfluoroaryl-cysteine SNAr chemistry or organometallic palladium reagents. This work lead to the discovery of a self-labeling four-residue sequence that enables regioselective conjugation at only one cysteine residue within an intact antibody containing natural amino acids. Recently, we discovered a new approach for the native conjugation of complex natural products such as vancomycin onto peptides and proteins without the introduction of linkers or chemical handles.


Thursday, February 2, 2017