Deconstructive Synthesis of Bridged and Fused Rings via Transition-Metal-Catalyzed "Cut-and-Sew" Reactions of Benzocyclobutenones and Cyclobutanones

Abstract

Bridged and fused rings are commonly found in biologically important molecules. Current tactics to construct these ring systems are primarily based on stepwise ring formation (i.e., making one ring first followed by making another) and cycloaddition reactions (e.g., Diels-Alder reaction). To seek a complementary and perhaps more unified ring-forming approach, a deconstructive strategy based on C-C bond activation of cyclic ketones has been conceived. The named "cut-and-sew" reaction uses cyclic ketones with a tethered unsaturated moiety as substrates, which involves oxidative addition of a transition metal into the ketone C-C bond followed by intramolecular insertion of the unsaturated unit. This strategy has proved successful to access diverse ring scaffolds that are nontrivial to construct otherwise.This Account offers a concise summary of our laboratory's systematic efforts in developing transition metal-catalyzed cut-and-sew reactions for the synthesis of bridged and fused rings over the past 10 years. In particular, we will focus on the reactions using readily available benzocyclobutenones and cyclobutanones. To date, the scope of the cut-and-sew reactions has been greatly expanded. First, diverse unsaturated moieties can serve as suitable coupling partners, such as alkenyl, alkynyl, allenyl, carbonyl, and iminyl groups. Second, a variety of reaction modes have been uncovered. In this account, (4 + 2), (4 + 2 - 1), and (4 + 1) cycloadditions that lead to a range of bridged or fused scaffolds will be summarized. Third, enantioselective transformations have been realized to efficiently construct chiral scaffolds, which are enabled by two strategies: enantio-determining migratory insertion and desymmetrization of cyclobutanones. Fourth, the synthetic applications have been demonstrated in streamlined total syntheses of a number of complex natural products. Compared to conventional synthetic logics, the cut-and-sew reaction allows the development of new bond-disconnecting strategies. Thus, the syntheses of (-)-cycloclavine, (-)-thebainone A, penicibilaenes, and the proposed cycloinumakiol are discussed in more detail.In addition to the narrative of the development of the cut-and-sew chemistry, this Account also aims to provide core guiding foundations and inspirations toward broader deconstructive synthetic applications through C-C bond cleavage. It is anticipated that more classes of cyclic compounds could serve as the substrates beyond benzocyclobutenones and cyclobutanones, and more diverse unsaturated moieties could be coupled. It can also be envisaged that more innovative utilization of this cut-and-sew strategy in complex organic syntheses will be revealed in the near future.

Scheme 1. Cut-and-Sew Reactions of Benzocyclobutenones and Cyclobutanones

Scheme 2. Rhodium-Catalyzed Intramolecular (4 + 2) Reactions between Benzocyclobutenones and Alkenyl Groups

Scheme 3. Rhodium-Catalyzed Asymmetric Cut-and-Sew Reactions between Benzocyclobutenones and Alkenyl Groups

Scheme 4. Rhodium-Catalyzed (4 + 2) Reactions between Benzocyclobutenones and Alkynyl Groups

Scheme 5. Cobalt-Catalyzed (4 + 2) Reactions between Benzocyclobutenones and Alkynyl Groups

Scheme 6. Rhodium-Catalyzed Asymmetric (4 + 2) Reactions between Benzocyclobutenones and Oxime Ethers

Scheme 7. Rhodium-Catalyzed Cut-and-Sew Reactions between Benzocyclobutenones and Ketones/Aldehydes

Scheme 8. Rhodium-Catalyzed Intramolecular (4 + 2) Reactions with Benzene Linkers

Scheme 9. Temporary Directing Group-Enabled Cut-and-Sew Reactions between Cyclobutanones and Alkenyl Groups

Scheme 10. Rhodium-Catalyzed Cut-and-Sew Reactions between Cyclobutanones and Alkenyl and Carbonyl Groups

Scheme 11. Rhodium-Catalyzed (4 + 2) Cut-and-Sew Reactions between Cyclobutanones and Alkynyl Groups

[Rh(C₂H₄)₂Cl]₂ (5 mol %), AgSbF₆ (10 mol %), (R)-DTBM-segphos (12 mol %), 1,4-dioxane, room temperature.

Scheme 12. Rhodium-Catalyzed (4 + 2) Reactions between α-Branched Cyclobutanones and Alkynyl Groups

Scheme 13. Kinetic Resolution of α-Branched Cyclobutanones via Fused-Ring Formation

Scheme 14. Rhodium-Catalyzed (4 + 2 – 1) Cut-and-Sew Reactions between Benzocyclobutenones and Alkynyl Groups

Scheme 15. Rhodium-Catalyzed (4 + 2 – 1) Reactions between Cyclobutanones and Alkenyl Groups

Scheme 16. Rhodium-Catalyzed (4 + 1) Cut-and-Sew Reactions between Benzocyclobutenones and Styrenes

Ratio of the (4 + 1) versus (4 + 2) products.

Scheme 17. Rhodium-Catalyzed (4 + 1) Cut-and-Sew Reactions between Cyclobutanones and Allenyl Groups

Scheme 18. Total Synthesis of Cycloinumakiol (Proposed Structure)

Scheme 19. Enantioselective Total Synthesis of (−)-Cycloclavine

Scheme 20. Deconstructive Asymmetric Total Synthesis of (−)-Thebainone A

Scheme 21. Total Syntheses of Penicibilaenes A and B