Citation: Qi Wang, Bichu Cheng, Minjie Liu, Fen-Er Chen. A concise asymmetric synthesis of (–)-oseltamivir phosphate via a biphasic Pd-catalyzed Heck-type cyclization[J]. Chinese Chemical Letters, ;2026, 37(5): 111555. doi: 10.1016/j.cclet.2025.111555 shu

A concise asymmetric synthesis of (–)-oseltamivir phosphate via a biphasic Pd-catalyzed Heck-type cyclization

Qi Wang ^b ,
Bichu Cheng ^{a, b} ,
Minjie Liu ^c ,
Fen-Er Chen ^{a, b, c, *,}

a.
Institute of Flow Chemistry and Engineering, College of Chemistry and Materials, Jiangxi Normal University, Nanchang 330022, China
b.
School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, China
c.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China

rfchen@fudan.edu.cn

Received Date: 30 April 2025
Revised Date: 21 June 2025
Accepted Date: 7 July 2025
Available Online: 11 July 2025

Figures(7)

A concise asymmetric synthesis of the anti-influenza drug (–)-oseltamivir phosphate (1) has been accomplished in 9 steps with an overall yield of 24%, starting from ethyl propiolate. The key features in this synthesis include an efficient biphasic Pd-catalyzed regioselectively intramolecular Heck-type cyclization to provide access to the highly valued chiral six-membered carbocyclic architecture, a regioselective and diastereoselective nitroso hetero-Diels-Alder reaction to construct the bicyclic oxazine 4 as well as a Cu(OTf)₂-mediated regioselective and diastereoselective nucleophilic substitution reaction of bicyclic oxazine 4 with 3-pentanol to yield the trans-1,2-substituted diamino cyclohexyl amyl ether 16 with the correct three contiguous stereocenters. This rapid functionalization of the advanced molecular framework would offer an effective strategy for the asymmetric synthesis of other oseltamivir phosphate analogues.
- Asymmetric synthesis,
- (–)-Oseltamivir phosphate,
- Heck-type cyclization,
- Hetero-Diels-alder reaction,
- Nucleophilic substitution reaction
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