A Regio- and Diastereoselective Intramolecular Nitrone Cycloaddition for Practical 3- and 2,3-Disubstituted Piperidine Synthesis from γ-Butyrolactone

Abstract

A fast and efficient route for diversity-oriented synthesis of 3- and 2,3-disubstituted piperidines, featuring an intramolecular nitrone cycloaddition with high regio- and diastereoselectivity, was achieved in six steps and 36-66% overall yield from commercially available gamma-butyrolactone or 1,4-butanediol. A new N-alkenyl nitrone enoate was used in this intramolecular nitrone cycloaddition, and the regioselectivity, diastereoselectivity, and reversibility of this cycloaddition were investigated.

A Common Synthetic Protocol for the Cyclic and Acyclic Core of Migrastatin, Isomigrastatin, and Dorrigocin via a Chiral β‐Hydroxy‐γ‐butyrolactone Intermediate

“…Our initial attempts at the cross metathesis14 of 21 with olefin partner 22 15 or the corresponding ( E )‐2,6‐heptadienoate 23 16 using Grubbs' second‐generation catalyst were not successful (Table 1, entries 1 and 2), however, the corresponding acetyl‐protected compound 26 (synthesized from 19 in three steps; Scheme ) underwent a smooth cross‐metathesis reaction with ethyl ester 23 to give the desired product (i.e., 28 ) (Table 1, entries 2 and 3) in moderate yields. The reaction proceeded slightly better in toluene than in dichloromethane.…”

Asymmetric Total Synthesis of Neobraclactone C

“…Fortunately, Corey–Kim oxidation worked well to afford the enolized product, quenched by tert -butyldimethylsilyl chloride (TBSCl), to access silyl enol ether 14 in an overall 56% yield on a 20 g scale . Then, compound 14 was treated with diisobutylaluminum hydride (DIBAL-H) at −78 °C, generating hemiacetal 15 in a 95% yield on a 10 g scale [diastereomeric ratio (dr) = 1.25:1] . The intermediate 15 was transformed into acetal in AlCl 3 /MeOH conditions, which was subjected to n -Bu 4 NF without further purification, obtaining ketones 9 in a 85% overall yield on a 10 g scale (dr = 1.25:1) with the chiral inversion of C7.…”

Multicomponent Assembly and Diversification of Novel Heterocyclic Scaffolds Derived from 2-Arylpiperidines

“…5 Although reductive cleavage of the N, O -bond in 37 with nickel boride was accompanied with extensive dehalogenation, use of zinc in aqueous HCl at 0 °C gave 38 in 83% yield (Scheme 7). 24 N -Acylation of 38 proceeded with concomitant O -acylation; however, the simple expedient of protecting the primary hydroxyl group in 38 in situ as a TMS ether enabled highly efficient amide formation as exemplified by a one-pot synthesis of 39 .…”

“…Several strategies for further transforming amino alcohols derived from isoxazolidines may be illustrated beginning with the cycloadduct 37 , which was prepared as previously described . Although reductive cleavage of the N–O bond in 37 with nickel boride was accompanied with extensive dehalogenation, use of zinc in aqueous HCl at 0 °C gave 38 in 83% yield (Scheme ) …”