DOI: 10.1002/chem.201500749
Communication
& Asymmetric Synthesis
Formal Asymmetric Organocatalytic [3 + 2] Cyclization between Enecarbamates and 3-Indolylmethanols: Rapid Access to 3-Aminocyclopenta[b]indoles Clment Lebe, Antti O. Kataja, Florent Blanchard, and Graldine Masson*[a] [3+2] cycloaddition reaction of 3-indolylarylmethanols and 3vinylindole, which could concisely furnish cyclopenta[b]indole in one synthetic operation, albeit with moderate selectivity (enantiomeric excess (ee) < 10 %).[4c] Subsequent to this, Shi et al. developed an efficient asymmetric [3+2] cyclization of 3hydroxy-3-indolyl-oxindoles with 3-methyl-2-vinylindoles[4d] or 3-methyl-7-vinylindoles[4e] in the presence of chiral phosphoric acid, leading to spirocyclic compounds with good enantioselectivity. Despite these elegant achievements, there is no convenient enantioselective [3+2] cycloaddition for the preparation of cyclopenta[b]indoles. In continuation of our research program in catalytic asymmetric cycloaddition with enamides,[5] we envisaged that the combination of a chiral phosphoric acid catalyst[6] and a 3-indolylarylmethanol would result in the formation of an alkylideneindoleninium ion,[3, 7, 8] which would then undergo enantioselective [3+2] cycloaddition with the polarized enamide double bond (Scheme 1).[9] Herein, we report a highly diastereo- and enantioselective one-pot [3+2] cycloaddition route to the synthesis of 3-aminocyclopenta[b]indoles with a broad scope (Scheme 1). We initiated our investigations by using (E)-N-(benzyl prop1-en-1-yl)carbamate (1 a), indolyl(phenyl)methanol (2 a), and 5 mol % of unsubstituted (S)-BINOL-derived phosphoric acid catalyst 4 a in CH2Cl2 at room temperature in the presence of 4 molecular sieves at room temperature (Table 1). To our delight, in less than an hour, the desired cyclopenta[b]indole 3 a was obtained in 70 % yield with excellent diastereoselectivity in favor of trans, trans[10] (diastereomeric ratio (d.r.) > 95:5). Encouraged by the rapid proof of concept, we screened the reaction with various chiral phosphoric acids (5 mol %). A clear effect of sterically bulky 3,3’-substituents was observed. For example, (S)-3,3’-bis(2,4,6-triisopropylphenyl)-BINOL (4 f) gave a very poor yield and stereoselectivity (Table 1, entry 6), whereas the simple phenyl-substituted 4 b gave the product in 57 % yield and with an ee of 67 % (Table 1, entry 1). In general, catalysts bearing polycyclic aromatic substituents (Table 1, entries 4 and 5) or 4-substituted aromatic substituents (entry 3) achieved consistently very good results. We found that the (S)3,3’-bis-9-phenanthryl–BINOL phosphoric acid (4 g, Table 1, entry 7) was the best catalyst in terms of diastereo- and enantioselectivity. A survey of reaction solvents (Table 1, entries 7– 10) revealed that the reaction proceeded with slightly higher enantioselectivity in CH2Cl2 (entry 7). Lowering the temperature did not significantly improve the ee or yield (Table 1, entries 11 and 12). It is worth mentioning that the cycloadduct 3 a can be enriched to > 99 % ee by a single recrystallization. Various
Abstract: A highly enantio- and diastereoselective synthesis of 3-aminocyclopenta[b]indoles has been developed through formal [3+2] cycloaddition reaction of enecarbamates and 3-indolylmethanols. This transformation is catalyzed by a chiral phosphoric acid that achieves simultaneous activation of both partners of the cycloaddition. Mechanistic data are also presented that suggest that the reaction occurs through a stepwise pathway.
Chiral cyclopenta[b]indole is a common structural motif in a variety of natural products carrying widely different biological activities[1] such as anti-implantation agents (Yuehchukene[1b]), cytotoxic, antifungal, and antimicrobial agents (Fischerindole L[1c]), tremorgenic alkaloids (Paxilline[1d] and Penitrem A[1e]), and apoptotic agents (Shearinine A[1f]). In this context, numerous elegant approaches have been developed to access to this class of synthetically complex heterocycles.[2] Among them, the direct inverse electron demand [3+2] cycloaddition of electron rich olefin with alkylideneindolenine intermediates[3] generated from indolylarylmethanols under acid conditions have been recognized as one of the most efficient and convergent methods (Scheme 1). However, to date, there are only limited successful enantioselective strategies that could realize this direct [3+2] dipolar cycloaddition route.[4a–c] In 2014, Guo and coworkers established a chiral phosphoric acid-catalyzed formal
Scheme 1. Catalytic enantioselective [3+2] cycloaddition synthesis of trisubstituted 3-aminocyclopenta[b]indoles
[a] C. Lebe,+ Dr. A. O. Kataja,+ F. Blanchard, Dr. G. Masson Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-Sud 91198 Gif-sur-Yvette Cedex (France) Fax: (+ 33) 1-69077247 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.org/10.1002/chem.201500749. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Optimization of catalytic enantioselective [3+2] cyclization.
Entry
Cat.
T [8C]
Solvent
Yield [%][a,b]
d.r.[c]
ee [%][d]
1 2 3 4 5 6 7 8 9 10 11 12 13[g] 14[h] 15[i]
4a 4b 4c 4d 4e 4f 4g 4g 4g 4g 4g 4g 4g 4g 4h
0 0 0 0 0 0 0 0 0 0
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 1,2-DCE Toluene CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
70 57 63 62 78 30 71 51 47 69 18 60 55 65 50
95:5 > 95:5 88:12 91:9 94:6 > 95:5 > 95:5 94:6 90:10 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 93:7
33 67 87 84 87 33 97 (> 99)[e,f] 90 85 96 97 94 91 96 81
to RT to RT to RT to RT to RT to RT to RT to RT to RT to RT 30 15 0 to RT 0 to RT 0 to RT
[a] General conditions: 1 a (0.11 mmol), 2 a (0.10 mmol) and Cat (5 mol %) in solvent (0.05 m) at T [8C] for 2 h with 4 MS. 1,2-DCE = 1,2-Dichloroethene. [b] Yield of the isolated pure product after column chromatography. [c] Determined by 1H NMR spectroscopy. [d] Determined by HPLC analysis on a chiral stationary phase. [e] The values in brackets show enantiomeric excess after recrystallization. [f] Absolute configuration (1S, 2R, 3S) was determined by X-ray crystal-structure analysis of a derivative of 3 a (see the Supporting Information).[10] [g] 3 MS was used. [h] 5 MS was used. [i] (Z)1 a was used instead of (E)-1 a.
activated desiccants were screened, but not much improvement was noticed (Table 1, entries 13 and 14). After establishing the optimal reaction conditions (Table 1, entry 7), the scope of the reaction was examined (Table 2). (E)N-Cbz-enecarbamates 1 bearing different linear alkyl substituents were found to function very well in the reaction, and the corresponding trisubstituted-cyclopenta[b]indoles were obtained in similar yields and stereoselectivities in comparison to the model reaction (3 b, 3 e, and 3 f). Larger and bulkier alkyl groups behaved likewise very well (3 c and 3 d), and additional functional handles (such as silyl ether, 3 f, Table 2, entry 5) could also be installed through the enecarbamate partner. Ntert-butoxycarbonyl (Boc) carbamate 1 g rendered the final product with slightly lower yield and enantioselectivity (Table 2, entry 6). In addition, a wide range of 3-substituted indoles bearing various substituted aryl groups were tolerated in this [3+2] cycloaddition (Table 2, entries 7–14). For instance, the indole bearing 4-trifluoromethylphenyl (Table 2, entry 10) or the electron-rich 4-methoxyphenyl (entry 11) group provided the corresponding 3-aminocyclopenta[b]indoles 3 k and 3 l, respectively, in high yields and with excellent enantioselectivities. Fluorine-substituted aryl groups gave an increasing trend &
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in the yield with respect to the substituent position (3 h–j, Table 2, entries 7–9), revealing a potential steric effect. 3-Indolyl(2’-naphthyl)methanol (Table 2, entry 12) was also suitable, providing the cycloadduct 3 m with 95 % ee. On the other hand, the introduction of a heteroaromatic group such as thiophene (Table 2, entry 13) led to a reduction in the yield, although a high level of enantioselectivity was retained. Remarkably, this condition was also applicable to indole derivatives bearing aliphatic group at the 1’-position (which have scarcely been used). Indeed, the 3-indolyl(isopropyl)methanol (Table 2, entry 14) provided the corresponding cycloadduct 3 o efficiently with excellent enantioselectivities. The indole bearing a linear alkyl chain (Table 2, entry 15) gave 3 p with only 4:1 diastereoselectivity and 67 % ee. However, we were pleased to find that when the reaction was carried out at 30 8C, the expected cycloadduct 3 p was isolated with a better ee (Table 2, entry 15). Although the enantioselectivity was maintained with C6 and C7-substituted indoles, the yield was slightly lower (Table 2, entries 16–18). To gain further insight into the mechanism of the cycloaddition, we attempted the treatment of 1 a with a Z-dipolarophile. As shown in Table 1, compound (Z)-1 a leads to the same major diastereomer (all trans, 14:1 d.r.) as that derived from (E)-1 a (Table 2, entry 15) albeit with lower enantioselectivity and yield. Additionally, in some cases, a small amount of aldehyde coming from uncyclized imine intermediate 7 was isolated (Scheme 2).[11] In addition, when the cycloaddition of 1 a with (E)-2 a was performed in presence of ethanol, the trapped iminium intermediate was isolated in 73 % yield as a mixture of diaste-
Scheme 2. Plausible reaction mechanism.
reomers (see the Supporting Information). These experiments are consistent with a stepwise mechanism comprising the following steps (Scheme 2): 1) Dehydration of 1 to generate vinyliminium ion 5; 2) Vinylogous Mannich reaction of 2 to 5, and 3) C2 alkylation of indole derivative to the resulting iminium ion 6. Further understanding of the mechanism is required to 2
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Communication enecarbamate would be activated simultaneously by the Lewis base and cation of 4, favoring addition from the Si face to 7. Finally, the utility of this methodology is illustrated by the synthesis of cyclopenta[b]indoline core found in various biologically active natural products (Scheme 3).[16] The recrystal-
Table 2. Scope of the organocatalytic enantioselective [3+2] cyclization.[a]
R1/R2 [1]
Entry 1 2 3
Et/Bn iPr/Bn cPr/Bn
4 5
R3/R4/R5 [2]
3
Ph/H/H Ph/H/H Ph/H/H
3 b 79 3 c 70 3 d 64
94 (> 95:5) 92 (> 95:5) 96 (90:10)
/Bn Ph/H/H
3 e 72
93 (> 95:5)
/Bn Ph/H/H
3f
82
97 (> 95:5)
3g 3h 3i 3j 3k 3l
61 88 74 65 69 70
89 89 92 97 93 93
6 7 8 9 10 11
Me/tBu Me/Bn Me/Bn Me/Bn Me/Bn Me/Bn
12
Me/Bn
13 14 15
Me/Bn Me/Bn Me/Bn
Ph/H/H p-FC6H4/H/H m-FC6H4/H/H o-FC6H4/H/H p-CF3C6H4/H/H m-MeOC6H4/ H/H 2-naphthyl/H/ H 2-thienyl/H/H iPr/H/H nBu/H/H
16 17 18 19
Me/Bn Me/Bn Me/Bn Me/Bn
Ph/5-MeO/H Ph/5-Br/H Ph/6-Br/H Ph/H/Bn
Yield ee [%][c] [%][b] (d.r.)[d]
3 m 78
Scheme 3. Application to the enantioselective synthesis of enantiopure 3aminocyclopenta[b]indoline 8. pTSA = p-Toluenesulfonic acid.
(94:6) (> 95:5) (> 95:5) (95:5) (> 95:5) (> 95:5)
lized cycloadduct 3 a was subjected to reductive conditions with NaBH3CN leading to the formation of enantiopure 3amino cyclopenta[b]indoline 8 in 83 % yield, with a complete control of configuration at all five stereocenters. The high diastereoselectivity can be explained by assuming that the reduction proceeded from the less hindered side of 3. In conclusion, we have discovered a rapid and highly stereoselective synthesis of 3-aminocyclopenta[b]indoles carrying three contiguous stereocenters from enecarbamate 1 and 3-indolylmethanol 2 by using chiral phosphoric acid catalysis. To the best of our knowledge, this is the first reported asymmetric synthesis of the 3-aminocyclopenta[b]indole scaffold. Considering the wide variability and easy synthesis of both reaction partners, this methodology offers convenient access to compounds hitherto unexamined for their biologic and pharmaceutical potential. Further mechanistic studies and expansion of the methodology is currently underway and will be reported in due course.
95 (> 95:5)
3 n 66[e] 91 (92:8) 3 o 70[e] 87 (> 95:5) 3 p 68[e] 67(84)[f] (80:20) 3 q 85[e] 91 (> 95:5) 3 r 68[e] 93 (> 95:5) 3 s 69[e] 88 (> 95:5) 3 t 44 0 (90:10)
[a] General conditions: 1 (0.11 mmol), 2 (0.10 mmol), and 5 f (5 mol %) in CH2Cl2 (0.05 m) at 0 8C to RT for 2 h with 4 MS. TBDPS = tert-Butyldiphenylsilyl ether; Bn = benzyl. [b] Yield of isolated pure product after column chromatography. [c] Determined by HPLC analysis on a chiral stationary phase. [d] Determined by 1H NMR spectroscopy. [e] Compound 2 (0.2 mmol) was used. [f] Reaction performed at 30 8C.
Acknowledgements
explain the high level of stereoselectivity. Based on our observation in the previous enantioselective reaction with both 1 and indolic substrates,[5, 12] we postulated that the vinyliminium ion 5 as well as the enecarbamate could be well-organized together with the bifunctional phosphoric acid catalyst. Hence, two activation modes of catalyst 4 with 1 can be proposed, such as hydrogen bonding or ion-pairing.[13] To distinguish them, the N-protected indole derivative, in which hydrogen bonding with 4 is not possible, was used in this cycloaddition. As shown in Table 2 (entry 19), the resulting product (3 t) was obtained in low yield and as a racemic mixture. Although the ion-pair activation cannot be completely ruled out,[14] this experiment seems more consistent with a hydrogen-bonding activation mode. As two hydrogen bonds between 4 and transition state can be formed, two catalysts can be involved in this stereoselective formal cycloaddition. However, the rather small positive nonlinear effect observed (see the Supporting Information), ruled out this hypothesis.[15] On the basis of these studies, we suggest the following transition state model to explain the observed stereoselectivity: The vinyliminium ion and Chem. Eur. J. 2015, 21, 1 – 5
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We thank ICSN and CNRS for financial supports and doctoral fellowships to C.L. A.K. gratefully acknowledges ICSN and CNRS for a postdoctoral fellowship. Both authors, A.K. and C.L., contributed equally to this work: A.K. designed the project and carried out the optimization, and C.L. designed and carried out the scope and mechanistic studies. Keywords: asymmetric synthesis · chirality · cycloaddition · enamide · iminium · indoles [1] a) P. S. Steyn, R. Vleggar, Fortschr. Chem. Org. Naturst. 1985, 48, 1 – 80; b) Y. C. Kong, K. F. Cheng, R. C. Cambie, P. G. Waterman, J. Chem. Soc. Chem. Commun. 1985, 47 – 48; c) A. Park, R. E. Moore, G. M. L. Patterson, Tetrahedron Lett. 1992, 33, 3257 – 3260; d) J. P. Springer, J. Clardy, J. M. Wells, R. J. Cole, J. W. Kirksey, Tetrahedron Lett. 1975, 16, 2531 – 2534; e) B. J. Wilson, T. Hoekman, W. D. Dettbarn, Brain Res. 1972, 40, 540 – 544; f) G. N. Belofsky, J. B. Gloer, D. T. Wicklow, P. F. Dowd, Tetrahedron 1995, 51, 3959 – 3968. [2] For selected syntheses of cyclopenta[b]indoles, see, for example: a) C.A. Harrison, R. Leineweber, C. J. Moody, J. M. J. Williams, J. Chem. Soc.
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sei, Chem. Soc. Rev. 2011, 40, 4539 – 4549; h) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114, 9047 – 9153. For recent examples not covered in reviews of Ref. [3], see: a) Z.-L. Guo, J.-H. Xue, L.-N. Fu, S.-E. Zhang, Q.-X. Guo, Org. Lett. 2014, 16, 6472 – 6475; b) W. Tan, B.-X. Du, X. Li, X. Zhu, F. Shi, S.-J. Tu J. Org. Chem. 2014, 79, 4635 – 4643; c) Y. Liu, H. H. Zhang, Y.-C. Zhang, Y. Jiang, F. Shi, S.-J. Tu, Chem. Commun. 2014, 50, 12054 – 12057; d) W. Dai, H. Lu, X. Li, F. Shi, S.-J. Tu, Chem. Eur. J. 2014, 20, 11382 – 11389; e) H.-H. Zhang, Y.-M. Wang, Y.-W. Xie, Z.-Q. Zhu, F. Shi, S.-J. Tu, J. Org. Chem. 2014, 79, 7141 – 7151; f) L.-J. Zhou, Y.-C. Zhang, J.-J. Zhao, F. Shi, S.-J. Tu, J. Org. Chem. 2014, 79, 10390 – 10398; g) X. Li, W. Tan, Y.-X. Gong, F. Shi, J. Org. Chem. 2015, 80, 1841 – 1848. For recent examples with other substrates forming a transient cation under chiral phosphoric acid catalysis, see: a) M. Rueping, U. Uria, M. Y. Lin, I. Atodiresei, J. Am. Chem. Soc. 2011, 133, 3732 – 3735; b) D. Wilcke, E. Herdtweck, T. Bach, Synlett 2011, 1235 – 1238; c) S. J. Gharpure, A. M. Sathiyanarayanan, P. K. Vuran, RSC Adv. 2013, 3, 18279 – 18282; d) O. ElSepelgy, S. Haselhoff, S. K. Alamsetti, C. Schneider, Angew. Chem. Int. Ed. 2014, 53, 7923 – 7927; Angew. Chem. 2014, 126, 8057 – 8061; e) C.-C. Hsiao, H. H. Liao, M. Rueping, Angew. Chem. 2014, 126, 13361 – 13474; Angew. Chem. Int. Ed. 2014, 53, 13258 – 13263; f) X. Tian, N. Hofmann, P. Melchiorre, Angew. Chem. 2014, 126, 3041 – 3044; Angew. Chem. Int. Ed. 2014, 53, 2997 – 3000; g) S. Saha, S. K. Alamsetti, C. Schneider, Chem. Commun. 2015, 51, 1461 – 1464. a) R. Matsubara, S. Kobayashi, Acc. Chem. Res. 2008, 41, 292 – 301; b) D. R. Carbery, Org. Biomol. Chem. 2008, 6, 3455 – 3460; c) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352, 753 – 819; d) K. Gopalaiah, H. Kagan, Chem. Rev. 2011, 111, 4599 – 4657; e) G. Bernadat, G. Masson, Synlett 2014, 2842 – 2867. The relative stereochemistry was first tentatively assigned trans, trans by NOE experiments, and later unambiguously determined by singlecrystal X-ray diffraction. CCDC-1036140 (3 a) 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), see the Supporting Information. For an alkylation of 3-indolyl(aryl)methanol by an enamide with the resulting imine intermediate being completely hydrolyzed to the corresponding ketone, see: Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z. Gong, Org. Lett. 2009, 11, 4620 – 4623. T. Courant, S. Kumarn, L. He, P. Retailleau, G. Masson, Adv. Synth. Catal. 2013, 355, 836 – 840. For recent reviews on chiral ion-pairing catalysis, see: a) M. Mahlau, B. List, Angew. Chem. Int. Ed. 2013, 52, 518 – 533; Angew. Chem. 2013, 125, 540 – 556. Unfavorable interactions between the benzyl group and the ion-pair complex of the iminium could also potentially explain the low enantioselectivity. For some discussions of nonlinear effects in chiral phosphoric acid catalysis, see: a) N. Li, X.-H. Chen, S.-M. Zhou, S.-W. Luo, J. Song, L. Ren, L.Z. Gong, Angew. Chem. Int. Ed. 2010, 49, 6378 – 6381; Angew. Chem. 2010, 122, 6522 – 6525; b) Y. Xie, Y. Zhao, B. Qian, L. Yang, C. Xia, H. Huang, Angew. Chem. Int. Ed. 2011, 50, 5682 – 5686; Angew. Chem. 2011, 123, 5800 – 5804. For observation of positive nonlinear effect with chiral metal phosphate catalysis, see Ref. [5 i]. For some examples of cyclopenta[b]indoline natural products, see: a) M. Gorman, N. Neuss, G. H. Svoboda, A. J. Barnes Jr., N. J. Cone, J. Am. Pharm. Assoc. 2006, 48, 256 – 257; b) F. Tillequin, M. Koch, Phytochemistry 1979, 18, 1559 – 1561; c) R. Hocquemiller, G. Dubois, M. Leboeuf, A. Cav, N. Kunesch, C. Riche, A. Chiaroni, Tetrahedron Lett. 1981, 22, 5057 – 5060; d) T. R. Govindachari, B. R. Pai, S. Rajappa, N. Viswanathan, W. G. Kump, K. Nagarajan, H. Schmid, Helv. Chim. Acta 1963, 46, 572 – 577.
Received: February 24, 2015 Published online on && &&, 2015
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COMMUNICATION & Asymmetric Synthesis C. Lebe, A. O. Kataja, F. Blanchard, G. Masson* && – &&
A perfect union: A highly stereoselective organocatalytic [3+2] cyclization between enecarbamates and 3-indolylmethanols was discovered. Under chiral phosphoric acid catalysis, the reaction
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partners cyclize to give 3-aminocyclopenta[b]indoles with three contiguous stereocenters. The scope of the reaction was broad and extendable even to 3-indolyl(alkyl)-methanols (see scheme).
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Formal Asymmetric Organocatalytic [3 + 2] Cyclization between Enecarbamates and 3Indolylmethanols: Rapid Access to 3-Aminocyclopenta[b]indoles
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Formal Asymmetric Organocatalytic [3 + 2] Cyclization between Enecarbamates and 3-Indolylmethanols: Rapid Access to 3-Aminocyclopenta[b]indoles Clment Lebe, Antti O. Kataja, Florent Blanchard, and Graldine Masson*[a] [3+2] cycloaddition reaction of 3-indolylarylmethanols and 3vinylindole, which could concisely furnish cyclopenta[b]indole in one synthetic operation, albeit with moderate selectivity (enantiomeric excess (ee) < 10 %).[4c] Subsequent to this, Shi et al. developed an efficient asymmetric [3+2] cyclization of 3hydroxy-3-indolyl-oxindoles with 3-methyl-2-vinylindoles[4d] or 3-methyl-7-vinylindoles[4e] in the presence of chiral phosphoric acid, leading to spirocyclic compounds with good enantioselectivity. Despite these elegant achievements, there is no convenient enantioselective [3+2] cycloaddition for the preparation of cyclopenta[b]indoles. In continuation of our research program in catalytic asymmetric cycloaddition with enamides,[5] we envisaged that the combination of a chiral phosphoric acid catalyst[6] and a 3-indolylarylmethanol would result in the formation of an alkylideneindoleninium ion,[3, 7, 8] which would then undergo enantioselective [3+2] cycloaddition with the polarized enamide double bond (Scheme 1).[9] Herein, we report a highly diastereo- and enantioselective one-pot [3+2] cycloaddition route to the synthesis of 3-aminocyclopenta[b]indoles with a broad scope (Scheme 1). We initiated our investigations by using (E)-N-(benzyl prop1-en-1-yl)carbamate (1 a), indolyl(phenyl)methanol (2 a), and 5 mol % of unsubstituted (S)-BINOL-derived phosphoric acid catalyst 4 a in CH2Cl2 at room temperature in the presence of 4 molecular sieves at room temperature (Table 1). To our delight, in less than an hour, the desired cyclopenta[b]indole 3 a was obtained in 70 % yield with excellent diastereoselectivity in favor of trans, trans[10] (diastereomeric ratio (d.r.) > 95:5). Encouraged by the rapid proof of concept, we screened the reaction with various chiral phosphoric acids (5 mol %). A clear effect of sterically bulky 3,3’-substituents was observed. For example, (S)-3,3’-bis(2,4,6-triisopropylphenyl)-BINOL (4 f) gave a very poor yield and stereoselectivity (Table 1, entry 6), whereas the simple phenyl-substituted 4 b gave the product in 57 % yield and with an ee of 67 % (Table 1, entry 1). In general, catalysts bearing polycyclic aromatic substituents (Table 1, entries 4 and 5) or 4-substituted aromatic substituents (entry 3) achieved consistently very good results. We found that the (S)3,3’-bis-9-phenanthryl–BINOL phosphoric acid (4 g, Table 1, entry 7) was the best catalyst in terms of diastereo- and enantioselectivity. A survey of reaction solvents (Table 1, entries 7– 10) revealed that the reaction proceeded with slightly higher enantioselectivity in CH2Cl2 (entry 7). Lowering the temperature did not significantly improve the ee or yield (Table 1, entries 11 and 12). It is worth mentioning that the cycloadduct 3 a can be enriched to > 99 % ee by a single recrystallization. Various
Abstract: A highly enantio- and diastereoselective synthesis of 3-aminocyclopenta[b]indoles has been developed through formal [3+2] cycloaddition reaction of enecarbamates and 3-indolylmethanols. This transformation is catalyzed by a chiral phosphoric acid that achieves simultaneous activation of both partners of the cycloaddition. Mechanistic data are also presented that suggest that the reaction occurs through a stepwise pathway.
Chiral cyclopenta[b]indole is a common structural motif in a variety of natural products carrying widely different biological activities[1] such as anti-implantation agents (Yuehchukene[1b]), cytotoxic, antifungal, and antimicrobial agents (Fischerindole L[1c]), tremorgenic alkaloids (Paxilline[1d] and Penitrem A[1e]), and apoptotic agents (Shearinine A[1f]). In this context, numerous elegant approaches have been developed to access to this class of synthetically complex heterocycles.[2] Among them, the direct inverse electron demand [3+2] cycloaddition of electron rich olefin with alkylideneindolenine intermediates[3] generated from indolylarylmethanols under acid conditions have been recognized as one of the most efficient and convergent methods (Scheme 1). However, to date, there are only limited successful enantioselective strategies that could realize this direct [3+2] dipolar cycloaddition route.[4a–c] In 2014, Guo and coworkers established a chiral phosphoric acid-catalyzed formal
Scheme 1. Catalytic enantioselective [3+2] cycloaddition synthesis of trisubstituted 3-aminocyclopenta[b]indoles
[a] C. Lebe,+ Dr. A. O. Kataja,+ F. Blanchard, Dr. G. Masson Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-Sud 91198 Gif-sur-Yvette Cedex (France) Fax: (+ 33) 1-69077247 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.org/10.1002/chem.201500749. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Optimization of catalytic enantioselective [3+2] cyclization.
Entry
Cat.
T [8C]
Solvent
Yield [%][a,b]
d.r.[c]
ee [%][d]
1 2 3 4 5 6 7 8 9 10 11 12 13[g] 14[h] 15[i]
4a 4b 4c 4d 4e 4f 4g 4g 4g 4g 4g 4g 4g 4g 4h
0 0 0 0 0 0 0 0 0 0
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 1,2-DCE Toluene CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
70 57 63 62 78 30 71 51 47 69 18 60 55 65 50
95:5 > 95:5 88:12 91:9 94:6 > 95:5 > 95:5 94:6 90:10 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 93:7
33 67 87 84 87 33 97 (> 99)[e,f] 90 85 96 97 94 91 96 81
to RT to RT to RT to RT to RT to RT to RT to RT to RT to RT 30 15 0 to RT 0 to RT 0 to RT
[a] General conditions: 1 a (0.11 mmol), 2 a (0.10 mmol) and Cat (5 mol %) in solvent (0.05 m) at T [8C] for 2 h with 4 MS. 1,2-DCE = 1,2-Dichloroethene. [b] Yield of the isolated pure product after column chromatography. [c] Determined by 1H NMR spectroscopy. [d] Determined by HPLC analysis on a chiral stationary phase. [e] The values in brackets show enantiomeric excess after recrystallization. [f] Absolute configuration (1S, 2R, 3S) was determined by X-ray crystal-structure analysis of a derivative of 3 a (see the Supporting Information).[10] [g] 3 MS was used. [h] 5 MS was used. [i] (Z)1 a was used instead of (E)-1 a.
activated desiccants were screened, but not much improvement was noticed (Table 1, entries 13 and 14). After establishing the optimal reaction conditions (Table 1, entry 7), the scope of the reaction was examined (Table 2). (E)N-Cbz-enecarbamates 1 bearing different linear alkyl substituents were found to function very well in the reaction, and the corresponding trisubstituted-cyclopenta[b]indoles were obtained in similar yields and stereoselectivities in comparison to the model reaction (3 b, 3 e, and 3 f). Larger and bulkier alkyl groups behaved likewise very well (3 c and 3 d), and additional functional handles (such as silyl ether, 3 f, Table 2, entry 5) could also be installed through the enecarbamate partner. Ntert-butoxycarbonyl (Boc) carbamate 1 g rendered the final product with slightly lower yield and enantioselectivity (Table 2, entry 6). In addition, a wide range of 3-substituted indoles bearing various substituted aryl groups were tolerated in this [3+2] cycloaddition (Table 2, entries 7–14). For instance, the indole bearing 4-trifluoromethylphenyl (Table 2, entry 10) or the electron-rich 4-methoxyphenyl (entry 11) group provided the corresponding 3-aminocyclopenta[b]indoles 3 k and 3 l, respectively, in high yields and with excellent enantioselectivities. Fluorine-substituted aryl groups gave an increasing trend &
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in the yield with respect to the substituent position (3 h–j, Table 2, entries 7–9), revealing a potential steric effect. 3-Indolyl(2’-naphthyl)methanol (Table 2, entry 12) was also suitable, providing the cycloadduct 3 m with 95 % ee. On the other hand, the introduction of a heteroaromatic group such as thiophene (Table 2, entry 13) led to a reduction in the yield, although a high level of enantioselectivity was retained. Remarkably, this condition was also applicable to indole derivatives bearing aliphatic group at the 1’-position (which have scarcely been used). Indeed, the 3-indolyl(isopropyl)methanol (Table 2, entry 14) provided the corresponding cycloadduct 3 o efficiently with excellent enantioselectivities. The indole bearing a linear alkyl chain (Table 2, entry 15) gave 3 p with only 4:1 diastereoselectivity and 67 % ee. However, we were pleased to find that when the reaction was carried out at 30 8C, the expected cycloadduct 3 p was isolated with a better ee (Table 2, entry 15). Although the enantioselectivity was maintained with C6 and C7-substituted indoles, the yield was slightly lower (Table 2, entries 16–18). To gain further insight into the mechanism of the cycloaddition, we attempted the treatment of 1 a with a Z-dipolarophile. As shown in Table 1, compound (Z)-1 a leads to the same major diastereomer (all trans, 14:1 d.r.) as that derived from (E)-1 a (Table 2, entry 15) albeit with lower enantioselectivity and yield. Additionally, in some cases, a small amount of aldehyde coming from uncyclized imine intermediate 7 was isolated (Scheme 2).[11] In addition, when the cycloaddition of 1 a with (E)-2 a was performed in presence of ethanol, the trapped iminium intermediate was isolated in 73 % yield as a mixture of diaste-
Scheme 2. Plausible reaction mechanism.
reomers (see the Supporting Information). These experiments are consistent with a stepwise mechanism comprising the following steps (Scheme 2): 1) Dehydration of 1 to generate vinyliminium ion 5; 2) Vinylogous Mannich reaction of 2 to 5, and 3) C2 alkylation of indole derivative to the resulting iminium ion 6. Further understanding of the mechanism is required to 2
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Communication enecarbamate would be activated simultaneously by the Lewis base and cation of 4, favoring addition from the Si face to 7. Finally, the utility of this methodology is illustrated by the synthesis of cyclopenta[b]indoline core found in various biologically active natural products (Scheme 3).[16] The recrystal-
Table 2. Scope of the organocatalytic enantioselective [3+2] cyclization.[a]
R1/R2 [1]
Entry 1 2 3
Et/Bn iPr/Bn cPr/Bn
4 5
R3/R4/R5 [2]
3
Ph/H/H Ph/H/H Ph/H/H
3 b 79 3 c 70 3 d 64
94 (> 95:5) 92 (> 95:5) 96 (90:10)
/Bn Ph/H/H
3 e 72
93 (> 95:5)
/Bn Ph/H/H
3f
82
97 (> 95:5)
3g 3h 3i 3j 3k 3l
61 88 74 65 69 70
89 89 92 97 93 93
6 7 8 9 10 11
Me/tBu Me/Bn Me/Bn Me/Bn Me/Bn Me/Bn
12
Me/Bn
13 14 15
Me/Bn Me/Bn Me/Bn
Ph/H/H p-FC6H4/H/H m-FC6H4/H/H o-FC6H4/H/H p-CF3C6H4/H/H m-MeOC6H4/ H/H 2-naphthyl/H/ H 2-thienyl/H/H iPr/H/H nBu/H/H
16 17 18 19
Me/Bn Me/Bn Me/Bn Me/Bn
Ph/5-MeO/H Ph/5-Br/H Ph/6-Br/H Ph/H/Bn
Yield ee [%][c] [%][b] (d.r.)[d]
3 m 78
Scheme 3. Application to the enantioselective synthesis of enantiopure 3aminocyclopenta[b]indoline 8. pTSA = p-Toluenesulfonic acid.
(94:6) (> 95:5) (> 95:5) (95:5) (> 95:5) (> 95:5)
lized cycloadduct 3 a was subjected to reductive conditions with NaBH3CN leading to the formation of enantiopure 3amino cyclopenta[b]indoline 8 in 83 % yield, with a complete control of configuration at all five stereocenters. The high diastereoselectivity can be explained by assuming that the reduction proceeded from the less hindered side of 3. In conclusion, we have discovered a rapid and highly stereoselective synthesis of 3-aminocyclopenta[b]indoles carrying three contiguous stereocenters from enecarbamate 1 and 3-indolylmethanol 2 by using chiral phosphoric acid catalysis. To the best of our knowledge, this is the first reported asymmetric synthesis of the 3-aminocyclopenta[b]indole scaffold. Considering the wide variability and easy synthesis of both reaction partners, this methodology offers convenient access to compounds hitherto unexamined for their biologic and pharmaceutical potential. Further mechanistic studies and expansion of the methodology is currently underway and will be reported in due course.
95 (> 95:5)
3 n 66[e] 91 (92:8) 3 o 70[e] 87 (> 95:5) 3 p 68[e] 67(84)[f] (80:20) 3 q 85[e] 91 (> 95:5) 3 r 68[e] 93 (> 95:5) 3 s 69[e] 88 (> 95:5) 3 t 44 0 (90:10)
[a] General conditions: 1 (0.11 mmol), 2 (0.10 mmol), and 5 f (5 mol %) in CH2Cl2 (0.05 m) at 0 8C to RT for 2 h with 4 MS. TBDPS = tert-Butyldiphenylsilyl ether; Bn = benzyl. [b] Yield of isolated pure product after column chromatography. [c] Determined by HPLC analysis on a chiral stationary phase. [d] Determined by 1H NMR spectroscopy. [e] Compound 2 (0.2 mmol) was used. [f] Reaction performed at 30 8C.
Acknowledgements
explain the high level of stereoselectivity. Based on our observation in the previous enantioselective reaction with both 1 and indolic substrates,[5, 12] we postulated that the vinyliminium ion 5 as well as the enecarbamate could be well-organized together with the bifunctional phosphoric acid catalyst. Hence, two activation modes of catalyst 4 with 1 can be proposed, such as hydrogen bonding or ion-pairing.[13] To distinguish them, the N-protected indole derivative, in which hydrogen bonding with 4 is not possible, was used in this cycloaddition. As shown in Table 2 (entry 19), the resulting product (3 t) was obtained in low yield and as a racemic mixture. Although the ion-pair activation cannot be completely ruled out,[14] this experiment seems more consistent with a hydrogen-bonding activation mode. As two hydrogen bonds between 4 and transition state can be formed, two catalysts can be involved in this stereoselective formal cycloaddition. However, the rather small positive nonlinear effect observed (see the Supporting Information), ruled out this hypothesis.[15] On the basis of these studies, we suggest the following transition state model to explain the observed stereoselectivity: The vinyliminium ion and Chem. Eur. J. 2015, 21, 1 – 5
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We thank ICSN and CNRS for financial supports and doctoral fellowships to C.L. A.K. gratefully acknowledges ICSN and CNRS for a postdoctoral fellowship. Both authors, A.K. and C.L., contributed equally to this work: A.K. designed the project and carried out the optimization, and C.L. designed and carried out the scope and mechanistic studies. Keywords: asymmetric synthesis · chirality · cycloaddition · enamide · iminium · indoles [1] a) P. S. Steyn, R. Vleggar, Fortschr. Chem. Org. Naturst. 1985, 48, 1 – 80; b) Y. C. Kong, K. F. Cheng, R. C. Cambie, P. G. Waterman, J. Chem. Soc. Chem. Commun. 1985, 47 – 48; c) A. Park, R. E. Moore, G. M. L. Patterson, Tetrahedron Lett. 1992, 33, 3257 – 3260; d) J. P. Springer, J. Clardy, J. M. Wells, R. J. Cole, J. W. Kirksey, Tetrahedron Lett. 1975, 16, 2531 – 2534; e) B. J. Wilson, T. Hoekman, W. D. Dettbarn, Brain Res. 1972, 40, 540 – 544; f) G. N. Belofsky, J. B. Gloer, D. T. Wicklow, P. F. Dowd, Tetrahedron 1995, 51, 3959 – 3968. [2] For selected syntheses of cyclopenta[b]indoles, see, for example: a) C.A. Harrison, R. Leineweber, C. J. Moody, J. M. J. Williams, J. Chem. Soc.
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Received: February 24, 2015 Published online on && &&, 2015
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2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
COMMUNICATION & Asymmetric Synthesis C. Lebe, A. O. Kataja, F. Blanchard, G. Masson* && – &&
A perfect union: A highly stereoselective organocatalytic [3+2] cyclization between enecarbamates and 3-indolylmethanols was discovered. Under chiral phosphoric acid catalysis, the reaction
Chem. Eur. J. 2015, 21, 1 – 5
partners cyclize to give 3-aminocyclopenta[b]indoles with three contiguous stereocenters. The scope of the reaction was broad and extendable even to 3-indolyl(alkyl)-methanols (see scheme).
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These are not the final page numbers! ÞÞ
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Formal Asymmetric Organocatalytic [3 + 2] Cyclization between Enecarbamates and 3Indolylmethanols: Rapid Access to 3-Aminocyclopenta[b]indoles
2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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