Stereoselective Approach to Hydroxyindolizidines:  Protection/Deprotection of the Nitrone Functionality via Cycloaddition/Retrocycloaddition

Abstract

The enantiomerically pure indolizidine (−)-21 has been synthesized starting from L-malic acid. The key intermediate 20 has been assembled through an intramolecular 1,3-dipolar cycloaddition of a nitrone generated in situ by retrocycloaddition from isoxazolidine 17 or 18. The configuration of the new three stereocenters was set up with complete control in the cycloaddition step. The presented synthetic route provides a general and highly selective methodology toward indolizidines having the [1,8a]-cis configuration.

Stereodivergent Approach to Enantiopure Hydroxyindolizidines Through 1,3-Dipolar Cycloaddition of 3-Hydroxypyrroline N-Oxide Derivatives

“…[11e] Nitrone 7 was therefore converted into an isoxazolidine before the removal of the THP group. Styrene (11), [4][11e] ethyl acrylate (12), and fumaronitrile (13) were used as dipolarophiles to create the temporary isoxazolidines 14Ϫ16. After deprotection, which occurred on the isoxazolidine without any problem, the hydroxy group was connected to the dipolarophile 4.…”

“…Its enantiomer (Ϫ)-24 could be synthesized from nitrone 7, in an enantiodivergent approach, by condensing the same intermediate isoxazolidine alcohols 14Ϫ15 [4] with pentenoate 4 under Mitsunobu esterification conditions, [13] which cause the inversion of configuration at C-4 (see below). The mixture of adducts 14 was treated with the pentenoate 4 in the presence of diethyl azodicarboxylate (DEAD) and polymer-supported Ph 3 P, to give the esters 25 with clean inversion of configuration at C-4 (59% yield) (Scheme 7).…”

“…[4] The dipolarophile chosen for this study contains a carboxylate moiety that plays a double role. It is able to steer the regioselectivity in the intermolecular reaction, and can serve as a removable tether to connect the dipolarophile temporarily to the nitrone for the intramolecular reaction.…”

Stereocontrolled Cyclic Nitrone Cycloaddition Strategy for the Synthesis of Pyrrolizidine and Indolizidine Alkaloids

“…The unprotected 3-hydroxy nitrone 52 itself has been proven to have a low configurational stability, and partial racemization also occurred from other protected precursors. [42] The success of the intramolecular strategy therefore required a protection step for the nitrone that should allow the introduction of the dipolarophile, followed by deprotection and cycloaddition. The issue of protection of a nitrone has been barely addressed in the literature.…”

Enantioselective Synthesis of Pachastrissamine (Jaspin B) Using Dirhodium(II)-Catalyzed C-H Amination and Asymmetric Dihydroxylation as Key Steps

“…The stereocenters of 5 should be constructed enantioselectively using Sharpless asymmetric dihydroxylation 22) of the corresponding known (E)-a,b-unsaturated ester (6). 23,24) Synthesis of the precursor of dirhodium-catalyzed C-H amination was started from known methyl (2E)-5-pmethoxybenzyl(PMB)oxy-2-pentanoate (6), 23,24) as illustrated in Chart 2. Asymmetric dihydroxylation of 6 was accomplished using AD-mix-a under usual conditions 22) to give diol (5) in 89%.…”