Synthesis of Dibromo Compounds Containing 2,6-Dioxabicyclo[3.1.1]heptane Similar to Core Moiety of Thromboxane A2

Abstract

-Thromboxane A 2 , a potent platelet aggregation factor, contains a labile 2,6-dioxabicyclo[3.1.1]heptane as the core moiety. Dibromo compounds with a similar core structure were synthesized by the cyclization of tribromides derived from D-glucal. While investigating the synthesis of crambescine B, a guanidine-containing marine alkaloid, 1 we accidentally observed the formation of spiro-oxetane acetal 2 when intermediate 1 was treated with PyHBr 3 and K 2 CO 3 in CH 2 Cl 2 -H 2 O, 2 a condition of cascade cyclization developed in our laboratory (Scheme 1). 3 Although the yield was low, to our surprise, the product was stable enough to allow for purification by column chromatography using a neutralized silica gel. A similar reaction was also observed in the case of a simpler substrate 3, indicating that the guanidine group was not responsible for this cyclization. To our knowledge, these compounds are the first and only examples of oxetane acetal with a 1,5-dioxaspiro[3.4]octane ring system synthesized to date. 4 The unusual stability of the strained oxetane acetal can be attributed to the strong electron-withdrawing characteristics of the bromo substitutions.Scheme 1. Formation of spiro-oxetane acetal by Br + -triggered cascade reaction