C-C fragmentation: origins and recent applications.

It has been 60 years since Eschenmoser and Frey disclosed the archetypal CC fragmentation reaction. New fragmentations and several variants of the original quickly followed. Many of these variations, which include the Beckmann, Grob, Wharton, Marshall, and Eschenmoser-Tanabe fragmentations, have been reviewed over the intervening years. A close examination of the origins of fragmentation has not been described. Recently, useful new methods have flourished, particularly fragmentations that give alkynes and allenes, and such reactions have been applied to a range of complex motifs and natural products. This Review traces the origins of fragmentation reactions and provides a summary of the methods, applications, and new insights of heterolytic CC fragmentation reactions advanced over the last 20 years.

Diastereoselective tin-free tandem radical additions to 3-formylchromones.

A tin-free tandem radical addition methodology onto 3-formylchromones is presented. This radical process yields functionalized chromone structures via two carbon-carbon bond-forming steps. These products contain up to three contiguous stereocenters with good to excellent dr's and yields.

Spirodiepoxide-based cascades: direct access to diverse motifs.

Allene epoxide formation/opening reaction sequences enabled direct access to diverse products. Described here are a single flask procedure for allene preparation and allene oxidation/derivatization reactions that give, among others, diendiol, diyndiol, α'-hydroxy-γ-enone, dihydrofuranone, butenolide, and δ-lactone products.

Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis.

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on ß-tubulin, provided a theoretical understanding of these successful experimental findings.

Allene synthesis via C-C fragmentation: method and mechanistic insight.

A new method of allene synthesis is described. Suitably functionalized vinyl triflates undergo fragmentation to give allenes in high yield. Computational and experimental data provide a mechanistic framework for allene formation and the complementary formation of alkynes. The method is stereospecific.

Synthesis of structurally simplified analogues of pancratistatin: truncation of the cyclitol ring.

Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.

Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones.

Pyrano[3,2- c]pyridone and pyrano[3,2- c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.

Novel three-component synthesis and antiproliferative properties of diversely functionalized pyrrolines.

Diversely substituted 2-pyrrolines have been prepared by a novel multicomponent process involving a reaction of various N-(aryl- and alkylsulfonamido)-acetophenones with aldehydes and malononitrile. While the reaction is highly regioselective, it is not stereoselective, generating a mixture of cis and trans 2-pyrrolines. A number of analogs from both cis and trans 2-pyrroline libraries were found to have antiproliferative activity in human cancer cell lines.

Three-component synthesis and anticancer evaluation of polycyclic indenopyridines lead to the discovery of a novel indenoheterocycle with potent apoptosis inducing properties.

A multicomponent reaction of indane-1,3-dione, an aldehyde and an amine-containing aromatic compound leading to the formation of indenopyridine-based heterocyclic medicinal scaffolds has been investigated. It was found that the yields significantly improve when oxygen gas is bubbled through the reaction mixture, facilitating the oxidation of the intermediate dihydropyridine-containing compounds to their aromatic counterparts. Investigation of the reaction scope revealed that formaldehyde, as well as various aliphatic, aromatic and heteroaromatic aldehydes, works well as the aldehyde component. In addition, substituted anilines and diverse aminoheterocycles can be utilized in this process as the amine-containing component. Preliminary biological evaluation of the synthesized library identified a pyrimidine-based polycycle, which rivals the anticancer drug etoposide in its toxicity and apoptosis inducing properties toward a human T-cell leukemia cell line.

Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis.

Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared by a straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative properties in a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerous Jurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytes under the same treatment conditions. The ease of synthesis and encouraging biological activities make the presented library of dihydropyridopyrazoles promising new leads in anticancer drug design.

Antiproliferative and apoptosis inducing properties of pyrano[3,2-c]pyridones accessible by a one-step multicomponent synthesis.

4-Arylpyrano-[3,2-c]-pyridones have been prepared by a one-step cyclocondensation of 4-hydroxy-1,6-dimethylpyridin-2(1H)-one with various substituted benzaldehydes and malononitrile. These heterocycles exhibit micromolar and submicromolar antiproliferative activity in HeLa and induce apoptosis in Jurkat cell lines. Structure-activity studies performed on a small library of these compounds show a pronounced cytotoxicity enhancing effect of the bromo substituent at the meta position of the C4 aromatic moiety.

Structural simplification of bioactive natural products with multicomponent synthesis: dihydropyridopyrazole analogues of podophyllotoxin.

A three-component condensation of 5-amino-3-methylpyrazole, tetronic acid, and various aromatic, heteroaromatic, and aliphatic aldehydes leads to the formation of dihydropyridopyrazole analogues of a cytotoxic lignan podophyllotoxin. This new heterocyclic scaffold-based library allows a drastic reduction of the structural complexity of the natural product with the retention of its potent cytotoxic properties. Similarly to podophyllotoxin, the presented analogues induce apoptosis in Jurkat cells.

Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents.

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.

Selectivity guidelines and a reductive elimination-based model for predicting the stereochemical course of conjugate addition reactions of organocuprates to gamma-alkoxy-alpha,beta-enoates.

Current models used to predict the stereochemical outcome of organocopper conjugate addition processes focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic isotope effect, and theoretical density functional studies strongly support the proposal that stereochemical preferences in these processes are dictated by the reductive elimination step, transforming Cu(III) to Cu(I) intermediates. A new model that considers various steric and stereoelectronic factors involved in the transition state of the reductive elimination step is proposed and then used to interpret the results of systematic studies of arylcuprate conjugate addition reactions with cis and trans gamma-alkoxy-alpha,beta-enoates. The results give rise to the following selectivity guidelines for this process. To achieve high anti-addition diastereoselectivities the use of trans esters with a bulky nonalkoxy substituent at the gamma-position is recommended. While stereoelectronics disfavor syn-addition, a judicious choice of properly sized gamma-substituents may lead to the predominant formation of syn-products, especially with cis enoates. However, high syn-selectivities may be achieved by using gamma-amino-alpha,beta-enoates.