Rhodium Carbenoid Initiated O–H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles

Abstract

A novel diazo-cascade approach has been developed for the synthesis of nine-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity.

Stereoselective Synthesis of Diverse Lactones through a Cascade Reaction of Rhodium Carbenoids with Ketoacids

“…Our hypothesis is inspired from our recently developed carbene cascade reaction, which proceeds through a carbene O−H insertion/aldol cyclization sequence to provide a substituted tetrahydrofuran intermediate that undergoes a thermally induced oxy-Cope rearrangement to yield functionalized oxacycles. 8 There have also been reports of alcohol O−H insertion/aldol cyclization in the literature for the synthesis of tetrahydrofurans (Scheme 1, eq 1); 9 however, there is no example in the literature of a ketoacid insertion/aldol cyclization for the synthesis of the corresponding γ-butyrolactones, which are common structural motifs found in about 10% of all natural products. 10 The incompatibility of carboxylic acids in carbene cascade reactions may be attributed to the competing insertion reaction via a proton transfer resulting from low pK a values of protonated carboxylic acids in the zwitterionic intermediate (Scheme 1, eq 2).…”

“…The compounds 4g−l were then subjected to the thermally induced oxy−Cope ring expansion reaction in refluxing toluene (boiling point 110 °C) as previously reported for the synthesis of medium-sized oxacycyles. 8,20 To our surprise, the reaction was found to be sluggish in refluxing toluene.…”

“…For the initial optimization, commercially available 2-acylbenzoic acid 1a and diazo 2a were selected as model substrates and exposed to our previously developed conditions for ketoalcohol O−H insertion/aldol cyclization (Table 1, entry 1). 8 As anticipated, Rh 2 (OAc) 4 in refluxing CH 2 Cl 2 exclusively provided insertion product 3a. In order to obtain the cascade reaction, we then examined different dirhodium carboxylates known to decompose diazoacetates (Table 1, entries 2−5).…”

“…As expected, the resulting hydroxyl group and carbonyl moiety of the diazo were found to be in a cis configuration as reported previously in the literature, including our own work on the carbene−heteroatom insertion/aldol cyclizations. 8,9 We also attempted a reaction with acceptor and acceptor/acceptor diazo compounds ethyl diazoacetate and benzyl diazoacetoacetate, respectively, but we only observed the insertion product without any aldol cyclization product.…”

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

“…[18] Furthermore, all the enolexo cyclizations for the tet/trig/dig systems follow the original Baldwin rules as seen in our previous work with rhodium carbenoid initiated cascade cyclizations. [4,19] For the initial optimization we exposed 1n to our optimized conditions that provided the 6-and 7membered spirocarbocycles. After refluxing for 3 h, Rh 2 (HFB) 4 /PPh 3 AuCl/(CuOTf) 2 tol only provided the sp 2 C-H functionalization product (Table 2, entry 1).…”