Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

Abstract

C-Functionalized morpholines are found in a variety of natural products and biologically active compounds, but have also for other reasons been applied in organic synthesis. This review deals with the biological relevance of C-substituted morpholines, their synthesis and important applications in other syntheses.

Dimethyl [(2R,3R,5S)‐5‐phenylmorpholine‐2,3‐diyl]diacetate as a Designer Substrate in the Syntheses of Important Heterocyclic Scaffolds

“…[8] Enthused by the successful synthesis of 1, we set out to explore its transformation to various heterocyclic scaffolds (2)(3)(4)(5). (2) is extensively utilized for synthesizing the Geissman-Waiss lactone; [9] as well as a precursor in the syntheses of various pyrrolizidine alkaloids, [10] and a key intermediate for synthesizing pyrrolidine trans-lactones.…”

“…The residue was washed with brine (2 10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , concentrated, and purified by chromatography on a silica gel column (MeOH/CH 2 …”

“…After 30 min, mesyl chloride (0.05 mL, 0.73 mmol) was added dropwise and the reaction mixture was stirred for another 3 h at 0 8C, then at ambient temperature for another 2 h. The reaction mixture was then quenched with saturated NH 4 Cl, washed with brine (2 10 mL), and extracted with EtOAc (3 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , concentrated, and purified by chromatography on a silica gel column (MeOH/CH 2 …”

“…Towards this endeavour, we designed dimethyl [(2R,3R,5S)-5-phenylmorpholine-2,3-diyl]diacetate (1) for constructing a variety of heterocyclic scaffolds, such as methyl [(2R,3S)-3-hydroxy-5-oxopyrrolidin-2-yl]acetate (2), methyl [(2R,3S)-3-amino-5-oxotetrahydrofuran-2-yl]acetate (3), (3R,4S)-4-aminohexane-1,3,6-triol (4), and 2-[(2R,3S)-3-aminotetrahydrofuran-2-yl]ethanol (5), as shown in Scheme 1. Morpholine or 1,4-oxazine structural motifs, apart from being a part of various molecules that possess biological and pharmaceutical activities, [2] are also finding applications as organocatalysts, [3] chiral auxiliaries, [4] chiral templates [5] and synthetic precursors. [6] The synthetic intermediates and precursors that are made from 1 are either used in the synthesis of biologically active natural products and pharmaceuticals or are substructures of natural products.…”

Dienamine Activation of Diazoenals: Application to the Direct Synthesis of Functionalized 1,4‐Oxazines

“…[1,2] Thediverse biological properties associated with the complex monocyclic, as well as fused 1,4-oxazines (Figure 1), [2] underscores the importance of efficient synthetic strategies for drug discovery applications.T he known approaches to the C-substituted oxazines [3][4][5][6][7][8][9][10][11] include SnAP reagents based imine radical cyclizations, [4] vinyl sulfone-b-amino alcohol annulations, [5] ring expansion of oxetanone spirocycles, [6] intramolecular heterocyclization of alkyne-derived ruthenium vinylcarbenes, [7] and hydroamination and hydroalkoxylation of olefins and alkynes. [8][9][10] With the ever increasing demand for biologically relevant chemical space, [12] strategies for the creation of functionalized oxazines,w herein the functional groups with their rich chemistry could be utilized to introduce structural diversity,w ould be highly useful to chemical biology and drug discovery research.…”