Alkenes intramolecular nitrone-alkene cycloadditions

The in situ formation of nitrones from oximes by 1,3-APT or 1,2-prototropy is clearly a powerful synthetic strategy but conventional nitrone generation, in particular hydroxylamine-carbonyl condensation, has been applied to numerous syntheses, in intra- and intermolecular mode (258). Accordingly, the ring systems similar to those synthesized using 1,3-APT/intramolecular nitrone-alkene cycloaddition (INAC) methodology by Heaney (313-315) (see Section 1.11.2) or Padwa and Norman (340) have been made using conventionally prepared nitrones (Scheme 1.67). As with the previous examples, once formed, the nitrones are suitably placed for a spontaneous intramolecular cycloaddition reaction with the... 

Tricyclic P-lactams not having a bridgehead nitrogen atom have been obtained by intramolecular Friedel-Crafls reactions <99T5567> and from the intramolecular Diels-Alder reactions of 1,3-dienes generated from a mesylate 79 <99TL1015>. Other tricyclic P-lactams e.g., 80 have been obtained by intramolecular nitrone-alkene cycloaddition <99TL5391>. 

In an approach to the clavine alkaloids [170] based on intramolecular nitrone-alkene cycloaddition, the condensed tetracyclic system is probably favored by steric factors. Equilibration at higher temperature leads to predominantly a bridged oxabicyclo-[3.2.1]nonae derivative in which a portion of the molecule contains polarity alternation sequence (OCOC=0, N-C-C-C=0). 

They have also reported a direct route to optically pure, fused, or bridged tricyclic (3-lactams (III and IV, Fig. 18) as further advances in the intramolecular nitrone-alkene cycloaddition reactions of monocyclic 2-azetidinone-tethered alkenyl-aldehydes [289]. 

The intramolecular nitrone-alkene cycloaddition of /raor-alkenylaldehyde (+)-34 results in a 75 25 mixture of bridged diastereomers (+)-35 and (+)-36 in 52% and 18% yield, respectively (Scheme 5). The stereochemistry of these isomers has been assigned using NOE data <2005EJ01680>. 

The cycloadduct 92 has been synthesized from 238 through a regio- and stereocontrolled intramolecular nitrone-alkene cycloaddition (Scheme 54) <2002SL85>. 

Similarly, regio- and stereoselective syntheses of optically pure fused or bridged 1,2,5-oxadiazepines have been reported via intramolecular nitrone-alkene cycloaddition <2005EJ01680>. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

The intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses 110 can proceed either via the exo-mode to give fused isoxazolidines 111 or the endo-mode to give the bridged 1,2-oxazocines 112 (Scheme 23). 

Intramolecular nitrone-alkene cycloaddition. Reaction of cycloalkanones substituted by a 3-(2-propenyl) or a 3-(3-butenyl) side chain with alkylhydroxylamines with azeotropic removal of water results in a bridged bicycloalkane fused to an isoxazolidine ring. The transformation involves formation of a nitrone that undergoes intramolecular cycloaddition with the unsaturated side chain. 

Intramolecular nitrone/alkene cycloaddition reactions3-9,35 can be performed with C-alkenyl or a-alkenyl nitrones at much lower temperatures than their intermolecular counterparts, as expected on the basis of entropy considerations. 

The Wittig-Horner olefination of the aldehyde 28 provided alkenes 29 which were subjected to radical cyclization leading to benzofused tricyclic j6-lactams 30, obtained as single diastereomers (Scheme 8) [36]. A convenient, direct regio- and stereoselective route to optically pure unusually fused or bridged tricyclic /3-lactams has been developed by the use of intramolecular nitrone-alkene cycloaddition reactions. For example, the aldehyde 21 can be transformed into nitrone 31 which subsequently was used for a variety... 

The cyclopentane (3), a potent a-mannosidase inhibitor, has been prepared from a previously-known intermediate made by intramolecular nitrone-alkene cycloaddition (see Vol. 13, p. 152) an epimerization at the carbon atom indicated was effected at the aldehyde oxidation level.3... 

The intramolecular oxime-alkene cycloaddition (lOAC) proceeds via N—H nitrones, in contrast to most other nitrone syntheses, which afford N-alkylated 1,3-dipoles. This process was used by WUdman and co-worker (332) in the synthesis of 6-hydroxybuphanidine and 6-hydroxypoweUine, and since then by... 

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