Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Article https://doi.org/10.1038/s41467-024-52419-x Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis Received: 6 June 2024 1234567890():,; 1234567890():,; Accepted: 5 September 2024 Check for updates Wen-Biao Wu 1,2,3,5, Bing Xu4,5, Xue-Chun Yang1,5, Feng Wu1, Heng-Xian He1, Xu Zhang2 & Jian-Jun Feng 1 The absence of catalytic asymmetric methods for synthesizing chiral (hetero) bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee. The development of asymmetric catalytic reactions, as well as the introduction of new catalytic methods and strategies for preparing chiral molecules in enantioenriched forms, is crucial for drug discovery and innovation. This importance is underscored by the fact that over half of all pharmaceuticals currently in use are chiral compounds containing carbon stereocenters1. Recently, the substitution of planar aromatic rings with bridged bicyclic scaffolds has been increasingly acknowledged as a potent approach to enhance the physicochemical and pharmacokinetic properties of drug analogs2–19. 1,3-Disubstituted phenyl rings and Nheterocycles are ubiquitous structural motifs found in a variety of small-molecule drugs, with pyridines ranking as the second most prevalent in marketed drugs (Fig. 1a)20. In this context, Anderson21 and Uchiyama22 independently demonstrated that bridgehead-substituted bicyclo[3.1.1]heptanes (BCHeps), prepared via ring-opening reactions of [3.1.1]propellanes, are suitable bioisosteres for meta-substituted benzenes (Fig. 1b). Subsequently, Mykhailiuk documented that azaBCHeps exhibit remarkable potential as pyridine bioisosteres23. Besides noncatalytic linear synthetic methods, several state-of-the-art catalytic strategies, including photocatalysis, boronyl radical catalysis, Lewis acid catalysis, and silver-promoted methods, have been developed by research groups led by Stephenson24, Molander25, Li26, Waser27, Wang28, Deng29, and Glorius30 for synthesizing BCHeps and aza-BCHeps through cycloadditions of bicyclo[1.1.1]pentanes (BCPs) or bicyclo[1.1.0]butanes (BCBs) (Fig. 1c)31–35. In 2021, Baran and co-workers successfully achieved enantiopure BCP bioisosteres through SFC separation. Furthermore, their study revealed that substituting benzenoids with either R- or S-enantiomers of BCPs results in distinct drug bioactivities36. Consequently, the development of catalytic asymmetric synthesis techniques for (hetero) bicyclo[n.1.1]alkanes is not only highly desirable but would also significantly accelerate the creation of drugs with superior properties. While chirality transfer and bio-catalysis strategies have been used to synthesize chiral BCPs and BCHs respectively37,38, before the elegant asymmetric (3 + 2) cycloadditions of BCBs reported by Bach39 and Jiang40, the only asymmetric difunctionalization reactions within the BCB framework were limited to ring opening processes41,42. Notably, the strategies employed by Bach39 and Jiang40, focus exclusively on 1 State Key Laboratory of Chemo/Biosensing and Chemometrics, Advanced Catalytic Engineering Research Center of the Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University, Changsha, P. R. China. 2School of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, P. R. China. 3School of Physics and Chemistry, Hunan First Normal University, Changsha, P. R. China. 4Department of Chemistry, Fudan University, e-mail: Shanghai, P.R. China. 5These authors contributed equally: Wen-Biao Wu, Bing Xu, Xue-Chun Yang. Nature Communications | (2024)15:8005 1 Article https://doi.org/10.1038/s41467-024-52419-x Fig. 1 | Outline of this work. a Occurrence frequency of selected rings in marketed small molecule drugs. b Synthesizing racemic or achiral bicyclo[n.1.1]alkanes. c Racemic or achiral aza-BCHep derivatives as the three-dimensional (3D) analogs of pyridines. d Asymmetric synthesis of enantiomerically pure bicyclo[n.1.1]alkanes from BCBs. e Enantioselective (3 + 3) cycloadditions of BCBs through asymmetric Lewis acid catalysis. asymmetric photochemical cycloadditions of BCBs. Our group has recently achieved palladium-catalyzed enantioselective [2σ + 2σ] cycloadditions of BCBs with vinyl oxiranes to synthesize O-BCHeps (Fig. 1d)43. Besides radical cycloadditions, polar cycloadditions of BCBs have been developed after Leitch’s pioneering research in Lewis acid catalysis44. Currently, the Lewis acid catalyzed (3+n) polar cycloadditions of BCBs can utilize ketenes45, aldehydes46, heteroarenes47,48, dienol ethers49, ynamides50 and imidazolidines51 as the cycloaddition partners. During the preparation of this manuscript, Deng pioneered the Eu(OTf)3-catalyzed cycloadditions of BCBs with nitrones29. This innovation resulted in the creation of a range of structurally unique and biologically intriguing 2-oxa-3-aza-BCHep skeletons, which show promise as bioisosteres for pyridines. Despite significant progress in this area, the enantioselective synthesis of (hetero)bicyclo[n.1.1]alkanes through Lewis acid catalysis is still unexplored and poses a significant challenge. A major challenge in achieving the asymmetric Lewis acidcatalyzed (3 + 3) cycloadditions of BCBs is identifying optimal ligand capable of overcoming the significant racemic background reaction29,52, thus facilitating the formation of two congested carbon centers together with a chiral carbon center with high enantioselective control53,54. In contrast to donor-acceptor cyclopropanes55–63, which feature two chelating, electron-withdrawing groups to form a stable chiral catalyst-substrate complex, achieving catalytic asymmetric reactions of BCBs with only a single electron-withdrawing group, leading to chiral environments with variable conformation, poses greater challenges. To address these challenges, we investigated the utilization of BCBs with bidentate coordinating groups and a chiral Lewis acid catalysis strategy in the asymmetric (3 + 3) cycloaddition of BCBs (Fig. 1e). spiro-ligand L3 (entry 3 versus 4), a series of bis(oxazolyl) binaphthyl ligands ((Ra,R,R)-L5-L7) were further examined, but no enhancement in enantioselectivity was observed. (Ra,S,S)-L5 was also examined, but it exhi (...truncated)