Rhodium-catalyzed intermolecular enantioselective Alder–ene type reaction of cyclopentenes with silylacetylenes

ARTICLE https://doi.org/10.1038/s41467-021-26955-9 OPEN Rhodium-catalyzed intermolecular enantioselective Alder–ene type reaction of cyclopentenes with silylacetylenes 1234567890():,; Dongquan Zhang1, Miaomiao Li1, Jiajia Li1, Aijun Lin 1 ✉ & Hequan Yao 1✉ The Alder–ene type reaction between alkenes and alkynes provides an efficient and atomeconomic method for the construction of C-C bond, which has been widely employed in the synthesis of natural products and other functional molecules. The intramolecular enantioselective Alder-ene cycloisomerization reactions of 1,n-enynes have been extensively investigated. However, the intermolecular asymmetric version has not been reported, and remains a challenging task. Herein, we describe a rhodium-catalyzed intermolecular enantioselective Alder-ene type reaction of cyclopentenes with silylacetylenes. A variety of chiral (E)-vinylsilane tethered cyclopentenes bearing one quaternary carbon and one tertiary carbon stereocenters are achieved in high yields and enantioselectivities. The reaction undergoes carbonyl-directed migratory insertion, β-H elimination and desymmetrization of prochiral cyclopentenes processes. 1 State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, P. R. China. ✉email: ; NATURE COMMUNICATIONS | (2021)12:6627 | https://doi.org/10.1038/s41467-021-26955-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-26955-9 T he production of synthetically valuable products from readily accessible substrates in a redox-neutral, atom- and step-economical approach is a long-standing goal in organic synthesis. The Alder-ene type reaction comprises a particularly efficient subset of this target1–6, which provides an appealing tool to construct C–C bond. Over the past decades, transition metal-catalyzed intramolecular enantioselective Alderene type cycloisomerization reactions of 1,6-enynes or 1,7-enynes have been extensively investigated for the rapid assembly of chiral five- or six membered carbo- and hetero-cyclic frameworks (Fig. 1a)7–17. However, the intermolecular Alder-ene reactions were mainly confined to less-hindered terminal alkenes18–25, and the studies on internal alkenes have rarely been reported26,27. Very recently, Trost and coworkers successfully implemented ruthenium-catalyzed intermolecular alkene–alkyne coupling reactions with well-designed vinyl boronate compounds to synthesize boron-functionalized 1,4-dienes (Fig. 1b)28,29, in which the boron substituent played a vital role to facilitate the transformations. However, the intermolecular enantioselective Alderene type reaction remains an unexplored territory. All-carbon chiral quaternary stereocenters are fundamental structural motifs present in natural products and pharmaceuticals, which could improve the metabolic stability and target selectivity of biologically active compounds30. However, the synthesis of chiral quaternary carbon centers is a challenging task, especially those that are not formed at the direct reaction site31–41. Asymmetric desymmetrization of prochiral compounds or meso-compounds offers a commendable synthetic tool for achieving this objective42–54. Herein, we describe an asymmetric desymmetrization of prochiral cyclopentenes with silylacetylenes enabled by rhodiumcatalyzed intermolecular enantioselective Alder-ene type reaction. This protocol allows access to chiral (E)-vinylsilane tethered cyclopentenes bearing one quaternary carbon and one tertiary carbon stereocenters in high yields and enantioselectivities (Fig. 1c). Results Reaction optimization. We commenced our studies with the employment of N,1-diphenylcyclopent-3-ene-1-carboxamide 1a and triisopropylsilylyne 2a as the model substrates. After considerable screening of the reaction parameters (see the Fig. 1 Transition metal-catalyzed Alder-ene type reaction. a Intramolecular enantioselective Alder-ene type cycloisomerization reaction (well-developed). b Intermolecular Alder-ene type reaction of internal alkenes (Trost’s work). c Intermolecular enantioselective Alder-ene type reaction (this work). 2 Supplementary Table 1 for details), the desired product 3a was obtained in 96% yield and 95% ee with [Rh(COD)OMe]2 as the catalyst, phosphoramidite L6 as the ligand, PhMe2CCO2H and NaBARF as the additives in DCM at 80 °C (Table 1, entry 1). The P,P-ligands L1, L2 and N,P-ligand L3 inhibited the transformation (entry 2). Phosphoramidite ligands L4 and L5 performed this reaction in less efficiency (entries 3 and 4). Rh(COD)2OTf and [Rh(COD)Cl]2 gave inferior results compared with [Rh(COD) OMe]2, [Cp*RhCl2]2 and Pd(dba)2 delivered trace amount yield of product 3a (entries 5–8). AcOH and PhCO2H offered 3a in diminished enantioselectivities (entries 9 and 10), and no product was detected in the presence of TsOH (entry 11). Using other additives, such as AgSbF6 and AgPF6 could not perform this transformation as well as NaBARF (entries 12 and 13). Conducting the reaction in CHCl3 and toluene led to lower yields and enantioselectivities (entries 14 and 15), and the reaction was completely suppressed in THF (entry 16). Substrate scope. With the optimized reaction conditions in hand, we then explored the generality of this rhodium-catalyzed intermolecular enantioselective Alder-ene type reaction (Fig. 2). Various aryl and heteroaryl substituted cyclopentenes (see the Supplementary Methods for details) performed the reactions well, affording the products 3b-3k in 90–94% ee. Replacing the aryl groups with a benzyl group or an alkyl group delivered the products 3l and 3m in 96 and 95% ee. Notably, the substrate 1n containing two alkene moieties, performed the reaction selectively with the endocyclic double bond to give the product 3n in 84% yield with 92% ee. The amino substituted cyclopentene 1o was also suitable substrate for this transfomation, furnishing chiral α-amino acid derivative 3o in 93% ee. N-benzylcyclopent-3-ene-1-carboxamide (R1 = H) offered the desired product 3p in 90% yield and 94% ee. Subsequently, the compatibilities of amide moiety were investigated, and the products 3q-3w with aryl and alkyl groups were achieved in 86–94% ee. The substrate 1x with tertiary amide group gave 3x in 63% yield with 96% ee under slightly modified conditions. Besides, the enantioenriched spirolactam 3y could also be synthesized in 78% yield and 90% ee. Ester or ketone groups substituted cyclopentenes proceeded this reaction efficiently, affording the products 3z-3ad in 72–93% yields with 90–93% ee. When substrate 1ae was subjected to the standard reaction conditions, no desired product 3ae was detected. After checking the character of cyclopentenes, we then turned our attention to the scope of alkynes. The reactions proceeded smoothly with diverse silylacetylenes, delivering products 3af-3ai in 93–94% ee. In addition, sterically hinder (...truncated)