Journal of Porphyrins and Phthalocyanines J. Porphyrins ... Waruna R. G. 542 Jois, Seetharama D. 352...

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Journal of Porphyrins and PhthalocyaninesJ. Porphyrins Phthalocyanines 2016; 20: 1569

Guest Editors: Roberto Paolesse, Ravindra K Pandey, Mathias O Senge, M Graa H Vicente

This special JPP issue is dedicated to Professor Kevin M. Smith (KMS) in cele-bration of his 70th birthday, and his contributions to porphyrin science over the past 50 years. The cover includes some structures of various macrocycles that illustrate just a small part of his research activities, and the glow of light represents his vision and guidance in the field. Professor Smiths contributions include more than 760 pub-lications, with over 23,000 citations, 8 patents, and 57 books edited or co-edited over his outstanding career.

About the Cover

Reviews

pp. 120Total synthesis of vitamin B12 a fellowship of the ringG. Wayne Craig*

In the synthesis of cobyric acid following an arduous 60-step plus synthesis of the corrigenolide (figure, structure left), Woodward demonstrated that ring cyclization yielded unexpectedly the corrin cyclic ether (figure, structure right). Its structure was chosen as the chemistry logo for the 1970 IUPAC meeting. It was a reminder that chemistry can be capricious and beautiful. This article is a tribute to the 50-year career in porphyrins of Kevin M. Smith and his early contributions with illustrious colleagues in the synthetic quest of another porphyrin relative, vitamin B12.

pp. 2134Recent advances in meso-alkylidenyl carba por phy-rinoidsKamaljit Singh, Abeje Abebayehu, Endale Mulugeta, Divya Sareen and Chang-Hee Lee*

The so called meso-alkylidenyl porphyrins have been reported recently as alternative modification methods of the porphyrin skeleton. These compounds possess one or more exocyclic double bonds at meso-positions and are usually non-aromatic systems. This review sumarized a generic synthesis, identification of structural identity, unique prototropy and spectroscopic properties up to date.

CONTENTS

J. Porphyrins Phthalocyanines 2016; 20: 1569

pp. 3544Thermal and photoinduced electron-transfer catalysis of high-valent metal-oxo porphyrins in oxidation of substratesShunichi Fukuzumi* and Wonwoo Nam*

Thermal and photoinduced electron-transfer catalysis of high-valent metal-oxo porphyrins, which are produced either by reductive activation of dioxygen with one-electron reductants or by oxidative activation of water with one-electron oxidants, has been reviewed for the catalytic oxidation of various substrates.

pp. 4560Synthesis of meso-substituted porphyrins using sus-tainable chemical processesSara M. A. Pinto, Csar A. Henriques, Vanessa A. Tom,

Marta Pieiro, Luis G. Arnaut and Mariette M. Pereira*

Recent strategies to synthesize meso-substituted porphyrins using alternative energy sources, reaction media and catalysts, namely microwave irradiation, water as solvent, or solid microporous acid catalysts are addressed, following the increasing demand for the development of new synthetic processes invol ving more sustainable chemical principles.

pp. 6175BODIPYsteroid conjugates: Syntheses and bio-logical applicationsSamira Osati, Hasrat Ali and Johan E. van Lier*

Steroids linked to BODIPY and aza-BODPY fluorophores are being developed as multimodal-imaging agents to monitor the mechanism of action of biologically active components in living systems.

pp. 7695CC bond forming reactions catalyzed by chiral metallo-porphyrins

and Dorota Gryko*

Optically active porphyrin complexes do exist in nature, but the stereogenic carbon atoms are located too far from the metal center to generate optically active products. However, synthetic, chiral metalloporphyrins has been inves-tigated as catalysts for functionalization of organic molecules with the goal of finding highly stereoselective transformations and explaining the roles of a metal center, the type of porphyrin, and the peripheral substituents and these endeavors are reviewed.


CONTENTS

pp. 96107The evolution of corrole synthesis from simple one-pot strategies to sophisticated ABC-corrolesMichael Knig, Felix Faschinger, Lorenz Michael Reith and Wolfgang Schfberger*

This review highlights synthesis procedures to obtain A3-, cis- and trans- A2B- and ABC- corroles. Synthesis methods from the early beginning of corrole chemistry in the 1960s, the acid-catalyzed condensation methods of various building blocks and possible side reaction during Brnsted acid catalyzed re-actions (scrambling), one-pot synthesis of corroles, and post-macrocyclization modification reactions of meso-substituted A3-corroles are discussed.

pp. 108116Coupled oxidation of iron tetraarylporphyrins as a synthetic tool for linear tetrapyrrolesTadashi Mizutani*

The coupled oxiation of meso-tetraarylporphyrin iron complexes has been stu died as a practial synthetic pathway to obtain linear tetra-pyrroles. Substituents on the aryl groups affected the selectivity of coupled oxidation. 5-Oxaporphyrin zinc complexes were obtained from bilindione, and it was ring-opened by various nuclephiles to yield substituted bilinones. These linear tetrapyrroles were used as a solvatochromic and thermochromic dyes, an allosteric host binding amines, and an active layer of electronic devices.

pp. 117133Structurally characterized bimetallic porphyrin com - plexes of Pb, Bi, Hg and Tl based on unusual coordi-nation modesStphane Le Gac and Bernard Boitrel*

This minireview highlights the unusual coordination geometries observed in bi-metallic complexes of mercury, thallium, lead and bismuth. These bimetallic complexes remain scarce and through an analysis of their X-ray structure, the various structural features that favorise them will be underlined.

pp. 134149A molecule for all seasons: The hemePaolo Ascenzi and Maurizio Brunori*

Almost all living creatures express one or more hemeprotein, which sustain a considerable number of vital functions showing that the specific chemistry is imposed on the heme-Fe by binding to different globins. These include O2 trans-port, reactive oxygen species (ROS) detoxification, reactive nitrogen species (RNS) scavenging, signal transduction and O2 sensing.

CONTENTS


pp. 150166Photodegradation of organic pollutants in water by immobilized porphyrins and phthalocyaninesLuca Fernndez, Valdemar I. Esteves, ngela Cunha, Rudolf J. Schneider and Joo P. C. Tom*

This minireview emphasizes the different methodologies for the immo-bilization of photosensitizers in the area of photodegradation of organic pollutants in water. In this field, Pors and Pcs have been covalently and non-covalently linked to diferent supports with outstanding perfor man ces and very good reusability rates.

pp. 167189Synthetic methodologies leading to porphyrin-quinone conjugatesMariana F. do C. Cardoso, Luana da S. M. Forezi, Fernando de C. da Silva, (the late) ngelo C. Pinto, Maria G.P.M.S. Neves, Vitor F. Ferreira* and Jos A. S. Cavaleiro*

This review focuses on synthetic strategies that have been established for the preparation of porphyrin-quinone conjugates of potential biological significance and as donoracceptor compounds for electron transfer processes.

pp. 190203Recent advances in CH bond aminations catalyzed by ruthenium porphyrin complexesDaniela Intrieri, Daniela Maria Carminati and Emma Gallo*

This review illustrates the state of the art of the catalytic use of ruthenium por-phyrin complexes to promote the transformation of low-cost compounds, such as hydrocarbons, into high-added value aminated compounds. In order to give an overview on the potentialities of ruthenium porphyrin-based catalytic proce-dures, the syntheses of a variety of aza-derivatives have been discussed as well as catalytic mechanisms involved.

pp. 204212Photophysical properties of tetraphenylporphyrin- sub phthalocyanine conjugatesMuthumuni Managa, John Mack*, Daniel Gonzalez-Lucas, Sonia Remiro-Buenamaana, Charmaine Tshangana, Andrew N. Cammidge* and Tebello Nyokong*

Novel tetraphenylporphyrin-subphthalocyanine conjugates have been prepared and characterized. An analysis of their optical spectroscopy and electronic struc-tures using fluorescence emission and MCD spectroscopy and TD-DFT calcula-tions, demonstrates that the two chromophores do not interact to any significant extent.

Articles


CONTENTS

pp. 213222Selective octabromination of tetraarylporphyrins based on meso-substituent identity: Structural and electrochemical studiesPatrick J. Commins, Jonathan P. Hill*, Yoshitaka Matsushita, Whitney A. Webre, Jan Labuta, Katsuhiko Ariga and Francis DSouza*

Synthesis and isolation of selectively brominated tetraarylporphyrin derivatives is reported. Direct bromination on different tetraarylporphyrins yields products exclusively 2,6-brominated at meso-aryl groups (where aryl groups are 3,4,5-trimethoxyphenyl) or at pyrrole -positions (for 3,5-di-t-butyl-4-hydroxyphenyl groups). Structures and elec-trochemistry of the products and their precursors were investigated.

pp. 223233

electronic properties of thioalkyl-porphyrazinesSandra Belviso*, Francesca Cammarota, Rocco Rossano and Francesco Lelj*

A novel polyfluorinated thioalkyl-porphyrazine was synthesized. A significant effect of fluorine on self-aggregation, electrochemical, and spectral properties of this class of molecules was observed. HOMO, LUMO, and band-gap values together with its mesomorphic properties make this compound a promising ma-terial for organic photovoltaics.

pp. 234244

the spacer and of the number of substituents on their structural and spectroscopic characteristicsClaudia Mazzuca, Benedetta Di Napoli, Sara Lentini, Daniel O. Cicero, Emanuela Gatto, Pietro Tagliatesta* and Antonio Palleschi

Mono- and bis--substituted ferrocenyl porphyrins have been characte-rized. The addition of a second substituent and of a phenyl group into the spacer between ferrocene(s) and porphyrin play a key role in determining their properties.

pp. 245253mesomeso Directly-linked trimeric and pen-

hy brid arraysHirotaka Mori and Atsuhiro Osuka*

mesomeso directly-linked trimeric and pentameric porphyrinhexaphyrin hybrid arrays comprising of electron-deficient porphyrin units were prepared by cross-condensation of monomeric and dimeric electron- deficient meso-formyl porphyrins with a tripyrrane. Their solid-state structures have been determined by single crystal X-ray diffraction analysis. That of the pentamer is the largest crystal structure of mesomeso linked multiporphyrinic array analogs reported to date.

CONTENTS


pp. 254264Characterization of the mixed axial ligand complex (4-cyanopyridine)(imidazole)(tetramesitylporphinato)-iron(III) perchlorate. Stabilization by synergic bondingJudith A. Serth-Guzzo, Ilona Turowska-Tyrk, Martin K. Safo, F. Ann Walker, Peter G. Debrunner and W. Robert Scheidt*

The combination of binding a -accepting and a -donating ligand leads to the mixed axial ligand iron(III) complex with the two axial ligands having a relative perpendicular orientation.

pp. 265273Quinoline-annulated chlorins and chlorin-analogsJoshua Akhigbe, Mengxi Yang, Michael Luciano and Christian Brckner*

The OsO4-mediated dihydroxylation of quinoline-annulated porphyrin gener-ates a quinoline-annulated dihydroxychlorin. The diol moiety is susceptible to functional group interconversions to generate the corresponding dione, lactone, and dialkoxymorpholine derivatives. The quinoline-annulated chlorin and deriv-atives are characterized by much broadened and red-shifted absorption spectra, with absorbance maxima in the NIR up to well above 800 nm.

pp. 274281Cobalt(III) and gallium(III) complexes of meso-free corroles with distinct position-dependent substituent effectsShota Ooi, Takayuki Tanaka* and Atsuhiro Osuka*

Cobalt(III) and gallium(III) metalations of 5,10-bis(pentafluorophenyl)corrole and 5,15-bis(pentafluorophenyl)corrole were achieved and their structures have been unambiguously revealed by X-ray diffraction analysis. Their optical and electrochemical properties indicate distinct substituent effects depending upon the substitution positions.

pp. 282291Studying the intersystem crossing rate and triplet quantum yield of meso-substituted porphyrins by

Tiago Gualberto Bezera de Souza, Marcelo Gonalves Vivas, Cleber Renato Mendona, Shane Plunkett, Mikhail A. Filatov, Mathias O. Senge and Leonardo De Boni*

The pulse train fluorescence technique is shown to be a useful method for the investigation of excited state dynamics such as intersystem crossing using a set of meso-substituted porphyrins bearing different electrondonor and acceptor groups.


CONTENTS

pp. 292301Synthesis of porphyrins bearing alkynyl- or aryl-alkynyl-meso-groupsHerv Dekkiche, Yoshihiro Kikkawa, Lydia Karmazin, Christophe Jeandon and Romain Ruppert*

The synthesis of new porphyrins bearing external coordination sites and long alkynyl chains is described. Two crystal structures of these new porphyrin derivatives were obtained. The synthesis of porphyrin dimers linked by a palladium(II) ion is also reported and some electronic con-sequences presented.

pp. 302306

sequential protocolDavid Kessel*

For a protocol involving sequential photodamage to lysosomes, then mitochon-dria, Photofrin can be utilized for either phase since fluorescent probes reveal that this agent can elicit both mitochondrial and lysosomal photodamage.

pp. 307317Determination of the activation energies for ND tautomerism and anion exchange in a porphyrin monocationCraig J. Medforth*, Patrick E. Berget, James C. Fettinger, Kevin M. Smith and John A. Shelnutt

Protonation of the highly substituted and saddle-shaped porphyrin H2OETPP is investigated with the goal of using this pre-deformed porphyrin to gene rate high concentrations of the normally elu-sive monocation. 1H NMR studies with 1 equivalent of picric acid (2,4,6,-trinitrophenol) in toluene-d8 show that approximately 70% of the porphyrin is present as the monocation H3OETPP

+ (picrate). NMR studies reveal the presence of two dynamic process for the monocation: picrate anion exchange in CD2Cl2 (G = 53 kJ.mol-1) and ND tautomerism in toluene-d8 (G = 42 kJ.mol-1).

pp. 318330Effects of porphyrin deformation on the 13C and 1H NMR

manganese(III) porphyrin complexesAkira Ikezaki* and Mikio Nakamura*

Both five- and six-coordinate high-spin (S=2) manganese(III) complexes with planar, ruffled, and saddled porphyrin ring have been prepared. The 13C NMR spectra have revealed that the meso, -, and -pyrrole signals are widely dis-persed depending on the deformation mode of the porphyrin ring. The results have been explained in terms of the strong metal-porphyrin orbital interactions.

CONTENTS


pp. 331336Indirect and direct damage to genomic DNA induced by

phenyl)porphyrin upon photodynamic actionMaria Bartolomeu, Snia Coimbra, ngela Cunha, Maria G.P.M.S. Neves, Jos A. S. Cavaleiro, Maria A. F. Faustino* and Adelaide Almeida*

In this study, it was compared, using 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide (Tri-Py+-Me-PF) as photosensiti-zing agent, the photodamage effects on genomic DNA extracted from photosen-sitized E. coli (indirect effect) with the direct effects observed on genomic DNA extracted from non-photosensitized cells but being subjected to the same PDT irradiation protocol.

pp. 337351How big is big? Separation by conventional me-thods, X-ray and electronic structures of po si-tio nal isomers of bis-tert-butylisocyano ad duct of 2(3),9(10),16(17),23(24)-te tra chloro-3(2),10(9), 17(16),24(23)-tetra(2,6-di-iso-propyl phe noxy)-phtha lo cyaninato iron(II) complexDerrick R. Anderson, Pavlo V. Solntsev, Hannah M. Rhoda and Victor N. Nemykin*

A two out of four positional isomers of bis-tert-butylisocyano adduct of 2(3),9(10),16(17),23(24)-tetrachloro-3(2),10(9),17(16),24(23)-tetra(2,6-di-iso-propylphenoxy)-phthalocyaninato iron(II) complex were separated and characterized by X-ray crystallography. DFT and TDDFT calcula-tions on each individual positional isomer were conducted to correlate electronic structures and vertical excitation energies with the experimental UV-vis and MCD spectra.

pp. 352366Targeting of the epidermal growth factor receptor with mesoporphyrin IX-peptide conjugatesKrystal R. Fontenot, Benson G. Ongarora, Logan E. LeBlanc, Zehua Zhou, Seetharama D. Jois* and M. Graa H. Vicente*

Four mesoporphyrin IX-peptide conjugates were synthesized and investigated for their ability to target EGFR. The most promising conjugate contains two LARLLT sequences linked to the propionic acid chains.

pp. 367377

geometry, electronic structure, hydrogen bonding, and tautomerization

Jacek Waluk*

Possible tautomeric forms of free-base corrphycene and its alkyl-substituted derivatives have been analyzed using calculations of geometry, vibrational and electronic structures, and electronic transition energies. The lowest energy structure always corresponds to the trans species. Predictions have been made regarding the influence of substitution on the degree of planarity, tautomeriza-tion rates, and electronic spectra.


CONTENTS

pp. 378387Synthesis, photophysical studies and 1O2 ge ne-ration of ruthenium phthalocyanine den dri mersFrancesca Setaro, Rubn Ruiz-Gonzlez, Santi Nonell*, Uwe Hahn* and Toms Torres*

A series of first to third generation ruthenium phthalocyanine (RuPc)-centred dendrimers is described. The study of the photophysical proper-ties evidenced a negative dendritic effect as manifested by the decrea-sing ability to generate singlet oxygen (1O2) in organic media. Likewise, a water-soluble RuPc has been obtained upon saponification and was found to be able to produce 1O2 in aqueous medium.

pp. 388396Zn-complex of a natural yellow chlorophyll cataboliteChengjie Li and Bernhard Krutler*

Coordination of zinc-ions to the hardly luminescenct natural yellow chlorophyll catabolite, forms 2:1 metal complexes (such as Zn(YCC-Me)2) and lightens-up green luminescence.

pp. 3974064-tert-Butylphenoxy substituted phthalocyanine with RGD motif as highly selective one-photon and two-photon imaging probe for mitochondria and cancer cellLiqiang Luan, Wenjuan Fang, Wei Liu*, Minggang Tian, Yuxing Ni, Xi Chen, Xiaoqiang Yu, Jing He, Yang Yang and Xiangzhi Li

An unsymmetrical phthalocyanine based one- and two-photon fluorescence imaging probe that substituted with 4-tert-butylphenol and RDGyK moieties was developed, of which the fluorescence is greatly enhanced in mitochondria along with a good selectivity towards carcinoma cells, making it a promising multifunctional imaging probe for mitochondria and cancer.

pp. 407412Boron complexes of cyclo[m]pyridine[n]pyrrolesZhan Zhang, Won-Young Cha, Vincent M. Lynch, Dongho Kim* and Jonathan L. Sessler*

Described here are the first boron complexes of a set of pyridine-pyrrole porphy-rin analogs, the so-called cyclo[m]pyridine[n]pyrroles (m + n = 6). The chemis-try of these macrocyclic systems, which are larger than porphyrins, is of interest because, in contrast to what is seen in porphyrins, only 1:1 complexes are ob-tained. Depending on the choice of ligand and the degree of protonation, either highly fluorescent or weakly fluorescent species are obtained.

CONTENTS


pp. 413420Improvement of electrocatalytic effect in voltammetric sensors based on phthalocyaninesMara L. Rodrguez-Mndez*, Cristina Medina-Plaza, Celia Garca-Hernndez, Silvia Rodrguez, Cristina Garca-Cabezn, David Paniagua, Miguel A. Rodrguez-Prez and Jos A. de Saja

Voltammetric sensors based on phthalocyanines have been widely applied for the analysis of a variety of compounds. Lutetium bisphthalocyanine (LuPc2) is of particular interest due to their excellent electrochemical properties. Classical LuPc2 electrodes can detect phenols with limits of detection in the range of 10-410-5 M. The performance can be improved by using nanostructured films. The enhanced surface to volume ratio produce an increase in the sensitivity of the sensors.

pp. 421428Synthesis of tetraferrocenylporphyrin and new metal com-plexes: Searching for reliable synthetic proceduresMartina Tiravia, Andrea Vecchi, Federica Sabuzi, Giuseppe Pomarico, Alessia Coletti, Barbara Floris, Valeria Conte and Pierluca Galloni*

Reaction conditions for the synthesis of 5,10,15,20-tetraferrocenylporphyrin (TFcP) have been explored in terms of catalyst, solvent and reagents concentration. The syn-thesis is strongly dependent on reaction conditions with respect to other aryl porphy-rins and, in particular, substrates concentration plays a crucial role in the overall yield. Moreover, Mg, Mn, Pd and Cd TFcP derivatives have been synthesized and the elec-tronic effects of the metal on the TFcP properties have been preliminary discussed.

pp. 429437New carbazole appended subporphyrin displaying intra-

Brijesh Chandra, Navendu Mondal, B. Sathish Kumar and Pradeepta K. Panda*

A new subporphyrinoid viz. hydroxo-5,10,15-tri(N-propyl-3-carbazolyl)sub por-phyrinato boron(III) has been synthesized, where carbazole is directly attached to subporphyrin core via CC bond. Macrocycle displays red shifted absorption and emission as well as intramolecular charge transfer (ICT) where carbazole acts as a donor and subporphyrin core acts as an acceptor. The macrocycle also exhibits solid state fluorescence, a first of its kind in this class of macrocycles.

pp. 438443Reorganization of porphyrin nanoparticle morphology driven by surface energeticsChang Xu, Albert Wan, Xianchang Gong, N.V.S. Dinesh K. Bhupathiraju, James D. Batteas* and Charles Michael Drain*

Organic nanoparticles (ONp) of an Fe(III) porphyrin appended with four N-polyethyleneglyco-pyridinium moieties prepared in acetonitrile were depo sited onto hydrophilic or hydrophobic Si surfaces. Self-organized by intermole cular in-teractions, ONp reorganize in response to environmental changes. Mechanisms for the control of nanoparticle morphologies and surface patterning by varying surface energies are discussed.


CONTENTS

pp. 444455

rescent and colorimetric sensing of cysteineQinghua Wu, Yangchun Wu, Min Zhang, Changjiang Yu, Erhong Hao and Lijuan Jiao*

Selective fluorescent and colorimetric sensing of cysteine in methanol-HEPES buffer over various common amino acids and related thiol containing compounds has been achieved based on the cyclization reaction between the formyl groups on 3-formylBODIPYs and Cys/Hcy. Upon addition of Cys/Hcy, 3-formylBODIPYs exhibited greatly enhanced fluo-rescence intensity as well as a nice absorption peak shift (2030 nm). The detection limits for Cys were in the range of 1.182.73 10-6 M. The detection mechanism was studied by NMR and DFT calculation.

pp. 456464Synthesis and electrochemistry of cobalt tetra bu-tanotriarylcorroles. Highly selective electrocatalysts for two-electron reduction of dioxygen in acidic and basic mediaJing Sun, Zhongping Ou*, Rui Guo, Yuanyuan Fang, Minyuan Chen, Yang Song and Karl M. Kadish*

Three cobalt tetrabutanotriarylcorroles were synthesized and characterized as to their electrochemistry and spectroelectrochemistry. The catalytic properties of the compound for reduction of dioxygen were also examined in acidic and basic solutions.

pp. 465474The scope of the -halogenation of triarylcorrolesSara Nardis*, Giuseppe Pomarico, Manuela Stefanelli, Sara Lentini, Daniel O. Cicero, Frank R. Fronczek, Kevin M. Smith and Roberto Paolesse

The use of inorganic acids has been investigated for the peripheral functionaliza-tion of corrole leading to the definition of a new synthetic protocol for the partial chlorination and bromination of the macrocycle free base. Different results have been obtained depending on the dimensions of the reactive species, for this reason a diverse approach has been chosen for the iodination reaction.

pp. 475489Synthesis and photophysical properties of meso-aryloxy linked BODIPY monomers, dimers, and trimerChangjiang Yu, Qinghua Wu, Zhonghua Tian, Tingting Li, Erhong Hao* and Lijuan Jiao*

A series of meso-aryloxy linked BODIPY monomers, dimers and trimer were synthesized by nucleophilic aromatic substitution (SNAr) reaction from phenols with meso-chloro BODIPY and their photophysical proper-ties were systematically studied by UV-vis and fluorescence spectroscopy. The relationship between their photophysical properties and the spatial arrangement of meso-aryloxy linked BODIPYs has been discussed. The monomers exhibited different extent solvent-dependent fluorescence and fluorescence quenching in polar solvents were found relative to the HOMO energies of the donor (meso-phenols), indicating possible PET effect from meso-phenols to the BODIPY fluorophore. Ortho-dimer showed unusual broad red-shifted emission bands centered at 550 nm with a larger Stokes shifts at the range of 29003400 cm-1, and low fluorescence quantum yields, which was in sharp contrast to those of other dimers and trimer, indicating of possible excimeric species formation due to slipped cofacial arrangement of ortho-dimer.

CONTENTS


pp. 490496A novel bacteriochlorin-gold nanoparticle cons-truct for photoacoustic imagingAvinash Srivatsan, Mansik Jeon, Yanfang Wang, Yihui Chen, Chulhong Kim* and Ravindra K. Pandey*

A water soluble bacteriochlorin joined to gold nanoparticle with sulfur linkage shows potential to develop a nonoconstruct for photoacoustic imaging.

pp. 497504Phthalocyanine-chalcone conjugatesFallia Aribi, Charlene Vey, Derya Topkaya, Sinem Tuncel

Devrim Atilla, Vefa Ahsen, Sylvie Ducki* and Fabienne Dumoulin*

Several phthalocyanine-chalcone conjugates were prepared with grafting modes for further SAR investigations.

pp. 505513MCD spectroscopy and TD-DFT calculations of magnesium tetra-(15-crown-5-oxanthreno)-phthalo cyanineJohn Mack*, Scebi Mkhize, Evgeniya A. Safonova, Alexander G. Martynov, Yulia G. Gorbunova, Aslan Yu. Tsivadze and Tebello Nyokong

An analysis of the MCD spectroscopy and TD-DFT calculations of magnesium te tra-(15-crown-5-oxanthreno)-phthalocyanine with the CAM-B3LYP functional is reported. This study provides a reassessment of an earlier study on the nature of the bands in UV-visible absorption spectra of magnesium and zinc tetra-(15-crown-5-oxanthreno)-phthalocyanine that was based on an analysis of TD-DFT calculations for a series of model complexes with the B3LYP functional.

pp. 514524Synthesis and characterization of trans-di-(4-pyridyl)porphyrin dimersSimone Pisano, Domenico Milano, Nicola Passoni, Elisabetta Iengo* and Paolo Tecilla*

A small library of symmetric trans-di-(4-pyridyl)porphyrin dimers have been prepared. The porphyrin dimers are differentiated by a phenyl-alkynyl bridge of increasing length at one meso-position, while for all the derivatives the two remaining opposite meso-positions are tailored with a phenyl moiety bearing a short polyether chain.


CONTENTS

pp. 525533NMR spectroscopy of the phenyl derivative of germanium(IV) 5,10,15-tritolylcorroleGiampaolo Ricciardi, Daniel O. Cicero, Sara Lentini, Sara Nardis, Roberto Paolesse and Angela Rosa*

Reported herein is a thoroughly structural characterization of (TTC)GePh (TTC = 5,10,15-tritolylcorrole; Ph = phenyl) in solution by a combination of 2D NMR (1H-1H COSY, 1H-1H ROESY, 1H-13C HSQC and 1H-13C HMBC) experiments and density functional theory (DFT) calculations of the shielding constants.

pp. 534541Photochemical hydrogen evolution using Sn-porphyrin as photosensitizer and a series of Cobaloximes as catalystsGeorgios Landrou, Athanassios A. Panagiotopoulos, Kalliopi Ladomenou and Athanassios G. Coutsolelos*

A photochemical hydrogen evolution system consisting of various cobalt based catalysts is reported: a metalated Sn porphyrin as photosensitizer and a trietha-nolamine as a sacrificial electron donor in acetonitrile/H2O (1:1) solution. Since a tin metalated porphyrin is used for the first time as photosensitizer in this type of systems, a systematic study was performed in order to elucidate the best conditions for H2 production.

pp. 542555Benzoporphyrins bearing pyridine or pyridine-N-oxide anchoring groups as sensitizers for dye-sensitized solar cellBenjamin Schmitz, Bihong Li, R. G. Waruna Jinadasa, Shashi B. Lalvani, Lei L. Kerr and Hong Wang*

Novel benzoporphyrins bearing pyridine or pyridine-N-oxide groups were prepared as sensitizers for dye-sensitized solar cells. Vicinal pyridine and vicinal pyridine-N-oxide groups were proved to be valid anchoring groups for dye-sensitized solar cell.

pp. 556569The conserved active site histidine-glutamate pair of ferrochelatase coordinately catalyzes porphyrin meta-lationGregory A. Hunter, Sai Lakshmana Vankayala, Mallory E. Gillam, Fiona L. Kearns, H. Lee Woodcock* and Gloria C. Ferreira*

The major question addressed in this study relates to which side of the proto-porphyrin IX macrocycle does ferrochelatase insert the ferrous iron substrate. A conserved active site HisGlu pair residing on the same side of the macro-cycle was examined. Enzyme (pre-steady and steady state) kinetics, pKa calcula-tions and molecular dynamic simulations indicated that the conserved active site His is deprotonated and the protonation state of the conserved active site Glu is associated with the conformational state of ferrochelatase.

AUTHOR INDEX (cumulative)

AAbebayehu, Abeje 21Ahsen, Vefa 497Akhigbe, Joshua 265Albrieux, Florian 497Ali, Hasrat 61Almeida, Adelaide 331Alpugan, Serkan 497Anderson, Derrick R. 337Aribi, Fallia 497Ariga, Katsuhiko 213Arnaut, Luis G. 45Ascenzi, Paolo 134Atilla, Devrim 497

BBartolomeu, Maria 331Batteas, James D. 438Belviso, Sandra 223Bennis, Khalil 497Berget, Patrick E. 307Bezera de Souza, Tiago Gualberto

282Bhupathiraju, N. V. S. Dinesh K. 438Boitrel, Bernard 117Brckner, Christian 265Brunori, Maurizio 134Bykeksi, Sebile Isk 497

CCalvete, Mrio J.F. 45Cammarota, Francesca 223Cammidge, Andrew N. 204Cardoso, Mariana F. do C. 167Carminati, Daniela Maria 190Cavaleiro, Jos A.S. 167, 331Cha, Won-Young 407Chandra, Brijesh 429Chen, Minyuan 456Chen, Xi 397Chen, Yihui 490Cicero, Daniel O. 234, 465, 525Ciszewski, ukasz W. 76Coimbra, Snia 331Coletti, Alessia 421Commins, Patrick J. 213

Conte, Valeria 421Coutsolelos, Athanassios G. 534Craig, G. Wayne 1Cucca, Mlissa 497Cunha, ngela 150, 331

DDabrowski, Janusz M. 45da Silva, Fernando de C. 167DSouza, Francis 213De Boni, Leonardo 282Debrunner, Peter G. 254Dekkiche, Herv 292de Saja, Jos A. 413Drain, Charles Michael 438Ducki, Sylvie 497Dumoulin, Fabienne 497

EEsteves, Valdemar I. 150

FFang, Wenjuan 397Fang, Yuanyuan 456Faschinger, Felix 96Faustino, Maria A.F. 331Fernndez, Luca 150Ferreira, Gloria C. 556Ferreira, Vitor F. 167Fettinger, James C. 307Filatov, Mikhail A. 282Floris, Barbara 421Fontenot, Krystal R. 352Forezi, Luana da S. M. 167Fournier-dit-Chabert, Jrmie 497Fronczek, Frank R. 465Fukuzumi, Shunichi 35

GGallo, Emma 190Galloni, Pierluca 421Garca-Cabezn, Cristina 413Garca-Hernndez, Celia 413Gatto, Emanuela 234Gillam, Mallory E. 556Gong, Xianchang 438Gonzalez-Lucas, Daniel 204

Gorbunova, Yulia G. 505Gorski, Alexandr 367Gryko, Daniel T. 76Gryko, Dorota 76Guo, Rui 456Grek, Ayse Gl 497

HHahn, Uwe 378Hao, Erhong 444, 475He, Jing 397Henriques, Csar A. 45Hill, Jonathan P. 213Hunter, Gregory A. 556

IIkezaki, Akira 318Intrieri, Daniela 190

JJeandon, Christophe 292Jeon, Mansik 490Jiao, Lijuan 444, 475Jinadasa Waruna R. G. 542Jois, Seetharama D. 352

KKadish, Karl M. 456Karmazin, Lydia 292Kearns, Fiona L. 556Kerr, Lei L. 542Kessel, David 302Kikkawa, Yoshihiro 292Kim, Chulhong 490Kim, Dongho 407Knig, Michael 96Kostakoglu, Sinem Tuncel 497Krutler, Bernhard 388

LLabuta, Jan 213Ladomenou, Kalliopi 534Lalvani, Shashi B. 542Landrou, Georgios 534LeBlanc, Logan E. 352Lee, Chang-Hee 21Le Gac, Stphane 117


JPP Volume 20 - Numbers 14 - Pages 1569

Lelj, Francesco 223Lengo, Elisabetta 514Lentini, Sara 234, 465, 525Lesniewska, Barbara 367Li, Bihong 542Li, Chengjie 388Li, Tingting 475Li, Xiangzhi 397Liu, Wei 397Luan, Liqiang 397Luciano, Michael 265Lynch, Vincent M. 407

MMack, John 204, 505Managa, Muthumuni 204Martynov, Alexander G. 505Matsushita, Yoshitaka 213Mazzuca, Claudia 234Medforth, Craig J. 307Medina-Plaza, Cristina 413Mendona, Cleber Renato 282Milano, Domenico 514Mizutani, Tadashi 108Mkhize, Scebi 505Mondal, Navendu 429Mori, Hirotaka 245Mulugeta, Endale 21

NNakamura, Mikio 318Nam, Wonwoo 35Napoli, Benedetta Di 234Nardis, Sara 465, 525Nemykin, Victor N. 337Neves, Maria G.P.M.S. 167, 331Ni, Yuxing 397Nonell, Santi 378Nyokong, Tebello 204, 505

OOngarora, Benson G. 352Ooi, Shota 274Orzanowska, Grazyna 367Osati, Samira 61Osuka, Atsuhiro 245, 274Ou, Zhongping 456

PPalleschi, Antonio 234Panagiotopoulos, Athanassios A. 534

Panda, Pradeepta K. 429Pandey, Ravindra K. 490Paniagua, David 413Paolesse, Roberto 465, 525Passoni, Nicola 514Pereira, Mariette M. 45Pieiro, Marta 45Pinto, ngelo C. 167Pinto, Sara M. A. 45Pisano, Simone 514Plunkett, Shane 282Pomarico, Giuseppe 421, 465

RReith, Lorenz Michael 96Remiro-Buenamaana, Sonia 204Rhoda, Hannah M. 337Ricciardi, Giampaolo 525Rodrguez, Silvia 413Rodrguez-Mndez, Mara L. 413Rodrguez-Prez, Miguel A. 413Rosa, Angela 525Rossano, Rocco 223Ruiz-Gonzlez, Rubn 378Ruppert, Romain 292Rybicka-Jasinska, Katarzyna 76

SSabuzi, Federica 421Safo, Martin K. 254Safonova, Eugeniya A. 505Sareen, Divya 21Sathish Kumar, B. 429Scheidt, Robert W. 254Schmitz, Benjamin 542Schneider, Rudolf J. 150Schfberger, Wolfgang 96Senge, Mathias O. 282Serth-Guzzo, Judith A. 254Sessler, Jonathan L. 407Setaro, Francesca 378Shelnutt, John A. 307Singh, Kamaljit 21Smith, Kevin M. 307, 465Solntsev, Pavlo V. 337Song, Yang 456Srivatsan, Avinash 490Stefanelli, Manuela 465Sun, Jing 456

TTagliatesta, Pietro 234Tanaka, Takayuki 274Taskn, Gke Canan 497Tecilla, Paolo 514Tian, Minggang 397Tian, Zhonghua 475Tiravia, Martina 421Tom, Joo P.C. 150Tom, Vanessa A. 45Topkaya, Derya 497Torres, Toms 378Tshangana, Charmaine 204Tsivadze, Aslan Yu. 505Turowska-Tyrk, Ilona 254

Vvan Lier, Johan E. 61Vankayala, Sai Lakshmana

556Vecchi, Andrea 421Vey, Charlene 497Vicente, M. Graa H. 352Vinagreiro, Carolina S. 45Vivas, Marcelo Gonalves 282

WWalker, F. Ann 254Waluk, Jacek 367Wan, Albert 438Wang, Hong 542Wang, Yanfang 490Webre, Whitney A. 213Woodcock, Lee H. 556Wu, Qinghua 444, 475Wu, Yangchun 444

XXu, Chang 438

YYang, Mengxi 265Yang, Yang 397Yu, Changjiang 444, 475Yu, Xiaoqiang 397

ZZhang, Min 444Zhang, Zhan 407Zhou, Zehua 352


AA3-corroles 96ABC-corroles 96acid catalyst 421advanced oxidation processes 150anchoring group 542anion exchange 307apoptosis 302autophagy 302aza-BODIPY 61

Bbilirubin 388biosensor 413bismuth 117bisphthalocyanine 413BODIPY 61, 444, 475boron complex 407boron dipyrromethene 475bromination 213butano-substitution 456

C13C NMR 318carbazole 429cationic porphyrin 331CH amination 190CH insertion 76chalcone 497CHARMM 556chelatase 556chiral porphyrins 76chlorin analogs 265chlorins 265chlorophyll 388cis- and trans-A2B-corroles 96cobaloxime 534cobalt corroles 456cobyric acid 1conjugate 397contracted porphyrin 429corrnorsterone 1corrole 274, 465corrphycene 367cross coupling reactions 167crystal structure 213, 307cyanobromide 1

cyclic voltammetry 274, 542cycloadditions 167cyclobutenediones 167cyclo[m]pyridine[n]pyrrole 407cyclopropanation 76cyclopropenation 76cysteine 444

Ddendrimers 378density functional theory 337DFT calculations 525dimer 475dioxygen reduction 456dipyrrin 475direct and indirect effect 331docking 352donor/acceptor groups 282dyads 234dyes 444dye-sensitized solar cell 542dynamic processes 307

EEGFR 352electrochemistry 456electronic structure 318electron-transfer catalysis 35enaminoketone 292environmentally friendly processes 45enzyme 556Escherichia coli 331evolution 134excited state spectroscopy 282exocyclic double bond 21expanded porphyrin 245

Fferrocene 234ferrocenylporhyrins 421ferrochelatase 556fluorescence 388, 475fluorescence imaging 490fluorescence spectra 234fluorine 223fold 134functionalization 96

Ggenomic DNA 331germanium(IV) corrole 525globin 134gold nanoparticles 490

H1H NMR 318halogenation 465hemoglobin 134heterogeneous photocatalysis 150hexaphyrin 245history of chemistry 1homocysteine 444homogenous catalysis 190hybrid 245hydrogen bonding 367hydrogen production 534

Iionic liquids 45iron 556iron(III) 254iron phthalocyanine 337intramolecular charge transfer 429

Llead 117linear tetrapyrrole 108liquid-crystals 223low-spin 254lysosomes 302

Mmanganese porphyrins 318MCD 337MCD spectroscopy 204, 505mercury 117meso-alkylidenyl porphyrin 21mesomorphism 223metal complex 274, 421metalation 407metalloporphyrins 35, 534metal-mediated self-assembling 514metal-metal interaction 421metal-oxo complexes 35microporous 150microporous materials 45

KEYWORD INDEX (cumulative)


JPP Volume 20 - Numbers 14 - Pages 1569


microwave irradiation 45mitochondria 302, 397mixed ligand 254molecular dynamic simulations 556molecular electronics 108molecular structure 318molecular wire 245monocation 307morpholinochlorins 265myoglobin 134

NN-alkylation 213nanoparticles 150, 413near infrared 490NH tautomerism 307NIR absorbance 265NIR absorption 21NMR analysis 234NMR spectroscopy 307, 525non-aromatic 21nonplanar 307nonplanar porphyrin 318nuclearity 117nucleic acids 331

Ooptical spectroscopy 407organic nanoparticles 438organic photovoltaics 223organic pollutants 150ortho-quinone methides 167oxidation 108

P-extended porphyrins 542peptide 352phenol 413photoacoustic imaging 490photocatalysis 534photocatalytic oxidation 35photodynamic action 331photodynamic therapy 490, 497

photosensitization 378photosensitizer 302, 352, 497photothermal therapy 490phthalocyanines 150, 413, 497, 505phyllobilin 388picrate 307pKa 556porphyrazines 223porphyrin dimers 292, 514porphyrin isomers 367porphyrin metalation 556porphyrinoids 108, 292porphyrins 45, 150, 167, 190, 204,

245, 265, 282, 302, 307, 352, 438, 534, 556

positional isomers 337probe 397PropKa 556protoheme 134protoporphyrin IX 556prototropy 21pyridine 542pyridine-N-oxide 542

Qquantum yields 282quinones 167

Rradical cation 465relaxation times 282ruthenium 190ruthenium phthalocyanines 378

Ssinglet oxygen 204, 378solid state fluorescence 429solvatochromism 108solventless reactions 45Sonogashira coupling 292steroid conjugates 61structure 388subphthalocyanines 204

subporphyrin 429substituent effect 274supramolecular chemistry 438surface chemistry 438synergic bonding 254synthesis 514

Ttautomerism 21, 367TD-DFT calculations 204, 505tetraphenylporphyrin 213tetrapyrrole 556thallium 117theoretical 444time-dependent density functional

theory 337TiO2 150total synthesis 1trans-di-(4-pyridyl)porphyrin 514transition metal complex 388transmission electron microscopy

490triplet state 282two-photon 397

UUV-vis 337

Vvascular disruption 497vitamin B12 1voltammetric sensor 413

Wwater treatment 150Woodward-Hoffmann rules 1

XX-ray crystallography 337X-ray diffraction 117X-ray diffraction analysis 274

Zzinc 388


DOI: 10.1142/S1088424615500960

Published at http://www.worldscinet.com/jpp/

Copyright 2016 World Scientific Publishing Company

INTRODUCTION

B12 is not a vitamin, its a fraternity!

Fanny Rosenblum, 1958 [1]

From the endearing quote above [1] this article highlights some of the early career contributions to the total synthesis of vitamin B12 from Professors Ian Fleming (b. 1935), Subramania Ranganathan (b. 1934), Yoshito Kishi (b. 1937), Jean-Marie Lehn (b. 1939), D. John Faulkner (19422002), Roald Hoffmann (b. 1937), Albert Eschenmoser (b. 1925) and Kevin M. Smith (b. 1942).1

I. EARLY VITAMIN B12 MILESTONES

From 19181926, George R. Minot (18851950), William P. Murphy (18921987), and George H. Whipple (19061976) determined that the fatal disease, pernicious anemia was reversible by dietary treatments with whole liver. Karl Folkers (19061997) at Merck and E. Lester Smith (19041992) at Glaxo independently isolated CN-cobalamin (Fig. 1) from liver tissue [2] in 1948 and between 19501957, Alexander R. Todd (19071997) and then postdoctorant, Alan W. Johnson (19171982)

could show by degradation studies that CN-cobalamin (Fig. 1a) contained four pyrrolidine rings, two of which were connected without an intervening carbon-bridge [3].

In 1956, Dorothy Hodgkin (19101994) solved the X-ray crystallographic structure by application of the heavy-metal effect to the cobyrinate c-lactam (Fig. 3) [4], a product which had unexpectedly crystallized from hydrolytic experiments [3, 5]. Analyses of vitamin B12-degradation samples of cobyric acid (i.e. the amino-phosphate-ribose-benzimidazole or alpha-loop replaced with OH in Fig. 1) verifed the presence of the corrin ring and nine stereocenters [2, 4] for which Hodgkin received the 1964 Nobel Prize for her determinations by X-ray techniques of the structures of important biochemical substances [6]. In 1958, Horace Barker (19072000) demonstrated that the biologically active coenzyme-B12 contained an adenosyl ligand (Fig. 1b) linked through a covalent carboncobalt bond. This hinted that the biologically active CN-cobalamin (Fig. 1) might have been an artifact produced by the cyanide-containing charcoal used in the early isolation procedure [7].

II. SYNTHETIC STRATEGIES TO THE B12 SYSTEM

Kevin M. Smith recalled a lecture before the Depart-ment of Chemistry, University of Liverpool 19641967

Total synthesis of vitamin B12 a fellowship of the ring

G. Wayne Craig*

Lead Finding Chemistry, Syncoba GmbH, Brachmattstrasse 4A, CH-4144 Arlesheim, Switzerland

Dedicated to Professor Kevin M. Smith to celebrate his 50-year career in porphyrin chemistry

Received 4 September 2015Accepted 8 October 2015

ABSTRACT: In the synthesis of cobyric acid following an arduous 60-step synthesis of the tetrapyrrole corrigenolide, Woodward demonstrated that ring cyclization yielded unexpectedly the corrin cyclic ether (Fig. 2). Its structure was chosen as the chemistry logo for the 1970 IUPAC meeting. It was a reminder that chemistry can be capricious and beautiful. This article is a tribute to the 50-year career in porphyrins of Professor Kevin M. Smith and describes his early contributions with colleagues in the synthetic quest of a related porphyrin molecule, vitamin B12 (Fig. 1a).

KEYWORDS: history of chemistry, total synthesis, vitamin B12, cobyric acid, corrnorsterone, cyanobromide, Woodward-Hoffmann rules.

SPP full member in good standing

*Correspondence to: G. Wayne Craig, email: [email protected]

Copyright 2016 World Scientific Publishing Company J. Porphyrins Phthalocyanines 2016; 20: 220

2 G. W. CRAIG

in which Johnson presented his early corrole synthesis (Scheme 1) [8]. Johnson remarked that when they heated the a,c-biladiene 7 with nickel and cobalt salts, it gave the desired corrole 8 but copper salts gave typically porphyrins 9, which he amusingly quipped, whenever

we end up with a porphyrin we throw it away [9]! Smith and mentor, George W. Kenner (19221978) must have been speechless because they were struggling with several other stepwise strategies to synthesize a wide variety of porphyrins. However, this new copper method evolved into a virtual goldmine for the stepwise synthesis of porphyrins, particularly unsymmetrical ones [9]. In retrospect, Johnsons strategy was a successful route to the parent planar corrole ring 8 but unsuitable for the synthesis of the desired non-planar B12 corrin system.

Fig. 1. (a) Cyanocobalamin, R = CN. (b) Coenzyme B12

Fig. 2. 1970 IUPAC logo

Scheme 1. Synthesis of corrole 8 versus porphyrin 9

Fig. 3. Hexa acid cobyrinate c-lactam


TOTAL SYNTHESIS OF VITAMIN B12 A FELLOWSHIP OF THE RING 3

The nonplanarity and its curtailed double-bond system of corrin 12 contrasted with the corrole 8 system which made this a challenging synthetic problem. But already underway in 1959, a young Swiss chemist, Albert Eschenmoser (b. 1925) developed a stepwise synthesis of a model corrin ring 12 which used imidoester chemistry to stitch the west and east halves 10 together (Scheme 2) [10]. This exciting development caught the attention of Woodward who had just completed the total synthesis of a less formidable but related chlorin tetrapyrrole containing just three stereocenters, chlorophyll-a (Fig. 4).

This early photograph of Eschenmoser (in back-ground) with chemistry doctorants (Photo 3) recorded that he aspired in stitching, well before he developed his intramolecular stitching-strategy which profited from the long sulfur-carbon bond to accomodate carbon-carbon-fusion of sterically hindered fragments later encountered on the path to the natural B12 ring [11].

In 1960, Wilhelm Friedrich and Konrad Bern-hauer announced a partial synthesis of CN-cobalamin by reconnection of the -loop (Fig. 1) onto cobyric acid [12].

III. THE MYTHICAL ROADMAPS TO VITAMIN B12

The chemists roadmaps outlined the total synthesis of vitamin B12 and the synthetic steps used to exploit the camphor stereochemistry. In reality, however an actual foreseen roadmap did not exist. Remember the chronological development of the sulfur-extrusion chemistry for the natural corrin system was not yet proven nor thought to be needed and the A/D-route became an early goal to streamline the convergency of the total synthesis but well after the B12 project had progressed two years. How can a retrosynthetic approach take these unforseen events into account? Indeed, these roadmaps designate simply where a selection of dedicated chemists made synthetic contributions to achieve vitamin B12 discussed in this article (Scheme 3).

IV. THE RELAY STRATEGY TO A-, B-, C-RINGS FROM (+)- AND TO D-RING FROM (-)-CAMPHOR

The 1960 initiation of Eschenmosers corrin east-west strategy preempted Woodwards strategic synthesis of the vitamin B12 west fragment which contained

Photo 3. (L to R) Jakob Schreiber (19211991), Rolf Schurter (b. 1938), Albert Eschenmoser and Jakob Meier (b. 1932) ca. 1957. Photograph by D. Felix, courtesy R. Schurter

Scheme 2. The East-West synthesis of the corrin ring

Fig. 4. Chlorophyll-a


4 G. W. CRAIG

six-contiguous stereocenters (Photo 4). An excellent chemical synopsis has been described by Nicolaou and Sorensen [13]. In 1962 the future Nobel Laureate recipient, John C. Cornforth (19172013) had noted that the (+)-camphor degradation product 17 contained identical structural elements in the C-ring of B12 [14, 15]. However, it was Woodwards genius to orchestrate the complex syntheses from natures own building blocks the chiral intermedi ates needed in the west fragment (Scheme 4) [16, 17].3 A key refinement by Eschenmosers A/D-approach went one step further and enabled all pyrrolidine A-, B-, C- and D-rings to be synthesized from a single racemate obtained by Woodwards favorite reaction, the DielsAlder!

Accounts of Woodwards synthetic transformations of camphor to pyrrolidine intermediates and partial synthesis of vitamin B12 from cobyric acid have been recently described by Babu and Ranganathan which also reveal an intimate perspective of Woodwards chemistry and personality [17, 18].

1. The synthesis of the D-ring from (-)-camphor

In 1963, two postdoctoral chemists were enlisted to investigate this strategy toward the synthesis of the

Scheme 3. The Harvard-ETH chemists mythical roadmaps to vitamin B12

Scheme 4. Correlation of A-, B-, C-rings with (+)-18 and D-ring with (-)-18-camphor

Photo 4. Robert Burns Woodward and Albert Eschenmoser, March 5, 1979. Photograph courtesy J. Seeman, USA



west fragment (Scheme 5) [19]. The European arrivals, Jean-Marie Lehn (Photo 5) and Ian Fleming (Photo 6) were given a personal Woodward overview of the B12 project and both were assigned to prepare 100 grams of the D-ring 15 by their own choice of reaction conditions [20]. Woodwards blackboard update lasted five hours in the course of two days! John Carnduff from Glasgow had already begun the degradation chemistry and arrived first with enantiomerically pure 15 but with only a few milligrams [20]. However, Fleming fondly recalled that he arrived, before Lehn with his required 100 grams, although Lehn had the better yield and with fewer steps [20]. Lehn recalled:

I was involved with some other activities, like following a quantum mechanics

course with John Baldeschwieler (then assistant professor and later at Caltech), doing nitrogen-14 NMR measurements on Baldeschwielers spectrometer, learning to use the IBM-1620 and doing calculations with Roald Hoffmann (a very good friend of mine at the time just after his Ph.D. with Lipscomb). As a consequence, I was running behind Ian [Fleming] in my synthetic efforts [21].

Following his postdoctoral studies, Lehn returned to Strasburg and over many years advanced the development of supramolecular chemistry. He was recognized with Donald J. Cram (19192001) and Charles J. Pedersen (19041989) for their development and use of molecules with structure-specific interactions of high selectivity with the award of the Nobel Prize in 1987.

2. The synthesis of the pentacyclenone

However, Flemings proficiency was rewarded with another challenging task, the synthesis of the A-ring tricycle 30 from 3-methyl indole (Scheme 6, 27) [18, 19]. This reaction sequence became one of the first examples of a beautifully stereocontrolled synthesis.4

Instead of painstakingly resolving the racemate, Fleming reacted the racemic (+/-)-tricyclic amine 30 with the chiral monocyclic acid chloride 15a, followed by base cyclization to yield a pair of (+/-)-trans-diastereomers (Scheme 6, 32) which were separated by column chromatography [1820].5 During an unannounced visit in the early afternoon, Woodward inquired about the two oily gums Fleming had isolated. Woodward scratched one of them for ca. 30 minutes with a glass rod before he remarked to Fleming, scratch it until it crystallizes Fleming reiterated if your chief was Woodward, then you followed his requests without hesitation [20]. Fleming scratched them for the rest of that evening not leaving until each diastereomer had crystallized [22]! Woodward returned to discover the beautiful crystals drying on Flemings lab-bench the next day!

After his arrival at Cambridge, Fleming made pioneering contributions to the development of organosilicon chemistry and its utilization in synthetic

Photo 5. Jean-Marie Lehn in the Harvard laboratory, 1964. Photograph courtesy J-M. Lehn, France

Scheme 5. Synthesis of the D-ring 15


6 G. W. CRAIG

strategies. His internationally published textbook, Frontier Orbitals and Organic Chemical Reactions clarified the theoretical application of frontier orbital symmetry and demystified the bane of stereochemistry in pericyclic reactions [23].

3. The WoodwardHoffmann [WH] rules

In 1962 prior to Flemings arrival, Subramania Ranganathan (Photo 7) had investigated the ClaisenCope rearrangement, an early variation to access the crucial trans-pentacyclenone 38 from 36. However, it was never incorporated into the total synthesis because it gave unexpected results that Woodward found exceedingly difficult to reconcile (Scheme 7) [24, 25]. In retrospect, this subtle hint from nature led him to a completely new perspective to understand reactions. The literature precedent had convinced Woodward that the (H/Me)-trans-pentacyclenone 38 must be the preferred ring-closure product and not the (H/Me)-cis-pentacyclenone 37 which was obtained with minor epimeric starting material 39.6 Ultraviolet (UV) irradiation further demonstrated that the ring-closure products stereospecifically opened to reform the reactants but in an entirely opposite stereochemical sense i.e. 36 from 38 and 39 from 37. Woodwards adamant rejection of these unprecedented results led to

the eventual recognition of the orbital symmetry rules. Ranganathan recalled how the crucial experiment was planned:

When I had ca. 100 mg of precursor, I informed RBW [Woodward] that we are ready for the cyclization reaction. This was around 5:30 PM. RBW generally sees no one at this time, but now he immediately called me in and to my surprise instructed how the first cyclization should be done. He personally drew the following picture.

He said, seal the end of the dropper, introduce few milligrams of precursor, (seal the) tube and heat it ca. 170 C in an oil bath and take the UV. I reported to RBW that the UV clearly showed cyclization had indeed taken place! The next morning I showed him a clear NMR which showed that he had a mixture! RBW was absolutely taken back, called for all the spectra, rubbed off my mark-ups and did it himself. No change.

Photo 6. Ian Fleming. Photograph by M. Bernard, courtesy I. Fleming, UK

Scheme 6. Synthesis of the pentacycle 32

Photo 7. Subramania Ranganathan. Photograph courtesy S. Ranganathan, India



It took one year but it revealed the crux of WH rules. I did point out to RBW a note from Oosterhoff (Tetrahedron, ca. 1958) of the possibility of interaction of occupied and unoccupied orbitals in chemical reactions! His [RBWs] foresight should have been rewarded [26a]!

These unexpected results did not dissuade Woodward from a personal repetition of Ranganathans own experiment! It was rather rare for a professor to carryout any experiment personally. In the final analysis, with Roald Hoffmanns comprehensive knowledge of quantum theory and Woodwards prophetic algebraic insight [25], they were able to communicate a new concept, the conservation of orbital symmetry, which completely altered the worldview of chemical reactions [27, 28].

In 1964, Ranganathan left Harvard to the Woodward Research Institute established by Ciba AG, Basel, Switzerland [26b]. His impressive research contributed to additional Woodwardian milestones such as the synthesis of cephalosporin, novel penem and -lactam analogs [29]. He was later appointed professor at the Indian Institute of Chemical Technology in Hyderabad.

By 1965, Woodward with Roald Hoffmann (Photo 8), a Harvard Junior Fellow, had resolved how to reconcile the experimental chemistry based on the (+) or (-) symmetry sign of the orbital and its bond-interactions in the highest occupied molecular orbital (HOMO). The WH formulation of the symmetry rules predicted that to

preserve orbital symmetry in a 4n + 2 -electron system, under thermal conditions (groundstate), the HOMO plane of symmetry required bond formation by a disrotatory motion of orbitals. However, under UV-conditions (excited state) the HOMO C2-rotation axis of symmetry required ring-opening by a conrotatory motion of orbitals (Scheme 7) [30].

In addition to his contribution to the WH rules, a wonderful reward from the vitamin B12 total synthe-sis, Hoffmann became an accomplished poet, play-writer and coauthored with steroid chemist-writer, Carl

Scheme 7. The Ranganathan dilemma in the Claisen-Cope reaction results

Photo 8. Roald Hoffmann ca. 1966. Photograph courtesy, R. Hoffmann, USA


8 G. W. CRAIG

Djerassi (19232015), the theatre play, Oxygen. In connection to writing, Hoffmann noted in an interview, With Woodward, writing was much more difficult. The language mattered to him (RBW) and he wrote in excruciating detail [31]. In 1981, Hoffmann and Kenichi Fukui (19181998 received the Nobel prize for their theories, developed independently, concerning the course of chemical reactions. However, an honorary chair remained tacitly reserved in-spirit forever for the Nobel laureate Woodward.

4. Synthesis of corrnorsterone

In RBWs Harvard notes (Photo 9/10, redrawn) [32a] from 19651967 Woodward assigned an international team of postdoctoral chemists. Among them, Heinz Gschwend (Switzerland), Ivan Ernest (Czechoslovakia), Ernest Hamanaka (Canada), Yoshito Kishi (Japan), and Alexander Wick (Switzerland) advanced various tricyclic intermediates 3032 en route to the - and -corrnorsterone stage.7

The synthesis of corrnorsterone 40 gave the undesired -C3-configuration 40. Fortunately, base-equilibration of - and -C3-configuration (1:15) favored the trans- over the cis-juxtaposition of acetate/propionate residues in the opened-lactam 41. Subsequent epimerization of -C3- to the desired -C3-configuration (Scheme 8), acidification and carboxyl methylation trapped essentially the desired epimer which cyclized to the -corrnorsterone 40. A typical Woodwardian hallmark involved following the reaction progress by monitor of the UV absorption change

of the carbonyl bond (Photo 10). Chemistry historian, Leo Slater noted that instrumental measurement of the spectral properties of molecules and analysis by the Woodward UV-rules became a standard philosophy to understand the chemical reaction [33].

5. Synthesis of cyanobromide

From 1967 to 1969, Kevin M. Smith (Photo 11), Edward D. Brown and Kenneth Richardson [34] were assigned to optimize transformation of -corrnorsterone 40 to cyanobromide (Scheme 9, 47) [34]. Lactam ring-opening and formation of the vinylogous thioester 42 from 40 were accomplished quantitatively. Subsequent ozonolysis of 42 at low temperature gave 100% regioselectivity to the ring-opened thioester-aldehyde (R = Ph, 43). Other sulfur-substituents (R = Me, Et, tBu or Bn) gave partially oxidized mixtures. Liquid ammonia treatment of thioester 43 followed by borohydride reduction gave quantitatively the desired amide-alcohol 45. Usage of methane sulfonyl anhydride led to dehydration of the amide group to a nitrile with concomitant formation of mesylate 46. Routine bromide SN2 substitution in nonpolar solvent gave a quantitative yield of the west-fragment cyanobromide 47 [35].

Despite the development of the highly efficient multi-step sequence, Smith experienced a moment of exasperation when Woodward arrived in the laboratory. Woodward, a crystal connoisseur, was immediately attracted to the beautiful colorless crystals that Smith had just isolated from the cyanobromide synthesis. While focusing his

Photo 9. RBWs notes-1 outlines the synthesis of the west fragment, cyanobromide 47 from corrnorsterone 40. Photograph courtesy KMS archive, M.G.H. Vicente, USA



magnifying-lens on a crystal, Woodward exclaimed, its amazing how similar the crystals of cyanobromide 47 compare to sodium sulfate! Remember, cyanobromide 47 was a colorless unconjugated corrin precursor. Smith

was taken back and promptly vanished from the laboratory, thinking he had isolated sodium sulfate crystals. The next day, Dodie, Woodwards secretary, summoned Smith to Woodwards office. While waiting, Smith pondered

Photo 10. RBWs notes-2 outlines the tricycle synthesis 30. Photograph courtesy KMS archive, M.G.H. Vicente, USA

Scheme 8. Epimerization of - to -corrnorsterone 40


10 G. W. CRAIG

whether he was to be reprimanded or even sent home for his egregious error. When Smith entered the office, Woodward greeted him immediately with a request for 100-grams of the crystalline cyanobromide 47 which indeed had the correct structure [36a]8!

After his return to Liverpool in 1969 as Lecturer, Smith moved to the University of California, Davis in 1977 where he was appointed Professor of Chemistry. From 1996 until 2001 he served as Vice-Chancellor of Research. In 2001 he was appointed Vice-Chancellor and Dean of the Graduate School at Louisiana State University. His prolific research made advanced contributions to the knowledge of the complex structures and properties of the bacteriochlorophylls-c, -d, and -e, elucidation of the biosynthesis of tetrapyrrole pigments, synthesis of novel porphyrins, and their usage for

understanding biological systems and their applications in photodynamic therapy [37].

6. The synthesis of the C-ring from (+)-camphor

While Woodward was lecturing in Europe, D. John Faulkner (Photo 12) completed the synthesis of the C-ring 17 by the degradation route from (+)-camphorquinone (Scheme 10, 49), based on early work by Cornforth [14, 15, 27].9 Alternatively, Eschenmosers group transformed the B-ring 53 into the thioamide of the C-ring 57 which improved the overall convergent strategy. Both B- and C-rings were then fused together to thiodextrolin 58 using the sulfur-extrusion chemistry [38]. Faulkner continued his passion for natural products research at the Scripps Institute of Oceanography where he became a resolute authority on marine natural products by the

Photo 11. Kevin M. Smith 2014. Photograph courtesy K.M. Smith, USA

Scheme 9. Synthesis of the west-fragment, cyanobromide 47

Photo 12. D. John Faulkner. Photograph courtesy Scripps Institute of Oceanography, USA



active discovery and chemical identification of many complex secondary metabolites particularly from marine sponges [39].

7. Fusion of the west and east fragments

The arduous task to fuse both east and west fragments fell to Woodwards future Harvard successor, Yoshito Kishi (Photo 13). The usage of Eschenmosers sulfur-extrusion method gave intermediate thioethers (type IIII isomers) from which neither type-I nor type-III were very stable. The predominant isomeric type-II

underwent sulfur extrusion but with mediocre yields (Scheme 11). Often, the unpredictable behavior of these thioethers required prior-metal chelation to assist sulfur-extrusion to form the desired CC-bond and stabilize the product [24, 38]. In 1971, Woodward confided in reference to the reactive instability of these thioether isomers, so variable in fact were our experiences that the occasionally successful practioner was regarded by his frustrated colleagues as quite as much a wizard as a scientist [24, 38].10

The problem concerned the allylic centers on the corrin-backbone periphery which were extremely prone to epimerization (Scheme 11, red circles). Microscale-reactions made tedious deoxygenation and anhydrous conditions near-impossible tasks to achieve. Despite these obstacles, the achievement of the corrigenolide (Scheme 11, 59a) was in Woodwards words, striking testimony of the experimental skill of its discoverer, Dr. Yoshito Kishi. All of the operations had to be conducted with every conceivable precaution in respect to purity of reagents, exclusion of oxygen and moisture, and with the greatest possible speed [35].11

During their overlapping year together, Smith and Kishi also shared a laboratory at Harvard. Smith related a story about Woodwards many laboratory visits to discuss with Kishi the next crucial molecule to be synthesized. Certainly, the en route series of strategic steps were highly complex and unforseeable even for the experienced postdoctorate. However, after Woodward left the laboratory, Kishi would quietly saunter over to his desk and open the drawer to reveal the discussed molecule which he had already taken the inititative to

Scheme 10. Synthesis of the C-ring 17 and sulfur analog 57

Photo 13. Yoshito Kishi, 2003. Photograph courtesy Yu, Wikimedia Commons.


12 G. W. CRAIG

synthesize. Smith never asked Kishi how many further intermediates were already awaiting Woodwards next visit [36b]!

In 1979, following Woodwards unexpected death, Kishi, then Professor of Chemistry at Harvard, assumed temporarily the reins of Woodwards research group to complete the ongoing synthesis of the macrocyclic lactone, erythromycin. In his career, Kishi went on to achieve a number of impressive total syntheses of exceedingly complex molecules. His chemistry has been typically described as breathtaking in design and ingenious in analysis [40]. His total synthesis of the polyether antibiotic, monensin and the daunting marine natural product, palytoxin containing 64-stereocenters still boggle the mind!

8. The total synthesis of cobyric acid

Following fusion of the west and east fragments, B-ring C8-lactonization functioned as an intramolecular shield to protect the C10-bridge and permitted a selective thiobenzylation-reduction sequence of the north-south C5/C15-bridge carbons (Scheme 12) to render the dimethylated corrin, cobyrinate f-amide 64.

The final steps to cobyric acid 66 were performed by Elmar Konz and Romeo Paioni (19422012) (Photo 14). The f-nitrile 63 was transformed by conversion to the corresponding amide 64 with cold sulfuric acid. Instead of the unselective hydrolytic conditions that also cleaved esters, the conversion of the primary amide 64 to carboxylic acid 66 was achieved by a nitrosation approach. At Harvard, Konz carried out the amide

nitrosation with dinitrogen tetroxide (NaOAc catalysis in CCl4) to produce yields in the 70100% range (Scheme 12) [41, 42]. However, his many attempts were sporadic and gave additionally C10-meso nitrosation as a competitive by-product. Sodium acetate assisted the transfer of the presumed nitrosoamine group formed from the amide (Scheme 13, 64).12

The non-trivial amidation of the six ester groups required a precise ratio of NH3-NH4Cl in a protic solvent with stringent deoxygenation of solvent and gas atmosphere to obtain cobyric acid 66. Usage of ethylene glycol as solvent minimized C13-epimerization side-products (Scheme 12) [42].13 The unnatural -C13-propionate or -epimer of cobyric acid which formed

Scheme 11. Synthesis of bis-norcobyrinic heptamethyl f-nitrile 60

Photo 14. Romeo Paioni. Photograph by J. Barratt, courtesy Novartis Archive, Switzerland



required intensive work to separate from the desired stereoisomer of cobyric acid 66 using rudimentary high pressure liquid chromatography (HPLC)14.

Following his postdoctorate, Paioni returned to Switzerland and began his industrial career at Ciba-Geigy AG where he was later appointed Head of Novartis Preclinical Development and Project Management, Basel in 1996 [41].

In 1975, Mark Wuonola repeated the Bernhauer partial synthesis [12] to complete the total synthesis of vitamin B12 (Fig. 1) but using totally-synthetic cobyric acid 66.

9. The new road A/D-synthesis of vitamin B12

Eschenmosers contributions to the A/B-synthesis of vitamin B12 were immeasurable. Through his exceptional chemical rationale, intuitive sense of nature, and his dynamic interaction with Woodward, he influenced all aspects of the total synthesis of vitamin B12 [42]. By the A/D-strategy for ring closure, Eschenmoser was able to vastly improve the synthetic convergence for each pyrrolidine ring originating from a single racemate. More attractive, the synthesis of the A/D-secocorrin 59

Scheme 12. Synthesis of cobyric acid 66

Scheme 13. The hypothetical nitrosative hydrolysis of f-amide 64


14 G. W. CRAIG

set the stage for a test of the newly discovered WH rules which predicted an allowed stereospecific ring-closure under excited state conditions but with two possible trans-C1/C19-configurations from an A/D-secocorrin 59. Although the product results did not rule-out a competing unconcerted ring-closure mechanism, the results were entirely consistent with the prediction of the WH rules.

Photochemical conrotatory ring-closure gave a 95% preference to corrin intermediate (Scheme 14, 60) containing the identical trans-configuration found in natural cobyric acid (Scheme 12, 66) [43, 44]. At first-glance, this presumed Darwinism must be considered coincidental. In fact, nature choreographs a completely different process to expel the original C20-meso-bridge as a CH3CO2H or CH3CHO group (aerobic or anaerobic pathway respectively) from uroporphrinogen-III 70 to obtain the natural trans-C1/C19-configuration [45]. Nature seemingly takes a multi-step pathway to methylate, oxidize, rearrange and then expel the C20-meso-bridge as a C2-unit rather than a direct transformation of the C20-bridge into the C1-methyl group, proven later to arrive

by enzymatic methylation by S-adenosylmethionine Scheme 15 [45]!

However, nature acts with a chemists mind by its choice of a single pyrrole building block, porphobilinogen 69, for sequential polymerization to produce the first closed-tetrapyrrole, uroporphrinogen-III 70 [45]. In this biomimetic sense, Eschenmoser streamlined the A/D-strategy such that each of the stereochemically rich A-, B-, C- and D-pyrrolidine rings were synthesized from racemic (+/-)-dilactone, a common DielsAlder building block and in-turn, each ring was stitched together by his powerful sulfur-extrusion chemistry. Overall, Eschenmosers aesthetic convergent A/D-strategy required fewer synthetic steps and gave a higher overall yield of bis-norcobyrinic hexamethyl f-nitrile 63 than the original A/B-strategy.

In his humorous but self-confident style, Eschenmoser signed Professor Nozoes autograph book alluding to the secret of the A/D-strategy, Never ask about the overall yield (Photo 15) [46]! It was a rather modest statement about a colossal crusade which involved more than 16 years, over 80 steps, 100 chemists, supported the WH

Scheme 14. Eschenmosers A/D-strategy to bis-norcobyrinic heptamethyl f-nitrile 60

Scheme 15. Biosynthesis of the corrin ring 71 from urogen-III 70. For clarity the N to metal chelation is not shown



rule for 16--electron systems and inspired fascinating new thoughts about the biosynthesis of vitamin B12! Today, Eschenmosers research explores these fundamental ideas in an electrifying journey to demystify chemical evolution, biogenesis and the origin of life [47].

V. PRE-FOURIER TRANSFORM (FT) INSTRUMENTATION IN TOTAL SYNTHESIS

Although, the complexity of the vitamin B12 structure alone was a formidable synthetic goal, its total synthesis attained a mythological status because it was success-fully completed before modern fourier-transform (FT) development of analytical instruments [33]. Nowadays common FT-instrumentation permits very minute quantities for precise atom-by-atom NMR-analysis. Ranganathan recalled often the conditions under which many chemists in those days performed reactions:

When I see those NMR taken in a 60-MHz instrument with 35 mg today, I am still

amazed at their clarity. We used tricks: raising and lowering the tube in the NMR well to maximize signals or usage of narrow bore ground NMR tubes (gave sharper peaks) but were difficult to clean so we threw them away. Dodie (RBWs secretary) was not happy (about the expensive NMR tubes) but RBW did not seem to mind. In these times, UV needed > 1 mg, IR ca. 3 mg and NMR ca. 5 mg! I never had more than ca. 10 mg of final samples. To please RBW our spectra needed to be top class and our products 100% pure. All samples for CHN-analysis were sent through RBWs office to Sweden and the results came directly to him! If the results were good he would come in and chat with you. If they were not he simply used to place them on our desk and walk away [26b].

VI. HALLMARK OF THE VITAMIN B12 SYNTHESIS

A daily reminder of the aesthetic reward of synthetic chemistry was symbolized in the photograph of the beautiful crystals, natural and synthetic vitamin B12, hanging in Smiths office (Photo 16) [32b]. It was an award of distinction to each chemist who had contributed to the monumental synthesis of vitamin B12. The total synthesis of vitamin B12 was the ultimate achievement in synthetic chemistry and still represents the highest standard today.

CONCLUSIONS

The completion of the WoodwardEschenmoser total synthesis of vitamin B12 remains an unparalleled achievement! By the late fifties vitamin B12 stood as the most complex natural product not yet achieved by total

Photo 15. Eschenmosers signature in Nozoes autograph book, April 4, 1964. Photograph courtesy, the Nozoe family

Photo 16. The Prize, vitamin B12 crystals. Photograph courtesy KMS Archive, M.G.H. Vicente, USA


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synthesis except for strychnine which was synthesized by Woodward in 1954 [48]. Ranganathan noted that, Woodward having already traveled the synthetic guantlet with ever increasing stereochemical complexity could have felt that the synthesis of vitamin B12 was forced on him [18, 49]. Certainly, this synthesis was recognized by most chemists as a near impossible if not unthinkable summit to attempt, but that was where Woodward thrived. He relished every moment of the ascent to vitamin B12 all the more because he had already conquered almost all the other mountain peaks first!

Woodward had an amazing prowess to envisage reaction mechanisms, their application to his synthetic programs and their salient connection to natures usage in biochemical reactions and biosynthesis of its own building blocks [50, 51]. Seeman superbly makes the

convincing case that Woodward was also an outstanding physical organic chemist [52]. Seemans perspective emphasizes that Woodwards superhuman abilities as a synthetic chemist had overshadowed RBWs outstanding insights in physical organic chemistry!

During an investigation of Woodwards 1950 total synthesis of a steroid, a historical photograph from the Natural Products Conference in Greynog, Wales (Photo 17) was discovered in the Novartis Archive. It captured the essence of the epic quest from Tolkien [53]. A few chemists such as Professors Jean-Marie Lehn, Alan R. Battersby (b. 1925), Albert Eschenmoser, Kevin M. Smith and Duilio Arigoni (b. 1928) are clearly identified whose careers were either historically involved in the total synthesis of vitamin B12 or inextractably connected to the elucidation of its biosynthesis. This historic conference is

Photo 17. The Natural Products Conference in Greynog, Wales 1971. (L to R) Row 1. Identified are Professors J-M. Lehn, A. R. Battersby, A. Eschenmoser and G. W. Kenner Row 2. Professors J. Knowles, K.M. Smith Row 3. Professor D. Arigoni. Photograph courtesy Novartis Archive, Switzerland

Photo 18. A fellowship of the porphyrin ring with Smiths /-chemists: Row 1. lying front, -Mike, kneeling (L to R) Professor -Graca H. Vicente and G. Wayne Craig. Row 2. (L to R) Professors Young Key Shim, Usha Pande, Kevin M. Smith, Lola Berber-Jimenez, Medin Isaac-Lam and Ravindra K. Pandey, ICPP 2014, Istanbul. Photograph courtesy M. Isaac-Lam



Photo 19. Kevin M. Smith, with his cornerstone, Mike. Photograph courtesy M.G.H. Vicente, USA

a reminder of the many years of natural products research these dedicated chemists have served to discover how nature creates complex molecules.

It remains a humbling experience to compare the years of synthesis which chemists require to the mere minutes or hours that nature requires to create any complex molecule. These sorts of questions infuse the spirit with exuberance to investigate these secrets which lie hidden around the next corner! Chemists and colleagues salute all of them for their historic endeavours in their fellowship of the ring and for their relentless dedication in the total synthesis of vitamin B12!

We take pause to congratulate Kevin M. Smith, chemist, mentor, professor, chancellor, husband, and father. There are moments when the chemistry must always work and the secret in his chemistry lies in which - or -form works the best, Mike or Graca (Photo 18). The chemistry community celebrates with Kevin M. Smith his 50-years of fabulous porphyrin research, shown here with his cornerstone, Mike (Photo 19). From your family, friends and colleagues, forever stay young!

Acknowledgements

It is my distinct pleasure to thank Professors Ian Fleming, Roald Hoffmann, Yoshito Kishi, Jean-Marie Lehn, Subramania Ranganathan and Kevin M. Smith for their permissions to reproduce their photographs and describe some of their personal Woodward reminiscences while they undertook B12 research at Harvard. In particular, I am grateful to Professor Ranganathan for his private thoughts during his experience in the Woodwardian era. It is a special honor to thank Professor Albert Eschenmoser for reading a version of this manuscript and for his meticulous clarification of salient points concerned with the factual history of the B12 syntheses. It was a pleasure to read a galley preprint of his Introductory Remarks

on the Publication Series, Corrin Syntheses, Parts IVI, in-press, Helvetica Chimica Acta. Additional thanks to Professor M. Graca H. Vicente who kindly provided photographs of RBWs Harvard notes and vitamin B12 crystals from the Kevin M. Smith personal archive.

Thanks to Professor Jeffrey Seeman for permission to reproduce his photograph of Woodward and Eschenmoser. I owe him lasting gratitude for obtaining special permission on my behalf to reproduce one of Eschenmosers autographs found in the Tetsuo Nozoe historical collection. I gratefully acknowledge Drs. Walter Dettwiler and Philipp Hafner for permission to reproduce photographs and information from the Novartis Archive. Lastly, my sincere appreciation is extended to Drs. Andrew J. F. Edmunds and Andre Jeanguenat for stimulating discussions and meticulous proofreading versions of this article before submission.

Above all, it is a pleasure to give honorable mention to the many chemists, not described in this article, but in-part acknowledged by Professors Woodward and Eschenmoser in their individual publications concerning the total synthesis of vitamin B12 and the early ETH corrin model studies so vital to its iminent success. A supplementary list of chemists was gleaned from the 2014 ACS presentation in San Francisco by ETH emeritus Professor Englebert Zass [34] and personal communication from ETH emeritus Professor Albert Eschenmoser [54].

Chemists that contributed to the two A/B- or A/D-total syntheses of vitamin B12 include David Hewitt, Ciril Schmidt, Ernest Hamanaka, Hans Reich, Pierre Deslongchamps, Daniel Berney, Fernando Duran, Ivan Ernest, Elmar Konz, Fritz Eckstein, Johannes Kech, Volker Jger, Werner Lenk, Wolfgang Trommer, Vasudewan Nair, Erno Mohacsi, Braham


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Shroot, Dinanth Rane, Koppaka V. Rao, Padmanathan Balaram, Tikal C. Jain, Brian McMurry, Dan Becker, Errol Lewars, Hiroyuki Nohirya, Kenichi Hirao, Satoshi Ushioda, Yoshiaki Kobuke, Helmut Hamberger, Kraft Hohenlohe, Chiu-Ming Wong, Chung-Yuan Chen, Tak-Hang (Bill) Chan, Yang-I Lin, Charles Moppett, David Dolphin, Edward D. Brown, Geoffrey Shelton, Graham Crawley, John Carnduff, John Leonard, John Martin, Kenneth Richardson, Michael Smith, Robert Ramage, Stanley Roberts, Stephen Davidson, Stephen Turner, Stuart McGeachin, Dennis Keith, Douglas Young, Fred Wudl, James Bloomer, John McCall, Joseph P. Marino, Mark A. Wuonola, Morris Brown, Pasquale (Pat) Confalone, Paul L. Dowd, Philip Keehn, Richard Frederic Borch, Richard H. Schlessinger, Robert Rosati, Stanley Pine, Alexander Yurlchenko, Leonid Yakhontov, Jakob (Schaggi) Schreiber, Jost Wild, Urs Locher, Alexander Wick, Lucius Werthemann, Peter Lliger, Ren Wiederkehr, Willy Huber, Paul Dubs, Walter Fuhrer, Hans Maag, Walter Schilling, Heinz Gschwend, Joseph M. Muchowski, Terry L. Bogard, James J. Sims, Reinhart Keese, David Coffen, Bernhard T. Golding, Fritz Karrer, Peter Schneider, Naoto Hashimoto, Naruyoshi Obata, Andrew B. Holmes, and Walter Hunkeler.

Chemists that contributed to the syntheses of corrins and corphins in the model series 19601973 include Ehrhard Bertele, Rolf Scheffold, Hanspeter Gribi, Helmut Boos, Werner Husermann, Ivo Felner-Caboga, Pius Wehrli, Albert Fischli, Ernst-Ludwig Winnacker, Hans-Ulrich Blaser, Martin Roth, Hans-Jakob Wild, Peter M. Mller, Erwin Gtschi, Niklaus Bhler, Bruno Hardegger, Gerd Kloster, August Rttimann, Mario Pesaro, Fritz Elsinger, Arthur Peter Johnson, Dusan Miljkovic, Dieter Bormann, Yasuji Yamada, Jrgen Schossig, Larry Ellis, Brian B. Place, and John Gleason.Deceased.

NOTES

1. Aboard a night ferry on the Bosporus Sea, a version of this article was presented at the 2014 International Conference for Porphyrins and Phthalocyanines, Istanbul, Turkey where Professor Kevin M. Smith

celebrated 50 years of porphyrin research in the company of his family, colleagues, former graduate and postdoctoral students.

2. Sufficient space precludes a complete designation of all participants in the B12 project, however see acknowledgments.

3. Opposite camphor antipodes were required to build the A/D-ring backbone of the west fragment.

4. See the A-ring correlation with (+)-camphor shown in Ref. 18.

5. Fleming was anxious to return to Europe because he had been offered a lectureship position by Todd at Cambridge, UK [20].

6. The thermal cyclization was serendipitously discovered when a melting point was attempted (R. B. Woodward, Sheffield Lecture July 8, 1966).

7. Corrnorsterone 40, the molecules name was coined by Woodward from the names, corrin and sterone, which emphasized its resemblance to the tetracyclic steroid skeleton. It also represented the all important cornerstone in the synthesis of the west fragment.

8. The corrnorsterone work by Smith, Richardson and Brown was carried out in the unnatural series [34].

9. Original synthetic work by Samuel and Manasse.10. Eschenmosers group showed that type-II isomer

indeed produced the corrigenolide 59b in 85% yield using trifluoroacetic acid, tris-(-cyanoethyl)-phosphine but only in sulfolane as solvent.

11. Each experimental procedure for the sulfur-extrusion method was often tailored dependent on the sulfur-containing intermediate involved.

12. In contrast, Eschenmosers chemical solution was a brilliant mechanistically planned amide-fragmentation which Woodward referred to as diabolically clever because it was conveniently performed on small scale reactions with cyclohexylnitrone and silver tetrafluoroborate and selectively fragmented the nitrosoamide intermediate without affecting ester functionality.

13. The natural-epimer preference for the propionate groups in the -stereochemistry (down) in the A- and B-rings was reversed in slight favor thermodynamically for the -stereochemistry (up) in the C-ring.

14. Jakob Schreiber (19211991), Eschenmosers first doctoral student and life-long friend developed the HPLC technique and painstakingly separated the cobyric acid diastereomers. However, Waters Corporation which later comercialized the HPLC instrument for industrial application was given undo credit for the historical cobyric acid purification performed at the ETH [44, 54].

REFERENCES

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3. Clark VM, Johnson AW, Sutherland I0 and Todd AR. J. Chem. Soc. (C) 1958; 32833289.

4. 100 Years of Crystallography Chem. & Eng. News August 11, 2014; p 38.

5. Battersby AR. Nat. Prod. Report 2000; 17: 507526. 6. The Nobel Prize Foundation, Dorothy Hodgkin,

www.nobelprize.org/nobel_prizes/chemistry/laureates/1964.

7. Barker HA, Smyth RD, Weissbach H, Toohey JI, Ladd JX and Volcani BE. J. Biol. Chem. 1960; 235: 480488.

8. Johnson AW. Structural Analogs of Porphyrins in Porphyrins and Metalloporphyrins, Smith KM. (Ed.) Elsevier Scientific Publishing, Co: Amsterdam, 1975; Chapter 18, pp. 730754.

9. Smith KM. In Cyclizations of a,c-Biladiene to Give Porphyrins and Their Derivatives, The Porphy-rin Handbook, Vol. 1, Kadish KM, Smith KM and Guilard R. (Eds.) Academic Press: Sidney?, 2000; Chapter 3, pp. 119120.

10. Bertele E, Boos H, Dunitz D, Elsinger F, Eschen-moser A, Felner I, Gribi HP, Gschwend H, Meyer EF, Pesaro M and Scheffold R. Angew. Chem. Int. Ed. 1964; 3: 490496.

11. Eschenmoser A. Studies on Organic Synthesis, 23rd Int. Congress of Pure and Applied Chemistry, Bos-ton, Pure Appl. Chem. 1971; Suppl. Vol. 2: 69106, Buttersworth, London.

12. Friedrich W, Gross G, Bernhauer K and Zeller P. Helv. Chim. Acta 1960; 43: 704712.

13. Vitamin B12 in Classics in Total Synthesis, Nicolaou KC and Sorensen EJ. (Eds.) VCH Verlagsgesell-schaft: Weinheim, 1996; Chapter 8, pp 99136.

14. Riether D and Mulzer J. Eur. J. Org. Chem. 2003; 3045.

15. Jackson AH and Smith KM. The Total Synthesis of Natural Products, Vol. 1, ApSimon JW. (Ed.) Wiley-Interscience: New York, 1973; Chapter 3, pp 143278.

16. Money T. Nat. Prod. Report 1985; 2: 253289. 17. Ranganathan R. Resonance 2014; 19: 586587. 18. Babu SM and Ranganathan S. Resonance 2014; 19:

593623. 19. Woodward RB. Pure Appl. Chem. 1968; 17:

519547. 20. Fleming I. University Chemical Laboratory, Lens-

field Road, Cambridge, England, June 30, 2014, personal communication.

21. Lehn J-M. Universit Strasburg, France, November 26, 2014, personal communication.

22.

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