Abstract
The preparation of novel 1,4-oxazepane-5-carboxylic acids bearing two stereocenters is reported in this article. Fmoc-HSe(TBDMS)-OH immobilized on Wang resin was reacted with different nitrobenzenesulfonyl chlorides and alkylated with 2-bromoacetophenones to yield N-phenacyl nitrobenzenesulfonamides. Their cleavage from the polymer support using trifluoroacetic acid (TFA) led to the removal of the silyl protective group followed by spontaneous lactonization. In contrast, TFA/triethylsilane (Et3SiH)-mediated cleavage yielded 1,4-oxazepane derivatives as a mixture of inseparable diastereomers. The regioselectivity/stereoselectivity depended on the substitution of the starting 2-bromoacetophenones and was studied in detail. Catalytic hydrogenation of the nitro group improved the separability of the resulting diastereomeric anilines, which allowed us to isolate and fully characterize the major isomers.
Highlights
Chiral seven-membered heterocycles bearing one or more heteroatoms in their skeleton are an interesting group of compounds with unique physico-chemical and biological properties
We reported the simple synthesis of chiral morpholines starting from resin-bound serine.[26]
The formation of the oxazepane scaffold was nonstereoselective, as in the case of serine-based analogs leading to chiral morpholines,[26] the separation and full characterization of major diastereomers was feasible
Summary
Chiral seven-membered heterocycles bearing one or more heteroatoms in their skeleton are an interesting group of compounds with unique physico-chemical and biological properties. We reported the simple synthesis of chiral morpholines starting from resin-bound serine.[26] Using either TFA- or TFA/Et3SiH-induced cleavage of the corresponding polymer-supported intermediates (Fig. 2), we synthesized either dihydrooxazine-3-carboxylic acids or morpholine-3-carboxylic acids with full control of the newly formed stereocenter. Later, we extended this method to the simple synthesis of fused [6 + 7]27,28 or [6 + 6]29,30 morpholines. We report on the applicability, regioselectivity and stereoselectivity of the proposed method
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