Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin

Abstract

Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels-Alder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin.

Scheme 1

Synthetic Strategy for Tetrodotoxin and Proposed Pairwise Oxidation/Cycloaddition Cascade

Scheme 2. Chemoselective Reactions of Heterocycloadducts^*

^*Conditions: ^aNaBH₄ (0.33 equiv), THF, 0 °C; ^bBr₂ (2.0 equiv), Me₂S (2.5 equiv), CH₂Cl₂, 0 °C to rt; ^cOsO₄ (1 mol %), NMO (6.0 equiv), THF/acetone/H₂O (5:5:1), 0 °C to rt; ^di. Pd/C (10 wt %), AcOH (5.0 equiv), MeOH, rt, ii. HCl in 1,4-dioxane (4 N, 25.0 equiv), rt; ^emCPBA (1.5 equiv), NaHCO₃ (2.0 equiv) CH₂Cl₂, rt; ^fHONH₂· HCl (1.5 equiv), NaOAc (2.0 equiv), THF, rt; ^gNaBH₄ (2.0 equiv), anhydrous MeOH, 0 °C; ^hp-O₂NC₆H₄COCl (2.2 equiv), TEA (3 equiv), DMAP (10 mol %), anhydrous THF, rt; ⁱNaH (60 wt %, 1.1 equiv), Me₃SO·I (1.1 equiv), anhydrous THF, 0 °C.

Scheme 3. Application of the Oxidation/Cycloaddition Cascade Procedure towards the TTX Core Structure^*

^*Conditions: ^ai. NaIO₄, MeOH/H₂O (2:1), ii. BnO₂CNHOH (2 equiv, 2 h addition), BnEt₃NCl (20 mol %), NaIO₄ (2.1 equiv), CH₂Cl₂/H₂O (1.3:1), 0 °C; ^bNaIO₄ (5.1 equiv), BnEt₃NCl (20 mol %), CH₂Cl₂/H₂O (1.3:1), rt then BnO₂CNHOH (4 equiv, 3 h addition), 0 °C; ^cOsO₄ (1 mol %), NMO (5.0 equiv), THF/acetone/H₂O (5:5:1), rt; ^dH₂, Pd/C (10 wt %), AcOH (5 equiv), MeOH/THF (3:2).