Palladium natural product synthesis

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

The relevance of the palladium-catalyzed amidocarbonylation for natural product synthesis has been demonstrated with the multi gram-scale preparation of the central amino acid of chloropeptin I ((S)-3,5-dichloro-4-hydroxyphenylglycine) as well as methionine and p-chlorophenyl alanine via the combination of amidocarbonylation and enzymatic hydrolysis (Table 4) [44]. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

Applications of this reaction are not limited to advanced materials, but can be applied to natural product synthesis. Indeed, indoles have quite recently (in 2008) been arylated in the presence of palladium acetate and silver oxide (Scheme 10.52).84... 

M. Toyota, M. Ihara, Development of Palladium-Catalyzed Cycloalkenylation and its Application to Natural Product Synthesis, Synlett 2002, 1211-1222. 

Stoichiometric palladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [140]. 

Organozinc reagents have been coupled with halides in the synthesis of dienes and other conjugated systems to form new carbon-carbon bonds such reactions have been reviewed477-479. In particular, the reaction of alkynyl zinc reagents with vinyl halides has been used in natural product synthesis, usually catalyzed by palladium complex catalysts. 

The preparation of amphimedine 7-46 published by Echavarren and Stille [512] is a noteworthy application of 2-aza-1,3-butadienes in natural product synthesis since it is an interesting combination of hetero Diels-Alder methodology with a palladium catalysed cross coupling. Thus, dienophile 7-44 was formed by Stille coupling of the triflate 7-42 with the stannyl aniline 7-43. This qui-none then underwent cycloaddition to the 2-aza-l,3-butadiene 7-45 an acid catalysed hydrolysis of the cycloadduct 7-47 and subsequent N-methylation completed the synthesis of amphimedine 7-46 (Fig. 7-11). 

After the intense use of concerted reactions for natural product synthesis, the related metal-catalyzed cyclizations gained ground in the 1980s and 1990s. Several authors demonstrated the effectiveness of these reaction types for the synthesis of dendrobine (82). Takano et al. and Zard et al. used the Pauson-Khand reaction as a key step for their EPC-synthesis efforts (144,165,166). Mori et al. relied on the more stable zirkonacycle in a related key step (167-169), while Trost et al. employed a palladium-catalyzed alkylation as well as a palladium-catalyzed ene reaction as key steps (170). Takano s efforts ended with the tricyclic skeleton of dendrobine, whereas Mori and Trost finished their formal EPC-syntheses with intermediates of Kende s and Roush s racemic S3mtheses, respectively. Both completed dendrobine synthesis would have necessitated more than 20 steps. 

Palladium on barium sulfate has been used in the hydrogenolysis of epoxides in natural product synthesis. The reaction in equation (25) illustrates its high level of functional group compatibility. 

Considering the industrial importance of cyclopropanes in the pesticide field, it is not surprising that chiral ferrocenylphosphines have been applied as control ligands for the palladium-catalyzed enantioselective formation of cyclopropanes from the dicarbonate of 2-butene-1,4-diol and malonates, leading to 70% ee (Fig. 4-32e) [179]. Ferrocenylphosphines also induce chirality in the reaction of sulfonyl-substituted propenyl carbonates and acrylic esters to methylenecyclopentanes (up to 78% ee (Fig. 4-321)) [180], with potential applications in natural product synthesis. These examples show that the synthetic potential of chiral ferrocene derivatives is not yet fully exploited, and one may look forward to new applications. 

The intermolecular examples of synthetic value are self-couplings, e.g. formation of the dimer (43) from benzylsesamol, in 85% yield using vanadium oxytrifluoride preparation of the biaryl (44 95%), from 4-methylveratrole, employing iron(III) chloride supported on silica and synthesis of 4,4 -dimeth-oxybiphenyl (69%) fr om anisole by oxidation with thallium(III) trifluoroacetate in the presence of catalytic palladium(II) acetate. This approach has been used in a natural product synthesis. The dimers (45) and (46) were prepared from appropriate derivatives of gallic acid, and transformed into schizandrin C (47) and an isomer respectively. ... 

Apart from the aforementioned results the usefulness of palladium-catalyzed aryl aminations is shown by applications in natural product synthesis. [18] In this regard the total synthesis of the toad poison dehydrobufetenine is... 

Cycloisomerization of enynes has been employed to construct an array of natural products.f " Although the precise mechanistic details of the reaction have not been elucidated, and may vary from case to case, one potential mechanism is shown in Scheme 28. Generation of an alkyl- or hydridopaUadium complex in the presence of enyne 183 may lead to carbo- or hydridopalladation to give an alkenyl palladium intermediate 184. Intramolecular cyclization (184 185) then follows to form five-, six-, or seven-membered rings followed by /3-hydride elimination to yield 1,4-diene 186 and/or 1,3-diene 187. There are also examples of yne-yne cyclizations in natural product synthesis. ... 

Figure 10.1 Palladium-catalyzed cross-coupling reactions in natural product synthesis and industrially prepared fine chemicals.

Corey and coworkers [45] later described the application of this reaction in the total synthesis of okaramine N (Scheme 9.16). Bisindole 110 was oxidatively cyclized using stoichiometric Pd(OAc)2 to form compound 111 in 38% yield. Although the yield was modest, the dihydroindoloazocine product could be elaborated in just two steps to afford okaramine N. This remarkably rapid synthesis highlights the efficacy of the palladium(II)-mediated oxidative Heck reaction to construct complex ring systems that can immediately expedite natural product synthesis. 

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