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1 Highly Enantioselective Construction of Polycyclic Spirooxindoles by Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by Proli...

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Highly Enantioselective Construction of Polycyclic Spirooxindoles by Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by Proline-Sulfonamide

Xiao, J. A., Liu, Q., Ren, J. W., Liu, J., Carter, R. G., Chen, X. Q., & Yang, H. (2014). Highly Enantioselective Construction of Polycyclic Spirooxindoles by Organocatalytic 1, 3‐Dipolar Cycloaddition of 2‐Cyclohexenone Catalyzed by Proline‐Sulfonamide. European Journal of Organic Chemistry, 2014(26), 5700-5704. doi: 10.1002/ejoc.201402953

10.1002/ejoc.201402953 John Wiley & Sons, Inc. Accepted Manuscript http://cdss.library.oregonstate.edu/sa-termsofuse

SHORT COMMUNICATION Highly Enantioselective Construction of Polycyclic Spirooxindole via Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by Proline-Sulfonamide Jun-An Xiao,[a] + Qi Liu,[a] + Ji-Wei Ren,[a] Jian Liu,[a] Rich G. Carter,[b] Xiao-Qing Chen,[a] and Hua Yang*[a] Abstract: An enantioselective 1,3-dipolar cycloaddition of 2-cyclohexene-1-one and azomethine ylide generated in situ from isatin and amino ester was developed by employing proline sulfonamide as the catalyst. Consequently, novel polycyclic spirooxindole scaffolds with three contiguous stereocenters were prepared in high yield (up to 95%) with excellent diastereo- (> 20:1 dr) and enantio-selectivity (up to 99% ee).

The natural alkaloids and relevant compounds featured with the spiro[pyrrolidin-3,2′-oxindole] ring system have proven to possess interesting biological activities, including antiinflammatory, anti-diabetic, anti-tumoric, anti-tubercular, or acetylcholinesterase (AChE) inhibitory activities.[1] Driven by the thorough investigation of biological activites of these compounds, much attention has been directed to develop the structurally diversified and stereocontrolled methodologies to access these spirooxindoles in last decades.[2] In particular, the 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient alkenes has been found to be a versatile and atom-economic pathway to prepare the spiro[pyrrolidin-3,2′-oxindole] scaffold.[3] However, the catalytic asymmetric synthesis of spiro-[pyrrolidin-3,2′oxindole] has still been posing a challenging task to date, since most of the established approaches are either racemic synthesis or employing enantiopure starting materials.[4] In recent years, organocatalysis has emerged as a versatile tool for asymmetric synthesis.[5] In 2012, Gong and co-workers described the first organocatalytic asymmetric method to construct spiro[pyrrolidin-3,2′-oxindole] via 1,3-dipolar cycloadditions of N-Ac-2-oxoindolin-3-ylidenes and in situ formed azomethine ylides.[6] Subsequently, Xu[3a] and Tu[3b] also employed the organocatalytic 1,3-dipolar cycloaddition strategy to enantioselectively prepare spiro-[pyrrolidin-3,2′oxindole]s. It should be noticed that only the linear dipolarophiles have been used in the asymmetric synthesis of spiro[pyrrolidin3,2′-oxindole]core and pyrrolidine derivatives.[3, 7] A review of the literature reveals that the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with cyclic dipolarophiles, especially cyclic α-enones showing comparatively lower reactivity toward this type of reaction, were rarely explored.[8] [a]

[b]

[+]

J. Xiao,[+] Q. Liu,[+] J. Ren, J. Liu, Prof. Dr. X. Chen, Prof. Dr. H. Yang College of Chemistry and Chemical Engineering Central South University Changsha 410083 (P. R. China) E-mail: [email protected] Prof. Dr. R. G. Carter Department of Chemistry Oregon State University Corvallis, Oregon 97331 (USA) E-mail: [email protected] These authors contributed equally to this work. Supporting information for this article is available on the WWW under http://dx.DOI: 10.1002/ejoc.201402953

Thus, it would be highly desirable to explore the 1,3-dipolar cycloadditions using cyclic enone, providing a facile access to novel polycyclic spirooxindole ring systems (as shown in Scheme 1) . On the other hand, the enones and enals activated by lowering the LUMO through the formation of iminium intermediates with chiral amine organocatalysts proved to be highly reactive toward the azomethine ylides in high stereoselectivity.[9] Usually, this protocol is limited to enal and linear enone dipolarophiles, which can easily form iminium species with amine. In 2007, Chen and coworkers reported their elegant work on the organocatalytic enantioselective 1,3-dipolar cycloaddition of cyclohexenone with azomethine imines catalyzed by 9-amino-9-deoxyepicinchona alkaloids.[10] Unfortunately, this research field on the organocatalytic 1,3dipolar cycloaddition using cyclic enone remained dormant since then.

Scheme 1. Construction of spiro[pyrrolidin-3,2′-oxindole] via organocatalytic 1,3-dipolar cycloaddition

In our previous work, proline p-dodecylphenylsulfonamide (Hua Cat®) was successfully employed to catalyze the [4+2] cycloaddition of cyclohexenone via the HOMO activation.[11] Our continued interest prompted us to investigate this catalytic system in 1,3-dipolar cycloadditions of cyclohexenone with azomethine ylide facilitated by the LUMO activation of cyclohexenone. Herein, we report an organocatalyzed asymmetric 1,3-dipolar cycloaddition using cyclic enone and azomethine ylides to construct novel polycyclic spiro[pyrrolidin3,2′-oxindole] scaffolds.

SHORT COMMUNICATION Table 1. Optimization of the 1,3-dipolar cycloaddition reaction[a]

entry

solvent

catalyst

additive (mol%)

time (h)

yield [b] (%)

ee (%) [c]

1[d]

DCM

5a

Et3N (10%)

36

67

94

2[d]

DCM

5b

Et3N (10%)

48

54

85

[d]

3

DCM

5c

Et3N (10%)

60

44

70

4[d]

DCM

5d

Et3N (10%)

36

68

96

[d]

5

DCM

6

Et3N (10%)

60

30

4

6[d]

DCM

6

-

48

86

17

[d]

7

DCM

7

Et3N (10%)

48

trace

n.d.

8[d]

DCM

8

Et3N (10%)

48

-

n.d.

[d]

DCM

5d

HAc (10%)

48

49

rac

10[d]

DCM

5d

DABCO (10%)

60

38

82

[d]

11

DCM

5d

-

60

51

12

12[d]

DCM

5d

Et3N (20%)

72

21

83

[e]

13

DCM

5d

Et3N (10%)

48

35

87

14[f]

DCM

5d

Et3N (10%)

48

50

86

[g]

15

DCM

5d

Et3N (10%)

48

49

90

16[h]

DCM

5d

Et3N (10%)

48

58

89

[i]

17

DCM

5d

Et3N (10%)

36

90

96

18[i]

DCM

5d

Et3N (5%)

48

57

89

9

[a]

Unless otherwise noted, the reaction was carried out in 0.2 mmol scale in DCM (4 mL) at RT with the molar ratio of 1a/2/3a = 1:1.2:1.5 and 20 mol% catalyst. [b]Isolated yield. [c]Determined by chiral HPLC. [d]1a/2/3a = 1:1.5:1.5. [e] 1a/2/3a = 1:1:1. [f]1a/2/3a = 1:1.5:1.2. [g]1a/2/3a = 1:1.2:2. [h]1a/2/3a = 1:1.5:1. [i] 1a/2/3a = 1:1.2:1.5. [j]TFT = α,α,α-trifluorotoluene. Other solvents were also evaluated in this reaction. (MeOH, 36 h, 70% yield, -28% ee; toluene, 36 h, 90% yield, 87% ee; DCE, 48 h, 86% yield, 94% ee; CHCl3, 60 h, 82% yield, 93% ee; α,α,α-trifluorotoluene, 12 h, 91% yield, 94% ee)

Initially, in the presence of triethylamine (10 mol%), proline pmethylphenylsulfonamide 5a was found to smoothly catalyze the three-component 1,3-cycloaddition using isatin 1a, 2cyclohexenone 2, and diethyl aminomalonate 3a in a ratio of 1a/2/3a = 1:1.5:1.5. To our delight, excellent diastereo- (>20:1)

and enantioselectivity (94% ee), albeit with moderate chemical yield (67%), were obtained (Table 1, entry 1). Encouraged by this result, various proline sulphonamide catalysts were screened and 5d gave the optimium yield and enantioselectivity (Table 1, entries 2-4). Interestingly, a bifunctional catalyst 6 bearing both secondary amine and tertiary amine motifs was therefore designed and synthesized via the direct coupling between N-Boc proline and 1-benzylpiperazine followed by deprotection of Boc protecting group. Presumably, it can activate 2-cyclohexenone and azomethine ylide simultaneously. Indeed, this catalyst afforded relatively higher yield without adding any additive. Unsatisfyingly, poor ee values were observed with or without additive (Table 1, entries 5-6). Noticeably, when using pyrrolidine as the catalyst, only the hemiaminal was formed. No desired product was observed using 2,2,6,6tetramethylpiperidine as the catalyst (Table 1, entries 7-8). In addition, different additives were also being screened for this reaction. It was found that the additive had a significant effect on this reaction. The addition of acetic acid afforded the racemic product in decreased chemical yield. DABCO was less efficient than triethylamine toward this reaction (Table 1, entries 9-10). Furthermore, this reaction was carried out without any additive and only moderate yield and poor ee (12%) were observed (Table 1, entry 11). Intriguingly, an increase in the amount of triethylamine (20 mol%) led to extremely sluggish reaction in decreased chemical yield and enantioselectivity (entry 12). Subsequently, the effect of molar ratio of reactants was studied for this reaction. It was found that the reaction with molar ratio of 1a/2/3a at 1:1.2:1.5 gave the best chemical yield and enantioselectivity (Table 1, entry 17). Next, the efficiency of different solvents was also tested. Dichloromethane was found to be the best for this transformation, although α,α,αtrifluorotoluene also can significantly facilitate the reaction and provide both excellent chemical yield and enantioselectivity (see table footnote). Having established the optimal conditions, the scope of this 1,3-dipolar cycloaddition was investigated (as shown in Chart 1). For 5- or 6-substituted isatins, the reaction proceeded well and moderate to good yields and excellent enantioselectivity were usually achieved to afford the corresponding cycloadduct 4a-4g. However, the empolyment of 7-chloro isatin (4h) significantly decreased the enantioselectivity (83% ee) and diastereoselectivity (7.7:1). Presumably, this could be explained as that the presence of chlorine at C7 of isatin introduced the steric hindrance for the N-H isatin moiety, interfering with the hydrogen bond formation of N-H with catalyst. Moreover, using different aminomalonic acid diester such as dimethyl aminomalonate and di-iso-propyl aminomalonate also showed good reactivity toward this 1,3-dipolar cycloaddition (4i-4o). Surprisingly, the employment of cyclopentenone and cycloheptenone in this reaction did not afford the corresponding cycloadduct. Finally, the absolute configuration of 4j was unequivocally established by X-ray crystallographic analysis of a single crystal.[12] We next turned our attention to examine the reactivities of Nprotected isatins in this reaction. However, to our surprise, the enantioselectivity were severely eroded when using N-methyl or benzyl isatin (Scheme 2), albeit with the maintained chemical yield. These results suggested that the N-H isatin moiety has a

SHORT COMMUNICATION sizable influence on the stereoselectivity and might be involved with the stereocontrol in this reaction. However, the exact catalytic mechanism still needs further investigation.

Chart 1. Scope of the 1,3-dipolar cycloaddition. [a]

Scheme 2. 1,3-Dipolar cycloaddition of N-protected isatins.

To further expand the synthetic utility of this cycloaddition reaction, the reduction and decarboxylation reaction of the corresponding spirooxindoles were carried out (Scheme 3). A simple protocol of sodium borohydride in methanol can successfully afford the corresponding alcohol 11 as a single isomer in 86% yield and 96% ee. On the other hand, the decarboxylated product was obtained via a two-step process, including the mono-hydrolysis of diester followed by decarboxylation. As a result, a mixture of exo:endo isomers (70:30) was obtained. No apparent erosion of enantioselectivity occurred and 91% and 95% ee were observed respectively. Presumably, the exo-isomer would be thermodynamically favourable. More interestingly, ibophyllidine-like compounds 14a-14c were synthesized in moderate yields and high enantiopurity via Fischer indole synthesis.[13] These resulting polycyclic structures simultaneously bear both indole and isatin motifs, which therefore might possess interesting biological activities.

Scheme 3. Transformation of the spirooxindole compounds. [a]

Unless otherwise noted, the reaction was carried out in 0.2 mmol scale in DCM (4 mL) at RT with a molar ratio of 1/2/3 at 1:1.2:1.5. [bDetermined by 1H NMR. [c]Isolated yield. [d]Determined by chiral HPLC.

In summary, an enantioselective 1,3-dipolar cycloaddition of cyclohexenone with azomethine ylide generated in situ from

SHORT COMMUNICATION isatin and aminomalonate diester, catalyzed by readily available proline p-dodecylphenylsulfonamide, was developed with high yield and excellent stereoselectivities (up to 99% ee, > 20:1 dr). This catalytic system could effectively activate the cyclohexenone and enable the formation of hydrogen-bonding between catalyst and dipole. It would significantly broaden the synthetic application of cyclic enone in the enantioselective 1,3cycloaddition reaction and afford a facile access to novel polycyclic spirooxindole ring systems, which could provide new opportunities for medicinal chemistry and drug discovery.

Experimental Section Typical experimental procedure for the asymmetric synthesis of polycyclic spirooxindole 4a: Isatin 1a (0.20 mmol), aminomalonate diester 3a (0.30 mmol, 1.5 equiv.), 2-cyclohexane-1-one 2 (23.0 mg, 0.24 mmol, 1.2 equiv.) and catalyst (20 mol%) were added to the designed solvent (2 mL) followed by adding triethylamine (2.00 mg, 10 mol%). After completion of the reaction (monitored by TLC), organic solvent was removed in vacuo. Then the residue was purified via flash chromatography to yield spirooxindole 4a as a white solid (72.0 mg, yield 90%, > 20:1 dr, 96% ee); m.p. 230-231°C; [α]D20 = +17.6 (c=0.3 in CHCl3); 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 4.08-4.28 (m, 4H), 3.92 (s, 1H), 3.30-3.34 (m, 2H), 1.19-2.11 (m, 2H), 1.64-1.81 (m, 4H), 1.18-1.23 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 207.9, 181.5, 170.1, 169.1, 143.0, 129.9, 129.7, 126.3, 121.6, 110.1, 76.7, 70.4, 62.0, 61.5, 59.5, 45.1, 40.1, 22.9, 22.5, 14.5, 14.3; IR (KBr) ν 3302, 2936, 1725, 1619, 1245, 1187, 1028, 851, 759 cm-1; HRMS (TOFES+) m/z: [M+Na]+ calcd for C21H24N2O6Na 423.1532, found 423.1519; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), tR = 14.3 min (minor), 19.9 min (major). Typical experimental procedure of indolospirooxindole 14a: To a solution of polycyclic spirooxindole 4a (0.2 mmol) in acetic acid (2 mL) was added phenylhydrazine 13 (43.3 mg, 0.4 mmol, 2 equiv.). The mixture was then refluxed for 2 hours, and cooled at rt. The acetic acid was removed under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with sat. aq. NaHCO3 (30 mL x 2). The aqueous phase was back extracted with EtOAc (5 mL x 2). The combined organic phase was dried, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography to give indolospirooxindole 14a as a white solid (59.6 mg, yield 63%, > 20:1 dr, 99% ee); m.p.>300°C; [α]D20 = +155.7 (c=0.5 in CHCl3); 1H NMR (DMSO-d6, 400 MHz) δ 10.17 (s, 1H), 10.13 (s, 1H), 7.29-7.31 (m, 1H), 6.93-6.97 (m, 2H), 6.85-6.91 (m, 2H), 6.69-6.84 (m, 2H), 6.52 (t, J = 7.2 Hz, 1H), 4.15-4.31 (m, 4H), 3.99 (d, J = 6.4 Hz, 1H), 3.81 (s, 1H), 2.63-2.94 (m, 2H), 1.84-2.00 (m, 2H), 1.22-1.26 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 181.53, 170.3, 169.3, 142.9, 136.9, 131.3, 130.6, 128.7, 126.4, 125.6, 125.6, 121.4, 120.8, 118.0, 111.2, 109.6, 109.5, 75.8, 69.9, 61.8, 61.4, 44.5, 43.8, 22.3, 19.6, 14.5, 14.3; IR (KBr) ν 3387 (br), 2979, 1732, 1620, 1469, 1248, 1108, 860, 746 cm-1; HRMS (TOF-ES+) m/z: [M+Na]+ calcd for C27H27N3O5Na 496.1848, found 496.1839; HPLC analysis: (CHIRALCEL OD-H, 25% i-propanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 26.4 min (minor), 29.1 min (major). Supporting Information (see footnote on the first page of this article): Experimental procedures, NMR spectral and analytical data for the 4a4o, 6, 10a, 10b, 11, 12, 14a-14c; HPLC chromatograms for the 4a-4o, 10a, 10b, 11, 12, 14a-14c .

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SHORT COMMUNICATION What proline sulphonamide organocatalyst can do? The highly enantioselective construction of polycyclic spirooxindole via 1,3-dipolar cycloaddition of cyclohexenone with azomethine ylide was achieved by employing prolinosulphonamides as the catalyst. This catalytic system essentially benefited from the iminium activation and hydrogen-bonding formation induced by the prolinosulphonamides.

Jun-An Xiao, [a] + Qi Liu, [a] + Ji-Wei Ren, [a] Jian Liu, [a] Rich G. Carter, [b] Xiao-Qing Chen [a] and Hua Yang, [a] * Page No. – Page No. Highly Enantioselective Construction of Polycyclic Spirooxindole via Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by Proline-Sulfonamide

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