Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications

Abstract

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh₂(carboxylate)₄ is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines.

Fig. 1. Catalytic cycloaddition & cyclization methods.

a Construction of aromatic ring-fused cyclobutanones & unknown structure of furan-fused cyclobutanone. b Catalytic carbocyclization & carbene/alkyne metathesis (CAM). c This study: catalytic 4-exo-dig carbocyclization process for the direct construction of furan-fused cyclobutanones vs competitive 5-endo-dig cyclization. d Synthetic applications of synthesized furan-fused cyclobutanones.

Fig. 2. Substrate scope for the synthesis of furan-fused cyclobutanones 2.

Reaction conditions: to a solution of Rh₂(OPiv)₄ (1.2 mg, 1.0 mol%), and 4 Å MS (100 mg) in EtOAc (1.0 mL), was added a solution of diazo compounds 1 (0.2 mmol) in EtOAc (1.0 mL) slowly over 10 min via a syringe under an argon atmosphere at 40 °C, and the reaction mixture was stirred for additional 1.0 h under these conditions. The yields are isolated yields. ^aThe reaction was carried out on a 5.0 mmol scale with 0.25 mol% of Rh₂(OPiv)₄ loading. ^bThe reaction was carried out in the presence of Rh₂(esp)₂ (1.0 mol%) in DCE at 80 °C.

Fig. 3. Synthetic applications of furan-fused cyclobutanone 2a.

a Synthesis of 4. b Synthesis of 5a. c Synthesis of 5b. d Synthesis of 6a and 6b. e Synthesis of 7. f Synthesis of 8.

Fig. 4. Synthesis of furan-embedded amide and ester derivatives.

Reaction conditions: 2 (0.1 mmol), amines or hydrochloride of amino acid esters (0.15 mmol, 1.5 equiv.), and Et₃N (0.2 mmol, 2.0 equiv.) in DCM (2.0 mL), and stirring for 48 h in an oil bath at 60 °C, unless otherwise noted. ^a2 (0.1 mmol), alcohols (0.15 mmol, 1.5 equiv.), and NaH (0.15 mmol, 1.5 equiv.) in dry THF (2.0 mL) at 0 °C, then warmed to 60 °C slowly and stirred for 1.0 h. All yields are isolated yields.

Fig. 5. Synthesis of benzocyclobutenones and poly-substituted benzene derivatives.

Reaction conditions: 2 (0.1 mmol), and maleimides (0.15 mmol, 1.5 equiv.) in a mixed solvent of toluene/DCE = 10/1 (1.0 mL) at 90 °C for 12 h. All yields are isolated yields. ^aBenzocyclobutenones (0.1 mmol), and piperidine (0.15 mmol, 1.5 equiv.) in DCM (2.0 mL), and stirring for 24 h in an oil bath at 60 °C.

Fig. 6. The cytotoxicity of the synthetic compounds in various human cell lines.

a The IC₅₀ curves of compound 21 on the inhibition of various human tumor cells. b The IC₅₀ curves of compound 29 on the inhibition of various human tumor cells. c The IC₅₀ curves of compound 50 on the inhibition of various human tumor cells.

Fig. 7. Control experiments.

a Control reaction of 1af in the presence of styrene under standard conditions. b Control reaction of 1af in the presence of BnOH under standard conditions. c Ring-opening reaction of 70 with methyl L-tryptophanate.

Fig. 8. The reaction mechanism and DFT calculation for the 4-exo-dig and 5-endo-dig carbocyclization using Rh₂(HCOO)₄ as catalyst.

The numbers in the parentheses are the free energies in kcal/mol, computed at SMD(EtOAc)/BMK/def2-TZVPP//B3LYP/def2-SVP, all the structures are obtained in the gas phase.

Fig. 9. The key transition states in the regioselectivity of the real system and the NCI plots.

Free energies are in kcal/mol, computed at SMD(EtOAc)/BMK/def2-TZVPP//SMD(EtOAc)/B3LYP/def2-SVP, all the structures are obtained in solution.