Intermolecular cycloadditions natural products

Intermolecular cycloadditions or Diels-Alder reactions have proved to be a successful route to several valuable intermediates for natural product syntheses. In creating new chiral centers, most of these reactions apply single asymmetric induction. As mentioned in Chapter 3, in the asymmetric synthesis of the octa-hydronaphthalene fragment, the Roush reaction is used twice. Subsequent intramolecular cyclization leads to the key intermediate, the aglycones, of several natural antitumor antibiotics. On the other hand, the Diels-Alder reaction of a dienophile-bearing chiral auxiliary can also be used intramolecularly to build... 

Both inter- and intramolecular [5 + 2] cycloaddition modes have been utilized in the synthesis of natural products. Successful intermolecular cycloaddition depends on making an appropriate selection of solvent, supporting electrolyte, oxidation potential, and current density. This is nicely illustrated in Schemes 23 to 25. For example, in methanol the controlled potential oxidation of phenol (101) affords a high yield (87%) of (102), the adduct wherein methanol has intercepted the reactive intermediate [51]. In contrast, a constant current electrolysis conducted in acetonitrile rather than methanol, led to an 83% yield of quinone (103). 

The anodic oxidation of 4-methoxyphcnols in acetic acid effectively stabilises the phenoxonium ion, in an equlibrium with the acetoxylation product. Tbis allows an intermolecular [5 + 2] bx-cycloaddition processes with some alkenes [110], The cycloaddition process has been used very successfully in the synthesis of a number of natural products [III]. The rate of cycloaddition is sensitive to substituents on the alkene bond and in imfavourable cases other reactions of the phenoxonium ion predominate. 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

The ability to produce 1,3-dipoles, through the rhodium-catalyzed decomposition of diazo carbonyl compounds, provides unique opportunities for the accomplishment of a variety of cycloaddition reactions, in both an intra- and intermolecular sense. These transformations are often highly regio- and diastereoselective, making them extremely powerful tools for synthetic chemistry. This is exemplified in the number of applications of this chemistry to the construction of heterocyclic and natural-product ring systems. Future developments are likely to focus on the enantioselective and combinatorial variants of these reactions. 

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. 

The intermolecular Diels-Alder reaction between the dibromoenone (111) and dienes (112) provides access to bicyclo[5.4.0]undecane systems (113) that are common core structures of many natural products (Scheme 32).118 The alio-threonine-derived O-(/ -biphenyl carbonyl oxy)-/i-phenyloxazaborolidi none catalyses the enan-tioselective Diels-Alder reaction of acyclic enones with dienes.119 The reversal of facial selectivity in the Diels-Alder cycloaddition of a semicyclic diene with a bro-moenone was induced by the presence of the bromo substituent in the dienophile.120 Mixed Lewis acid catalyst (AlBr3/AIMe3) catalyses the Diels-Alder reaction of hindered silyloxydienes with substituted enones to produce highly substituted cyclohexenes.121 Chiral /V-enoyl sultams have been used as chiral auxiliaries in the asymmetric Diels-Alder reactions with cyclopentadiene.122... 

The catalyst Col2(dppe)-Zn/ZnI2 catalyses the 6 + 2-cycloaddition of cyclohepta-triene with terminal alkynes to afford 7-alkylbicyclo[4.2.1]nona-2,4,7-trienes in good yields 239 The intermolecular 6 + 3-cycloaddition of fulvenes (213) with 3-oxidopy-rylium betaines (212) yields (214), which, after a 1,5-hydrogen shift, yields the 5,8-fused oxabridged cyclooctanoids (215). This methodology can be used for the preparation of fused cyclooctanoid natural products such as dactylol and precapnella-diene (Scheme 60).240... 

Intermolecular.- Reviews have described some of the photochemical (2+2)-cycloaddition reactions of enones used in the synthesis of natural products. Other reports have also focussed on such additions as key steps in the design of natural products. Thus the photoadducts obtained by the cycloaddition of the enone (61) to the alkene (62) have been used as the starting materials for the synthesis of terpenoid intermediates. ... 

Natural products presumably biosynthesized through a [4 + 2] cycloaddition frequently occur in the literature. Several reviews on natural Diels-Alder-type cycloadducts covered more than 300 cycloadducts, including polyketides, terpenoids, phenylpropanoids, alkaloids, and natural products formed through mixed biosynthetic pathways. Representative examples of natural [4 + 2] adducts are shown in Figure 1. These include intramolecular adducts pinnatoxin (5) and nargenicin (6), a simple intermolecular adduct... 

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-... 

Intermolecular Cycloaddition - Cycloaddition reactions continue to be a valued route to compounds that are key intermediates in the synthesis of natural products or other compounds of general interest. 

The azaphenanthrene alkaloid eupolauramine appeared to be an ideal target for exploring the applicability of an intramolecular Kondrat eva pyridine synthesis in the construction of natural products. Despite the fact that 2-phenyloxazoles are unreactive in intermolecular cycloadditions, the Diels-Alder reaction of oxazole-olefin 97 was expected to provide the tricyclic framework of eupolauramine... 

Carbonyl ylides, most often in the form of isomunchnones (formed by decomposition of diketo diazo compounds in the presence of rhodium (II) acetate, and subsequent cyclization of the intermediate rhodium carbenoid species) are by far the most studied 1,3-dipolar cycloaddition partners for indole derivatives. These cycloadditions have been employed in elegant examples of complex ring construction en route to a number of polycyclic indole-containing natural products. Preliminary work by Pirrung [54, 55] (Scheme 23) on simple intermolecular cycloadditions was followed shortly by the utilization of intramolecular examples by Padwa, Boger and others. 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

Intermolecular " or intramolecular [2+2+2]-cycloadditions " of 1,6-enynes and carbonyl compounds take place in the presence of cationic gold catalysts. The latter have been used successfully in natural products synthesis. A skeletal rearrangement of a gold carbene intermediate is the key step in these transformations. 

The influence of solvents [64] and comparisons with catalysts of the diarylpro-linol series [65] were reported. For theoretical calculations on stereocontrol see Reference [66]. In addition, imidazolidin-4-one catalyzed cycloadditions have been used in several total syntheses of natural products. Intramolecular Diels-Alder reactions (IMDA) were reported as key steps in the synthesis of bicyclo-undecenes [67], amaminols [68], solanapyrones [69], telomerase inhibitor UCS1025A [70], englerin A [71], (-)-nor-platencin [72], and muironolide A [73]. In addition, asymmetric [3-1-2]-cycloadditions of azomethines were accomphshed in the presence of chiral imidazoUdinones [74]. Intermolecular cycloadditions of dihydropyridine 53 and acrolein catalyzed by imidazolidin-4-ones were reported. The chiral azabicyclo-octenol 54 was isolated as the important key intermediate in the total synthesis of lycopodium alkaloids [75] (e.g., ludduline) and oseltamivir (Scheme 4.19) [76]. 

In 2010, Wender et al. reported a cascade reaction by combining Rh and Ag catalysis, affording the commonly encountered bicyclo[5.3.0]decane ring systems [15]. This chanistry merged a Rh-catalyzed intermolecular [5+2] cycloaddition and a Lewis add-promoted Nazarov cycUzation, highlighting the cascade catalysis in the facile construction of natural product scaffolds (Scheme 9.12). 

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