Asymmetric 1,3-Dipolar Cycloaddition of Nitrones with an Electron-Withdrawing Group to Allylic Alcohols Utilizing Diisopropyl Tartrate as a Chiral Auxiliary

Abstract

The asymmetric 1,3-dipolar cycloaddition of nitrones possessing an electron-withdrawing group to allylic alcohols was achieved by the use of diisopropyl (R,R)-tartrate as a chiral auxiliary to afford the corresponding isoxazolidines with high regio-, diastereo-, and enantioselectivity. In the case of nitrones possessing an electron-withdrawing cyano or t-butoxycarbonyl group, 1,3-dipolar cycloaddition to 2-propen-1-ol occurred to produce the corresponding 3,5-trans-isoxazolidines with high enantioselectivity. To the contrary, nitrones possessing an amide moiety afforded the corresponding optically active 3,5-cis-isoxazolidines with completely opposite diastereoselectivity. A catalytic asymmetric 1,3-dipolar cycloaddition of nitrones possessing the N,N-diisopropylamide moiety to allylic alcohols was achieved to afford di- or trisubstituted isoxazolidines with excellent enantioselectivity of up to over 99% ee. The present asymmetric 1,3-dipolar cycloaddition was applied to the synthesis for the (2S,4R)-4-hydroxyornithine derivative.

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

“…As a representative example of the current state of the art, isoxazolidines produced by catalytic asymmetric 1,3-DC reactions of acyclic aldonitrones with different kinds of dipolarophiles are highlighted in Figure : compounds 5 – 8 from electron-rich dipolarophiles (vinyl ethers), − compounds 9 and 10 from neutral ones (allylic alcohols), , and compounds 11 – 25 from electron-poor ones (enals, enamides, enones, nitro olefins, methylene malonates). ,− Only a limited number of examples concern nitrones bearing protecting groups at the nitrogen atom, mainly using a benzyl group. In other cases, N -substituents are an aryl or a methyl group.…”

“…In this aim, the broad use of chiral auxiliaries (typically used under simple thermal conditions) or of chiral catalysts (Lewis acid or organocatalysts) has been developed as mentioned in several reviews. [29][30][31]38,39,41 As a representative example of the current state of the art, isoxazolidines produced by catalytic asymmetric 1,3-DC reactions of acyclic aldonitrones with different kinds of dipolarophiles are highlighted in Figure 8: compounds 5−8 from electron-rich dipolarophiles (vinyl ethers), 43−47 compounds 9 and 10 from neutral ones (allylic alcohols), 48,49 and compounds 11−25 from electron-poor ones (enals, enamides, enones, nitro olefins, methylene malonates). 39,50−83 Only a limited number of examples concern nitrones bearing protecting groups at the nitrogen atom, mainly using a benzyl group.…”

A Modular Synthesis of Polysubstituted Indolizines

“…2‐Chloro‐2‐(4‐chlorophenyl)acetonitrile ( 1c )26 and the nitroolefins 3a – d , 3f and 3g 19,21 were synthesized from the corresponding aldehydes according to literature procedures. Nitroolefin 3e was obtained from commercial sources, 1‐(cyanomethyl)pyridinium bromide ( 5 )15b,27 and 2‐(cyanomethyl)isoquinolinium bromide ( 12e ) were prepared according to literature procedures.…”

Metal complexes versus organocatalysts in asymmetric 1,3-dipolar cycloadditions

“…52 An efficient regio-, diastereo-, and enantioselective transformation of several nitrones with allylic alcohols promoted by the chiral complex formed by diethylzinc and (R,R)-diisopropyl tartrate (DIPT) was achieved 84 (20 mol%, Figure 7). 53 In several examples, this reaction provided an approach to highly functionalised 3,5-transisoxazolidines with almost complete enantioselectivity (up to 83% yield and up to > 99% ee). But the scope of this transformation is very narrow because, when a structural modification of the starting materials was introduced, dramatic changes in the regio-, diastereo-, and enantioselections were observed.…”