Highly Enantioselective Synthesis of Chiral Cyclopropyl Nucleosides

Letter pubs.acs.org/OrgLett

Highly Enantioselective Synthesis of Chiral Cyclopropyl Nucleosides via Catalytic Asymmetric Intermolecular Cyclopropanation Jian-Ping Li, Guo-Feng Zhao, Hai-Xia Wang, Ming-Sheng Xie,* Gui-Rong Qu, and Hai-Ming Guo* 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 construct chiral cyclopropyl purine nucleoside analogues has been established via the catalytic asymmetric Michael-initiated ring-closure reactions of α-purine acrylates with α-bromo-carboxylic esters. Using (DHQD)2AQN as the catalyst, various chiral cyclopropyl purine nucleoside analogues with a chiral quaternary stereocenter were obtained in 72−98% yields, excellent diastereoselectivities, and 93−97% ee. Through simple functional group transformations, diverse chiral cyclopropyl purine nucleosides with hydroxymethyl group or carboxyl group were obtained.

C

(1′S,2′R)-A5021 is nearly 100 times more active than its enantiomer against herpes simplex virus-1 (HSV-1).5b Therefore, searching for an efficient route to the synthesis of chiral cyclopropyl carbocyclic purine nucleoside analogues would be highly desirable. For the synthesis of chiral cyclopropyl purine nucleosides, the traditional approach has been to start from a chiral synthon to construct a chiral cyclopropylamine, and this is followed by construction of the purine skeleton through a reaction with 4,6dichloro-5-formamidopyrimidine (Scheme 1a).6 Nevertheless, the generation of the chiral cyclopropylamine often requires an equivalent chiral starting material and multiple steps that often proceed in low total yields. In 2016, our group reported a highly enantioselective intramolecular cyclopropanation of 3-(purin-9yl) allyl 2-diazoacetates,7 which gives the corresponding cyclopropyl purine nucleoside analogues with three contiguous stereocenters in up to 99% yield and 99% ee (Scheme 1b). However, the formation of 3-(purin-9-yl) allyl 2-diazoacetates always requires multiple steps. The catalytic asymmetric Michael-initiated ring-closure (MIRC) reactions of electrophilic alkenes with ylides or alkyl halides represent one of the most attractive routes to synthesize optically pure cyclopropanes.8−10 In the context of ongoing projects for the synthesis of chiral nucleosides,11 we now wish to report an enantioselective construction of chiral cyclopropyl purine nucleoside analogues via asymmetric MIRC reactions of α-purine acrylates with αbromo carbonyl compounds (Scheme 1c). It is noteworthy that the process yields the chiral cyclopropyl purine nucleoside analogues that have a chiral quaternary stereocenter, which would normally be challenging for construction with good stereocontrol by other methods.12 Initially, α-purine substituted acrylate 1a was selected as a model electrophilic alkene to react with diethyl bromomalonate

arbocyclic nucleosides have attracted considerable attention due to the absence of the labile N-glycosidic bond and have thus far led to the regulatory approval of Abacavir, Carbovir, and Entecavir for the treatment of an infectious viral disease.1 As for carbocyclic nucleosides containing different sizes of the ring, cyclopropyl carbocyclic purine nucleosides have received increasing interest owing to their fixed conformation and potent biological activities.2 As shown in Figure 1, the cyclopropyl

Figure 1. Carbocyclic purine nucleosides with antiviral activities.

carbocyclic purine nucleoside Besifovir was approved as an antihepatitis B virus (HBV) drug in 2017; it exhibits the same antiviral properties as Entecavir over 96 weeks of treatment for chronic HBV patients.3 Meanwhile, the chiral cyclopropyl carbocyclic nucleoside MBX1616 retains good in vitro activity against several common Ganciclovir-resistant UL97 kinase variants of human cytomegalovirus (HCMV).4 In particular, the absolute configuration of the chiral center in cyclopropyl carbocyclic purine nucleoside usually plays a pivotal role in their relevant biological activities.5a Taking A5021 as an example, the © 2017 American Chemical Society

Received: October 5, 2017 Published: November 22, 2017 6494

DOI: 10.1021/acs.orglett.7b03110 Org. Lett. 2017, 19, 6494−6497

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Organic Letters

Table 1. Optimization of the MIRC Reaction Conditionsa

Scheme 1. Different Strategies To Construct Chiral Cyclopropyl Purine Nucleoside Analogues

2a using Cs2CO3 as the base in CH3CN at 0 °C (Table 1). With quinine 4a as the organocatalyst, the MIRC reaction proceeded well, generating the corresponding cyclopropanation product 3aa in 92% yield, albeit in a racemic form (entry 1). After screening several organocatalysts, only racemic 3aa was observed (see Supporting Information for details). Then, α-bromoacetophenone 2b was employed as the nucleophile. However, with quinine 4a as the catalyst, the desired cyclopropanation adduct 3ab was also obtained in a racemic form (entry 2). To our delight, in the case of tert-butyl bromoacetate 2c as the nucleophile, the MIRC adduct 3ac was formed as a single product in 33% yield, >20:1 dr and 76% ee under the same reaction conditions as above (entry 3). Other cinchona alkaloids including dihydroquinine 4b and dihydroquinidine 4c were screened, and the corresponding chiral cyclopropyl purine nucleoside analogue 3ac could be obtained in 23% yield and 80% ee catalyzed by dihydroquinidine 4c (entries 4−5). After that, several C2-symmetric (bis)cinchona alkaloid derivatives 4d−4f based on dihydroquinidine were evaluated, for which (DHQD)2AQN 4f was the better one to give 3ac in 85% yield and 96% ee (entries 6−8). It was found that the base also played a vital role in the reaction. Other inorganic bases, such as Na2CO3, were ineffective, and the K2CO3 was proved slightly inferior to Cs2CO3 (entries 9−11). Subsequently, various solvents were examined, and CH2Cl2 was found to be the better one (entries 11−14). Surprisingly, when the reaction was performed in a mixture solvent of CH2Cl2/CH3CN for 48 h, the cyclopropyl purine nucleoside analogue 3ac arose in improved yield and enantioselectivity (95% yield and 97% ee) (entry 15). When the catalyst loading was lowered from 10 mol % to 5 mol %, the ee value of 3ac was still maintained, but the yield diminished (entry 16). With a decrease of temperature to −10 or −20 °C, the yield of 3ac also decreased, and the ee value was basically stable (entries 19−20). Thus, the optimal reaction conditions were as follows: tert-butyl bromoacetate 2c as the nucleophile, Cs2CO3 as the base, (DHQD)2AQN 4f (10 mol %) in CH2Cl2/CH3CN (2:1) at 0 °C for 48 h (Table 1, entry 15).

entry

2

cat.

base

solvent

1 2d 3 4 5 6 7 8 9e 10 11 12f 13 14 15

2a 2b 2c 2c 2c 2c 2c 2c 2c 2c 2c 2c 2c 2c 2c

4a 4a 4a 4b 4c 4d 4e 4f 4f 4f 4f 4f 4f 4f 4f

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Na2CO3 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

16g

2c

4f

Cs2CO3

17h

2c

4f

Cs2CO3

18i

2c

4f

Cs2CO3

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH2Cl2 dioxane THF DCE CH2Cl2/CH3CN (2:1) CH2Cl2/CH3CN (2:1) CH2Cl2/CH3CN (2:1) CH2Cl2/CH3CN (2:1)

t (h)

yield (%)b

ee (%)c

12 12 24 24 24 24 24 24 24 24 48 48 48 48 48

92 47 33 20 23 71 51 85 NR 32 56 36 23 61 95

0 0 −76 −77 80 90 84 96

48

42

97

48

89

97

48

36

97

94 97 91 96 95 97

a

Unless otherwise noted, the reaction conditions are as follows: 1a (0.1 mmol), 2a−2c (0.11 mmol), cat. (10 mol %), and base (1.1 equiv) in solvent (1 mL) at 0 °C. bIsolated yield. cDetermined by chiral HPLC analysis. dThe main product was obtained with a 4:1 dr, which was determined by crude 1H NMR analysis. eNR = no reaction. f At rt. gCatalyst: 5 mol %. hAt −10 °C. iAt −20 °C.

Under the optimized reaction conditions, the substrate scope of the asymmetric MIRC reactions was explored (Scheme 2). First, several 6-chloro-purine derived acrylates 1a−1e with different ester groups were investigated, and the desired chiral cyclopropyl purine nucleoside analogues 3ac−3ec were afforded in 89−95% yields with 95−97% ee. The absolute configuration of the chiral cyclopropyl purine nucleoside analogue 3ac was determined to be (1S,2R) by the single-crystal X-ray diffraction analysis. Next, the cyclopropanation reactions of α-purine substituted acrylates 1f−1m with amino, alkoxy, or alkyl sulfide group at the C6 position were performed, generating the corresponding cyclopropyl purine nucleoside nucleosides 3fc− 3mc in 84−98% yields with 93−97% ee. In the case of acrylates 6495

DOI: 10.1021/acs.orglett.7b03110 Org. Lett. 2017, 19, 6494−6497

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Organic Letters Scheme 2. Substrate Scope of the Reactionsa

bromoacetate 2e, or isopropyl 2-bromoacetate 2f was used, the corresponding cyclopropyl purine nucleoside analogues 3ad− 3af were afforded in 79−92% yields with 94−96% ee. As for benzyl 2-bromoacetate 2g, the desired cyclopropanation adduct 3ag was generated in 90% yield and 94% ee. It should be noted that the diastereoselectivities are >20:1 for all the chiral cyclopropyl purine nucleoside analogues. To further evaluate the prospect of using the methodology for constructing chiral cyclopropyl purine nucleoside analogues, the MIRC reaction was carried out on 1 mmol scale (Scheme 3). In Scheme 3. Scale-up Synthesis of 3ac

the presence of 10 mol % of 4f, 1 mmol of α-purine substituted acrylate 1a reacted smoothly with tert-butyl bromoacetate 2c, affording 0.32 g (87% yield) of the desired adduct 3ac with 92% ee, which could be improved to 99% ee after a single recrystallization. Subsequently, additional functional group transformations of the cyclopropanation product 3ac were performed to obtain diverse chiral cyclopropyl purine nucleoside analogues (Scheme 4). When NaBH4 was used as the reducing Scheme 4. Synthesis of Diverse Nucleoside Analogues

a

Unless otherwise noted, the reaction conditions were as follows: 1 (0.1 mmol), 2 (0.11 mmol), Cs2CO3 (0.11 mmol), 4f (10 mol %) in CH2Cl2/CH3CN = 2/1 (0.66 mL/0.34 mL) at 0 °C for 48 h. The yields refer to the isolated yield, and the ee values were determined by HPLC analysis. bAt 0 °C for 72 h. cIn THF (1.0 mL).

agent, only the ethyl ester group was reduced to the hydroxymethyl group, giving nucleoside 4ac in 92% yield and 97% ee, which could be further reduced to nucleoside 5ac with two vicinal hydroxymethyl groups in 61% yield and 96% ee under DIBAL-H conditions (Scheme 4a). In the presence of the excess of DIBAL-H, both the ethyl ester and tert-butyl ester groups in 3ac could be reduced, affording the nucleoside 5ac with two vicinal hydroxymethyl groups in 42% yield and 97% ee, which could be converted to the adenine-derived cyclopropyl purine nucleoside 6ac in 52% yield and 95% ee (Scheme 4b). Moreover, the tert-butyl ester group in 3ac could be hydrolyzed, giving

1n−1o with a phenyl or hydrogen at the C6 position of purines, the desired cyclopropyl purine nucleoside analogues 3nc−3oc were obtained in 72−90% yields with 95−97% ee. Furthermore, these α-purine substituted acrylates 1p−1r with a chlorine atom at the C2 position were also good partners, delivering the desired cyclopropyl purine nucleoside analogues 3pc−3rc in 86−95% yields with 93−95% ee. Subsequently, several α-bromocarboxylic esters 2d−2g with different ester groups were investigated. When methyl 2-bromoacetate 2d, ethyl 26496

DOI: 10.1021/acs.orglett.7b03110 Org. Lett. 2017, 19, 6494−6497

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Organic Letters

Yoon, S. K.; Lee, J. W.; Park, N. H.; Kweon, Y. O.; Sohn, J. H.; Lee, J.; Kim, J. A.; Han, K. H.; Yuen, M. F. Gut 2014, 63, 996. (c) Yuen, M.-F.; Ahn, S. H.; Lee, K. S.; Um, S. H.; Cho, M.; Yoon, S. K.; Lee, J.-W.; Park, N. H.; Kweon, Y.-O.; Sohn, J. H.; Lee, J.; Kim, J.-A.; Lai, C.-L.; Han, K.H. J. Hepatol. 2015, 62, 526. (4) (a) Chou, S.; Komazin-Meredith, G.; Williams, J. D.; Bowlin, T. L. Antimicrob. Agents Chemother. 2014, 58, 1809. (b) Komazin-Meredith, G.; Chou, S.; Prichard, M. N.; Hartline, C. B.; Cardinale, S. C.; Comeau, K.; Williams, J. D.; Khan, A. R.; Peet, N. P.; Bowlin, T. L. Antimicrob. Agents Chemother. 2014, 58, 274. (5) (a) Rybak, R. J.; Hartline, C. B.; Qiu, Y.-L.; Zemlicka, J.; Harden, E.; Marshall, G.; Sommadossi, J.-P.; Kern, E. R. Antimicrob. Agents Chemother. 2000, 44, 1506. (b) Choi, J.-R.; Cho, D.-G.; Roh, K. Y.; Hwang, J.-T.; Ahn, S.; Jang, H. S.; Cho, W.-Y.; Kim, K. W.; Cho, Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. Chem. 2004, 47, 2864. (6) (a) Zhao, Y.; Yang, T.; Lee, M.; Lee, D.; Newton, M. G.; Chu, C. K. J. Org. Chem. 1995, 60, 5236. (b) Zhao, Y.-F.; Lee, M. G.; Yang, T.-F.; Chun, B. K.; Du, J. F.; Schinazi, R. F.; Chu, C. K. Nucleosides, Nucleotides Nucleic Acids 1995, 14, 303. (7) (a) Huang, K.-X.; Xie, M.-S.; Zhao, G.-F.; Qu, G.-R.; Guo, H.-M. Adv. Synth. Catal. 2016, 358, 3627. (b) Racine, S.; de Nanteuil, F.; Serrano, E.; Waser, J. Angew. Chem., Int. Ed. 2014, 53, 8484. (c) Xie, M.S.; Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2016, 18, 4344. (8) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (b) Pellissier, H. Tetrahedron 2008, 64, 7041. (c) Candeias, N. R.; Paterna, R.; Gois, P. M. P. Chem. Rev. 2016, 116, 2937. (d) Shitama, H.; Katsuki, T. Angew. Chem., Int. Ed. 2008, 47, 2450. (e) Lacasse, M.-C.; Poulard, C.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440. (9) (a) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 13410. (b) Khan, A. T.; Das, D. K. Tetrahedron Lett. 2012, 53, 2345. (c) Sousa, J. L. C.; Talhi, O.; Mendes, R. F.; Almeida Paz, F. A.; Bachari, K.; Silva, A. M. S. Eur. J. Org. Chem. 2016, 2016, 3949. (d) Muller, D. S.; Marek, I. J. Am. Chem. Soc. 2015, 137, 15414. (e) Fedotova, A. I.; Komarova, T. A.; Romanov, A. R.; Ushakov, I. A.; Legros, J.; Maddaluno, J.; Rulev, A. Y. Tetrahedron 2017, 73, 1120. (f) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (10) (a) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 4641. (b) Johansson, C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024. (c) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828. (d) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596. (e) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024. (f) Zhang, Y.; Lin, L.; Chen, Y.; Liu, X.; Feng, X. Adv. Synth. Catal. 2017, 359, 1831. (g) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (11) (a) Liang, L.; Xie, M.-S.; Qin, T.; Zhu, M.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2017, 19, 5212. (b) Sun, H.-L.; Chen, F.; Xie, M.-S.; Guo, H.M.; Qu, G.-R.; He, Y.-M.; Fan, Q.-H. Org. Lett. 2016, 18, 2260. (c) 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. (d) Yang, Q. L.; Xie, M.-S.; Xia, C.; Sun, H.-L.; Zhang, D.-J.; Huang, K.-X.; Guo, Z.; Qu, G.-R.; Guo, H.-M. Chem. Commun. 2014, 50, 14809. (12) (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5363. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591.

cyclopropanecarboxylic acid 7ac in 72% yield and 93% ee, which was determined by conversion to methyl esterification product 3ad (Scheme 4c). In summary, we have developed an efficient route to chiral cyclopropyl purine nucleoside analogues via the organocatalytic Michael-initiated ring-closure reactions of α-purine acrylates with α-bromo-carboxylic esters. In the presence of (DHQD)2AQN 4f as the catalyst, a variety of chiral cyclopropyl purine nucleoside analogues were obtained with a chiral quaternary stereocenter in 72−98% yield, >20:1 dr, and 93− 97% ee. The cyclopropanation products further underwent functional group transformations to afford new chiral cyclopropyl purine nucleosides containing hydroxymethyl and carboxyl groups.

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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.7b03110. Experimental procedures, synthesis method of the starting materials, and compound characterization data (PDF) Accession Codes

CCDC 1585063 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 emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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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.

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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (No. 21472037 and U1604182), the Plan for Scientific Innovation Talent of Henan Province (164200510008), China Postdoctoral Science Foundation funded project (2016M592293), Program for Innovative Research Team in Science and Technology in University of Henan Province (15IRTSTHN003), and the 111 Project (No. D17007).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03110 Org. Lett. 2017, 19, 6494−6497