Alkenes are found in a great number of biologically active molecules and are employed in some of the most widely used transformations used to access them (such as hydrogenations, epoxidations, hydroborations, dihydroxylations, cyclopropanations, allylic substitutions, hydroformylations and cycloadditions). Many olefins exist as E or higher energy Z isomers. Processes that allow access to each isomeric form efficiently, reliably, with high selectivity and in a cost-effective fashion are therefore of substantial significance to chemistry, biology and medicine. Especially valuable are catalytic procedures for stereoselective formation of alkenes;however, such methods are uncommon. Particularly scarce are catalytic protocols that deliver Z alkenes. Research in this program is focused on the design, synthesis and development of a range of molybdenum- and tungsten-based catalysts that can be used for one of the most powerful and efficient methods for olefin synthesis: catalytic olefin metathesis. A variety of concepts, originally conceived in this NIH-funded program, will be used to introduce catalysts that can be manipulated in air and yet offer exceptional reactivity and selectivity when placed in solution in the presence of a substrate. Such catalysts will allow chemists to obtain reactivity and/or selectivity levels that remain entirely out of reach. Olefin metathesis catalysts will be developed that promote Z-selective cross-metathesis reactions of allylic ethers, epoxides, boronates, silanes as well as vinylbornates, dienes and 1,2-unsaturated carbonyls. Catalysts will be introduced that will allow chemists to prepare Z di- or trisubstituted macrocyclic alkenes, without having to forfeit nearly half of their valuable materials as the undesired stereoisomer at the late stages of a multi-step total synthesis. The new catalysts and methods will generate entities commonly viewed as the "bread and butter" of synthetic chemists, and yet their preparation often requires long and impractical routes. The special utility of the concepts, strategies, catalysts and protocols that will emerge from the proposed investigations will be highlighted through efficient approaches to syntheses of biologically significant molecules such as antimutagenic falcarindiol, antiviral chlorosufolipids, cytotoxic disorazole C1, gibberellin biosynthesis inhibitor cladospolide B, antibacterial and anticancer nakadomarin A, and anticancer agents epothilone B and neopeltolide.

Public Health Relevance

Our ability to prepare various medicinally active agents in a cost-effective, reliable, efficient and selective manner is most critical to advances in human health care. The proposed research will afford unique, inexpensive and highly potent catalysts that promote efficient formation of one of the most common units found in a large number of biologically significant molecules, and that cannot be accessed easily by other methods.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM059426-15
Application #
8608535
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Gao, Fang; Carr, James L; Hoveyda, Amir H (2014) A broadly applicable NHC-Cu-catalyzed approach for efficient, site-, and enantioselective coupling of readily accessible (pinacolato)alkenylboron compounds to allylic phosphates and applications to natural product synthesis. J Am Chem Soc 136:2149-61
Townsend, Erik M; Hyvl, Jakub; Forrest, William P et al. (2014) Synthesis of Molybdenum and Tungsten Alkylidene Complexes That Contain Sterically Demanding Arenethiolate Ligands. Organometallics 33:5334-5341
Hoveyda, Amir H (2014) Evolution of catalytic stereoselective olefin metathesis: from ancillary transformation to purveyor of stereochemical identity. J Org Chem 79:4763-92

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