Bicyclo[2.1.1]hexane (BCH) serves as a highly promising saturated bioisostere for meta‑substituted benzene rings. Incorporation of BCH moieties into drug candidates increases the fraction of sp³‑hybridized carbons, improves aqueous solubility and metabolic stability, and thus enhances druggability. Nevertheless, efficient enantioselective construction of chiral 1,3‑disubstituted bicyclo[2.1.1]hexanes remains a long‑standing synthetic challenge. Most existing methodologies suffer from limited substrate generality, requirement for pre‑synthesized sophisticated intermediates, and poor enantiocontrol.

To address these bottlenecks, the research group of Prof. Shu‑Li You and Prof. Yuan‑Zheng Cheng at Shanghai Institute of Organic Chemistry developed a one‑pot tandem iridium‑catalyzed asymmetric allylic‑allylation / intramolecular crossed [2+2] photocycloaddition. Using readily available allylic alcohols and allylsilanes as starting materials, an iridium catalytic system built upon BINOL‑derived chiral phosphoramidite ligand is combined with the photocatalyst [Ir(dFCF₃ppy)₂(dtbbpy)]PF₆.Key 1,5‑diene intermediates are generated in situ. Without intermediate isolation, chiral 1,3‑disubstituted bicyclo[2.1.1]hexanes are efficiently accessed. This transformation features broad substrate scope, up to 90 % yield, regioselectivity >20:1 and excellent enantioselectivity exceeding 99 % ee.

Mechanistic studies confirm that formation of the 1,5-diene intermediate is irreversible. The iridium complex coordinated with BINOL-derived phosphoramidite-alkene ligand mediates solely the preceding allylic substitution step and does not interfere with the subsequent photocycloaddition. The photo-driven [2+2] cycloaddition proceeds via triplet excited-state pathways. This work provides a concise and practical synthetic strategy toward chiral caged saturated bioisosteres.

Multiple Lewis-acid additives were surveyed; Eu(OTf)₃ delivered optimal yield and stereoselectivity. Control experiments verify that both the iridium thermal catalyst and visible-light photocatalyst are indispensable. No target product is detected in dark conditions or in the absence of photocatalyst.

A wide variety of allylic alcohols and allylsilanes are well tolerated. Aromatic, heteroaromatic substrates, and substrates bearing halogen, boronate, silyl-alkyne, ester, trifluoromethyl substituents afford target bicyclo[2.1.1]hexane products in good-to-excellent yields with >20:1 rr and generally high ee values. Single-crystal X-ray diffraction (CCDC: 2551849) confirms the absolute configuration of product.

The reaction can be scaled-up to 2 mmol scale with maintained high yield and stereoselectivity. The bicyclo[2.1.1]hexane products can undergo versatile orthogonal transformations: epoxidation, oxidative cleavage, cyclopropanation, hydroboration-oxidation, hydrogenation, DIBAL-H reduction, etc., furnishing various functionalized cage-shaped building blocks with retention of high enantiopurity.

To facilitate related research, Kaitailai Platinum (Anhui) Co., Ltd. supplies a portfolio of BINOL-derived chiral phosphoramidite ligands as well as iridium-based photocatalysts shown in this article. Custom synthesis service is available for academic and industrial clients worldwide. Global inquiries and cooperation are warmly welcomed.

Wen-Jie Shen, Yiliang Gong, Yifeng Chen, Yuan-Zheng Cheng*, Shu-Li You*. Enantioselective Synthesis of 1,3-Disubstituted Bicyclo[2.1.1]hexanes via Cascade Allylic Allylation/Intramolecular Crossed [2+2] Photocycloaddition. CCS Chemistry. DOI:10.31635/ccschem.026.202608392