Dynamic Kinetic Resolution of α-Purine Substituted Alkanoic Acids

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Dynamic Kinetic Resolution of α‑Purine Substituted Alkanoic Acids: Access to Chiral Acyclic Purine Nucleosides Huifang Zhang, Mingsheng Xie,* Guirong Qu, and Junbiao Chang* Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China

Downloaded via YORK UNIV on December 17, 2018 at 23:31:45 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An efficient route to construct chiral acyclic purine nucleoside analogues via dynamic kinetic resolution of αpurine substituted alkanoic acids is reported. Using (S)-BTM as the catalyst, diverse chiral acyclic purine nucleoside analogues were obtained in moderate to good yields (up to 93%) and high enantioselectivities (up to 98% ee). Chiral acyclic purine nucleosides could be obtained from the esterified products via reduction reaction, which could then be transferred into Tenofovir analogues.

C

and imides, providing chiral acyclic nucleoside analogues with excellent results (Scheme 1a, top).6a Later, Hartwig and coworkers developed a catalytic asymmetric N-allylation reaction of purines with allylic carbonates, affording chiral N-allylated purines with high regio- and enantioselectivities (Scheme 1a, bottom).7a In 2016, our group introduced an acrylate fragment functionalized to the N9 position of purines and reported the rhodium catalyzed asymmetric hydrogenation of α-purine substituted acrylates (Scheme 1b).8a A number of chiral acyclic purine nucleoside analogues were produced in which the R group was limited to H, Me, or an aryl group. In order to enrich chiral acyclic nucleosides, we introduced an alkanoic acid moiety to the N9 position of purines and synthesized chiral acyclic nucleoside analogues via dynamic kinetic resolution (DKR)9,10 of α-purine substituted alkanoic acids (Scheme 1c). Recently, the kinetic resolution (KR) of racemic α-substituted alkanoic acids has proven to be an efficient route to construct optically active α-substituted alkanoic acids.11−14 In 2008, Shiina and co-workers developed the first KR11a of racemic 2arylalkanoic acids catalyzed by Birman’s benzotetramisole (BTM).12a,14 Later in 2011, Birman et al. reported for the first time the nonenzymatic DKR12f of α-(arylthio)- and α(alkylthio)alkanoic acids where a chiral homobenzotetramisole (HBTM)12c,14 was employed. Subsequently, the nonenzymatic DKR of racemic α-arylalkanoic acids and 2-(1H-pyrrol-1yl)alkanoic acids catalyzed by (R)-BTM was reported by Shiina and co-workers.11g In 2016, Chi and co-workers developed a carbene-catalyzed DKR of carboxylic esters for the synthesis of α,α-disubstituted carboxylic esters with excellent results.13 However, to the best of our knowledge, no examples of catalytic DKR for α-purine substituted alkanoic acids have been reported to date. Herein, we report a catalytic DKR of α-purine

hiral acyclic nucleosides and their phosphonates have received increasing attention due to their significant antivirus activities.1,2 Representative examples are displayed in Figure 1. Tenofovir alafenamide, a phosphoramidate prodrug of

Figure 1. Selected chiral acyclic nucleosides with bioactivities.

Tenofovir, has been approved by the FDA in 2016 for the treatment of HBV infection with outstanding therapeutic effects. 3 (2S,3R)-Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) is an inhibitor of adenosine deaminase.4 Furthermore, the absolute configuration of the chiral center in the side chain has been shown to play an important role in the relevant bioactivities. The S-enantiomer of Cidofovir shows a higher anticytomegalovirus (CMV) activity compared to the Renantiomer.5 Therefore, developing an efficient method to synthesize chiral acyclic nucleosides is highly desirable. Traditional routes to construct chiral acyclic purine nucleoside analogues are based on the nucleophilicity of the N9 position in purines.6−8 In 2005, the Jacobsen’s group reported an aza-Michael addition of purines to α,β-unsaturated ketones © XXXX American Chemical Society

Received: November 7, 2018

A

DOI: 10.1021/acs.orglett.8b03555 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Different Strategies for the Synthesis of Chiral Acyclic Purine Nucleoside Analogues

substituted alkanoic acids, where successive reactions including racemization and selective esterification were involved to synthesize chiral acyclic purine nucleoside analogues (Scheme 1c). Initially, the reaction of α-purine substituted propionic acid 1a and di(1-naphthyl)methanol 2a was selected as a model reaction using i-Pr2NEt as the base and Piv2O as the anhydride in CH2Cl2 at 25 °C (Table 1). When a chiral N-heterocyclic carbene precatalyst C1 was employed, the desired chiral acyclic purine nucleoside analogue 3aa could be formed, albeit in low yield and with poor enantioselectivity (entry 1). As for chiral 4aminopyridine catalyst C2, improved results with an overall 37% yield and 32% ee were obtained (entry 2). When Birman’s (S)-BTM catalyst C3 was used, an up to 73% ee value was observed for product 3aa (entry 3). Then, Birman’s (R)-HBTM catalyst C4 was further examined and similar enantioselectivity was observed along with a low yield (entry 4 vs 3). In the presence of C3 as the catalyst, different nucleophiles including isopropanol 2b, diphenylmethanol 2c, and phenol 2d were studied; however, no improved results were obtained (entries 5−7). Moreover, the screening of anhydrides and bases did not result in any improved results (see Supporting Information for details). Furthermore, several solvents were tested, and the higher polar solvent DMF proved to be the better solvent, providing compound 3aa in 89% yield and 94% ee (entries 8− 11). Lowering the reaction temperature to 15 °C resulted in a slight increase of the ee value (96% ee, entry 12), but a further temperature decrease to 0 °C or −20 °C was detrimental to the yield (entries 13−14). Upon increasing the reaction temperature to 40 °C, the yield for 3aa was maintained, but the enantioselectivity diminished (entry 15). When the catalyst loading was raised from 2 mol % to 5 mol %, the yield of 3aa

entry

cat

ROH

solvent

T (°C)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d

C1 C2 C3 C4 C3 C3 C3 C3 C3 C3 C3 C3 C3 C3 C3 C3

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

DCM DCM DCM DCM DCM DCM DCM toluene CH3CN THF DMF DMF DMF DMF DMF DMF

25 25 25 25 25 25 25 25 25 25 25 15 0 −20 40 15

17 37 67 43 54 53 71 58 77 NR 89 81 58 57 89 93

−29 32 73 74 13 58 5 72 73 − 94 96 95 95 88 96

a

Unless otherwise noted, 1a (0.1 mmol), 2 (0.12 mmol), and catalyst (2 mol %) were added in a test tube. Then, Piv2O (0.36 mmol), iPr2NEt (0.48 mmol), and solvent (1 mL) were added and the reaction was performed for 4 days. NR = No Reaction. bIsolated yield based on 1a. cDetermined by chiral HPLC analysis. dC3 (5 mol %), DMF (1 mL), 4 days.

improved and a yield up to 93% with 96% ee was observed (entry 16). Thus, the optimal reaction conditions were as follows: di(1naphthyl)methanol 2a as the nucleophilic alcohol, Piv2O as the anhydride, and i-Pr2NEt as the base, 5 mol % of (S)-BTM C3 in DMF (1 mL) at 15 °C and stirring for 4 days (entry 16). Under these optimized reaction conditions, the substrate scope of α-purine substituted propionic acids was investigated and the corresponding data can be found summarized in Scheme 2. First, the DKR reaction of α-purine substituted propionic acids 1a−1h with various amino groups at the C6 position of purines was evaluated, generating the corresponding chiral acyclic purine nucleoside analogues 3aa−3ha in moderate to good yields with 94−98% ee. Propionic acids 1i−1k bearing electron-rich alkoxy groups on the C6 position of the purine skeleton were also shown to be suitable reactants, providing the desired products 3ia−3ka in 73−83% yields and 85−92% ee. In the case of propionic acid 1l with an alkyl sulfide substituent on the C6 position of the purine, the chiral acyclic purine nucleoside analogue 3la was produced in good yield, albeit with slightly low enantioselectivity. As for the 6-phenylpurine derived propionic acid 1m, the DKR reaction proceeded well, generating product 3ma in 87% yield and 93% ee. When 6chloropurine derived propionic acid 1n was used, good B

DOI: 10.1021/acs.orglett.8b03555 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scope of α-Purine Substituted Propionic Acidsa

Scheme 3. Substrate Scope of α-Purine Substituted Alkanoic Acidsa

a Unless otherwise noted, reaction conditions were as follows: 1 (0.1 mmol), 2a (0.12 mmol), C3 (5 mol %), Piv2O (0.36 mmol) and iPr2NEt (0.48 mmol) in DMF (1 mL) at 15 °C for 4 days. Isolated yields are reported. The ee values were determined by chiral HPLC analysis. bIn DMF (2 mL) at 0 °C for 8 days.

pentanoic acid 1t and α-purine substituted hexanoic acid 1u, the corresponding esterified products 3ta and 3ua were produced in 72% ee and 76% ee, respectively. Unexpectedly, the isopropylbearing alkanoic acid derivative 1s afforded a better result than Et, n-Pr, or n-Bu substituted alkanoic acid substrates.12f Afterward, the α-purine substituted iso-valeric acids 1v−1x with different amino groups in the C6 position of purines were investigated and the corresponding chiral acyclic purine nucleoside analogues 3va−3xa were obtained with excellent enantioselectivities. When α-purine substituted phenylacetic acid 1y was tested, the desired esterified product 3ya was obtained in 88% yield and 14% ee. It might be the competitive π−π interaction between the aromatic purine moiety and the phenyl group of the substrate 1y with the C2-phenyl group of the catalyst C3.11e,12f To further demonstrate the synthetic applicability using this methodology for constructing chiral acyclic purine nucleoside analogues, the DKR reaction was performed on a 1 mmol scale (Scheme 4a). In the presence of 5 mol % of (S)-BTM C3, the αpurine substituted propionic acid 1a (1 mmol) reacted smoothly with di(1-naphthyl)methanol 2a, affording the desired esterified product (S)-3aa in 90% yield (0.47 g) with 96% ee. Further reduction of (S)-3aa with NaBH4 resulted in the formation of the chiral acyclic purine nucleoside (S)-4aa in 82% yield with 95% ee (Scheme 4a). With adenine derived esterified product 3da as the starting material, the reduction using NaBH4 proceeded well, providing the chiral acyclic purine nucleoside 4da in 78% yield with 96% ee. The latter compound could then

a

Unless otherwise noted, reaction conditions were as follows: 1 (0.1 mmol), 2a (0.12 mmol), C3 (5 mol %), Piv2O (0.36 mmol) and iPr2NEt (0.48 mmol) in DMF (1 mL) at 15 °C for 4 days. Isolated yields are reported. The ee values were determined by chiral HPLC analysis. bIn DMF (2 mL) at −20 °C for 8 days. cIn DMF (2 mL) at 0 °C for 8 days.

enantioselectivity for product 3na could be observed by lowering the reaction temperature to −20 °C. In addition, αpurine substituted propionic acids 1o and 1p, with an amino group in the C2 position of the purines, also proved to be suitable, providing the chiral acyclic purine nucleoside analogues 3oa and 3pa with 90% ee and 94% ee, respectively. Upon using the 2-chloro-6-amino purine derived propionic acid 1q, the corresponding product 3qa was obtained in 98% ee. Via singlecrystal X-ray diffraction analysis, the absolute configuration of the chiral acyclic nucleoside analogue 3qa (CCDC 1867621) was determined to be the (S)-configuration. Subsequently, α-purine substituted alkanoic acids with alkyl groups of different lengths were evaluated in this DKR reaction (Scheme 3). When α-purine substituted butyric acid 1r was examined at 0 °C, the corresponding chiral acyclic nucleoside analogue 3ra was obtained in 84% ee. In the case of α-purine substituted iso-valeric acid 1s, the desired esterified product 3sa was obtained with 93% ee. Upon using α-purine substituted C

DOI: 10.1021/acs.orglett.8b03555 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

■

Scheme 4. Scaled-up Synthesis of 3aa and Derivatization of the Esterified Products

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03555. Experimental procedures, the synthesis method of the starting materials, and compound characterization data (PDF) Accession Codes

CCDC 1867621 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.

■

REFERENCES

(1) (a) De Clercq, E.; Holý, A. Nat. Rev. Drug Discovery 2005, 4, 928. (b) De Clercq, E. Antiviral Res. 2007, 75, 1. (2) (a) Berti, P. J.; McCann, J. A. B. Chem. Rev. 2006, 106, 506. (b) Xie, M.-S.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Tetrahedron Lett. 2014, 55, 7156. (3) (a) Viganò, M.; Loglio, A.; Grossi, G.; Lampertico, P. Expert Rev. Anti-Infect. Ther. 2018, 16, 153. (b) De Clercq, E. Biochem. Pharmacol. 2018, 153, 2. (4) Bessodes, M.; Bastian, G.; Abushanab, E.; Panzica, R. P.; Berman, S. F.; Marcaccio, E. J.; Chen, S.-F.; Stoeckler, J. D.; Parks, R. E. Biochem. Pharmacol. 1982, 31, 879. (5) Pack, E. J.; Bleiberg, B.; Rosenberg, I. E. Chirality 1990, 2, 275. (6) (a) Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 2393. (b) Guo, H.-M.; Yuan, T.-F.; Niu, H.-Y.; Liu, J.-Y.; Mao, R.Z.; Li, D.-Y.; Qu, G.-R. Chem. - Eur. J. 2011, 17, 4095. (c) Wu, H.; Tian, Z. Q.; Zhang, L. L.; Huang, Y. D.; Wang, Y. M. Adv. Synth. Catal. 2012, 354, 2977. (7) (a) Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8971. (b) Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2017, 56, 1520. (c) Kang, S.; Jang, S. H.; Lee, J.; Kim, D.; Kim, M.; Jeong, W.; Rhee, Y. H. Org. Lett. 2017, 19, 4684. (d) Liang, L.; Xie, M.-S.; Qin, T.; Zhu, M.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2017, 19, 5212. (e) Wang, H.; Yu, L.; Xie, M.; Wu, J.; Qu, G.; Ding, K.; Guo, H. Chem. - Eur. J. 2018, 24, 1425. (8) (a) 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. (b) Zhang, Q.; Ma, B.-W.; Wang, Q.-Q.; Wang, X.-X.; Hu, X.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2014, 16, 2014. (9) (a) Pellissier, H. Tetrahedron 2003, 59, 8291. (b) Pellissier, H. Tetrahedron 2008, 64, 1563. (c) Pellissier, H. Tetrahedron 2011, 67, 3769. (10) (a) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org. Lett. 2008, 10, 3191. (b) Lee, S. Y.; Murphy, J. M.; Ukai, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 15149. (c) Piotrowski, D. W.; Kamlet, A. S.; Dechert-Schmitt, A.-M. R.; Yan, J.; Brandt, T. A.; Xiao, J.; Wei, L.; Barrila, M. T. J. Am. Chem. Soc. 2016, 138, 4818. (d) Kinens, A.; Sejejs, M.; Kamlet, A. S.; Piotrowski, D. W.; Vedejs, E.; Suna, E. J. Org. Chem. 2017, 82, 869. (e) Xie, M.-S.; Chen, Y.-G.; Wu, X.-X.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2018, 20, 1212. (11) (a) Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem. 2008, 2008, 5887. (b) Shiina, I.; Nakata, K. Tetrahedron Lett. 2007, 48, 8314. (c) Shiina, I.; Nakata, K.; Sugimoto, M.; Onda, Y.; Iizumi, T.; Ono, K. Heterocycles 2009, 77, 801. (d) Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A. Chem. - Eur. J. 2010, 16, 167. (e) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.; Itagaki, M. J. Am. Chem. Soc. 2010, 132, 11629. (f) Shiina, I.; Ono, K.; Nakata, K. Catal. Sci. Technol. 2012, 2, 2200. (g) Tokumaru, E.; Tengeiji, A.; Nakahara, T.; Shiina, I. Chem. Lett. 2015, 44, 1768. (12) (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (b) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006, 128, 6536. (c) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115. (d) Li, X.; Liu, P.; Houk, K. N.; Birman, V. B. J. Am. Chem. Soc. 2008, 130, 13836. (e) Yang, X.; Birman, V. B. Adv. Synth. Catal. 2009, 351, 2301. (f) Yang, X.; Birman, V. B. Chem. - Eur. J. 2011, 17, 11296. (13) Chen, X.; Fong, J. Z. M.; Xu, J.; Mou, C.; Lu, Y.; Yang, S.; Song, B.-A.; Chi, Y. R. J. Am. Chem. Soc. 2016, 138, 7212. (14) (a) Joannesse, C.; Johnston, C. P.; Concellón, C.; Simal, C.; Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914. (b) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714. (c) West, T. H.; Daniels, D. S.; Slawin, A. M.; Smith, A. D. J. Am. Chem. Soc. 2014, 136, 4476. (d) Wang, H.-Y.; Yang, K.; Yin, D.; Liu, C.; Glazier, D. A.; Tang, W. Org. Lett. 2015, 17, 5272. (e) Wang, H.-Y.; Simmons, C. J.; Zhang, Y.; Smits, A. M.; Balzer, P. G.; Wang, S.; Tang, W. Org. Lett. 2017, 19, 508. (15) Jeffery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron 2000, 56, 5077.

be further transformed into the Tenofovir analogue via phosphomethylation.15 In summary, we have developed an efficient route to synthesize chiral acyclic purine nucleoside analogues via dynamic kinetic resolution of α-purine substituted alkanoic acids using (S)-BTM as a catalyst. A variety of chiral acyclic purine nucleoside analogues were obtained in 64−93% yields with up to 98% ee. This methodology may provide a practical approach for the synthesis of chiral acyclic purine nucleosides and Tenofovir analogues. Furthermore, chiral acyclic purine nucleosides could be obtained from the esterified products via reduction reaction.

■

Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Mingsheng Xie: 0000-0003-4113-2168 Junbiao Chang: 0000-0001-6236-1256 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. 81330075, U1604283, and 21778014) and the 111 Project (No. D17007). D

DOI: 10.1021/acs.orglett.8b03555 Org. Lett. XXXX, XXX, XXX−XXX