Nitrones, addition

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Many other functional groups are reduced by Sml. For example, sulfonyl halides are converted to disulfides. The reduction of nitro compounds by this reagent enables synthesis of 1,2-diamines based on a reaction sequence initiated by nitronate addition to aldimines, and in the presence of nitriles it furnishes amidines, and that of isothiocyanates in the presence of conjugated esters, the half thioamide derivatives of succinic esters. 

Recent intramolecular cycloadditions of nitrones have been effectively used in the synthesis of alkaloids. Further examples of the synthetic utility of nitrone additions are given in Scheme 8. 

An intermolecular cyclization approach to C3 asymmetric oxindoles has been devised by Smith and coworkers who paired chiral A-phenylnitrone nucleophiles with ketene electrophiles, e.g., intermolecular fusion of 54 and 55 [37]. As illustrated in Scheme 16, the oxindole skeleton 57 materialized in 87% ee following a proposed sequence of nitrone addition to the ketene, a hetero-Claisen rearrangement, imine hydrolysis and, finally, cyclization to generate the lactam linkage. As an extension of this methodology, (5)-3-allyl-3-phenyloxindole 57 was transformed into enantiopure 3-phenyl-hexahydropyrroloindole scaffold 58. 

At equilibrium, all four compounds are present in the exchange pool with some slight selectivity for the two nitrones. Addition of any maleimide species irreversibly transferred the nitrone structmes from the DCL into the product pool by forming the isoxazolidine cycloadduct. In the case of the recognition-disabled methyl ester 57, reaction with the nitrone species was slow and unselective. Both nitrones were converted in the same extent, and the... 

The amino-oxazoline 37, and hence the trehalose inhibitor trehazolin 38, have been prepared by nitrone addition to a hexenal derivative obtained from D-glucose. Compound 38 has also been synthesized together with analogues 39 (both epimers) from myo-inositol to establish the correct structures of trehazolin and its epimer trehalostatin. >102... 

An open transition state has also been evoked for nitronate addition to sulfinamide 253. The reaction was used as part of a sequence to synthesise an LpxC inhibitor 255 for the treatment of bacterial infections (Scheme 14.83). ° Compound 254 was obtained in 96% de. 

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