Substituent-Directed Cycloisomerization Reduction Cascade for Synthesizing Oxacycles

Key words

hydroalkoxylation - cycloisomerization - morpholines - 1,4-oxazepanes

Significance

Pharmaceutical research widely uses morpholines and oxazepanes as building blocks for the fine-tuning or enhancement of pharmacological properties of the intended drug molecules. Many methods are available for the synthesis of these 1,4-heterocycles; however, intramolecular cyclization to form these oxacycles through hydroalkoxylation of alkynes is not completely explored (e.g., S. V. Ley and co-workers Angew. Chem. Int. Ed. 2008, 47, 209). Here, oxacycles are formed not only in diastereoselective fashion but also with complete control over the regioselectivity, which was governed by using terminal or internal alkynes. The intramolecular hydroalkoxylation–cycloisomerization reduction cascade was further utilized in the synthesis of agrochemicals, namely tridemorph (4) and fenpropimorph.

Comment

N-Sulfonylated alkynyl amino alcohols 1 furnished the desired morpholines 2a–e, while the benzyl- or Cbz-protected alkynols (1f,g) failed to afford any products (2f,g). The optimized reaction conditions using catalytic amounts of Ag(OTf) provided the products in excellent yield and with exquisite diastereoselectivity (dr ≥ 19:1). Likewise, 1,4-oxazepanes 3a–e were prepared in good yields and with high diastereoselectivity (dr ≥ 19:1) with internally placed alkynes. Mechanistically, morpholines 2 were formed through 6-exo-dig hydroalkoxylation–cyclization of terminal alkynes followed by reduction with Et₃SiH, whereas 1,4-oxazepanes 3 were formed via hydration of internal alkynes following a 7-endo-dig cyclization pathway and then reduction with Et₃SiH. Overall, this heterocyclomerization protocol could be a good addition to the toolbox for the stereoselective construction of desirable O/N/S-heterocycles in drug discovery research.

Publication History

Article published online:
13 September 2024