catalysts Article One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael– Hemiaminalization Sequence Yanqing Liu 1,†, Liang Ouyang 2,†, Ying Tan 3, Xue Tang 1, Jingwen Kang 1, Chunting Wang 2, Yaning Zhu 3, Cheng Peng 1,* and Wei Huang 1,* 1 State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; [email protected] (Y.L.); [email protected] (X.T.); [email protected] (J.K.) 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; [email protected] (L.O.); [email protected] (C.W.) 3 China Resources Sanjiu (Ya’an) Pharmaceutical Company Limited, Ya’an 625000, China; [email protected] (Y.T.); [email protected] (Y.Z.) * Correspondence: [email protected] (C.P.); [email protected] (W.H.); Tel.: +86-28-861-800-234 (C.P.); +86-28-861-800-231 (W.H.) † These authors contributed equally to this work. Academic Editor: Aurelio G. Csákÿ Received: 14 December 2016; Accepted: 22 January 2017; Published: 4 February 2017 Abstract: A highly enantioselective organocatalytic Wolff rearrangement–amidation–Michael– hemiaminalization stepwise reaction is described involving a cyclic 2-diazo-1,3-diketone, primary amine and α,β-unsaturated aldehyde. Product stereocontrol can be achieved by adjusting the sequence of steps in this one-pot multicomponent reaction. This approach was used to synthesize various optically active spirocyclic piperidones with three stereogenic centers and multiple functional groups in good yields up to 76%, moderate diastereoselectivities of up to 80:20 and high enantioselectivities up to 97%. Keywords: organocatalysis; asymmetric synthesis; one-pot reaction; multicomponent reaction; aminocatalysis; spirocyclic piperidone 1. Introduction Chiral piperidine frameworks exist widely in biologically active natural products and pharmaceuticals and are highly desirable targets in organic synthesis [1]. Over the past decade, asymmetric organic catalysis [2–17], quite powerful for synthesizing various heterocyclic molecules, has formed the basis of several elegant approaches to construct chiral single-heterocycle piperidine skeletons with high efficiency and low toxicity under environmentally friendly conditions [18–39]. In contrast, relatively few organocatalytic methods have been described to stereo-selectively form spirocyclic piperidine derivatives [30–36], particularly ones with a quaternary stereocenter [37–39]. In 2010, Chen’s group used formal [2 + 2 + 2] annulation to develop a one-pot tandem reaction to synthesize diverse spirocyclic oxindoles incorporating a piperidine motif [40]. In 2012, Wang and co-workers used organocatalytic inverse-electron-demand Diels–Alder reactions to efficiently construct spiro-piperidine skeletons [41]. In addition, Rodriguez and co-workers developed a different approach for asymmetric synthesis of spiro-piperidines, in which α-branched β-ketoamide-based [3 + 3] cycloaddition is catalyzed by bifunctional thiourea-tertiary amine [42]. Despite these advances, Catalysts 2017, 7, 46; doi:10.3390/catal7020046 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 46 2 of 12 Catalysts 2016, 6, x FOR PEER REVIEW 2 of 4 additional efficient organo-catalytic methods for asymmetric synthesis of spiro-piperidine scaffolds 44are stilladditional in high efficient demand. organo-catalytic methods for asymmetric synthesis of spiro-piperidine scaffolds 45 areRecently, still in high the groupsdemand. of Rodriguez and Coquerel generated various spirocyclic piperidones using 46 Recently, the groups of Rodriguez and Coquerel generated various spirocyclic piperidones a microwave-assisted three-component system [43] in which the reaction of primary amine with 47 using a microwave-assisted three-component system[44] in which the reaction of primary amine with α,β-unsaturated aldehyde generates 1-azadiene in situ, which then undergoes formal [4 + 2] cycloaddition 48 α,β-unsaturated aldehyde generates 1-azadiene in situ, which then undergoes formal [4+2] with acylketene, previously generated via Wolff rearrangement of the cyclic 2-diazo-1,3-diketone 49 cycloaddition with acylketene, previously generated via Wolff rearrangement of the cyclic 2-diazo- 50(Scheme 1,3-d1iketonea). Although (Scheme this 1a). approach Although can this provide approach spirocyclic can provide piperidine spirocyclic backbones piperidine in backbones high yield in and 51excellent high yield diastereoselectivity, and excellent diasteroselectivity, it has not been adaptedit has not tobeen asymmetric adapted to synthesis. asymmetric synthesis. 52 53 54 Scheme 1. Synthesis of spirocyclic piperidones. Scheme 1. Synthesis of spirocyclic piperidones. (a) Previous method from Rodriguez and Coquerel; 55 (b) OurAs part synthetic of our strategy. ongoing research program on organocatalytic synthesis of various drug-like 56 spirocyclic scaffolds [45-48], we wondered whether we could synthesize chiral spirocyclic 57 piperidonesAs part of via our asymmetric ongoing researchcatalysis programif we adjusted on organocatalytic the sequence of synthesisreaction steps of variousin this one drug-like-pot 58spirocyclic stepwise scaffolds reaction. [ 44We–47 hypothesized], we wondered that whetherwe could we begin could with synthesize heat-assisted chiral Wolff spirocyclic rearrangement piperidones- 59via asymmetricamidation of catalysis the cyclic if 2 we-diazo adjusted-1,3-diketone the sequence with primary of reaction amine. steps The in resulting this one-pot cyclic stepwise β-ketoamide reaction. 60We hypothesizedwould directly that participate we could in begin the withsecondary heat-assisted amine-catalytic Wolff rearrangement–amidation cycle by serving as donor of thein cyclican 612-diazo-1,3-diketone asymmetric Michael with reaction primary involving amine. enal The under resulting iminium cyclic activation.β-ketoamide Subsequent would directly hydrolysis participate and 62in thehemiaminalization secondary amine-catalytic would provide cycle the desired by serving spiro as-hem a donoriaminal in (Scheme an asymmetric 1b). Here we Michael present reaction the 63 results of experiments to verify whether this Wolff rearrangement-amidation-Michael- involving enal under iminium activation. Subsequent hydrolysis and hemiaminalization would 64 hemiaminalization tandem reaction can efficiently furnish chiral spiro-piperidine derivatives. provide the desired spiro-hemiaminal (Scheme1b). Here, we present the results of experiments to 65verify 2. Results whether and this Discussion Wolff rearrangement–amidation–Michael–hemiaminalization tandem reaction can efficiently furnish chiral spiro-piperidine derivatives. 66 We began with the Wolff rearrangement-amidation of cyclic 2-diazo-1,3-diketone 1a and p- 672. Resultstoluenesulfonamide and Discussion 2a. After both substrates were nearly consumed, cinnamyl aldehyde 3a, 68 Hayashi-Jørgensen catalyst C1 and acid additive were added to the reaction mixture. We were 69 delightedWe began to withfind that the the Wolff reaction rearrangement–amidation afforded the expected hemiaminalization of cyclic 2-diazo-1,3-diketone product 4a. Direct1a and p-toluenesulfonamide 2a. After both substrates were nearly consumed, cinnamyl aldehyde 3a, Catalysts 2017, 7, 46 3 of 12 Hayashi–Jørgensen catalyst C1 and acid additive were added to the reaction mixture. We were delighted to findCatalysts that 201 the6, 6 reaction, x FOR PEER afforded REVIEW the expected hemiaminalization product 4a. Direct protection3 ofof 4 the hydroxyl with trimethylchlorosilane gave the more stable corresponding product 5a in 43% total yield 70with protection moderate of enantioselectivitythe hydroxyl with trimethylchlorosilane but poor diastereoselectivity gave the more (Table stable1, entry corresponding 1). Various product catalysts 71 were5a screened in 43% total in order yieldto with enhance moderate stereoselectivity enantioselectiv (entriesity but 2–5).poor MacMillan’sdiastereo-selectivity imidazolidinone (Table 1, entry catalyst 72 1). Various catalysts were screened in order to enhance stereoselectivity (entries 2-5). MacMillan’s C5 in the presence of 20 mol % trifluoroacetic acid was found to be the most promising catalyst for 73 imidazolidinone catalyst C5 in the presence of 20 mol% trifluoroacetic acid was found to be the most the conversion (entry 5). Screening of acidic additives allowed us to improve the enantioselectivity 74 promising catalyst for the conversion (entry 5). Screening of acidic additives allowed us to improve 75(entries the enantioselectivity 6–8): adding benzoic (entry acid 6-8): generated adding benzoic product acid5a generatedwith 90% product ee. Screening 5a with solvents 90% ee. allowedScreening us to 76improve solvents diastereoselectivity allowed us to improve (entries diastereoselectivit 9–13): conductingy (entry the 9-13): reaction conducting in a mixture the reaction of dichloromethane in a mixture 77and of toluene dichloromethane (2:1, v/v) enhancedand toluene the (2:1, diastereomeric v/v) enhanced ratiothe diastereoselectivity (dr) to 75:25 (entry to 12).75:25 dr (entry 12). 78 TableTable 1 1.. OptimizationOptimization of ofreaction reaction conditions conditions a. a. 79 80 Entry Catalyst Additive Solvent 1 Solvent 2 b dr c d Entry Cat. Additive Solvent 1 Solvent 2 YieldYield (%) (%)b dr c ee (%) dee (%) 1 1 C1C1 BzOHBzOH Tol TolTol