1.3.4- Oxadiazoles intramolecular cycloadditions

Introduction Preparation of 1,3,4,-oxadiazoles Intermolecular cycloadditions of 1,3,4-oxadiazoles Tandem intermolecular-[4+2]/intramolecular-[3+2] cycloadditions of 1,3,4-oxadiazoles... 

However, its implementation in tandem intramolecular cycloadditions could expand the range of oxadiazoles that participate in the reaction cascade, extend their use to unsymmetrical dienophiles and oxadiazoles, control the cycloaddition regioselectivity, and increase the utility of tandem Diels Alder/l,3-dipolar cycloaddition reactions of such heterocyclic azadienes [196]. 

SCHEME 16.109 Effect of the C(5) substituent on the tandem, double intramolecular cycloaddition of 1,3,4-oxadiazoles. 

The tandem, double intramolecular cycloadditions of 1,3,4-oxadiazoles has also been used for the syntheses of several other pentacyclic Aspidosperma alkaloids (+)-fendleridine (also known as aspidoalbidine 520, Scheme 16.110), (+)-ace-tylaspidoalbidine 521 (Scheme 16.110), (—)-aspidospermine,... 

A systematic exploration of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

More recently, some examples of intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloaddition reactions of especially designed 1,3,4-oxadiazole derivatives have been described (Scheme 3). The... 

Intramolecular thermal [4+2] cycloaddition occurs smoothly, though at a high temperature, upon heating of the appropriately substituted electron-poor oxadiazole containing electron-rich alkene fragment (Equation 1) <2002JOC7361>. 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

A-phenylmaleimide/ ° The complex nitrile oxide (736), prepared from dichloroglyoxime (HON=CCl—CC1=N0H) and dipropargylamine, forms the intramolecular cyclo-adduct 137) 3,6-Diphenylpyridazine 1,2-dioxide (738) rearranges photochemically to the isoxazolo-isoxazole (739), which is also produced by the oxidation of the dioxime HON=CPhCH=CHCPh=NOH. Regiospecific cycloaddition of benzonitrile oxide to the pyrazoline (740) affords the pyrazolo-oxadiazole (741)/ ... 

Yuan ZQ, Ishikawa H et al (2005) Total synthesis of natural (+)- and ent-(—)-4-desacetoxy-6, 7-dihydrovindOTosine and natural aud eut-minoviue oxadiazole tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reaction. Org Lett 7 741—744... 

Elliott GI, Fuchs JR et al (2006) Intramolecular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles. J Am Chem Soc 128 10589-10595... 

The Diels-Alder cycloaddition has played an important role in the synthesis of Narcissus alkaloids and related structures. Roger has prepared anhydrolycorinone using an intramolecular hetero-Diels-Alder reaction in which a 1,3,4-oxadiazole... 

As illustrated in the Scheme 13.19, the key transformation was initiated by an intramolecular [4 -i- 2] cycloaddition reaction of a 1,3,4-oxadiazole 124 with a tethered dienophile, where the intrinsic regioselectivity was dictated by the linking... 

Dipolar cycloadditions of nitrile oxides to the various unsaturated alditol derivatives 92 led to pairs of isoxazolidine regio-isomers, e.g. 93 and 94, each as predominantly one stereoisomer (Scheme 16). The isoxazole 95 was the major product from addition of bromoformonitrile oxide to the nitro-alkene. The nitrile moiety of D-mannononitrile pentabenzoate was transformed into either a 3-substituted 5-methyl-1,2,4-oxadiazole moiety (with NH2OH then AC2O) or a 5-substituted 2-methyl-1,3,4-oxadiazole moiety (with NH4N3 then AC2O, Py) cf. Vol.24, p.l35. The synthesis of 2-(alditol-l-yl) substituted 2-aza-3,7-dioxabicy-clo[3.3.0]octanes by intramolecular dipolar cyclization of 2-0-d y -aldehydo-sugar nitrones is covered in Chapter 24. 

The tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of 1,3,4-oxadiazoles developed by Boger and coworkers (Scheme 16.1) are also well represented. In this process, a 1,3,4-oxadiazole acts as an electron-poor heterodiene and engages in an inverse-electron-demand [4 + 2] cycloaddition. This step is followed by a retro-[3 + 2] cycloaddition that generates a dipole, reacting further via a [3 + 2] cycloaddition step. This cycloaddition has been used as the key step in the total syntheses of several Vinca alkaloids. Only tandem cascade cycloadditions of this type have been reported. 

The Influence of the Tether Length on Reactivity in Tandem, Double Intramolecular [4+2]/[3+2] Cycloadditions of 1,3,4-Oxadiazole For the syntheses of Aspi-dosperma alkaloids, a four-atom tether to the dienophile is required to form the six-membered lactam 500a... 

The need for the high reaction temperature has been a major obstacle in developing the tandem cycloadditions of 1,3,4-oxadiazoles. As a consequence, chemoselectivity of such processes is poor. Successfiil activafion of the [4 + 2] step in such a tandem process using high pressure or Lewis acids is unknown. Only highly symmetrical products could be prepared until recently via double intermolecular and itner-[4 + 2]/intra-[3 + 2] variants. The chemoselectivity of a double intramolecular variant of the tandem process is not plagued by these limitations and it has been employed in the syntheses of Vinca alkaloids and their analogs. 

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