The Horner–Wadsworth–Emmons (HWE) reaction is a fundamental reaction in organic chemistry, widely used to create conjugated carbonyl compounds. Conjugated carbonyl compounds are used in many industries for synthesizing perfumes, plastics, and pharmaceuticals and are also involved in biological processes. Consequently, methods for improving HWE reactions are an active area of research.
One potential application of HWE reactions is to develop (E)-isomers of conjugated carbonyl compounds that are useful for synthesizing chemicals called hynapene analogues with promising anti-cancer properties. Unfortunately, traditional HWE reaction methods are sometimes inconsistent in their (E)- and (Z)-selectivity and require several steps to get further elongated compounds. Several studies have investigated new reagents to improve the selectivity of HWE reactions. However, the reason for their enhanced selectivity has not yet been examined enough, nor has the range of substrates suitable for these Weinreb amide-type HWE reagents been fully explored. Additionally, the effect of different reaction conditions on the HWE reaction using the same substrate hasn’t been studied.
In a breakthrough, a research team from the Department of Applied Chemistry at Tokyo University of Science (TUS), Japan, led by Assistant Professor Takatsugu Murata, including Mr. Hisazumi Tsutsui and Professor Isamu Shiina from TUS, conducted a detailed study on HWE reactions and developed a robust and highly (E)-selective Weinreb amide-type HWE reaction with a broad substrate scope. “The reaction we developed is faster than traditional methods such as the Wittig reaction and the corresponding ester-type HWE reaction, and the applicable compounds can be used in an extremely wide range of applications, including the synthesis of pharmacologically active analogues,” says Murata. “A key achievement is the isolation of the active species in the reaction, which allows us to efficiently synthesize the important precursor for producing pharmacologically active compounds on a larger scale by preparing the active species in advance.” Their study was made available online on October 11, 2024, and was published in Volume 89 Issue 21 of The Journal of Organic Chemistry on November 1st, 2024.
In this study, the researchers systematically tested the effect of different bases, solvents, cations, reaction concentrations, and temperatures on the reactivity and selectivity of the Weinreb amide–type HWE reaction. They discovered that using isopropyl magnesium bromide (iPrMgBr) as a base resulted in high (E)-selectivity, thanks to the formation of a magnesium phosphonoenolate intermediate. The structure of the intermediate and the valence of the metal cation were key to improving selectivity. Moreover, replacing bromine with chlorine in the base further improved selectivity.
Interestingly, the researchers also found that the magnesium phosphonoenolate intermediate formed using the iPrMgCl base was stable enough to be isolated. This isolated intermediate was exceptionally stable, showing no deterioration when stored at room temperature in an argon atmosphere for over six months. This intermediate could be directly used in HWE reaction with high (E)-selectivity.
The team further optimized the amount of iPrMgCl, solvents, and the Weinreb amide–type HWE reagent to maximize the yield of the reaction. The optimized conditions worked well across a wide range of substrates, including various aliphatic saturated aldehydes, aliphatic a, β-unsaturated aldehydes, and aromatic aldehydes, demonstrating the robustness and scalability of the method. To demonstrate its application, the team applied their novel reaction methodology to synthesize various complex organic compounds, including products from successive elongation processes, the HWE reaction of a cyclic ketone, and Weinreb ketone synthesis.
“Currently, hynapene analogues are being tested in various drug efficacy studies, including animal studies, and their development is highly anticipated, leading to more efficient drug development,” remarks Murata. Looking ahead, he adds, “We are committed to improving this method further and conducting more studies to gain better insights into the reaction mechanisms.”
We hope that this groundbreaking study offers a pathway towards novel anti-cancer drugs with potential benefits for countless patients.
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Reference
DOI: https://doi.org/10.1021/acs.joc.4c01140
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society," TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
Website: https://www.tus.ac.jp/en/mediarelations/
About Associate Professor Takatsugu Murata from Tokyo University of Science
Dr. Takatsugu Murata is an Assistant Professor in the Faculty of Science Division I, Department of Applied Chemistry at the Tokyo University of Science. Prof. Murata completed his undergraduate degree in 2014 from the Tokyo University of Science and went on to earn his Master's and Doctoral degrees from the Graduate School of Chemical Sciences and Technology in 2016 and 2019, respectively. His research interest lies in organic chemistry, particularly in the field of organic synthetic chemistry. With a notable research background, Prof. Murata has authored 19 published papers and has been granted a patent.
Funding information
This study was supported by JST, the establishment of university fellowships toward the creation of science technology innovation, grant number JPMJFS2144 and a SUNBOR Grant from the Suntory Foundation for Life Sciences.
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