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.     

R. B. Woodward's Letters: Revealing,Elegant and Commanding

A collection of excerpts from letters written by R. B. Woodward to his friends, colleagues, young students and others is presented. These excerpts are representative of Woodward 's lengthy correspondence and illustrate many aspects of his personality and philosophies of life.     

From Decades to Minutes: Steps Toward the Structure of Strychnine 1910–1948 and the Application of Today's Technology

Between 1910 and 1947, Robert Robinson (primarily), among others, published numerous proposed structures for strychnine. Robinson published 17 of his strychnine papers with his doctoral advisor William Henry Perkin, Jr., though all but two appeared after Robinson had taken his first permanent academic position. This Essay analyzes 20 key publications leading up to Robinson's (correct, then incorrect, then correct again though not definitively) proposal and Woodward's assignment of the actual structure of strychnine. We subjected the assignment of the strychnine structure to a modern computational quantum chemistry workflow. By computing, with density functional theory, ¹H and ¹³C NMR chemical shifts for the literature‐proposed strychnine structures, we were able to rule out most incorrect structures. ¹³C NMR predictions were better at this, but ¹H NMR chemical shifts were helpful. A comparison is made between the consequences of publishing erroneous ideas in the first half of the 20th century and doing so in the 21st century.     

From Decades to Minutes: Steps Toward the Structure of Strychnine 1910–1948 and the Application of Today's Technology

Between 1910 and 1947, Robert Robinson (primarily), among others, published numerous proposed structures for strychnine. Robinson published 17 of his strychnine papers with his doctoral advisor William Henry Perkin, Jr., though all but two appeared after Robinson had taken his first permanent academic position. This Essay analyzes 20 key publications leading up to Robinson's (correct, then incorrect, then correct again though not definitively) proposal and Woodward's assignment of the actual structure of strychnine. We subjected the assignment of the strychnine structure to a modern computational quantum chemistry workflow. By computing, with density functional theory, ¹H and ¹³C NMR chemical shifts for the literature-proposed strychnine structures, we were able to rule out most incorrect structures. ¹³C NMR predictions were better at this, but ¹H NMR chemical shifts were helpful. A comparison is made between the consequences of publishing erroneous ideas in the first half of the 20th century and doing so in the 21st century.     

An alternative Route to (±)-Warburganal Synthon

The transformation of the ketone (1) to the unsaturated diester (11) a potential intermediate for the warburganal (12) is described. The Wittig reaction of theketone (1) with methylenetriphenylphosphorane afforded the olefin (2) which reacts with Woodward's reagent (MeCOOAg, I₂ and MeCOOH and H₂O) to give the diol (13). This on heating with dimethylsulfoxide afforded the tetralin (14)     

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.     

Carboxylic n,N-diphenylcarbamic anhydrides. New acylating agents

Carboxylic N,N-diphenylcarbamic anhydrides have been isolated from the reaction of carboxylate salts with 1-(N,N-dipheriylcarbamoyl)pyridinium chloride in aqueous or ethanolic solution. These anhydrides have been shown to be stable, crystalline derivatives and to be very reactive in acylation reactions. A comparison of pyrazinecarboxylic acid derivatives demonstrated these products to be more reactive than cyanomethyl esters or the so-called Woodward's esters, acyloxyacrylamides.     

Unraveling the Composition of Rembrandt's Impasto through the Identification of Unusual Plumbonacrite by Multimodal X‐ray Diffraction Analysis

Rembrandt (1606–1669) is renowned for his impasto technique, involving his use of lead white paint with outstanding rheological properties. This paint was obtained by combining lead white pigment (a mixture of cerussite PbCO₃ and hydrocerussite Pb₃(CO₃)₂(OH)₂) with an organic binding medium, but the exact formulation used by Rembrandt remains a mystery. A powerful combination of high‐angle and high‐lateral resolution x‐ray diffraction was used to investigate several microscopic paint samples from four Rembrandt masterpieces. A rare lead compound, plumbonacrite (Pb₅(CO₃)₃O(OH)₂), was detected in areas of impasto. This can be considered a fingerprint of Rembrandt's recipe and is evidence of the use of an alkaline binding medium, which sheds a new light on Rembrandt's pictorial technique.     

2‐Ethyl­phenyl acridine‐9‐carboxyl­ate and 2,5‐dimethyl­phenyl acridine‐9‐carboxyl­ate

The title compounds, 2‐ethyl­phenyl acridine‐9‐carboxyl­ate, C₂₂H₁₇NO₂, (I), and 2,5‐dimethyl­phenyl acridine‐9‐carboxyl­ate, C₂₂H₁₇NO₂, (II), form triclinic and monoclinic crystals, respectively. Related by a centre of symmetry, adjacent molecules of (I) are linked in the lattice via a network of C—H·π and non‐specific dispersive interactions. As a result, acridine moieties and independent phenyl moieties of (I) are parallel in the lattice. The molecules of (II), arranged in a `head‐to‐tail' manner and related by a centre of symmetry, form pairs stabilized via C—H·π interactions. These are linked in the crystal via dispersive interactions. Acridine and independent phenyl moieties lie parallel within the pairs, while adjacent pairs are perpendicular, forming a herring‐bone pattern.     

Zeise,Liebig, Jensen,Hückel,Dewar, and the Olefin π‐Complex Bonds

Zeise's salt, KPt(C₂H₄)Cl₃, was the first characterized organometallic compound; it was also the first olefin π‐complex. It was published in 1825–1830 in the middle of a fight between Dumas on the one hand and Berzelius and Liebig on the other, who defended the etherin (ethylene) and radical theories, respectively. Although Zeise's formulation as a compound containing ethylene was vindicated, the fight went on for many years. This was a time when the theories of organic chemistry were being developed, before any clear understanding of the nature of molecules, bonding, and structure. Zeise thought of the structure of his salt as a product of the addition of PtCl₂ to ethylene. Jensen assumed a central bonding to ethylene but needed theoretical assistance to explain it. His attempt to obtain such an explanation from Hückel failed, and it was Dewar who explained the nature of π‐complexes in molecular orbital terms in 1951.     

Die Woodward‐Doering‐/Rabe‐Kindler‐Totalsynthese von Chinin: ein Mythos?

1918 beschrieben Paul Rabe und Karl Kindler die dreistufige Umwandlung von d‐Chinotoxin in Chinin. Robert B. Woodward und William von Eggers Doering veröffentlichten 1944 die Totalsynthese von Homomerochinen und d‐Chinotoxin aus 7‐Hydroxyisochinolin. Auf der Grundlage der Umsetzungen von Rabe und Kindler beanspruchten Woodward und Doering im Titel zweier Arbeiten von 1944 und 1945 die “Total Synthesis of Quinine”. In den Jahren 2000 und 2001 stempelte Gilbert Stork Woodwards und Doerings Anspruch aber als ungültig, weil sie in Cambridge nur Homomerochinen und d‐Chinotoxin, nicht aber synthetisches Chinin hergestellt hatten. Tatsächlich haben Rabe und Kindler die experimentellen Einzelheiten ihrer Umwandlung von d‐Chinotoxin in Chinin nie veröffentlicht. Dieser Aufsatz stellt die Ergebnisse einer detaillierten Untersuchung der Synthesechemie von Cinchona‐Alkaloiden vor und gibt anhand von bisher unveröffentlichtem Material sowie zahlreichen Interviews einen Einblick in das Leben der Hauptpersonen dieser fast 100 Jahre währenden Geschichte.     

Synthesis and spectral characterization of N‐[2‐(4‐halophenoxy)‐3‐(3‐chlorophenyl)‐3, 4‐dihydro‐2H‐1,3,2‐λ5‐benzoxazaphosphinin‐2‐yliden]‐N‐substituted amines by the Staudinger reaction

The synthesis of the title compounds was accomplished in four steps. The synthetic route involves the preparation of Schiff's base by reacting salicylaldehyde with m‐chloroaniline in EtOH. The Schiff's base was then reduced with NaBH₄/MeOH. In the second step, PCl₃ was reacted with p‐chlorophenol/p‐bromophenol in THF in the presence of Et₃N to obtain P(III) dichloride derivatives. The reduced Schiff's base and dichloride derivatives were reacted in equimolar quantities in the presence of Et₃N in THF to get the cyclized product. Alkyl azides were prepared by reacting alkyl bromides with sodium azide, and then alkyl azides were treated with the cyclized product to obtain the title compounds. The structure of these novel compounds was elucidated by elemental analysis, IR, ¹H, ¹³C, ³¹P NMR, and mass spectroscopy. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:499–504, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20639     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Synthesis of 3‐[4‐Acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as Novel Potassium Channel Openers

Potassium channel openers (KCO's) have been demonstrated to possess potent relaxant‐activity on smooth muscle. Tissue‐selective KCO's may find use in the treatment of a variety of diseases, such as hypertension, asthma, and urinary incontinence. We have previously reported a series of 1,9‐dioxa‐4‐aza‐phenanthrene‐6‐carbonitriles, including compounds 2 & 3 , as bladder‐selective KCO's. As a continuation of our efforts, we have designed 3‐[4‐acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as ring‐opened analogs of compounds 2 & 3 . In this report, we describe the efficient construction of the novel 2,3‐disubstituted morpholine structure, as represented by the synthesis of compounds 4‐7 . Compounds 4‐7 showed potent and selective relaxant‐activity on rat bladder detrusor strip preparation. In this series, the most potent derivatives are Boc‐substituted analogs 4 & 6 (IC₅₀ = 3.9 and 2.9 μM, respectively).     

Macrocyclization of polymers via ring‐closing metathesis and azide/alkyne‐“click”‐reactions: An approach to cyclic polyisobutylenes

The end‐to‐end cyclization of telechelic polyisobutylenes (PIB's) toward cyclic polyisobutylenes is reported, using either ring‐closing metathesis (RCM) or the azide/alkyne‐“click”‐reaction. The first approach uses bisallyl‐telchelic PIB's (M_n = 1650, 3680, 9770 g mol^?1) and Grubbs 1st‐, 2nd‐, and 3rd‐generation catalyst leading to cyclic PIB's in 60–80% yield, with narrow polydispersities (M_w/M_n = 1.25). Azide/alkyne‐“click”‐reactions of bisalkyne‐telechelic PIB's (M_n = 3840 and 9820 g mol^?1) with excess of 1,11‐diazido‐undecane leads to the formation of mixtures of linear/cyclic PIB's under formation of oligomeric cycles. Subsequent reaction of the residual azide‐moieties in the linear PIB's with excess of alkyne‐telechelic PEO enables the chromatographic removal of the resulting linear PEO‐PIB‐block copolymers by column chromatography. Thus pure cyclic PIB's can be obtained using this double‐“click”‐method, devoid of linear contaminants. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 671–680, 2010     

End‐functionalization of polystyrene by malto‐oligosaccharide generating aggregation‐tunable polymeric reverse micelle

This article describes that glucose, maltose, maltotriose, maltotetraose, maltopentaose, and maltohexaose ( a , b , c , d , e , and f , respectively) were introduced into the initiating chain‐end of polystyrene (PSt) through the 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO)‐mediated radical polymerization. A series of glycoconjuaged TEMPO‐adducts, 1a–f , was synthesized and used as the initiators for the polymerization of styrene (St) for 6 h at 120 °C to afford the end‐functionalized PSt's with the acetyl saccharides, 2a–f , in the yields of 37–43%. For 2a–f obtained by the polymerizations using the [St]/[ 1 ] of 125, 250, and 500, the number‐average molecular weights determined by size exclusion chromatography (SEC), M_n,SEC's, were 4800–6300, 8800–10,600, and 18,400–25,200, respectively, which fairly agreed with the predicted values. The end‐functionalized PSt's with saccharides, 3a–f , which were obtained from the deacetylation of 2a–f using sodium methoxide in dry THF, formed the polymeric reverse micelles consisting of a saccharide‐core and a PSt‐shell in chloroform and toluene. The static laser light scattering (SLS) measurements provided the average molar mass of the aggregates in toluene, M_w,SLS's, which ranged from 7.50 × 10⁴ to 1.77 × 10⁵ for 3a , from 1.90 × 10⁵ to 4.93 × 10⁵ for 3b , from 4.41 × 10⁵ to 7.21 × 10⁵ for 3c , from 5.85 × 10⁵ to 8.51 × 10⁵ for 3d , from 7.55 × 10⁵ to 8.53 × 10⁵ for 3e , and from 8.54 × 10⁵ to 9.26 × 10⁵ for 3f . The aggregation numbers, N_agg's, which were calculated from the M_w,SLS's, were from 7 to 24 for 3a , from 20 to 37 for 3b , from 34 to 89 for 3c , from 39 to 116 for 3d , from 41 to 145 for 3e , and from 31 to 146 for 3f . It was confirmed that the aggregation property, such as the M_w,SLS or N_agg values, was strongly related to the polymerization degrees of St (DP's) or the number of the glucose residues (n's) for 3a–f . © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4864–4879, 2006     

Transition‐Metal‐Free Oxidative Cross‐Coupling of Tetraarylborates to Biaryls Using Organic Oxidants

Readily prepared tetraarylborates undergo selective (cross)‐coupling through oxidation with Bobbitt's salt to give symmetric and unsymmetric biaryls. The organic oxoammonium salt can be used either as a stoichiometric oxidant or as a catalyst in combination with in situ generated NO₂ and molecular oxygen as the terminal oxidant. For selected cases, oxidative coupling is also possible with NO₂/O₂ without any additional nitroxide‐based cocatalyst. Transition‐metal‐free catalytic oxidative ligand cross‐coupling of tetraarylborates is unprecedented and the introduced method provides access to various biaryl and heterobiaryl systems.     

Tetrakis(2‐methyl‐2‐phenyl­propyl)­stannane at 150 K

The structure of the title compound, tetrakis(2‐methyl‐2‐phenyl­propyl)­stannane, (PhCMe₂CH₂)₄Sn, has been determined at 293 K by Reuter & Pawlak (1998). This present determination was carried out at 150 K and as a result gives cell, coordinate and displacement parameters with much reduced s.u.'s. As is pointed out in the the above paper, the bonds and angles are similar to those in related Sn compounds although it is worth emphasizing that there are no intra‐ or intermolecular ring–ring interactions but that there are a numberof C—H...Cg(π‐ring) interactions at the 3.0 Å level.     

Polymorphism of 3‐(5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)‐ and 3‐[5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐2‐yl]‐2H‐chromen‐2‐ones

This study of 3‐(5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)‐2H‐chromen‐2‐one, C₁₇H₁₀N₂O₃, 1 , and 3‐[5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐2‐yl]‐2H‐chromen‐2‐one, C₁₆H₉N₃O₃, 2 , was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the `head‐to‐head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar‐layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.     

Synthesis of New Tetrahydro‐1,5‐benzodiazepin‐3‐yl‐2‐phenylacetamides via Isocyanide‐Based Multicomponent Reactions

New tetrahydro‐1H‐1,5‐benzodiazepin‐2‐phenylacetamides were synthesized in good yields by a four‐component reaction of benzylidene Meldrum's acid, benzene‐1,2‐diamines, isocyanides, and water in CH₂Cl₂ at room temperature.