Cyclization by intramolecular carbolithiation of alkyl- and vinyllithiums prepared by reductive lithiation: surprising stereochemistry in the lithium oxyanion accelerated cyclization

The versatility of intramolecular carbolithiation of simple alkenes to yield cyclopentylmethyllithiums by unconjugated organolithiums is greatly increased (1) by generating the organolithiums by reductive lithiation of phenyl thioethers with aromatic radical anions and (2) by using allylic or homoallylic alcohol groups on the receiving alkene. This type of reductive lithiation allows virtually any kind of organolithium to be generated, usually in a connective manner. Furthermore, the allylic or homoallylic lithium oxyanionic groups on the alkene greatly accelerate the reactions and lead in most cases to completely stereoselective cyclization at -78 degrees . Most significantly, the trans stereoselectivity is the opposite from that observed when the organometallic is allylic. A four-membered ring has also been generated by this method.     

Synthesis of dimethyl gloiosiphone a by way of palladium-catalyzed domino cyclization

The synthesis of a spiro[4.4]nonane skeleton by the palladium-catalyzed domino cyclization of a linear 7-methylene-2,10-undecadienyl acetate is described. The pi-allylpalladium intermediate underwent intramolecular alkene insertion with high intraannular diastereoselectivity, followed by intramolecular Heck-type cyclization, leading to a spiro[4.4]nonane system. Oxidation of the allylic ether moiety and transformation of the vinyl group to an exo-methylene unit provided 3, which is the known synthetic intermediate of dimethyl gloiosiphone A (2).     

The magnesium-ene cyclization stereochemically directed by an allylic oxyanionic group and its application to a highly stereoselective synthesis of (+/-)-matatabiether. Allylmagnesium compounds by reductive magnesiation of allyl phenyl sulfides

The first example of a magnesium-ene cyclization stereochemically directed by an allylic oxyanionic group is demonstrated by a highly stereoselective synthesis of the bicyclic terpene matatabiether 10. The synthetic method is particularly valuable, not only because of the stereochemical control and the utility of the versatile hydroxyl group introduced into the product, but also because the precursor of the allylmagnesium is an allyl phenyl sulfide, which is more stable and more easily prepared in a connective fashion than the usual allyl halide precursor. Since the presence of lithium ions encourages undesirable proton transfer to the cyclized organometallic and is detrimental to the stereochemical control, the conversion of the allylic thioether to the allylmagnesium utilizes a lithium-free method involving direct reductive magnesiation in the presence of the magnesium-anthracene complex.     

An experimental and computational study of 1,2-hydrogen migrations in 2-hydroxycyclopentylidene and its conjugate base

Thermal decomposition of alpha-hydroxydiazirine 2 gives primarily cyclopentanone and some allylic alcohol, in similar amounts as the known cyclohexyl analogue 1. Calculations (B3LYP/6-31+G) also show cyclopentanone to be the major product of this carbene rearrangement. Diazirine 2 and the lithium salt of the corresponding conjugate base 3 were decomposed by photolysis. The proportion of ketone formed increases with deprotonation, a trend also found computationally. In comparison, the base-induced isomerization of cyclopentene oxide, which proceeds via alpha-elimination to a carbenoid intermediate similar to that obtained from 3, yields primarily allylic alcohol rather than ketone; neither ring size nor charge thus accounts for the unusual product distribution observed. Interestingly, the calculations reveal that in the gas phase with no counterion, the singlet, oxyanionic carbene, and the alpha-deprotonated epoxide are the same, rather than discrete structures. This intramolecular complexation stablilizes the oxyanionic carbene by 20-25 kcal/mol.     

Thermal Cyclodimerization of Aliphatic Secondary C,N-Dilithioallylamine Derivatives

beta-Nitrogen-functionalized vinylic organolithium compounds derived from secondary aliphatic allylamines have been found to undergo upon heating (reflux of THF) either a dimerization or a regio- and stereoselective cyclodimerization reaction affording diamino 1,4-dienes or cis-2,3-disubstituted 4-methylenepyrrolidines, respectively, according to reaction time. In contrast, the corresponding dianions derived from aromatic allylamines underwent protonation by the solvent under analogous thermal treatment. A mechanism accounting for all these results has been proposed, which involves a spontaneous beta-elimination of lithium hydride and an intramolecular nucleophilic cyclization by addition of a lithium amide to an alkene group as critical steps. In addition, experimental evidence is provided about the formation of 3-lithio-1-aza 1,3-dienes as intermediates in these unusual thermal transformations.     

Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides

A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported. The redox-neutral intramolecular hydrofunctionalization is enabled by a dual catalyst system comprised of 9-mesityl-N-methyl acridinium tetrafluoroborate and phenyl disulphide and exhibits complete selectivity for the anti-Markovnikov regioisomeric products. The cyclization of allylic thioamides is postulated to operate via a modified mechanism in which oxidation of the thioamide, rather than the alkene, is responsible for the observed reactivity.     

Studies on the intramolecular cyclizations of bicyclic delta-hydroxynitriles promoted by triflic anhydride

Studies have been conducted to investigate the reactivity of several bicyclic delta-hydroxynitriles with triflic anhydride in dichloromethane. The reactions of the analogues derived from 1-indanone and 1-tetralone lead to annulated enones. These products arise from an initial elimination reaction that generates an alkene, followed by the addition of the carbon-carbon double bond to the activated cyano group. The intramolecular cyclization of the derivative obtained from 1-benzosuberone unexpectedly followed a different path, giving a cyclic imidate as the major product. In this case, the activated cyano group is directly attacked by the hydroxyl group of the starting delta-hydroxynitrile. Theoretical calculations provide a rationale for the observed reactivity pattern. Both the formation of the triflate via its protonated form, its subsequent ionization to the carbocation, and the cyclization of the resulting alkene to the enone become less favorable when the size of the ring increases due to conformational effects. The opposite trend is observed for the competing Pinner-type cyclization to the imidate. An alternative mechanism for the formation of the lactams from the cyclic imidates under acid-catalyzed conditions has also been proposed.     

Cyclization via carbolithiation of alpha-amino alkyllithium reagents

We report a new route to tertiary alpha-amino stereocenters by sequential alkylation of alpha-amino nitriles followed by reductive lithiation of the nitrile and cyclization onto an alkene. Reductive lithiation of alpha-amino nitriles using lithium 4,4'-di-tert-butylbiphenylide (LiDBB) and subsequent intramolecular carbolithiation proceeded with modest to high diastereoselectivity to deliver cyclic or spirocyclic ring systems. The stereoselectivity of these intramolecular carbolithiations was examined using density function calculations to evaluate plausible transition state models.     

Stereoselectivity and regioselectivity in the segment-coupling Prins cyclization

The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined in Scheme 1 and involves esterification of a homoallylic alcohol (1), reductive acetylation to give the alpha-acetoxy ether (3), and cyclization on treatment with a Lewis acid to produce a tetrahydropyran (4). Alkene geometries dictate the product configurations, with E-alkenes leading to equatorial substituents and Z-alkenes leading to axial substituents (Table 1). Not unexpectedly, applying the method to allylic alcohols leads to fragmentation rather than a disfavored 5-endo-trig cyclization. Dienols in which one alkene is allylic and the other alkene is homoallylic cyclize efficiently and produce the tetrahydropyrans 49-54, Table 3. Dienols with two homoallylic alkenes cyclize with modest to high regioselectively, generating tetrahydropyrans 40-45, Table 2. The relative rates for cyclization decrease in the order of vinyl > Z-alkene > E-alkene > alkyne. The configurations of the products are consistent with cyclization via a chair conformation, Figure 1. The 2-oxonia Cope rearrangement may be a factor in the regioselectivity of diene cyclizations and in the erosion of stereoselectivity with Z-alkenes. This investigation establishes the stereoselectivity and regioselectivity for a number of synthetically useful segment-coupling Prins cyclizations.     

Palladium-catalyzed tandem reactions to form 1-vinyl-1h-isochromene derivatives

The palladium-catalyzed reaction of pinacolone with tert-butyldimethyl(3-(2-bromophenyl)allyloxy)silane results in direct formation of 1-vinyl-3-tert-butyl-1H-isochromene. This is the result of a ketone arylation followed by an intramolecular cyclization of the enolate with the allylic system. The use of a lithium diamide base appears to be essential for success. The tert-butyldimethylsilyl protecting group is also an essential choice as it furnishes the appropriate reactivity to promote allylic substitution after the aryl coupling process. The use of more effective leaving groups, such as acetate, results in reaction of the allylic group, and no aryl coupling is observed. Through the appropriate selection of phosphine ligand and solvent, either the cyclized isochromene product or the noncyclized intermediate may be formed selectively. A short combinatorial study of the scope and limitations of the reaction, involving 24 ketones, is described.     

Controlling cyclization pathways in palladium(ii)-catalyzed intramolecular alkene hydro-functionalization via substrate directivity

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is generated, even in cases that are disfavored based on Baldwin''s rules and in cases where there is an inherent preference for an alternative pathway. DFT studies shed light on the origins of pathway selectivity in these processes.

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles.     

Stereoselection in the Prins-pinacol synthesis of acyltetrahydrofurans

[reaction: see text]. Depending upon the nature of the alkene and allylic substituents, acid-promoted rearrangements of acetals derived from anti allylic diols give 12 or stereoisomeric acyltetrahydrofurans 13. Stereoelectronic effects of the allylic substituents and the extent of bonding in the Prins cyclization transition state are central features of a proposed new model for predicting stereoselection in the Prins-pinacol synthesis of acyltetrahydrofurans.     

Tandem polar/radical crossover sequences for the formation of fused and bridged bicyclic nitrogen heterocycles involving radical ionic chain reactions,and alkene radical cation intermediates,performed under reducing conditions: scope and limitations

It is demonstrated that phosphorylated forms of beta-nitro alcohols provide an excellent means of entry into beta-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux. These radicals then undergo heterolytic cleavage of the phosphate group to yield alkene radical cation/phosphate anion contact ion pairs which are trapped intramolecularly in a tandem polar/radical crossover sequence involving radical ionic chain reactions by allylic and propargylic amines. The substitution pattern of the alkene radical cation dictates the cyclization mode, and this may be engineered to form fused ring systems by an initial exo-mode nucleophilic cyclization or bridged bicyclic systems when the nucleophilic attack takes place in the endo-mode.     

A metal-free approach to the synthesis of indoline derivatives by a phenyliodine(III) bis(trifluoroacetate)-mediated amidohydroxylation reaction

A novel approach to the synthesis of indoline derivatives is presented. The key cyclization step features the phenyliodine(III) bis(trifluoroacetate)- (PIFA-) mediated formation of a N-acylnitrenium ion and its succeeding intramolecular trapping by the olefin fragment. In addition, difunctionalization of the alkene moiety is achieved since the in situ generation of an additional hydroxy group at the terminal position of the original double bond accompanies the intramolecular C-N bond formation.     

Palladium-catalyzed stereospecific synthesis of 2,6-disubstituted tetrahydropyrans: 1,3-chirality transfer by an intramolecular oxypalladation reaction

PdCl2(CH3CN)2 (10 mol %) catalyzed reactions of non-3-ene-2,8-diols 1 and 2 gave 2,6-disubstituted tetrahydropyrans 3 and 4 in excellent yields with high diastereoselectivities (>20:1). Intramolecular cyclizations of the hydroxy nucleophile to the chiral allylic alcohol take place efficiently under mild conditions. A new stereogenic center is generated on the tetrahydropyran ring by 1,3-chirality transfer from the chiral allylic alcohol via a syn-SN2' type process. Cis tetrahydropyran 3E was formed from syn-2,8-diols 1a and 2a, and trans tetrahydropyran 4E was formed from anti-2,8-diol 1b, stereospecifically. Cis tetrahydropyran bearing a cis alkene 3Z was obtained from 2b at -40 degrees C, while 4E was formed from 2b in the presence of catalytic amount of water at -40 degrees C. The face selectivity of these cyclizations can be rationalized by taking a favorable conformation of the intermediary Pd pi-complex with allylic alcohols, escaping the allylic strain and 1,3-diaxial interactions. A stereocontrolled synthesis of optically pure 2-alkenyl-6-methyltetrahydropyran 17 was achieved efficiently in four steps from 6-silyloxy-1-heptyne 13 with an aldehyde and included asymmetric alkynylation, partial reduction of alkyne, deprotection of the silyl group, and the stereospecific cyclization.     

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.     

Stereoselectivity of intramolecular SN' cyclizations of alkyllithium reagents on methoxy alkenes

The cyclization of alkyllithium reagents onto methoxy alkenes has been investigated. The alkyllithium reagent was generated by reductive lithiation of an alkyl nitrile. In an unbiased substrate, a methoxy leaving group attached to a stereogenic secondary carbon atom led to the cyclization product with high optical purity. The configuration of the product demonstrated that the cyclization had proceeded with high syn-S(N)' selectivity. Previously we have shown that 2-lithiotetrahydropyran reagents cyclize to form spirocycles with the alkene cis to the pyran oxygen. Substrates were prepared to evaluate the importance of the configuration of the secondary allyl methyl ether against the alpha-alkoxy alkyllithium configuration. In the matched case (cyano acetal 38), a very selective cyclization ensued. In the mismatched case (cyano acetal 39), the spiro ether selectivity dominated. The syn-S(N)' selectivity overcame the normal E selectivity in the cyclization and accounted for the major product, Z-alkene 45. Thus the stereochemical preference in these alkyllithium cyclizations is dominated by the spiroether effect, followed by the syn-S(N)' selectivity and finally the preference for E-alkene formation.     

Intramolecular coupling of allyl carboxylates with allyl stannanes and allyl silanes: a new type of reductive elimination reaction?

The palladium-catalyzed intramolecular coupling of allyl stannanes with allyl carboxylates provides a general synthesis of five- and six-membered-ring carbocycles. The intramolecular coupling leads selectively to trans five-membered carbocycles and cis six-membered carbocycles, regardless of the cis or trans configuration of the allylic functions in the starting material. For example, the stereoselective synthesis of 10-epi-elemol demonstrated the cis configuration of the six-membered carbocycles. The related Oppolzer cyclization leads to lower yields, or fails completely, with substrates substituted at C-3 of the allyl and/or alkene terminus. The palladium-catalyzed intramolecular coupling of allyl silanes with allyl trifluoroacetates allows the synthesis of trans five-membered-ring carbocycles and requires the use of a bicyclic phosphite as the ligand. DFT calculations suggest that the preferred pathway for the intramolecular allyl/allyl coupling is by formation of the Cbond;C bond between the C-3 termini of the allyl ligands of bis(eta(3)-allyl)palladium complexes.     

Intramolecular carbolithiation reactions of chiral alpha-amino-organolithium species

Enantiomerically enriched alpha-amino-organolithium species, in which the lithium atom is attached to a stereogenic carbon centre, have been found to be chemically stable at room temperature in a solvent of very low polarity and undergo intramolecular carbolithiation onto an unactivated alkene. The configurational stability of the chiral organolithium species, bearing a variety of N-alkenyl substituents, was probed by studying the enantiomeric purity of the cyclization products. With N-but-3-enyl-2-lithiopyrrolidine, cyclization to the five-membered ring is more rapid than racemization and a high yield of the pyrrolizidine alkaloid (+)-pseudoheliotridane was obtained with no loss of optical purity. In contrast, with N-pent-4-enyl-2-lithiopyrrolidine, cyclization to the six-membered ring was found to occur with significant loss of optical purity. The cyclization to the six-membered ring was determined to occur with a half-life, t(1/2) approximately 90 min at 23 degrees C. The epimerization of this organolithium species in hexane/Et2O 4:1 was calculated to have a half-life, t(1/2) approximately 30 min at 23 degrees C. Enhanced levels of enantioselectivity for the formation of the indolizidine ring system were obtained using an alkene bearing a terminal phenylthio substituent. With N-[(3-phenylthio)-prop-2-enyl]-2-lithiopyrrolidine, cyclization to the four-membered ring occurs with poor enantioselectivity at low temperature in THF but is highly enantioselective at room temperature in a solvent of very low polarity.     

Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.