Intramolecular double-cyclization

On the other hand, the triflate 254 was treated with sodium azide, followed by reduction of the lactone carbonyl function, and subsequent mesylation, complete removal of the protecting groups and reprotection by EtsSiCl, to afford 259 (Scheme 25). Sodium hydrogen telluride reduction of the azide function in 259 followed by intramolecular double cyclization with sodium acetate afforded the bicycle 260, which on deprotection furnished 261 in 45% overall yield from the triflate 254. 

In the dihydro-1,2,4-trithiin series, the solid-state structures of the dimer 58 <1997AXC748> (obtained as a side product during the intramolecular double cyclization of m-disodium ethene-l,2-dithiolate with I2/KI at —10°C in a... 

Our studies commenced with exploring various catalysts and promoters of the aldol reactions (Table 2). To simplify the analysis, only diastereomerically pure Michael adduct 14a was used in the screening of reaction conditions. Initially, the intramolecular double-cyclization proved to be difficult as pro-line catalysis (entry 1), soft enolization (entry 2), and tertiary amines (entries 3 and 4) were unsuccessful. Acidic conditions (pTSA) provided a positive result as the steroid diol 24 with the unnatural C13/C14 configuration was formed. Unfortunately, the formation of significant side products along with 24 complicated isolation of this product. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

If a molecule has a multiple bond and a nucleophilically mobile chlorine atom, then the fluoride ion attacks the double bond, generating a carbanion stabilized by two trifluoromethyl groups, and intramolecular nucleophilic cyclization forming a five-membered heterocycle 48 is possible. 

These examples demonstrate the efficiency of using the C=C double bond for heterocycle formation. In this case, the intramolecular nucleophilic cyclization involves the nucleophilic center of the nucleophile at the double bond of the functional fragment together with the heteronucleophile generated in the course of the reaction under conditions of nucleophilic catalysis by the fluoride ion. 

The reaction of perfluoro-4-methyl-2-pentene with ethylene glycol also leads to 2-fluoro-2-trifluoromethyl-3-(2,2,2-trifluoro-1 -trifluoromethylethy-lidene)-l,4-dioxane 106 (96ZOB1995). The formation of the six-membered heterocycle occurs via generation of the intermediate carbanion and fluoride ion elimination from the y-position. Subsequent intramolecular nucleophilic cyclization involving the O-nucleophilic center and the internal double bond leads to a 1,4-dioxane derivative (route e). 

Apparently, ethylenediamine initially attacks the carbon atom of the double bond to give an anion. Elimination of the fluoride ion from the CF3 group and elimination of HF affords A(2-(trifhioromethyl)-perfluoropent-1 -en-3-ylidene)ethylene-1,2-diamine. Subsequent transformations of this compound can follow different pathways. For instance, one pathway includes intramolecular nucleophilic cyclization, resulting in compound A. This product can react with perfluoro-2-methylpent-2-ene... 

Reaction of aryl Grignard compounds, obtained in situ by iodine-magnesium exchange, with C0CI2, presumably generates aryl radicals. In the presence of a double bond or aromatic ring an intramolecular radical cyclization may take place. This reaction was used for the synthesis of spiro-indolines.244 Oshima has applied cobalt-mediated tandem radical cyclization-cross-coupling reaction for the synthesis of benzyl-substituted heterocycles (Scheme 80).245... 

An intramolecular double nitrile oxide cycloaddition with alkyne and olefin moieties was exploited in the synthesis of novel unsymmetrical hybrid spiro (isoxazole-isoxazoline) ligands 14 which were effective in promoting a Pd-catalyzed tandem cyclization <07TA919>. 

Double cyclizations to butenolides and furanes. Radicals can undergo intramolecular addition to triple bonds when separated by three carbons. This strategy can be used for synthesis of butenolides (equation 1) and -substituted furanes (equation II). Cyclization of vinyl bromides." Fused and bridged ring systems can be prepared... 

C to —10°C) followed by a Dess-Martin oxidation provided the necessary azidoaldehyde. An intramolecular Staudinger cyclization followed by reduction of the resultant amine provided azepine 364. Treatment of 364 with iodine induced an interesting double cyclization. Initial iodination of the double bond is followed by aziridinium ion formation 365. An intramolecular and stereospecific ring opening by the carboxylate provides the target (—)-stemospironine. 

Synthesis of Cyclopropanes. Chiral imide enolates which contain y-halide substituents undergo intramolecular displacement to form cyclopropanes. Halogenation of y,5-unsamrated acyl imides occurs at the y-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61). 

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