Unprotected Xylose‐Derived Nitrone in Stereodivergent Synthesis of 4‐Hydroxypiperidine Enantiomers: Weak Lewis Acid Induced Alteration of Stereochemistry in 1,3‐Dipolar Cycloaddition

Abstract

A one‐pot, two‐step synthesis of chiral 7‐oxa‐1‐azabicyclo[2.2.1]heptane derivatives from unprotected D‐xylose was achieved by an intramolecular 1,3‐dipolar cycloaddition of the N‐(γ‐alkenyl)‐substituted nitrone intermediate. The stereochemical course of the cycloaddition was altered by the addition of an achiral Lewis acid. The bicyclic byproducts were employed in a concise synthesis of two new enantiomeric piperidine‐type iminosugars.

Diversity‐Oriented Synthesis and Biological Evaluation of Iminosugars from Unprotected 2‐Deoxy‐d‐ribose

“…Although the previously reported intramolecular 1,3‐DC of the N ‐(3‐alkenyl)nitrones obtained from unprotected xylose gave moderate stereoselectivity, its stereochemical course was easily tunable and could be altered by the addition of a weak Lewis acid, for example, MgBr 2 · Et 2 O. We postulated that, in nitrones derived from unprotected sugars, the configuration of the stereogenic center at the 2‐position controls the course of the reaction both in the presence and absence of a Lewis acid . Therefore, sugar 1 (see Scheme ) would be a suitable model to verify the correctness of the proposed stereoinduction mechanism in the intramolecular 1,3‐DC of UpS‐derived N ‐(3‐alkenyl)nitrones.…”

“…Nitrone I was synthesized from pentose 1 and hydroxylamine 2 under the conditions described previously . As expected, nitrone formation was followed by its intramolecular 1,3‐DC to afford a mixture of diastereoisomers of 7‐oxa‐1‐azabicyclo[2.2.1]heptane derivatives 3a and 3b (Scheme ).…”

“…We postulated that, in nitrones derived from unprotected sugars, the configuration of the stereogenic center at the 2-position controls the course of the reaction both in the presence and absence of a Lewis acid. [15] Therefore, sugar 1 (see Scheme 1) would be a suitable model to verify the correctness of the proposed stereoinduction mechanism in the intramolecular 1,3-DC of UpS-derived N- (3-alkenyl)nitrones. The lack of a hydroxy group at the 2-position of 1 should impact both the stereoselectivity of the reaction and the influence of the Lewis acid on its stereochemical direction.…”

“…The oxidation of triols 3a and 3b with excess sodium periodate followed by aldehyde reduction under mild conditions and N-O bond hydrogenolysis gave iminosugars 9a and 9b containing the piperidine scaffold homologous to the piperidines available from other aldopentoses (Scheme 4). [15] The use of triacetoxyborohydride in the synthesis of alcohols 8 was essential. As had been previously observed for xylose derivatives, Table 2.…”

“…Encouraged to combine these two interesting fields of research, that is, iminosugars and UpS chemistry, we have recently described the first application of a UpS, namely D-xylose, in the direct synthesis of nitrones and their subsequent 1,3dipolar cycloaddition (1,3-DC) reactions. The products of the 1,3-DC reactions were further transformed into enantiomeric iminosugars containing the piperidine scaffold, [15] thus developing a new approach towards the direct synthesis of iminosugars from UpSs. However, the method suffered from rather low atom economy, because most of the sugar chain, including all the stereogenic centers, was eventually degraded.…”