Ring-rearrangement metathesis of 3,6-dialkoxy-3,6-dihydro-2H-pyrans

The first RCM-ROM-RCM sequence using a non-strained heterocycle as relay moiety is described. The course of the reaction strongly depends on the nature and relative configuration of the substituents in the starting trienic system. In addition, for a productive reaction to be observed, the site of initiation of the metathesis cascade is crucial. The compounds thus obtained may be useful for the synthesis of unusual polydeoxydisaccharides.     

Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

Synthetic studies on taxanes: A domino-enyne metathesis/Diels-Alder approach to the AB-ring

A domino enyne cross-metathesis/intramolecular Diels-Alder reaction has been successfully used to synthesize a bicyclo[5.3.1] undecene, corresponding to AB-ring of taxol without the gem dimethyl group.     

A ring-closing metathesis approach to secosteroidal macrocycles

An efficient synthesis of secosteroidal macrocycles has been achieved via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps.     

New strategies to symmetric and unsymmetric cyclic sulfamide analogs of DMP 323: a ‘sulfur linchpin’/RCM approach

The synthesis of 7-membered cyclic sulfamides utilizing the RCM reaction is described herein. Two major synthetic strategies that expand the scope and utility of our previously reported sulfamide and sulfamoyl carbamate chemistry are employed. Both Mitsunobu alkylation and simple alkylation of core sulfamides and sulfamoyl carbamates coupled with RCM are used to efficiently install lipophilic groups into the P1/P1′ and P2/P2′ periphery of the cyclic sulfamides. Overall, the routes described are applicable to the synthesis of a variety of cyclic 7-membered sulfamides.     

A novel synthesis of substituted quinolines using ring-closing metathesis (RCM): its application to the synthesis of key intermediates for anti-malarial agents

A method for synthesizing substituted quinolines using ruthenium-catalyzed ring-closing metathesis as a key step has been developed. Substituted 1,2-dihydroquinolines, 4-silyloxy-1,2-dihydroquinoline and 4-methoxy-1,2-dihydroquinoline, were successfully synthesized in excellent yields via ene-ene metathesis and silyl or alkyl enol ether-ene metathesis, respectively. The synthetic intermediates of the antimalarial agents quinine, chloroquine, and PPMP-quinine hybrid were efficiently synthesized by this methodology.     

The first example of ring-closing olefin metathesis of dehydroamino acids: an application to the synthesis of azabicyclo[X.Y.0]alkanes

The first example of ring-closing metathesis reaction of dehydroamino acids using ruthenium-based catalyst leading to the azabicyclo[X.Y.0]alkanes has been demonstrated. A preliminary investigation into the scope and limitations of the method will be presented.     

Metathesis cascade strategies (ROM-RCM-CM): a DOS approach to skeletally diverse sultams

The development of a ring-opening metathesis/ring-closing metathesis/cross-metathesis (ROM-RCM-CM) cascade strategy to the synthesis of a diverse collection of bi- and tricyclic sultams is reported. In this study, functionalized sultam scaffolds derived from intramolecular Diels-Alder (IMDA) reactions undergo metathesis cascades to yield a collection of tricyclic sultams. Additional appendage-based diversity was achieved by utilizing a variety of CM partners.     

A tandem enyne/ring closing metathesis approach to the synthesis of novel angularly fused dioxa-triquinanes

Triquinanes and their oxygenated congeners, oxa- and dioxa-triquinanes, exhibit versatile biological activities in conjunction with synthetically challenging molecular architecture. Owing to these properties, several new strategies have been developed to accomplish the synthesis of these sesquiterpenes. Among the new strategies, cascade radical cyclization strategy has been broadly explored and well studied. Herein, we report our efforts in detail for the synthesis of dioxa-triquinanes using a domino enyne/RCM strategy as the key step. Carbohydrate based synthesis not only allows the use of inexpensive and optically pure starting materials, but also the furanose derivatives, which already possess one of the requisite dihydro-furan moieties in the desired dioxa-triquinane. The other two five-membered rings were constructed simultaneously by the cascade enyne/RCM reaction using the Grubbs' second-generation catalyst. During the course of our synthesis it was observed that the acetonide protection hinders the RCM reaction, after the initial enyne metathesis reaction. The reaction underwent smoothly under argon atmosphere, whilst use of ethylene atmosphere was found to hinder the formation of the tandem enyne/RCM product. The effect of substitution on the key reaction is described here.     

Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis-Hillman adduct of o-nitrobenzaldehyde

A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncommon 3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an aza-Baylis-Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.     

Ring-closing metathesis: novel routes to aromatic heterocycles

Olefin metathesis has been established as an important and general reaction in synthetic organic chemistry. Recently, it has attracted interest as a powerful tool for the construction of aromatic heterocycles. The importance of heteroaromatic motifs in medicinal chemistry and biology, as well as the efficiency and wealth of metathesis transformations, have resulted in significant success in this rapidly developing area.     

Metathesis of a novel dienediyne system: A unique example involving the usage of in situ generated ethylene as cross-enyne metathesis partner

A unique example of sequential ring-closing metathesis and cross-enyne metathesis is reported. Here, the in situ generated ethylene by product from ring-closing metathesis is trapped by alkyne moiety. No metathesis product formation was observed with more reactive second generation catalyst in the absence of ethylene. Differential chemoselectivity with the first and second generation Grubbs’ catalyst has been observed when the reaction was performed in presence of the external source of ethylene.     

A ring-closing metathesis approach to a synthesis of the B ring of eleutherobin

A short and efficient RCM route is reported for the construction of the key nine-membered B ring of eleutherobin starting from the readily available 1,2,5,6-diisopropylidene-d-glucose.     

Reactivity of spiroanthraceneoxazolidines with cyclopropanes: An approach to the oxindole alkaloid scaffold

The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3′-indolin]-2-ones in the presence of MgI₂ formed the corresponding spiro[pyrrolidine-3,3′-indolin]-2-ones in 42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.     

CrystalDock: a novel approach to fragment-based drug design

We present a novel algorithm called CrystalDock that analyzes a molecular pocket of interest and identifies potential binding fragments. The program first identifies groups of pocket-lining receptor residues (i.e., microenvironments) and then searches for geometrically similar microenvironments present in publically available databases of ligand-bound experimental structures. Germane fragments from the crystallographic or NMR ligands are subsequently placed within the novel binding pocket. These positioned fragments can be linked together to produce ligands that are likely to be potent; alternatively, they can be joined to an inhibitor with a known or suspected binding pose to potentially improve binding affinity. To demonstrate the utility of the algorithm, CrystalDock is used to analyze the principal binding pockets of influenza neuraminidase and Trypanosoma brucei RNA editing ligase 1, validated drug targets in the fight against pandemic influenza and African sleeping sickness, respectively. In both cases, CrystalDock suggests modifications to known inhibitors that may improve binding affinity.     

Sulfonamidoglycosylation of methyl ribofuranosides: a novel approach to furanosylsulfonamides

The sulfonamidoglycosylation of benzylated methyl ribofuranosides using boron trifluoride etherate as catalyst, proceeded effectively to give the new sulfonamidofuranosides with good to high yields.