Natural product synthesis intermolecular reactions

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. 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

However, from the outset of this field, the limitations as well as the potentials of this cycloaddition were also apparent. For instance, the efficiency of this cycloaddition in an intermolecular manner was typically low unless strained olefins were used. Moreover, the use of unsymmetrical alkenes led to a mixture of the cyclopentenone regioisomers. Synthetic utility of this reaction is considerably expanded by the emergency of the intramolecular reaction. Schore introduced the first intramolecular version forming several rings simultaneously, which is now the most popular synthetic strategy in natural product synthesis because of its conceptual and operational simplicity. Additionally, the regiochemistry is no longer the problem in this variation. 

Chiral cyclohexenones have been frequently employed in intermolecular [2 + 2]-photocydoaddition reactions directed towards natural product synthesis. A further case in point is the reaction of cydohexenone 32 with trans-1,2-dichloroethylene... 

Both inter- and intramolecular cycloaddition modes have been explored and utilized in the synthesis of natural products. Successful intermolecular cycloaddition depends upon making an appropriate selection of solvent, supporting electrolyte, oxidation potential, and current density. This is nicely illustrated in the equations portrayed in Schemes 22 and 23. For example, in methanol the controlled-potential oxidation of phenol 251 affords a high yield (87%) of 252, the adduct wherein methanol has intercepted the reactive intermediate [62]. In contrast, another constant-current electrolysis afforded an 83% yield of quinone 253 when the reaction was conducted in acetonitrile, rather than in methanol. 

Reductive cyclizations have recently been reviewed [206], and applications to natural product synthesis can be found in Chapter 19. In this section only intramolecular reactions involving carbon-carbon multiple bonds (i.e., similar to the intermolecular reactions discussed earlier) will be treated. 

Rhodium(II)-mediated reactions have found many applications. The literature up to 1985 in intramolecular and intermolecular cyclopropanations, including choice of catalysts and mechanistic aspects, has been thoroughly reviewed by Maas [9]. More recent reviews are available that focus on the ligand effects and mechanism [10], and on their utilization in fine organic synthesis as well as in natural product synthesis [11]. All of these reviews, and in particular McKervey s comprehensive review [11a] on organic synthesis with a-diazocarbonyl compounds, deal with the utilization of functionalized diazo compounds as carbenoid precursors. Herrmann et al. surveyed the organometallic chemistry of diazoalkanes [11c, lid]. 

Beside the retro Diels-Alder procedure, we have extensively applied intermolecular and intramolecular Diels-Alder reaction for natural products synthesis. Palitantin (44), one of the highly oxygenated cyclohexane derivatives, was isolated from Pemcillium... 

Owing to the interest in cycloadducts of dioxinones in the synthesis of natural products, the intermolecular 2 -i- 2 photocycloaddition reaction of numerous dioxinones has been generalized [159]. In an attempt to control the regioselectivity of the cycloaddition and the configuration of the asym-... 

Schore introduced the first examples of intramolecular Pauson-Khand reaction (Scheme 2-13), resolving the regioselectivity issue observed in the intermolecular Pauson-Khand reaction. The intramolecular version employs a carbon tether, linking the alkene and alkyne moieties, leading to the formation of a bicyclic product. Since the debut of this reaction, it has been extensively used as the key step in natural product synthesis. ... 

Stille reactions are finding increasing use in natural product synthesis, employing both intermolecular and the more attractive intramolecular reaction mode. The individual coupling that is most frequently used is that between vinyltins and vinyl... 

NATURAL PRODUCTS SYNTHESIS VIA INTERMOLECULAR [4+3] CYCLOADDITION REACTIONS... 

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