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

Abstract

The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily prepared from l-malic acid and used as starting materials for enantiospecific syntheses of stereodifferentiated polyhydroxyindolizidines. Selection of the appropriate modality (interor intramolecular) for 1,3-dipolar cycloaddition of the cyclic nitrone with 5-hydroxypentenoic acid derivatives gave access to either [1,8a]-trans-or -cis-hydroxyindolizidines 31 and 24, respectively, through elaboration of the primary cycloadducts. Moreover, the choice of the esterification conditions (Ph 3 P/DEAD or DIC/DMAP) used in linking the nitrone and the dipolarophile moieties in the intramolecular approach determined the absolute configuration of the final product, allowing the selective synthesis of both enantiomers, (−)-24 and (+)-24. This strategy required protection of the nitrone functionality to avoid racemization of the unpro-

A Concise Total Synthesis of (+)‐Heliotridine

“…To the best of our knowledge, this is the first total synthesis of 1 based on a 1,3‐dipolar cycloaddition as the key step for the construction of the pyrrolizidine skeleton and among the shortest syntheses reported in the literature. The methodology can be applied to the synthesis of other necine bases, simply by changing the configuration of the starting nitrone 2 and by selecting an inter‐ or intramolecular approach between the cycloaddition partners 12.…”

Strategies for the Synthesis of Stemona Alkaloids

“…To extent the scope of the cyclic nitrone approach to the group of alkaloids related to stenine, we evaluated the sequence depicted in Scheme . The starting nitrone 168 can be prepared from ( S )‐malic acid on a multi‐gram scale 112. Because of the stereogenic center at the THP protecting group, this nitrone is obtained as a mixture of two epimers.…”

Synthesis of densely functionalized enantiopure indolizidines by ring-closing metathesis (RCM) of hydroxylamines from carbohydrate-derived nitrones

“…We accomplished the total syntheses of some indolizidine alkaloids and of several non-natural analogues employing chiral nitrones as key intermediates, either as dipolarophiles in 1,3-dipolar cycloaddition chemistry [ 19 , 20 ] or as electrophiles in the addition of organometallic reagents. [ 21 , 22 ] Recently, we developed a general protocol for the synthesis of α,α'-disubstituted enantiopure hydroxylamines 1 through the stereoselective double addition of an excess of a Grignard reagent to C -phenyl- N -erythrosylnitrone 2 (Scheme 1 ).…”