Stereoselective Polymer-Supported Synthesis of Morpholine- and Thiomorpholine-3-carboxylic Acid Derivatives

Abstract

Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers.

Synthesis of Disubstituted Pyrazino‐Oxazine Derivatives with Controlled Stereochemistry

“…Interestingly, only a trace amount of the expected product was detected, which indicates the regioselective amination of the ester functionality. After the cyclative cleavage, the cleavage cocktail consisting of piperidine and dimethylformamide (DMF) was removed from 8 ( 2 , 1 ) by lyophilization, and the resulting material was treated with 50 % TFA/DCM to trigger the cleavage of the t Bu group and subsequent cyclization of the morpholine scaffold . Surprisingly, intermediate 9 ( 2 , 1 ) underwent only the protective group cleavage, and the spontaneous cyclization was only partially observed, even at increased temperature.…”

“…In the field of drug discovery, enantiomerically pure heterocycles bearing more than one stereocentre are very attractive. However, researchers have struggled to develop approaches to achieve such scaffolds . Owing to their optical purity, synthetically transformable structure/functionality and chiral centres, AAs have also become an important tool for asymmetric synthesis and chiral catalysis …”

“…The cyclization of dihydro‐oxazine, prepared from the coupling of morpholine with the appropriate Fmoc‐amino acid chloride, was carried out in the same manner . As a continuation of our previous research in the field of chiral morpholines, we herein describe a novel approach for the modular synthesis of pyrazino‐oxazines starting from immobilized serine. The key features of this method are 1) the simple and rapid reactions using only common coupling reactions and reagents, 2) a large number of readily available building blocks to introduce diverse substituents and 3) fully controlled configurations of both stereocentres in the final scaffold.…”

A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

“…It is well known that the presence of proline in peptide chain is crucial for protein structural and dynamic properties; thence, cyclic amino acids attract increasing attention in medicinal chemistry, and thus, structurally variable six‐membered‐ring heterocyclic amino acids have been introduced as building blocks for the preparation of bioactive compounds . Thus, intensive research efforts have been dedicated to their preparation, particularly pipecolic acid 1 , piperazine‐2‐carboxylic acid 2 , morpholine‐3‐carboxylic acid 3 , and thiomorpholine‐3‐carboxylic acid 4 . Additionally, these cyclic amino acids have also been used as precursors for the preparation of more complex scaffolds exhibiting pharmacological activities or acting as organocatalysts .…”

Use of Triethylsilane for Directed Enantioselective Reduction of Olefines: Synthesis of Pyrazino[2,1‐c][1,4]oxazine‐6,9‐diones with Full Control of the Absolute Configuration

“…In this context, TES/ TFA reductions of indoles, [42] indolinones [43] or pyridines [44] yield enantiomerically pure products; however, a mechanistic explanation of the stereoselectivity was not provided. In recent work, we used TES/TFA for the stereoselective syntheses of pharmacologically relevant chiral morpholines, [45][46][47] benzox-was completely dependent on the overall conformation of the oxazine scaffold, which was a consequence of the C 9 configuration of the starting material. The results prove that triethylsilane can be used for directed enantioselective syntheses of single or fused morpholine-based heterocycles.…”