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Article

One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence

by
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
2
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
3
China Resources Sanjiu (Ya’an) Pharmaceutical Company Limited, Ya’an 625000, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Catalysts 2017, 7(2), 46; https://doi.org/10.3390/catal7020046
Submission received: 14 December 2016 / Revised: 18 January 2017 / Accepted: 22 January 2017 / Published: 4 February 2017
(This article belongs to the Special Issue Metal-free Organocatalysis)
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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%.

Graphical Abstract

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 [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17], 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 [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. In contrast, relatively few organocatalytic methods have been described to stereo-selectively form spirocyclic piperidine derivatives [30,31,32,33,34,35,36], particularly ones with a quaternary stereocenter [37,38,39].
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, additional efficient organo-catalytic methods for asymmetric synthesis of spiro-piperidine scaffolds are still in high demand.
Recently, the groups of Rodriguez and Coquerel generated various spirocyclic piperidones using a microwave-assisted three-component system [43] in which the reaction of primary amine with α,β-unsaturated aldehyde generates 1-azadiene in situ, which then undergoes formal [4 + 2] cycloaddition with acylketene, previously generated via Wolff rearrangement of the cyclic 2-diazo-1,3-diketone (Scheme 1a). Although this approach can provide spirocyclic piperidine backbones in high yield and excellent diastereoselectivity, it has not been adapted to asymmetric synthesis.
As part of our ongoing research program on organocatalytic synthesis of various drug-like spirocyclic scaffolds [44,45,46,47], we wondered whether we could synthesize chiral spirocyclic piperidones via asymmetric catalysis if we adjusted the sequence of reaction steps in this one-pot stepwise reaction. We hypothesized that we could begin with heat-assisted Wolff rearrangement–amidation of the cyclic 2-diazo-1,3-diketone with primary amine. The resulting cyclic β-ketoamide would directly participate in the secondary amine-catalytic cycle by serving as a donor in an asymmetric Michael reaction involving enal under iminium activation. Subsequent hydrolysis and hemiaminalization would provide the desired spiro-hemiaminal (Scheme 1b). Here, we present the results of experiments to verify whether this Wolff rearrangement–amidation–Michael–hemiaminalization tandem reaction can efficiently furnish chiral spiro-piperidine derivatives.

2. Results and Discussion

We began with the Wolff rearrangement–amidation of cyclic 2-diazo-1,3-diketone 1a and p-toluenesulfonamide 2a. After both substrates were nearly consumed, cinnamyl aldehyde 3a, Hayashi–Jørgensen catalyst C1 and acid additive were added to the reaction mixture. We were delighted to find that the reaction afforded the expected hemiaminalization product 4a. Direct protection of the hydroxyl with trimethylchlorosilane gave the more stable corresponding product 5a in 43% total yield with moderate enantioselectivity but poor diastereoselectivity (Table 1, entry 1). Various catalysts were screened in order to enhance stereoselectivity (entries 2–5). MacMillan’s imidazolidinone catalyst C5 in the presence of 20 mol % trifluoroacetic acid was found to be the most promising catalyst for the conversion (entry 5). Screening of acidic additives allowed us to improve the enantioselectivity (entries 6–8): adding benzoic acid generated product 5a with 90% ee. Screening solvents allowed us to improve diastereoselectivity (entries 9–13): conducting the reaction in a mixture of dichloromethane and toluene (2:1, v/v) enhanced the diastereomeric ratio (dr) to 75:25 (entry 12).
Using these optimized conditions (Table 1, entry 12), we explored the scope and limitations of this method using α,β-unsaturated aldehyde 3, cyclic 2-diazo-1,3-diketone 1 and primary amine 2 (Table 2). Generally, the reaction was flexible in affording the desired spirocyclic piperidones. Halogen substitutions such as -F, -Cl, and -Br at the meta or para positions of aryl groups in enal 3 (entries 2–5) gave better yields and stereoselectivities than such substitutions at the ortho position (entries 6 and 7). Strong electron-withdrawing aryl groups on enal 3 (entries 8 and 9) gave slightly higher yields and stereoselectivities than electron-donating aryl groups (entries 10–12). The heteroaromatic group furan led to the desired product 5m with high ee and good dr value (entry 13). The crotonaldehyde delivered the alkyl-functionalized product 5n in 53% yield with poor diastereoselectivity, probably due to the polymerization tendency of the crotonaldehyde (entry 14). Introducing a methyl moiety in cyclic 2-diazo-1,3-diketone 1 gave the corresponding products with two quaternary carbon centers in good yields with 70%–73% ee and 72:28–75:25 dr (entries 15–17). Using benzenesulfonyl- and methylsulfonyl-substituted primary amines provided the expected spiro-products 5r and 5s (entries 18 and 19). In terms of the alkyl primary amine, benzyl was also compatible with this reaction system, generating the products 5t in good results (entry 20). Importantly, the benzyl group can be deprotected by hydrogenation more easily than the sulfonyl group. When using BocNH2 or AcNH2 as material, the carbonyl protecting groups were not stable enough in the reaction condition of high temperature, and the desired spiro-piperidones could not be obtained directly. Chemoselective reduction of hemiaminal using Et3SiH and BF3-Et2O at −10 °C provided the dehydroxylation spiro-product 5s (entry 21). The absolute configuration of 5m was determined by X-ray crystallography to be 5R,8R,10S (Figure 1) [48]. The absolute configurations of other spiro-piperidone derivatives 5 were assigned by analogy.
To explain the observed stereochemistry of our asymmetric organocatalytic relay tandem reaction, we propose a possible reaction transition state based on the MacMillan group’s model of the iminium intermediate (Figure 2) [49,50]. In terms of the enantioselectivity of the α,β-unsaturated aldehyde’s stereocenter, the steric hindrance of the benzyl group and tertiary butyl group on the catalyst framework blocks one face (up face), so the nucleophilic enol attacks from the Si face of the iminium intermediate (bottom face). Thus, the selectivity of the α,β-unsaturated aldehyde stereocenter can be explained. In terms of the control of the stereocenter of the ketoamide substrate, the cyclopentanone moiety with folded structure possesses more steric hindrance than the benzenesulfonyl moiety with planar structure. So, if carbon–carbon bond formation takes place from the Re face of the enol (Figure 2, left), the steric repulsion between the bulky cyclopentenol moiety of the β-ketoamide and the β-substituent of the unsaturated aldehyde could be avoided. The major isomer can be obtained with (R,S)-configuration, which is observed in the isolated product. Otherwise, when carbon–carbon bond formation takes place from the Si face of the enol (Figure 2, right), the steric repulsion between the bulky cyclopentenol moiety of the β-ketoamide and the β-substituent of the unsaturated aldehyde is obvious, which is unfavored.

3. Materials and Methods

3.1. General Information

NMR data were obtained for 1H at 400 MHz, and for 13C at 100 MHz (Varian, Palo Alto, CA, USA). Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance in CDCl3 solution as the internal standard. ESI-HRMS (Electrospray Ionization, High Resolution Mass Spectrum) was performed on a SYNAPT G2-Si (Waters, Milford, MA, USA). Enantiomeric ratios were determined by comparing HPLC analyses of products (Figures S2–S22) on chiral columns with results obtained using authentic racemates. The following Daicel Chiralpak columns and Kromasil columns were used: AD-H (250 mm× 4.6 mm), OD-H (250 mm× 4.6 mm), IC (250 mm× 4.6 mm) or AmyCoat (250 mm × 4.6 mm). UV detection was performed at 210, 220 or 254 nm. Optical rotation values were measured with MCP (Modular Compact Polarimeter) 200 (Anton Parar GmbH, Shanghai, China) operating at λ = 589 nm, corresponding to the sodium D line at 20 °C. Column chromatography was performed on silica gel (200–300 mesh) using an eluent of ethyl acetate and petroleum ether. Thin Layer Chromatography (TLC) was performed on glass-backed silica plates; products were visualized using UV light and I2. Melting points were determined on a Mel-Temp apparatus (Electrothermal, Staffordshire, UK) and were not corrected. All chemicals were used from Adamas-beta (Adamas, Shanghai, China) without purification unless otherwise noted.

3.2. General Procedure for the Synthesis of Chiral Spirocyclic Piperidones 5

A mixture of cyclic 2-diazo-1,3-diketone 1 [51] (0.1 mmol) and primary amine 2 (0.1 mmol) was refluxed at 140 °C in toluene (1.0 mL) for 3 hours until both of the substrates were nearly consumed (monitored by TLC, petroleum ether/ethyl acetate = 3:1). After the reaction was cooled to room temperature, α,β-unsaturated aldehyde 3 (0.12 mmol), amine catalyst C5 (0.02 mmol) and benzoic acid (0.04 mmol) were added in CH2Cl2 (2.0 mL). The reaction mixture was stirred until the reaction was completed (monitored by TLC, petroleum ether/ethyl acetate = 2:1). Then, the reaction mixture was concentrated and the residue was purified by elaborative chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to give the hemiaminal 4.
To a solution of hemiaminal 4 in CH2Cl2 (1.0 mL) was added Triethylamine (TEA) (0.3 mmol in 0.5 mL CH2Cl2) at ice bath, after which Trimethyl Chlorosilane (TMSCl) (0.2 mmol in 0.5 mL CH2Cl2) was added. The reaction mixture was stirred until the reaction was completed (monitored by TLC). Then, the reaction was quenched with aqueous NaHCO3, extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 8:1) to give the spirocyclic piperidine 5 (Figure S1) which was dried under vacuum and further analyzed by 1HNMR, 13C-NMR, HRMS (High Resolution Mass Spectrometer), chiral HPLC analysis, etc.
(5R,8R,10S)-10-Phenyl-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5a): white solid, 35.0 mg, 72% yield, dr 75:25, ee 90%, [α]D20 = −13.6 (CH2Cl2, c = 1.06); mp 193–194 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.31–7.28 (m, 5H), 7.11 (d, J = 7.2 Hz, 2H), 6.18 (br s, 1H), 4.19 (d, J = 13.6 Hz, 1H), 2.50 (t, J = 13.6 Hz, 1H), 2.43 (s, 3H), 2.34–2.56 (m, 1H), 2.17–2.08 (m, 3H), 1.85–1.64 (m, 2H), 1.05–0.95 (m, 1H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.1, 172.5, 144.5, 137.9, 136.2, 129.2 128.6, 128.6, 128.5, 127.6, 77.9, 77.3, 77.2, 77.0, 76.7, 63.0, 39.9, 36.5, 34.3, 30.8, 21.6, 19.2, 0.2; HRMS (ESI): m/z calculated for C25H31NO5SSiNa+: 508.1590, found: 508.1588.
(5R,8R,10S)-10-(3-Fluorophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5b): white solid, 36.3 mg, 72% yield, dr 72:28, ee 93%, [α]D20 = −19.5 (CH2Cl2, c = 1.05); mp 190–192 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 8.4 Hz, 2H), 7.31–7.21 (m, 3H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 6.90–6.82 (m, 2H), 6.17 (t, J = 2.8 Hz, 1H), 4.20 (dd, J = 13.2, 1.6 Hz, 1H), 2.47 (dd, J = 13.6, 2.4 Hz, 1H), 2.43 (s, 3H), 2.38–2.20 (m, 1H), 2.19–2.04 (m, 3H), 1.90–1.68 (m, 2H), 1.14–1.04 (m, 1H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.7, 172.2, 162.9 (d, JCF = 245.6 Hz), 144.6, 140.7 (d, JCF = 6.8 Hz), 136.3, 130.3 (d, JCF = 8.1 Hz), 129.3, 128.6, 124.5 (d, JCF = 2.9 Hz), 115.7 (d, JCF = 21.5 Hz), 114.7 (d, JCF = 20.8 Hz), 77.8, 62.9, 39.9, 36.4, 34.4, 30.9, 21.7, 19.3, 0.3; HRMS (ESI): m/z calculated for C25H30FNO5SSiNa+: 526.1496, found: 526.1496.
(5R,8R,10S)-10-(4-Fluorophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5c): White solid, 37.3 mg, 74% yield, dr 75:25, ee 94%, [α]D20 = −9.9. (CH2Cl2, c = 1.00); mp 174–175 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.10–7.06 (m, 2H), 6.99 (t, J = 8.4 Hz, 2H), 6.17 (t, J = 2.8 Hz, 1H), 4.18 (dd, J = 13.6, 2.0 Hz, 1H), 2.47 (dd, J = 13.6, 2.8 Hz, 1H), 2.43 (s, 3H), 2.37–2.28 (m, 1H), 2.19–2.03 (m, 3H), 1.90–1.78 (m, 1H), 1.73–1.65 (m, 1H), 1.13–1.03 (m, 1H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.9, 172.6, 162.2 (d, JCF = 245.5 Hz), 144.6, 136.3, 133.8 (d, JCF = 3.3 Hz), 130.3 (d, JCF = 7.8 Hz), 129.3, 128.6, 115.7 (d, JCF = 21.1 Hz), 77.9, 63.0, 39.9, 35.9, 34.6, 30.7, 21.7, 19.3, 0.3; HRMS (ESI): m/z calculated for C25H30FNO5SSiNa+: 526.1496, found: 526.1498.
(5R,8R,10S)-10-(4-Chlorophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5d): white solid, 38.5 mg, 74% yield, dr 73:27, ee 95%, [α]D20 = −11.2 (CH2Cl2, c = 1.07); mp 189–190 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.89 (d, J = 6.8 Hz, 2H), 7.27–7.24 (m, 4H), 7.02 (d, J = 6.8 Hz, 2H), 6.14 (br s, 1H), 4.14 (d, J = 13.6 Hz, 1H), 2.46–2.43 (m, 1H), 2.39 (s, 3H), 2.32–2.24 (m, 1H), 2.11–2.04 (m, 3H), 1.87–1.76 (m, 1H), 1.71–1.63 (m, 1H), 1.10–1.08 (m, 1H), 0.18 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.8, 172.2, 144.7, 136.6, 136.3, 133.7, 130.1, 129.3, 129.0, 128.6, 77.9, 63.0, 39.9, 36.1, 34.5, 30.7, 21.8, 19.3, 0.3; HRMS (ESI): m/z calculated for C25H30ClNO5SSiNa+: 542.1200, found: 542.1202.
(5R,8R,10S)-10-(4-Bromophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5e): white solid, 41.2 mg, 73% yield, dr 75:25, ee 96%, [α]D20 = −9.2 (CH2Cl2, c = 1.09); mp 182–183 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.92(d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.17 (t, J = 2.4 Hz, 1H), 4.16 (d, J = 12.4 Hz, 1H), 2.47 (dd, J = 13.6, 2.4 Hz, 1H), 2.42 (s, 3H), 2.37–2.29 (m, 1H), 2.17–2.00 (m, 3H), 1.91–1.79 (m, 1H), 1.70 (dt, J = 18.0, 8.0 Hz, 1H), 1.18–1.08 (m, 1H), 0.21 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.8, 172.2, 144.7, 137.1, 136.3, 131.9, 130.5, 129.3, 128.6, 121.8, 77.8, 62.9, 39.9, 36.1, 34.4, 30.7, 21.8, 19.3, 0.3; HRMS (ESI): m/z calculated for C25H30BrNO5SSiNa+: 586.0695, found: 586.0692.
(5R,8R,10S)-10-(2-Fluorophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5f): white solid, 34.8 mg, 69% yield, dr 70:30, ee 94%, [α]D20 = −14.4 (CH2Cl2, c = 1.01); mp 151–152 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.26–7.23 (m, 1H), 7.15–7.05 (m, 3H), 6.27 (t, J = 2.8 Hz, 1H), 4.17 (dd, J = 13.6, 2.4 Hz, 1H), 3.31 (td, J = 14.0, 1.2 Hz, 1H), 2.74–2.66 (m, 1H), 2.43 (s, 3H), 2.14–1.98 (m, 2H), 1.85–1.75 (m, 2H), 1.68–1.62 (m, 1H), 1.14–1.03 (m, 1H), 0.24 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.8, 170.2, 160.8 (d, JCF = 244.0 Hz), 144.5, 136.5, 129.4 (d, JCF = 9.2 Hz), 129.3 (d, JCF = 3.4 Hz), 129.3, 128.7, 126.2 (d, JCF = 13.7 Hz), 124.9 (d, JCF = 3.6 Hz), 115.9 (d, JCF = 23.3 Hz), 78.4, 62.1, 39.9, 34.1, 32.9, 32.6, 21.8, 20.0, 0.3; HRMS (ESI): m/z calculated for C25H30FNO5SSiNa+: 526.1496, found: 526.1493.
(5R,8R,10S)-10-(2-Chlorophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5g): white solid, 35.4 mg, 68% yield, dr 70:30, ee 91%, [α]D20 = −11.9 (CH2Cl2, c = 1.09); mp 139–140 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 8.0 Hz, 2H), 7.42–7.40 (m, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.22–7.14 (m, 3H), 6.25 (br s, 1H), 4.49 (d, J = 12.8 Hz, 1H), 3.26 (t, J = 13.2 Hz, 1H), 2.70–2.63 (m, 1H), 2.43 (s, 3H), 2.15–2.07 (m, 2H), 1.85–1.64 (m, 3H), 1.10–1.00 (m, 1H), 0.25 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.1, 170.0, 144.3, 136.9, 136.4, 134.8, 130.2, 129.1, 129.1, 128.9, 128.6, 127.5, 78.3, 62.5, 39.9, 36.2, 34.7, 32.3, 21.7, 19.9, 0.2; HRMS (ESI): m/z calculated for C25H30ClNO5SSiNa+: 542.1200, found: 542.1199.
(5R,8R,10S)-10-(2-Nitrophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5h): white solid, 37.2 mg, 70% yield, dr 72:28, ee 93%, [α]D20 = +8.2 (CH2Cl2, c = 0.95); mp 196–197 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.90 (d, J = 8.4 Hz, 2H), 7.68 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (dt, J = 7.6, 1.2 Hz, 1H), 7.43 (dt, J = 7.6, 1.2 Hz, 1H), 7.35 (dd, J = 7.6, 0.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.26 (t, J = 2.8 Hz, 1H), 4.35 (dd, J = 13.2, 2.4 Hz, 1H), 3.34 (td, J = 13.2, 2.4 Hz, 1H), 2.69–2.62 (m, 1H), 2.43 (s, 3H), 2.15 (dt, J = 18.4, 7.6 Hz, 1H), 1.91 (dt, J = 13.6, 2.8 Hz, 1H), 1.87–1.65 (m, 3H), 1.06–0.97 (m, 1H), 0.27 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.9, 169.4, 151.6, 144.5, 136.3, 132.4, 132.4, 129.4, 129.2, 128.7, 128.6, 124.2, 78.0, 62.0, 39.9, 34.7, 34.6, 33.1, 21.7, 19.8, 1.0, 0.2; HRMS (ESI): m/z calculated for C25H30N2O7SSiNa+: 553.1441, found: 553.1444.
(5R,8R,10S)-10-(4-Nitrophenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5i): white solid, 40.3 mg, 76% yield, dr 78:22, ee 97%, [α]D20 = +9.4 (CH2Cl2, c = 1.00); mp 199–200 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.17 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 4H), 6.20 (t, J = 2.8 Hz, 1H), 4.34–4.30 (m, 1H), 2.53 (td, J = 13.6, 2.8 Hz, 1H), 2.43 (s, 3H), 2.40–2.34 (m, 1H), 2.24–2.18 (m, 1H), 2.13 (dt, J = 13.6, 2.8 Hz, 1H), 2.01–1.85 (m, 2H), 1.70 (dt, J = 18.4, 8.0 Hz, 1H), 1.19–1.09 (m, 1H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.1, 171.5, 147.4, 145.6, 144.7, 136.0, 129.8, 129.3, 128.6, 123.8, 77.6, 62.7, 39.6, 36.5, 34.3, 30.5, 21.7, 19.2, 0.2; HRMS (ESI): m/z calculated for C25H30N2O7SSiNa+: 553.1441, found: 553.1444.
(5R,8R,10S)-10-(2-Methoxyphenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5j): white solid, 33.0 mg, 64% yield, dr 70:30, ee 91%, [α]D20 = +11.9 (CH2Cl2, c = 0.97); mp 191–192 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.23 (td, J = 8.0, 1.6 Hz, 1H), 7.05 (dd, J = 8.0, 1.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.24 (t, J = 2.8 Hz, 1H), 4.38 (d, J = 12.0 Hz, 1H), 3.82 (s, 3H), 3.26 (td, J = 13.6, 2.4 Hz, 1H), 2.66–2.59 (m, 1H), 2.42 (s, 3H), 2.10–2.01 (m, 2H), 1.75–1.61(m, 3H), 1.06–0.96 (m, 1H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.4, 170.7, 157.4, 144.3, 136.7, 129.2, 128.7, 128.7, 127.8, 121.1, 111.6, 78.8, 62.6, 55.6, 39.9, 34.4, 32.5, 21.8, 19.9, 0.3; HRMS (ESI): m/z calculated for C26H33NO6SSiNa+: 538.1696, found: 538.1694.
(5R,8R,10S)-10-(p-tolyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5k): white solid, 33.0mg, 66% yield, dr 72:28, ee 91%, [α]D20 = −22.9 (CH2Cl2, c = 0.91); mp 150–151 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.17 (t, J = 2.8 Hz, 1H), 4.15 (dd, J = 13.6, 2.0 Hz, 1H), 2.48 (dd, J = 13.6, 2.8 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.30–2.25 (m, 1H), 2.14–2.08 (m, 3H), 1.85–1.64 (m, 2H), 1.09–0.99 (m, 1H), 0.21 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.1, 172.6, 144.4, 137.3, 136.4, 134.9, 129.3, 129.2, 128.5, 77.9, 63.1, 39.9, 36.2, 34.4, 30.9, 29.7, 21.7, 21.0, 19.3, 1.0, 0.2; HRMS (ESI): m/z calculated for C26H33NO5SSiNa+: 522.1746, found: 522.1744.
(5R,8R,10S)-10-(4-(Dimethylamino)phenyl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5] decane-1,6-dione (5l): white solid, 32.8 mg, 62% yield, dr 68:32, ee 90%, [α]D20 = −63.5 (CH2Cl2, c = 1.02); mp 186–187 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 6.15 (t, J = 2.4 Hz, 1H), 4.09 (dd, J = 13.6, 2.0 Hz, 1H), 2.92 (s, 6H), 2.45 (dd, J = 13.8, 2.4 Hz, 1H), 2.41 (s, 3H), 2.32–2.24 (m, 1H), 2.16–2.06 (m, 3H), 1.83–1.66 (m, 2H), 1.12–1.06 (m, 1H), 0.20 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.5, 172.9, 149.7, 144.3, 136.5, 129.3, 129.2, 128.5, 125.3, 112.3, 78.1, 63.3, 40.4, 39.9, 35.8, 34.6, 30.9, 21.6, 19.7, 0.3; HRMS (ESI): m/z calculated for C27H36N2O5SSiNa+: 551.2012, found: 551.2011.
(5R,8R,10S)-10-(Furan-2-yl)-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5m): white solid, 35.7 mg, 75% yield, dr 80:20, ee 96%, [α]D20 = −62.3 (CH2Cl2, c = 1.09); mp 140–141 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.90 (d, J = 8.4 Hz, 2H), 7.29 (m, 3H), 6.29 (dd, J = 3.2, 1.6 Hz, 1H), 6.15 (t, J = 2.8 Hz, 1H), 6.04 (d, J = 3.2 Hz, 1H), 4.20 (dd, J = 13.2, 2.0 Hz, 1H), 2.42 (s, 3H), 2.34 (dd, J = 13.6, 2.4 Hz, 1H), 2.23–1.85 (m, 6H), 1.30–1.20 (m, 1H), 0.24 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.1, 171.8, 152.6, 144.5, 142.1, 136.3, 129.2, 128.5, 110.4, 107.5, 77.8, 61.7, 39.3, 32.7, 32.2, 31.8, 21.6, 19.0, 0.2; HRMS (ESI): m/z calculated for C23H29NO6SSiNa+: 498.1383, found: 498.1381.
(5R,8R,10S)-10-Methyl-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5n): white solid, 22.5 mg, 53% yield, dr 64:36, ee 50%, [α]D20 = −16.9 (CH2Cl2, c = 1.10); mp 146–147 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.2 Hz, 2H), 6.00 (t, J = 2.8 Hz, 1H), 2.98–2.90 (m, 1H), 2.56–2.47 (m, 1H), 2.40 (s, 3H), 2.18–2.04 (m, 4H), 1.89–1.80 (m, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.23 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.8, 172.6, 144.4, 136.5, 129.1, 128.6, 78.5, 62.1, 39.8, 37.1, 29.4, 26.2, 21.6, 19.3, 15.7, 0.2 ; HRMS (ESI): m/z calculated for C20H29NO5SSiNa+: 446.1433, found: 446.1430.
(5R,8R,10S)-3,3-Dimethyl-10-phenyl-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5o): white solid, 36.0 mg, 70% yield, dr 72:28, ee 91%, [α]D20 = −33.9 (CH2Cl2, c = 1.14); mp > 210 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, J = 8.4 Hz, 2H), 7.32–7.27 (m, 5H), 7.13–7.11 (m, 2H), 6.14 (t, J = 2.4 Hz, 1H), 4.18 (dd, J = 13.2, 2.0 Hz, 1H), 2.45–2.40 (m, 4H), 2.38–2.32 (m, 1H), 2.14–2.05 (m, 2H), 1.96 (d, J = 14.4 Hz, 1H), 1.51 (d, J = 18.4 Hz, 1H), 1.02 (s, 3H), 0.23 (s, 3H), 0.19 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 215.0, 172.9, 144.4, 138.3, 136.3, 129.3, 129.2, 128.7, 128.6, 127.8, 77.9, 65.4, 55.0, 43.5, 37.1, 34.5, 32.9, 30.5, 29.7, 21.6, 0.2; HRMS (ESI): m/z calculated for C27H35NO5SSiNa+: 536.1903, found: 536.1907.
(5R,8R,10S)-10-(4-Bromophenyl)-3,3-dimethyl-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5] decane-1,6-dione (5p): white solid, 42.1 mg, 71% yield, dr 74:26, ee 91%, [α]D20 = −17.9 (CH2Cl2, c = 1.04); mp 206–207 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.93 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.13 (t, J = 2.8 Hz, 1H), 4.14 (dd, J = 13.6, 2.0 Hz, 1H), 2.44–2.39 (m, 4H), 2.40–2.33 (m, 1H), 2.05–2.00 (m, 3H), 1.04 (s, 3H), 0.90–0.82 (m, 1H), 0.28 (s, 3H), 0.19 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 214.6, 172.6, 144.5, 137.5, 136.2, 131.7, 131.0, 129.2, 128.7, 121.9, 77.8, 65.4, 55.0, 43.5, 36.4, 34.5, 32.9, 30.4, 29.9, 21.7, 0.2; HRMS (ESI): m/z calculated for C27H34BrNO5SSiNa+: 614.1008, found: 614.1005.
(5R,8R,10S)-10-(Furan-2-yl)-3,3-dimethyl-7-tosyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5q): white solid, 36.8 mg, 73% yield, dr 78:22, ee 95%, [α]D20 = −13.4 (CH2Cl2, c = 0.97); mp 108–109 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.91 (d, J = 8.0 Hz, 2H), 7.32–7.26 (m, 3H), 6.29 (dd, J = 2.8, 2.0 Hz, 1H), 6.11 (t, J = 2.4 Hz, 1H), 6.08 (d, J = 2.8 Hz, 1H), 4.21 (dd, J = 13.2, 2.4 Hz, 1H), 2.50 (d, J = 18.0 Hz, 1H), 2.41 (s, 3H), 2.33 (td, J = 14.0, 2.8 Hz, 1H), 2.14–2.10 (m, 2H), 2.00–1.89 (m, 2H), 1.07 (s, 3H), 0.48 (s, 3H), 0.21 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 214.1, 172.3, 152.6, 144.5, 142.1, 136.3, 129.1, 128.6, 110.6, 108.5, 77.8, 64.0, 54.4, 44.8, 33.2, 33.0, 32.6, 30.6, 30.1, 21.6, 0.2; HRMS (ESI): m/z calculated for C25H33NO6SSiNa+: 526.1696, found: 526.1698.
(5R,8R,10S)-10-Phenyl-7-(phenylsulfonyl)-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5r): white solid, 35.8 mg, 76% yield, dr 76:24, ee 94%, [α]D20 = −13.5 (CH2Cl2, c = 0.99); mp 193–194 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.08–8.04 (m, 2H), 7.62–7.58 (m, 1H), 7.53–7.48 (m, 2H), 7.31–7.27 (m, 3H), 7.12–7.10 (m, 2H), 6.19 (t, J = 2.8 Hz, 1H), 4.12 (dd, J = 13.6, 2.0 Hz, 1H), 2.51 (td, J = 13.6, 2.4 Hz, 1H), 2.29 (ddd, J = 18.0, 8.4, 6.8 Hz, 1H), 2.16–2.10 (m, 3H), 1.84–1.64 (m, 2H), 1.06–0.96 (m, 1H), 0.22 (s, 9H).13C-NMR (100 MHz, CDCl3) δ (ppm): 215.9, 172.6, 139.3, 137.9, 133.5, 128.7, 128.7, 128.6, 128.4, 127.6, 78.0, 63.1, 39.8, 36.6, 34.4, 30.9, 19.3, 0.2; HRMS (ESI): m/z calculated for C24H29NO5SSiNa+: 494.1433, found: 494.1433.
(5R,8R,10S)-7-(Methylsulfonyl)-10-phenyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5s): white solid, 30.7 mg, 75% yield, dr 80:20, ee 95%, [α]D20 = −32.75 (CH2Cl2, c = 0.97); mp 165–166 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.34–7.28 (m, 3H), 7.14 (dd, J = 8.4, 2.0 Hz, 2H), 5.99 (t, J = 2.4 Hz, 1H), 4.24 (dd, J = 14.0, 2.4 Hz, 1H), 3.31 (s, 3H), 2.49 (td, J = 13.6, 2.4 Hz, 1H), 2.43–2.35 (m, 1H), 2.23–2.13 (m, 2H), 2.05 (dt, J = 14.0, 2.8 Hz, 1H), 1.92–1.70 (m, 2H), 1.20–1.10 (m, 1H), 0.18 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.3, 174.5, 138.0, 129.1, 129.0, 128.0, 79.1, 77.6, 77.3, 77.0, 63.4, 42.9, 40.1, 37.0, 34.3, 30.8, 19.5, 0.3; HRMS (ESI): m/z calculated for C19H27NO5SSiNa+: 432.1277, found: 432.1277.
(5R,8R,10S)-7-Benzyl-10-phenyl-8-((trimethylsilyl)oxy)-7-azaspiro[4.5]decane-1,6-dione (5t): white solid, 29.5 mg, 70% yield, dr 73:27, ee 90%, [α]D20 = −20.1 (c = 1.08 in CH2Cl2); mp 164–165 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.37–7.23 (m, 8H), 7.16–7.14 (m, 2H), 5.16 (d, J = 15.2 Hz, 1H), 5.01 (dd, J = 7.6, 6.8 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H), 3.65–3.58 (m, 1H), 2.51–2.42 (m, 1H), 2.39–2.30 (m, 1H), 2.28–2.21 (m, 2H), 2.19–2.13 (m, 1H), 1.94–1.80 (m, 2H), 0.91–0.84 (m, 1H), 0.08 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 217.7, 171.9, 138.2, 136.3, 128.0, 128.1, 127.9, 127.1, 126.9, 126.6, 79.0, 60.6, 44.0, 39.5, 38.8, 34.6, 30.1, 19.3, −0.3; HRMS (ESI): m/z calculated for C25H31NO3SiNa+: 444.1971, found: 444.1974.
(5R,10S)-10-Phenyl-7-tosyl-7-azaspiro[4.5]decane-1,6-dione (5u): white solid, 27.8 mg, 70% yield, dr 74:26, ee 95%, [α]D20 = +32.7 (CH2Cl2, c = 0.99); mp 140–141 °C; 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.30–7.27 (m, 3H), 7.14–7.12 (m, 2H), 4.46 (ddd, J = 12.0, 5.2, 2.0 Hz, 1H), 3.78 (td, J = 12.0, 4.4 Hz, 1H), 3.19–3.08 (m, 1H), 2.99 (dd, J = 13.6, 2.8 Hz, 1H), 2.74 (dt, J = 15.6, 8.0 Hz, 1H), 2.43 (s, 3H), 2.10–1.95 (m, 3H), 1.80–1.70 (m, 1H), 1.66–1.57 (m, 1H), 1.00–0.86 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ (ppm): 216.1, 170.4, 144.7, 139.1, 135.9, 129.4, 128.9, 128.5, 128.4, 127.9, 62.1, 48.9, 46.2, 40.0, 33.6, 25.5, 21.7, 19.7; HRMS (ESI): m/z calculated for C22H23NO4SNa+: 420.1245, found: 420.1246.

4. Conclusions

In summary, we have developed an organocatalytic stepwise reaction to achieve the asymmetric assembly of cyclic 2-diazo-1,3-diketones, primary amines and α,β-unsaturated aldehydes into chiral spirocyclic piperidone architectures bearing up to three stereogenic centers and multiple functional groups in good yields with moderate diastereoselectivities and high enantioselectivities. The reaction proceeds via sequential Wolff rearrangement–amidation–Michael–hemiaminalization. Product stereocontrol can be achieved by adjusting the sequence of steps in this one-pot multicomponent reaction. We are now investigating the application of these pharmacologically interesting chiral spiro-piperidine derivatives to the discovery of lead compounds, and the results will be reported in due course.

Supplementary Materials

The supplementary materials are available online at www.mdpi.com/2073-4344/7/2/46/s1. Figure S1, Structure of compounds 5a–5u; Figures S2–S22, HPLC chromatograms and NMR spectra.

Acknowledgments

We are grateful for the financial support from the National Natural Science Foundation of China (81573589, 81630101 and 81673290), the National High Technology Research and Development Program (863 Program) of China (2014AA020706), and the Science & Technology Department of Sichuan Province (2017JQ0002).

Author Contributions

Wei Huang and Cheng Peng conceived and designed the experiments; Yanqing Liu, Liang Ouyang, Xue Tang and Chunting Wang performed the experiments; Jingwen Kang analyzed the data; Ying Tan and Yaning Zhu contributed reagents and materials; Wei Huang wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 07 00046 sch001 550
Scheme 1. Synthesis of spirocyclic piperidones. (a) Previous method from Rodriguez and Coquerel; (b) Our synthetic strategy.
Scheme 1. Synthesis of spirocyclic piperidones. (a) Previous method from Rodriguez and Coquerel; (b) Our synthetic strategy.
Catalysts 07 00046 sch001
Catalysts 07 00046 g001 550
Figure 1. Oak Ridge Thermal Ellipsoid Plot (ORTEP) drawing of compound 5m.
Figure 1. Oak Ridge Thermal Ellipsoid Plot (ORTEP) drawing of compound 5m.
Catalysts 07 00046 g001
Catalysts 07 00046 g002 550
Figure 2. Proposed catalytic models to explain stereochemistry.
Figure 2. Proposed catalytic models to explain stereochemistry.
Catalysts 07 00046 g002
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Catalysts 07 00046 i001
EntryCatalystAdditiveSolvent 1Solvent 2Yield (%) bdr cee (%) d
1C1BzOHTolTol4355:4542
2C2BzOHTolTol4558:4248
3C3BzOHTolTol4158:4246
4C4TFATolTol6660:4070
5C5TFATolTol6862:3876
6C5TsOHTolTol6560:4074
7C5AcOHTolTol6462:3882
8C5BzOHTolTol6465:3584
9C5BzOHTolMeCN7362:3880
10C5BzOHTolTHF7060:4078
11C5BzOHTolDCM6870:3086
12 eC5BzOHTolDCM7275:2590
13 fC5BzOHTolDCM7073:2788
a Unless noted otherwise, reactions were performed with 0.1 mmol of 1a, 0.1 mmol of 2a in 1 mL of solvent 1 at 140 °C, after which 0.12 mmol of 3a, 0.02 mmol of catalyst and 0.02 mmol of acidic additive were added in 1 mL of solvent 2 at r.t.; b Yield of isolated major isomer 5a over two steps; c Calculated based on 1H-NMR analysis of the crude reaction mixture; d Determined by chiral HPLC analysis of the major diastereoisomer; e 2 mL of solvent 2 was used; f 3 mL of solvent 2 was used.
Table
Table 2. Investigation of the scope of the tandem reaction using the optimized conditions a.
Table 2. Investigation of the scope of the tandem reaction using the optimized conditions a.
Catalysts 07 00046 i002
EntryR1R2R3Yield (5) (%) bdr cee (%) d
1HTsPh72 (5a)75:2590
2HTs3-FC6H472 (5b)72:2893
3HTs4-FC6H474 (5c)75:2594
4HTs4-ClC6H474 (5d)73:2795
5HTs4-BrC6H473 (5e)75:2596
6HTs2-FC6H469 (5f)70:3094
7HTs2-ClC6H468 (5g)70:3091
8HTs2-NO2C6H470 (5h)72:2893
9HTs4-NO2C6H476 (5i)78:2297
10HTs2-MeOC6H464 (5j)70:3091
11HTs4-MeC6H466 (5k)72:2891
12HTs4-(Me)2NC6H462 (5l)68:3290
13HTs2-furyl75 (5m)80:2096
14HTsMe53 (5n)64:3650
15MeTsPh70 (5o)72:2891
16MeTs4-BrC6H471 (5p)74:2691
17MeTs2-furyl73 (5q)78:2295
18HPhSO2Ph76 (5r)76:2494
19HMeSO2Ph75 (5s)80:2095
20HBnPh70 (5t)73:2790
21 eHTsPh70 (5u)
Catalysts 07 00046 i003		74:2695
a See entry 12 and footnote a in Table 1; b Yield of isolated major isomer 5 over two steps; c Calculated based on 1H-NMR analysis of the crude reaction mixture; d Determined by chiral HPLC analysis of the major diastereoisomer; e Reduction in the hydroxy group of hemiaminal intermediate.

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MDPI and ACS Style

Liu, Y.; Ouyang, L.; Tan, Y.; Tang, X.; Kang, J.; Wang, C.; Zhu, Y.; Peng, C.; Huang, W. One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence. Catalysts 2017, 7, 46. https://doi.org/10.3390/catal7020046

AMA Style

Liu Y, Ouyang L, Tan Y, Tang X, Kang J, Wang C, Zhu Y, Peng C, Huang W. One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence. Catalysts. 2017; 7(2):46. https://doi.org/10.3390/catal7020046

Chicago/Turabian Style

Liu, Yanqing, Liang Ouyang, Ying Tan, Xue Tang, Jingwen Kang, Chunting Wang, Yaning Zhu, Cheng Peng, and Wei Huang. 2017. "One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence" Catalysts 7, no. 2: 46. https://doi.org/10.3390/catal7020046

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