γ-Functionalized primary alcohols are widely found in natural products and drug molecules. Extensive studies have focused on α- and β-functionalization of primary alcohols. However, γ-position transformation remains a formidable synthetic challenge due to the remote reactive site, intrinsically low reactivity and difficult stereocontrol.

Very recently, the team of Prof. Xiaohong Huo and Prof. Wanbin Zhang at Shanghai Jiao Tong University reported a relay-synergistic ternary Ir / chiral amine / Ni catalytic strategy. Starting from allylic primary alcohols, iridium-mediated borrowing-hydrogen oxidation generates α,β-unsaturated aldehydes. Subsequent stereodetermining Michael addition is cooperatively catalyzed by chiral amine and chiral-nickel complexes. An iridium-hydride species finally delivers γ-functionalized primary alcohols bearing vicinal γ,δ-stereocenters.

By switching the configurations of chiral-amine and chiral-bisoxazoline-nickel catalysts, all four stereoisomers can be selectively accessed. The reaction affords up to 94 % yield, >20:1 diastereomeric ratio and >99 % enantiomeric excess. The catalytic system rapidly reduces labile Michael-adduct intermediates and effectively suppresses retro-Michael side-reactions to guarantee excellent diastereoselectivity. Kinetic-isotope-effect experiments confirm that borrowing-hydrogen oxidation of allylic primary alcohol constitutes the rate-determining step. Broad substrate scope, gram-scale preparation and diverse product derivatization further demonstrate synthetic practicality.

A set of iridium borrowing‑hydrogen catalysts, chiral amine organocatalysts, chiral bisoxazoline‑nickel Lewis‑acid catalysts and Brønsted‑acid additives were systematically evaluated. The combination of iridium catalyst, chiral amine (S)‑A4 and bisoxazoline ligand (R,S)‑M3 with *p‑nitrophenol as Brønsted‑acid additive delivers optimal yield and stereoselectivity. Changing ligand steric bulk (M1, M2, M4, M5) leads to obvious dr deterioration. Control experiments verify that each catalytic component is indispensable.

A broad library of allylic primary alcohols and 2-acylimidazole nucleophiles are well tolerated. Aryl substrates bearing electron-donating / electron-withdrawing groups, heteroaromatic moieties, natural-product-derived fragments are compatible. Most examples deliver high yields together with >10:1->20:1 dr and >99 % ee. Late-stage modification of bioactive molecular skeletons such as helichrysin, oxaprozin and lithocholic acid can be realized.

Full stereodivergence is achieved by pairwise adjustment of configurations of chiral-amine catalyst and chiral bisoxazoline-nickel catalyst. All four stereoisomers (S,S), (S,R), (R,R), (R,S) of γ-functionalized primary alcohols with vicinal stereocenters can be individually obtained in good yields and maintained high stereoselectivity.

To support related scientific research, Kaitailai Platinum (Anhui) Co., Ltd. offers a full series of chiral bisoxazoline ligands. Custom‑tailored synthesis service is available for academic and industrial‑R&D customers worldwide. Global inquiries and cooperation are warmly welcomed.

Rui Ding, Guanlin Li, Ziyun Lai, Haoyang Wang, Xinxin Yuan, Wanbin Zhang*, Xiaohong Huo*. Stereodivergent Synthesis of γ‑Functionalized Primary Alcohols via Relay‑Synergistic Ir/Amine/Ni Catalysis. J. Am. Chem. Soc. DOI:10.1021/jacs.6c16883