Improved synthesis of 8-oxabicyclo[3.2.1]octanes via tandem C–H oxidation/oxa-[3,3] Cope rearrangement/aldol cyclization

Abstract

A tandem C-H oxidation/oxa-[3,3] Cope rearrangement/aldol reaction of allylic silylethers promoted by TBF(tempo oxoammonium tetrafluoroborate)/ZnBr has been successfully developed allowing the efficient construction of 8-oxabicyclo[3.2.1]octanes and their analogs with a wide substrate scope.

Total Synthesis of (±)-Furanether A

“…Inspired by the pioneering works mentioned above and in connection with our interest in the development of efficient synthetic methodologies toward the synthesis of bioactive molecules, a C–H oxidation/cyclization/rearrangement cascade has been developed toward the construction of a benzyl-fused oxabicyclo[3.2.1]­octane moiety and was applied to the total synthesis of (−)-brussonol and (−)-przewalskine E in 2015 (Scheme a) . Aiming to develop a more general approach toward the synthesis of bioactive molecules with an oxabicyclo[3.2.1]­octane framework, we further envisioned a C–H oxidation/oxa-[3,3] Cope rearrangement/aldol cyclization strategy enabled by tempo oxoammonium tetrafluoroborate and ZnBr 2 (Scheme b) . On the basis of these results, in particular the structural features of the products, we envisioned that it might be viable to use such a novel strategy to complete the total synthesis of furanether A (Scheme c).…”

“…The target molecule could be derived from the advanced intermediate 4 , which contains the tetracyclic core structure of furanether A, through a deformaldehyde reaction. As for the key oxabicyclo[3.2.1]­octane skeleton and two vicinal quaternary carbon centers of aldehyde 4 , it could be constructed from TBS-protected allylic alcohol 5 by one of the two tandem reaction-based strategies developed by us. , Compound 5 could be obtained directly from Weinreb amide 6 via a Shapiro reaction along with subsequent reduction and protection manipulations . Meanwhile, amide 6 would be generated from epoxide 7 through an acid-promoted epoxy ring opening/cyclization/aromatization sequence followed by a desulfuration step .…”

“…Uneventfully, treatment of 14 with N , O -dimethylhydroxylamine hydrochloride and i -PrMgCl in THF at −20 °C afforded the desired Weinreb amide 6 in 81% yield (Scheme ). , …”

“…10 Aiming to develop a more general approach toward the synthesis of bioactive molecules with an oxabicyclo[3.2.1]octane framework, we further envisioned a C−H oxidation/oxa- [3,3] Cope rearrangement/aldol cyclization strategy enabled by tempo oxoammonium tetrafluoroborate and ZnBr 2 (Scheme 2b). 11 On the basis of these results, in particular the structural features of the products, we envisioned that it might be viable to use such a novel strategy to complete the total synthesis of furanether A (Scheme 2c). Therefore, as a vivid exhibition of the utility of such a strategy, furanether A, which possessed the rigid tetracyclic skeleton with a unique transannular ether ring, was selected as a synthetic target at this time.…”

“…13 Uneventfully, treatment of 14 with N,O-dimethylhydroxylamine hydrochloride and i-PrMgCl in THF at −20 °C afforded the desired Weinreb amide 6 in 81% yield (Scheme 4). 10,11 With Weinreb amide 6 in hand, we next attempted the Shapiro reaction between 6 and hydrazone 15, which was prepared from 3,3-dimethylcyclopentan-1-one with the corresponding sulfonyl hydrazide, affording enone 16 in 86% yield with excellent regioselectivity. 12 Subsequently, Luche reduction of enone 16 led to allylic alcohol 17a and 17b in 81% yield and a 1.7:1 diastereoisomeric ratio, 17 and the secondary hydroxyl groups were then protected by TBSOTf to give key rearrangement precursors 5a and 5b in a total yield of 92%.…”