The Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.

https://www.ch.ic.ac.uk/local/organic/pericyclic/DA.pdf

The Diels--Alder reaction in total synthesis.

In spite of the considerable progress made in recent years toward the understanding of the chemistry and biological function of the cobalt-containing B(12) group of compounds, much of the information still is more descriptive than definitive in nature. In general terms, it is known that the free vitamin forms can function as methyl group carriers and that the 5'-deoxyadenosyl or coenzyme forms serve as hydrogen carriers; but the mechanism of these processes is not understood in detail. More systematic studies of the pure chemistry of these complex molecules containing a carbon-cobalt covalent bond are needed before the biochemist can interpret many of his observations on the enzyme-catalyzed reactions. Even in relatively simple solutions it is difficult to ascertain the state of oxidation of several of the vitamin forms, and these problems are compounded when the reactive thiol compounds and complex proteins of the biological systems also are present. For example, both vitamin B(12r) (the Co(2+) form) and corresponding analogs are known to disproportionate in solution to B(12s) (Co(1+)) and B(12a) (Co(3+)) under a variety of mild conditions (12, 57). This means that in the biological systems it is exceedingly difficult to ascertain the chemical nature of many B(12) intermediates and reaction products. The role of the protein moiety of the various B(12)-linked enzymes in the catalytic processes is little known as is, also, the mode of binding of the B(12) derivative to the protein. These types of questions perhaps can be answered eventually by the crystallographers, whose art is becoming increasingly sophisticated. Note added after preparation of manuscript. In contrast to the values given in Table 4 for the molecular weights of the two dissimilar protein moieties of glycerol dehydrase, a recent report (57a), gives a value of 188,000 for the molecular weight of a stable, catalytically inactive complex of 1 mole of hydroxocobalamin and 1 mole of the apoenzyme complex of glycerol dehydrase. The latter is presumed to contain one equivalent of each of the two dissimilar protein subunits. The original estimate of 240,000 as the molecular weight of the unstable sulfhydryl protein moiety (39) was undoubtedly made on partially aggregated material.

Vitamin B 12.

Publisher Summary This chapter discusses the X-ray structural analyses of organolithium compounds. Lithium compounds, perhaps the most widely used organometallic synthetic intermediates, have fascinating structures. Nevertheless, organic chemistry textbooks often treat organolithium compounds merely as “carbanions” or as monomers. The chemical behavior of lithium compounds cannot be understood without the knowledge of the structures, the degree of aggregation, and the extent and nature of solvation. “Terminally bonded” organolithium compounds afford, in principle, the simplest examples of lithium–carbon σ–bonds. This class comprises lithium compounds with a single contact between lithium and a carbon atom. The dimer of lithiobicyclo butane, and of lithiodimethylsulfide, illustrates the bridging between sp 3 -hybridized carbon atoms while phenyllithium exemplifies bridging between sp 2 carbon atoms. A few organolithium compounds crystallize in aggregates with more than four subunits. Such compounds, derived from substituted acetylenic substrates (excluding simple acetylides), form oligomeric structures involving bridging lithium atoms and possible interactions of the lithium atoms with acetylenic π system. The benzophenonedilithium compound 50, formed by the reduction of benzophenone with lithium metal, crystallizes as a dimer. A large number of mixed-metal organometallic compounds have been prepared in which the hydrocarbon ligands bridge the lithium and the other metal atoms. A number of lithium/transition-metal compounds involving metal–metal multiple bonds as well as lithium–alkyl group interactions have been structurally characterized. The structure of lithium compounds without lithium–carbon bonds summarizes the structures of some lithium compounds that do not involve Li–C contacts.

X-ray structural analyses of organolithium compounds

Stereocontrolled cyclofunctionalizations of double bonds through heterocyclic intermediates

The achievement of a synthesis of a complex organic molecule involves a number of distinctly identifiable operations which, however, are not strictly independent of one another. These include the choice of the molecule to be synthesized, the development of a synthetic strategy and plan in general outline, the selection of specific individual steps and their ordering, and the experimental execution of the synthesis. The absence of a clean separation between component elements makes the task of analysing and understanding Synthesis as an intellectual discipline appear quite forbidding, especially in the most crucial aspect, derivation of a general plan. Further, the enormous diversity and number of organic structures now known to exist, the incredibly broad spectrum of reactions available for synthesis, and the uncertain and severe limits on the applicability of any given reaction all combine to create an impression that the design of a synthesis is apt to be tenuously hypothetical and is mainly a function of the unique circumstances in each particular case and, moreover, that considerations of a highly general nature are neither dominant nor very useful. None the less, a sufficiently great number and variety of syntheses have now been completed to encourage attempts at setting down in a generalized form the process by which a synthetic chemist devises an original but valid synthetic route to a complicated structure. Such an effort surely is more than an intriguing theoretical exercise; it is a prerequisite to a deeper comprehension of Synthesis and the methodologies which are fundamental to it, and it is likely to be a keystone in the rational development of Synthesis to still higher forms. For example, any technique for the automatic generation of synthetic schemes by a computer will require a complete and detailed definition of the elements of Synthesis and their mutual interaction, in a most general sense.

/pdf/general-methods-for-the-construction-of-complex-molecules-32igh4lpwb.pdf

General methods for the construction of complex molecules

Some 25 years have elapsed since the topic of metalation reactions was reviewed by Gilman and Morton. The intervening years have been notable for intensive explorations in this area, in part because many organolithium reagents are now commercially available. Specifically, research efforts have been characterized by the discovery of new functional groups that promote metalation, elaboration of novel heterocyclic and olefinic substrates as metalatable species, recognition of new types of lithiating agents, and the continuation of efforts to define accurately the mechanism of metalation. Accordingly, heteroatom-facilitated lithiation has become recognized as an increasingly important tool, not only in the elaboration of carbocyclic aromatic and heteroaromatic systems, but also in synthetic aliphatic chemistry. A few recent reviews have covered the topic in a more limited or less specific sense. It is the purpose of this chapter to survey and classify the vast accumulation of heteroatom-facilitated lithiations recorded since the first coverage in Organic Reactions.



As outlined by Gilman and Morton, the terms “metalation” in general and “lithiation” in particular denote any replacement of a hydrogen atom by metal or lithium. In this review, however, lithiation is defined as the exchange of a hydrogen atom attached to an sp2-hybridized carbon atom by lithium to form a covalent lithium-carbon bond. More specifically, discussion is limited to those metalations that, through the influence of a heteroatom, are characterized by rate enhancement and regioselectivity. In fact, lithiation reactions of this type are noted for an extraordinarily high degree of regioselectivity, metalation generally occurring on the sp2-carbon atom closest to the heteroatom. Based on the relative position of the heteroatom, such lithiations are conveniently classified into two principal categories: alpha and beta (ortho) lithiations.



In alpha lithiations the metalating agent deprotonates the sp2-carbon atom alpha to the heteroatom to form a carbonlithium bond. This sp2-carbon atom may be part of an olefinic or heteroaromatic π system.



In beta lithiations the metalating agent is directed to deprotonate the sp2-carbon atom beta to the heteroatom-containing substituent. The sp2-carbon atom can be part of an aromatic or an olefinic π system. It should be noted that the designation “ortho metalation” is used specifically for the beta metalation of carbocyclic aromatic systems.



This chapter surveys all systems in which alpha and beta lithiations have been observed, with the exception of ferrocenes.


Keywords:

lithiations;
alpha lithiations;
beta lithiations;
scope;
limitations;
alpha activating atom;
oxygen;
sulfur;
nitrogen;
selenium;
tellurium;
halogens;
beta-directing atom;
substrates;
enamines;
vinyl isocyanides;
formamides;
pyrroles;
indoles;
pyrazoles;
imidazoles;
triazoles;
tetrazoles;
alkyl vinyl ethers;
pyrazoles;
pyridines;
pyrimidines;
furans;
oxazolines;
oxazoles;
sulfides;
sulfoxides;
thiophenes;
electron-withdrawing groups;
vinyl halogens;
amines;
ethers;
sulfones;
amides;
alcohols;
ketones;
experimental procedures

Heteroatom‐Facilitated Lithiations

Am Beispiel der Synthese des Nickel(II)-Komplexes des (±)-1.8.8.13.13-Pentamethyl-trans-corrins wird ein synthetischer Zugang zum Verbindungstyp der Corrine aufgezeigt. Durch die mehrfache Verwendung des Triathyloxonium-tetrafluorborats bietet die Arbeit eine Illustration der praparativen Bedeutung der von H. Meerwein und Mitarbeitern entdeckten Trialkyloxoniumsalze.

Ein synthetischer Zugang zum Corrinsystem

The synthesis of the nickel(II) complex of (±)-1,8,8,13,13-pentamethyl-trans-corrin illustrates a synthetic route to the corrin system. Repeated use of triethyloxonium tetrafluoroborate in this synthesis demonstrates the preparative value of the trialkyloxonium salts discovered by Meerwein et al.

A Synthetic Route to the Corrin System

2-Pyrazolyl-benzophenones, e.g. those of the formula ##STR1## R = H or alkyl R o = H, alkyl, (HO, alkoxy, amino)-alkyl, aralkyl, or aryl R', r" = h, alkyl, alkoxy, halo or CF 3 Am = open or cyclic amino Corresponding ketals, or therapeutically useful acid addition salts thereof exhibit antianxiety and antidepressant effects.

2-Pyrazolyl-benzophenones

α-Phenyl-zimtaldehyd (I) liefert nach bekannten Verfahren den homologen Aldehyd (II), aus dem uber eine Boranatreduktion der Imine die Amine (III) erhalten werden konnen.

Heinz W. Gschwend

Papers

Heteroatom‐Facilitated Lithiations

Ein synthetischer Zugang zum Corrinsystem

A Synthetic Route to the Corrin System

2-Pyrazolyl-benzophenones

Rates of intramolecular Diels-Alder reactions of pentadienylacrylamides