Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with

Jan 5, 2018 - The formation of a O–Cu bond with the carbonyl oxygen atom of the enone and dissociation of the amine nitrogen of L2 from the Cu(I) ce...
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Cite This: J. Am. Chem. Soc. 2018, 140, 2272−2283

Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)Catalyzed Asymmetric 1,3-Dipolar Cycloadditions Shan Xu, Zhan-Ming Zhang, Bing Xu, Bing Liu, Yuanyuan Liu,* 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, PR China S Supporting Information *

ABSTRACT: An unprecedented ligand-controlled regiodivergent Cu(I)-catalyzed asymmetric intermolecular (3 + 2) cycloaddition reaction of α-substituted iminoesters with βfluoromethyl β,β-disubstituted enones was developed. This novel strategy provides an efficient method for the enantioselective regiodivergent synthesis of pyrrolidines bearing two adjacent quaternary stereocenters or two discrete quaternary stereocenters, opening up a new era for medicinal chemistry and diversity-oriented synthesis. DFT calculations showed that the P,N-ligand L2 acts as a pseudobidentate ligand. The formation of a O−Cu bond with the carbonyl oxygen atom of the enone and dissociation of the amine nitrogen of L2 from the Cu(I) center occurs during the catalytic cycle; this is the main reason for the tuning the regioselectivity of the cycloaddition reaction caused by switching of the ligand. The salient features of this work include high yields (up to >99%), a general substrate scope, the use of commercially available ligands, and high regio-(up to >20:1 rr), diastereo- (up to >20:1 dr), and enantioselectivity (up to >99% ee).



of the low reactivity of trisubstituted olefins and α-substituted iminoesters. Moreover, two (aza)-quaternary stereocenters are constructed which gives rise to a pyrrolidine ring bearing six substituents, thus these ring systems are more sterically congested compared to those reported in our previous work. Herein, we wish to report the first enantioselective and regiodivergent synthesis of valuable pyrrolidines with two adjacent or two discrete quaternary stereocenters10 via a ligandcontrolled Cu(I)-catalyzed asymmetric (3 + 2) cycloaddition of α-substituted iminoesters with β-fluoromethyl β,β-disubstituted enones (Scheme 1c). This methodology performs well with a broad range of substrates, giving the desired products in high yields, and with high regio-, diastereo-, and enantioselectivity. In addition, theoretical calculations relating to the transition states and control experiments have been carried out in order to explain the unusual regioselectivity.

INTRODUCTION A large number of studies concerning the catalytic asymmetric 1,3-dipolar cycloaddition of iminoesters1−4 have been conducted, in particular with regards to the synthesis of pyrrolidine ring systems, core structural motifs found in an array of natural products, pharmaceuticals, and catalysts.5 In most cases, the iminoester tends to undergo (3 + 2) cycloadditions exclusively which are triggered by C2-nucleophilic attack (resonance form Ia) rather than C4-nucleophilic attack (resonance form Ib) (Scheme 1a).1,3,4,6 To the best of our knowledge, only the Gong group had realized a Brønsted acid catalyzed asymmetric three-component 1,3-dipolar cycloaddition providing products with the opposite regioselectivity, this being due to Ib being more stable than its resonance form Ia in the presence of acid and thus C4 is more nucleophilic than C2 in this case (Scheme 1b).7 Enantioselective regiodivergent synthesis8 of two different chiral products from identical staring materials is obviously very appealing but is extremely challenging. In the context of the (3 + 2) cycloaddition of iminoesters, no any example describing ligand-controlled enantioselective regiodivergent reactions has been reported thus far. Therefore, the development of such reactions by simply changing the chiral ligand is greatly desired. In continuation of our recent studies concerning the (3 + 2) cycloaddition of iminoesters,9 we envisaged that chiral pyrrolidines, bearing two adjacent aza- and all carbonquaternary stereocenters, may be modified by the use of αsubstituted iminoesters with β-trifluoromethyl β,β-disubstituted enones. Of course, this hypothesis is difficult to realize because © 2018 American Chemical Society



RESULTS AND DISCUSSION We began our study by choosing α-methyl iminoester 1a and enone 2a as the model substrates (Table 1). The screening was initiated by the examination of a series of commercially available chiral P,N- and P,P-ligands (Figure 1). To our surprise, two different types of pyrrolidines with opposite regioselectivity could be obtained when using ferrocenyl P,NReceived: November 16, 2017 Published: January 5, 2018 2272

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society Scheme 1. Asymmetric (3 + 2) Cycloadditions of Iminoesters with Olefins

Figure 1. Known chiral ligands.

type ligand (S,Sp)-iPr-Phosferrox (L1) and (S,Rp)-PPFA (L2) (Table 1, entries 1 and 2, respectively). Next, (R,S)-O-PINAP (L3) and (S)-TF-BiphamPhos (L4) were examined. Although product 4 could be obtained using these catalysts, none of them were capable of inducing satisfactory regio- and enantioselectivity (Table 1, entries 3 and 4). Furthermore, only trace amounts of the desired cycloadducts were detected when P,Ntype ligands L5 and L6, and P,P-type ligands (R)-BINAP (L7) and SDP (L8) were used as chiral ligands (see Table S1). To our delight, after many attempts (Table 1, entries 5−15), cycloadduct 3aa was obtained in 88% yield and >99% ee using [Cu(CH3CN)4]BF4 as the precatalyst in the presence of chiral ligand L1, Cs2CO3 as base, and a mixed solvent (THF/MTBE) system at −30 °C (Table 1, entry 10). Conversely, another pyrrolidine 4aa with opposite regioselectivity was obtained in 87% yield and 92% ee when commercially available ligand (L2) Table 1. Optimization of Reaction Conditionsa

entry

L/[Cu]

solvent

3:4:5b

1 2 3 4 5 6 7 8f 9f 10g 11 12 13 14 15

L1/Cu(CH3CN)4BF4 L2/Cu(CH3CN)4BF4 L3/Cu(CH3CN)4BF4 L4/Cu(CH3CN)4BF4 L1/Cu(CH3CN)4BF4 L1/Cu(CH3CN)4BF4 L1/Cu(CH3CN)4BF4 L1/Cu(CH3CN)4PF6 L1/Cu(CH3CN)4ClO4 L1/Cu(CH3CN)4BF4 L2/Cu(CH3CN)4BF4 L2/Cu(CH3CN)4BF4 L2/Cu(CH3CN)4BF4 L2/Cu(CH3CN)4ClO4 L2/Cu(CH3CN)4PF6

Et2O Et2O Et2O Et2O THF MTBE i Pr2O MTBE MTBE THF/MTBE THF MTBE toluene Et2O Et2O

9/0.2/1 0/14/1 0/1/0 0/4/1 35/1/0.5 21/1/1.3 21/1/3.3 17/1/1.5 18/1/1.3 26/1/0.5 0/12/1 0/12/1 0/8/1 0/15/1 0/15/1

yield (ee) (%)c,d 45 87 15 11 50 80 78 70 74 88 84 85 80 84 82

(99) (92) (−28)e (23) (99) (99) (99) (99) (99) (99) (90) (90) (89) (83) (75)

a Unless otherwise noted, entries 1−4 and 11−15 were carried out with 0.12 mmol of 1a, 0.1 mmol of 2a, and 5 mol % catalyst ([Cu]/ligand = 1:1.1) in 2.0 mL of solvent at −55 °C for 16 h. Entries 5−10 were carried out with 0.15 mmol of 1a, 0.1 mmol of 2a, and 7.5 mol % catalyst at −30 °C for 16 h. bThe ratio was determined by 1H, 19F NMR analysis of the crude products. cNMR yield with CH2Br2 as an internal standard for major product. d The ee was determined by chiral HPLC. eThe opposite enantiomers as compared with the results of entries 2 and 4. fUsed 10 mol % catalyst. g VMTBE/THF = 1/1 and 0.2 mmol of 1a were used. MTBE = methyl tert-butyl ether; THF = Tetrahydrofuran.

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DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society Table 2. Exploration of Enone Scope for Generating 3a

entry

R4/R5

rrb

drb

3/yield (%)/ee (%)c,d

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

4-ClC6H4/Me (2a) 4-FC6H4/Me (2b) 4-BrC6H4/Me (2c) 4-NO2C6H4/Me (2d) 4-CF3C6H4/Me (2e) 4-CNC6H4/Me (2f) Ph/Me (2g) 4-CH3C6H4/Me (2h) 2-ClC6H4/Me (2m) 3,4-Cl2C6H3/Me (2n) 2-Naph/Me (2o) 2-Thienyl/Me (2q) 4-ClC6H4/Et (2r)

>20:1 >20:1 >20:1 >20:1 20:1 >20:1 15:1 18:1 >20:1 >20:1 >20:1 >20:1 3:1

>20:1 12:1 >20:1 >20:1 >20:1 >20:1 18:1 14:1 >20:1 >20:1 >20:1 15:1 >20:1

3aa/90/99 3ab/81/>99 3ac/90/98 3ad/95/>99 3ae/95/>99 3af/92/98 3ag/85/99 3ah/83/99 3am/90/98 3an/93/>99 3ao/94/>99 3aq/76/>99 3ar/48/98 (4ar/18/97)

a

Unless otherwise noted, all reactions were carried out with 0.4 mmol of 1a, 0.2 mmol of 2, and 7.5 mol % catalyst ([Cu] to L1 = 1:1.1) in 2.0 mL of VTHF/MTBE = 1:1 at −30 °C for 6−24 h. bThe rr was the yield of (3+5)/4, dr was 3/5. cIsolated yield of major isomer 3. dThe ee was determined by HPLC analysis. eAt 0 °C, 10 mol % catalyst, 0.6 mmol of 1 were used for 24−70 h. fUsed 0.8 mmol of substrate 1a. gThe number in parentheses are the yield and ee of 4.

Table 3. Exploration of Iminoester Scope for Generating 3

a

entry

R1/R2/R3

rr

dr

yield (%)/ee (%)

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

4-FC6H4/Me/Et (1b) 4-ClC6H4/Me/Et (1c) 4-CF3C6H4/Me/Et (1e) Ph/Me/Et (1f) 4-CH3C6H4/Me/Et (1g) 4-PhC6H4/Me/Et (1h) 4-CH3OC6H4/Me/Et(1i) 2-ClC6H4/Me/Et (1j) 3-BrC6H4/Me/Et (1k) 2-Naph/Me/Et (1n) 4-BrC6H4/Et/Et (1q) 4-BrC6H4/Me/Me (1u)

>20:1 17:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 3:2 >20:1

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 12:1 13:1 >20:1 >20:1 12:1

3ba 86/99 3ca 81/>99 3ea 88/99 3fa 97/>99 3ga 82/98 3ha 83/>99 3ia 82/>99 3ja 87/>99 3ka 90/90 3na 83/99 3qa 46/82 (4qa 31/91) 3ua 75/>99

At −50 °C, 10 mol % catalyst was used. bThe numbers in parentheses are the yield and ee of 4.

7,8,11). The cycloaddition of 1a with thienyl-derived enone 2q also worked well, delivering 3aq in 76% yield with >99% ee (Table 2, entry 12). When the R5 group was substituted by an Et group, the regioselectivity was adversely affected but not the enantioselectivity, with the products 3ar and 4ar being obtained in 48% yield/98% ee and 18% yield/97% ee, respectively (Table 2, entry 13). We then turned our attention to the substrate scope of αsubstituted iminoesters 1 using the optimal reaction conditions (Table 3). Iminoesters bearing electronically divergent substituents at the para-position of the phenyl ring reacted smoothly with 1a, giving the corresponding products (3ba− 3ia) in excellent yields (81−97%) and with high regio-, diastereo-, and enantioselectivity (≥98% ee) (Table 3, entries 1−7). Halogen groups at the ortho- and meta- positions of the

was employed as the chiral ligand, [Cu(CH3CN)4]BF4 as the copper catalyst and Et2O as the solvent at −55 °C with Cs2CO3 as the base (Table 1, entry 2). (See Table S1−S3 and the Supporting Information for details.) Substrate Scope for (3 + 2)-Cycloaddition Reaction of Product 3. With the optimal conditions in hand, we next examined the substrate scope of enones 2 (Table 2). Gratifyingly, enones having either electron-donating or -withdrawing groups on the aromatic ring reacted with 1a to generate the desired products 3 with up to >20:1 regioselectivity, >20:1 diastereoselectivity in 81−95% yields, and excellent enantioselectivity (≥98% ee) using of L1 as the chiral ligand (Table 2, entries 1−10). It is worth noting that the reactions of enones 2g, 2h, and 2o required a higher reaction temperature to increase the yield (0 °C, Table 2, entries 2274

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society phenyl ring were also tolerated, but meta-substituted halogenated substrates gave the corresponding products with comparatively lower ee (Table 3, entries 8−9, >99 vs 90% ee). 2-Naphthylaldehyde derived iminoester 1n was also suitable for this annulation reaction, providing adduct 3na selectively in 83% yield and with 99% ee (Table 3, entry 10). To our surprise, replacing the α-methyl group in the iminoester with an ethyl group led to a significant drop in the regioselectivity (Table 3, entry 11; 3qa/4qa = 3/2), further showing that the construction of two adjacent quaternary stereocenters is indeed very challenging. Finally, cycloaddition product 3ua was obtained with high enantioselectivity when a methyl iminoester was utilized (Table 3, entry 12). Substrate Scope for (3 + 2)-Cycloaddition Reaction of Product 4. After examining the reaction scope of the normal regioselective cycloaddition with L1 as the chiral ligand, we next investigated the reaction scope of cycloaddition reactions that provide the desired products with opposite regioselectivity. At first, various β,β-disubstituted enones 2 were reacted with iminoester 1a in the presence of ligand L2 (Table 4). In

with 80% ee, and the styryl group provides an additional handle for further transformations (Table 4, entry 16). The α-substituent of iminoesters 1 were also altered and examined (Table 5). It was observed that α-methyl iminoesters Table 5. Exploration of Iminoester Scope for Generating 3

Table 4. Exploration of Enone Scope for Generating 4a

entry

R4/R5

4

rrb

yield (%)

ee (%)

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

4-ClC6H4/Me (2a) 4-FC6H4 /Me (2b) 4-BrC6H4/Me (2c) 4-NO2C6H4/Me (2d) 4-CF3C6H4 /Me (2e) Ph/Me (2g) 4-CH3C6H4/Me (2h) 4-PhC6H4/Me (2i) 4-CH3OC6H4/Me (2j) 2-CH3OC6H4/Me (2k) 3-CH3OC6H4/Me (2l) 3,4-Cl2C6H3/Me (2n) 2-Naph/Me (2o) 2-Furyl/Me (2p) 4-ClC6H4/Et (2r) Ph/Styryl (2s)

4aa 4ab 4ac 4ad 4ae 4ag 4ah 4ai 4aj 4ak 4al 4an 4ao 4ap 4ar 4as

14:1 15:1 13:1 6:1 11:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 8:1 >20:1 20:1 >20:1 5:1

87 81 87 68 84 92 92 93 83 79 91 88 87 81 99 62

92 90 92 93 94 93 90 96 94 92 95 91 93 93 90 80

entry

R1/R2/R3

4

rr

yield (%)

ee (%)

1 2 3 4 5 6a 7 8 9 10 11 12 13 14b,c 15b,c 16b,c 17d 18 19

4-FC6H4/Me/Et (1b) 4-ClC6H4/Me/Et (1c) 4-NCC6H4/Me/Et (1d) 4-CF3C6H4/Me/Et (1e) Ph/Me/Et (1f) 4-CH3C6H4/Me/Et(1g) 4-PhC6H4/Me/Et (1h) 3-BrC6H4/Me/Et (1k) 3-ClC6H4/Me/Et (1l) 3-CF3C6H4/Me/Et(1m) 2-Naph/Me/Et (1n) Styryl/Me/Et (1o) 2-furyl/Me/Et (1p) 4-BrC6H4/Et/Et (1q) 4-BrC6H4/nPr/Et (1r) 4-BrC6H4/Bn/Et (1s) 4-BrC6H4/Ph/Et (1t) 4-BrC6H4/Me/Me (1u) 4-BrC6H4/Me/iPr (1v)

4ba 4ca 4da 4ea 4fa 4ga 4ha 4ka 4la 4ma 4na 4oa 4pa 4qa 4ra 4sa 4ta 4ua 4va

13:1 14:1 >20:1 >20:1 14:1 6:1 11:1 16:1 17:1 >20:1 4:1 >20:1 >20:1 3:1 5:1 4:1 >20:1 11:1 10:1

85 90 >99 96 90 85 90 88 93 84 72 99 96 69 (24) 73 (13) 77 (16) 81 74 86

91 91 94 95 90 90 84 92 91 94 85 83 81 94/− 94/− 96/− 87 92 93

a

The overall yield of 4ga and 5ga. bThe number in parentheses is the yield of 5. cThe ee for minor product 5 was not determined. dUsed 10 mol % catalyst and 0.3 mmol of 1t.

1b−1p derived from various aryl and heteroaryl aldehydes and cinnamaldehyde could furnish corresponding pyrrolidines 4ba−4pa with 72−99% yields and 81−95% ee (Table 5, entries 1−13). Furthermore, ethyl (1q), propyl (1r), and benzyl (1s) α-alkyl substituents were also compatible, but provided lower ratios of 4/5, indicating that the α-substituent has some effect on the regioselectivity but not enantioselectivity (Table 5, entries 14−16 vs Table 4, entry 1). To our delight, DL-phenylglycine derived α-phenyl iminoester 1t furnished desired pyrrolidine 4ta as the single product in 81% yield with 87% ee (Table 5, entry 17). Notably, methyl and isopropyl iminoesters 1u and 1v were also well-tolerated, furnishing desired cycloadducts 4ua and 4va in good yields and with high ee (Table 5, entries 18−19). Encouraged by the above successes, we next tried to expand the substrate scope of the enones by replacing the β-CF3 substituent with β-CHF2 and βCH2F groups. To our delight, β-CHF2-β,β-disubstituted enones 2t and 2u were amenable to this ligand controlled enantioselective regiodivergent cycloaddition reaction (Scheme 2A), delivering corresponding products 3 (3at, 3au, 3ft, 3fu) in 82−91% yields with ≥98% ee and products 4 (4at, 4au, 4ft, 4fu) in high yields (72−94%) with 87−92% ee. Moreover, β-CFH2-β,β-disubstituted enone (2v) was also well-tolerated under the mild reaction conditions, furnishing the desired products 3av and 4av (Scheme 2B). It should be noted that β-CCl3-β,βdisubstituted enone and β,β-dimethyl enone were not amenable

a

Unless otherwise noted, all reactions were carried out with 0.24 mmol of 1a, 0.2 mmol of 2, and 5 mol % catalyst ([Cu] to L2 = 1:1.1) in 2.0 mL of Et2O at −55 °C for 6−16 h. bThe ratio of rr was 4/5, determined by 1H and 19F NMR analysis of the crude products. cUsed 0.3 mmol of 1a.

general, the desired products were obtained with good yields, and high regio-, diastereo-, and enantioselectivity, regardless of the electronic properties or the position of the substituents on the aromatic R4 (Table 4, entries 1−12). We also found that the presence of electron-deficient substituents on the aryl moiety (R4) of 2 resulted in comparatively lower regioselectivity than those bearing electron-donating substituents on the aryl moiety. Additionally, 2-naphthyl- and 2-furyl-derived enone cycloadducts 4ao and 4ap were obtained with 93% ee (Table 4, entries 13 and 14). The methyl R5 group could be replaced with an ethyl group and also delivered good results (4ar, Table 4, entry 15). Surprisingly, with a styryl group as R5, the desired cycloadduct 4as could still be prepared in 62% isolated yield 2275

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society Scheme 3. Synthetic Transformations of 4aaa

Scheme 2. (3 + 2) Cycloaddition of α-Substituted Iminoesters with β-CF2H-β,β-Disubstituted Enones and βCFH2-β,β-Disubstituted Enone

a

Conditions: (a) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.0 equiv), toluene, 50 °C, 55 h. (b) meta-Chloropebenzoic acid (mCPBA, 2.5 equiv), dichloromethane (DCM), RT, 6 h. (c) m-CPBA (1.1 equiv), DCM, 0 °C, 3 h. (d) NaOH (15 equiv), VTHF/CH3OH = 1:1, RT, 2 h.

situ 19F NMR spectroscopy.12 Interestingly, the process appeared to be overall zero-order with respect to substrate (Scheme 4A) (reaction monitored until 51% conversion). When (S,Sp)-iPr-Phosferrox (L1) was used as the ligand (Scheme 4B), the reaction kinetics differed significantly as compared with the L2/Cu-catalyzed reaction (reaction monitored until 72% conversion).13 Initial rate experiments were next performed with 1a and 2a to gather information about the catalyst for the catalytic cycle of Cu/L2-catalyzed cycloaddition process (Scheme 5). A clear first-order dependence was observed for the catalyst. Nonlinear effect studies on the enantiomeric composition of chiral ligand L2 and product 4aa indicated a linear relationship (Scheme 6). These results are consistent with an active catalyst/ligand being of a monomeric nature and with the reaction possessing a firstorder dependence on catalyst. DFT Calculation for Ligand-Controlled Switchable Regioselectivity. With the above preliminary kinetic experimental results in hand, we next decided to investigate the factors controlling the regioselectivity. We carried out DFT calculations at the M06−2x/SDD-6-31G(d,p) level. For each transition state and intermediate, we searched all possible conformers by adjusting the flexible rotating bonds and minimizing them to the lowest conformers while fixing the rigid backbone of the molecule. DFT calculations using compounds 1u and 2a as the model substrates were performed. First, the electron distribution, in terms of natural population analysis (NPA) charges, was calculated respectively over the two carbon atoms C2 and C4 of complexes L1-Cu(I) and L2Cu(I) with deprotonated 1u (Figure 2).7 The calculations show that in the L1-Cu(I)-1u complexes, the C2 carbon is more negatively charged than C4 in the iminoester when the aryl group of the iminoester is oriented toward the upper-side of the oxazoline ring of L1, far away from the isopropyl group of the ring (L1-Ar-up). However, when the aryl group of the iminoester is oriented in the opposite direction (L1-Ardown), the negative charge of C4 is closer to that of C2. The situations are similar for that of L2-Cu(I)-1u complexes, but the corresponding, relatively more stable complexes are different for these two ligands. L1-Ar-up complex is more stable for L1, whereas the energies of L2-Ar-up complex and L2-Ar-down complex are similar. The difference in charge distribution of different coordination forms may therefore be

to the reaction conditions, indicating that the fluoro-substituent is crucial for reactivity. Gram-scale synthesis and synthetic applications. The absolute configuration of the products 3ua, 4ad, and 5qa have been unambiguously established by single crystal X-ray diffraction analysis (see Figure S1). In order to explore the synthetic transformations of the product, a gram-scale synthesis of 4aa was carried out without any loss in efficiency and selectivity (Scheme 3). Highly substituted 1-pyrroline 6 with >99% yield and 92% ee could be obtained by treatment of 4aa with DDQ. Remarkably, two oxidation products, 7 and 8, were prepared by reaction with different equivalents of the oxidant m-CPBA. Furthermore, 4aa was easily hydrolyzed in the presence of aqueous NaOH in VTHF/CH3OH = 1:1, giving corresponding proline derivative 9 in 90% yield and with 92% ee.



MECHANISTIC STUDY To uncover the factors controlling the regioselective cycloaddition, kinetic experiments and DFT calculations were conducted. Kinetic Studies. Since many mechanistic studies of Cucatalyzed (3 + 2) cycloaddition have been reported1,11 and the (3 + 2) reaction catalyzed by Cu/L1 gave the products with normal regioselectivity, kinetic studies mainly focused on the Cu/L2 catalytic system. Initial studies began with the investigation of the reaction profile of the cycloaddition of substrates 1a and 2a using the Cu/L2 catalytic system and in 2276

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society Scheme 4. Reaction Progress Monitored by in Situ 19F NMR

Scheme 5. Rate Dependence on Catalyst Loading (Cu/L2)

Scheme 6. Nonlinear Effect Study

one explanation for the ligand-controlled switchable regioselectivity. However, it can be concluded that C2 is more nucleophilic than C4 in all of these complexes, which means that the differences in charge distribution of the different coordination forms is not functional enough to switch regioselectivity to the significant degree that we found in our experiments. Therefore, we decided to gain further insight into the factors controlling regioselectivity. There are in total 16 possible pathways in which C1symmetric prochiral 2a can attack the L-Cu(I)-1u complexes for each ligand (each of the four complexes mentioned above can be attacked by 2a from either the phosphine side or the nitrogen side of the ligand in eight possible manners). Since the regioselectivity was the main focus of our calculations, only the methods of attack that generated 3−5 were selected (their corresponding enantiomers were not considered). Although complexes L1-Ar-up and L2-Ar-down are relatively more stable

than L1-Ar-down and L2-Ar-up, respectively, the energy difference is not great enough to exclude the possibility that major products are formed from the unstable isomers.14 The calculated results of the HOMO orbital energies for L1-Ar-up and L1-Ar-down as well as for L2-Ar-up and L2-Ar-down indicate that the reactivities of these four complexes toward the (3 + 2) addition are also similar (Figure 2; LUMO energy for 2a is −1.19 eV). Therefore, all of these four complexes were considered for further transition state calculations. DFT Calculation for L1/Cu-Catalyzed (3 + 2) Cycloaddition. For complex L1-Ar-up, the dipolarophile 2a can attack the ylide from the phosphine side via one of four pathways, to generate exo-products (3 and 10) and endo2277

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society

Figure 2. Relative energies expressed in terms of enthalpy and of free energy in parentheses, and computed natural population analysis (NPA) and HOMO energies of L-Cu(I)-1u complexes via M06−2x/SDD-6-31G(d,p) calculations (Energies in kcal/mol).

Figure 3. Relative attacking pathways for the generation of 3−5 and 10 with complexes L1-Ar-up.

Figure 4. Cycloaddition to generate 3 with complex L1-Ar-up and its competing pathways.

products (4 and 5), the structures of which are shown in Figure 3. The calculations for these four pathways during the reactions

of L1-Ar-up and 2a, indicate that this (3 + 2) cycloaddition proceeds through a two-step process.15 In the first step, carbon 2278

DOI: 10.1021/jacs.7b12137 J. Am. Chem. Soc. 2018, 140, 2272−2283

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Journal of the American Chemical Society

Figure 5. Structures of L1-Ar-up-TS1 for generating 3 and 4.

Figure 6. Cycloaddition to generate 4 with complex L2-Ar-up and its competing pathways.

C2 or C4 of the iminoester attacks the β-position of substrate 2a to generate an enolate-imine intermediate. In the second step, the enolate then attacks the imine intramolecularly to generate the catalyst-linked product. From these calculations, we found that the energy barriers for other pathways are higher than for the pathway that generates 3, as shown in Figure 4. If we suggested that the formation of L1-Ar-down and L1-Ar-up was in a state of rapid equilibrium, then the direction of the reaction would be determined by the energy barrier of the following transition state. For the pathways with L1-Ar-down (left of Figure 4), the energies of L1-Ar-down-TS1s for generating the products are higher than that of pathways with L1-Ar-up. The pathways for the reaction of L1-Ar-down and 2a are not favored due to the steric-hindrance resulting from the stereogenic substituent on the oxazoline ring as compared with the pathway generating 3 from L1-Ar-up. Thus, the generation of 3 with complex L1-Ar-up is the favored pathway, as shown in Figure 4. We found that strong π−π interactions between the two aryl rings of 1u and 2a are present in the first (P3-L1-Ar-up-TS1, Figure 5) and second TSs when 3 is generated, resulting in 3 being the favored product. Steric interactions between several groups of 1u and 2a and between two substrates and ligand in L1-Ar-up-TS1 and L1-Ar-up-TS2 leading to the generation of 4 and 5, respectively, make these two compounds the minor

products (Figure 5, only L1-Ar-up-TS1 for 4 was shown: P4L1-Ar-up-TS1). DFT Calculations for L2/Cu-Catalyzed (3 + 2) Cycloaddition. Similar to L1, the calculated results for the corresponding pathways that generate 3−5 during the reactions of L2-Ar-down and 2a have higher energy barrier transition states for the first step of the cyclization (Figure 6, left). This suggests that in addition to the electron distribution of the LCu(I)-1u complexes (Figure 2) there are other factors controlling the regioselectivity. Therefore, the four possible pathways for the reactions of L2-Ar-up and 2a were also calculated (Figure 6, right). To our surprise, although 2a attacks both complexes from the phosphine side of these two ligands, the mechanisms for the generation of endo-products (4 and 5) are different for different ligands (Scheme 7). With regards to the attack of 2a on L1-Ar-up, the carbonyl oxygen atom of 2a does not coordinate with Cu(I) in the transition states and intermediates (Scheme 7A). In other words, the coordination mode of Cu(I) is the same in both the transition states and intermediate to that of the L1-Ar-up complex. However, for the reaction of 2a with L2-Ar-up, the C4−Cβ bond is formed, with the formation of the O−Cu bond via the carbonyl oxygen atom of 2a and the dissociation of nitrogen of L2 from the Cu(I) center (Scheme 7B). This signifies that ligand L2 is a pseudobidentate ligand for this reaction. This suggests that chiral monophosphine ligands may also promote 2279

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Although the energy of P4-L2-Ar-up-TS2 is slightly higher than that of P4-L2-Ar-up-TS1 leading to 4, it is still much lower than those of P5-L2-Ar-up-TS1 and P3-L2-Ar-up-TS1 leading to 5 and 3 (Figure 6). Thus, the reaction with L2 undergoes the pathway generating L2-Ar-up-4, which finally leads to 4 as the major product after dissociation from the Cu(I)-catalyst. Since the rate-limiting step proceeds after the coordination of the two substrates with the catalyst, this mechanism for Cu/L2 catalysis is consistent with the conclusions gained from kinetic experiments (Schemes 4A and 5).

Scheme 7. Different Coordination Modes Leading to Different Products



CONCLUSIONS In summary, we have developed a unique ligand-controlled Cu(I)-catalyzed asymmetric intermolecular (3 + 2) cycloaddition of α-substituted iminoesters with β-fluoromethyl β,βdisubstituted enones. This methodology provides an efficient and economic access to a regiodivergent and enantioselective synthesis of valuable pyrrolidines bearing two adjacent or discrete quaternary stereocenters. Examples also include a fluoromethylated, all-carbon quaternary stereocenter. The regioselectivity could be switched by selection of an appropriate chiral ligand. This work also represents the first example of a transition metal catalyzed (3 + 2) cycloaddition of iminoesters with opposing regioselectivities. The salient features of this cycloaddition include outstanding functional group tolerance, high regio-, diastereo-, and enantioselectivity, promising scalability and allows for synthetic transformations to valuable compounds. In addition, preliminary mechanistic studies have also been conducted to gain some important information for DFT calculations. Computational results have provided insights into the origins of the regioselective control of the cycloaddition. When ligand L1 is used, the phosphorus and nitrogen atoms of the ligand remain coordinated to the Cu(I) throughout the whole catalytic process, and 3 is obtained as the main product due to a combination of the electron distribution across the complex, steric hindrance effects, and a π−π interaction between the two aryl rings of the iminoester and enone. Ligand L2 has been shown to be a pseudobidentate ligand for this (3 + 2) cycloaddition. The formation of a Cu− Oenone bond with the amine nitrogen of L2 dissociated from the Cu(I) center results in a switch in the regioselectivity. The unique direction of the P−Cu bond resulting in the formation of several O−H hydrogen bonds in the transition states leading to 4 stabilizes the corresponding structures.

the cycloaddition and generate endo products (4 and 5). Two experiments using these types of ligands, MOP and Feringer’s ligand, gave the product 4aa as the major product (Scheme 7C) without formation of 3aa, which support this proposal and the following DFT calculation results. In the transition states P4-L2-Ar-up-TS1, P4-L2-Ar-up-TS2, P5-L2-Ar-up-TS1, and P5-L2-Ar-up-TS2, and intermediates P4-L2-Ar-up-IM and P5-L2-Ar-up-IM (Figure 7), the carbonyl oxygen atom of 2a coordinates with Cu(I) to generate 4 or 5. Conversely, in the pathways that generate 3, the carbonyl oxygen atom of 2a is far from the Cu(I) center (Figure 7; P3L2-Ar-up-TS1, P3-L2-Ar-up-IM); therefore, the mechanism is the same as that involving L1 (Figure 6A). We propose that −NMe2 is a weaker coordinating group for Cu(I) than oxazoline;16 hence, this oxygen coordination and nitrogen dissociation process (Scheme 7B) occurs only in the L2-Cu catalyzed (3 + 2) cycloaddition. On the basis of the calculations, we found that the energy of the first transition state, P4-L2-Ar-up-TS1, and intermediate P4-L2-Ar-up-IM for generating 4 is much lower than the corresponding transition state intermediate that leads to 5 or 3 (Figure 6, right), which may be explained by the presence of several O−H hydrogen bonds and less steric hindrance in this transition state and intermediate (Figure 7; P4-L2-Ar-up-TS1, P4-L2-Ar-up-IM). Of note is the unique direction of the P−Cu bonds of P4-L2Ar-up-TS1 and P4-L2-Ar-up-IM toward the unsubstituted Cp ring, while in the corresponding intermediate that leads to 5 or 3 (Figure 7; P5-L2-Ar-up-TS1, P3-L2-Ar-up-TS1, P5-L2-Arup-IM, and P3-L2-Ar-up-IM), it points in the opposite direction. The unique direction of the P−Cu bonds of P4L2-Ar-up-TS1 and P4-L2-Ar-up-IM causes the carbonyl oxygen of the iminoester to be closer to the unsubstituted Cp ring to form hydrogen bonds and causes the benzene ring of the iminoester to be further away from the −NMe2 group to reduce steric hindrance. In addition, intermediate P4-L2-Ar-upIM bears a relatively standard tetrahedral Cu(I) coordination structure, while in P5-L2-Ar-up-IM and P3-L2-Ar-up-IM, the Cu(I) complexes are grossly distorted tetrahedral structures (Figure 7). These structures constitute a crowded Cu center and thus possess high energies.



COMPUTATIONAL METHODS

All DFT calculations were performed with the Gaussian 09 software package.17 Solution-phase relaxed PES scans and geometry optimizations of all the minima and transition states involved were carried out at the M06-2X18/6-31G(d,p) level in THF, using the integral equation formalism polarizable continuum model (IEF-PCM), employing UFF radii.19 The SDD basis set20 (Stuttgart/Dresden ECP) was used for copper and iron, and the 6-31G(d,p) basis set for the other atoms. We labeled this basis set as SDD-6-31G(d,p). The keyword “5D” was used to specify that five d-type orbitals were used for all elements in the calculations. Frequency calculations at the same level were performed to validate each structure as either a minimum or a transition state and to evaluate its zero-point energy and thermal corrections at 298 K. All discussed energies were Gibbs free energies unless otherwise specified. Enthalpies were also given for reference. 3D structures for transition states and intermediates were prepared with CYLview.21 HOMO orbital images and weak interaction analysis images were prepared with Multiwfn22 and VMD.23 2280

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Figure 7. Structures of L2-Ar-up-TS1 and L2-Ar-up-IM for generating 4, 5, and 3.



Notes

ASSOCIATED CONTENT

The authors declare no competing financial interest.

S Supporting Information *



The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b12137. Experimental procedure, optimization tables, and characterization data for all the products (PDF) Crystallographic structure of 3ua (CIF) Crystallographic structure of 4ad (CIF) Crystallographic structure of 5qa (CIF)



ACKNOWLEDGMENTS We gratefully acknowledge the funding support of NSFC (21425205, 21502052, and 21672067), 973 Program (2015CB856600), the Program of Eastern Scholar at Shanghai Institutions of Higher Learning, and the Innovative Research Team of Ministry of Education. The computation was performed at the Supercomputer Center of ECNU. We thank Prof. Zhi-Xiang Yu and Dr. Yi Wang of Peking University for helpful discussions.

AUTHOR INFORMATION



Corresponding Authors

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

REFERENCES

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ORCID

Junliang Zhang: 0000-0002-4636-2846 Author Contributions

S.X. and Z.-M.Z. contributed equally to this work. 2281

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published on January 24, 2018. The abstract graphic has been corrected and the paper was re-posted on January 30, 2018.

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