Other Cationic Cyclizations

Scheme 11). Alternatively the quaternary salts can be converted thermally into acyliron chelate complexes which can then be oxidized to azetidinones (Scheme 12). Extension of the method to the synthesis of a condensed azetidinone is illustrated in Scheme 13, but the scope of the procedure has not been evaluated. It will also be of interest to assess the utility of other cationic organometallic complexes preliminary studies have shown that molybdenum complexes behave in an analogous manner but the oxidative cyclization is inefficient (Scheme 14). 

Other radical cyclization approaches to the synthesis of piperidines include a CAN-mediated stereoselective cyclization of epoxypropyl cinnamyl amines <06TL705> and a cyclization of (-trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality <06JOC8481>. 

Two possible mechanisms are proposed. Primarily the enol radical cation is formed. It either undergoes deprotonation because of its intrinsic acidity, producing an a-carbonyl radical, which is oxidized in a further one-electron oxidation step to an a-carbonyl cation. Cyclization leads to an intermediate cyclo-hexadienyl cation. On the other hand, cyclization of the enol radical cation can be faster than deprotonation, producing a distonic radical cation, which, after proton loss and second one-electron oxidation, leads to the same cyclo-hexadienyl cation intermediate as in the first reaction pathway. After a 1,2-methyl shift and further deprotonation, the benzofuran is obtained. Since the oxidation potentials of the enols are about 0.3-0.5 V higher than those of the corresponding a-carbonyl radicals, the author prefers the first reaction pathway via a-carbonyl cations [112]. Under the same reaction conditions, the oxidation of 2-mesityl-2-phenylethenol 74 does not lead to benzofuran but to oxazole 75 in yields of up to 85 %. The oxazole 75 is generated by nucleophilic attack of acetonitrile on the a-carbonyl cation or the proceeding enol radical cation. 

The previous chapter covered radical cation cyclization reactions that were a consequence of single-electron oxidation. In the following section, radical anion cyclization reactions arising from single-electron reduction will be discussed. In contrast to the well documented cyclization reactions via carbon-centered free radicals [3, 4], the use of radical anions has received limited attention. There are only a few examples in the literature of intramolecular reductive cyclization reactions via radical anions other than ketyl. Photochemi-cally, electrochemically or chemically generated ketyl radical anions tethered to a multiple bond at a suitable distance, have been recognized as a promising entry for the formation of carbon-carbon bonds. 

Johnson in 1993 described an approach to racemic p-amyrin involving application of a biomimctic polyene cyclization.7 In the same year Corey accomplished the enantioseleetive synthesis of compound 4. a key intermediate that opened the way to stereoselective preparation of compounds I, 2. and 3 8 A key step in the synthesis of P-amyrin (1) was the introduction of chiral oxazaboroli-dines for enantioseleetive carbonyl reduction. Ba ed on these methods, generation of an enantiomerically pure epoxide and its stereoselective cationic cyclization led to the pentacyclic system of structure 1 Diastereoselective cyclopropanation and an intramolecular protonation of a carbanion represent other interesting steps in this total synthesis. 

Cationic cyclization of trienone 276 can be controlled by the choice of the reagent. Thus, fluorosulphonic acid in 2-nitropropane at —70°C afforded a 14 9 1 mixture (70% yield) of cyclic products398, whereas other acidic conditions (95% H2SO4, 85% H3PO4 or SnCLO gave inferior results398,399. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

The primarily formed radical cation can undergo dimerization (path a), which very often is followed by intramolecular cyclization via an amino group to give symmetrically substituted pyrrols [Eq. (23)] [145]. In other cases, cyclization takes place via oxygen functions leading to bischromones [Eq. (24)] [146] or to furans [Eq. (25)] [147]. 

In many respects the Pummeter reaction can be regarded as the sulfur version of the Polonovski reaction (and vice versa), and by analogy to the Polonovski reaction the central intermediate is a sulfur-stabilized carbocation (thionium ion). Although the existence of this species is only transient, it reacts to give a number of different products, e.g. a-acetoxy sulfides, vinyl sulfides, cationic cyclization products, etc., depending upon the sulfoxide structure and reaction conditions. Other reaction pathways ate specific to the Pummerer reaction as a result of sulfur s ability to expand its valence shell (additive Pum-merer reactions). A moderate degree of asymmetric induction is also observed in certain Pummerer reactions, where optically pure sulfoxides are substrates. 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

In addition to their use in Mannich (and variant) reactions, iminium ions are useful for other cationic type cyclizations. Corey employed a novel tandem iminium ion cyclization as part of an elegant cascade used for the synthesis of aspidophytine. The reaction of tryptamine 292 and dialdehyde 293 in CH3CN at ambient temperature afforded the pentacyclic skeleton of the alkaloid (296 Scheme 54) (99JA6771). Condensation of the free amino functionality of 292 with the dialdehyde produced a dihydropyridinium intermediate 294 that then cyclized onto the indole n-bond to give 295. The iminium ion so produced underwent a second cyclization with the tethered allylsilane moiety to give 296. Protonation of the enamine in 296 provided still another iminium ion (297) that was then reduced with NaCNBH3 to furnish 298 in 66% yield. All of the above reactions could be made to occur in a single pot. 

Other Six-ring Syntheses.— The direct cationic cyclization of the aj8-unsaturated ketone (98) under acidic conditions has been reported, and provides a convenient route to 9-methyldecalin-2-ol-5-one (99), a useful intermediate in eudesmane... 

On the other hand, cyclization of primary alcohol 42, bearing juxtaposed groups for cation stabilization (Me, H), gave predominantly products resulting from rearrangement. 

The cationic cyclization of polyisoprene with acid catalysts is well documented. The same reaction in polybutadienes requires much more severe conditions, higher temperatures and more acidic catalysts, and until recently has received much less attention. A cyclized polymer with a reduction of 35—40% of the initial unsaturation, can be prepared by treating cis-l,4-polybutadiene with an alkyl aluminium chloride-organic halide catalyst in xylene solution at >100 C."- Such polymers, containing polycyclic sequences apparently at random within the chains, have better skid resistance and tensile properties than the parent polymer. Cyclization has been reported to accompany other reactions in polydienes, for example the radiation-induced addition of carbon tetrachloride to 1,2-polybutadiene, and the direct addition of a o j unsaturated carboxylic acids (acrylic and cinnamic) to polydienes and polypentenamers. It is reported that the thermal isomerization of cis-transoidal poly(phenylacetylene) is accompanied by cyclization, and additionally chain scission and aromatization at temperatures >120°C. ... 

Facile cycloalkenylations of carbonyl groups have been carried out with cyclopropylphosphonium fluoroborates . Complex carbocyclic systems, such as the sesquiterpene a-cedrene, can be effectively constructed by cationic cyclization Epoxide cleavage which follows upon dissolving metal reduction of proximal cyclopropane rings makes possible the ready synthesis of functionalized strained ring compounds inaccessible by other methods... 

One early example was reported by Chatteijee in 1979 for stereospecific synthesis of the sesquiterpene isocomene by transannular cationic cyclization. The acid-catalyzed cyclization of epoxide 152 through transannular participation of the remote double bond led to the formation of 153 (Scheme 20.37), which was further transformed to isocomene. The reaction was stereoselective since formation of any other diastereomers will lead to the formation of much strained polycyclic systems with trans-fased cyclopentanes. 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

Acyclic C5. The C5 petroleum feed stream consists mainly of isoprene which is used to produce rubber. In a separate stream the linear C5 diolefin, piperylene (trans and cis), is isolated. Piperylene is the primary monomer in what are commonly termed simply C5 resins. Small amounts of other monomers such as isoprene and methyl-2-butene are also present. The latter serves as a chain terminator added to control molecular weight. Polymerization is cationic using Friedel-Crafts chemistry. Because most of the monomers are diolefins, residual backbone unsaturation is present, which can lead to some crosslinking and cyclization. Primarily, however, these are linear acyclic materials. Acyclic C5 resins are sometimes referred to as synthetic polyterpenes , because of their similar polarity. However, the cyclic structures within polyterpenes provide them with better solvency power and thus a broader range of compatibility than acyclic C5s. 

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