Letter pubs.acs.org/OrgLett
Construction of Distant Stereocenters by Enantioselective Desymmetrizing Carbonyl−Ene Reaction Weiwei Luo,† Lili Lin,† Yu Zhang,† Xiaohua Liu,*,† and Xiaoming Feng*,†,‡ †
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China S Supporting Information *
ABSTRACT: An efficient desymmetrizing carbonyl−ene reaction of 1-substituted 4-methylenecyclohexanes with glyoxal derivatives was thus executed by a chiral N,N′-dioxide/NiII catalyst, providing facile access to cyclohexene derivatives bearing two remote 1,6-related stereocenters. This distal stereocontrol methodology originates from the efficient interaction between the catalyst with enophiles, discrimination of the two chair conformations of olefinic components, and the intrinsic six-membered transition-state structure of ene process.
T
1b).3 However, to the best of our knowledge, a comprehensive study on the asymmetric synthesis of 1,6-related or more distant stereogenic centers has not been carried out, except that a single example of a desymmetrizing glyoxylate−ene reaction was reported with low diastereoselectivity and excellent enantioselectivity using a chiral titanium complex.4 The challenges of such cases are associated not only with their truly substantial distance but also with a weak and unclear stereocommunication between the substrates and catalyst. Enantioselective desymmetrization represents an elegant and powerful strategy to access enantioenriched chiral molecules with complex structures.5 One of the challenges in asymmetric desymmetrization reactions is the controlling stereochemistry remote from the reaction site, and usually enzymes or catalysts of comparable dimensions are needed to differentiate these distant enantiotopic sites.5a,b Over the past decade, remarkable progress has been made in the desymmetrization reactions of prochiral cyclohexanones, such as aldol reaction,6a,b Baeyer−Villiger oxidation,6c Friedländer condensation,6d,e and so on.6f−m The desymmetrization of 4-substituted cyclohexanone-derived phenylhydrazones7a and α,α-dicyanoalkenes7b were also documented by the groups of List and Chen, respectively. All of these approaches required an anchoring group (e.g., −CO, −CN, or −CN) in the 1-position, which is believed to provide a key interaction with the catalyst for asymmetric induction (Figure 1). Therefore, additional catalytic methods without an anchoring group remain in high demand. Desymmetrization of a symmetrical diolefinic substrate by the glyoxylate−ene reactions was demonstrated by the Mikami group with the 1,4-relationship of two hydroxyl groups being
he controlled construction of two stereogenic centers with high levels of diastereo- and enantioselectivity is of great interest to synthetic chemists. Extensive efforts have been made in the establishment of these stereoarrays in close proximity (e.g., 1,2- or 1,3-relationship). In contrast, direct asymmetric entries to stereocenters at more remote sites are less common, although compounds bearing two long-range stereocenters could be obtained from chiral precursors under distant asymmetric induction.1 Noteworthy in this context is the work by Jørgensen on trienamine-mediated formal [4 + 2]-cycloadditions to afford 1,4-related stereogenic centers (Scheme 1a).2b,d Until now, only a single example of a catalytic mode to establish 1,5-related stereogenic centers was reported by the Rueping group, who developed a Brønsted acid promoted desymmetrization of meso1,3-dicarbonyl compounds with o-quinone methides (Scheme Scheme 1. Strategies in Asymmetric Synthesis of Remote Stereocenters
Received: May 2, 2017 Published: June 14, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01329 Org. Lett. 2017, 19, 3374−3377
Letter
Organic Letters
diastereoselectivity (entries 1−3). Poor results were observed by using the aniline-derived ligand L-PiPh, while increasing the steric bulk of the amide substituents benefited the yield and diastereoselectivity (entries 4 and 5). Moreover, decreasing the reaction temperature from 30 to 20 °C resulted in a loss of reactivity but a slight improvement of the diastereoselectivity (entry 6). Further attempts to improve the efficiency were focused on the reaction concentration and temperature. Performing the reaction at 10 °C and increasing the reaction concentration as well as prolonging the reaction time of 4 days furnished the corresponding product in 80% yield with 91:9 dr and 99% ee (entry 8). With the optimized reaction conditions in hand (Table 1, entry 8), the substrate scope of the reaction was next investigated. With respect to the glyoxal derivatives, the diastereo- and enantiocontrol of the reaction were not sensitive to either the electronic properties or the steric hindrance of substituents on the phenyl ring of arylglyoxal, although the yields changed from moderate to excellent (Table 2, entries 1−16). The less reactive substrates containing electron-withdrawing groups or halogen substituents required 20 °C to achieve higher conversions (entries 6, 12, 13, and 16). Moreover, fused-ringsubstituted and heteroaromatic substrates also proved applicable in the reaction, and the corresponding adducts were obtained in
Figure 1. Desymmetrization of substituted cyclohexanone derivatives.
established.8a In 2008, Jacobsen and co-workers reported a desymmetrization of bis(alkenyl) aldehydes and alkenyl dialdehydes via an intramolecular ene process, providing these stereoarrays in very close proximity.8b Employing a catalytic desymmetrizing carbonyl−ene strategy in the synthesis of two distant stereogenic centers with high diastereo- and enantioselectivities is still a challenge, although significant progress has been made in the carbonyl−ene reaction.9 In this paper, we realize this transformation enabled by a chiral Ni(II)−N,N′dioxide complex,9i,10 which may be useful for the construction of more challenging 1,6-related stereocenters (Scheme 1c). Initially, we chose the phenylglyoxal (1a) and 1-tert-butyl-4methylenecyclohexane (2a) as the model substrates to optimize the reaction conditions. Preliminary studies showed that Ni(ClO4)2·6H2O was the potentially optimal metal salt (see the Supporting Information for details). The desired product 3aa was obtained in 45% yield and 77.5:22.5 dr with 99% ee in the presence of Ni(ClO4)2·6H2O and L-proline-derived L-PrPr2 (Table 1, entry 1). Next, chiral ligands with various backbone moieties and steric hindrance were evaluated (entries 2−5). As for the chiral backbone moiety, the L-pipecolic acid derived N,N′dioxide L-PiPr2 was superior to L-proline-derived L-PrPr2 and Lramipril derived L-RaPr 2 in terms of the yield and
Table 2. Substrate Scope for the Glyoxal Derivativesa
Table 1. Optimization of the Reaction Conditionsa
entry
entry
ligand
T (°C)
time (h)
yieldb (%)
drc
eec (%)
1 2 3 4 5 6 7d 8d
L-PrPr2 L-PiPr2 L-RaPr2 L-PiPh L-PiPr3 L-PiPr3 L-PiPr3 L-PiPr3
30 30 30 30 30 20 20 10
24 24 24 24 24 48 72 96
45 73 68 16 82 54 95 80
77.5:22.5 80.5:19.5 80:20 77:23 88:12 90.5:9.5 90:10 91:9
99 99 99 79 99 99 98 99
R1
3
yieldb (%)
1 2 3 4 5 6d
C6H5 2-MeC6H4 3-MeC6H4 3-MeOC6H4 3-ClC6H4 3-O2NC6H4
3aa 3ba 3ca 3da 3ea 3fa
80 94 79 81 79 47 (64)
7 8 9d 10 11 12d
4-MeC6H4 4-tBuC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4
3ga 3ha 3ia 3ja 3ka 3la
75 76 67 81 74 57 (65)
13d 14 15
4-NCC6H4 4-F3CC6H4 3,4(MeO)2C6H3 3,4-Cl2C6H3 1-naphthyl 2-naphthyl 2-thienyl c-hexyl
3ma 3na 3oa 3pa 3qa 3ra 3sa 3ta
16d 17 18 19 20
drc
eec (%) 99 >99 >99 99 >99 >99 (>99)
41 (58) 84 67
91:9 89:11 90:10 91:9 90.5:9.5 90.5:9.5 (89:11) 91:9 90:10 90.5:9.5 90.5:9.5 90:10 91:9 (89.5:10.5) 91:9 (89:11) 99 (>99) >99 99 98 99
98 98 97 >99 >99 >99 (>99) >99 (>99) >99 97
a
Unless specified otherwise, all reactions were performed with Ni(ClO4)2·6H2O/L-PiPr3 (1:1, 10 mol %), 1 (0.1 mmol), 2a (0.5 mmol) in 0.5 mL of CH2Cl2 at 10 °C for 4 days. bIsolated yield, average of two runs. cDetermined by HPLC or SFC analysis on a chiral stationary phase. dThe results in parentheses were obtained at 20 °C for 4 days.
a
Unless specified otherwise, all reactions were performed with Ni(ClO4)2·6H2O/L (1:1, 10 mol %), 1a (0.1 mmol), 2a (0.3 mmol) in 1.0 mL of CH2Cl2. bIsolated yield. cDetermined by HPLC analysis on a chiral stationary phase. dUsing 2a (0.5 mmol) in 0.5 mL of CH2Cl2. 3375
DOI: 10.1021/acs.orglett.7b01329 Org. Lett. 2017, 19, 3374−3377
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Organic Letters high yields with good diastereoselectivities and excellent enantioselectivities (entries 17−19). The catalyst system was also effective when an aliphatic substrate was applied, albeit with a moderate yield (entry 20). Then various 1-substituted 4-methylenecyclohexanes were examined (Scheme 2). The diastereoselectivity increased
Scheme 3. (a) Glyoxylate−Ene Reaction. (b) Gram-Scale Version of the Reaction. (c) Synthetic Utility
Scheme 2. Substrate Scope for 1-Substituted 4Methylenecyclohexanesa
crystallographic analysis of 4a.11 In the meantime, the actual metrics for compound 4a defined a 4.7 Å distance between the two remote stereocenters. Moreover, the ene adduct can also be utilized for the allylcarboxaldehyde synthesis (Scheme 3c).12 Cleavage of hydroxy ketone 3qa with sodium periodate yielded allylcarboxaldehyde bearing a remote stereocenter on the cyclohexene ring. Then the carbonyl group in 5 underwent a facile reduction with NaBH4 to provide homoallylic alcohol 6 in 86% yield with 82% ee. Wittig olefination of the aldehyde group could also give the 1,4-diene in moderate yield with a good ee value. In addition, alkynylative homologation of the aldehyde group (70% yield), followed by a classical click reaction under copper(I)-mediated conditions, led to 1,2,3-triazole 9 in 83% yield with the maintained enantioselectivity.13 In the meantime, the corresponding ketone derivative could be accessed in 90% yield with a dramatic erosion of the chiral center (50% ee) by gold-catalyzed alkyne hydration.14 On the basis of the experimental results and our previous work,9i,10a,b a possible transition-state model is described in Figure 2. The glyoxal derivative is activated through coordination
The reactions were performed with Ni(ClO4)2·6H2O/L-PiPr3 (1:1, 10 mol %), 1a (0.1 mmol), 2 (0.5 mmol) in 0.5 mL of CH2Cl2 at 10 °C for 4 days. bIsolated yield is the average yield of two runs. cThe dr and ee values of the products were determined by HPLC or SFC analysis on a chiral stationary phase. dThe results in parentheses were obtained at 20 °C for 4 days. a
gradually along with improvement of the steric hindrance of the alkyl group, which suggests that the stable conformation of the prochiral methylenecyclohexane could probably benefit the stereocontrol (3aa−ah). Particularly noteworthy is the high enantioselectivity of 98% ee with the modest yield and diastereoselection (46% yield and 66:34 dr) in the silyloxysubstituted product 3ai, probably due to the flexible conformation of the substrate structure. Moreover, the arylsubstituted substrates were applicable, resulting in moderate yields (47−57%) with good diastereoselectivities (between 86:14 and 89:11 dr) and excellent enantioselectivities (up to >99% ee). On the other hand, the 1,1-disubstituted substrate, 4methylene-1-phenylcyclohexane-1-carbonitrile, was totally unreactive. Next, the use of this catalytic system for the glyoxylate−ene reaction was also explored. The freshly distilled 1u reacted well with the olefinic substrates to give the corresponding adducts in comparable yields and stereoselectivities (Scheme 3a). To show the prospect of using this methodology in synthesis, a gram-scale synthesis of 3qa was performed. Treatment of 3.5 mmol of 1q under the optimal reaction conditions smoothly proceeded without compromising the yield or stereoselectivity (Scheme 3b, 95% yield, 90:10 dr, 99% ee). Furthermore, manipulation of the alkenyl group offers opportunities to generate epoxide with low yield, results we attribute to the steric factors and increased complexity with the existence of hydroxyketone moiety (full conversion as monitored by TLC). Therefore, the absolute configuration of 3ka was determined to be (2S,7S) by the X-ray
Figure 2. Proposed stereochemical model. 3376
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(5) For selected reviews, see: (a) García-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313−354. (b) García-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2011, 111, PR110−PR180. (c) Borissov, A.; Davies, T. Q.; Ellis, S. R.; Fleming, T. A.; Richardson, M. S. W.; Dixon, D. J. Chem. Soc. Rev. 2016, 45, 5474−5540. (6) For selected examples, see: (a) Jiang, J.; He, L.; Luo, S.-W.; Cun, L.F.; Gong, L.-Z. Chem. Commun. 2007, 736−738. (b) Companyó, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R. Chem. - Eur. J. 2009, 15, 6564−6568. (c) Zhou, L.; Liu, X. H.; Ji, J.; Zhang, Y. H.; Hu, X. L.; Lin, L. L.; Feng, X. M. J. Am. Chem. Soc. 2012, 134, 17023−17026. (d) Li, L.; Seidel, D. Org. Lett. 2010, 12, 5064−5067. (e) Ren, L.; Lei, T.; Gong, L.Z. Chem. Commun. 2011, 47, 11683−11685. (f) Luo, S.-Z.; Zhang, L.; Mi, X.-L.; Qiao, Y.-P.; Cheng, J.-P. J. Org. Chem. 2007, 72, 9350−9352. (g) Yao, L.; Liu, K.; Tao, H.-Y.; Qiu, G.-F.; Zhou, X.; Wang, C.-J. Chem. Commun. 2013, 49, 6078−6080. (h) Liu, K.; Teng, H.-L.; Yao, L.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2013, 15, 2250−2253. (i) Chen, Y. M.; Lee, P.-H.; Lin, J.; Chen, K. Eur. J. Org. Chem. 2013, 2013, 2699−2707. (j) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834−8837. (k) Liu, R.-R.; Li, B.-L.; Lu, J.; Shen, C.; Gao, J.-R.; Jia, Y.-X. J. Am. Chem. Soc. 2016, 138, 5198−5201. (l) Nimmagadda, S. K.; Mallojjala, S. C.; Woztas, L.; Wheeler, S. E.; Antilla, J. C. Angew. Chem., Int. Ed. 2017, 56, 2454−2458. (m) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem., Int. Ed. 2017, 56, 3694−3698. (7) (a) Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534−18537. (b) Kang, T.-R.; Xie, J.-W.; Du, W.; Feng, X.; Chen, Y.-C. Org. Biomol. Chem. 2008, 6, 2673−2675. (8) (a) Mikami, K.; Narisawa, S.; Shimizu, M.; Terada, M. J. Am. Chem. Soc. 1992, 114, 6566−6568. (b) Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1469−1472. (9) For representative reviews and examples, see: (a) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021−1050. (b) Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003−9031. (c) Liu, X. H.; Zheng, K.; Feng, X. M. Synthesis 2014, 46, 2241−2257. (d) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111, 1940−1941. (e) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824−5825. (f) Yuan, Y.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2003, 42, 5478−5480. (g) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006−8007. (h) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed. 2008, 47, 6798−6801. (i) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc. 2008, 130, 15770− 15771. (j) Zhao, J.-F.; Tsui, H.-Y.; Wu, P.-J.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2008, 130, 16492−16493. (k) Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2014, 53, 6468−6472. (10) (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, 44, 574−587. (b) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem. Front. 2014, 1, 298−302. (c) Zhao, J. N.; Fang, B.; Luo, W. W.; Hao, X. Y.; Liu, X. H.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2015, 54, 241−244. (d) Li, J.; Lin, L. L.; Hu, B. W.; Zhou, P. F.; Huang, T. Y.; Liu, X. H.; Feng, X. M. Angew. Chem., Int. Ed. 2017, 56, 885−888. (11) CCDC 1537907 (4a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre. (12) Achmatowicz, O.; Białecka-Florjańczyk, E.; Goliński, J.; Rozwadowski, J. Synthesis 1987, 1987, 413−415. (13) Liang, X.; Lee, C.-J.; Zhao, J.; Toone, E. J.; Zhou, P. J. Med. Chem. 2013, 56, 6954−6966. (14) Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448−449.
to the nickel(II) in a bidentate fashion by the dicarbonyl group. The Re face of the glyoxal derivative is blocked by the 2,4,6triisopropylphenyl group of the ligand, leading to the predominant Si-face addition. Another stereocontrolling factor is the 1,5-hydrogen shift of the allylic hydrogen. The chair conformation equilibria of the prochiral methylenecyclohexane is affected by the catalyst structure (see the Supporting Information for details), and the preferred conformation loses the adjacent allylic hydrogen based on the model of a six-membered cyclic transition state. Thus, simultaneous discrimination of the prochiral faces of both ene component and enophile results in the generation of the (2S,7S)-configured product. In conclusion, we have developed an efficient catalytic desymmetrization of 1-substituted 4-methylenecyclohexanes by carbonyl−ene reaction, providing expedient access to cyclohexene derivatives bearing two stereocenters in a 1,6-relationship. In particular, this novel strategy proceeds under mild conditions and exhibits a broad substrate scope and functionalgroup tolerance. The excellent stereocontrol is presumably attributed to the efficient interaction between the catalyst with enophiles, discrimination of the two conformations of ene components, and the cyclic pretransition state structure of the process. Further studies on the asymmetric synthesis of more distant stereogenic centers are underway.
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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/acs.orglett.7b01329. Experimental procedures, full spectroscopic data for all new compounds, and 1H and 13C NMR, HPLC, and SFC spectra (PDF) X-ray crystallographic data for compound 4a (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xiaoming Feng: 0000-0003-4507-0478 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We appreciate the National Natural Science Foundation of China (Nos. 21372162 and 21432006) for financial support. REFERENCES
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DOI: 10.1021/acs.orglett.7b01329 Org. Lett. 2017, 19, 3374−3377
