Stereospecific Cyclization Strategies for α,ε-Dihydroxy-β-amino Esters: Asymmetric Syntheses of Imino and Amino Sugars

Abstract

A range of biologically significant imino and amino sugars [1,4-dideoxy-1,4-imino-D-allitol, 3,6-dideoxy-3,6-imino-L-allonic acid, (3R,4S)-3,4-dihydroxy-L-proline, 1,5-anhydro-4-deoxy-4-amino-D-glucitol, and 1,5-anhydro-4-deoxy-4-amino-L-iditol] has been prepared via stereospecific cyclization of α,ε-dihydroxy-β-amino esters. These substrates are readily prepared via conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to enantiopure α,β-unsaturated esters (β-substituted with cis- and trans-dioxolane units) coupled with in situ enolate oxidation with camphorsulfonyloxaziridine (CSO). Activation of the ε-hydroxyl group allowed cyclization to either the corresponding pyrrolidine or the tetrahydropyran scaffold, with the course of the cyclization process being dictated by the relative configuration of the dioxolane unit. When the α,ε-dihydroxy-β-amino ester bears a cis-dioxolane unit, cyclization occurs upon attack of the β-amino substituent to give the corresponding pyrrolidine after in situ N-debenzylation. In contrast, when the α,ε-dihydroxy-β-amino ester bears a trans-dioxolane unit, cyclization occurs upon attack of the α-hydroxyl substituent to give the corresponding tetrahydropyran.

Asymmetric Syntheses of 3-Deoxy-3-aminosphingoid Bases: Approaches Based on Parallel Kinetic Resolution and Double Asymmetric Induction

“…This result suggests that there are significant levels of enantiorecognition between the intermediate enolate [derived from conjugate addition of lithium amide ( R )- 10 to α,β-unsaturated ester ( R )- 44 ] and the enantiomers of CSO. Although this aminohydroxylation process is usually under the dominant stereocontrol of the substrate (i.e., intermediate enolate) when applied to an achiral α,β-unsaturated ester and use of either enantiomer of CSO produces similar efficiency, we have previously observed a similarly high level of enantiorecognition (indicating the inherent chirality of both substrate and reagent is important) during investigations into the aminohydroxylation of a chiral α,β-unsaturated ester (Scheme ).…”

“…A one-pot DIBAL-H reduction and Wittig olefination was next attempted on lactone 55 . The choice of solvent proved critical for the success of this process: the optimum protocol involved treatment of 55 in PhMe (2 volumes) with DIBAL-H, followed by the addition of an excess (5 equiv) of the ylide derived from deprotonation of [C 13 H 27 PPh 3 ] + [Br] − in THF (1 volume) which produced an ∼50:50 mixture of two compounds, 57 and 58 , with chromatography giving an ∼50:50 mixture of 57 and 58 in 73% combined yield. Peak overlap in the 1 H NMR spectrum of the purified mixture of 57 and 58 precluded 3 J coupling constant analysis, although the 13 C NMR chemical shifts of the allylic carbon atoms [C(4) and C(7)] of both 57 and 58 were consistent with the presence of olefin isomers: the chemical shift values associated with these carbons of 57 were ∼5 ppm higher than the corresponding resonances for 58 , consistent with the so-called γ-effect and hence signifying that 57 is the ( E )-isomer and 58 is the ( Z )-isomer.…”

Asymmetric Syntheses of (2R,3S)-3-Hydroxyproline and (2S,3S)-3-Hydroxyproline

“…Subsequent cleavage of the O -acetyl group upon treatment of 18 O- 28 with K 2 CO 3 and MeOH gave diol 29 , thereby confirming that the isotopic label was indeed located within the acetyl group and that the reaction outcome is therefore consistent with our mechanistic hypothesis (Scheme ). O -Tosylation of 28 followed by heating a solution of the resultant tosylate in MeCN promoted cyclization and loss of the N -α-methylbenzyl group from the resultant pyrrolidinium intermediate to give pyrrolidine 30 in 78% overall yield (Scheme ). The relative configuration within 30 was unambiguously established via single crystal X-ray diffraction analysis (Figure ), and the absolute ( S , S )-configuration of 30 was confirmed upon refinement of a Flack x parameter of −0.03(15); this analysis therefore also confirmed the assigned configuration of 28 .…”