Et2AlCl-promoted asymmetric phenylseleno group transfer radical cyclization reactions of unsaturated beta-hydroxy esters

We have developed a new method for asymmetric phenylseleno group transfer radical cyclization of unsaturated beta-hydroxy esters. Various unsaturated alpha-phenylseleno beta-hydroxy esters underwent radical cyclization in the presence of Et(2)AlCl in benzene with sunlamp irradiation at 25-30 degrees C to give mono- and bicyclic group-transferred products in an efficient and highly regioselective and diastereoselective manner. To rationalize the high diastereoselectivities observed in this reaction, we propose a model based on chelation control of the aluminum alkoxides that are formed in situ. We devised a general method to prepare chiral radical precursors from which we obtained highly optically pure mono- and bicyclic group transfer products. The synthetic advantages of this method are demonstrated by our formal total synthesis of (-)-wilforonide. This paper presents the first examples of stereoselective group transfer radical cyclizations that occur via 1,2-asymmetric induction.     

Lewis acid promoted cyclization of enyne triesters and diesters

Reactions of enynes with three or two ester groups (1-4) in the presence of halogen-ligand Lewis acids gave cyclized products with halide incorporation (5-8) with high generality. The cyclization process was also analyzed in a theoretical study. Facile isomerization and dehydrohalogenation of five-membered products 5 and 8 by Al(2)O(3) or Et(3)N were also observed; this process introduces conjugated moieties into the products.     

Lewis acid-mediated radical cyclization: stereocontrol in cascade radical addition-cyclization-trapping reactions

An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid-mediated cascade radical addition-cyclization-trapping reaction proceeded smoothly with good enantio- and diastereoselectivities, providing various chiral γ-lactams.     

Catalytic asymmetric Nazarov reactions promoted by chiral Lewis acid complexes

Divinyl ketones bearing alpha-ester or alpha-amide groups undergo Nazarov cyclizations to give cylopentenones using copper-bisoxazoline Lewis acid complexes with moderate to good ees. [reaction: see text]     

Atom transfer radical cyclization reactions (ATRC): synthetic applications

Atom transfer cyclization reactions (ATRC) provide rapid access to functionalized γ-butyrolactones.     

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.     

Synthesis of beta-substituted alpha-amino acids via Lewis acid promoted enantioselective radical conjugate additions

[Chemical reaction: See text] Lewis acid promoted radical conjugate additions to beta-substituted alpha,beta-unsaturated alpha-nitro esters and amides were investigated. With achiral Lewis acids, there was competition between the desired radical conjugate addition and undesired alkene reduction mediated by Bu3nH. Zinc Lewis acids provided the greatest amounts of addition products with both substrate classes. Studies with Bu3nD indicated that the acidic alpha-stereocenter of the alpha-nitro ester products does not racemize under controlled workup conditions. The corresponding alpha-nitro amides racemized significantly during chromatography, but this problem could be greatly minimized by subjecting the crude adducts to subsequent transformations. Indium-mediated reduction of the nitro group followed by acylation of the resulting amine provided good yields of beta-substituted alpha-amino acid derivatives with mimimal levels of racemization. Attempts to use chiral Lewis acids in a stereoselective variant of this process revealed that Kanemasa's DBFOX/Ph ligand (14a) was uniquely effective. Moderate to good ee's and low dr's were obtained with amide substrates. Determination of the absolute configurations of the syn and anti isomers of adduct 7b showed that the hydrogen atom abstraction step was significantly more stereoselective than the radical conjugate addition step. A model for substrate binding to the chiral Lewis acid is presented.     

Lewis acid initiated or high pressure promoted reactions of isoprene with phenylsulphinyl chloride

Lewis acid initiated reaction of isoprene with PhSOCl proceeds in a ene fashion with the formation of 2-phenylsulphinylmethyl-1,3-butadiene. High pressure promoted addition produces Z-1-phenylsulphinyl-4-chloroadduct presumably $\text{via}$ [4+2]cycloaddition.     

Synthesis of 2H-indazoles via Lewis acid promoted cyclization of 2-(phenylazo)benzonitriles

Lewis-acid promoted "coarctate" cyclization of 10 2-(phenylazo)benzonitrile derivatives furnishes the isoindazole ring system in ca. 65-95% yield. A plausible mechanism for this unusual transformation is proposed.     

Lewis acid-catalyzed atom transfer radical cyclization of unsaturated β-keto amides

The Lewis acid-catalyzed atom transfer radical cyclization reactions of olefinic -bromo β-keto amides were investigated. It was found Lewis acid Yb(OTf)₃ or Mg(ClO₄)₂ not only promoted the cyclization reactions, but also resulted in excellent trans stereocontrol in the cyclization products. With the catalysis of Lewis acid Yb(OTf)₃ or Mg(ClO₄)₂ at −78°C in the presence of Et₃B/O₂, the cyclization reactions of C-olefinic β-keto amides provided cyclic ketones, while the cyclization reactions of N-olefinic β-keto amides led to the formation of γ-lactams, which could be converted to 3-aza-bicyclo[3,1,0]hexan-2-ones.     

Synthesis of tryptophans by Lewis acid promoted ring-opening of aziridine-2-carboxylates: optimization of protecting group and Lewis acid

The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The ratio of tryptophan to oxazolidinone products can be optimized through a judicious choice of Lewis acid and N-protecting group.     

Studies dealing with thionium ion promoted mannich cyclization reactions

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.     

Room temperature intramolecular hydro-O-alkylation of aldehydes: sp3 C-H functionalization via a Lewis acid catalyzed tandem 1,5-hydride transfer/cyclization

[reaction: see text] The scope and limitations of intramolecular hydro-O-alkylation of aldehyde substrates leading to spiroketals and bicyclic ketals and aminals is reported. The direct transformation of tertiary and sterically hindered secondary sp(3) C-H bonds into C-O bonds under the action of a catalytic amount of a variety of Lewis acids is described. The mechanism of these transformations is proposed to involve a tandem hydride transfer/cyclization sequence.     

Rate constants for anilidyl radical cyclization reactions

[reaction: see text] N-Aryl-5,5-diphenyl-4-pentenamidyl radicals (3) were produced by 266 nm laser-flash photolysis of the corresponding N-(phenylthio) derivatives, and the rate constants for the cyclizations of these radicals were measured directly. The 5-exo cyclization reactions were fast (k(c) > 2 x 10(5) s(-1)), and radicals 3 generally behaved as electrophilic reactants with a Hammett correlation of rho = 1.9 for five of the six radicals studied. However, the p-methoxyphenyl-substituted radical 3f cyclized much faster than expected from the Hammett analysis. Variable temperature studies of parent radical 3a (aryl = phenyl) gave an Arrhenius function with log k = 9.2 - 4.4/2.3RT (kcal/mol). The rate constant for the reaction of p-ethylphenyl-substituted anilidyl radical 3b with Bu(3)SnH at 65 degrees C was k(T) = 4 x 10(5) M(-1) s(-1).     

On the 6-exo atom transfer radical cyclization reactions of 3-butenyl 2-iodoalkanoates

Bis(tributyltin)-initiated atom transfer cyclization reactions of 3-butenyl iodoalkanoates in the presence of BF3.OEt2 as the catalyst afforded the 6-exo cyclization products as a mixture of 3,4-cis- and trans-substituted tetrahydro-2H-pyran-2-ones in 53-71% yield with the major isomers being the cis ones. Ab initio calculations at the B3LYP/6-31G level on the transition states of the radical cyclization and on the cyclized products revealed that the reactions are kinetically controlled and the transition states for the 6-exo radical cyclization are in boat conformations. Moreover, the cis-oriented transition states are of lower energy than the corresponding trans-oriented ones, which are in excellent agreement with experimental results.     

Cyclisation reactions of alkenyl β-ketoesters involving a novel phenylseleno group migration

A number of alkenyl-substituted α-phenylseleno β-ketoesters can be cyclised in the presence of acidic catalysts in which a novel migration of phenylseleno moiety occurs.