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Synlett 2018; 29(16): 2120-2121
DOI: 10.1055/s-0037-1610998
cluster
© Georg Thieme Verlag Stuttgart · New York

Cluster Preface: Atropisomerism

Jay S. Siegel*
Further Information

Publication History

Received: 03 September 2018

Accepted: 03 September 2018

Publication Date:
21 September 2018 (online)

 
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Jay S. Siegel received his Ph.D. from Princeton (1985), was a Swiss Universities Fellow at ETH Zurich (1983-4), and NSF–CNRS postdoctoral fellow at the University of Louis Pasteur in Strasbourg (1985-6). He began as Assistant Professor of Chemistry (1986) at UCSD, was promoted to Associate Professor (1992) and Full Professor (1996). In 2003, he was appointed as Professor and co-director of the Organic chemistry institute of the University of Zurich (UZH) and Director of its laboratory for process chemistry research (LPF). He served as Dean of Studies and Head of the Research Council for the Faculty of Sciences at UZH. He moved to Tianjin University in 2013 as dean and joined the Schools of Pharmaceutical and Life Sciences into a new Health Science Platform. His research is in the area of Stereochemistry and Physical Organic Chemistry.


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Although atropisomerism has been an issue for structural chemistry since the beginning, the first clear case of isolated isomers due to restricted rotation about an aryl–aryl bond was reported by Christie and Kenner in 1922.[1] A decade later, Richard Kuhn coined the name "atropisomer" in a chapter of Freudenberg’s three-volume collection on Stereochemistry.[2] That chapter is essentially a direct German translation of Kuhn’s 1931 Solvay conference proceedings published in French[3] describing all the stereoisomeric phenomena without the use of the term “atropisomer”. In the chapter, he added of a parenthetical use of “(Atropisomerie)” in the title and a smattering few uses in the text. No explanation of the etymology is given.

It took nearly a decade (1941) before Luettringhaus published what appears to be the first subsequent use of atropisomerismin when he introduced the isomers of ansa-cyclophanes.[4] In 1951 the first natural product was described as "atropisomeric".[5]

Searching the literature with SciFinder in two-decade blocks shows the rough frequency in the use of atropisomerism: 1930–50 (5); 1950–70 (1–2/year); 1970–90 (10–20/year); 1990–2010 (100+/year); 2010–2018 (ca 200/year). The period 1950–70 specifically saw contributions from Kurt Mislow through his seminal work on establishing the absolute configuration of chiral biaryl atropisomers,[6] which set the stage for a rethinking of stereochemistry beyond the valence bond.[7]

Later chroniclers like Eliel in his classic text[8] added the specific interpretation of Atropos (Greek: not turning). Oki[9] [10] focuses on restricted rotation about a single bond but modifies the definition to include isolability criteria through minimum lifetimes or energy barriers. However, Prelog and others admonished against the idea of stipulating specific rates or barriers when discussing fundamental definitions such as those for conformation and conformers.[11]

Although Kuhn, Luttringhaus and Mislow crafted a classical definition of atropisomerism as: isomerism arising from restricted rotation about a single bond, subsequent comments by Mislow and Luttringhaus indicate that they view atropisomerism more generally and would even project it to encompass a broad class of conformational isomers (cf. atropos = inflexible).[12] Unquestionably though, chirality is not a criterion for atropsiomerism, the definition of which applies equally well to achiral isomers.

A half-century after the original definition, the classical concept of atropisomerism was inappropriately conflated to the ill-founded concept of axial chirality. This is clearly an incorrect interpretation of the definition and this interpretation sullies atropisomerism with the highly touted jargon of elements of chirality, which has no theoretically foundation in chirality. Configurational stability of atropsiomers became further conflated with geometric chirality when people began to talk of center-to-axial chirality transfer and the like. They simply mean to describe a process in which a stereocenter is converted to a stereoaxis without losing its configurational identity – chirality is not transferred and chirality elements are immaterial.

Presently, the clear and simple concept of atropisomerism, developed rigorously by the pioneers of stereochemistry, has been adopted and distorted with a focus on stereoselective processes, such as directed synthesis of stereoisomers or specific stereoisomer/enzyme interactions. Use of the term atropisomerism is sadly varied and harried.

Looking to current trending in this area, one finds a quiz in C&ENews[13a] that claims the “chiral element” conflated definition of atropisomerism and an article purporting to have found a new fundamental type of stereoisomerism, coined as akamptisomerism.[13b] Both place serious restrictions on the concept of atropisomerism at a time when conceptual inclusiveness and simplification should be paramount. With nearly 200 articles a year claiming to deal with atropisomerism in some context, developments that muddy the definition betray a lack of clarity in thinking, and that cannot be seen as a good thing.

The present themed volume of Synlett highlights the importance of atropisomerism in chemical synthesis. It features atropsiomerism in a broad spectrum of contexts that will allow the reader to enjoy the historical, contemporary and future development and use of atropisomerism in molecular science.


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