Cationic cascade cyclization

Scheme 2 7 A cationic cascade cyclization to synthesize 8-oxabicyclo[3,2,l]octanes.

Jiricek, J., Blechert, S. (2004). Enantioselective synthesis of (—)-gilbertine via a cationic cascade cyclization. Journal of the American Chemical Society, 126, 3534-3538. 

As presented in this chapter, olefins can become protonated under acidic conditions, leading to the formation of electrophilic and cationic carbon atoms. Furthermore, because olefins have nucleophilic character, they can add to sites of positive charge. The cascading of this mechanism, illustrated below, generates polycyclic systems through the cation-77 cyclization. 

Goeller, F., Heinemann, C., Demuth, M., Investigations of Cascade Cyclizations of Terpenoid Polyalkenes via Radical Cations. A Biomimetic type Synthesis of ( ) 3 Hydroxy spongian 16 one, Synthesis 2001, 1114 1116. 

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. 

The distyrylbenzene derivative (141) is photochemically reactive on irradiation in solution. The solvent of choice is acetonitrile/benzene/water (7 2 1) saturated with ammonia. The reactions encountered with this system are derived from electron transfer initiated by p-dicyanobenzene as the electron accepting sensitizer. This process yields the radical cation (142) of the starting material and also the cyclized radical cation (143). These species are trapped by ammonia to yield the final products (144) and (145) in the yields shown. The naphthyl system [141, R-R = (CH=CH)2] is also reactive and affords the analogous products (146) and (147). A study has examined the photochemically-induced cyclization of tetraenes such as (148) under SET conditions in aqueous acetonitrile solution. A variety of electron accepting sensitizers was used. In the example cited the sensitizer (149) was effective and the cascade cyclization yielded the product (150). 

Platinum Phosphine-platinum(II) electrophiles can initiate the biomimetic polyalkene cascade cyclization that does not require special terminating groups. Cationic platinum(n) complexes [( bpy)Pt(Ph)(L)]+ [ bpy=4,4 -di-t-butyl-2,2 -bipyridyl L = THF (tetrahydrofuran), NC5F5, or NCMe] have been reported to catalyse the hydrophenylation of ethylene, producing ethylbenzene and isomers of diethylbenzene. Mechanistic studies support a reaction pathway involving ethylene coordination to Pt(n), followed by insertion of ethylene into the Pt-phenyl bond, and... 

A triflic acid-catalysed cascade cyclization of arenyl 1,7-enynes apparently proceeds through acetylene-cation cyclization followed by Friedel-Crafts reaction (Scheme 38)7 ... 

In 2007, Gagne s group succeeded in a regio- and diastereoselective oxidative polycyclization of di- and trienols catalyzed achiral [(dppe)Pt] dications, wherein turnover was achieved by the trityl cation abstracting a hydride from a putative [(dppe)Pt-H] intermediate [32i]. One year later, Gagne s group developed the catalytic enantioselective polyene cyclization induced by [(S)-(xylyl-PHANEPHOS) Pt][(BF )j] catalyst, which was prepared from (S)-(xylyl-PHANEPHOS)PtIj and AgBF in situ (Scheme 9.21) [32j]. This asymmetric catalysis enables the oxidative cascade cyclization of polyalkene substrates [32k] (Scheme 9.15). 

Along the same lines, Kilburn and coworkers have shown that BF3 AcOH, a mild Lewis acid, is able to promote the cascade cyclization of trimethylsilyl-substituted methylene cyclopropyl ketone (146) to afford the oxabicyclic compound (147) through the intermediacy of the allyl cation (148) (Equation 88) [90]. 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

A very impressive multiple cationic domino reaction was used in the enan-tioselective total synthesis of (-)-gilbertine (1-190), described by Blechert and coworkers [50]. When the tertiary alcohol 1-184 is treated with TFA, a carbocation is formed which undergoes a cascade of cyclizations to afford 1-190 in very good yield (61 %) (Scheme 1.44). The cations 1-185 to 1-189 can be assumed as intermediates. 

Four cationic palladium intermediates in the Pd(0)-catalysed three-component cascade double addition-cyclization of organic halides, 2-(2,3-allenyl)malonates, and imines have been characterized by the high-resolution ESI-FTMS technology.84... 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

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). 

Curiously, certain cyclases, notably (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase, are capable of cyclizing, at relatively slow rates, the 3S-linalyl pyrophosphate enantiomer to the respective antipodal products, (-)-bornyl pyrophosphate and (+)-endo-fenchol (74,75). Since both (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase produce the designated products in optically pure form from geranyl, neryl and 3R-linalyl pyrophosphate, the antipodal cyclizations of the 3S-linalyl enantiomer are clearly abnormal and indicate the inability to completely discriminate between the similar overall hydrophobic/hydrophilic profiles presented by the linalyl enantiomers in their approach from solution. The anomalous cyclization of the 3S-enantiomer by fenchol cyclase is accompanied by some loss of normal regiochemical control, since aberrant terminations at the acyclic, monocyclic and bicyclic stages of the cationic cyclization cascade are also observed (74). The absolute configurations of these abnormal co-products have yet to be examined. 

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