Intramolecular reactions, control constraint

The factors — or at least some of them — which control reactivity in intramolecular reactions are relevant to enzyme catalysis, which also involves reactions between functional groups brought together in close and precisely defined proximity (Kirby, 1980). This has been an area of lively discussion in the recent literature [for a brief summary and leading references see Paquette et al. (1990)]. The main difficulty in making generalizations about the dependence of reactivity on geometry based on results from systems in which proximity is covalently enforced lies in the constraints imposed by particular systems. These may well affect reactivity... 

In intermolecular Diels-Alder reactions, the combination of these effects, particularly with cyclic dienophiles, often leads to a preference for the endo adduct in the kinetically controlled reaction. In intramolecular reactions, the endo rule can be a good guide to the stereochemistry of the product, but as described in the next section, geometrical constraints may outweigh other factors and the exo product may predominate. 

Intramolecular reactions of the two arene components linked by a tether can occur regioselectively because of the geometric constraints. An example of an intramolecular direct arylation controlled by a temporary tether is shown in Equation 19.148. In this synthesis of dioncophylline C, two important features of intramolecular direct arylation are illustrated. First, intramolecular arylation reactions are typically used for the construction of five-, six- (as shown in Equation 19.148), and seven-membered rings. Second, direct arylation tends to occur at the less-hindered aryl C-H bond. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

Anodic C, C-coupling is a very powerful tool to synthesize cyclic compounds with high regio- and stereoselectivity. It involves inter- and intramolecular coupling of arylolefins, dienes, enolethers, phenol ethers, and aromatic amines and often opens a quick entry into complex natural products in a few steps. Although the mechanism is fully established in only a few cases, it does appear to involve the coupling of two radical cations at the site of their highest radical density and is further controlled by steric constraints. This important type of reaction is reviewed in Chap. 5 and in Refs. [89, 90]. 

In the solid state photorearrangement of cw-l,2-dibenzoylalkenes, intramolecular carbon to oxygen phenyl migration is reported to be controlled by synlanti conformational constraints, and in the photolysis of tmm-2,3-diphenyloxirane, quantum yields for formation of the trans ylid, cw-2,3-diphenyloxirane, benzalde-hyde, and deoxybenzoin have been measured. This reaction gives both orbital symmetry-allowed and -forbidden products. Photolysis of 2,3-diaroylaziridines... 

Intramolecular cyclizations offer a versatile method for the preparation of bicyclic and polycyclic ketones. Indeed, in favorable cases, reaction can ensue on simply heating the acyl halide " as well as on treatment with a Lewis acid, offering control of the product isolated (Scheme 3). However, the structural constraints imposed in detailed examination of specific ring systems in which the stereochemistry of cyclization can be determined may well preclude the deduction of more general conclusions about stereochemical control. 

Intramolecular Cyclopropanation. The resultant a-diazo-acetyl ester from the reaction of (1) and an unsaturated alcohol undergoes cyclization in the presence of transition metals to give cyclopropyl derivatives (eq 3, 4) the reaction proceeds via an intermediary carhene species. Owing to the geometric constraints of the intramolecular cyclopropanation, the substituents and the product acquire all-c/5 configurations. This is in contrast to the bimolecular cyclopropanation, which is unable to achieve stero-chemical control, resulting in mixtures of products. 

Substrate-controlled stereoselective dearomatizations provide cycloheptatriene derivatives in high diastereomeric excess, and the reaction has been used to prepare 7-membered ring systems found in several natural products. Scheme 15.27a illustrates the Rh(II)-catalyzed conversion of diazo derivative 72 to polycyclic cycloheptatriene 73, which was subsequently converted to har-ringtonolide [78]. Note that the initial cycloheptatriene product of the Buchner reaction is converted to a more stable isomer by the action of DBU. In some instances, intramolecular Buchner reactions afford norcaradiene products that are not in equilibrium with the corresponding cycloheptatrienes. These examples arise as a consequence of conformational constraints inherent in the substrates. Cu-catalyzed Buchner reactions have been anployed to access derivatives of stable norcaradiene fragments found in several natural products (e.g., gibberellin GA j and (-r)-salvileucalin B, Scheme 15.27b and c, respectively) [79]. 

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