Alkenes Heck cyclization

These reaction conditions have been employed in two total syntheses of ( )-gelsemine 93 on similar intermediates (Scheme 15). In one synthesis the key reaction (94- 5) is heavily sterically biased due to the presence of the bulky CHjOTDS group. In spite of this obstacle, a 2 1(95/96) ratio of oxindoles favoring spirocycle 95 is produced. The reaction will also tolerate a tetrasubstituted alkene. Heck cyclization of vinylogous carbamate 97 under cationic conditions stereoselectively delivers oxindole 99 en route to... 

In an extension of this work, the Shibasaki group developed the novel transformation 48—>51 shown in Scheme 10.25c To rationalize this interesting structural change, it was proposed that oxidative addition of the vinyl triflate moiety in 48 to an asymmetric palladium ) catalyst generated under the indicated conditions affords the 16-electron Pd+ complex 49. Since the weakly bound triflate ligand can easily dissociate from the metal center, a silver salt is not needed. Insertion of the coordinated alkene into the vinyl C-Pd bond then affords a transitory 7t-allylpalladium complex 50 which is captured in a regio- and stereocontrolled fashion by acetate ion to give the optically active bicyclic diene 51 in 80% ee (89% yield). This catalytic asymmetric synthesis by a Heck cyclization/ anion capture process is the first of its kind. 

The N-heterocyclic alkenes derived from ring-closing metathesis are useful substrates for further transformation. In a synthesis directed toward the insecticidal cripowellin 12, Dieter Enders of RWTH Aachen has shown (Angew. Chem. Int. Ed. 2005,44, 3766) that the tertiary amide 8 cyclizes efficiently to the nine-membered alkene 9. The vision was that an intramolecular Heck cyclization could then deliver the cripowellin skeleton. Indeed, the Heck did proceed, and, depending on conditions, could be directed toward either 10 or 11. Unfortunately, the conformation of 9 is such that the cyclization proceeded cleanly across the undesired face. Nevertheless, both 10 and 11 appear to be valuable intermediates for further transformation. 

Finally, the Heck reaction can be conducted as an intramolecular process where the -hydride elimination after the cyclizing alkene insertion is hampered, resulting in a highly reactive alkyl Pd species. Kim and Ahn [66] have introduced a sequential Heck-cyclization-Suzuki coupling that provides an... 

Although mechanistically ambiguous, Williams and co-workers, synthesis of (-p)-paraherquamide B (79) could exemplify an alternative strategy for initiating a Heck cyclization (Scheme 6-13) [281. In this case, indole 77 was exposed to a stoichiometric amount of PdCl2, which potentially generated a 2-palladated intermediate [29]. Intramolecular insertion of the disubstituted alkene and reduction of the resulting neopentyl cr-alkylpalladium intermediate with sodium borohydride provided 78 in 63-80% yield. 

Two distinct types of intramolecular Heck reactions are important in the chemistry of furans. The most straightforward are transformations involving halofurans reacting intramolecularly with alkenes. For example, 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 [139], Under Jeffery s phase-transfer catalysis conditions, substrate 158 is converted to tricyclic derivatives 159 and 160 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

A series of aryl radical cyclizations were reported by a group at Novartis [10], and some of these processes were also compared with bond formation by Pd-mediated Heck cyclization of the same substrates. The tributyltin hydride-mediated reaction of iodo alkenes 7 (Scheme 3), immobilized on polystyrene resin through a linker, gave dihydrobenzofurans 8 [11]. It was also possible to perform a tandem cyclization using allyltributyltin to give the allylated product 9, although the yields were less satisfactory. The radical cyclization onto enol ethers was demonstrated [12] by the conversion of 10 to 11. For best results, the tributyltin hydride and AIBN were added portionwise every 5-8 h. The impressive 95% yield was in fact higher than that for the solid-phase Heck cyclization of 10. Similarly, cyclization of anilide 12 afforded the phenanthridine 13. 

Trost and co-workers have made great strides in developing the palladium-catalyzed cycloisomerization of enynes into a powerful ring-forming method [39]. In most cases, the intimate details of these reactions are unknown. They are considered here, since a Heck cyclization is a potential step of one possible mechanistic sequence [40]. Two plausible mechanisms for palladium-catalyzed cycloisomerization of enynes are depicted in Scheme 6-17. In the Heck pathway (101 102 -> 103 - 104), hydropalladation of the alkyne is followed by alkene insertion and /3-hydride elimination to provide cyclic diene 104. 

The 5-exo intramolecular Heck reaction has been employed to construct both meso-chimonanthine 105 and (-)-chimonanthine 106 (Scheme 16). The synthetically most challenging structural features of these bispyrroloindoline alkaloids are their vicinal quaternary centers. The synthetic plan relies on two sequential 5-exo carbopallada-tions to stereoselectively produce pentacycles 102 and 104 from closely related intermediates. Heck cyclization of 100 requires a challenging tetrasubstituted alkene insertion to provide 101. A second 5-exo carbopalladation reaction adjacent to the newly formed quaternary center installs the second quaternary center and oxindole unit. The tartrate-derived ene-diamide 100 underwent bis-5-cJct) carbopalladation when... 

Carbopalladation has also been employed in the construction of six-membered rings. Most examples are 6-exo cyclizations as is the pyran ring synthesis (107—>108) used in the construction of ( )-6a-epipretazettine 109 and ( )-tazettine (Scheme 17). The Heck cyclization formed a quaternary center with a diastereoselectivity in excess of 20 1. The selectivity of the reaction is of particular interest in this case as it provides information about the orientation of the carbon-palladium a bond and the reacting aUcene in the carbopalladation transition state. Two limiting transition state geometries for the closure are intermediate 110, which leads to the observed product, and intermediate 111, which would lead to a diastereomer. In the preferred transition state 110, the carbon-palladium (7 bond and alkene are eclipsed, which is a lower energy state than the corresponding twisted orientation 111. 

In contrast to intramolecular carbonylative Mizoroki-Heck cyclizations, the intermolecular carbonylative reaction of aryl halides with alkenes has been much less explored. Figure 3.10 depicts one of these rare examples using a carbon monoxide pressure of 5 atm [62], Small... 

It is interesting to note that the substitution pattern of nonactivated alkene functions also has only minor influence on the 5-endo- ng Mizoroki-Heck cyclization (Scheme 5.15). The Mizoroki-Heck reaction of alkene 71 without terminal substitution proceeded well and provided indanone 72 in 65% yield (71 72) [40]. Furthermore, terminal substitution is tolerated -configured 73 was cyclized in moderate yield (52%) (73 74) [31], while... 

Jin and Weinreb [137, 138] reported enantioselective total syntheses of the 5,11-methanomorphanthridine Amaryllidaceae alkaloids (—)-pancracine and (-)-coccinine. They nsed a specific Mizoroki-Heck-cyclization to convert bromo olefin 197 into seven-membered exocyclic alkene 198 in good yield (Scheme 6.57). 

To date, a fully satisfactory explanation of enantioselective Mizoroki-Heck cyclizations that follow a neutral reaction pathway remains elusive. Direct halide ionization and alkene coordination (4->10) has been excluded as a possible pathway for this transformation, because different results are obtained when the same substrate is cyclized under cationic or neutral conditions. It is proposed that pentacoordinate complex 12 is an intermediate in... 

Overman and Rosen [76] reported a total synthesis of spirotryprostatin B (137), a structurally novel diketopiperazine alkaloid, that featured a cascade Mizoroki-Heck cyclization/jj -allylpalladium capture process and the exploration of a related catalytic asymmetric sequence (Scheme 16.36). The plan was to relay the relative configurations of the quaternary stereocentre and the adjacent tertiary stereocentre in the natural product from the geometry of the trisubstimted alkene in the Mizoroki-Heck cyclization substrate. It was anticipated that the favoured 5-exo intramolecular Mizoroki-Heck cyclization of enantiopure triene precursor 135 would generate an -allylpalladium intermediate, with a chiral palladium catalyst controlling the absolute configuration of the initially formed quaternary carbon stereocentre. 

This fundamental experiment has strong implications on related catalyst-controlled Mizoroki-Heck cyclizations of precursors of this type. As axial chirality in 113 sets the stereochemistry in 114, enantioinduction was rationalized to arise from a dynamic kinetic resolution of (at elevated temperature) rapidly interconverting enanhomers of 113 in the oxidative addition step, rather than in the alkene coordination-migratory insertion event. Such a dynamic kinetic resolution process has been previously proposed by Stephenson et al. within their mechanistic study regarding the conformations of helically chiral 2-iodoanilides in intramolecular asymmetric Mizoroki-Heck reactions [72],... 

In addition, vinyl bromides (2) bearing an extra alkene tether were used for the preparation of differently sized, fused bicyclic -lactames of nonconventional structure via Heck cyclization. 

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