Ernest L. Eliel as âHidden Advisorâ - ACS Symposium Series (ACS

Chapter 2

Ernest L. Eliel as “Hidden Advisor”

Downloaded by UNIV OF ROCHESTER on January 13, 2018 | http://pubs.acs.org Publication Date (Web): November 2, 2017 | doi: 10.1021/bk-2017-1257.ch002

Jeffrey I. Seeman* Department of Chemistry, University of Richmond, Richmond, Virginia 23173, United States *E-mail: [email protected]

Ernest L. Eliel was a titan in the global chemical enterprise. In addition to his enormous scientific and professional contributions, he was also a mentor to many other scientists and a warm and helpful friend. In this tribute, the author summarizes the highlights of Eliel’s scientific achievements. He also describes Eliel the man. He then reminisces upon his long-term association with Eliel and provides first-hand description of Eliel as his own “hidden advisor” and friend.

Introduction In 2000, 25 eminent chemists wrote essays in a memorial volume dedicated to Derek H. R. Barton, who had died just two years previously. That book entitled The Bartonian Legacy (1) was fittingly published by Imperial College Press, where Barton had received his Ph.D. in 1940, and where he taught for over 20 years, from 1957 to 1978. One of the chapters in that book was written by Ernest L. Eliel. That chapter is entitled, Derek Barton as “Hidden Advisor” (1). Eliel began his chapter as follows,

“Most scientists, when you ask them who most influenced their early careers, will give you the names of their Ph.D. advisor, their postdoctoral supervisor and, if they did an undergraduate thesis, perhaps their undergraduate mentor. However, the persons who have had the greatest influence on my career are two Nobel laureates with whom I was never officially associated: D. H. R. Barton and V. Prelog. But whereas I © 2017 American Chemical Society Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


have spent considerable amount of time with Prelog – six weeks when he was a Reilly lecturer at the University of Notre Dame in 1950 and a whole year when I was at the ETH in Zürich on a sabbatical leave in 1967-68 – I have never spent more than a day at a time with Derek Barton. Nevertheless he is largely responsible for the development of the directions of my research” (1).

Well, Ernest was most certainly one of this author’s hidden advisors. And he most certainly was either a visible or hidden advisor to all those who have contributed to the symposium, Connectivity and the Global Reach of Chemistry: Honoring the Life and Scientific Contributions of Ernest L. Eliel, held on August 22, 2016, at the 252nd ACS National Meeting in Philadelphia (Figure 1 and its predecessor, Figure 2). This chapter and many other chapters in this volume (2) stem directly from that symposium. Indeed, this volume is testament to the many others who so much valued the man who was Ernest L. Eliel that they requested that they, too, could participate in Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel. This book is edited by H. N. Cheng, Cynthia Maryanoff, Bradley D. Miller, and Diane Grob Schmidt. Grob Schmidt was the 2015 ACS President; she, Cheng and Maryanoff all served in the ACS governance with Ernest for many years. Cheng and Maryanoff have also served in the ACS International Activities Committee. Miller is Director, ACS International Activities, and worked closely with Ernest in his lifelong endeavor to improve the lot of chemists in developing countries. In this chapter I shall reveal Ernest as my hidden advisor. In addition, the editors of this volume also asked me to summarize Ernest’s scientific career. I am delighted to do so. I shall not discuss the details of his activities with the American Chemical Society (former ACS President, Chair of the Board of Directors, and many other positions) nor his many years of activities on behalf of chemists in developing countries, primarily though not exclusively in Latin America. Interested readers may look up one reference written earlier by me (3) and one by Ernest himself (4) that cover these topics. For those who wish to learn more about Ernest Eliel, I first and foremost recommend his own full length autobiography published in 1990, From Cologne to Chapel Hill (5) (Figure 3), as well as his four books (6–9), his short booklet Science & Serendipity (10), his Official [Campaign for ACS President] Statement printed in Chemical and Engineering News (C&EN) (11), and his many articles in the Journal of Chemical Education (12–21) on the topics he loved so dearly: stereochemistry and conformational analysis. One can also read an interview of him conducted by Istvan Hargittai (22) and Rudy Baum’s three-page C&EN biographical article announcing Eliel’s receipt of the Priestley Medal (23). Eliel was also co-editor of the first 21 volumes in the series Topics in Stereochemistry.

14 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 1. Five of the participants in the August 22, 2016 symposium on Connectivity and the Global Reach of Chemistry: Honoring the Life and Scientific Contributions of Ernest L. Eliel. (L to R) Kenso Soai, William Bailey, Jeffrey Seeman, Eusebio Juaristi, and Anthony Serianni. Photograph courtesy of J. I. Seeman.

Figure 2. An earlier photograph of several of several individuals shown in Figure 1. During a swimming adventure at the 1980 Gordon Conference on Stereochemistry. (L to R) Fritz Vierhapper, Kenso Soai, William Bailey, Eliel, and Eusebio Juaristi. Curiously enough but perhaps not randomly, the order (left to right) of Soai, Bailey, and Juaristi has spontaneously repeated itself in Figure 1, 36 years later. Photograph courtesy of K. Soai.



Figure 3. Cover of Eliel’s autobiography published in 1990 by the American Chemical Society in the series Profiles, Pathways and Dreams (5). And there is more documentation. In 1972 Notre Dame Magazine published an article by Ernest entitled The Importance of Being Ernest (24). I’ve written several biographical essays on Ernest since the publication of his autobiography. In 2002 I published a biographical essay that covered Ernest’s scientific achievements, his life experiences, and his philosophies (25). In 2009 I reviewed Ernest’s contributions to a cause that was most close to his heart: his work on behalf of chemists and chemistry in the underdeveloped countries of Latin America (3). In 2014, following Ernest’s death and at the invitation of the National Academy of Sciences, I wrote a comprehensive biography of Ernest for the Biographical Memoirs of the National Academy of Sciences (26).

Ernest Eliel, the Scientist: The First Steps An Early Interest in Stereochemistry Ernest’s independent research began at the University of Notre Dame in the late 1940s. This work was a harbinger of what would be his research focus for the next 40 years: stereochemistry and synthesis. Knowledgeable readers – those of you who knew or know of Ernest– likely have sat up straight in your chairs and reflectively thought, “What is Seeman saying? Eliel was not a synthetic organic chemist.” Here is the story. You judge for yourself. Shortly after World War II, the stable and radioactive isotopes of hydrogen and carbon were beginning to become commercially available. These would almost immediately become tools that organic chemists would seize upon to investigate the simplest aspects of chemical structure and the most complex concepts of reaction mechanism and biosynthesis. Eliel was one of those 16 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


early pioneers to use 2H (deuterium). In 1949 Eliel wanted to determine if the one-neutron difference between 1H and 2H would be sufficient such that a compound of structure having a carbon atom to which is attached four different groups – two of which were 1H and 2H – would have a nonzero optical rotation. In essence, Eliel was to prepare a compound R1R2C1H2H = R1R2CHD in nonracemic form. He chose as his target C6H5CHDCH3 (2) and the related 4-substituted derivatives 3 and 4 (27). The syntheses of homochiral 2 and its enantiomer were rather straight-forward (Scheme 1). Racemic α-phenethylalcohol was converted to the half ester of phthalic acid, which was resolved via the brucine salt. Reaction of (-)-α-phenethyl chloride with lithium aluminum deuteride/lithium deuteride led to 2. Friedel-Crafts acylation led to 3, and ultimately to crystalline oxime 4, which was prepared and purified via multiple crystallizations to obtain an ultra-pure 4 necessary to establish the absence of an optically active impurity (Scheme 1). The substantial and non-zero rotations of 2 – 4 established that “a compound of the type R1R2CHD is capable of rotating the plane of polarized light” (27). Optical rotatory measurements on 2 prepared by other methods by Ronald L. Eisenbaumer and Harry S. Mosher in 1979 showed that Eliel’s reported values of his 2 “agree[d] well with ours both in sign and magnitude” (28).

Scheme 1. Eliel’s scheme for obtaining non-racemic compounds of the general structure R1CHDR2 (27). In 1949, Eliel did not know the absolute configuration of these compounds nor did he know their enantiomeric excess. This was determined 30 years after Eliel’s publication by Eisenbaumer and Mosher (28).

This early contribution of Eliel’s is noteworthy for another reason. The title of his paper is The Reduction of Optically Active Phenylmethylcarbinyl Chloride with Lithium Aluminum Deuteride (27). This title ignores the primary objective of Eliel’s research project, though it does highlight another important – as of 1949 – observation, the Walden inversion-stereochemical pathway in the reaction of secondary chlorides with lithium aluminum hydride/lithium hydride. Why Eliel chose this title over another such as Demonstration that Compounds of Type R1R2CHD are Capable of Rotating the Plane of Polarized Light is lost to history. Both results, however, speak to Ernest’s career-long interest in stereochemistry. In the same time period, Eliel began a program to synthesize yohimbine, an indole alkaloid derived from the bark of the Pausinystalla yohimbe tree found in western and central Africa. Of course, this effort was doomed to failure, in large measure because the synthetic technology needed to synthesize yohimbine was some time in the future. The other reason was that Eliel, not being trained as a synthetic chemist, had bitten off too much for him to chew. It was not until 1969, 17 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


twenty years later, that the first total synthesis of yohimbine was reported in full detail by Eugene van Tamelen and his group, then at the University of Wisconsin (29).

Ironically, one of the co-authors of van Tamelen’s yohimbine papers was Albert W. Burgstahler, who had been an undergraduate in Eliel’s laboratory at Notre Dame. Van Tamelen states in his 1969 full paper that he began this work in 1954 and it was completed in 1958. Why van Tamelen needed a decade from his 1958 communication (30) to full paper (29) is not evident and may be lost to history. By an interesting coincidence of timing, in the issue of the Journal of the American Chemical Society in which this Eliel paper’s The Reduction of Optically Active Phenylmethylcarbinyl Chloride with Lithium Aluminum Deuteride appeared, John D. Roberts published the syntheses of cyclobutanone, cyclobutanol, cyclobutene and cyclobutane (31), Donald J. Cram published the first paper in his multifold series of papers entitled Studies in Stereochemistry (32), Carl Djerassi published the preparation of several desoxycorticosterone analogues (33), and Russell Marker published the preparation of cortisone-like compounds from steroidal sapogenines (34). As Eliel himself related in his autobiography, his first years at Notre Dame were not outstandingly productive. Indeed, Eliel stated that “the academic year 1952—1953 may have marked the nadir in my scientific career.” Nonetheless, he was somewhat productive, Notre Dame was not then a powerhouse in chemistry, and thus he was promoted to assistant professor in 1950 and associate professor with tenure in 1953. The yohimbine project and several others were put to bed, never to arise, but certain events would shortly and compactly occur and would form the basis for the rest of Eliel’s research career. During 1950-1953, Eliel experienced several intellectual stimuli that would meld together in his mind and pivotally shape his scientific career. In these years, he got to interact closely with Barton and Vladimir Prelog and become infused with the latest ideas of stereochemistry and conformational analysis. Barton published his Nobel Prize-propelling paper on conformational analysis in 1950 (35). Eliel was also receiving reports from Burgstahler, who as a graduate student at Harvard, had listened attentively to Barton’s lectures at Harvard. Barton was filling in for Robert B. Woodward, who was on sabbatical leave (though he remained physically in Cambridge) in 1949-1950. Shortly after Eliel heard Barton’s “electrifying lecture” at Notre Dame on conformational analysis, he (Eliel) “was intrigued by an article by [John] Read [and William J. Grubb] (36) concerning the nitrobenzolylation of the four 18 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


diastereomeric menthols and especially by the fact that neoisomenthol (3) reacted three-times faster than neomenthol [4]” (25) (Scheme 2). This observation led Eliel to write his first paper (1953) on the relationship between the conformational properties of compounds and their chemical reactivity.

Scheme 2. Neoisomenthol (7), which exists in two conformations of relatively equal composition, reacts three times faster than neomenthol (8) which exists primarily in the conformation 8a in which the two alkyl groups are equatorial and the hydroxyl group is axial. Relative rates of reaction data are from Read and Grubb (36). See the text for Eliel’s explanation of these results and literature references. Eliel explained the relative rates of acylation reported by Read and Grubb (36) on the basis of (a) an estimate of the relative concentrations of conformations “e” and “a” of the four menthol isomers 5-8 (Scheme 2), and (b) the principle, first 19 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


enunciated by Barton in 1950 (35), that acylation of equatorial hydroxyl groups would proceed faster than acylation of axial (then called “polar”) hydroxyl groups. Eliel’s explanation was slightly refined in 1983 in discussions with this author, as reported in footnote 278 of a Chemical Reviews publication (37). In his 1953 paper (38), Eliel understood and explained that for compounds that exist in multiple conformations, one must consider the proportion of each reactive conformation and the reaction rate constant for each conformation. The quantitative explanation of these ideas would follow within several years and is discussed below.

John Read – Possibly One of Ernest Eliel’s Hidden (though “By Literature Only”) Advisors In his 1953 paper Eliel cites John Read’s kinetic results (Scheme 2) as stimulating his interest in the role of conformations on chemical reactivity. Almost certainly, Read’s publications influenced Eliel far more than Eliel has indicated, not to say that Eliel was hiding anything. Read’s influence, like the influence of many individuals on each of us, simply often went unspoken. Perhaps Read was a hidden advisor for Eliel. What is the connection between John Read and Eliel, other than Eliel’s use (38) of Read’s menthol results (36) summarized in Scheme 2? When Eliel began his research on the preparation of compounds of type R1R2CHD in the late 1940s, his literature search surely included the preparation and optical resolution of compounds of type R1R2 R3R4C where none of the substituents contain a carbon atom. In 1914 Read and his mentor, William Jackson Pope, reported,

“Amongst the most fundamental stereochemical problems that have hitherto remained unsolved, the question of determining the greatest degree of molecular simplicity which is compatible with the persistence of optical activity stands out as prominent. No optically active substance the molecule of which contains less than three carbon atoms has up to the present been satisfactorily characterized. . . In the present paper we describe the preparation of the externally compensated chloroiodomethanesulphonic acid, CHClI•SO3H [9], and show that this substance can be resolved into optically active components . . . ” (39).

Indeed, Read’s research, stereochemistry and optical activity began even earlier than 1914. In 1909 William Henry Perkin, Jr., Otto Wallach, and Pope published a paper entitled Optically Active Substances Containing no Asymmetric Atom. 20 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

1-Methylcyclohexylidene-4-acetic acid [10] (40). This paper ended with the statement, “Our thanks are due to Dr. John Read for the care with which he has carried out much of the experimental work involved in the present paper” (40).


The Perkin, Wallach and Pope (and Read) paper began with the statement, “A perusal of van’t Hoff’s early work on optical activity makes it clear that he adopted the view, first advanced by Pasteur, that the optical activity of amorphous substances is due to enantiomorphism of molecular configuration. . . The optical activity is, in fact, not, as is still sometimes stated, due to the presence of an asymmetric carbon atom, but originates in the enantiomorphous molecular configuration. . . No case has, in fact, been experimentally realized of a substance exhibiting optical activity in the amorphous state and containing no asymmetric carbon (nitrogen, Sulphur, selenium tin, or silicon) atom. . . it appeared desirable to attempt, by modern synthetic methods, the preparation of such compounds. . . therefore [we] synthesized the 1-methyl-cyclohexylidene-4-acetic acid” (10) (40).

That paper also reported that “By a curious coincidence, Marckwald and Meth were at the same time engaged upon the synthesis of the same compound for the same purpose…” (28, 40). However, Marckwald and Meth actually prepared isomers of 10, namely 11. The racemix mixture 11 could be resolved into its optically active enantiomers, its optical activity was due to the presence of a chiral atom, C4. This is an early example in organic chemistry of what Robert K. Merton called “multiple simultaneous independent discoveries” (41). However, in this instance, Perkin, Pope, Wallach and Read’s compound was, indeed, 10 while Marckwald and Meth’s compound was 11, all of which are chiral. 21 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Thus, the research of the very early stereochemist John Read (1884 – 1963) (42) served as the basis for much of Eliel’s early work in the field. Like Eliel, Read contributed to a wide range of activities: he authored a number of textbooks and lectured and wrote on the history of chemistry. In 1959, Read was the fourth recipient of the Dexter Award for history of chemistry given by the Division of History of Chemistry of the American Chemical Society – a still active award program, though now called the HIST Award for Outstanding Achievement in the History of Chemistry. Read’s award lecture appeared in the Journal of Chemical Education in 1960 (43), and Read appeared on the cover of the March 1960 issue of that journal.

Ernest Eliel, the Scientist: From Stereochemistry to Synthesis Having a qualitative understanding of the role of conformation on chemical reactivity was a major step forward in organic chemistry. The next step was a quantitative theory. Eliel jumped immediately into that challenge. The simplest set of reactions that describes the role of conformational multiplicity on chemical reactivity is shown in equation 1. First, consider a molecule that exists in two conformations (A2 and A3) (equation 1). The following discussion holds for molecules that exist in more than two conformations; the equations are just a bit more complex. One major question was, and is, what is the equilibrium distribution of the conformations, K? Today there are many spectroscopic tools which could solve this problem, even more than the abundance discussed in Eliel and Wilen’s massive 1994 book on the Stereochemistry of Organic Compounds (7). But in the early 1950s there was no known method to determine the equilibrium distribution of the conformations, K, in equation 1. Well, that’s not exactly true. There was a method, or at least there was a method that had been used. In the early 1950s a number of reports asserted that the equilibrium distribution K was equal to the observed or product ratio in a reaction described by equation 2 (whether first order or second order, taking into consideration a reagent). For example, in alkylation of various tropane derivatives (equation 5), the literature wrongly concluded that the major conformation was that from which the minor product was alkylated. David Y. Curtin and Louis P. Hammett shortly thereafter explained that “the ratio of products [(equations 4 and 5)] depends only on the difference in [free] energy of the two transition states [leading to product, equation 3], as postulated by Curtin and Hammett” and as taught by Eliel in 1962 (6). This statement is true provided the rates of reaction are much faster (44) than the rates of conformational interchange. 22 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


This teaching of the Curtin-Hammett principle immediately and successfully discounted the previous attempts to equate equilibrium distributions to product distributions, or the converse (equation 1). However, it was not until thirty years later that an alternative but equivalent formulation of the Curtin-Hammett principle (equation 4) was proposed and used to fully characterize the kinetic system shown by equations 2, 5 and 6 (45). Eliel included this important update in his 1994 book (7).

Back to the early 1950s. With the recognition that there was no obligatory 1:1 relationship between the equilibrium distribution K and the product ratio in equation 2 chemistry, a new method of conformational analysis was required. Into the fray jumped Eliel and, quite independently and simultaneously, the great physical organic chemist Saul Winstein. Both Eliel and Winstein independently proposed the Kinetic Method of Conformational Analysis. At the time, one of 23 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Derek Barton’s former graduate students Ned Holness was a postdoctoral student with Winstein from the beginning of 1952 to mid-1954. Holness was well-versed in conformational analysis, and it was quite natural that Winstein would make his sole contribution to the field of conformational analysis with Holness. Eliel and R. S. Ro (46), as well as Winstein and Holness (47), proposed a clever reaction model to estimate the equilibrium distribution K in equation 1. It was not by coincidence that they both focused their attention to equation 2 chemistry because that was and is, as mentioned above, the simplest example of the role of conformations on chemical reactivity. Winstein and Holness derived equation 7 from the kinetics of equation 2. Eliel and Ro derived equation 8 from the kinetics of equation 2. Equations 7 and 8 can readily be shown to be equivalent. Both Winstein and Holness (47) and Eliel and Ro (46) made the following conceptual leap: Both groups imagined that having a conformationally-fixed analogue of A2 could be a model for A2; and that a conformationally-fixed analogue of A3 could be a model for A3. If k′21 could be measured and used as an equivalent for k21; and if k′34 could be measured and used as an equivalent for k34 (equation 9), then substituting those numbers into equation 8 and determining kobs for the parent reaction, it followed that K could then be calculated. Or, as Winstein and Holness said,

“Considering equation [7] further, we see that one could solve for n2 and n3 whose sum is unity, if k21 and k34 could be estimated from other sources. In this way, rate measurements could be made the basis of a quantitative method of conformational analysis” (47).



Eliel and Ro (46) calculated the equilibrium distribution of cyclohexyl tosylate (12a ⇌ 12e) to be ca. 3.3 using the solvolyses of cis-4-tert-butylcyclohexyl tosylate (13) and trans-4-tert-butylcyclohexyl tosylate (14) as models for the unsubstituted cyclohexyl tosylate (12, see equations 11a and 11b as models for equation 10).

This clever multiple simultaneous discovery by Eliel and Winstein unfortunately suffered from a fatal flaw. tert-Butyl substituents were very soon thereafter found to significantly alter the conformational properties of the cyclohexane rings to which they were attached, thereby rendering their use as models for the unsubstituted cyclohexane ring invalid (48–51). That this just-discussed kinetic method of conformation analysis failed to meet its objective should not distract from the fact that equation 7 remains a valid kinetic expression describing equation 2. Indeed, the combination of equation 4 and equation 7 has proven to be a very important and useful device to determine the reaction rate constants of the two conformations in systems described by equation 2. In 1980, Seeman et al. determined the overall methylation rate constants kobs and the equilibrium distributions K for a variety of nicotine analogues shown in equation 6 and, using equations 4 and 7, calculated the individual reaction rate constants of the two conformations (44). In 1957, Eliel and Ro published (52) what Eliel termed the Equilibrium Method of Conformational Analysis. This method is illustrated in equation 12 and certainly establishes the equilibrium distribution for the model system. However, to equate K for the system shown in equation 12 to that for K for the unsubstituted cyclohexanol again relies on the assumption that the tert-butyl substituent does not cause structural and other consequential distortions.



Following a 1958 fall semester sabbatical in John D. Roberts’s laboratory at Caltech, Eliel recognized that the Winstein-Holness equation 7 could be adapted to properties other than reaction rate constants, namely NMR parameters (equation 13). Thus, in 1959 Eliel published (53) a Citation Classic (54) entitled Conformational Equilibria by Nuclear Magnetic Resonance Spectroscopy. Thirty years later (7), Eliel discussed the strengths and weaknesses of this NMR method, including the use of low temperature NMR to freeze the individual conformations and then measure relevant chemical shifts and coupling constants, the temperature dependence of chemical shifts and the relative insensitivity of coupling constants to temperature. Conformational energies, originally referred to as A-factors, of many common and less common substituents have been determined using these methods, often by Eliel, two pages of which are tabulated in Eliel’s reference text (7).

In the 1960s and 1970s Eliel’s group at Notre Dame (Figure 4) and then at the University of North Carolina studied the conformational properties of a wide range of saturated heterocyclic compounds, see Scheme 3.

Scheme 3. A summary of various saturated heterocycles whose conformational analysis was studied by the Eliel group in the 1960s (55–59). 26 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 4. In front of the chemistry building, Notre Dame, ca. 1960. Photograph courtesy of the Eliel family. In 1970 Franz Nader examined the Grignard reaction with several conformationally fixed ortho esters (Scheme 4) (60, 61). The axially-substituted ortho ester 15 reacted to furnish nearly all axially-substituted 2-alkyl-1,3-dioxanes (16) while the equatorially-substituted ortho ester 17 was largely unreactive. This was the entry point for Eliel’s enantioselective syntheses. Shortly thereafter, Armando Hartmann examined the Corey-Seebach reaction of 1,3-dithaines with n-butyllithium, but with conformationally-fixed substrates (Scheme 5) (62, 63). According to Eliel, “the results proved startling . . . leading to enzymelike stereoselectivity [which] might be harnessed to a highly stereoselective (asymmetric) synthesis” (5). And in ensuing years, ‘Eliel-the- physical organic chemist’ transformed himself to ‘Eliel-the-natural products synthetic chemist’! The key chiral template in the asymmetric synthesis of secondary and tertiary α-hydroxy aldehydes and the derived acids and glycols in greater than 90% enantiomeric excess is the benzoxathiin 22 was first prepared by Lynch in 1984 (Scheme 6) (64). In recognition of the utility of this reagent, an Organic Synthesis preparation is now available (65, 66). An example of the use of this chiral template was achieved by Frey in the synthesis of the enantiomers of mevalolactone (Scheme 7) via the common intermediate, the diol 23 (67). Scheme 8 illustrates a variety of the compounds synthesized by the Eliel group using enantioselective methodologies. 27 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 4. First observation of stereospecific reactivity in the saturated heterocyclics in Eliel’s research program (60, 61).

Scheme 5. Stereoselective reactions (62, 63) leading subsequently to enantioselective syntheses.

Scheme 6. Preparation of Eliel’s chiral template (64), now an Organic Synthesis preparation (65, 66).



Scheme 7. Synthesis of the enantiomers of mevalolactone in very high enantiomeric excess by Frye and Eliel (67).

As the story of Ernest Eliel’s research career draws to a close, it is important to recognize the evolution of Eliel’s research program. In the earliest days of his independent career, he studied the relationship between conformations and chemical reactivity. He then examined a wide range of carbocyclic and heterocyclic compounds and identified their conformational preferences; and lastly, he combined all this knowledge to perform enantioselective syntheses (Figure 5).

Ernest Eliel, the Man A Citizen of the Global Chemical Community The assignment given to me by the editors of this volume was to cover Ernest’s science and my own relationship with him. So, as stated above, I shall not discuss the details of his extensive activities with the American Chemical Society nor his many years of activities on behalf of chemists in undeveloped countries. Brad Miller has contributed a chapter in this volume on Ernest’s activities with the ACS Office of International Activities.



Scheme 8. Examples of compounds synthesized by the Eliel group using the enantioselective methodologies illustrated in the previous three schemes.

I shall not discuss Ernest’s contributions as a teacher at Notre Dame or at the University of North Carolina except to say that his graduate students and postdoctoral students have very strong positive feelings about their former mentor. One example is illustrative. As required by the ACS, I sent a request for permission to Susan L. Morris-Natschke to include a photograph of her in this chapter. Morris-Natschke, now a research professor at UNC’s Eshelman School of Pharmacy, immediately responded in the affirmative and wrote a very lovely remembrance of Ernest in her email to me. An excerpt of this remembrance follows: I can remember Professor Eliel reducing a whole page from my dissertation draft down to essentially one paragraph. But his comments in the margin were not negative at all. Instead, they were extremely positive and just mentioned how his reductions made the point much clearer. This experience was definitely a lesson to remember in science and in life as well. –Susan L. Morris-Natschke, 2017 30 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 5. Celebrating a high enantiomeric excess at his 58th birthday with his research group, December 28, 1979. At the far left is Joseph Lynch. Looking at Lynch is Boyd Keys. At the far right is Muthiah Manoharan. Just behind Manoharan, only a portion of her face appearing, is Joy Carter, Eliel’s administrative assistant. To the left of Carter, also partially hidden, is Susan Morris-Natschke. Photograph courtesy of the Eliel Family and K. Soai.

I shall also not dwell on Ernest’s important textbooks, except to say that some chemists believe that they are the most important contribution Ernest made to chemistry. How did Ernest feel about his textbooks? He wrote once to me,

“They are part of my educational function. I am very proud of the fact that some 100,000 chemists from all over the world have read my 1962 book (6); many have expressed their appreciation to me personally. (Just tonight, at a Jewish Federation affair, I met a man who had just retired from IBM (!) who told me, when I was introduced to him, that ‘I was his hero’ in as much as he had studied from my book in graduate school at MIT in the late 1960’s)” (68).


Ernest the Athlete In 2001, at the age of 79, Ernest wrote to me: “I swim 500m (10 laps) every day at lunch time (unless I am sick or have an overriding commitment which is rare). It used to take me 20 minutes but now that I am getting older it takes 25. Incidentally I was a fair tennis player as a teenager, but lost that skill during emigration when I had no chance to play. (Cuba was too hot.) When I took it up with Eva again in 1949, I was no longer any good, got disgusted and gave it up” (68). Downloaded by UNIV OF ROCHESTER on January 13, 2018 | http://pubs.acs.org Publication Date (Web): November 2, 2017 | doi: 10.1021/bk-2017-1257.ch002

One of the reviewers of this chapter wrote, “I can provide corroboration on the swimming prowess because I was often in the same pool and getting clobbered despite being over 40 years younger!” Eva (Figure 6) told me that she continued to play tennis well into her 80s. She was an accomplished and talented individual. For many years, Eva was a classic music announcer/host of her program with WUNC, the national public radio station in Chapel Hill. She died on March 23, 2013, in Chapel Hill at the age of 89, not quite five years after Ernest.

Figure 6. Ernest and Eva after a luncheon with the author at an ACS National Meeting, 1996. Photograph courtesy of J. I. Seeman.


A Hint of Sadness


In Ernest’s autobiography, buried in the middle of a paragraph on page 72, are several telling and even sad sentences. Of course, I mean that these words reveal a sadness of Ernest’s. He wrote that in the 1960s, he was “quite happy at Notre Dame . . . By the early 1970s, the situation had changed . . . the ecumenism that had developed so mightily under Pope John XXIII was beginning to abate, and the University of Notre became preoccupied once again with its Catholic character and that of its faculty. An endowed professorship had been established in the Chemistry Department, but it was not offered to me. In the summer of 1971, in response to a second offer, I accepted a W. R. Kenan, Jr., professorship at the University of North Carolina, with the move to be effective on July 1, 1972. In April 1972, I was elected a member of the National Academy of Sciences. Although I was, of course, very happy about this singular honor, my colleagues at Notre Dame, for obvious reasons, viewed it with mixed emotions” (5). Ernest was not a man to bemoan his travails nor life’s unfairness. In this essay, I have not recounted his escape in 1938 as a 16-year-old from Nazi Germany to Scotland just months before Kristallnacht; his separation from his parents, who fled to Palestine, and from his two brothers, one of whom lived in the UK and the other in Brazil during the war; his time in internment camps near Liverpool, on the Isle of Man and ultimately in Canada; and his five years abandonment in Havana, where he learned Spanish, worked in the pharmaceutical laboratory of George Rosenkranz (subsequently, famous for his scientific leadership of Syntex in Mexico City) and received an undergraduate degree from the University of Havana. Only in 1946 did Ernest arrive in the United States, again as a refugee. His optimism and resilence are illustrated by one of his principles of life, when dealing with such life events, as follows: “A very wise friend told me that ‘wherever you are, act as though you were going to spend the rest of your life there’ ” (26). For more of Ernest’s life story including details of his childhood and time in Scotland and Cuba, see his autobiography From Cologne to Chapel Hill (5), a biographical memoir written for the National Academy of Sciences (26) and other papers (3, 24, 25).

Eliel’s “Happiest Moments in Life, in Science” I interviewed Eliel several times for my biographical paper Ernest L. Eliel: A Life of Purpose, Determination, and Integrity (25), which was included in a February 2002 special issue of the journal Chirality (69) to honor his receipt of the 1996 Chirality Medal bestowed by the Società Chimica Italiana and, by happy 33 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

coincidence, his 80th birthday. Several quotes from those interviews were not included in that 2002 article. Here’s one:


JIS: “Ernest, what were the happiest moments in your life, in science?” ELE: “One happy moment was when I arrived in this country, after waiting almost nine years. Another was when I finished my Ph.D. and got my first job. Another was when I got married. Another was when I was promoted to full professor at Notre Dame. Interestingly not when I got tenure, because I never doubted that would happen. But when I was promoted to full professor, I felt I was somehow part of the establishment. When I became a member of the National Academy and when I got my first honorary degree, at Duke in 1983 [Figure 7]. The Jefferson Award of UNC, for service to the University. Then, of course, when I got the Priestley Medal [Figure 8], when I was elected president of the ACS . . . ” (70).

Figure 7. After receipt of the D.Sc. degree at Duke University, May 8, 1983. Photograph courtesy Eliel family.



Figure 8. The cover of Chemical & Engineering News on the occasion of his receipt of the Priestley Medal. Photograph courtesy of the American Chemical Society. Ernest’s was a life full of opportunities seized, adventures lived, achievements recorded, and awards received. He also faced and overcame life-threatening dangers and mountainous obstacles.

Ernest’s Interest in “Hidden Advisors” Ernest was fascinated by the hidden aspects of the sociology of science. Here are two instances separated by 30 years. First, on January 9, 1970, at the age of 48, Ernest wrote to the eminent R. B. Woodward and asked if Woodward’s close 35 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


friend and associate Derek Barton had served as Woodward’s “hidden coworker in some of the beautiful syntheses you have accomplished?” (71)See Figure 9.

Figure 9. In his January 9, 1970, letter to R. B. Woodward (71), Eliel asks if Woodward considered Barton to be his “hidden coworker” in some of his syntheses. Eliel refers to a “reprint,” almost certainly Eliel’s essay published in the November 7, 1969, issue of Science discussing Barton’s receipt of the 1969 Nobel Prize in Chemistry (71). In that essay, Eliel refers Barton’s “principle of conformational stereochemical control used by R. B. Woodward in his total synthesis of reserpine” (72). Letter courtesy of the Eliel family. Second, as noted at the top of this essay, shortly after Derek Barton’s death in 2000, Eliel wrote that Barton was his (Eliel’s) “hidden advisor” (1).

Ernest as My “Hidden Advisor” The invitation to contribute a lecture to the symposium honoring Ernest Eliel and to write a chapter based on that lecture came with a dual request from the symposium organizers and volume editors: that I describe Ernest’s scientific 36 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


achievements as well as share my own personal relationship with him. I know full well that Ernest would have been embarrassed by what I am now to write and you to read. But even if he were still alive – Oh! so much I wish! – I would write no differently, except perhaps that I would have more items to include in the following pieces of advice I received from Ernest. Here is my rather abbreviated story about my friend (Figure 10) and about Ernest Eliel as My “Hidden Advisor.”

Figure 10. Ernest and the author at a Virginia plantation just east of Richmond, Virginia, ca. 1996. Photograph courtesy of J. I. Seeman. I got to know Ernest during the research for and writing of my 1983 review article entitled Effect of Conformational Change on Reactivity in Organic Chemistry. Evaluations, Applications, and Extensions of Curtin-Hammett/Winstein-Holness Kinetics in the early 1980s. Inexplicably missing from that title are the words “and a Historical Overview,” for indeed, the last section of that review is a 12-page historical perspective on the development of the Curtin-Hammett principle and the Winstein-Holness (Eliel-Ro) equation. Ernest not only participated in providing information and quotes about his own participation in the development of conformational analysis, but it was he who counseled me on where my review article should be published and it was he who introduced me to the then editor of Chemical Reviews, Anthony Trozzolo. The publication of my article (37) in Chemical Reviews was a milestone in many ways and a turning point for me and my career. First, Chemical Reviews had 37 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


not previously included a historical section in their articles, but editor Anthony Trozollo showed no hesitancy – quite the reverse. I acknowledge Tony and Joe Bunnett, who first initiated that article, with much gratitude. Second, over the course of the following years and even up to 2016, folks have commented to me on that article. Less frequently, they have complimented me on the detailed kinetic analyses: it is the history section that they mostly extoll. That publication and those compliments led me to my career as a historian of chemistry. I recognized that within the community of chemists, there was an eager audience for the history of their science and for a discussion of the human side of chemistry. I was eager to contribute to that knowledge and that discussion. At about the same time, I engaged Ernest in a conversation about my future, that is, my future as an academic. At the time, I had been in industry for a decade and was eager, or so I thought, to move into academia. The very same Trozzolo had moved from industry, Bell Telephone Laboratories, to Notre Dame just a few years after Ernest had moved from Notre Dame to the University of North Carolina. Ernest advised that I should consider writing a book, for it was his 1962 book Stereochemistry of Organic Compounds which, Ernest thought, had really brought him enormous recognition (Figure 11). That suggestion immediately connected with another project I was considering.

Figure 11. Eliel holding what is likely to have been the manuscript of his 1962 book Stereochemistry of Carbon Compounds (6) at the Notre Dame post office, 1960. Photograph courtesy of the Eliel family.



In my early 1980s fantasy of being an academic, I had envisioned teaching a course that focused on the achievements of a handful of renowned chemists. My idea was to select one key paper for every decade of each chemist’s career, discuss how each paper was important at the time of its publication and how each paper was important even years later. I would then reveal how one paper led to the next and so on, thereby illustrating the development of each chemist’s career as a whole. But the final coup would be that, when all the lessons were completed, the course would reveal the growth of organic chemistry as a field. Ernest’s suggestion in 1984 that I write a book was timely. I would write the story of 20 or 25 chemists for the course I had imagined. As this idea took root, I realized that it ought not be my task to identify the six or so seminal publications of these chemists. I would ask the chemists to select their own papers. It was just a short jump to realize that these should be autobiographical rather than biographical chapters. Eventually, the one volume coffee table book of autobiographical chapters became the 20-volume series of autobiographies called Profiles, Pathways and Dreams. One of the volumes is Ernest’s (6). Ernest’s next major “hidden advisory role” was caused by a most alarming and unanticipated crisis. In November or December 1989, Vladimir Prelog informed me that David Ginsburg’s translation of the manuscript for his (Prelog’s) Profiles autobiography was unacceptable. Ginsburg had suffered a stroke and thus was severely limited in his translational abilities. I asked Prelog to send me the translation and the original in German for Ernest’s review. Why Ernest? Because Ernest and Prelog were close friends. Because Ernest was fluent in German. Because Ernest was a physical organic chemist with a specialization in stereochemistry, as was Prelog. And because Ernest was familiar with the Profiles project, being an author himself. Ernest confirmed that the translation was lacking. But he steadfastly refused to re-translate Prelog’s manuscript, for he was too busy writing his own autobiography and he was in the midst of being Chair of the Board of Directors of the American Chemical Society. My gloom was only brief. Ernest immediately recommended another person to perform the translation, Otto Theodor Benfey (Figure 12). Ted Benfey is also fluent in German, for Ted, like Ernest, is a native German-speaker who had escaped Nazi Germany as a youth. Benfey is also a Ph.D. organic chemist – a student of Christopher Ingold of the Cahn-Ingold-Prelog (CIP) rule. And Benfey is a historian of chemistry, a former editor himself (of the ACS journal Chemistry), and a translator of scientific manuscripts from German (and French) to English. And, quite fortunately for Prelog, the readers of the Profiles volumes, and for me, Benfey immediately agreed to and did retranslate Prelog’s manuscript. Thus began my relationship and special friendship with Ted Benfey which continues happily to this day. Indeed, at the same ACS National Meeting which hosted the Eliel symposium, I organized a symposium held within the domain of the Division of History of Chemistry honoring the 90th birthday of Ted Benfey.



Figure 12. Ted Benfey, Greensboro, NC, 2015. Photograph courtesy of J. I. Seeman.

Next on my short list of memorable moments of Eliel’s “hidden advisorships” with me is his receipt of the Priestley Medal in 1996. Ernest was surely one of the most deserving of Priestley Medalists, having contributed to science (see above), to education (his many textbooks and his 10 articles in the Journal of Chemical Education), to professional societies (he was President and Chair of the Board of Directors of the American Chemical Society in addition to holding many other positions; he was also Vice Chair and then Chair of the Council of Scientific Society Presidents), and to the worldwide profession of chemistry (his many activities on behalf of chemists from undeveloped countries). Actually, it was not his receipt of the Priestley Medal that was a pedagogical moment for me. Rather, it was his request that I review his notes and drafts of his Priestley Medal address that demonstrated, in a very personal fashion, that no matter how prestigious one is, one can always learn and benefit from the knowledge and advice of others. Years later, when I was archiving Ernest’s files for the Chemical Heritage Foundation, I found the notes I had sent to him on that occasion and was reminded how helpful those ideas were to him. (I also remembered sitting at his table at the ACS Awards Banquet, with Eva and his daughters, Carol and Ruth ant their husbands. With us was another man – also an author in this volume – who considers Ernest his non-hidden advisor, Eusebio Juaristi [see Figures 1 – 2]). Ernest influenced me in many ways. I remember a phone call, one spring, when I inquired whether he had any students who might be interested in a summer position in my laboratory. After a pleasant chat, Ernest then read back a perfect announcement that he had written during our conversation. That is my model for efficiency. I remember many UNC-Duke University basketball games where this otherwise subdued Ernest turned into a loudly cheering basketball fan. 40 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


I remember attending a 65th birthday symposium held at UNC for Ernest. The after-dinner speaker, an eminent chemist from the mid-West, referred to Ernest as “Ernie.” My suspicions were well founded. When I asked Ernest about the name “Ernie,” he grimaced as if he had just been forced to drink the most ugly tasting cough medicine. I remember his tales of swimming 10 laps every afternoon but also enjoying, as a reward, a very sugary Danish – much to the chagrin of his wife, Eva. Indeed, this classically educated, classically-styled man could simultaneously be known as a “bulldog” by his professional colleagues yet meekened by Eva. Ernest had a lot of patience with me as an editor of his autobiography. But as the “bulldog” nickname suggests, he could easily and rapidly draw a line in the sand. He could be testy, too. As an editor, I had experienced others reacting negatively when I asked for more and more from them but not Ernest. While collecting “data” for my Chirality biography of Ernest (25), I asked more and more questions. Toward the end, Ernest wrote in an email, “This is not how we had agreed to play the game. You asked for ‘spontaneous answers’ [to your questions] and now you are asking for more on the same subjects! There seems to be a contradiction there! In any case, I cannot deal with a geometric progression of e-mails! However, I gather you will have a chance to follow up personally” (68). (Ernest was surely referring to his and Eva’s annual visit with me in Richmond, on their way north to the annual spring meeting of the National Academy of Sciences.) When I interviewed him for the Chirality paper, I asked, “Do you feel any letdown, no longer being ACS President or on the Board of Directors?” He answered, “No. I am reconciled to getting older and less involved (and I am still quite involved with ACS). It is only when I get mad at an action of the ACS Board that I wished I were still a member!” (73) This is a model for aging gracefully. Yes, I have many memories of Ernest L. Eliel. I think of him often, and in writing this essay, I am reminded of how much of him remains within me. Of course, role models are not reproductions but rather adoptions and incorporations of the best we see, as defined by its relevance to oneself. I wonder how many others consider Ernest their Hidden Advisor. I suspect many.

Our Last Time Together In June 2008 the Division of Organic Chemistry of the ACS held the 32nd Reaction Mechanism Conference at the University of North Carolina at Chapel Hill. Malcolm Forbes, one of the meeting’s organizers, asked if I would give a 41 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


biographical lecture about Ernest at a session honoring him. By then, Ernest was too ill to attend. I joined many of his former students at that somewhat somber event, Friday, June 27th. I stayed only one day. My talk was at 8:30 am, and I left shortly after lunch. I had been visiting Ernest frequently over those past several years, witnessing his steady decline caused by an undiagnosed neuromuscular disease related to Parkinson’s. Previously, I would visit Ernest and Eva at their home. This time, he was in the nursing home section of the senior living community where Eva and he had relocated from their comfortable Chapel Hill home several years earlier. I wrote the following mini-essay that evening, shortly after I arrived home in Richmond, a three hour drive from Chapel Hill. Once more, Ernest (December 28, 1921 – September 18, 2008) was a role model for me, demonstrating how to say goodbye in peace and with friendship. He died shortly thereafter.

A Parting I hold on to things. Like friends. And, as a matter of principle, I don’t like partings. I much prefer shalom. “Shalom” means hello, goodbye, peace and harmony, all rolled up into a package of six letters. Well, six letters in English. I guess there are times when friendships . . . acquaintances . . . simply and slowly disappear. In those instances, they are often without even a goodbye. The last time was not anticipated to be the last time, it just was. Some time later, we recognize it for what it was, for what it is. And so, this brings me back to today, this afternoon, just a while ago and 200 miles away. I was sitting with Ernest and Eva, friends for 30 years. Ernest is a special man and a special scientist. Ernest has been a special friend. He and I have been many places together. We have been serious together. We have had fun together. We have shared meals all around the country. I can hardly remember all the places. Together, we saw quite a number of UNC-Duke basketball games, rising in unison at the climax of many a UNC near-halftime resurrection. This, from a classic German scholar who really wasn’t all that interested in basketball! He and Eva stayed with me in Richmond many times, and of course, I stayed with them in Chapel Hill. Good friends. Ernest also has had a major effect on my professional career as he has on the careers of my others. I can tell you more about that, but for now, just believe me. And I mean major. Today, I thanked him for so much. I asked him, had I thanked him before. We were both certain that I had. But I just wanted to cover the territory again. Compulsively, just in case. Actually, that wasn’t really the reason. There was just so little more to say. I wanted to stay longer. I wanted to leave immediately. I didn’t know what I wanted. So, for about 30 minutes, I tried to leave. Eva kept on interrupting my goodbye with one seemingly irrelevant story or another, as if she were trying to keep me there. 42 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Finally, I was up and gave him a hug. I walked around to his other side, around his bed, and gave him another hug. The light just did not shine in his eyes anymore. They did, the last time I was with him, just a few weeks earlier. Not this visit, not once. He said, “It is a parting.” I leaned over, “What did you say?” knowing exactly what he had said. “A parting,” he repeated. I wept as I left.


Acknowledgments The author thanks the organizers of the Eliel symposium (Cynthia Maryanoff and Diane Grob Schmidt) and the editors of this volume (Maryanoff and Grob Schmidt along with H. N. Cheng and Bradley D. Miller) for their kindness in inviting me to participate in these events. The author also thanks Cheng and two reviewers for their help in preparing this chapter for publication and the photographers/owners of the various photographs reproduced and cited herein for their permission to include their photographs. Finally, the author salutes the lives and accomplishments of Ernest and Eva Eliel and thanks their daughters Carol and Ruth for their encouragement and cooperation.

Dedication This chapter is dedicated to Joseph Gal, an expert in the areas of stereochemistry, chirality, and history of chemistry as was Ernest Eliel, on the occasion of Gal’s 75th birthday.

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3. 4. 5. 6. 7. 8.

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30. van Tamelen, E.; Shamma, M.; Burgstahler, A.; Wolinsky, J.; Tamm, R.; Aldrich, P. The Total Synthesis of Yohimbine. J. Am. Chem. Soc. 1958, 80, 5006–5007. 31. Roberts, J. D.; Sauer, C. W. Small-Ring Compounds. III. Synthesis of Cyclobutanone, Cyclobutanol, Cyclobutene and Cyclobutane. J. Am. Chem. Soc. 1949, 71, 3925–3929. 32. Cram, D. J. Studies in Stereochemistry. I. The Stereospecific Wagner-Meerwein Rearrangement of the Isomers of 3-Phenyl-2-Butanol. J. Am. Chem. Soc. 1949, 71, 3863–3870. 33. Djerassi, C.; Scholz, C. R. The Preparation of Two Aromatic Analogs of Desoxycorticosterone Acetate. J. Am. Chem. Soc. 1949, 71, 3962–3966. 34. Marker, R. E. Steroidal Sapogenins. 174. 17-Hydroxy-20-Ketopregnanes from Steroidal Sapogenins. J. Am. Chem. Soc. 1949, 71, 4149–4151. 35. Barton, D. H. R. The Conformation of the Steroid Nucelus. Experientia 1950, VI, 316–320. 36. Read, J.; Grubb, W. J. Researches in the Menthone Series. Part XIII. Relative Molecular Configurations of the Menthols and Menthylamines. J. Chem. Soc. 1934, 1779–1783. 37. Seeman, J. I. Effect of Conformational Change on Reactivity in Organic Chemistry. Evaluations, Applications, and Extensions of Curtin-Hammett/ Winstein-Holness Kinetics. Chem. Rev. 1983, 83, 83–134. 38. Eliel, E. L. The Origin of Steric Hindrance in Cyclohexane Derivatives. Experientia 1953, 9, 91–93. 39. Pope, W. J.; Read, J. LXXXIII. -- The Optical Activity of Compounds of Simple Molecular Constitution. Ammonium D- and L-Chloroidomethanesulphonates. J. Chem. Soc. 1914, 811–821. 40. Perkin, W. H.; Pope, W. J.; Wallach, O. Optically Active Substances Containing No Asymmetric Atom. 1-Methylcyclohexylidene-4-acetic Acid. J. Chem. Soc. 1909, 1789–1802. 41. Merton, R. K. Singletons and Multiples in Scientific Discovery: A Chapter in the Sociology of Science. Proc. Am. Philos. Soc. 1961, 105, 470–486. 42. Hirst, E. L. John Read. 1884-1963. Biogr. Mem. Fellows R. Soc. 1963, 9, 236–260. 43. Read, J. Science, Literature, and Human Thought. J. Chem. Educ. 1960, 37, 110–117. 44. Seeman, J. I.; Farone, W. A. Analytical Solution to the Curtin-Hammett/ Winstein-Holness Kinetic System. J. Org. Chem. 1978, 43, 1854–1864. 45. Seeman, J. I.; Secor, H. V.; Hartung, H.; Galzerano, R. Steric Effects in Conformationally Mobile Systems. The Iodomethylation of 1-Methyl2-Arylpyrrolidines Related to Nicotine. J. Am. Chem. Soc. 1980, 102, 7741–7747. 46. Eliel, E. L.; Ro, R. S. Conformational Effects in SN2 Reactions. Chem. Ind. (London) 1956, 251–252. 47. Winstein, S.; Holness, N. J. Neighboring Carbon and Hydrogen. XIX. tButylcyclohexyl Derivatives. Quantitative Conformational Analysis. J. Am. Chem. Soc. 1955, 77, 5562–5578. 45 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


48. Kwart, H.; Takeshita, T. Evaluation of the Relative Importance of ChargeDipole Interactions and Steric Strain Acceleration in Conformationally Mobile Systems. J. Am. Chem. Soc. 1964, 86, 1161–1166. 49. Mateos, J. L.; Perez, C.; Kwart, H. Direct Evidence of Limitations in the Applicability of the Kinetic Method of Conformational Analysis. J. Chem. Soc., Chem. Commun. 1967, 125–127. 50. Eliel, E. L.; Biros, F. J. Conformational Analysis. XII. Acetylation Rates of Substituted Cyclohexanols. The Kinetic Method of Conformational Analysis. J. Am. Chem. Soc. 1966, 88, 3334–3343. 51. McKenna, J. Conformational Analysis by Kinetic Methods: A Critique: Theory and Experimental Development of Procedures Based on Very Fast Chemical Reactions. Tetrahedron 1974, 30, 1555–1562. 52. Eliel, E. L.; Ro, R. S. Conformational Analysis. III. Epimerization Equilibriua of Alkylcyclohexanols. J. Am. Chem. Soc. 1957, 79, 5992–5994. 53. Eliel, E. L. Conformational Equilibria by Nuclear Magnetic Resonance Spectroscopy. Chem. Ind. (London) 1959, 568. 54. Eliel, E. L. This Week’s Citation Classic: Eliel, E. L. Conformational Equilibria by Nuclear Magnetic Resonance Spectroscopy. Chem. Ind. 1959 (18), 568. Current Contents 1982 (October 24), 22. 55. Willy, W. E.; Binsch, G.; Eliel, E. L. Conformational Analysis. XXIII. 1,3Dioxolanes. J. Am. Chem. Soc. 1970, 92, 5394–5402. 56. Eliel, E. L.; Hutchins, R. O. Conformational Analysis. XVIII. 1,3-Dithianes. Conformational Preferences of Alkyl Substituents and the Chair-Boat Energy Difference. J. Am. Chem. Soc. 1969, 91, 2703–2715. 57. Eliel, E. L.; Giza, C. A. Conformational Analysis. XVII. 2-Alkoxy- and 2Alkylthiotetrahydropyrans and 2-Alkoxy-1,3-Dioxanes. Anomeric Effect. J. Org. Chem. 1968, 33, 3754–3758. 58. Eliel, E. L.; Knoeber, M. C., Sr. The “Size” of a Lone Pair of Electrons. Evidence for an Axial t-Butyl Group. J. Am. Chem. Soc. 1966, 88, 5347–5349. 59. Eliel, E. L.; Knoeber, M. C., Sr. Conformational Analysis. XVI. 1,3-Dioxanes. J. Am. Chem. Soc. 1968, 90, 3444–3458. 60. Eliel, E. L.; Nader, F. W. Conformational Analysis. XX. The Stereochemistry of Reaction of Grignard Reagents with Ortho Esters. Synthesis of 1,3-dioxanes with Axial Substituents at C-2. J. Am. Chem. Soc. 1970, 92, 584–590. 61. Eliel, E. L.; Nader, F. W. Stereochemistry of the Reaction of Grignard Reagents with Ortho Esters. A Case of Orbital Overlap Control Synthesis of Unstable Polyalkyl-1,3-Dioxanes. J. Am. Chem. Soc. 1969, 91, 536–538. 62. Hartmann, A. A.; Eliel, E. L. Protonation and Methylation of Conformationally Fixed 2-Lithio-1,3-dithianes. Some Reactions of Remarkable Stereoselectivity. J. Am. Chem. Soc. 1971, 93, 2572–2573. 63. Eliel, E. L.; Hartmann, A. A.; Abatjoglou, A. G. Organosulfur Chemistry. Ii. Highly Stereoselective Reactions of 1,3-Dithianes. “Contrathermodynamic” Formation of Unstable Diastereoisomers. J. Am. Chem. Soc. 1974, 96, 1807–1816. 46 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


64. Lynch, J. E.; Eliel, E. L. Asymmetric Syntheses Based on 1,3-Oxathianes. 2. Synthesis of Tertiary a-Hydroxy Aldehydes, a-Hydroxy Acids, Glycols (RR′C(OH)CH2OH) and Carbinols (RR′C(OH)CH3) in High Yield. J. Am. Chem. Soc. 1984, 106, 2943–2948. 65. Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V. Chiral 1,3-Oxathiane from (+)Pulegone: Hexahydro-4,4,7-Trimethyl-4H-1,3-Benzoxathiin. Org. Synth. 1987, 65, 215–219. 66. Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V. Chiral 1,3-Oxathiane from (+)Pulegone: Hexahydro-4,4,7-Trimethyl-4H-1,3-Benzoxathiin. Org. Synth. 1993, 8, 302–306. 67. Frye, S. V.; Eliel, E. L. Nonenzymatic Synthesis of (R)-(-)- and (S)-(+)-Mevalolactone in High Enantiomeric Purity. J. Org. Chem. 1985, 50, 3402–3404. 68. Eliel, E. L. Email to Seeman, J. I., Chapel Hill, NC, January 15, 2001. 69. Berova, N.; Bailey, W. F. Editor’;s Note: Special Issue Honoring Professor Ernest Eliel. Chirality 2002, 14, 97. 70. Eliel, E. L. Interview with Seeman, J. I., Richmond, VA, 2001. 71. Eliel, E. L. Letter to Woodward, R. B., Notre Dame, IN, January 9, 1970. 72. Klein, L. R.; Eliel, E. L.; Goldberger, M. L. Nobel Laureates in Economics, Chemistry, and Physics. Science 1969, 166, 715–722. 73. Eliel, E. L. Email to Seeman, J. I., Chapel Hill, NC, January 18, 2001.


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