Abstract
The synthesis of conformationally-restricted 1,3-dioxanes with a phenyl moiety fixed in an axial orientation at the acetalic center is described. Starting with diethyl 3-hydroxyglutarate (15), benzaldehyde acetal 12a and acetophenone ketal 12b bearing a protected 1,3,5-trihydroxypentyl side chain in the o-position were prepared. The first acid-catalyzed intramolecular transacetalization gave a mixture of diastereomeric 2-benzofurans 18 (ratio of diastereomers 2:2:1:1). After OH group deprotection, the second intramolecular transacetalization afforded tricyclic alcohol 14a (2-(1,5-epoxy-1,3,4,5-tetrahydro-2-benzoxepin-3-yl]ethan-1-ol). Analogous cyclizations led to the corresponding silyl ether 22a (19%) and azide 23a (13%). Whereas tricyclic alcohol 14a was obtained as a 1:1 mixture of diastereomers, the silyl ether 22a and the azide 23a afforded only one diastereomer. This observation indicates a faster cyclization of the minor diastereomers providing the thermodynamically-favored compounds with equatorially-oriented substituents in the 3-position of the tricyclic 1,5-epoxy-2-benzoxepine system. In general, acetophenone-derived ketalic compounds (b-series) required very mild reaction conditions and gave lower yields than the corresponding acetalic compounds (a-series).
Highlights
Heterocycles with two O-atoms in the acetalic position, such as 1,3-dioxoles, 1,3-dioxolanes, and homologous 1,3-dioxanes, are found in several important biologically-active compounds.The 1,3-dioxole ring is present in the natural product galipinine (1), found in the roots of Galipea officinalis, which is active against some chloroquine-resistant Plasmodium falciparum strains [1].The broad-spectrum antifungal agents ketoconazole (2), terconazole (3), and itraconazole (4) [2,3,4], contain the 1,3-dioxolane ring
1,3-dioxolane- and 1,3-dioxane-based NMDA receptor antagonists led to the hypothesis that one phenyl moiety in an axially perpendicular orientation at the acetalic 2-position of the oxygen heterocycle is moiety in an axially perpendicular orientation at the acetalic 2-position of the oxygen heterocycle is required for high NMDA receptor affinity [5,10,11]. 1,3-Dioxane 8 with an equatorially oriented required for high NMDA receptor affinity [5,10,11]. 1,3-Dioxane 8 with an equatorially oriented phenyl phenyl moiety at the 2-position shows rather low PCP affinity, but rather high σ1 receptor affinity [5]
The synthesis of 1,3-dioxanes is reported, which are bearing a phenyl moiety in the axial orientation at the acetalic center without any freedom to rotate around the phenyl-C-bond
Summary
Heterocycles with two O-atoms in the acetalic position, such as 1,3-dioxoles, 1,3-dioxolanes, and homologous 1,3-dioxanes, are found in several important biologically-active compounds. Enlargement of the 1,3-dioxolane ring of dexoxadrol (5) and etoxadrol (6) led to 1,3-dioxanes with with high NMDA and σ1 receptor antagonistic activity. Structure-activity-relationship (SAR) studies with flexible dioxolane- and 1,3-dioxane-based NMDA receptor antagonists led to the hypothesis that one phenyl. 1,3-dioxolane- and 1,3-dioxane-based NMDA receptor antagonists led to the hypothesis that one phenyl moiety in an axially perpendicular orientation at the acetalic 2-position of the oxygen heterocycle is moiety in an axially perpendicular orientation at the acetalic 2-position of the oxygen heterocycle is required for high NMDA receptor affinity [5,10,11]. 1,3-Dioxane 8 with an equatorially oriented phenyl phenyl moiety at the 2-position shows rather low PCP affinity, but rather high σ1 receptor affinity [5]. Position of the position of the 1,3-dioxane ring without any rotational freedom
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
