Heck reaction natural products carbopalladation

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

D.i.b. Insertion of Another Alkenyl Unit In certain cases, however, the 3-exo-trig process may be retarded and an additional alkene moiety participates in the cascade carbopalladation. A pioneering example of this kind has been demonstrated by Overman and co-workers in their total synthesis of scopadulcic acid A, starting from an iodoaUcenyl-substituted methylenecycloheptene derivative (Scheme 24). The first intramolecular carbopalladation occurs across the disubstituted double bond of the exomethylene group, and the trisubstituted endocyclic double bond acts as the terminator to give a tricyclic system, which was further elaborated to the natural product (Scheme 24). It is remarkable that all three quaternary carbon centers can be created by intramolecular Heck reactions. 

Another common use of carbopalladation is to effect a net annelation by side chain installation followed by cyclization. One example from the synthesis of a protected form of the 2-quinolone portion of streptonigrin 40 begins with iodide 37 (Scheme Heck reaction of this electron-rich fully substituted aryl iodide 37 with methyl acrylate provides the substimtion product 38. Extended reflux of 38 under acidic conditions promotes double deprotection, isomerization, and cyclization reaction yielding enamide 39. Another example from the synthesis of ( )-aurantioclavine 41 involves coupling of aryl bromide Standard Heck conditions provide the substitution product 43 in excellent yield at the appropriate oxidation state for cyclization to form the azepine ring en route to the natural product... 

Intramolecular carbopalladation has widely been used to assemble the polycyclic frameworks of natural products. The majority of these carbopalladations are intramolecular Heck reactions and examples of 5-exo, 6-exo, 1-exo, -exo, 6-endo, S-endo, and macro-cyclic ring closures will be presented (Scheme 12). Examples fall into two basic categories vinylic substitution (75- 76) and quaternary center construction (77- 78). Investigation of domino reactions like polyene cyclizations (79- 80) and asynunetric Heck reactions (81 82) has been fruitful. 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treaunent) from a total synthesis of ( )-physostigmine 203 (Scheme The reaction occurs in 84% yield with 95% ee,... 

Initial attempts to extend this methodology to the formation of cyclohexane derivatives were unsuccessful.The carbopalladation reaction of dimethyl 5-hexenylmalonate in the presence of phenyl iodide only gave rise to products issued from the classical Heck reaction (Table 2). No traces of the desired 6-exo cyclization product were detected. Further investigation, however, showed that the course of the reaction is strongly affected by the nature of the nucleophile. When one or both of the malonate esters were replaced by a nitrile, then no Heck reaction was observed under identical conditions. Instead, the cyclization products 31 were obtained. 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

During the carbopalladation two possible alkylpalladium(II) intermediates can be formed resulting in two different products 1,1- or 1,2-disubstitued olefins. A number of strategies have been disclosed regarding the control of the regiose-lectivity in the Heck reaction, which can be influenced by factors such as the ligands, solvents, additives and the nature of the electrophile and the olefin. The difference between the two possible outcomes originates from the fundamental mechanisms of the carbopalladation, represented by the neutral and the cationic pathway (Schemes 1.11 and 1.19) [73, 74]. 

Some heterocycles undergo facile inter- and intramolecular arylations. Two mechanistic explanations of the arylation are possible. The Heck-type reaction is one of them. Carbopalladation of one of two double bonds with Ar-Pd-X gives la, which is stabilized by jr-allylpalladium formation. Pd and jS-H is anti in la and hence syn f-H elimination is not possible. Therefore, in stereoisomerization from anti la to syn lb a relationship between Pd and jS-hydrogen occurs, and syn y3-H elimination from lb affords the arylation product (path a). Another explanation is electrophilic substitution with Ar-Pd-X. Since arylations occur mainly at electron-rich carbons of heterocycles, they can be understood as electrophilic substitutions (path b). In some cases, a Heck-type mechanism seems to be more reasonable. Certainly arylations proceed by one of these mechanisms depending on the electronic nature of the substrates and reaction conditions, and hence further mechanistic studies are necessary. 

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