Intramolecular cycloadditions synthesis applications

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

There are many types of Diels-Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

The intramolecular cycloaddition reaction of enamides has recently been exploited in alkaloid synthesis (81JOC3763). Application of A2-piperideine derivatives resulted in the... 

Less well-established cycloaddition chemistry has also found application in the synthesis of heterocyclic compounds in recent years. An example is the intramolecular cycloaddition of silyl nitronates that has been employed by Ishikawa and Saito to afford 136 in their synthesis of amino polyols (Scheme 14) <2003OL3875>. 

Ishikawa T, Shimizu Y, Kudoh T, Saito S (2003) Conversion of D-glucose to cychtol with hydroxymethyl substituent via intramolecular silyl nitronate cycloaddition reaction application to total synthesis of (+)-cyclophelhtol. Org Lett 5 3879-3882... 

Ishikawa, T., Shimizu, Y., Kudoh, T., Saito, S. Conversion of D-Glucose to Cyclitol with Hydroxymethyl Substituent via Intramolecular Siiyi Nitronate Cycloaddition Reaction Application to Total Synthesis of (+)-Cyclophellitol. Org. Lett. 2003, 5, 3879-3882. 

During the past few years, Weinreb and co-workers have published a series of papers on studies of intramolecular imino Diels-Alder cycloadditions and applications of this methodology to alkaloid total synthesis.84 These cycloadditions have involved Af-acylimines as the dienophiles, generated thermally (hot tube pyrolysis) by acetic acid elimination of methy-lol acetates [Eq. (26)].85... 

The first application of intramolecular cycloaddition to the construction of natural products was to a total synthesis of hirsutene (52) [21]. Initially, an electron-withdrawing group was appended to the diylophile in order to assure the selective... 

For the synthesis of the sequiterpene (— )-cyclocopacamphene (6.112) an elegant application of an intramolecular cycloaddition, forming the annellated pyrazole derivative 6.111 followed by a photolytic azo-extrusion to the cyclopropane, was described by Piers et al. (1971). 

Microwave-induced 1,3-dipolar cydoaddition reactions involving azomethine ylides have been widely reported in the literature. In 2002 many examples were described in a book chapter by de la Hoz [3j], which provides extensive coverage of the subject. The objective of this section is to highlight some of the most recent applications and trends in microwave synthesis, and to discuss the impact of this technology. Highly stereoselective intramolecular cycloadditions of azomethine ylides have been performed under solvent-free microwave conditions. 

A domino Wittig intramolecular cycloaddition has been used in total synthesis several times [15,23,24]. Herdeis et al. showed an application of... 

Some intramolecular cycloaddition reactions of alkyl azidoformates are particularly successful and have useful applications in synthesis. An example is a route to derivatives of (-)-bestatin, an aminopeptidase inhibitor, in which the key steps are the formation of the bicyclic aziridine 25 followed by ring opening (Scheme 6.13). ... 

Intramolecular Cycloadditions.—Application of certain intramolecular reactions allows the synthetic chemist to generate complex carbon skeletons more readily than by using intermolecular processes, and to exercise considerable control over regio- and stereo-specificity. It is not surprising, therefore, that this area of endeavour has become increasingly popular in recent years. Dominant among the reactions under study has been the intramolecular [4 + 2] cycloaddition (i.e. the intramolecular variant of the Diels-Alder reaction), some examples of which have already been noted in earlier sections. The reaction has also been applied in total syntheses of steroids, ( )-cedrol, eudesmane sesquiterpenes, and norpatchoulenol. The intramolecular [3 + 2] cycloaddition, a related process, has been used by Confalone et al. in a synthesis of ( )-biotin. The key steps are... 

Recent synthetic applications of the photochemical [2 + 2] cycloaddition of unsaturated sulfones have been noted. Musser and Fuchs84 have effected an intramolecular [2 + 2] addition of a 6-membered ring vinyl sulfone and a five-membered ring vinylogous ester in excellent yield, as part of a synthetic approach to the synthesis of the mould metabolite, cytochalasin C. The stereospecificity of the addition was only moderate, however, and later problems with this synthetic approach led to its abandonment. Williams and coworkers85 have used the facile [2 + 2] photoaddition of 73 and... 

An in depth account of intramolecular 1,3-dipoIar cycloadditions involving dipoles such as nitrUe oxides, sUyl nitronates, H-nitrones, azides, and nitrUimines is presented with particular emphasis on the stereochemistry during the cycloaddition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed. 

Other applications of the [6 + 2]- and [6 + 4]-cycloaddition reactions in total synthesis have been reviewed.127 The two representative examples shown in Scheme 38 illustrate their use in the total synthesis of /3-cedrene and the taxane ABC ring system. The total synthesis of /3-cedrene utilized an intramolecular [6 + 2]-reaction128 to set up a tricyclic intermediate and the synthesis of the taxane ABC ring system is accomplished via a [6+ 4]-cycloaddition. 

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