Direct Asymmetric Formal [3 + 2] Cycloaddition Reaction of

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Direct Asymmetric Formal [3 + 2] Cycloaddition Reaction of Isocyanoesters with β‑Trifluoromethyl β,β-Disubstituted Enones Leading to Optically Active Dihydropyrroles Bing Xu, Zhan-Ming Zhang, Lujia Zhou, and Junliang Zhang* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China S Supporting Information *

ABSTRACT: A highly enantioselective copper-catalyzed [3 + 2] cycloaddition reaction of α-isocyanoesters with β,β-disubstituted enones has been developed. Dihydropyrroles were obtained in excellent yields and enantioselectivity by employing an inexpensive copper catalyst. This process provides a scalable and efficient route for the synthesis of highly enantioselective 2,3-dihydropyrroles bearing a trifluoromethylated all-carbon quaternary stereocenter. The salient feautures of this reaction include high efficiency, operational simplicity, high diastereoselectivity and enantioselectivity, a broad substrate scope, outstanding functional group tolerance, and products exhibiting high utility for further transformations. Scheme 1. [3 + 2] Cycloaddition of α-Isocyanoesters with Disubstituted α,β-Unsaturated Compounds

T

he chiral 2,3-dihydropyrrole skeleton is a privileged structural motif found in a number of biologically active compounds.1,2 In addition, it has been widely employed as an important building block in the synthesis of natural products and other complex molecules.3 Over the past few decades, a number of elegant strategies for the asymmetric synthesis of 2,3-dihydropyrroles4 bearing a chiral stereocenter at the 2position have been developed.5,13 Recently, the catalytic asymmetric 1,3-dipolar [3 + 2]-cycloaddition of α-isocyanoesters6−13 with electron-deficient alkenes has emerged as an elegant and powerful strategy for the construction of chiral highly substituted 2,3-dihydropyrroles bearing two adjacent stereocenters. For example, Gong et al.13a,b have demonstrated asymmetric [3 + 2] cycloaddition reactions of isocyanoesters with nitroolefins and α,β-unsaturated carbonyl compounds to afford chiral 2,3-dihydropyrroles using either a silver salt as a catalyst or an organocatalyst (Scheme 1). However, these methods remain limited to the synthesis of chiral 2,3dihydropyrroles bearing a tertiary stereocenter. Despite Shi et al. reporting the asymmetric Michael addition of α-aryl isocyanoacetates to β-trifluoromethylated enones,14 the synthesis of chiral 2,3-dihydropyrroles possessing one all-carbon quaternary stereocenter15 has not been reported, presumably due to the use of more sterically hindered and less reactive β,βdisubstituted unsaturated compounds.16 Herein, we now present the first example of a copper-catalyzed highly diastereoand enantioselective intermolecular [3 + 2] cycloaddition reaction of α-isocyanoesters with β-trifluoromethyl β,βdisubstituted enones for the high yielding synthesis of enantioenriched 2,3-dihydropyrroles bearing a trifluoromethylated all-carbon quaternary stereocenter16d,f,g,17 (Scheme 1). Initially, the asymmetric [3 + 2] cycloaddition reaction of αisocyanoester 1a with enone 2 in the presence of a copper © XXXX American Chemical Society

catalyst in THF at rt was selected as the model reaction. A series of chiral biaryl-based phosphine ligands L1−L7 (Figure 1) were examined (Table 1, entries 1−7). Among them, a combination of Cu(CH3CN)4ClO4 and (R)-DTBM-SEGPHOS (L7) was able to provide the desired product 3aa in good yield with excellent diastereoselectivity (>20:1) and promising enantioselectivity. To further improve the enantioselectivity of the reaction, a number of Cu(I) salts, such as Cu(CH3CN)4ClO4, Cu(CH3CN)4NTf2, and Cu(CH3CN)4PF6, were tested, but none of these were able to provide better stereoselectivity (Table 1, entries 8−10). Changing the metal salt from Cu(CH3CN)4BF4 to Ag2CO3, Ag2O, and AgOAc led to an obvious decrease in the diastereoReceived: March 21, 2018

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DOI: 10.1021/acs.orglett.8b00925 Org. Lett. XXXX, XXX, XXX−XXX

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likely due to the poor solubility of the product (Table 1, entry 18). To our delight, replacing 1a with tert-butyl isocyanoacetate 1c18 provided the corresponding product with a higher ee of 93% (Table 1, entry 20). When 1.5 equiv of enone 2a were used, the desired product was obtained in a higher yield (Table 1, entry 21; 94% yield, >20:1 dr, 93% ee). It is noteworthy that no satisfactory results were obtained when chiral bases were used either with transition metals or on their own (more detail see the Supporting Information (SI)). With the optimal reaction conditions in hand, we examined the reaction scope by varying the enone component 2. As summarized in Table 2, a variety of substituted enones engaged Figure 1. Screened ligands.

Table 2. Exploration of β-Alkyl Enone Scopea

Table 1. Optimization of the Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16e 17e 18e 19e,f 20e,g 21e,g,h

drb

NMR yield (ee)/%c,d

rt rt rt rt rt rt rt rt

>20:1 15:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

89(7) 80(0) 61(−29) 93(18) 85(28) 78(26) 80(55) 82(49)

NaOAc NaOAc

rt rt

19:1 20:1

79(57) 80(43)

− − − Na2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

rt rt rt rt rt rt 0 −40 −40 −40 −40

1.8:1 2.4:1 1:1 >20:1 >20:1 >20:1 >20:1 >20:1 20:1 >20:1 >20:1

60(9) 69(8) 58(15) 78(55) 84(56) 84(76) 67(82) 68(69) 89(88) 86(93) 94(93)

[M]/L

base

Cu(CH3CN)4BF4/L1 Cu(CH3CN)4BF4/L2 Cu(CH3CN)4BF4/L3 Cu(CH3CN)4BF4/L4 Cu(CH3CN)4BF4/L5 Cu(CH3CN)4BF4/L6 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4ClO4/ L7 Cu(CH3CN)4PF6/L7 Cu(CH3CN)4NTf2/ L7 Ag2CO3/L7 Ag2O/L7 AgOAc/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7 Cu(CH3CN)4BF4/L7

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc

t/°C

entry

R1

R

3

dr

yieldb (ee)/%

1 2 3c 4 5 6c 7c 8 9 10c 11c 12c 13c 14c,d 15c 16c 17c,e 18c,e 19c,e 20c,e 21c,e 22c,d 23c,d

4-ClC6H4 4-BrC6H4 4-FC6H4 4-NO2C6H4 4-CNC6H4 4-CF3C6H4 4-MeO2CC6H4 4-CH3C6H4 4-MeOC6H4 4-PhC6H4 Ph 3,4-Cl2C6H3 2-naphthyl 2-furanyl 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-ClC6H4 cyclohexyl PhCH2CH2

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Et Bu Ph 4-ClC6H4 4-FC6H4 4-CF3C6H4 4-MeOC6H4 Me Me

3ca 3cb 3cc 3cd 3ce 3cf 3cg 3ch 3ci 3cj 3ck 3cl 3cm 3cn 3co 3cp 3cq 3cr 3cs 3ct 3cu 3cv 3cw

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 6:1 6:1 7:1 6:1 7:1 7:1 >20:1 6:1 5:1

94(93) 80(94) 85(90) 99(90) 91(94) 89(94) 85(93) 79(91) 68(93) 87(96) 70(90) 85(93) 71(90) 76(90) 98(90) 76(90) 76(94) 74(93) 75(95) 70(95) 57(82) 77(61) 67(50)

a

Unless otherwise noted, all reactions were carried out with 0.45 mmol of 1c, 0.3 mmol of 2, 5 mol % of catalyst ([Cu] to L7 = 1:1.1) in 6.0 mL of MTBE at −40 °C for 12−20 h. bIsolated yield. c0.3 mmol of 1c and 0.36 mmol of 2 was used. dAt −20 °C for 16 h. eCuBF4(CH3CN)4 (20 mol %), (R)-DM-SEGPHOS (L6), and Cs2CO3 (1.0 equiv) were used in 6.0 mL Et2O at −30 °C for 12 h.

a

Unless otherwise noted, all reactions were carried out with 0.1 mmol of 1a, 0.12 mmol of 2a, 5 mol % of catalyst ([Cu] to L = 1:1.1) in 2.0 mL of THF at rt for 6−12 h. bThe diastereomeric ratio was determined by 1H, 19F NMR analysis of the crude product. cNMR yield with CH2Br2 as an internal standard. dDetermined by chiral HPLC. eMTBE was used as the solvent. f1b was used. g1c was used. h 0.15 mmol of 1c and 0.1 mmol of 2a was used in the reaction for 20 h.

in the reaction, delivering the corresponding cycloadducts in good yields and with high enantioselectivity. For example, enones bearing either electron-rich or -poor substituted aryl groups (R1) were amenable to the reaction (Table 2, entries 1− 11) with the desired products 3ca−3ck being obtained in 68− 99% yields, 90−96% ee’s, and >20:1 dr. For the 3,4dichlorophenyl substituted enone 2l, the corresponding product 3cl was prepared in 85% yield and with 93% ee as a single diastereomer (Table 2, entry 12). Furthermore, the 2naphthyl substituted enone 2m and the 2-furanyl substituted enone 2n were also well tolerated, delivering the corresponding

and enantioselectivity (Table 1, entries 11−13). Subsequently, we focused on optimization of the base and solvent (Table 1, entries 14−16). When the base and solvent were changed to K2CO3 and MTBE, respectively, the desired product 3aa was obtained in 84% yield with >20:1 dr and 76% ee. Subsequently, when the temperature was lowered to 0 °C, the ee was further increased to 82% (Table 1, entries 16−17); however, the ee decreased when the temperature was lowered to −40 °C, most B

DOI: 10.1021/acs.orglett.8b00925 Org. Lett. XXXX, XXX, XXX−XXX

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note is that all of these transformations occurred with no loss in enantio- and diastereoselectivity.

compounds 3cm and 3cn in good yields with excellent dr and ee’s (Table 2, entries 13−14). Of note is that variation of the R group significantly affected the diastereoselectivity rather than the enantioselectivity. For example, β-ethyl enone 2o and βbutyl enone 2p gave their corresponding products 3co and 3cp with 90% ee but with 6:1 diastereoselectivity (Table 2, entries 15−16). Gratifyingly, the reaction could also be successfully extended to β-trifluoromethyl β-aryl enones. Interestingly, for these substrates, the electronic character of the aryl group influenced both the diastereoselectivity and enantioselectivity of the reaction; however, the reason for this is unclear (Table 2, entries 17−21). For example, the products 3cq−3cu were generally obtained with excellent enantioselectivities (57−76% yields, 82−95% ee’s). In addition, the enones bearing alkyl groups (R1) were also converted to the desired product with moderate ee (Table 2, entries 22−23). In addition, different fluorinated enones were tested (βCHF2, β-CH2F, and β-Me enones). As shown in Table 3, lower

Scheme 2. Synthetic Transformations of 3ca

Table 3. Effect of Fluorinea

entry

R

3

dr

yieldb/%

ee/%

1 2 3 4

CF3 CF2H CFH2 Me

3ca 3cx 3cy 3cz

>20:1 8:1 4:1 −

94 84 60 trace

93 84 75 −

In summary, we have developed the first highly diastereoand enantioselective copper-catalyzed [3 + 2] cycloaddition reaction of α-isocyanoesters with β-trifluoromethyl β,βdisubstituted enones. This method provides a reliable strategy for the enantioselective construction of highly substituted 2,3dihydropyrroles bearing a trifluoromethylated all-carbon quaternary stereocenter. In view of the high reaction efficiency and operational simplicity (the use of an inexpensive copper salt as the precatalyst, and no need for an inert atmosphere), the copper-catalyzed asymmetric cycloaddition reaction of isocyanides with enones can be expected to find wide synthetic applications.

a

Unless otherwise noted, all reactions were carried out with 0.45 mmol of 1c, 0.3 mmol of 2, 5 mol % of catalyst ([Cu] to L7 = 1:1.1) in 6.0 mL of MTBE at −40 °C for 18−24 h. bIsolated yield.

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reactivity and stereoselectivity is observed when the number of fluorine atoms is reduced (Table 3) indicating that the βtrifluoromethyl backbone of the enone is essential for achieving high reactivity and stereocontrol. The cycloaddition could be carried out on a gram-scale in some instances. Thus, 1.67 g of 3ca was obtained in 86% yield with excellent diastereo- and enantioselectivities (>20:1 dr, 93% ee), indicating that the present methodology is amenable to large scale synthesis. Gratifyingly, enantiopure 3ca (>99% ee) could be easily obtained by simple recrystallization of the crude product from petroleum ether and DCM. To demonstrate the general synthetic utility of our methodology, several transformations of the 2,3-dihydropyrrole product 3ca were carried out. For example, treatment of 3ca with DDQ gave the highly substituted 3H-pyrrole 4 in 50% yield. The ester group allowed for 3ca to be readily converted into a series of prolinol derivatives (5a−5d) using different aryl lithium reagents. The chlorine atom present on the aryl group (R1) of the prolinol derivatives (5a) could be reduced to hydrogen, giving the prolinol derivative 6. The absolute configuration of product 6 was established by single-crystal X-ray diffraction analysis (CCDC 1574712). Additionally, the ester group of 3ca could also be reduced with DIBAL-H, leading to the corresponding prolinol derivative 7 in 72% yield which could be readily protected with a benzyl (Bn) group to give 8, via reaction with benzyl bromide (BnBr) and tBuOK (Scheme 2). Of particular

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00925. Experimental procedures, spectroscopic data for the substrates and products (PDF) Accession Codes

CCDC 1574712 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 data_ [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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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Junliang Zhang: 0000-0002-4636-2846 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b00925 Org. Lett. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS We gratefully acknowledge the funding support of NSFC (21425205, 21672067), 973 Program (2015CB856600), the Program of Eastern Scholar at Shanghai Institutions of Higher Learning, and the China Postdoctoral Science Foundation (2017M610236).

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DOI: 10.1021/acs.orglett.8b00925 Org. Lett. XXXX, XXX, XXX−XXX