Asymmetric Dearomative Formal [4 + 2] Cycloadditions of N,4

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Asymmetric Dearomative Formal [4 + 2] Cycloadditions of N,4Dialkylpyridinium Salts and Enones To Construct Azaspiro[5.5]undecane Frameworks Ru-Jie Yan,† Ben-Xian Xiao,† Qin Ouyang,‡ Hua-Ping Liang,*,‡ Wei Du,† and Ying-Chun Chen*,†,‡ †

Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China ‡ State Key Laboratory of Trauma, Burn and Combined Injury, and College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China Org. Lett. Downloaded from pubs.acs.org by TULANE UNIV on 12/11/18. For personal use only.

S Supporting Information *

ABSTRACT: The asymmetric dearomative formal [4 + 2] cycloaddition reaction of activated N,4-dialkylpyridinium salts and acyclic α,β-unsaturated ketones was developed by the cascade iminium ion−enamine catalysis of a cinchona-derived amine. A spectrum of valuable azaspiro[5.5]undecane architectures was efficiently constructed with high to excellent diastereoselectivity and enantioselectivity.

D

Scheme 1. Organocatalytic Dearomative Reactions of Diverse Pyridinium Salts

ihydropyridine and the related saturated piperidine frameworks are ubiquitous in abundant pharmaceuticals and natural products.1 Consequently, the development of effective protocols to construct these skeletons, especially in a stereoselective manner, provokes increasing interest of modern organic and medicinal chemists.2 Considering the ready availability of heteroaromatic pyridine systems, the direct asymmetric dearomative addition reaction with electrophilically enhanced pyridinium salts represents one of the most convenient and efficient approaches to access chiral dihydropyridine derivatives. Traditional-metal-catalyzed asymmetric reactions have been applied to typically furnish 1,2dihydropyridines.3 Recently, efforts have been focused on organocatalytic methods that can directly furnish 1,4dihydropyridines enantioselectively. A seminar nucleophilic dearomative reaction with in situ generated N-acylpyridiniums has been developed by Mancheño using an anion-binding catalysis (Scheme 1a).4 Subsequently, a few significant contributions have appeared dealing with the asymmetric dearomatizations of convenient and bench-stable activated Nalkylpyridinium salts, based on hydrogen bonding,5 Nheterocyclic carbene (NHC),6 or even enamine catalytic strategies (Scheme 1b).7 On the other hand, nitrogen-containing six-membered heteroarenes (azaarenes) feature an embedded imine (C N) group with electron-withdrawing characteristics. As a result, 2-alkylazaarenes can be utilized as pro-nucleophilic species in diverse asymmetric reactions, usually assisted by coordination with Lewis acids.8 The Wang group also accomplished the direct asymmetric alkylation of 4-methyl-3-nitropyridine with enals via iminium ion activation.9 Inspired by the abovementioned studies, we envisioned that, by taking advantage of iminium ion−enamine tautomerization of the novel 4-methylN-alkylpyridinium salts, as outlined in Scheme 1c, the © XXXX American Chemical Society

dienamine-type intermediates would be more effectively generated under mild basic conditions, which would be enantioselectively trapped by α,β-unsaturated ketone substrates activated by formation of iminium ions with a chiral amine. Subsequently, an intramolecular dearomative process10 would be followed to produce chiral azaspiro[5.5]undecane derivatives in a formal [4 + 2] cycloaddition pattern.11 It should be noted that the azaspiro[5.5]undecane skeletons have Received: November 8, 2018

A

DOI: 10.1021/acs.orglett.8b03576 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters been widely applied as important pharmacophores in chemistry,12 as exemplified in a potent GPR120 agonist (Scheme 1).13 Moreover, there still are very few methods in the literature involving the construction of enantioenriched azaspiro[5.5]undecane derivatives.14 To test the feasibility, we initially explored the reaction between simple N-benzyl-4-methylpyridinium salt 1a and benzylidene acetone 2a under different catalytic conditions, but without any success. Therefore, another new activated pyridinium substrate 1b with a 3-nitro group was synthesized. To our gratification, the desired dearomative formal [4 + 2] reaction with 2a proceeded efficiently in CHCl3 at 40 °C in the presence of chiral primary amine C1 (20 mol %), salicylic acid A1 (40 mol %), and TEA (1.2 equiv). High diastereoselectivity was observed (>15:1 dr), and the pure spirocyclic product 3a was isolated in 63% yield after 36 h, whereas the enantioselectivity was moderate (Table 1, entry 1). Subsequently, a few cinchona-derived primary amine catalysts were

evaluated (Table 1, entries 2−6). The results indicated that 2′tert-butyl-substituted amines C5 and C6 provided better yield and enantioselectivity (Table 1, entries 5 and 6). Further improved data were obtained by combining amine C6 with a mandelic acid-type additive A2−A4 (Table 1, entries 7−9). Moreover, replacing TEA with sodium benzoate increased the yield (Table 1, entry 10), and high enantioselectivity (91% ee) was attained at a lower temperature (Table 1, entry 11). Solvents were briefly screened, with comparable results (Table 1, entries 12 and 13). Finally, the base additives were further investigated (Table 1, entries 14 and 15), and excellent yield (94%), diastereoselectivity (>19:1 dr), and enantioselectivity (95% ee) were gained with sodium acetate (Table 1, entry 15). In contrast, slightly reduced results were observed without addition of the chiral acid A4 (Table 1, entry 16). The reaction still proceeded well on a larger scale, and similar high yield and stereoselectivity were attained (Table 1, entry 17). With the optimal catalytic conditions in hand, we then explored the substrate scope and limitations of this new dearomative formal [4 + 2] cycloaddition reaction. The results are summarized in Table 2. At first, a number of alkylidene acetones were tested with activated pyridinium salt 1b. In general, excellent diastereo- and enantioselectivity were obtained for β-aryl enones with diverse electron-withdrawing or -donating groups (Table 2, entries 2−11), except for that with a 4-nitrophenyl one (Table 2, entry 6). Good diastereoselectivity and high enantiocontrol were also produced for enones bearing a heteroaryl or 2-styryl group (Table 2, entries 12−14); nevertheless, only moderate enantioselectivity was gained for enones with a 2-methyl-1propenyl or linear alkyl group (Table 2, entries 15 and 16). The enones with an α′-benzyl-type group were further studied, and lower stereoselectivity was observed (Table 2, entries 17 and 18).15 On the other hand, a few differently substituted pyridinium salts were investigated. Changing the N-substitution had a marginal effect on the reactions (Table 2, entries 19−22). Unfortunately, both diastereoselectivity and enantioselectivity were significantly decreased for a pyridinium salt with a larger 4-(2-phenylethyl) group, probably due to the formation of a mixture of Z- and E-dienamine-type intermediates (Table 2, entry 23). Pleasingly, a pyridinium salt with a 3-cyano group exhibited good reactivity under the same catalytic conditions, and high enantioselectivity and exclusive diastereoselectivity were attained (Table 2, entry 24).16 Furthermore, an N-benzyl-4-methylquinolinium salt 4 was prepared and tested in the reaction with enone 2a. It showed similar reactivity, but the diastereoselectivity was only fair. The pure major isomer 5 was isolated in moderate yield and enantioselectivity (Scheme 2). Some transformations were conducted with the dearomative product 3a. As illustrated in Scheme 3, the dihydropyridine structure could be fully hydrogenated with Pd/C and H2, and the nitro group and N-benzyl group was simultaneously reduced and protected in an N-Boc form in the presence of Boc2O, whereas the product 6 was obtained with fair diastereoselectivity. Interestingly, an unexpected ring-opening reaction occurred by treating 3a with BF3·Et2O in CH2Cl2, and a 4-methylene-1,4-dihydropyridine derivative 7 was efficiently furnished in excellent stereoselectivity. In conclusion, we have designed and prepared a new type of bench-stable activated N,4-dialkylpyridinium salts that were easily deprotonated to generate active dearomative dienamine-

Table 1. Screening Conditions of Dearomative [4 + 2] Reaction of Pyridinium Salt 1b and Enone 2aa

entry

C

A

base

solvent

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11d 12d 13d 14d 15d 16d 17e

C1 C2 C3 C4 C5 C6 C6 C6 C6 C6 C6 C6 C6 C6 C6 C6 C6

A1 A1 A1 A1 A1 A1 A2 A3 A4 A4 A4 A4 A4 A4 A4

TEA TEA TEA TEA TEA TEA TEA TEA TEA BzONa BzONa BzONa BzONa DIPEA AcONa AcONa AcONa

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 toluene THF CHCl3 CHCl3 CHCl3 CHCl3

63 60 67 74 60 70 80 80 82 90 93 91 78 90 94 92 92

64 −50 53 41 80 77 81 80 84 84 91 91 97 94 95 93 90

A4

a

Unless noted otherwise, reactions were performed with pyridinium salt 1b (0.06 mmol, 1.2 equiv), enone 2a (0.05 mmol, 1.0 equiv), amine C (20 mol %), acid A (40 mol %), and base (0.06 mmol, 1.2 equiv) in solvent (0.5 mL) at 40 °C for 36 h. bIsolated yield of pure 3a. cDetermined by HPLC analysis on a chiral stationary phase; in general, dr >15:1 by 1H NMR analysis. dAt 5 °C for 60 h. eAt a 1.0 mmol scale. B

DOI: 10.1021/acs.orglett.8b03576 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Substrate Scope and Limitations of Dearomative Formal [4 + 2] Cycloadditionsa

Scheme 2. Dearomative Formal [4 + 2] Cycloaddition Reaction of Quinolinium Salt 4

Scheme 3. Synthetic Transformations of Spiro Product 3a

stereoselectivity, which might have high potential in organic synthesis and medicinal chemistry. The application of these N,4-dialkylpyridinium salts in other asymmetric transformations is under investigation, and the results will be reported in due course.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03576. Complete experimental procedures and characterization of new products; NMR spectra and HPLC chromatograms (PDF) Accession Codes

CCDC 1877488 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

a

Unless noted otherwise, reactions were performed with pyridinium salt 1 (0.12 mmol, EWG = NO2, 1.2 equiv), enone 2 (0.1 mmol, 1.0 equiv), amine C6 (20 mol %), acid A4 (40 mol %), and AcONa (0.12 mmol, 1.2 equiv) in CHCl3 (1.0 mL) at 5 °C for 36−72 h. bYield of isolated diastereomer. cDetermined by 1H NMR analysis. dDetermined by HPLC analysis on a chiral stationary phase. eIn CHCl3 (0.2 mL) at 25 °C. fThe absolute configuration of enantiopure 3s was determined by X-ray analysis. The other products were assigned by analogy. gEWG = CN.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

type intermediates and subsequently participated in an asymmetric formal [4 + 2] cycloaddition reaction with acyclic α,β-unsaturated ketones through cascade iminium ion−enamine catalysis of a cinchona-derived amine. An array of azaspiro[5.5]undecane derivatives with multiple functionalities was effectively constructed with moderate to excellent

ORCID

Qin Ouyang: 0000-0002-1161-5102 Ying-Chun Chen: 0000-0003-1902-0979 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b03576 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21772126) and the Open Project of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (SKLKF201601).

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DOI: 10.1021/acs.orglett.8b03576 Org. Lett. XXXX, XXX, XXX−XXX