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

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%.

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.
Catalysts 2016, 6, x FOR PEER REVIEW 2 of 4 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 [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 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 diasteroselectivity, it has not been adapted to asymmetric synthesis.
As part of our ongoing research program on organocatalytic synthesis of various drug-like spirocyclic scaffolds [45][46][47][48], 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 rearrangementamidation 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 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-Michaelhemiaminalization tandem reaction can efficiently furnish chiral spiro-piperidine derivatives.

Results and Discussion
We began with the Wolff rearrangement-amidation of cyclic 2-diazo-1,3-diketone 1a and ptoluenesulfonamide 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 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.

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 8-9) gave slightly higher yields and stereoselectivities than electron-donating aryl groups (entries 10-12).The heteroaromatic 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][16][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 BocNH 2 or AcNH 2 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 Et 3 SiH and BF 3 -Et 2 O 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.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).
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 spiropiperidones could not be obtained directly.Chemoselective reduction of hemiaminal using Et3SiH and BF3-Et2O at -10 o 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) [49].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 βsubstituent of the unsaturated aldehyde is obvious, which is unfavored.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.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 βsubstituent of the unsaturated aldehyde is obvious, which is unfavored.

General Information
NMR data were obtained for 1 H at 400 MHz, and for 13 C at 100 MHz (Varian, Palo Alto, CA, USA).Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance in CDCl 3 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 I 2 .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.
To a solution of hemiaminal 4 in CH 2 Cl 2 (1.0 mL) was added Triethylamine (TEA) (0.3 mmol in 0.5 mL CH 2 Cl 2 ) at ice bath, after which Trimethyl Chlorosilane (TMSCl) (0.2 mmol in 0.5 mL CH 2 Cl 2 ) was added.The reaction mixture was stirred until the reaction was completed (monitored by TLC).Then, the reaction was quenched with aqueous NaHCO 3 , extracted with CH 2 Cl 2 .The organic layer was dried over Na 2 SO 4 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 1 HNMR, 13 C-NMR, HRMS (High Resolution Mass Spectrometer), chiral HPLC analysis, etc.

a
See entry 12 and footnote a in Table1; b Yield of isolated major isomer 5 over two steps; c Calculated based on 1 H-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.

Figure 2 .
Figure 2. Proposed catalytic models to explain stereochemistry.Figure 2. Proposed catalytic models to explain stereochemistry.

Figure 2 .
Figure 2. Proposed catalytic models to explain stereochemistry.Figure 2. Proposed catalytic models to explain stereochemistry.

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .

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 .
a See entry 12 and footnote a in Table1; b Yield of isolated major isomer 5 over two steps; c Calculated based on1H-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.a See entry 12 and footnote a in Table 1; b Yield of isolated major isomer 5 over two steps; c Calculated based on a See entry 12 and footnote a in Table 1; b Yield of isolated major isomer 5 over two steps; c Calculated based on 1 H-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.