Asymmetric Organocatalytic [4 + 1] Annulations: Enantioselective

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

pubs.acs.org/OrgLett

Asymmetric Organocatalytic [4 + 1] Annulations: Enantioselective Construction of Multifunctionalized Spirocyclopentane Oxindoles Bearing α,α-Disubstituted α‑Amino-β-keto Esters Chuan-Chuan Wang,† Jian Huang,† Xin-Hao Li,† Søren Kramer,§ Guo-Qiang Lin,†,‡ and Xing-Wen Sun*,† †

Department of Chemistry, Fudan University, Shanghai 200433, China CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China § Department of Chemistry, Technical University of Denmark, 2800 Kongens Lyngby, Denmark ‡

S Supporting Information *

ABSTRACT: The highly enantioselective preparation of spirooxindoles bearing α,α-disubstituted α-amino-β-keto esters was achieved through [4 + 1] annulation of oxindoles and αimine-β-oxo-γ,δ-unsaturated esters under mild conditions in good yields (up to 82%) and stereoselectivities (up to >20:1 dr, 96% ee). The reaction is amenable to gram scale synthesis using catalyst loading as low as 1 mol %. The corresponding chiral α,α-disubstituted α-amino-β-keto esters could be easily transformed into cyclopenta[b]indole derivatives without erosion of enantiopurity.

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reactions of methyleneindolinones with MBH carbonates or allenoates,8 as well as organocatalytic tandem reactions such as Michael/Henry,9 Michael−aldol,10 Michael−alkylation,11 and Michael/Michael additions12 are common approaches to synthesize these alkaloids. In addition, asymmetric [4 + 1] annulations have proven to be a powerful strategy for the construction of five-membered spiro compounds.13 Surprisingly, the asymmetric organocatalytic [4 + 1] annulation strategy was rarely applied to construct functionalized spirooxindoles. Shi and co-workers reported the phosphinecatalyzed [4 + 1] annulation of MBH carbonates with activated α,β-unsaturated ketones to prepare spirooxindoles.14 More recently, Chen and co-workers reported the enantioselective synthesis of spirodihydropyrrole oxindole compounds through [4 + 1] annulation of 3-bromooxindoles and 1-azadienes catalyzed by cinchona alkaloid-based catalysts.15 However, to the best of our knowledge, enantioselective synthesis of spirooxindoles by organocatalysis to access cyclopentanone motifs through [4 + 1] annulations has not been uncovered. Hence, development of asymmetric protocols to construct functionalized spirocyclopentanone oxindoles via [4 + 1] annulations with high levels of stereoselectivity is highly desirable. In 2015, we developed an efficient enantio- and diastereoselective route to chiral spirocyclopentane oxindole compounds using a Michael/Mannich tandem reaction of methyleneindolinones with ketimines, prepared from dicarbonyl compounds and nitrosoarenes, through a polarity reversal

nnulations are the most powerful synthetic methods for the construction of natural products and bioactive molecules with complex ring frameworks.1 Accordingly, development of novel annulations has attracted considerable attention over the past decades.2 Among them, [3 + 2] annulations3 and [4 + 1] annulations4 are efficient approaches to construct multifunctionalized five-membered carbo- and heterocycles. For [3 + 2] annulations, regioselectivity issues can occur when using sterically or electronically nonbiased C2 synthons.5 In contrast, [4 + 1] annulations, which integrate only one atom, eliminate such intrinsic selectivity issues. Functionalized spirocyclopentane oxindoles are remarkable scaffolds since they are prevalent in various natural products and synthetic bioactive molecules (Figure 1).6 The key challenge for building such architectures lies in the formation of multiple stereocenters, especially those containing contiguous stereocenters. Various organocatalytic synthetic routes to spirooxindoles have been explored to achieve enantioenriched molecules with complex architectures.7 Among them, tertiary phosphine-catalyzed asymmetric [3 + 2] cycloaddition

Figure 1. Natural compounds containing spirocyclopentane oxindole scaffold. © XXXX American Chemical Society

Received: March 21, 2018

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DOI: 10.1021/acs.orglett.8b00927 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

strategy.16 Driven by our strong interest in developing efficient organocatalytic cascade reactions to construct spirooxindoles, and inspired by our previous works,17 we envisioned that α,βunsaturated keto esters (Nazarov reagents)18 could react with nitrosoarenes to form C4 synthons containing two electrophilic sites (Scheme 1). Such C4 synthons could further react with a Scheme 1. General Outline of the Novel [4 + 1] Annulation Strategy Employed Herein

suitable C1 synthon promoted by a bifunctional catalyst. As shown in Scheme 1, this [4 + 1] annulation through a tandem Michael/Mannich process leads to a spirocyclopentane oxindole with an α-amino-β-keto ester unit bearing three continuous stereocenters (two quaternary). However, several challenges need to be addressed for the development of a successful cascade sequence: (1) the influence on the overall yield by the initial reaction of keto esters with nitrosoarenes to form imine intermediates, (2) the creation of highly functionalized cyclopentanone possessing five substituents, and (3) the control of enantio- and diastereoselectivity, considering the simultaneous generation of three continuous stereocenters, two of which are quaternary. Considering that both Nazarov reagents and oxindoles are nucleophilic, we initiated the investigation of the one-pot process through consecutive addition of substrates (Table 1). First, Nazarov reagent 1a and nitrosobenzene 2a were allowed to react in the presence of 5 mol % of squaramide catalyst 3a in CH2Cl2 at room temperature for 2 h. After the nitrosobenzene was consumed, N-Boc-protected oxindole 4a was introduced. To our delight, the proposed reaction proceeded smoothly with high conversion in 10 h, providing spirocyclopentane oxindole in 70% yield with 10:1 diastereoselectivity and 91% ee (entry 1). The influence of the stoichiometry of the substrates on the reaction outcome was evaluated. It was found that a 1.2:1.1:1 molar ratio of 1a:2a:4a provided superior results (see the Supporting Information (SI)). To improve stereoselectivity, the reaction was conducted at lower temperature (0 °C), providing enhancement in both yield and enantioselectivity; however, further decreasing the reaction temperature did not lead to additional improvements (entries 2−4). Catalyst 3b did not enhance the yield and enantioselectivity, and the diastereoselectivity was very disappointing (entry 5). To further optimize the reaction, we tried to investigate the influence of the solvent and catalyst loading. These efforts indicated that CH2Cl2 was the best solvent (see the SI) and that reducing the catalyst loading slightly enhanced the yield and diastereoselectivity (entry 6). Variation of the N substituent on oxindole showed that tertbutyloxycarbonyl was the best group. The reactions with unprotected, benzyl-protected, or acetyl-protected oxindoles failed to provide the desired products (entries 8−11). Benzyloxycarbonyl-protected oxindole afforded the desired product, albeit with decreased stereoselectivity (entry 11). For enantioselective synthetic methods, it is highly valuable to have easy access to both enantiomers of the product. In

entry

cat.

R

T (°C)

yieldb (%)

drc

eed (%)

1 2 3 4 5 6e 7g 8 9 10 11 12 13 14

3a 3a 3a 3a 3b 3a 3a 3a 3a 3a 3a 3c 3d 3e

Boc Boc Boc Boc Boc Boc Boc H Bn Ac Cbz Boc Boc Boc

rt 0 −5 −10 0 0 0 0 0 0 0 0 0 0

70 76 70 69 51 78 (75f) 68 trace trace trace 75 28 37 70

10:1 14:1 16:1 16:1 1.2:1 17:1 16:1 nd nd nd 10:1 3:1 3:1 10:1

91 94 94 94 90 95 93 nd nd nd 77 −72h −88h −91h

a

Unless noted otherwise, the reaction was performed with 0.12 mmol of 1a, 0.11 mmol of 2a, 0.005 mmol of 3, 25 mg 4 Å M.S., and 0.1 mmol of 4 in 0.2 mL of CH2Cl2. bYield of major diastereoisomer determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. cThe dr was determined by 1H NMR spectroscopy of the crude reaction mixtures. dThe ee was determined by HPLC analysis on a chiral stationary phase. e0.002 mmol of 3a was used. fIsolated yield of the major diastereoisomer. g0.001 mmol of 3a was used. h Opposite enantiomer.

order to target the other enantiomer of the spirooxindole product 5, we tested different cinchonine- or quinidine-derived squaramides (3c−e) (entries 12−14). Fortunately, catalyst 3e provided the opposite enantiomer with essentially identical enantioselectivity and yield. The diastereoselectivity is also high, albeit slightly lower than for 3a. With the optimized conditions in hand (Table 1, entry 6), we next examined the substrate scope of the asymmetric [4 + 1] annulation for the synthesis of spirocyclopentane oxindoles (Scheme 2). Overall, the reactions proceeded smoothly to give the desired spirooxindoles in good yields (48−82%) with good to excellent stereoselectivities (6:1 to 20:1 dr and 76 to 96% ee). A series of Nazarov reagents with different steric and electronic features was tested first. When the ethyl group of the Nazarov reagents was replaced by an i-Pr or t-Bu group, the enantioselectivity was retained, but with slight loss of yield (5b,c). However, the reaction yield and enantioselectivity seemed to be mostly insensitive to the steric hindrance and electronic features of the aryl substituent on the Nazarov reagents (5d−j). Keto esters with an electron-donating group or a weak electron-withdrawing group at the para position of the phenyl ring gave good to excellent yields and enantioselectivities (5d−g). The introduction of a strong electron-withdrawing group at the para position led to a drop in ee value (5h). Sterically hindered o-MeO- or m-F-substituted keto esters led to lower yield or stereoselectivity, respectively (5i,j). Ring-condensed naphthyl and piperonyl were also B

DOI: 10.1021/acs.orglett.8b00927 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of the Reactiona

the standard conditions (Scheme 3). The spirooxindole 5x was obtained in a comparable yield (78%) and with maintained Scheme 3. Gram-Scale Synthesis of 5x

stereoselectivity (19:1 dr, 94% ee). Reducing the loading of catalyst to 1 mol % barely affected the reaction outcome, and the desired spirooxindole was obtained in good yield (71%) with maintained enantioselectivity (94% ee) and only a slight loss in diastereoselectivity (12:1 dr). The optically enriched spirooxindole products obtained in our cascade reaction can easily undergo further transformations, providing easy access to additional important structural motifs (Scheme 4). The cyclopenta[b]indole core is contained in Scheme 4. Transformation of Spirooxindoles 5

a

Unless noted otherwise, the reaction was performed with 0.24 mmol of 1, 0.22 mmol of 2, 0.004 mmol of 3a, 50 mg of 4 Å M.S., and 0.2 mmol of 4 in 0.4 mL of CH2Cl2. The listed yield is isolated yield of the major diastereoisomer. The dr was determined by 1H NMR spectroscopy of the crude reaction mixtures. The ee was determined by HPLC analysis on a chiral stationary phase. bX-ray. c0.004 mmol of 3e was used as a catalyst. dOpposite enantiomer.

many natural and unnatural products that exhibit biological activities. 19 In order to access this key motif, chiral spirooxindole 5r was treated with different Lewis acids to facilitate an intramolecular Friedel−Crafts reaction. To our delight, 5r cyclized smoothly in the presence of ZnBr2, and the Boc group was removed simultaneously. Cyclopenta[b]indole derivative 6 was achieved in 74% yield with no erosion of enantiopurity. The absolute configuration of the new chiral center on cyclopenta[b]indole 6 was determined by X-ray diffraction analysis (see the SI). Interestingly, when t-Bu ester substrate 5x was subjected to the ZnBr2 conditions, removal of tert-butyl group and subsequent decarboxylation reaction occurred instead of the Friedel−Crafts reaction. Most likely, the decarboxylation proceeds through a six-membered ring transition state with the neighboring ketone carbonyl group and the resulting enol form isomerizes to the ketone product 7. During this process, inversion of the stereocenter linked to the amino group had occurred. This was confirmed by X-ray diffraction analysis of spirooxindole 7 (see the SI). Finally, for 5a, it was demonstrated that Boc deprotection with trifluoroacetic acid at 0 °C afforded compound 8 in 99% yield with no erosion of enantiopurity. In conclusion, N-Boc-protected oxindoles and α-imine-βoxo-γ,δ-unsaturated esters can undergo tandem Michael/ Mannich reaction under mild conditions to afford five-

applicable substrates, offering the corresponding products in 64−72% yields with 93−95% ee (5k,l). Moreover, the heteroaromatic substituted keto esters were also applicable substrates for the cascade reaction (5m,n). Furthermore, we evaluated the influence of the electronic properties of the nitrosoarene. Both p-MeO- and Br-substituted nitrosobenzene gave the desired products in 48−61% yields and good enantioselectivities (5o−p, 92−93% ee). Finally, substituted N-Boc-protected oxindoles were evaluated under the standard reaction conditions. Both electron-donating and electronwithdrawing groups at the indole ring of 4 were well tolerated, and the desired products were obtained in good yields (67− 83%) and with good to excellent diastereoselectivities (13:1 to >20:1 dr) and enantioselectivities (5q−x, 88−94% ee). The enantiomers of spirooxindoles 5v and 5x were obtained with identical enantioselectivities, but slightly lower diastereoselectivities, when quinidine-derived squaramide 3e was used as a catalyst. The absolute configuration of spirooxindole 5g was determined by X-ray diffraction analysis (see the SI). To further illustrate the preparative utility of this asymmetric annulation reaction, a gram-scale reaction was carried out under C

DOI: 10.1021/acs.orglett.8b00927 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters membered spirocyclic oxindoles bearing α,α-disubstituted αamino-β-keto esters with three contiguous stereocenters (two quaternary) in good yields (up to 82%) and stereoselectivities (up to >20:1 dr, 96% ee). Our tandem [4 + 1] annulation is scalable and proceeds well in the presence of 1 mol % of a bifunctional squaramide catalyst. Further expansion of new tandem reactions based on α-imine-β-oxo-γ,δ-unsaturated esters as C4 synthons, as well as investigation of the biological activity of the produced spirooxindoles, are underway in our laboratory.

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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.8b00927. Experimental details, characterization data, and spectral data (PDF) Accession Codes

CCDC 1579826, 1579832, and 1579838 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]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xing-Wen Sun: 0000-0003-0432-7935 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (21472019). REFERENCES

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DOI: 10.1021/acs.orglett.8b00927 Org. Lett. XXXX, XXX, XXX−XXX