Annulation of

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Diastereodivergent Asymmetric Carboamination/Annulation of Cyclopropenes with Aminoalkenes by Chiral Lanthanum Catalysts Huai-Long Teng,† Yong Luo,‡ Masayoshi Nishiura,†,‡ and Zhaomin Hou*,†,‡ †

Advanced Catalysis Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Organometallic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

‡

S Supporting Information *

Scheme 1. Lanthanum-Catalyzed Synthesis of Chiral Bicyclic Aminocyclopropanes

ABSTRACT: Stereodivergent asymmetric catalysis is an important technology that can allow efficient access to various stereoisomers of a given product with multiple stereocenters from the same set of starting materials, but its application to the synthesis of a highly strained cyclopropane compound has remained unexplored to date. We report here the first diastereodivergent enantioselective synthesis of bicyclic aminocyclopropanes by lanthanum-catalyzed asymmetric carboamination/annulation of cyclopropenes with aminoalkenes. This protocol features 100% atom efficiency, good yield (up to 90%), and high chemo- (up to >20:1) and stereoselectivity (up to >20:1 dr and 99% ee), constituting a unique route for the efficient synthesis of two different diastereoisomers of a given chiral bicyclic aminocyclopropane compound.

C

hiral bicyclic aminocyclopropanes are of great interest and importance, as the unique aminocyclopropane moieties are not only important components in many biologically active compounds and natural products,1 but they can also serve as synthetically useful precursors through selective CC bond cleavage of the highly strained three-membered carbocycle.2 Considerable efforts have been devoted to the search for efficient routes for the synthesis of bicyclic aminocyclopropane compounds.3 However, the enantioselective construction of chiral bicyclic aminocyclopropane skeletons in a catalytic and atom-efficient fashion has remained almost unexplored to date. In particular, the catalyst-controlled stereodivergent synthesis of a chiral bicyclic aminocyclopropane structure has not been reported previously, despite intense interest and recent rapid advances in stereodivergent catalysis for organic synthesis.4 The asymmetric functionalization of cyclopropenes has recently received much attention as an efficient route for the construction of chiral functionalized-cyclopropane derivatives.5−12 In principle, the intermolecular enantioselective hydroamination of a cyclopropene compound with an aminoalkene followed by intramolecular CC bond formation (annulation) could constitute a 100% atom-efficient route for the synthesis of a chiral bicyclic aminocyclopropane derivative (see Scheme 1b). However, such transformation (either racemic or asymmetric) has not been reported previously. Obviously, to make this transformation operative, it is necessary to develop efficient and selective catalysts that can not only show high compatibility with the highly strained cyclopropene (or cyclopropane) skeleton without causing ring-opening, but also show © 2017 American Chemical Society

high stereoselectivity as well as high activity for CC double bond insertion (or annulation) versus protonation. We report herein the catalyst-controlled diastereodivergent asymmetric carboamination/annulation of cyclopropenes with aminoalkenes by chiral lanthanum catalysts. This protocol provides an efficient route for the selective synthesis of two different diastereoisomers of a given chiral bicyclic aminocyclopropane compound from the same set of starting materials with excellent enantioselectivity (see Scheme 1a). In a preliminary survey of a series of chiral half-sandwich rareearth complexes (such as Sc-1, Y-1 and Sm-1 in Figure 1) that were previously used in other asymmetric transformations,10,11,13 we found that the complexes having a larger metal ion14 showed better performance (higher activity and higher stereoselectivity) for the carboamination/annulation of 3-methyl-3-phenyl cyclopropene (2a) with N-allyl-benzylamine (1a). The smallest scandium complex Sc-1 showed no activity (Table 1, entry 1), whereas the larger yttrium analog Y-1 (2.5 mol %) gave a 4:1 mixture of the simple hydroamination product (4a) and the annulation product (1:1 diastereoisomers 3a and 3a′) in 92% yield (Table 1, entry 2). The further larger Sm-1 complex Received: October 10, 2017 Published: November 8, 2017 16506

DOI: 10.1021/jacs.7b10786 J. Am. Chem. Soc. 2017, 139, 16506−16509

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Journal of the American Chemical Society

dr, 99% ee) (Table 1, entry 4). The undesired simple hydroamination byproduct 4a was not observed, suggesting that the larger La metal enables faster intramolecular CC carbometalation (annulation, Scheme 1b) versus intermolecular protonation with 1a to release 4a.10 The use of hexane as a solvent in place of toluene further raised the diastereoselectivity of 3a (15:1), with the enantioselectivity remaining high (99% ee) (Table 1, entry 5). The configuration of 3a was unequivocally determined by the X-ray crystallographic analysis of its ammonium chloride salt (see Table 2). When the half-sandwich Table 2. Synthesis of Chiral Bicyclic Aminocyclopropanes by La-1a Figure 1. Rare-earth complexes bearing chiral cyclopentadienyl (Cp) ligands.

Table 1. Reaction of 1a with 2a by Chiral Cp-Ligated Rare Earth Catalystsa

Entry

[Ln]

Solvent

Yield (%)b

(3a+3a′)/4ac

3a/3a′c

Ee (%)d

1 2 3 4 5 6 7 8e

Sc-1 Y-1 Sm-1 La-1 La-1 La-2 La-2 La-2

Toluene Toluene Toluene Toluene Hexane Toluene Hexane Toluene

0 92 90 86 85 85 72 76

1:4 1:3 >20:1 >20:1 3:1 3:1 12:1

1:1 1:1 10:1 15:1 1:7 1:5 1:9

90 99 99 94 90 97

a Reaction conditions: [Ln] (2.5 mol %), 1a (0.20 mmol), 2a (0.30 mmol), solvent (2 mL, c = 0.1 M), 25 °C, 12 h, unless otherwise noted. bIsolated yield. cDetermined by 1H NMR. dDetermined by HPLC. eToluene (20 mL, c = 0.01 M), La-2 (5 mol %).

showed higher enantioselectivity (90% ee), although the product distribution was not significantly improved (Table 1, entry 3). To further examine the metal effect, we became interested in the analogous lanthanum half-sandwich complex, because La is the largest in the rare earth series.14 However, attempts to obtain a half-sandwich lanthanum complex bearing the same Cp ligand (as that of Sm-1) by a 1:1 reaction of La(CH2-C6H4-NMe2-o)3 with the Cp-H ligand precursor were not successful,10,11,13 which always gave an inseparable mixture of the mono(Cp)- and bis(Cp)-ligated complexes as a result of ligand redistribution. When the reaction of La(CH2-C6H4-NMe2-o)3 with the Cp-H ligand was carried out in a 1:2 molar ratio, the bis(Cp)-ligated complex La-1 (Figure 1) was exclusively formed (see Supporting Information for details). In order to obtain a mono(Cp)-ligated half-sandwich lanthanum complex analogous to Sm-1, we then employed a more sterically demanding ligand that bears a SiMe3 substituent at the Cp ring. The 1:1 reaction of La(CH2-C6H4NMe2-o)3 with the Me3Si-substituted Cp-H ligand selectively afforded the corresponding half-sandwich lanthanum complex La-2,10 which did not undergo ligand redistribution in solution. In the presence of 2.5 mol % of the bis(Cp)-ligated lanthanocene complex La-1, the reaction of 1a with 2a in toluene at room temperature exclusively gave the annulation product in 86% yield, in which the diastereoisomer 3a with the configuration (1R, 4S, 5R, 6S) was predominantly formed (10:1

a

Reaction conditions: La-1 (2.5 mol %), 1 (0.20 mmol), 2 (0.30 mmol), hexane (2 mL, c = 0.1 M), 25 °C, 12 h, unless otherwise noted. Yield is given in isolated yield. The dr was determined by 1H NMR and ee by HPLC.

lanthanum complex La-2, which bears the Me3Si-substituted Cp ligand, was used as a catalyst, the diastereoisomer 3a′ having the configuration (1R, 4R, 5R, 6S) was formed as a major product (3a/3a′ = 1:7, (3a+3a′)/4a = 3:1) (Table 1, entry 6). When the reaction was carried out in a diluted toluene solution (c = 0.01 M), further higher chemoselectivity (3a+3a′)/4a = 12:1) and stereoselectivity (9:1 dr and 97% ee) of 3a′ were observed (Table 1, entry 8). These results demonstrate that the lanthanum complexes La-1 and La-2 could serve as efficient catalysts for the diastereodivergent enantioselective carboamination/annulation of a cyclopropene compound with an aminoalkene. On the basis of the above experimental results, we then first used La-1 as a catalyst to examine the reactions of various 3,3disubstituted cyclopropenes with aminoalkenes. Some representative results are shown in Table 2. Similar to 3-methyl-3phenylcyclopropene (2a), 3-methyl-3-(p-tolyl)-cyclopropene 16507

DOI: 10.1021/jacs.7b10786 J. Am. Chem. Soc. 2017, 139, 16506−16509

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Journal of the American Chemical Society (2b) and 3-methyl-3-(p-anisyl)-cyclopropene (2c) also worked well with 1a, affording the corresponding bicyclic products 3b and 3c in 72% and 70% isolated yields, respectively, with high diastereoselectivity (14:1 dr) and high enantioselectivity (99% ee). Aromatic CF, CCl, and CBr bonds were compatible with the catalyst, so that the halogen-containing bicyclic products 3d−3g were obtained in high yields (68−82%) and high stereoselectivity (14:1−19:1 dr, 92−99% ee). 2-Naphthyl methyl cyclopropene 2h was also suitable for this reaction, giving the corresponding product 3h in 83% yield with 15:1 dr and 99% ee. A thienyl group in the cyclopropene substrate was compatible with this catalyst system, affording the corresponding annulation product 3i in 62% isolated yield and 99% ee, albeit with low diastereoselectivity (2:1 dr). In the reaction of 3-ethyl-3-phenyl cyclopropene (2j) with 1a, the desired bicyclic product 3j was obtained in 90% yield with excellent stereoselectivity (>20:1 dr, 99% ee). The reaction of 3-methyl-3-cyclohexyl cyclopropane (2k) with 1a also afforded the desired product 3k with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (99% ee), albeit in a moderate yield (58%). Polycyclic compounds containing a spiro-quaternary stereocenter (such as 3l and 3m) were easily prepared from the corresponding spirocyclopropene precursors in high yields (76−84%) and high stereoselectivity (8:1 to 10:1 dr, 98% ee). The reaction of m-methoxybenzyl allyl amine with 3-methyl-3-phenylcyclopropene (2a) also worked well, giving the corresponding bicyclic product 3n in 72% yield with 10:1 dr and 99% ee. Diallylamine was also suitable for the reaction with 2a, affording the corresponding N-allyl-substituted bicyclic product 3o in 65% yield with excellent stereoselectivity (>20:1 dr, 99% ee). Internal aminoalkenes bearing a Me or Ph substituent at the end of the CC double bond gave only the hydroamination products, probably due to steric hydrance that could slower the cyclization reaction. Next, we examined La-2 for the reactions of various 3,3disubstituted cyclopropenes with aminoalkenes. The results are summarized in Table 3. Overall, the functional group or substrate compatibility of La-2 was similar to that of La-1. As observed in the case of 3a′ (Table 1), all of the annulation products 3a′−3o′ prepared by La-2 possessed the (1R, 4R, 5R, 6S) configuration, in contrast with the corresponding diastereoisomers 3a−3o (1R, 4S, 5R, 6S) prepared by La-1. Good to high diastereoselectivity (6:1 to >20:1 dr) and enantioselectivity (89−99% ee) were observed, except in the case of 3j′, which showed relatively poor diastereoselectivity (2:1 dr) although the enantioselectivity (99% ee) remained high. In the case of 2-thienyl-substituted cyclopropene, the annulation product 3i′ was obtained in 27% yield along with the simple hydroamination product 4i′ (38% yield). The configuration of 3h′ was unequivocally determined by X-ray crystallographic analysis of its ammonium chloride salt (Table 3). In addition to aminoalkenes, aminoalkynes could also be used for the present carboamination/annulation transformation. As shown in Scheme 2, the reaction of N-benzyl-2-butyn-1-amine (5a) with 2a in the presence of 2.5 mol % La-1 gave the corresponding bicyclic product 6a in 80% yield with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (99% ee). The resulting exoalkenyl unit adopted a Z-configuration (Z/E ratio > 20:1) as confirmed by the NOE analysis. Similarly, the reaction of N-benzyl-2-octyn-1-amine (5b) with 2a afforded the corresponding annulation product 6b in 75% yield with >20:1 dr and 99% ee. In the case of the N-allylaminoalkyne 5c, the annulation reaction took place exclusively at the alkyne unit, affording the corresponding N-allyl-substituted bicyclic product

Table 3. Synthesis of Chiral Bicyclic Aminocyclopropanes by La-2a

a

Reaction conditions: La-2 (5 mol %), 1 (0.20 mmol), 2 (0.30 mmol), toulene (20 mL, c = 0.01 M), 25 °C, 12 h, unless otherwise noted. Yield is given in isolated yield. The dr was determined by 1H NMR and ee by HPLC.

Scheme 2. Asymmetric Carboamination/Annulation of Cyclopropene 2a with Aminoalkynes

6c with an exo-(Z)-alkenyl group in 72% yield with excellent stereoselectivity (Z/E > 20:1, >20:1 dr, 99% ee). Scheme 3 shows the most favored transition states proposed for the diastereodivergent control of the carboamination/ annulation of 3-methyl-3-phenyl cyclopropene (2a) with Nallyl-benzylamine (1a) by La-1 and La-2. The initial aminometalation of 2a with 1a promoted by either La-1 or La-2 would generate the corresponding amino-substituted cyclopropyl lanthanum species (see Supporting Information for details).10 In the case of La-1, a transition state with the intramolecular coordination of the CC double bond to the La metal in a Sifashion (A) would be the most favored to avoid repulsion 16508

DOI: 10.1021/jacs.7b10786 J. Am. Chem. Soc. 2017, 139, 16506−16509

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Retailleau, P.; Six, Y. Org. Biomol. Chem. 2010, 8, 5591. (d) Zhao, G.; Kwon, C.; Wang, A.; Robertson, J. G.; Marcinkeviciene, J.; Parker, R. A.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett. 2013, 23, 1622. (e) Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer, M. P.; Nair, A. G.; Mazzola, R.; Kim, J.-H.; Sha, D.; Yin, J.; Ruck, R. T.; Davies, I. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia, E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.; Feng, K.-I.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. J. Med. Chem. 2017, 60, 290. (2) Selected examples on C−C bond cleavage of cyclopropanes: (a) Larquetoux, L.; Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 4654. (b) Maity, S.; Zhu, M.; Shinabery, R. S.; Zheng, N. Angew. Chem., Int. Ed. 2012, 51, 222. (c) De Nanteuil, F.; De Simone, F.; Frei, R.; Benfatti, F.; Serrano, E.; Waser, J. Chem. Commun. 2014, 50, 10912. (d) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410. (e) Fumagalli, G.; Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117, 9404. (3) (a) Hanessian, S.; Buckle, R.; Bayrakdarian, M. J. Org. Chem. 2002, 67, 3387. (b) Madelaine, C.; Six, Y.; Buriez, O. Angew. Chem., Int. Ed. 2007, 46, 8046. (c) Wolan, A.; Soueidan, M.; Chiaroni, A.; Retailleau, P.; Py, S.; Six, Y. Tetrahedron Lett. 2011, 52, 2501. (d) Cao, B.; Xiao, D.; Joullié, M. M. Org. Lett. 1999, 1, 1799. (e) Pedroni, J.; Saget, T.; Donets, P. A.; Cramer, N. Chem. Sci. 2015, 6, 5164. (f) Chen, C.; Kattanguru, P.; Tomashenko, O. A.; Karpowicz, R.; Siemiaszko, G.; Bhattacharya, A.; Calasans, V.; Six, Y. Org. Biomol. Chem. 2017, 15, 5364. (g) Semakul, N.; Jackson, K. E.; Paton, R. S.; Rovis, T. Chem. Sci. 2017, 8, 1015. (4) Selected reviews on stereodivergent catalysis: (a) Miller, L. C.; Sarpong, R. Chem. Soc. Rev. 2011, 40, 4550. (b) Mahatthananchai, J.; Dumas, A. M.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 10954. (c) Schindler, C. S.; Jacobsen, E. N. Science 2013, 340, 1052. (d) Zhan, G.; Du, W.; Chen, Y.-C. Chem. Soc. Rev. 2017, 46, 1675. (e) Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 5627. (f) Lin, L.; Feng, X. Chem. - Eur. J. 2017, 23, 6464. (5) Hydroboration: (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198. (b) Parra, A.; Amenós, L.; Guisán-Ceinos, M.; López, A.; García Ruano, J. L.; Tortosa, M. J. Am. Chem. Soc. 2014, 136, 15833. (6) Hydrostannation: (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004, 126, 3688. (7) Hydroacylation: (a) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354. (b) Liu, F.; Bugaut, X.; Schedler, M.; Fröhlich, R.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 12626. (8) Hydroformylation: Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804. (9) Hydronitronylation: Li, Z.; Zhao, J.; Sun, B.; Zhou, T.; Liu, M.; Liu, S.; Zhang, M.; Zhang, Q. J. Am. Chem. Soc. 2017, 139, 11702. (10) Hydroamination: Teng, H.-L.; Luo, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2016, 55, 15406. (11) Hydroalkylation: Luo, Y.; Teng, H.-L.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2017, 56, 9207. (12) Carbometalation: (a) Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600. (b) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978. (c) Krämer, K.; Leong, P.; Lautens, M. Org. Lett. 2011, 13, 819. (d) Didier, D.; Delaye, P.-O.; Simaan, M.; Island, B.; Eppe, G.; Eijsberg, H.; Kleiner, A.; Knochel, P.; Marek, I. Chem. - Eur. J. 2014, 20, 1038. (e) Müller, D. S.; Marek, I. J. Am. Chem. Soc. 2015, 137, 15414. (f) Dian, L.; Müller, D. S.; Marek, I. Angew. Chem., Int. Ed. 2017, 56, 6783. (g) Müller, D. S.; Werner, V.; Akyol, S.; Schmalz, H.-G.; Marek, I. Org. Lett. 2017, 19, 3970. (13) Song, G.; O, W. W. N.; Hou, Z. J. Am. Chem. Soc. 2014, 136, 12209. (14) Ionic radius (with coordination number of six): Sc3+ (0.745 Å) < Y3+ (0.900 Å) < Sm3+ (0.958 Å) < La3+ (1.032 Å). See: Shannon, R. D. Acta Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr. 1976, 32, 751.

Scheme 3. Diastereoselectivity Induction by La-1 (A) and La2 (A′)

between the aminomethyl unit and a phenyl substituent in the Cp ligand, thus leading to formation of (1R, 4S, 5R, 6S)-3a. In the case of La-2, the CC double bond coordination to the La atom in a Re-face (A′) would be preferred to give (1R, 4R, 5R, 6S)-3a′, to avoid repulsion between the bulky SiMe3 group at the Cp ring and the aminomethyl unit. In summary, by using two chiral lanthanum complexes (La-1 and La-2) bearing different cyclopentadienyl ligands, we have achieved for the first time the diastereodivergent asymmetric carboamination/annulation of cyclopropenes with aminoalkenes. This transformation involves stereoselective tandem CN and CC bond formation with a highly strained threemembered carbocycle, affording a series of enantiopure unique bicyclic aminocyclopropane derivatives in a 100% atom-efficient fashion with high stereoselectivity.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b10786. Experimental details (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Zhaomin Hou: 0000-0003-2841-5120 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by a Grant-in-Aid for Scientific Research (S) (26220802) and a Grant-in-Aid for Scientific Research on Innovative Areas (17H06451) from JSPS.

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REFERENCES

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DOI: 10.1021/jacs.7b10786 J. Am. Chem. Soc. 2017, 139, 16506−16509