Radical asymmetric intramolecular α-cyclopropanation of aldehydes towards bicyclo[3.1.0]hexanes containing vicinal all-carbon quaternary stereocenters

ARTICLE DOI: 10.1038/s41467-017-02231-7 OPEN Radical asymmetric intramolecular α-cyclopropanation of aldehydes towards bicyclo [3.1.0]hexanes containing vicinal all-carbon quaternary stereocenters 1 1234567890 Liu Ye1, Qiang-Shuai Gu1, Yu Tian1, Xiang Meng1, Guo-Cong Chen1 & Xin-Yuan Liu The development of a general catalytic method for the direct and stereoselective construction of cyclopropanes bearing highly congested vicinal all-carbon quaternary stereocenters remains a formidable challenge in chemical synthesis. Here, we report an intramolecular radical cyclopropanation of unactivated alkenes with simple α-methylene group of aldehydes as C1 source via a Cu(I)/secondary amine cooperative catalyst, which enables the single-step construction of bicyclo[3.1.0]hexane skeletons with excellent efficiency, broad substrate scope covering various terminal, internal alkenes as well as diverse (hetero)aromatic, alkenyl, alkyl-substituted geminal alkenes. Moreover, this reaction has been successfully realized to an asymmetric transformation, providing an attractive approach for the construction of enantioenriched bicyclo[3.1.0]hexanes bearing two crucial vicinal all-carbon quaternary stereocenters with good to excellent enantioselectivity. The utility of this method is illustrated by facile transformations of the products into various useful chiral synthetic intermediates. Preliminary mechanistic studies support a stepwise radical process for this formal [2 + 1] cycloaddition. 1 Department of Chemistry, South University of Science and Technology of China 518055 Shenzhen, China. Liu Ye and Qiang-Shuai Gu contributed equally to this work. Correspondence and requests for materials should be addressed to X.-Y.L. (email: ) NATURE COMMUNICATIONS | (2018)9:227 | DOI: 10.1038/s41467-017-02231-7 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-02231-7 C hiral bicyclo[3.1.0]hexanes bearing one or more all-carbon quaternary stereocenters are significant structural motifs occurring in a large number of natural and unnatural compounds with important biological activities (Fig. 1a)1–6. In particular, such skeletons have also been widely applied as highly useful chiral building blocks in organic synthesis because of unique chemical reactivity for fragmentation and rearrangement7–10. Various approaches to access these structurally unique scaffolds have been developed11–18, and most of them are based on the asymmetric intramolecular cyclopropanation of olefins with metallocarbenes as the C1 component19–27. Despite these significant achievements in the field of metallocarbene chemistry, reactive prefunctionalized reagents, such as diazos, sulfonyl hydrazones, and ylides, have been mostly used as the metallocarbene precursors as the C1 component in this system11–27. On the other hand, it is well-known that the efficient construction of chiral all-carbon quaternary stereocenter generally represents a significant and highly important task, but is among the most challenging objectives in organic synthesis due to the inherently unfavorable steric hindrance and relatively small steric differences for efficient enantiocontrol28–31. Noteworthy is that the efficient formation of bicyclo[3.1.0]hexane scaffolds containing two sterically congested vicinal all-carbon quaternary stereocenters with conventional metallocarbene strategies remains a formidable challenge19–27. To circumvent the aforementioned challenges, the invention of a catalytic enantioselective intramolecular cyclopropanation method capable of constructing structurally diverse bicyclo[3.1.0]hexane skeletons containing vicinal all-carbon quaternary stereocenters, preferably by using readily available and simple methylene group as C1 source, is highly desirable and will be of great synthetic importance. a Recently, impressive progress has been achieved in the development of intermolecular cyclopropanation of olefins using simple methyl group as C1 source32–35, which has obvious advantages over reactive prefunctionalized precursors with respect to availability of the starting materials, operation safety, environmental benignity, and atom economy. In particular, Antonchick and co-workers reported a seminal work on copper (I)-catalyzed intermolecular [2 + 1] cycloaddition of electrondeficient alkenes with the methyl group in aryl methyl ketones as C1 source for the construction of cyclopropanes with good efficiency through a radical process33. Compared with these attractive racemic attributes, the development of catalytic asymmetric variant of this type of reaction remains a formidable unexplored challenge, which might be attributed to the relatively harsh reaction conditions (at 110 °C) and the highly reactive nature of the involved radical species36–43. With our continuing interest in developing the challenging asymmetric radical reactions with the dual-catalytic system through the combination of transition metal catalysis and organocatalysis44–48, we became interested in employing Cu(I)/chiral amine cooperative catalysis49–54 for realizing the asymmetric radical intramolecular cyclopropanation of alkenes with a simple α-methylene of aldehydes for the efficient construction of structurally diverse bicyclo[3.1.0]hexane skeletons containing two crucial vicinal all-carbon quaternary stereocenters. In this scenario, we envisaged that the enamine intermediate, in situ generated from a chiral secondary amine with an aldehyde of the rationally designed alkenyl aldehyde substrate 1, could undergo a selective single electron transfer (SET)55–59, followed by 6-endo-trig cyclization and cyclopropanation to afford the optically enriched bicyclo[3.1.0]hexane motif with H CH2 OH O O H H OH O Cycloeudesmol H OH OR H Echinopine A (R = H) Echinopine B (R = CH3 ) O Ph H Dichapetalin A O O MeO HO HO NH2 O HO OH HO OH Key fragment for vitamin D analogs Biological probe Ailanthol b O R H N H oxidant N N + Cu • R H R R OHC Cun L H X X X 1 X 2 √ Dual-catalytic system composed of Cu(I) and chiral amine √ Construction of two vicinal all-carbon quaternary stereocenters Fig. 1 Bicyclo[3.1.0]hexane skeletons-containing compounds and our synthetic proposal. a Representative natural and unnatural products containing bicyclo[3.1.0]hexanes bearing quaternary stereocenters. b Our envisioned catalytic asymmetric radical cyclopropanation of alkenyl aldehyde 2 NATURE COMMUNICATIONS | (2018)9:227 | DOI: 10.1038/s41467-017-02231-7 | www.nature.com/naturecommunications ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-02231-7 Table 1 Optimization of reaction conditions O CO2Me H CuI (20 mol%) Ligand (10 mol%) Pyrrolidine (20 mol%) Oxidant (2 equiv) CO2Me OHC MeCN, 60 °C, 12 h MeO2C MeO2C CO2Me 1a 2a Oxidants AcO I Ligands tBu OH OAc OH I I O F Entry 1 2 3 4c 5 6 7d 8 9 10e 11f 12g 13h N N N N N N O O PIDA CO2Me O BI-OH F-BI-OH Oxidant PIDA PhIO BI- (...truncated)