不对称Smiles重排反应研究进展

doi:10.6023/cjoc202604048

摘要/Abstract

Smiles重排反应是一类通过分子内芳基迁移实现碳-碳键高效构建的重要合成策略, 广泛应用于药物分子、天然产物与功能材料的合成中, 但其不对称转化发展相对滞后, 目前尚无系统综述. 此文以反应机理为主线, 将不对称Smiles重排反应划分为离子型与自由基型两大类型, 并从手性底物诱导、手性试剂介导、手性催化三大立体控制策略出发, 系统总结了各反应体系的设计原理、反应特点与适用范围. 最后, 总结了当前该领域面临的核心挑战, 并对其未来发展方向与应用前景进行了展望, 旨在为相关手性合成方法学研究提供有益参考.

关键词: Smiles重排, 不对称合成, 季碳手性中心, 芳基迁移

The Smiles rearrangement is an important synthetic strategy for the efficient construction of carbon-carbon bonds via intramolecular aryl migration, which has been widely applied in the synthesis of pharmaceutical molecules, natural products, and functional materials. However, the development of its asymmetric transformation lags relatively behind, and no systematic review has been reported to date. This review classifies asymmetric Smiles rearrangements into two fundamental classes based on their reaction mechanisms: ionic and radical pathways. It systematically summarizes the design principles, reaction characteristics, and synthetic scope of each system under three well-established stereocontrol strategies: chiral substrate, chiral reagent, and chiral catalysis. Finally, the key challenges in this field are identified, and perspectives on future development directions and application prospects are presented, with the goal of providing a valuable reference for the development of new chiral synthetic methodologies.

Key words: Smiles rearrangement, asymmetric synthesis, chiral quaternary carbon stereocenter, aryl migration

引用此文

郭振广, 高登元, 葛洛, 邓卫平. 不对称Smiles重排反应研究进展[J]. 有机化学, 2026, 46(9): 3523-3545.

Zhenguang Guo, Dengyuan Gao, Luo Ge, Weiping Deng. Research Progress on Asymmetric Smiles Rearrangement[J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3523-3545.

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图/表 34

图式1. Smiles重排

Scheme 1. Smiles rearrangement

图式2. α-甲基苄基脲的不对称芳基迁移反应

Scheme 2. Asymmetric aryl migration reaction of α‑methylbenzylurea

图式3. α-甲基苄基脲的立体选择性芳基迁移反应机理

Scheme 3. Mechanism of stereoretentive aryl migration in α-methylbenzylureas

图式4. 基于吡啶基迁移的不对称Smiles重排反应

Scheme 4. Pyridyl migration in asymmetric Smiles rearrangement

图式5. 自稳定非外消旋烯醇盐的立体选择性分子内α-芳基化反应

Scheme 5. Stereoselective intramolecular α-arylation of self- stabilized non-racemic enolates

图式6. 氨基甲酸酯的不对称芳基迁移反应

Scheme 6. Asymmetric aryl migration of carbamates

图式7. 脯氨酸磺酰胺参与的Smiles重排

Scheme 7. Smiles rearrangement of proline sulfonamides

图式8. 硫代氨基甲酸酯分子内芳基化实现叔硫醇的对映选择性合成

Scheme 8. Enantioselective synthesis of tertiary thiols by intramolecular arylation of thiocarbamates

图式9. 氨基酸衍生物的不对称α-芳基化

Scheme 9. Asymmetric α-arylation of amino acid derivatives

图式10. 烯丙基硫代氨基甲酸酯的分子内芳基化实现叔硫醇的对映选择性合成

Scheme 10. Enantioselective synthesis of tertiary thiols from allylic thiocarbamates

图式11. 伪麻黄碱导向的α-氨基酸衍生物不对称α-芳基化

Scheme 11. Pseudoephedrine-directed asymmetric α-arylation of α-amino acid derivatives

图式12. N-酰胺基脯氨酸酯的非对映选择性分子内芳基化

Scheme 12. Intramolecular diastereoselective arylation of N‑carboxamido proline ester

图式13. 基于手性中心自再生策略(SRS)的氨基酸不对称芳基化

Scheme 13. Asymmetric arylation of amino acids by self-regeneration of stereocenters

图式14. 基于反式-2-氨基环己醇辅基导向的对映选择性芳基迁移反应

Scheme 14. Enantioselective aryl migration reaction directed by trans-2-aminocyclohexanol auxiliary

图式15. 有机锂介导的Smiles重排合成手性氮杂环庚烷

Scheme 15. Synthesis of chiral azepanes by organolithium-me- diated Smiles rearrangement

图式16. 可调控的Smiles重排合成轴手性苯胺衍生物

Scheme 16. Switchable Smiles rearrangement for the synthesis of axially chiral aniline derivatives

图式17. 非对映选择性合成具有α-芳基季碳手性中心的双环乙内酰脲衍生物

Scheme 17. Diastereoselective synthesis of bicyclic hydantoin derivatives bearing α-aryl quaternary stereocenters

图式18. 不对称锂化-芳基化串联反应

Scheme 18. Asymmetric tandem lithiation-arylation reaction

图式19. 基于乙烯基脲的对映选择性碳锂化-Smiles重排串联反应构筑手性叔胺

Scheme 19. Amines bearing tertiary substituents by tandem enantioselective carbolithiation-Smiles rearrangement of vinylureas

图式20. 苄胺衍生物的对映选择性分子内α-芳基化

Scheme 20. Enantioselective intramolecular α-arylation of benzylamine derivatives

图式21. 环脲衍生物的不对称扩环与缩环反应

Scheme 21. Asymmetric ring expansion and stereochemically retentive re-contraction of cyclic ureas

图式22. 可见光驱动亚磺酰基的不对称自由基型Smiles重排

Scheme 22. Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement

图式23. 光诱导自由基二氧化硫插入-Smiles重排串联反应

Scheme 23. Photoinduced radical sulfur dioxide insertion and Smiles rearrangement

图式24. 基于电合成的烯丙基胺立体选择性迁移杂芳基三氟甲基化反应

Scheme 24. Stereoselective migratory heteroaryltrifluoromethylation of allylic amines via electrosynthesis

图式25. 基于亚磺酰基-Smiles重排的不对称远程C(sp3)—H芳基化

Scheme 25. Asymmetric, remote C(sp3)—H arylation via sulfinyl-Smiles rearrangement

图式26. 光催化不对称酰基自由基Smiles重排

Scheme 26. Photocatalytic asymmetric acyl radical Smiles rearrangement

图式27. N-亚磺酰基丙烯酰胺与溴代二氟乙酰胺的光氧化还原自由基Smiles重排

Scheme 27. Photoredox radical Smiles rearrangement of N-sulfinyl acrylamides with bromodifluoroacetamides

图式28. 手性亚砜介导的不对称Smiles重排

Scheme 28. Asymmetric Smiles rearrangement with chiral sulfoxides

图式29. 可见光介导芳基偶氮砜参与的自由基Smiles重排

Scheme 29. Visible-light-mediated radical Smiles rearrangement via arylazo sulfones

图式30. 光诱导不对称Smiles重排与自由基二氧化硫插入反应

Scheme 30. Photoinduced asymmetric Smiles rearrangement and radical sulfur dioxide insertion

图式31. 基于手性芳基亚磺酰胺的可见光催化烯烃不对称氨基芳基化

Scheme 31. Chiral arylsulfinylamides as reagents for visible light-mediated asymmetric alkene aminoarylations

图式32. 手性芳基亚磺酰胺双功能试剂介导烯烃的自由基不对称氨基芳基化

Scheme 32. Asymmetric radical aminoarylation of alkenes using chiral arylsulfinamides as bifunctional reagents

图式33. 手性亚砜亚胺试剂介导的光诱导烯烃不对称氨基杂芳基化

Scheme 33. Photoinduced asymmetric alkene aminohetarylation with chiral sulfoximine reagents

图式34. 基于P450自由基芳基迁移酶催化不对称Smiles重排

Scheme 34. Catalytic enantioselective Smiles rearrangement enabled by the directed evolution of P450 radical aryl migratases

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