Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Synthesis of Carbocyclic Nucleosides via Asymmetric [3 + 2] Annulation of α‑Purine-Substituted Acrylates with MBH Carbonates Ke-Xin Huang,† Ming-Sheng Xie,*,‡ Qi-Ying Zhang,‡ Gui-Rong Qu,‡ and Hai-Ming Guo*,†,‡ †
School of Environment and ‡Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China S Supporting Information *
ABSTRACT: An efficient route to chiral carbocyclic nucleoside analogues containing a quaternary stereocenter and a CC double bond has been established via a highly enantioselective [3 + 2] annulation of Morita−Baylis−Hillman (MBH) carbonates with α-purine-substituted acrylates. With 20 mol % (S)-SITCP as the catalyst, various chiral carbocyclic nucleoside analogues with a quaternary stereocenter and a CC double bond were obtained in high yields (up to 92%) with good diastereoselectivities (up to 10:1 dr) and excellent enantioselectivities (up to 96% ee). Furthermore, the corresponding products were subjected to diverse transformations to afford interesting and potentially useful chiral carbocyclic nucleosides.
D
been devoted to the construction of more elaborated chiral carbocyclic nucleosides that also feature potential antiviral activities.4 For example, abacavir,5a carbovir,5b and entecavir,5c featuring a CC double bond in the cyclopentyl moiety, have been approved by the FDA for the treatment of HIV and HBV infection, respectively. Therefore, the development of efficient routes to synthesize chiral carbocyclic nucleosides containing a quaternary stereocenter and a CC double bond still represents a crucial goal in synthetic organic chemistry. The construction of chiral carbocyclic nucleosides typically involves two separate approaches: (1) Traditional methods have been based on a linear approach or a convergent synthesis requiring multiple steps from an equivalent chiral pool.6 Recently, Zhang and co-workers reported the asymmetric hydroformylation of cyclopentenes, providing chiral carbocyclic nucleosides via a linear approach. (Scheme 1a).7 (2) Other approaches such as ring-closing metathesis8 and cycloaddition reactions9 have been shown to be more efficient and favorable. For example, in 2015, our group reported the Pd-catalyzed asymmetric annulation of α-nucleobase-substituted acrylates with vinyl cyclopropanes.9b Chiral carbocyclic nucleosides were obtained with moderate to good enantioselectivities, but the corresponding diastereoselectivities were very low (Scheme 1b). As part of our ongoing interest in constructing chiral nucleoside analogues,10 we now report an efficient route for the synthesis of more elaborated chiral carbocyclic nucleosides. The phosphinecatalyzed [3 + 2] annulation between electron-deficient olefins
uring the past decade, chiral cyclic nucleosides and their derivatives have attracted considerable attention because of the outstanding antivirus and antitumor activities exhibited by this compound class.1 In addition to bioactive natural nucleoside products, a series of more elaborate nucleoside scaffolds have also been developed. As shown in Figure 1, sofosbuvir2a and EfdA,2b containing a quaternary stereocenter, have demonstrated interesting biological activities. In particular, GS-5734 was found to be active against the Ebola virus.3 Here, the 1′-CN group and C-linked nucleobase have been shown to be necessary for the corresponding activity. Since the cyclopentyl group exhibits structural similarity to the furan moiety, efforts have
Figure 1. Selected chiral cyclic nucleosides exhibiting biological activities. © XXXX American Chemical Society
Received: November 27, 2017
A
DOI: 10.1021/acs.orglett.7b03625 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Different Strategies To Construct Chiral Carbocyclic Nucleoside Analogues
and Morita−Baylis−Hillman (MBH) carbonates represents a particularly attractive route for the construction of optically pure cyclopentanes, affording the corresponding cyclopentane products in high yields with excellent enantioselectivities.11 To the best of our knowledge, only a few examples of enantioselective reactions involving carbocyclic nucleoside analogues have been reported to date. In this work, we have implemented this strategy to provide enantioenriched carbocyclic nucleosides with a quaternary stereocenter and a CC double bond in the cyclopentyl moiety from α-purinesubstituted acrylates and MBH carbonates (Scheme 1c). We initiated our methodological studies with α-purinesubstituted acrylates 1a and MBH carbonate 2a using C1 as the catalyst in CH2Cl2 at room temperature (Table 1). Unfortunately, no corresponding product was obtained (entry 1). Fortunately, when the biphosphine catalyst C2 was used, the carbocyclic nucleoside analogue 3aa was obtained in 81% yield with 5:1 dr and 25% ee (entry 2). Afterward, we focused our attention on the use of other biphosphine catalysts C3−C5, but no improved results were obtained (entries 3−5). Furthermore, the bifunctional phosphine catalyst C611n and the Kwon phosphine catalyst C711m exhibited poor catalytic abilities (entries 6 and 7). However, when the spirocyclic chiral phosphine catalyst C8 was used, the desired product was obtained in 85% yield with 9:1 dr and 72% ee (entry 8). Moreover, various solvents were tested in the presence of 20 mol % C8, and CH2Cl2 was demonstrated to be the best solvent (entries 8−11). Further evaluation of the reaction temperature showed that −10 °C was the appropriate choice, delivering 3aa in 83% yield with 9:1 dr and 91% ee (entries 12−14). In order to increase the stereoselectivity of carbocyclic nucleoside analogue 3, different ester groups were screened (Table 2). When α-purine-substituted methyl acrylate 1c was used and the steric hindrance of the ester group in the MBH carbonate was increased from methyl (2a) to ethyl (2b) or tertbutyl (2c), the diastereoselectivity and enantioselectivity decreased significantly (entries 2−4). Furthermore, various ester groups in the α-purine-substituted acrylate were tested (entries 5 and 6). In doing so, we demonstrated that the αpurine-substituted methyl acrylate species 1c and methyl MBH carbonate 2a represented the most suitable reaction partners, delivering 3ca in 89% yield with 9:1 dr and 94% ee (entry 2).
entry
cat.
temp (°C)
solvent
yield (%)b
drc
ee (%)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14
C1 C2 C3 C4 C5 C6 C7 C8 C8 C8 C8 C8 C8 C8
rt rt rt rt rt rt rt rt rt rt rt 0 −10 −20
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF toluene DCE CH2Cl2 CH2Cl2 CH2Cl2
NR 81 92 89 12 21 NR 85 trace 85 74 86 83 trace
− 5:1 5:2 3:1 − − − 9:1 − 9:1 9:1 9:1 9:1 −
− 25 17 10 7 3 − 72 − 70 72 87 91 −
a Reaction conditions: cat. (20 mol %), 1a (0.05 mmol), and 2a (0.06 mmol) in solvent (1.0 mL) under N2 atmosphere for 4 days. bIsolated yields. cDetermined by 1H NMR analysis of the crude products. d Determined by chiral HPLC analysis.
Table 2. Screening of Various Reactant Ester Groupsa
entry
1 (R3)
2 (R4)
product
yield (%)b
drc
ee (%)d
1 2 3 4 5 6 7e
1a (Et) 1c (Me) 1c (Me) 1c (Me) 1a (Et) 1b (t-Bu) 1c (Me)
2a (Me) 2a (Me) 2b (Et) 2c (t-Bu) 2b (Et) 2a (Me) 2a (Me)
3aa 3ca 3cb 3cc 3ab 3ba 3ca
83 89 87 52 87 82 56
9:1 9:1 8:1 7:1 8:1 7:1 9:1
91 94 86 60 77 76 89
a
Reaction conditions: C8 (20 mol %), 1 (0.05 mmol), and 2 (0.06 mmol) in CH2Cl2 (1.0 mL) under N2 atmosphere for 4 days. bIsolated yields. cDetermined by 1H NMR analysis of the crude products. d Determined by chiral HPLC analysis. eCatalyst: 10 mol %.
When the catalyst loading was lowered from 20 to 10 mol %, the ee value along with the yield decreased significantly (entry 7). With the optimal reaction conditions in hand, the substrate scope of α-purine-substituted acrylates was investigated. The corresponding data are summarized in Scheme 2. In most cases, the reaction proceeded well and was complete within 4 days. B
DOI: 10.1021/acs.orglett.7b03625 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scope of α-Purine-Substituted Acrylatesa
Table 3. Substrate Scope of MBH Carbonatesa
entry
R5
product
yield (%)b
drc
ee (%)d
1 2 3 4 5 6 7 8 9 10 11 12 13
Ph 3-FC6H4 3-ClC6H4 3-BrC6H4 2-ClC6H4 4-NO2C6H4 4-CNC6H4 4-CH3C6H4 4-CH3OC6H4 1-naphthyl 2-naphthyl 3,4-Cl2C6H3 3,4-(CH3)2C6H3
3ca 3cd 3ce 3cf 3cg 3ch 3ci 3cj 3ck 3cl 3cm 3cn 3co
89 82 86 85 73 87 86 81 83 87 82 84 85
9:1 9:1 9:1 9:1 10:1 9:1 10:1 9:1 9:1 10:1 9:1 9:1 9:1
94 90 92 94 92 92 90 96 94 96 92 92 96
a
Reaction conditions: C8 (20 mol %), 1c (0.05 mmol), and 2d−o (0.06 mmol) in CH2Cl2 (1.0 mL) at −10 °C under N2 atmosphere for 4 days. bIsolated yields. cDetermined by 1H NMR analysis of the crude products. dDetermined by chiral HPLC analysis.
with good diastereoselectivities (9:1−10:1 dr) and excellent enantioselectivities (90−96% ee) (entries 2−9). When 1naphthyl- and 2-naphthyl-substituted MBH carbonates were used, the desired products 3cl and 3cm were obtained with excellent enantioselectivities (92%−96% ee) (entries 10 and 11). In the case of dichloro- and dimethyl-substituted MBH carbonates, the corresponding reactions provided the desired products 3cn and 3co in 84−85% yield with 9:1 dr and 92−96% ee (entries 12 and 13). However, no desired product was obtained when methyl-substituted MBH carbonate was employed in this reaction. To evaluate the potential of the chiral cyclopentyl purine nucleosides, additional transformations were conducted (Scheme 3). In the presence of NaBH4, hydrogenation of the
a
Unless otherwise noted, the reaction conditions were as follows: C8 (20 mol %), 1c−l (0.05 mmol), and 2a (0.06 mmol) in CH2Cl2 (1.0 mL) at −10 °C under N2 atmosphere for 4 days. The dr values were determined by 1H NMR analysis of the crude products. Yields refer to the isolated products. The ee values were determined by chiral HPLC analysis. b0 °C, 5 days.
Interestingly, introducing different substituents into the purine skeleton seemed to have little effect on the reaction outcome. The presence of α-purine-substituted acrylates bearing halogen, amino, alkoxy, phenyl, alkyl sulfide, and hydrogen substituents at C6 on the purine skeleton resulted in the formation of the corresponding carbocyclic nucleoside analogues 3ca−ia in high yields (83−92%) with good diastereoselectivities (9:1−10:1 dr) and excellent enantioselectivities (90−94% ee). However, a low yield was observed in the annulation of 3ja using a 2,6dichloropurine-derived acrylate, and full conversion and excellent ee were achieved at a reaction temperature of 0 °C with a longer reaction time. Other substrates bearing a chloro substituent at C2 of the purine skeleton were also demonstrated to perform well using the standard conditions, delivering the desired products 3ka−la in 83−85% yield with 9:1−10:1 dr and 92% ee. When guanine-derived acrylate 1m was evaluated, the desired carbocyclic nucleoside analogue 3ma was obtained in 32% yield with 7:1 dr and 85% ee. By single-crystal X-ray diffraction analysis, the absolute configuration of carbocyclic nucleoside analogue 3ca was determined to be (1R,2S). The scope of the MBH carbonates was also explored (Table 3). In general, different substituent patterns were tolerated. Both electron-withdrawing groups (Me, OMe) and electron-donating groups (F, Cl, Br, NO2, CN) on the aromatic ring could provide the carbocyclic nucleoside analogues 3cd−ck in 73−87% yield
Scheme 3. Transformations of 3ca
product 3ca proceeded smoothly, affording the desired product 4ca in 92% yield with 93% ee. Furthermore, reduction of the enantioenriched carbocyclic nucleoside 4ca with DIBAL-H generated 5ca with two hydroxymethyl groups in 57% yield with 91% ee. Finally, the dihydroxylation of 3ca could be conducted efficiently, affording the carbocyclic nucleoside 6ca in 81% yield with 16:1 dr. C
DOI: 10.1021/acs.orglett.7b03625 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Orden, S.; Esplugues, J. V. Antiviral Res. 2017, 141, 179. (c) Langley, D. R.; Walsh, A. W.; Baldick, C. J.; Eggers, B. J.; Rose, R. E.; Levine, S. M.; Kapur, A. J.; Colonno, R. J.; Tenney, D. J. J. Virol. 2007, 81, 3992. (6) (a) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875. (b) Katagiri, N.; Nomura, M.; Sato, H.; Kaneko, C.; Yusa, K.; Tsuruo, T. J. Med. Chem. 1992, 35, 1882. (c) Vázquez-Romero, A.; Rodríguez, J.; Lledó, A.; Verdaguer, X.; Riera, A. Org. Lett. 2008, 10, 4509. (d) Marcé, P.; Díaz, Y.; Matheu, M. I.; Castillón, S. Org. Lett. 2008, 10, 4735. (e) Trost, B. M.; Madsen, R.; Guile, S. G.; Elia, A. E. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1569. (f) Boyle, G. A.; Edlin, C. D.; Li, Y.; Liotta, D. C.; Morgans, G. L.; Musonda, C. C. Org. Biomol. Chem. 2012, 10, 1870. (7) You, C.; Wei, B.; Li, X.; Yang, Y.; Liu, Y.; Lv, H.; Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 6511. (8) (a) Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jung, Y. H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490. (b) Jin, Y. H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu, C. K. J. Org. Chem. 2003, 68, 9012. (c) Fang, Z.; Hong, J. H. Org. Lett. 2004, 6, 993. (d) Mulamoottil, V. A.; Nayak, A.; Jeong, L. S. Asian J. Org. Chem. 2014, 3, 748. (e) Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2017, 56, 1520. (9) (a) Racine, S.; de Nanteuil, F.; Serrano, E.; Waser, J. Angew. Chem., Int. Ed. 2014, 53, 8484. (b) Xie, M.-S.; Wang, Y.; Li, J.-P.; Du, C.; Zhang, Y.-Y.; Hao, E.-J.; Zhang, Y.-M.; Qu, G.-R.; Guo, H.-M. Chem. Commun. 2015, 51, 12451. (10) (a) Liang, L.; Xie, M.-S.; Qin, T.; Zhu, M.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2017, 19, 5212. (b) Li, J.-P.; Zhao, G.-F.; Wang, H.-X.; Xie, M.S.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2017, 19, 6494. (c) Xie, M.-S.; Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2016, 18, 4344. (d) Huang, K.-X.; Xie, M.-S.; Zhao, G.-F.; Qu, G.-R.; Guo, H.-M. Adv. Synth. Catal. 2016, 358, 3627. (11) (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (b) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (c) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (d) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. (e) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (f) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc. 2011, 133, 4672. (g) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426. (h) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2012, 354, 783. (i) Ni, H.; Yu, Z.; Yao, W.; Lan, Y.; Ullah, N.; Lu, Y. Chem. Sci. 2017, 8, 5699. (j) Liu, Y.; Yang, W.; Wu, Y.; Mao, B.; Gao, X.; Liu, H.; Sun, Z.; Xiao, Y.; Guo, H. Adv. Synth. Catal. 2016, 358, 2867. (k) Wang, K.-K.; Jin, T.; Huang, X.; Ouyang, Q.; Du, W.; Chen, Y.-C. Org. Lett. 2016, 18, 872. (l) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Angew. Chem., Int. Ed. 2016, 55, 2147. (m) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding, L.; Dudding, T.; Kwon, O. J. Am. Chem. Soc. 2014, 136, 11890. (n) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837. (o) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew. Chem., Int. Ed. 2010, 49, 4467. (p) Zhong, F.; Chen, G.Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764.
In summary, we have developed a simple and efficient approach to chiral cyclopentyl purine nucleosides via highly enantioselective [3 + 2] annulation of aryl MBH carbonates with α-purine-substituted acrylates. With 20 mol % (S)-SITCP as the catalyst, various chiral cyclopentyl purine nucleoside analogues containing a quaternary stereocenter and a CC double bond were obtained in 32−92% yield with 7:1−10:1 dr and 85%−96% ee. Furthermore, the products could undergo diverse transformations to afford interesting and potentially useful chiral carbocyclic nucleosides.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03625. Experimental procedures, synthesis of the starting materials, and compound characterization data (PDF) Accession Codes
CCDC 1587043 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Hai-Ming Guo: 0000-0003-0629-4524 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21372066, 21472037, 21672055, and 21602045), the Plan for Scientific In n o v a t i o n T a l e n t o f H e na n Pr o v i n c e (164200510008), the Program for Innovative Research Team in Science and Technology in University of Henan Province (15IRTSTHN003), and the 111 Project (D17007) for support.
■
REFERENCES
(1) (a) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122, 5947. (b) Kakuda, T. N. Clin. Ther. 2000, 22, 685. (2) (a) Zhen, L.; Dai, L.; Wen, X.; Yao, L.; Jin, X.; Yang, X.-W.; Zhao, W.; Yu, S.-Q.; Yuan, H.; Wang, G.; Sun, H. J. Med. Chem. 2017, 60, 6077. (b) Kageyama, M.; Nagasawa, T.; Yoshida, M.; Ohrui, H.; Kuwahara, S. Org. Lett. 2011, 13, 5264. (3) Siegel, D.; Hui, H. C.; Doerffler, E.; Clarke, M. O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B.; Wang, Q.; Wolfe, L.; Jordan, R.; Soloveva, V.; Knox, J.; Perry, J.; Perron, M.; Stray, K. M.; Barauskas, O.; Feng, J. Y.; Xu, Y.; Lee, G.; Rheingold, A. L.; Ray, A. S.; Bannister, R.; Strickley, R.; Swaminathan, S.; Lee, W. A.; Bavari, S.; Cihlar, T.; Lo, M. K.; Warren, T. K.; Mackman, R. L. J. Med. Chem. 2017, 60, 1648. (4) Boutureira, O.; Matheu, M. I.; Díaz, Y.; Castillón, S. Chem. Soc. Rev. 2013, 42, 5056. (5) (a) Wang, L. H.; Chittick, G. E.; McDowell, J. A. Antimicrob. Agents Chemother. 1999, 43, 1708. (b) Alvarez, A.; Rios-Navarro, C.; BlanchRuiz, M. A.; Collado-Diaz, V.; Andujar, I.; Martinez-Cuesta, M. A.; D
DOI: 10.1021/acs.orglett.7b03625 Org. Lett. XXXX, XXX, XXX−XXX
