Hydroxylamines, intermolecular nitrone

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

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... 

Fisera et al. used the SmIa-HaO reagent system for the intermolecular coupling of nitrone 65 and methyl acrylate to give hydroxylamine 66 in high yield and diastereoisomeric ratio (Scheme 22). The anti relationship of the two acetonides proved crucial for efficient coupling. Using this strategy, 3,7a-di-epz-hyacinthacine Aj was synthesized in 13% overall yield from o-ribose. 

When 90 was heated in toluene, the hydroxylamine added to the alkyne to afford nitrone 91 (after tautomerization of a presumed intermediate N-hydroxyenamine) which was trapped by styrene in an intermolecular 1,3-dipolar cycloaddition to provide 92. An oxidation state adjustment (with removal of the chiral auxiliary) gave 93. The TBDPS protecting group was removed and the resulting primary alcohol was oxidized with IBX (94) (related to the Dess-Martin periodinane) to give aldehyde 95. Application of the Yamamoto variation of the Peterson olefmation gave 96 with decent control over olefin geometry. 

In a manner different from Zhu s, Rueping and coworkers [17] utilized -substituted hydroxylamines 32 as starting materials for the generation of the key intermediate nitrones 35 under visible-light-induced aerobic oxidation conditions (Scheme 13.6). Following intermolecular cycloaddition with 33, intermediate 35 was transformed into a range of isoxazolidines. Three possible pathways for the formation of the nitrone intermediate were proposed, and none could be ruled out. 

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