Jiaxin Xie

Couple-close as a synthetic paradigm has the potential to change the way that synthetic organic chemists approach cyclic scaffold construction. One class of cyclic molecules that has been increasingly sought after is semisaturated cyclic scaffolds, whose specific blend of Csp ² - and Csp ³ -hybridized components confers distinct properties to these species. However, existing methods to construct these scaffolds are limited, often relying on arene saturation or annulations that require lengthy de novo syntheses. Herein, we describe a unified and highly modular couple-close strategy for the synthesis of semisaturated scaffolds. This approach installs bifunctional linkers onto aromatic rings through a range of bond-forming reactions, and subsequent cyclization furnishes semisaturated bicyclic adducts. Key to this approach is a mechanistically distinct cobalt-catalyzed dehydrogenative radical cyclization that proceeds efficiently even on electronically unbiased arenes, enabling a broad substrate scope under mild reaction conditions.

The development of efficient C(sp³)-C(sp³) cross-coupling methods that expand access to a pharmaceutically relevant three-dimensional chemical space represents a key frontier in organic synthesis. Traditional cross-coupling strategies readily achieve C(sp²)-C(sp²) and C(sp²)-C(sp³) bond formation but face significant challenges in C(sp³)-C(sp³) coupling due to issues of sluggish inner sphere reductive elimination, β-hydride elimination, and limited cross-selectivity. Recent advances in C(sp³)-C(sp³) cross-coupling have highlighted the potential of an alternative bond-forming mechanism, bimolecular homolytic substitution (S_H2), as an outer sphere pathway to overcome these limitations. This strategy leverages a "radical sorting effect", in which sterically distinct alkyl radicals are partitioned based on their substitution patterns. This perspective provides a comprehensive analysis of S_H2-mediated C(sp³)-C(sp³) cross-coupling reactions from 2021 to 2024, focusing on iron, nickel, and cobalt catalysis and their powerful applications in quaternary carbon center (QCC) formation. We also highlight emerging opportunities in single functional group cross-coupling and alkene functionalization, demonstrating the versatility of S_H2 in accessing complex molecular architectures from abundant feedstock chemicals. By addressing key challenges in C(sp³)-C(sp³) cross-coupling, S_H2 radical sorting catalysis holds significant promise for expanding the C(sp³)-rich chemical space and enabling transformative advances in organic synthesis.

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target and maximizing exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp ³ )–C(sp ³ ) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity. In this work, we report a nickel radical sorting–mediated cross-alcohol coupling wherein two alcohol fragments are deoxygenated and coupled in one reaction vessel, open to air.

In this Review, the underrecognized utilities of the cyclopropylcarbinyl cation chemistry are summarized in cyclopropane synthesis and skeletal rearrangements, and their applications in natural product total synthesis are highlighted.

Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure-activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.

Here we report the total synthesis of phainanoid A, a unique dammarane-type triterpenoid (DTT), using an unusual bidirectional synthetic strategy. It features two transition-metal-mediated highly diastereoselective transformations to access the two challenging strained ring systems that branch toward opposite directions from the tricyclic core. This work also highlights the strategic use of ketones (or enol triflates) as versatile handles for rapid growth of molecular complexity in all key transformations, which paves the way for efficient preparations of complex and biologically significant DTTs.

An efficient strategy to synthesize the western part of phainanoids is reported. The benzofuranone-based 4,5-spirocyclic motif is constructed diastereoselectively via a palladium-catalyzed intramolecular alkenylation. The computational study suggests that the remarkably high diastereoselectivity is attributed to the stabilizing interaction between the 2′ carbonyl moiety and the palladium catalyst in the favored transition state.