R. B. Woodward: A Larger‐than‐Life Chemistry Rock Star

To mark the 100th birthday of R. B. Woodward (April 10, 1917–July 8, 1979), a discussion and analysis of Woodward's persona is given. The fundamental theme is that “Woodward experienced his own exceptionality,” as described by Albert Eschenmoser, Woodward's partner in the vitamin B₁₂ project. Woodward's rock star personality is explored and discussed as one of his legacies in addition to his scientific achievements. Woodward presented himself to his students, colleagues, and fellow chemists with an aura of nobility and romanticism.     

The Woodward Research Institute,Robert Burns Woodward (1917–1979) and Chemistry behind the Glass Door

Certainly a highlight in the career of Nobel Laureate Professor Robert Burns Woodward (1917–1979) was the foundation of the Woodward Research Institute (WRI) at Ciba AG in Basel, Switzerland, in 1963. Woodward's remarkable accomplishments in the development of organic chemistry altered not only our concepts of molecular structure, but also our comprehension of physico‐chemical properties. In his legacy, Woodward devised innovative strategies for natural product syntheses based on brilliant rationale of their properties and an uncanny sense of Nature. The chemistry community benefited not only at Harvard but especially in Basel and Zürich from Woodward's inspiring lectures and the opportunity to learn from the chemistry Meister. This article highlights parts of the chemistry and some personalities that contributed to forefront investigations at the Woodward Research Institute which began at the former Novartis legacy company, Ciba AG, Basel.     

Why Woodward and Hoffmann? And Why 1965?**

Previous publications in this series on the history of the development of the Woodward–Hoffmann rules revealed why Woodward and Hoffmann were prime candidates to solve the pericyclic no-mechanism problem. This publication explains why it was the collaborative team of R. B. Woodward and Roald Hoffmann who did solve this mechanistic problem in a series of five communications in the Journal of the American Chemical Society in 1965. That is, the reasons why Woodward and Hoffmann were the perfect team, and why their individual capabilities, experiences, and qualities provided the perfect synergy are described. In part, this was the right time and the right place for them both, but the synergies were fundamental, intrinsic and idiosyncratic as a collaborative pair. Their orbital symmetry rules provided the mechanism of all concerted pericyclic reactions including electrocyclizations, cycloadditions, and sigmatropic rearrangements. Why it was 1965 and not earlier is also discussed.     

Die Valenzisomerisierung des trans-15, 16-Dimethyl-dihydropyrens - ein beitrag zur frage nach der aktivierungsenergie symmetrie-verbotener prozesse. Vorläufige mitteilung

Concerted electrocyclic processes which are forbidden according to the symmetry conservation rules of Woodward & Hoffmann, may nevertheless take place at low activation energies. The necessary conditions are exemplified by the unique case of the trans-15, 16-dimethyl-dihydropyrene ? 15, 16-dimethyl-[2.2]metacyclophane-4,9-diene system.     

Louis Pasteur,Chemical Linguist: Founding the Language of Stereochemistry

Pasteur’s major discovery in chemistry was the recognition of molecular chirality, in 1848. He understood that his new science needed its own language, and introduced new terminology and nomenclature, thereby launching modern stereochemical language. He was eminently prepared for this task as a refined user of language, skills recognized by his election to the Académie française, the supreme institution for the protection and promotion of the French language. The terms chiral and chirality did not exist at the time and he adopted the French word dissymmétrie (dissymmetry) for the phenomenon of handedness. Although in his time almost nothing was known about molecular constitution and configuration, his insights allowed him to create useful language some of which is still used today in stereochemistry, e. g., racemic for the 1 : 1 mixture of the two enantiomers, and the use of the prefixes levo‐ and dextro‐ in the names of optically active substances. On the other hand, the limitations in the knowledge of organic chemistry at the time prevented him from creating some needed terms, e. g., for the phenomenon of diastereoisomerism. He also failed to adopt the enantio terminology introduced in the 1850s by German mineralogist Carl Friedrich Naumann. Analysis of Pasteur’s linguistic innovations is of interest from the point of view of the history of chemistry and is also useful in throwing light on the fundamental nature of the concepts of stereochemistry. Such understanding has acquired a new relevance due to the considerable misuse and misunderstanding of this language seen in the literature today.     

Activation hardness and cycloadditions of even linear polyenes

Modes of thermal and photochemical cycloaddition of even linear polyenes are examined using the simple concept of activation hardness. The results are in agreement with the well-known Woodward–Hoffman rules. [R.B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry (Academic Press, New York, 1989)]. © 1994 John Wiley & Sons, Inc.     

Louis Pasteur,Chemist: An Account of His Studies of Cinchona Alkaloids

Pasteur carried out pioneering work on cinchona alkaloids and their derivatives and his studies led to important discoveries. He examined crystals of cinchona alkaloids for his correlation of crystal hemihedrism with molecular chirality, studies that led Pasteur to the discovery of physicochemical differences between diastereoisomeric salts of tartaric acids with optically active cinchona bases, an important insight into fundamentals of molecular chirality. These physicochemical differences also led to Pasteur’s invention of the vital method of racemate resolution through diastereoisomeric derivatives. Pasteur clarified the confusion around the cinchona alkaloids by elucidating their identities and relations. He discovered the conversion of the major cinchona alkaloids to quinicine and cinchonicine, a finding subsequently of considerable importance in studies of the structure and synthesis of the major cinchona alkaloids. The reaction producing quinicine and cinchonicine led Pasteur to the discovery of the racemization of tartaric acid and the finding of meso‐tartaric acid, fundamental breakthroughs in the development of stereochemistry.     

The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight

In 1918, Paul Rabe and Karl Kindler reported the three-step conversion of d-quinotoxine into quinine. In 1944 Robert B. Woodward and William von Eggers Doering reported the total synthesis of homomeroquinene and d-quinotoxine from 7-hydroxyisoquinoline. Based on the transformations by Rabe and Kindler, Woodward and Doering asserted the "Total Synthesis of Quinine" (the title of their 1944 and 1945 papers). In 2000 and 2001, Gilbert Stork concluded that the claim by Woodward and Doering is a "myth" because they had synthesized only homomeroquinene and d-quinotoxine; no synthetic quinine had been made in Cambridge. In fact, Rabe and Kindler never published the experimental details of their conversion of d-quinotoxine into quinine. This Review presents the results of a detailed examination of the synthesis of cinchona alkaloids, and previously unpublished material combined with unpublished material and numerous interviews give insight into the lives of the personalities in this nearly 100-year saga.     

Conservation of Orbital Symmetry can be Circumvented in Mechanically Induced Reactions

In first‐principles molecular dynamics simulations of the mechanically induced ring‐opening of substituted benzocyclobutene we observe both con‐ and disrotatory ring‐opening reactions. We show that this finding does not contradict the fundamental principle that the orbitals develop continuously in time. However, it constitutes an exception from the principle of the conservation of orbital symmetry and thus is indeed an exception from the Woodward–Hoffmann rules. In contrast, the ring‐opening of unsubstituted cyclobutene proceeds in a conrotatory fashion. This shows that the breaking of the Woodward–Hoffmann rules is significantly facilitated by the substituents.     

Science and Arts,Philosophy and Science: Why after All? Why Not?

This perspective summarizes some interdisciplinary aspects of science and the relation to philosophy, also including the basic motivations and aims as they might be discussed with young scientists starting their careers and presented also in the form of a commencement speech. The contents of this speech were repeatedly discussed also with Jack Dunitz, who showed great interest in it, given his broad interests. The speech also referred to an earlier commencement speech by Jack Dunitz in 1989. In the introduction of our essay, we mention the early common history of science and humanities under the name of philosophy. This early history can be traced back to ancient Greek philosophy and the ‘academy’ of Platon in Athens with a history of more than 1000 years until closure in 529 AD, in modern times revived as the National Greek Academy in Athens in the 19th and 20th centuries. Other ‘academies’ in Europe started in the 17th century and had publications under various names involving ‘philosophy’ with a focus on what we call science (natural science) today. After about 1800 there was increasing fragmentation of the various fields of knowledge and philosophy was considered to be part of the modern ‘humanities’ quite separate from science, and the natural sciences were fragmented into physics, chemistry, biology etc., and even finer subdivisions. The essay also describes an effort at ETH Zurich, reintegrating the various subfields of science and also stressing an education of scientists and engineers in the humanities. The essay concludes with a discussion of several global risks for mankind and a scientific imperative to maintain life on Earth. The common aspects and the foundations of all sciences as fields of knowledge aiming for an understanding of the world around us and of human beings as part of it are discussed from various perspectives.     

On the Structural Assignments Underlying R. B. Woodward's Most Personal Data That Led to the Woodward–Hoffmann Rules: Subramania Ranganathan's Key Role and Related Research by E. J. Corey and A. G. Hortmann

In the early 1960s, as part of R. B. Woodward's isoxazole route to vitamin B₁₂, Subramania Ranganathan uncovered two coupled sets of stereospecific reactions, a thermal set and a photochemical set. These four reactions illustrated the alternating configurations that were the major data points that prompted the solution of the no-mechanism problem. Though Ranganathan's reactions played a major role, according to Woodward, in the development of the Woodward–Hoffmann rules, they were published only as part of the documentation of a lecture given by Woodward in 1966. The authors of this paper have uncovered Subramania Ranganathan's 1964 postdoctoral report and have used modern quantum chemical theory to predict the ¹H NMR spectra for Ranganathan's key compounds, providing support for the structure assignments made by Woodward and Ranganathan. A similar set of alternating, stereospecific reactions was observed by E. J. Corey and Alfred Hortmann in their 1963 total synthesis of dihydrocostunolide. We also have applied the computational process used for Ranganathan's compounds to Hortmann's compounds, now also including the calculation of coupling constants, and find computational support for Corey and Hortmann's structure assignments.     

The question mark at uranium

Being excerpts from pages 187, 203, 204, 207, 208, 209, 210 and 211 of Uncle Tungsten, extracted by Michael Laing with the consent of the author, Professor Oliver Sacks, and Picador Publishers.     

Highly Polar Triterpenoid Saponins from the Roots of Saponaria officinalis L.

Five new triterpenoid saponins, including 3‐O‐β‐d ‐galactopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)]‐β‐d ‐glucuronopyranosyl quillaic acid 28‐O‐β‐d ‐glucopyranosyl‐(1→3)‐β‐d ‐xylopyranosyl‐(1→4)‐α‐l ‐rhamnopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)‐(4‐O‐acetyl)‐β‐d ‐quinovopyranosyl‐(1→4)]‐β‐d ‐fucopyranoside ( 1 ), 3‐O‐β‐d ‐galactopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)]‐β‐d ‐glucuronopyranosyl quillaic acid 28‐O‐(6‐O‐acetyl)‐β‐d ‐glucopyranosyl‐(1→3)‐[β‐d ‐xylopyranosyl‐(1→4)]‐α‐l ‐rhamnopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)‐(4‐O‐acetyl)‐β‐d ‐quinovopyranosyl‐(1→4)]‐β‐d ‐fucopyranoside ( 2 ), 3‐O‐β‐d ‐galactopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)]‐β‐d ‐glucuronopyranosyl quillaic acid 28‐O‐β‐d ‐xylopyranosyl‐(1→4)‐α‐l ‐rhamnopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)‐(4‐O‐acetyl)‐β‐d ‐quinovopyranosyl‐(1→4)]‐β‐d ‐fucopyranoside ( 3 ), 3‐O‐β‐d ‐galactopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)]‐β‐d ‐glucuronopyranosyl quillaic acid 28‐O‐β‐d ‐glucopyranosyl‐(1→3)‐β‐d ‐xylopyranosyl‐(1→4)‐α‐l ‐rhamnopyranosyl‐(1→2)‐[(4‐O‐acetyl)‐β‐d ‐quinovopyranosyl‐(1→4)]‐β‐d ‐fucopyranoside ( 4 ), 3‐O‐β‐d ‐galactopyranosyl‐(1→2)‐[β‐d ‐xylopyranosyl‐(1→3)]‐β‐d ‐glucuronopyranosyl quillaic acid 28‐O‐(6‐O‐acetyl)‐β‐d ‐glucopyranosyl‐(1→3)‐[β‐d ‐xylopyranosyl‐(1→4)]‐α‐l ‐rhamnopyranosyl‐(1→2)‐[(4‐O‐acetyl)‐β‐d ‐quinovopyranosyl‐(1→4)]‐β‐d ‐fucopyranoside ( 5 ) together with two known congeners, saponariosides A ( 6 ) and B ( 7 ) were isolated from the roots of Saponaria officinalis L. Their structures were elucidated by extensive spectroscopic methods, including 1D‐ (¹H, ¹³C) and 2D‐NMR (DQF‐COSY, TOCSY, HSQC, and HMBC) experiments, HR‐ESI‐MS, and acid hydrolysis.     

Synthetic approaches toward the reserpine

Reserpine is an indole alkaloid, antipsychotic, and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms. It was first isolated in 1952 from the dried root of Rauwolfia serpentina whose molecular structure was established in 1953 and natural configuration was published in 1955. The first total synthesis of reserpine was reported by Woodward in 1958. This review article updates current multistep synthetic approaches toward the reserpine natural product and its analogues.     

Oligoene‐Based π‐Helicenes or Dispiranes? Winding up Oligoyne Chains by a Multiple Carbopalladation/Stille/(Electrocyclization) Cascade

A domino approach consisting of up to five consecutive steps to access either highly substituted dispiranes or π‐helicenes from oligoyne chains is reported. The domino sequence consists of several carbopalladation reactions, a Stille cross‐coupling to obtain the helicenes, and, depending on the steric demands of the helicene, a final 6π‐electrocyclization to afford the dispiranes. Formally, the latter transformation contravenes the Woodward–Hoffmann rules, as revealed by X‐ray crystallography of the dispirane. Additionally, the racemization barrier of the (Z,Z,Z)‐triene‐based helicene has been determined by a kinetic analysis and compared with results from density functional theory calculations. Characteristic points on the reaction coordinate were further analyzed according to their relaxed force constants (compliance constants).     

Crossing the Boundaries between Marine and Muguet: Discovery of Unusual Lily‐of‐the‐Valley Odorants Devoid of Aldehyde Functions

Since 6‐isopropyl‐ ( 11 ) and 6‐isobutyl‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one ( 12 ) instead of the expected marine odor had been reported to possess lily‐of‐the‐valley notes, albeit weaker than benchmark odorants, the influence of a cyclopropyl ring instead of a methyl branching on the olfactory properties was investigated. 6‐Cyclopropyl‐ ( 27 ), 6‐(2′‐methylcyclopropyl)‐ ( 32 ) and 6‐(cyclopropylmethyl)‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one ( 39 ) were thus synthesized from 2,3‐dimethoxybenzaldehyde ( 22 ) by a synthetic sequence consisting of Wittig methylenation/ethylenation/homologation with (methoxymethyl)triphenylphosphonium chloride, followed by cyclopropanation, demethylation, Williamson etherification with 3‐chloro‐2‐(chloromethyl)prop‐1‐ene, and Katsuki–Sharpless oxidation. The odor thresholds of the target structures 27 , 32 , and 39 , which are all floral‐green lily‐of‐the‐valley odorants, lie in the range of that of Lilial ( 1 ), with the 6‐cyclopropyl derivative 27 being the most potent (th 0.065 ng/l air). Particularly impressive was the close resemblance of the 6‐(cyclopropylmethyl) derivative 39 with Bourgeonal ( 3 ), which was rationalized by a superposition analysis.     

Phenylethanoid Glycosides from the Roots of Digitalis ciliata Trautv.

Three new phenylethanoid glycosides, named digicilisides A – C ( 1  –  3 , resp.), have been isolated from the roots of Digitalis ciliata, along with five known phenylethanoid glycosides. The structures of 1  –  3 were identified as 2‐(4‐hydroxy‐3‐methoxyphenyl)ethyl β‐d ‐glucopyranosyl‐(1→3)‐[α‐l ‐rhamnopyranosyl‐(1→6)]‐4‐O‐[(E)‐feruloyl]‐β‐d ‐glucopyranoside ( 1 ), 2‐(3,4‐dihydroxyphenyl)ethyl α‐l ‐arabinopyranosyl‐(1→2)‐[β‐d ‐glucopyranosyl‐(1→3)]‐[α‐l ‐rhamnopyranosyl‐(1→6)]‐4‐O‐[(E)‐feruloyl]‐β‐d ‐glucopyranoside ( 2 ), and 2‐(3,4‐dihydroxyphenyl)ethyl β‐d ‐glucopyranosyl‐(1→3)‐{6‐O‐[(E)‐feruloyl]‐β‐d ‐glucopyranosyl‐(1→6)}‐4‐O‐[(E)‐caffeoyl]‐β‐d ‐glucopyranoside ( 3 ).     

Niels Bohr (1885–1962): On the Wing of a Butterfly,Johann J. Balmer (1825–1898)

By the year 1913, a number of revolutionary events had begun to transform the landscape of physics. In 1900, Max Planck (1858–1947) had proposed that energy radiated in quanta or packets. The announcement of the photoelectric effect in 1905 by an unassuming Swiss patent worker by the name of Albert Einstein (1879–1955) clearly implicated that light energy, or the photon, later coined by Gilbert N. Lewis (1875–1946) in 1926, was also quantized and showed unprecedented particle‐like properties. More startling was the discovery by Ernest Rutherford (1871–1937) who demonstrated that the atom consisted of a hard positive center surrounded by electrons. Niels Bohr (1885–1962), then a young postgraduate, was deeply involved in understanding the structure of the atom. He needed physical or experimental evidence to substantiate his intuitive ideas. Ironically, that evidence had already been published in the year of his birth by Johann J. Balmer (1825–1898), a Swiss mathematics teacher at a secondary school for girls.     

Myrothecoside,a Novel Glycosylated Polyketide from the Terrestrial Fungus Myrothecium sp. GS‐17

Based on the chemical analysis and targeted bioactivity screening, a new polyketide glycoside, myrothecoside, was isolated from a terrestrial halotolerant fungus, Myrothecium sp. GS‐17. The structure of myrothecoside was elucidated on the basis of extensive spectroscopic analysis including 1D‐ and 2D‐NMR (¹H,¹H‐COSY, HSQC, HMBC, and NOESY) experiments, combined with mass spectroscopic data and physicochemical properties. This compound exhibited weak cytotoxicity against human leukemia (HL‐60) cancer cell with an IG₅₀ value of 63.61 μm , and also antifungal activities against plant pathogenic fungi Rhizoctonia solani and Fusarium oxysporum using standard agar diffusion tests at 20 μg/disk.