A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols

Abstract

A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products.

Rhodium/Gold Dual Catalysis in Carbene sp2 C−H Functionalization/Conia‐ene Cascade for the Stereoselective Synthesis of Diverse Spirocarbocycles

“…[9] For the initial investigation, we synthesized diazo-acetoacetamide 1a as a model substrate and exposed it to our previously developed synergistic Rh(II)/Au(I) conditions known for carbene heteroatom insertion/Conia-ene cyclization. [4] The reaction proceeded very cleanly and provided a major product, in which the characteristic ketone peak (~200 ppm) in 13 C NMR spectrum was missing. Further structural analyses revealed the formation of an unexpected exo-glycal product 3a (Scheme 1b).…”

“…[3h] Recently, our laboratory has developed a Rh(II)/Au(I) dual catalytic system for a cascade reaction involving a carbene heteroatom insertion/Conia-ene cyclization for the stereoselective synthesis of diverse heterocycles, including spirocores. [4] In this cascade reaction, we efficiently trapped diazo derived rhodium carbenoids with a variety of gold activated alkynoic acids, alkynols, and amino alkynes to access biologically relevant γbutyrolactones, [4a] spiroethers, [4b] and spiropyrrolidines. [4c] Figure 1.…”

A Stepwise Synthesis of Spiroindoline Compounds via Ring Opening of Aziridines and C−H Activation/Cyclization

“…In particular, spiroindoline furans [3] and spiroindoline pyrans, [4] as two important categories of spiroindolines, are also frequently found in many natural products, pharmaceuticals, and biologically active compounds (Figure 1). Typical strategies for the synthesis of these valuable spirocyclic compounds include formal [3+2] and [3+3] cycloadditions of isatins, [5] formal [4+1] cycloadditions of 3‐diazoindolin‐2‐ones, [6] cyclizations of isatin diketals, [7] cyclizations of 3‐hydroxyoxindoles, [8] intramolecular enyne metathesis of oxindole enynes [9] and dearomatization reactions of 3‐substituted indoles, [10] etc. Noticeably, these methods generally rely on manipulation indole derivatives, which need to be pre‐prepared by multistep synthesis.…”

RhII‐Catalyzed Cycloaddition of α‐Diazo Homophthalimides and Nitriles Delivers Oxazolo[5,4‐c]isoquinolin‐5(4H)‐one Scaffold

“…Metal‐catalyzed cycloaddition reaction of α‐diazo carbonyl compounds with nitriles is a versatile way of preparing 1,3‐oxazoles and represents only a fraction of the myriad ways diazo compounds can be employed in the synthesis of heterocycles via the formation of metal carbenoid species At the same time, compounds where an α‐diazo carbonyl moiety is incorporated in a heterocyclic system are exceedingly rare though their use in [3+2] cycloadditions with nitriles would be a facile entry into structurally diverse heterocycle‐fused 1,3‐oxazoles. Common illustrative examples of compounds having an α‐diazo carbonyl as a part of a heterocyclic system include 5‐diazo‐1,3‐disubstituted barbituric acids ( 1 ), 3‐diazooxindoles ( 2 ), 3‐diazopyrrolidine‐2,4‐diones ( 3 ) and 5‐diazo‐1,3‐dioxane‐4,6‐diones (Meldrum's acids) ( 4 ) . However, none of these heterocyclic systems have been reported as a partner in cycloaddition reactions with nitriles.…”