Morpholine scaffolds

Functionalized sugars and amino acids have been used to create unique morpholine scaffolds which were further elaborated to create a second generation of morpholino derivatives following the precepts of the build/couple/pair approach [73]. 

The method of piperazinedione synthesis [119] illustrated above (Scheme 22) is an example of scaffold proliferation by branching out from common intermediate structures ( divergent library design ). Resin-bound bromides such as 97 are suitable for bromine displacement with primary amines to obtain acyclic precursors of piperazinediones, but direct treatment with TFA also induces cycliza-tion, providing an efficient route to analogous morpholine derivatives. The intramolecular displacement of bromine by the carboxylate seems to occur in the cleavage solution, once the acyclic intermediate has been released from the solid support. 

Kim and co-workers have recently described their efforts towards 3,5-substituted morpholin-2-one scaffolds via a three-component variant of the classic U-4CR. The use of amino acids (e.g., 35) as both the amine and carboxylic acid components in the reaction represents a particularly interesting development. By varying the length of the tether in the starting amino acid, Kim deploys this strategy to successfully prepare [2.4.0]-, [3.4.0]-, and [4.4.0]-bicycles (36). Overall, good to excellent yields are reported. 

Stereoselective Synthesis of 3,5-Disubstituted Morpholines After successful use of the carboamination reaction of amino alkenes for the synthesis of pyrrolidines, pyrazolidines, and piperazines, the same group reported on the synthesis of another important heterocyclic scaffold morpholine. Morpholines are also widely applicable and present in various biologically important natural and... 

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