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Organocatalytic Enantioselective Friedel-Crafts Reaction: An Efficient Access to Chiral Isoindolo-βcarboline Derivatives

Cite this: DOI: 10.1039/x0xx00000x

Fang Fang,a Genghong Hua,a Feng Shib* and Pengfei Lia*

Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/

An organocatalytic asymmetric Friedel-Crafts reaction between indole and indole-derived hydroxylactams has been realized to furnish isoindolo-β-carbolines in good to excellent yields (up to > 99%) and generally high enantioselectivities (up to > 99% ee). The methodology offers an efficient access to functionalization of isoindolo-β-carbolines and preparation of chiral isoindolo-β-carboline derivatives. Terpene indole alkaloids with tetrahydro-β-carboline subunit found in many naturally occurring products and animals have received appreciable attention in recent years. The structural diversities of these terpene indole alkaloids account for a wide range of biological activities (Figue 1).1,2 Notably, isoindolo-β-carbolines containing two bioactive units of tetrahydro-β-carboline and isoindole also exhibit interesting pharmacological activities.3 Therefore, both preparation and functionalization of those isoindolo-β-carbolines, especially in an asymmetric manner, are very essential in the discovery of chiral drugs.4 Due to biomedical importance of indole alkaloids,5 we aim to develop an organocatalytic enantioselective Friedel-Crafts reaction between indole and isoindolo-β-carboline-

N H H H (+)-yohimbine 2b MeO C 2

H

N

N

N H

MeO

HO CO2Me (+)-vincamine 2c

MeO2C R = 3,4,5-(MeO)3-C6H2-CO2

N N H (b) a1-adrenergic

cloned dopamine receptors3a

receptors antagonists3b

N H

R

R2

R3

2

OH

OH O

R1

N R2 H

OH

N N H

R2

P O O O O H

R3

O

R1

N

O N H

O  P O O

O

CPA

N N H

R N H

O

R1

N

2

N H

OMe

R1 N H (a) inhibitor of human

N

Scheme 1. CPA-catalyzed functionalization of isoindolo-β-carbolines

H

(-)-reserpine 2d

R2

Fig. 1 Selected tetrahydro-β-carboline and isoindolo-β-carboline alkaloids

This journal is © The Royal Society of Chemistry 2012

R3

R2 R

N

N HO H

N HO H

H

O

R1

N CPA

OH H

N

O

R1

+

N H H (R)-harmicine 2a

Our previous work 13

This work R1

H

N

N

derived hydroxylactam for the construction of complex polycycles containing three bioactive units of tetrahydro-β-carboline, isoindole and indole.

+

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Catalytic asymmetric addition to imines is one of the most useful reactions for the synthesis of optically active amines in organic synthesis. In the presence of chiral phosphoric acid (CPA), Nacyliminium ion was generated in situ from hydroxylactam to form chiral ion-pair with CPA anion and the subsequent nucleophilic attack resulted in enantioenriched product.6,7 Applications of this strategy in enantioselective functionalization of hydroxylactam have been reported by several groups, such as Rueping,8 Wang and Zhou,9

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You,10 Lete,11 and Masson.12 Recently, we have successfully realized CPA-catalysed stereoselective formal alkenylation of isoindolo-βcarbolines (Scheme 1).13 Based on this work and as a continuation of our efforts in enantioselective functionalization of isoindolo-βcarbolines, we expect that isoindolo-β-carboline-derived hydroxylactam and indole would be activated by CPA via chiral ionpair catalysis and hydrogen-bonding interaction, respectively, thus facilitating the Friedel-Crafts reaction14 of indole with Nacyliminium ion to furnish the enantioenriched products (Scheme 1).

O

1a

O

N

N CPA

+

N HO H

N H

RT, 12 h

N 2a H R

O O

N H

Ar O O

P OH Ph

O

Ph

O

R Ia: R = SiPh3; Ib: R = Ph;

O

O P OH

OH Ar Ar = 3,5-(CF3)2-C6H3

Id: R = 2,4,6-(i-Pr)3-C6H2;

Table 2. Substrate scope of Friedel-Crafts reactiona

III

Ie: R = 9-anthyl

CPA Ia (10 mol%) Ib (10 mol%) Ic (10 mol%) Id (10 mol%) Ie (10 mol%) II (10 mol%) III (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (10 mol%) Ic (5 mol%) Ic (2 mol%) Ic (1 mol%) Ic (0.5 mol%) Ic (1 mol%) Ic (1 mol%) Ic (1 mol%) Ic (1 mol%) Ic (1 mol%)

O

P

Ic: R = 3,5-(CF3)2-C6H3;

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

3aa

II

Solvent toluene (1 mL) toluene (1 mL) toluene (1 mL) toluene (1 mL) toluene (1 mL) toluene (1 mL) toluene (1 mL) xylene (1 mL) PhF (1 mL) PhCl (1 mL) PhBr (1 mL) CH2Cl2(1 mL) THF (1 mL) Et2O (1 mL) MeOt-Bu (1 mL) PhOMe (1 mL) 1,4-dioxane (1 mL) 1,4-dioxane (1 mL) 1,4-dioxane (1 mL) 1,4-dioxane (1 mL) 1,4-dioxane (1 mL) 1,4-dioxane (2 mL) 1,4-dioxane (4 mL) 1,4-dioxane (8 mL) 1,4-dioxane (16 mL) 1,4-dioxane (24 mL)

Yield (%)b 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

ee (%)c -23 -3 39 36 -17 -24 37 43 48 47 50 26 28 41 44 42 63 65 68 68 56 75 76 78 77 76

a

Unless noted, the reaction was carried out as follows: a mixture of hydroxylactam 1a(0.1 mmol), indole2a(0.1 mmol) and catalyst I-III in 1,4dioxane (8 mL) was stirred at room temperature for 12 h. b Isolated yield of 3aa. c The ee of 3aa was determined by chiral stationary phase HPLC.

Reaction condition optimization studies began with the model reaction between isoindolo-β-carboline-derived hydroxylactam 1a and indole 2a, and the results are summarized in Table 1. Several BINOL-derived chiral phosphoric acids were firstly investigated. All

2 | J. Name., 2012, 00, 1-3

5

1 7 5

R2 6

1,4-dioxane R2 RT, time

2 7

R1 (1) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) 4-Cl (1b) 5-Me (1c) 5-MeO (1d) 5-F (1e) 5-Cl (1f) 6-Cl (1g)

N

Ic (1 mol%)

4 1N H

O

R1

N

1 2 N HO H 3

6

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

O

4 R1 3

+

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Table 1. Optimization of reaction conditionsa

reactions furnished desired product 3aa in excellent yields. Interestingly, either (S)-3aa (Table 1, entries 1, 2, 5 ) or (R)-3aa (Table 1, entries 3, 4) could be obtained as a major product in the presence of (S)-BINOL-derived phosphoric acids, which depended on the substituents linked to the (S)-BINOL skeletons. CPA Ic afforded better results and (R)-3aa was obtained in 99% yield with 39% ee (Table 1, entry 3). Besides, (R)-phosphoric acid II furnished (S)-3aa in 99% yield with 24% ee (Table 1, entry 6), while CPA (S)III afforded (R)-3aa in 99% yield with 37% ee (Table 1, entry 7). So, CPA Ic was selected as the most suitable catalyst. In order to enhance the enantioselectivity, reaction media was then surveyed in the presence of CPA Ic. The reaction in xylene furnished (R)-3aa with 43% ee (Table 1, entry 8). Using halogenated benzene as solvent resulted in moderate ee values (Table 1, entries 9-11). Both CH2Cl2 and THF generated inferior asymmetric induction (Table 1, entries 12-13). To our delight, 1,4-dioxane was found to be more suitable for this model reaction after careful screening of ethers (Table 1, entries 14-17). Moreover, decreasing the catalyst loading led to higher ee value without compromising the yield (Table 1, entries 18-20). It should be noted that 99% yield and 68% ee were obtained even with 1 mol% catalyst loading. However, with a catalyst loading of 0.5 mol%, 99% yield and 56% ee were obtained (Table 1, entry 21). Further enhancement of enantioselectivity was achieved by increasing the amount of solvent (Table 1, entries 2226). And the best results of 99% yield and 78% ee were obtained in the presence of 1 mol% CPA Ic in 8 mL of 1,4-dioxane (Table 1, entry 24).

N H

2

R2 (2) H (2a) 5-Me (2b) 5-MeO (2c) 5-BnO (2d) 5-F (2e) 5-Cl (2f) 5-Br (2g) 6-Me (2h) 6-BnO (2i) 6-F (2j) 6-Cl (2k) 6-Br (2l) 7-Me (2m) 7-Br (2n) 6-Br (2l) 6-Br (2l) 6-Br (2l) 6-Br (2l) 6-Br (2l) 6-Br (2l)

N H

Time (h) 12 3 3 3 3 24 24 24 24 24 24 24 3 24 24 24 24 24 24 24

Yield (%)b 3aa, 99 3ab, 99 3ac, 99 3ad, 99 3ae, 99 3af, 71 3ag, 60 3ah, 60 3ai, 89 3aj, 91 3ak, 80 3al, 83 3am, 99 3an, 32 3bl, 86 3cl, 58 3dl, 74 3el, 68 3fl, 64 3gl, 78

3

ee (%)c 78 79 70 75 80 70 81 81 88 80 92 99 76 70 >99 93 89 >99 >99 94

a

Unless noted, the reaction was carried out as follows: a mixture of hydroxylactams 1 (0.1 mmol), indoles 2 (0.1 mmol) and catalyst Ic (1 mol%) in 1,4-dioxane (8 mL) was stirred at room temperature for the time given. b Isolated yields of 3. c The ee of 3 was determined by chiral stationary phase HPLC.

With the optimal reaction conditions in hand, we investigated the substrate scope of CPA Ic-catalyzed enantioselective Friedel-Crafts

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reaction between isoindolo-β-carboline-derived hydroxylactam1a and a series of indoles 2 (Table 2). All the probed reactions furnished desired products in moderate to excellent yields with good to excellent asymmetric induction. Both electronic effect and steric effect of the substituents R2 linked to the indole moiety were studied. Substituted indoles 2b-2d containing an electron-rich group (Me, MeO, BnO) at 5-position of the indole ring reacted with hydroxylactam 1a quite smoothly to form 3ab-3ad in quantitative yield of 99% and good enantioselectivity ranging from 71% to 79% ee within 3 h (Table 2, entries 2-4). The Ic-catalyzed asymmetric Friedel-Crafts reaction between 5-fluoro-1H-indole 2e and 1a also proceeded smoothly to afford 3ae in 99% yield with 80% ee within 3 h (Table 2, entry 5). Comparatively, both 5-chloro-1H-indole 2f and 5-bromo-1H-indole 2g were found to react with 1a slowly. But 3af in 71% yield with 70% ee (Table 2, entry 6) and 3ag in 60% yield with 81% ee (Table 2, entry 7) were still obtained after a longer reaction time. C6-Substituted indoles containing either electrondonating (Table 2, entries 8-9) or electron-withdrawing groups (Table 2, entries 10-12) could be well tolerated, affording corresponding poly-cyclic products in 60-91% yield with 80-99% ee. Particularly noteworthy was that more than 99% ee and 83% yield were obtained from the reaction of hydroxylactam 1a and 6-bromo1H-indole 2l (Table 2, entry 12). The Friedel-Crafts reaction between hydroxylactam 1a and 7-methyl-1H-indole 2m proceeded smoothly to afford 3am in 99% yield with 76% ee within 3 h (Table 2, entry 13). Longer reaction time was required for the formation of 3an by the reaction of 1a and 7-bromo-1H-indole 2n (Table 2, entry 14). Considering the high enantioselectivity of the reaction involving 6-bromo-1H-indole 2l, CPA Ic-catalyzed enantioselective FriedelCrafts reaction between 6-bromo-1H-indole 2l and a series of isoindolo-β-carboline-derived hydroxylactams 1 were investigated. All the substituted hydroxylactams 1 with either an electron-rich group (Me, MeO) or an electron-poor group (F, Cl) at different positions of the indole ring reacted with 6-bromo-1H-indole 2l smoothly to afford corresponding products in moderate to good yields and high enantioselectivities of no less than 89% ee (Table 2, entries 15-20). Particularly, more than 99% ee was achieved when 2l was reacted with 4-chloro, 5-fluoro and 5-chloro-substituted substrates 1 (Table 2, entries 15, 18, 19). Then, in order to verify our suggested activation mode in Scheme 1, we investigated the CPA Ic-catalyzed enantioselective FriedelCrafts reaction between N-methyl-protected indole 2o and hydroxylactam 1a (Scheme 2). As expected, only 29% ee was obtained, which indicated that the N-methyl group blocked the formation of hydrogen bond between CPA Ic and indole 2o, thus leading to the observed low enantioselectivity. So, this result is in line with the reaction mechanism we mentioned above. O

1a

O

N

N Ic (1 mol%)

+

N HO H

N H

1,4-dioxane RT, time

N 2o

Me

3ao

N Yield: 84% Me ee: 29%

Scheme 2. Control experiment to verify the activation mode

The absolute configuration of product 3al was unambiguously determined by single-crystal X-ray crystallography, which enabled

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the absolute configuration of the product to be assigned as R (Figure 2).15 The stereochemistry of other products was assigned by analogy.

Fig. 2 X-ray crystal structure of product 3al

Conclusions In summary, we have developed an efficient organocatalytic enantioselective Friedel-Crafts reaction between isoindolo-βcarboline-derived hydroxylactam and indole for the construction of complex polycycles containing three bioactive units of tetrahydro-βcarboline, isoindole and indole. In the presence of CPA Ic with a loading of 1 mol%, desired products were obtained in moderate to excellent yields (up to 99%) and generally high enantioselectivities (up to > 99% ee). Particularly noteworthy is the high efficiency of this methodology as well as the broad substrate scope. Moreover, several enantiomerically pure complex polycycles can be obtained directly via this methodology. The organocatalytic transformation described herein provides an efficient access to functionalization of isoindolo-β-carbolines and preparation of chiral isoindolo-βcarboline derivatives.

Acknowledgements We gratefully thank the Startup Fund from South University of Science and Technology of China (SUSTC) and National Natural Science Foundation of China (NSFC 21302089) for financial support.

Notes and references a

Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, P. R. China.*E-mail: [email protected] b School of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, P. R. China. *E-mail: [email protected] † Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/c000000x/ 1

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Journal Name 14 For a tutorial review, see: a) S.-L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190; b) H.-H. Lu, F. Tan, W.-J. Xiao, Curr. Org. Chem. 2011, 15, 4022. 15 CCDC 1045078 [for 3al, C26H18BrN3O, Unit Cell Parameters: a 11.7456(2), b 13.5528(3), c 13.0646(9), space group P212121] contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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