The mild cyanating agent trimethylsilyl cyanide adds with total stereoselectivity to α-alkoxy cyclic nitrones to afford the corresponding
trans-hydroxyaminonitriles. The addition of Lewis acids to ...precomplexing the nitrones does not affect the stereoselectivity of these additions significantly. In all of the cases examined, excellent yields of diastereomerically homogeneous products were obtained. On the other hand, the use of diethylaluminum cyanide as cyanating agent leads to low diastereoselectivities. Both NMR studies and theoretical calculations show that whereas the addition of trimethylsilyl cyanide takes place through a concerted mechanism, in the addition of diethylaluminum cyanide, a complex is formed prior to the intramolecular delivery of the cyanide ion.
Graphic
The diastereofacial selection in addition reactions to biased rigid systems can be modulated by the action of Lewis acids. As an example, the stereoselectivity of the nucleophilic addition of vinyl ...magnesium bromide (VMB) to cyclic nitrones in the presence of diethylaluminum chloride (DEAC) shows a strong dependence on the temperature and the carbon substituent adjacent at the reaction center; it is remarkable that whereas a high selectivity is obtained at higher temperatures, in the presence of DEAC, a trend to invert the stereochemical course of the reaction is observed at lower temperatures, provided the substituent at C3 of the pyrrolidine ring allows delivery of the vinyl moiety. This behavior and difference in selectivity is to be attributed to the high conformational barriers of the intermediate nitroneDEACVMB complex. A clear inversion of the selectivity is observed at −78 °C for the reaction of the nitrone protected as an O‐methyl derivative. The present study provides a rationalization for the stereocontrolled addition of nucleophiles to rigid systems (cyclic nitrones).
Diastereofacial discrimation: The vinylation of cyclic nitrones in the presence of diethylaluminum chloride shows a strong dependence on both temperature and steric hindrance at C3 (see scheme; s=solvent). Experimental, theoretical, and spectroscopic studies have been used for rationalizing the observed inversion of selectivity at low temperature.
Both the intramolecular cycloaddition of diastereomeric homochiral
N-alkenyl nitrones and the corresponding theoretical calculations using DFT and ab initio methods provided evidences of a thermal ...3,3 sigmatropic rearrangement of the nitrones with a complete chirality transfer.
Iteration of organometallic addition to chiral hydroxylated pyrroline N-oxides through an addition-oxidation-addition synthetic sequence allowed highly stereoselective double alkylation of ...pyrrolidine at C-2 or at C-2 and C-5 depending on the regioselectivity of the oxidation step. Application of this methodology has been exemplified by the synthesis of the all-substituted pyrrolidine alkaloid (−)-codonopsinine and of proline-type amino acid precursors possessing a quaternary stereogenic center, whose configuration can be controlled.
The stereocontrolled addition of allylic metals to chiral non-racemic nitrones promoted by the addition of Lewis acids is described. Whereas for α-alkoxy nitrones the stereocontrol depends on the ...Lewis acid used as an activator, for α-amino nitrones the diastereofacial course of the reaction depends on the protection of the α-amino group. The successful implementation of the methodology is represented by the enantiodivergent synthesis of
d- and
l-allylglycine.
The nucleophilic addition of lithiated allylphenylsulfone to nitrones at −80
°C proceeds exclusively α to the phenylsulfonyl group affording
anti adducts in high yield. At 0
°C isoxazolidines are ...obtained with complete all-
trans selectivity. The formation of these compounds involves isomerization of the allylsulphonyl moiety to give a transient vinylsulfone that then undergoes a subsequent intramolecular Michael addition. The addition to several nitrones has been studied and theoretical calculations have been refined to accurately explain the selectivity of the allylation reaction.
Graphical Abstract
The 1,3-dipolar cycloaddition of enantiopure cyclic hydroxylated nitrones and allyl nucleobases has been exploited for the preparation of a novel class of homonucleoside mimetics, where the furanose ...ring is replaced by a pyrrolo1,2-
bisoxazolidine system. The nitrones were easily prepared starting from
l-malic and
l-tartaric acids and gave cycloadducts in a diastereoselective manner, which were deprotected to give good yields of the homo-N,O-nucleoside mimetics. The reduction of the isoxazolidine ring, a 1,3-aminoalcohol equivalent, allows easy access to other new pyrrolidine nucleoside mimetics.
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