Solid-phase synthesis of carbocyclic nucleosides

[formula: see text] An efficient solid-phase synthesis of carbocyclic nucleosides has been developed. The key step is the palladium-catalyzed coupling of a purine derivative to a resin-bound allylic benzoate. The resulting products may be further functionalized on the solid phase. Acidic cleavage affords carbocyclic nucleosides, a class of compounds with demonstrated biological activity and substantial current interest.     

Synthesis of a conformationally locked version of puromycin amino nucleoside

[reaction: see text] A conformationally locked carbocyclic version of puromycin amino nucleoside was synthesized via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine without interference from the azido group reacting with triphenylphosphine. The requisite 3-azido-substituted carbocyclic pseudosugar was prepared by a double inversion of configuration at C3' (nucleoside numbering) involving a nucleophilic displacement with azide.     

Unconventional catalytic allylation of 5-norbornene-2,3-dicarboxylic anhydrides: 7-oxa and 7-aza analogues

The catalytic allylation of 7-oxanorbornene, 7-azanorbornene, and bicyclo[2.2.2]octenoic anhydride was performed for the first time. It was found that the structures of allylation products and ratios between them were analogous to those for corresponding carbocyclic derivatives. The presence of a substituent at the double bond of a substrate makes this reaction impossible. Comparative experiments were performed for evaluating the relative reactivity of double bonds in 7-oxanorbornene, 7-azanorbornene, and their carbocyclic analogs.     

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction

Synthesis of medium-sized carbocyclic ketones via the intramolecular B-alkyl Liebeskind-Srogl coupling reaction is described. The sequence of hydroboration of ω-alkenyl thiol ester with 9-BBN and the Liebeskind-Srogl reaction results in the formation of medium-sized carbocyclic ketones with good yield.     

A new entry to carbocyclic nucleosides: oxidative coupling reaction of cycloalkenylsilanes with a nucleobase mediated by hypervalent iodine reagent

A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By applying the method, a novel carbocyclic cytidine derivative having bis(hydroxymethyl)cyclohexene as a pseudosugar moiety, designed as a potential anti-HIV agent, was successfully synthesized.     

Reaction of Dichlorocarbene with Substituted Cyclopentadienones Under Phase Transfer Conditions

The cycloaddition reactions involving dichlorocarbene generated under phase transfer conditions have been studied extensively in the past few years due to the simplicity of the procedure involved.¹ The facile formation of dichlorocyclopropanes provides an easy entry to functionalised aromatics and expanded carbocyclic compounds.² The dichlorocarbene generated under phase transfer conditions is capable of adding even to electron deficient olefins. We describe here the cyclo-addition reaction of dichlorocarbene to tetrasubstituted cyclopentadienones.     

Synthetic studies on the taxane skeleton: effective construction of eight-membered carbocyclic ring by palladium-catalyzed intramolecular α-alkenylation of a methyl ketone

A new method for the construction of the eight-membered carbocyclic ring in the taxane skeleton is described. The palladium-catalyzed intramolecular α-alkenylation of a methyl ketone effectively constructed the eight-membered carbocyclic ring in the taxol model compound. To the best of our knowledge, this reaction is the first example of forming an eight-membered carbocyclic ring by the palladium-catalyzed intramolecular α-alkenylation of a ketone.     

The selective mono and difunctionalization of carbocyclic cleft molecules with pyridyl groups and X-ray crystallographic analysis

The diesterification and selective mono and dialkylation of carbocyclic analogues of Tröger’s base with pyridyl groups has been achieved in high yield and good selectivity giving access to a novel range of cleft molecules capable of binding events. Reaction conditions for the selective functionalization of this carbocyclic cleft molecule are discussed as well as the solid state structures of these newly synthesized ligands.     

Cyclobutanone mimics of penicillins: effects of substitution on conformation and hemiketal stability

The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as beta-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan-6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3beta substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3alpha substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d4.     

Application of aryl siloxane cross-coupling to the synthesis of allocolchicinoids

In this communication, we report a new approach to the allocolchicine carbocyclic skeleton based upon an aryl siloxane coupling reaction and a phenanthrol ring expansion. These key steps allow for the selective functionalization of every carbon within the carbocyclic framework. The siloxane coupling-phenanthrol sequence was applied to the synthesis of two allocolchicinoids, including the first fully synthetic approach to N-acetyl colchinol-O-methyl ether (NCME).     

Two-carbon ring expansion of cyclobutanone skeletons by nickel-catalyzed intermolecular alkyne insertion

The reaction of cyclobutanone with an alkyne in the presence of a nickel(0) catalyst formally achieves intermolecular alkyne insertion between the carbonyl carbon and the α-carbon of a cyclobutanone, providing a six-membered carbocyclic skeleton.     

Synthesis of 2',3'-dideoxy-6',6'-difluorocarbocyclic nucleosides

2',3'-Dideoxy-6',6'-difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring via ring-closing metathesis and the incorporation of gem-difluoromethylene group by way of silicon-induced Reformatskii-Claisen reaction of chlorodifluoroacetic ester 3.     

The [4 + 3]-cycloaddition/quasi-Favorskii process. Synthesis of the carbocyclic core of tricycloclavulone

[reaction: see text] The [4 + 3]-cycloadduct derived from the reaction of 2,5-dibromocyclopentanone with cyclopentadiene was converted via a quasi-Favorskii rearrangement and ring-opening, ring-closing metathesis sequence to the carbocyclic core of the prostanoid tricycloclavulone.     

Synthesis of a novel conformationally locked carbocyclic nucleoside ring system

[reaction: see text] A fast and efficient synthetic route to novel Northern locked carbocyclic nucleosides (as precursors of carbocyclic locked nucleic acids or cLNAs) is described. The target nucleoside with a oxabicyclo[2.2.1]heptane ring system was prepared from a simple starting material, diethyl malonate. Ring closure by intramolecular O-alkylation provided the target ring system as the major isomer over the [3.2.0] oxetane system. The adenine moiety was introduced through a reactive triflate after inversion of the stereochemistry of the corresponding alcohol by oxidation and reduction.     

Novel cycloalkene indole carbazole alkaloids via the ring closing metathesis reaction

Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chemistry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon lengths. The bottom carbocyclic ring system is formed through a ring closing metathesis reaction, and allows the installation of four, five, and six member ring sizes.     

A Boron Alkylidene–Alkene Cycloaddition Reaction: Application to the Synthesis of Aphanamal

We describe an unusual net [2+2] cycloaddition reaction between boron alkylidenes and unactivated alkenes. This reaction provides a new method for the construction of carbocyclic ring systems bearing versatile organoboronic esters. Aside from surveying the scope of this reaction, we provide details about the mechanistic underpinnings of this process, and examine its application to the synthesis of the natural product aphanamal.     

A new synthetic route to nucleosides: dissymmetric construction of a cyclopentene system by double [3,3]-sigmatropic rearrangement and double ring-closing metathesis

[reaction: see text] The dissymmetric synthesis of a carbocyclic nucleoside was achieved by a novel double [3,3]-sigmatropic rearrangement/double ring-closing metathesis strategy with a high stereoselectivity.     

Substrate-dependent dihydroxylation of substituted cyclopentenes: toward the syntheses of carbocyclic sinefungin and noraristeromycin

Carbocyclic nucleosides are of considerable interest for the development of new therapeutic agents. A key reaction in the preparation of many such nucleoside analogues is dihydroxylation of appropriately substituted cyclopentenes. Although often considered a routine reaction, in this paper, we report the dramatic influence of substituents on the facial selectivity of dihydroxylations. The substituted cyclopentene substrates are derived from acylnitroso cycloaddition reactions of cyclopentadiene, followed by N-O reduction and efficient enzymatic resolution. The results are directly utilized in a very efficient asymmetric synthesis of an antiviral carbocyclic nucleoside, noraristeromycin 5. Extensions toward the synthesis of carbocyclic sinefungin 7 document the importance of realizing the substituent dependence of the dihydroxylation reaction.     

Total synthesis of marine diterpenoid stolonidiol

Marine dolabellane diterpenoid stolonidiol was synthesized from l-ascorbic acid. The method for this total synthesis involves formation of the bicyclo[2.2.1]heptane derivative using a diastereoselective sequential Michael reaction, formation of cyclopentane derivative by the retro-aldol reaction and construction of an 11-membered carbocyclic ring through the intramolecular Horner–Wadsworth–Emmons reaction.     

Nickel-catalyzed intermolecular alkyne insertion into cyclobutanones

Cyclobutanones reacted with alkynes in the presence of nickel(0) catalysts to produce cyclohexenones. Oxidative cyclization of the carbonyl group of the cyclobutanone and the alkyne with the nickel(0) was followed by beta-carbon elimination from the resulting oxanickelacyclopentene and subsequent reductive elimination. This reaction achieves a formal alkyne insertion between the carbonyl carbon and the alpha-carbon, providing a six-membered carbocyclic skeleton.