Stereoselective Construction ofcis-2,6-Disubstituted Tetrahydropyransviathe Reductive Etherification of δ-Trialkylsilyloxy Substituted Ketones: Total Synthesis of (−)-Centrolobine

We have recently developed a two-component etherification reaction for the diastereoselective construction of cis- and trans-2,6-di- and trisubstituted tetrahydropyrans in excellent yield.2,3

P. Andrew Evans

2003

Scholarcy highlights

  • The stereoselective construction of cyclic ethers remains a topical area of synthetic interest, with respect to C-glycosides that are ubiquitous in biologically important natural products. This may be attributed to their diverse and significant biological activity and the challenges associated with the design of stereochemically flexible approaches that provide access to either diastereoisomer
  • We have demonstrated that the two-component etherification is catalyzed by hydrogen bromide and bismuth oxybromide, derived from the hydrolysis of bismuth tribromide
  • Preliminary studies focused on the hypothesis that bismuth tribromide and triethylsilyl bromide provide an in situ source of hydrogen bromide, which functions as the active Brønsted acid catalyst
  • The reductive etherification reactions are consistent with Brønsted acid rather than Lewis acid catalysis
  • We envisioned that the reductive etherification using bismuth tribromide and triethylsilane would provide an expeditious route to this agent, as outlined in Scheme 2
  • Enantioselective allylation of aldehyde 5,15 and protection of the resulting secondary alcohol, furnished the triethysilyl ether 6 in 77% overall yield, as detailed in Scheme 3.16 The alkene 6 was subjected to crossmetathesis by using the second-generation Grubbs' catalyst, to afford the corresponding α,βunsaturated ketone
  • We have demonstrated that the intramolecular reductive etherification using bismuth tribromide and triethylsilane provides a versatile route for 2,6-disubstituted tetrahydropyrans
  • These studies provide additional support for the notion that the hydrolysis of bismuth tribromide leads to the generation of hydrogen bromide, which functions as a Brønsted acid catalyst

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