Internal olefins are present in a large number of biologically active compounds including therapeutics that are used for a diverse range of clinical applications. They also serve as useful building blocks for more complex molecules. Internal olefins can exist as either the E or Z-stereoisomer. The geometry of the olefin directly impacts the overall conformation of the molecule and, therefore, the physical, chemical, and biological properties of the molecule. As a result, methods to selectively synthesis the E or Z-stereoisomer are of great importance. Recent developments in olefin metathesis have revealed catalysts capable of selectively synthesizing the Z-stereoisomer. However, current olefin metathesis catalysts typically rely on the reversible nature of the metathesis reaction to selectively form th thermodynamically favorable E-stereoisomer. This substrate-controlled approach is often unpredictable, and many examples exist where the thermodynamic preference of the product is small leading to a mixture of E and Z-stereoisomers that are difficult to separate. To date, olefin metathesis catalysts capable of selectively synthesize the (E)-olefin under kinetic control remain elusive. This proposal outlines a detailed, systematic approach for the development and application of kinetically E-selective olefin metathesis catalysts. Guided by a promising preliminary result, initial investigations will focus on ring-opening cross metathesis (ROCM). Strategic changes will be made to the N-heterocyclic carbene (NHC) ligand of the NHC-ruthenium carbene complex to determine the relationship between catalyst structure and E- selectivity. These studies will be aided by computational studies geared towards understanding the origin of the E-selectivity. Once promising E-selective catalysts have been identified, they will be tested against a series of substrates known to undergo ROCM with low E-selectivity. This investigation should differentiate between catalyst structures and enhance our understanding of the factors that control E-selectivity. Finally, the insights gained from the ROCM studies will be applied to designing catalysts to achieve E-selective cross metathesis and macrocyclic ring-closing metathesis.

Public Health Relevance

(E)-Olefins are present in many commonly prescribed drugs (e.g. Crestor(r), Singulair(r), and Lumigan(r)) that are used for a diverse range of clinical applications including lowering cholesterol, relieving asthma symptoms, and treating ocular hypertension. In addition, (E)-olefins are useful building blocks for the synthesis of more complex targets. This proposal describes a systematic approach for the development of a practical, efficient method for the highly selective synthesis of (E)-olefins from readily availabl starting materials.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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California Institute of Technology
Schools of Arts and Sciences
United States
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Chu, Crystal K; Ziegler, Daniel T; Carr, Brian et al. (2016) Direct Access to ?-Fluorinated Aldehydes by Nitrite-Modified Wacker Oxidation. Angew Chem Int Ed Engl 55:8435-9