Phase-Transfer-Catalyzed, Enantioselective Vinylogous Conjugate

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

pubs.acs.org/OrgLett

Phase-Transfer-Catalyzed, Enantioselective Vinylogous Conjugate Addition−Cyclization of Olefinic Azlactones To Access Multifunctionalized Chiral Cyclohexenones Bo Zhu,† Bohua Lu,† Huifang Zhang,† Xinyao Xu,† Zhiyong Jiang,*,†,‡ and Junbiao Chang*,† †

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Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P.R. China ‡ Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan 475004, P.R. China S Supporting Information *

ABSTRACT: An asymmetric, phase-transfer-catalyzed vinylogous conjugate addition−vinylogous cyclization cascade of olefinic azlactones with 4-nitro-5-styrylisoxazoles is reported. In the presence of an L-tert-leucine-derived urea−quaternary ammonium salt as a bifunctional phase-transfer catalyst and KF, two series of valuable optically pure cyclohexenones featuring two and three stereocenters were obtained in high yields with good to excellent enantio- and diastereoselectivities. reactions of β-ketoesters and β-ketoamides with α,β-unsaturated ketones (Scheme 1A).6 The Ye and Enders groups described [4 + 2] cycloaddition reactions of acyl chlorides7a or enals7b with electron-deficient alkenes (Scheme 1A). These works presented an alarming indication that simultaneously achieving excellent enantio- and diastereoselectivities is quite difficult. The one-step construction of three stereocenters7c-e on a cyclohexenone could furnish multifunctionalized compounds in a straightforward manner, making this task highly desirable as well as formidable. To this end, we speculated that the vinylogous conjugate addition−cyclization of 3-substituted propenyl carbonyl compounds I with activated 1,2-alkenes II would be a viable synthetic approach (Scheme 1B). In addition to the abstraction of the inactive γ-proton and the construction of two remote stereocenters γ and δ to the carbonyl in the vinylogous addition,8 the cyclization via the removal of the carbonyl substituents of II by carbanions would be a substantial challenge; to the best of our knowledge, no related studies involving asymmetric vinylogous reactions have been reported. Given that the driving force of the ring opening is usually compatible with accepting a nucleophilic anion, we hypothesized that the carbonyl of I being in a strained ring would facilitate the reaction. In addition, since the carbonyls of esters or amides, as the common cyclization groups, are less hard than those of ketones, the electron-withdrawing ability of the activated group of II should not be too strong, which would make the α-carbanions relatively soft and suitable nucleophiles for attacking carbonyls. However, this concomitantly disfavors the vinylogous addition, which is a necessary sacrifice.

C

yclohexenone is a common structural scaffold in a number of natural products and bioactive compounds.1 The development of catalytic strategies for the asymmetric synthesis of its chiral derivatives has attracted substantial attention from chemists. The groups of List, Akiyama, Luo, Nishiyama, and others have reported desymmetrization reactions of meso substrates, such as 1,5-diones,2 1,3-diones,3 4-substituted cyclohexanones,4 and 4,4-disubstituted cyclohexadienones,5 directly providing enantioenriched cyclohexenones possessing a stereocenter (Scheme 1A). To build two chiral centers, Zhao and co-workers reported asymmetric Robinson-type annulation Scheme 1. Outline of This Work

Received: March 21, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b01001 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of Reaction Conditionsa

Therefore, exploring feasible reaction partners and an efficient catalytic method to restore the high reactivity and provide stereocontrol is crucial for achieving this task. Herein, we report the first catalytic asymmetric synthesis of such multifunctionalized cyclohexenones through the development of an enantioselective, phase-transfer-catalyzed vinylogous conjugate addition−vinylogous cyclization cascade of olefinic azlactones9 with 4-nitro-5-styrylisoxazoles (Scheme 1C). By using an L-tert-leucine-derived urea−quaternary ammonium salt as a bifunctional phase-transfer catalyst with a mild inorganic base, the additions proceed with complete γ-selectivity, good to excellent enantio- and diastereoselectivities, and high configurational control of the double bond, which is pivotal to the subsequent cyclization. The method is effective for olefinic azlactones with diverse alkyl groups attached to the olefinic moiety, including not only methyl but also ethyl and cyclic alkyl groups, which are unprecedented in such systems, and the reaction leads to various chiral hexenones with two or three stereogenic centers. Following Jørgensen’s elegant work involving olefinic azlactones as vinylogous nucleophiles undergoing asymmetric 1,4- and 1,6-additions to enals and 2,4-dienals,10 Xu and coworkers demonstrated the feasibility of opening azlactone rings using oxygen anions when using an activated ketone as the reaction partner.11 On the other hand, 4-nitro-5-styrylisoxazoles as electrophiles were introduced by Adamo and co-workers,12 and because 4-nitroisoxazoles are less electron withdrawing than nitro groups, 4-nitroisoxazole-containing species were less reactive than nitroolefins. Given the advantages of directly embedding biologically and synthetically important isoxazoles in chiral molecules, many transformations of 4-nitro-5-styrylisoxazoles have been developed.13 Among them, several cycloaddition reactions have been realized through the addition of the in situ generated 5-α-carbanions of 4-nitroisoxazoles to isothiocyanates,13d activated alkenes13e and imines.13g These results suggest that such carbanions should be well suited for cyclization reactions. Recently, we developed a phase-transfer14,15 bifunctional catalyst to enable the direct deprotonation of 5-alkyl-4-nitroisoxazoles.15c,d This catalytic system would facilitate the cyclization of 5-alkyl 4-nitroisoxazoles even though the protonation of the 5-α-carbanion species occurs competitively. As such, we were intrigued to explore the reactions of olefinic azlactones with 4-nitro-5-styrylisoxazoles to furnish the desired chiral multifunctionalized cyclohexenones. We began our studies by selecting simple olefinic azlactone 1a and 4-nitro-5-styrylisoxazole 2a as model substrates (Table 1). No reaction occurred when Et3N was used as the catalyst (entry 1). The superbase 1,1,3,3-tetramethylguanidine (TMG), which has a stronger basicity than Et3N, was tested next (entry 2). Two products, conjugate addition adduct 3a with the E-configuration and desired cyclization adduct 4a, were obtained. The poor yield was due to the incomplete conversion of 1a and the unsatisfactory Z/E selectivity. These results revealed the high pKa of the methyl protons of 1a, the low reactivity of the addition, and the original unsatisfactory Z selectivity of the double bond. Certainly, the high reactivity of the cyclization and the excellent diastereoselectivity were encouraging. To address the indicated challenges, we speculated that our developed bifunctional phase-transfer-catalytic system would be effective on the basis of our previous works.15 Therefore, we tested 10 mol % L-phenylalanine-derived urea−quaternary ammonium salt C1 as the catalyst with 2.0 equiv of K2HPO4 (entry 3). To our delight, 4a was generated in 32% yield with moderate

4a entry

cat.

1 2 3 4 5 6 7 8 9 10 11 12f

Et3N TMG C1 C2 C3 C4 C5 C3 C3 C3 C3 C3

base

solvent

3a/4ab

yieldc (%)

eed (%)

K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K3PO4 Cs2CO3 CsF KF KF

Tol Tol Tol Tol Tol Tol Tol Tol Tol Tol Tol Tol

1:1 1:3 1:4 1:15 trace 1:7 1:15 1:17 1:17 1:16 1:16

nd 26 32 41 56 nd 47 62 75 72 63 91

nd NA 52e 30e 92e nd 91e 90e 84e 81e 93e 93e,g

a Reaction conditions: 1a (0.05 mmol), 2a (0.05 mmol), catalyst (0.005 mmol), inorganic base (0.1 mmol), solvent (0.5 mL). b Determined by 1H NMR analysis. cYield was determined following isolation by flash column chromatography. dDetermined by HPLC analysis on a chiral stationary phase. eThe dr was >19:1 as determined from the crude 1H NMR spectrum. f0.1 mmol of 1a and 0.25 mmol of KF were used in 0.25 mL of solvent. gNo reaction was observed in the absence of KF.

enantioselectivity and a similar excellent diastereoselectivity. More importantly, the ratio of 4a/3a was improved to 3:1. We then tested catalysts C2 and C3 prepared from L-phenylglycine and L-tert-leucine, respectively (entries 4 and 5). The branching of the catalysts had a tremendous impact on both the chemoselectivity and enantioselectivity, and in the best reaction, 3a was obtained in 56% yield with 92% ee (entry 5). When the urea moiety of C3 was changed to a thiourea (C4), essentially no reaction was detected, indicating the importance of the urea as a Lewis acid to promote the transformation (entry 6). Catalyst C5, with a six-membered ring instead of a five-membered ring (C3) in the quaternary ammonium moiety, gave 4a in a slightly lower yield but a similar enantioselectivity (entry 7). A solvent screening was then carried out (Table S1), and the reaction outcomes were not improved. The effect of the inorganic bases was also evaluated (entries 8−11), and 4a was obtained in 63% yield with 93% ee when KF was utilized (entry 11). The fact that the moderate yield stems from the low reaction rate and not the chemoselectivity inspired us to increase the loadings of 1a and KF. Finally, 4a was obtained in 91% yield with 93% ee and >19:1 dr (entry 12). Notably, no reaction was observed in the absence of KF (footnote g). With the optimal reaction conditions in hand, the scope of this asymmetric vinylogous conjugate addition−vinylogous cyclization protocol was examined. To better understand the reaction, we first investigated the transformations of diverse olefinic azlactones 1 containing a methyl group on the exocyclic olefins and various 4-nitro-5-styrylisoxazoles 2 to furnish chiral cyclohexenones with two stereocenters (Scheme 2). All of the reactions were complete within 60−72 h and led to B

DOI: 10.1021/acs.orglett.9b01001 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope with Respect to the Formation of Two Chiral Centersa

Scheme 3. Substrate Scope with Respect to the Formation of Three Chiral Centersa

a

Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), C3 (0.01 mmol), KF (0.5 mmol), tol (0.5 mL), 25 °C. All dr ratios were >19:1 as determined from the crude 1H NMR spectra.

a

Reaction conditions: 5 (0.2 mmol), 2 (0.1 mmol), C3 (0.01 mmol), KF (0.5 mmol), tol (0.5 mL), 25 °C. All dr values were determined by 1 H NMR spectroscopy. b20 mol % C3. ct = 96 h, T = 15 °C.

corresponding products 4a−aa in 43%−99% yields with 90%− 94% ee’s and >19:1 dr values. 4-Nitro-5-styrylisoxazoles bearing aromatic rings with both electron-withdrawing and electrondonating substituents at various positions (4a−o), fused aromatic rings (e.g., 2-naphthyl (4p)), and heteroarenes [e.g., 2-thienyl (4q) and 2-furyl (4r)] on the alkene presented excellent enantioselectivities and good yields. No reaction was detected with an alkyl substituent on the alkene of the 4-nitro-5styrylisoxazole. For olefinic azlactones 1, comparable results were achieved regardless of the presence of another exocyclic substituent on the aromatic ring (4s−x), their electronic properties, their substitution patterns, and the presence of alkyl groups (4y−aa). As a result, aryl and alkyl groups were successfully installed at the 3-position of cyclohexenones. This is the first example of the use of olefinic azlactones with two exocyclic alkyl groups on the alkene in asymmetric catalysis. Notably, the moderate yields of 4y−aa stemmed from the sluggish reaction rates. The absolute configurations of these adducts were assigned based on the structure of 4i, which was solved by single-crystal X-ray diffraction (see the SI). These successes encouraged us to synthesize more complex chiral cyclohexenones with three contiguous stereocenters by using olefinic azlactones with alkyl groups other than methyl as pronucleophiles (Scheme 3). When 5a, with an ethyl group instead of the methyl group seen in 1a, was subjected to the reaction with 2a, the transformation was sluggish; even when the catalytic loading of C3 was increased to 20 mol %, corresponding adduct 6a was obtained in 35% yield with 84% ee and >19:1 dr. No reaction was observed for other olefinic

azlactones in which the methyl group was replaced by longer alkyl chains or benzyl. Notably, the configuration of the outside double bond of the dienolate intermediates formed from these olefinic azlactones was preferentially E owing to its lower steric hindrance relative to the Z isomer. This selectivity results in the fact that the conjugate addition with bifunctional catalyst C3 can be interrupted. From this standpoint, we questioned whether olefinic azlactones with cyclic substituents on the olefin were viable given the formation of a rigid Z-double bond. As such, 5b was prepared and tested. We were pleased to find that product 6b was obtained in 74% yield with 91% ee and 15:1 dr after 96 h when the transformation was conducted in the presence of 10 mol % of C3 at 15 °C. Other 4-nitro-5-styrylisoxazoles 2 were subjected to the reaction with 5b and furnished a wide range of chiral cyclohexenones 6b−p featuring a 3,4-fused six-membered ring and two other stereocenters in 56−98% yields with 87−95% ee’s and 11:1 to >19:1 dr values. In most cases, high stereoselectivities were achieved even at 25 °C. Due to the wide variety of 3,4-fused rings present in bioactive cyclohexenones,16 other olefinic azlactones were tested, and adducts 6q−s with a 3,4-fused five-membered ring or a 3,4-fused sixmembered heterocycle were obtained with satisfactory results. The absolute configurations of these adducts were assigned on the basis of the structure of 6p, which was solved by singlecrystal X-ray diffraction (see the SI). Several control experiments were carried out, and a plausible mechanism was thus proposed wherein, in addition to providing the stereocontrolling environment, the catalytic system is responsible for activating the inert C

DOI: 10.1021/acs.orglett.9b01001 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Accession Codes

nucleophiles to deprotonation, controlling the formation of the dienolate intermediates with high Z selectivity, and facilitating the conjugate addition (see the Supporting Information for details). Although the obtained chiral multifunctionalized cyclohexenones have the potential for important bioactivities, experiments to verify the utility of this method have been performed (Scheme 4). A gram-scale synthesis was first carried

CCDC 1874522 and 1874533 contain 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.

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Scheme 4. Gram-Scale Preparation and Transformations of the Corresponding Adducts

AUTHOR INFORMATION

Corresponding Authors

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

Zhiyong Jiang: 0000-0002-6350-7429 Junbiao Chang: 0000-0001-6236-1256 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National NSFC (21672052, U1804283), the National Postdoctoral Program for Innovative Talents (BX201700071), and a project funded by the China Postdoctoral Science Foundation (2017M622348).

■ out under the standard reaction conditions, and 6j was obtained without compromising the yield, ee value, and dr (Scheme 4A). In the presence of SnCl2, the 4-nitroisoxazole group of 6j could be smoothly removed, affording product 7 with two adjacent stereocenters in 78% yield with 92% ee and 19:1 dr (Scheme 4B). Moreover, the sulfone group was successfully embedded in a chiral cyclohexanone by oxidizing the sulfur atom of 6s with mchloroperoxybenzoic acid (m-CPBA), and the reaction provided product 8 in 67% yield with no erosion of the enantiopurity. In summary, we have developed an asymmetric phasetransfer-catalyzed vinylogous conjugate addition−vinylogous cyclization of olefinic azlactones with 4-nitro-5-styrylisoxazoles. By using an L-tert-leucine-derived urea−quaternary ammonium salt as the phase-transfer catalyst with KF as a mild inorganic base, two series of enantioenriched cyclohexenones were obtained in high yields with good to excellent enantio- and diastereoselectivities. This method represents the first catalytic asymmetric synthesis of valuable chiral cyclohexenones featuring three contiguous quaternary stereocenters.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01001. Experimental procedures, synthesis method of the starting materials, and compound characterization data (PDF) D

DOI: 10.1021/acs.orglett.9b01001 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b01001 Org. Lett. XXXX, XXX, XXX−XXX