Stereoselective cyclopropanation of serine- and threonine-derived oxazines to access new morpholine-based scaffolds

Abstract

A general strategy for the synthesis of novel, orthogonally protected scaffolds based on the unique 2-oxa-5-azabicyclo[4.1.0]heptane structure is presented. The described reaction sequence takes advantage of easily available starting materials such as serine and threonine and leads to stereochemically dense structures in few, high-yielding synthetic steps. We show how the stereochemistry can be easily tuned by starting from different b-hydroxy-a-amino acids and also by means of a transition metal-catalyzed cyclopropanation step. The compounds find application as constrained templates for the construction of geometrically diversified libraries of compounds.

Diversity‐Oriented Synthesis of Morpholine‐Containing Molecular Scaffolds

“…Investigations by X‐ray crystallography of compound 34 13 revealed an interesting propensity of the substituents at the dihydro‐oxazine nucleus to retain a diaxial orientation (Figure 3). This behavior is consistent with previous NMR analysis on the cyclopropane‐containing molecule 33 ,6b indicating a strong preference for the axial orientation of both the methyl and the carbonyl groups of the six‐membered ring.…”

“…The introduction of the cyclopropane on the double bond was achieved on the Cbz‐morpholine derivative 29 by stereoselective Cu I ‐catalyzed cyclopropanation in the presence of a BOX ligand, as reported,6b to give compound 33 as the main stereoisomer, with a d.r. of 10:1 (Scheme ).…”

Synthesis of Novel Iminosugar‐Based Trehalase Inhibitors by Cross‐Metathesis Reactions

“…Two different allyl-iminofuranoses were synthesized and used for the CM reaction (Scheme 4), pos- The synthesis of α-C-allyl iminoarabinofuranosyl derivative 24 (Scheme 4A) proceeded by Grignard addition to nitrone 28, [19] as recently described. [20] Final carbamoylation of intermediate 29 by Cbz-chloride in water/dioxane [21] afforded 24 (80 %). [20] On the contrary, the synthesis of β-C-allyl iminoribofuranosyl derivative 25 is not reported in the literature and is presented here from nitrone 30, [22] as illustrated in Scheme 4B.…”

Two-step one-pot synthesis of dihydropyrazinones as Xaa-Ser dipeptide isosteres through morpholine acetal rearrangement

“…20,21 The reaction of morpholine acetal 1 in a two-step one-pot process consisting of amide bond formation followed by transacetalization reactions was initially studied using Fmoc-L-Val-Cl as the coupling agent, and applying different acids and reaction conditions to achieve the ring rearrangement, as reported in Table 1. The process was initially studied by changing the reaction conditions in the acid-mediated second step.…”