Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution for the Construction of Carbocyclic N3-Purine Nucleosides

Qiying Zhang Yiming Zhang Erjun Hao Juan Bai Guirong Qu Haiming Guo

Citation:  Zhang Qiying, Zhang Yiming, Hao Erjun, Bai Juan, Qu Guirong, Guo Haiming. Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution for the Construction of Carbocyclic N3-Purine Nucleosides[J]. Chinese Journal of Organic Chemistry, 2020, 40(2): 376-383. doi: 10.6023/cjoc201907053 shu

通过不对称氢转移/动态动力学拆分合成碳环N3-嘌呤核苷

    通讯作者: 郭海明, ghm@htu.edu.cn
  • 基金项目:

    国家自然科学基金 U1604283

    高等学校学科创新引智计划 D17007

    国家自然科学基金 21602045

    国家自然科学基金(Nos.21602045,U1604283)和高等学校学科创新引智计划(111计划,No.D17007)资助项目

摘要: N3-嘌呤核苷由于可能同时被嘌呤和嘧啶代谢酶识别,因而有望作为双靶点药物应用于抗病毒治疗.报道了一种以α-(N3-嘌呤)取代的环烷酮为原料,通过不对称氢转移反应实现动态动力学拆分,高收率高立体选择性地合成系列碳环N3-嘌呤核苷化合物.该催化体系也适用于α-嘧啶取代的环烷酮底物,且产物通过进一步衍生,合成了2'-F-,AcS-,N3-修饰的碳环嘧啶核苷.

English

  • In antiviral chemotherapy, chiral nucleosides analogs have played an important role, [1] however, because of arising viral resistances, many current chemotherapeutics have become less effective.[2] For example, lamivudine[2c] and emtricitabine have shown a strong inhibitory effect against HBV, however, drug resistance became increasingly prominent after their long-term use.[3] Recently, the success of dual inhibitors has opened new avenues for circumventing viral resistances. Among the dual inhibitors, one type of inhibitors could be recognized by two different enzymes in the same, or different mechanistic pathways that are involved in the same disease.[4] This would increase the chances for the effective inhibition of the virus replication. Furthermore, the dual inhibitors altered the classical way of thinking about the structures of nucleoside analogues as antiviral agents. We envisioned that a nucleoside drug could be possibly recognized by both purine- and pyrimidine-metabolizing enzymes if it contained the key structural features of the purine and pyrimidine nucleobases scaffolds. Accordingly, we selected N3-purine nucleoside as a crucial target compound because it resembled both purine and pyrimidine nucleoside and could be viewed as either N3-ribosylated purine or 5, 6-disubstituted pyrimidine, as shown in Figure 1. Despite the considerable efforts devoted to the research of chiral nucleoside analogs, [5, 6] the enantioselective preparation of N3-purine nucleosides is more challenging and less explored probably because of the difficulty in the formation of 3H-purine.[7, 8] In 2009, Seley-Radtke et al.[8a] synthesized several N3-purine nucleosides from an equivalent pyrimidine nucleoside using a multi-step procedure. Therefore, the development of general and practical methods for the enantioselective synthesis of N3-purine nucleosides is highly desirable.

    Figure 1

    Figure 1.  Examples of chiral carbocyclic N3-purine nucleosides

    Dynamic kinetic resolution (DKR) via asymmetric transfer hydrogenation (ATH) has been extensively studied to produce the chiral β-aminocycloalkanols.[9~11a] Especially, the synthesis of chiral β-heteroarylamino cycloalkanols has attracted considerable attention as building blocks in pharmaceutical drug synthesis.[10] To date, ATH/ DKR for synthesis of enantiopure vicinal cycloalkanols along with various N-heteroaryls, such as benzimidazole, benzotriazole and 9H-purine, has been developed.[11a] However, to the best of our knowledge, there is no report to synthesize chiral β-(purin-3-yl)cycloalkanols via the catalytic ATH/DKR. Herein, we proposed that the rac-α- (purin-3-yl)cyclopentones could be afforded via nucleophilic substitution of purines with α-chlorocycloalkanones in the presence of K2CO3 and 2, 2, 2-trifluoroethanol (TFE). Through the ATH/DKR of rac-α-(purin-3-yl)cyclopen- tones, a series of carbocyclic N3-purine nucleosides were produced with excellent yields and enantioselectivities (Scheme 1).

    Scheme 1

    Scheme 1.  Our strategy for the synthesis of chiral carbocyclic N3-purine nucleosides

    The ATH reaction of 2-(6-(diethylamino)-3H-purin-3- yl)cyclopentan-1-one (1a) was studied for optimizing reaction conditions, as shown in Table 1. On the basis of typically efficient catalysts for various ATH reactions, some chiral 1, 2-diamine-based Ru(Ⅱ) catalysts were examined for the hydrogenation of the model substrate. In the case of (R, R)-A and (R, R)-B as catalysts, yields of 91%~92% and 80%~85% ee were obtained (Table 1, Entries 1, 2). Low yield was observed by using Noyori's catalyst (R, R)-C with good enantioselectivity (26% yield, 81% ee, Table 1, Entry 3). When catalyst (R, R)-D was employed, the reaction proceeded well, affording the corresponding product 2a with 93% yield and 96% ee (Table 1, Entry 4). Subsequently, other solvents were further screened using (R, R)-D as the best catalyst, however, the obtained results were not further improved (Table 1, Entries 5~11). Therefore, we selected dioxane as the optimal solvent for subsequent studies. Further variation in the ratios of formic acid/triethylamine (FA/TEA) did not lead to improved results (Table 1, Entries 12, 13). Finally, the effect of catalyst loading was also investigated (Table 1, Entries 14, 15). Interestingly, the catalyst loading of 1 mol% was sufficient to produce a high yield of up to 93% without loss of ee (Table 1, Entry 14). Decreasing the catalyst loading to 0.5 mol% resulted in a decrease in the reactivity (85% yield, Table 1, Entry 15).

    Table 1

    Table 1.  Screening of reaction conditionsa, b
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    Entry Catalyst (mol%) Solvent Temp./℃ Yieldc/% eed/%
    1 (R, R)-A(2) Dioxane 27 91 85
    2 (R, R)-B(2) Dioxane 27 92 80
    3 (R, R)-C(2) Dioxane 27 26 81
    4 (R, R)-D(2) Dioxane 27 93 96
    5 (R, R)-D(2) CHCl3 27 91 94
    6 (R, R)-D(2) EtOAc 27 93 94
    7 (R, R)-D(2) DCM 27 92 73
    8 (R, R)-D(2) THF 27 95 93
    9 (R, R)-D(2) CH3OH 27 92 69
    10 (R, R)-D(2) Acetone 27 73 88
    11 (R, R)-D(2) CH3CN 27 93 91
    12e (R, R)-D(2) Dioxane 27 91 96
    13f (R, R)-D(2) Dioxane 27 45 91
    14 (R, R)-D(1) Dioxane 27 93 97
    15 (R, R)-D(0.5) Dioxane 27 85 97
    a Unless otherwise noted, the reaction was performed with rac-α-(purin-3- yl)cyclopentone 1a (0.1 mmol), 70 μL of FA/TEA (molar ratio is 1:1) in solvent (1.0 mL) for 24 h. b > 20:1 dr. c Isolated yields. d Determined by chiral HPLC analysis. e FA/TEA (molar ratio is 2.5:1) was used. f FA/TEA (molar ratio is 0.2:1) was used.

    With the optimized reaction conditions in hand, a range of different rac-α-(purin-3-yl)cyclopentones were hydrogenated in the presence of catalyst (R, R)-D by using FA/TEA ((molar ratio is 1:1) as the hydrogen source (Table 2). In general, the reactions worked considerably well and a series of corresponding chiral carbocyclic nucleosides were obtained with high yields and excellent enantioselectivities. The configuration of carbocyclic nucleosides was determined to be (1R, 2S) by the X-ray analysis of 2a and 2b, and those of the other products were similarly assigned by analogy. When the substrate 1b bearing dimethylamino at the C6 on the purine was used, the reaction smoothly proceeded and delivered the corresponding product 2b with 95% yield and 99.9% ee. Substrates 1c~1f with increasingly bulky groups, such as pyrrolidino, piperidino, morpholino and azepano groups at the C6 of purine were evaluated and their reductions proceeded well in excellent yields and ee's (2c~2f, 87%~93% yields, 95%~99.9% ee). Obviously, the introduction of different amino into the purine skeleton appeared to have little effect on the reactivity and enantioselectivities, probably because the electron-donating effect of substituents is stronger than their steric hindrance effect. When the substrates having OEt or S(CH2)2CH3 at the C6 of purine were reduced, the desired products 2g~2h were produced with 94%~95% yields and 94%~95% ee. Gratifyingly, in the case of cyclohexanone 1i, the hydrogenation reaction proceeded well with 91% yield and 99.9% ee.

    Table 2

    Table 2.  Substrate scopea
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    Further investigation of substrate scope was focused on the rac-α-pyrimidyl cycloalkanones 3a~3h (Table 3). The configuration of these products was determined to be (1R, 2S) by the X-ray analysis of 6b, and those of the other products were similarly assigned by analogy.[10b] When rac-α-pyrimidyl cycloalkanones 3a~3c bearing increasingly bulkier substituents, such as Me or Et at C5 of thymine skeleton were examined, excellent yields and enantioselectivities were obtained (4a~4c, 92%~96% yields, 95%~97% ee). Fortunately, removing the protecting group at N3 on the thymine skeleton had no noticeable effect on the yield and enantioselectivity (4d, 92% yield, 97% ee). When 4-ClC6H4CO was used as a protecting group at N3 on the thymine skeleton, excellent yield and enantioselectivity were still achieved (4e, 91% yield, 95% ee). Moreover, varying the carbocyclic ring size had no effect on the enantioselectivities (4f~4g, 97%~99% ee), although cycloheptanone caused yield to decrease to 75%. Furthermore, benzo-fused cyclopentone 3h was also efficiently reduced to the desired product 4h with 83% yield and 93% ee.

    Table 3

    Table 3.  Substrate scopea
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    In light of the above results and our previous study on the asymmetric hydrogenation[11, 12], the possible transition state models were proposed (Scheme 2). The amine hydrido Ru complex easily forms a 6-membered pericyclic transition state with S-1b or S-3a, due to hydrogen bonds between the NH unit and the carbonyl oxygen atom. Meanwhile, the interaction between nucleoside base with the Ru atom could facilitate reactivity and stereoinduction.

    Scheme 2

    Scheme 2.  The proposed transition state models

    To further investigate the synthetic potential of the current methodology, a gram-scale reaction of 1a was conducted under the optimal conditions (Scheme 3a). The desired product was generated with 91% yield and the completely maintained enantioselectivity. Moreover, to evaluate the potential application of the synthesized nucleosides, some derivatization experiments on product 4b were also carried out (Scheme 3b). In the presence of diethylaminosulfurtrifluoride (DAST), 2'-F-modified carbocyclic nucleoside 5b was achieved with 51% yield and 93% ee. The mesylation of 2'-OH of product 4b was also performed, delivering the desired product 6b with 94% yield and 95% ee. Subsequently, a sulfur atom was introduced into the carbocycle of 6b through nucleophilic substitution using AcSK, and the chiral thionucleoside derivative 7b was obtained with 57% yield and 93% ee. Finally, the nucleophilic substitution of 6b with NaN3 was performed, delivering the 2'-N3-modified nucleoside 8b with 76% yield and 93% ee.

    Scheme 3

    Scheme 3.  Gram-scale reaction of 1a and the further transformations of 4b

    An efficient ATH/DKR of rac-α-(purin-3-yl)cyclopen- tones to produce a wide range of carbocyclic N3-purine nucleosides has been developed in high yields and excellent stereoselectivities. Moreover, the catalytic system was suitable for rac-α-pyrimidinyl cyclopentones. Through further transformations of product, several 2'-F-, AcS-, N3-modified carbocyclic nucleosides could be afforded with good to excellent yields and excellent enantioselectivities.

    1H NMR spectra were recorded on a Bruker Avance Ⅲ HD 600 or an Avance 400 MHz spectrometer. 13C NMR data were collected on commercial instruments (100 or 150 MHz) with complete proton decoupling. HRMS were obtained on a Bruker microToF Ⅱ Mass Spectrometer (ESI Source). Single crystal X-ray crystallography data were obtained on a Supernova Atlas S2 CCD detector. Melting point (m.p.) data were obtained on an X-5 micro melting point apparatus. All reagents were reagent grade quality and purchased from commercial sources unless otherwise indicated.

    α-Substituted cycloalkanones (0.1 mmol), (R, R)-D (0.7 mg, 0.001 mmol), dioxane (1.0 mL) and FA/TEA (70 μL, 3.0 equiv.) were added to the reaction tube respectively. The mixture was stirred at 27 ℃ for 24 h. Subsequently, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/MeOH (V: V=30:1) as the eluant to afford the corresponding product.

    (1R, 2S)-2-(6-(Diethylamino)-3H-purin-3-yl)cyclopen-tan-1-ol (2a): 25.6 mg, 93% yield, 97% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=25:75, flow rate=0.3 mL/min, λ=250 nm, retention time: 13.391, 17.803 min. White solid, m.p. 92.7~97.9 ℃; [α]D20-61.77 (c 0.10, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.82~7.81 (m, 1H), 4.94~4.88 (m, 1H), 4.59~4.54 (m, 2H), 4.24~4.14 (m, 2H), 3.88~3.79 (m, 1H), 3.70~3.63 (m, 1H), 2.43~2.33 (m, 1H), 2.18~2.00 (m, 3H), 1.90~1.83 (m, 1H), 1.76~1.67 (m, 1H), 1.31~1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 152.2, 150.9, 150.0, 141.0, 120.1, 71.4, 63.9, 44.5, 43.4, 32.9, 26.9, 20.2, 14.2, 13.2; IR (KBr) ν: 3162, 2973, 1600, 1414, 1264, 1084, 775, 655 cm-1; HRMS (ESI-TOF) calcd for C14H22N5O [M+H]+ 276.1819, found 276.1817.

    (1R, 2S)-2-(6-(Dimethylamino)-3H-purin-3-yl)cyclo-pentan-1-ol (2b): 23.5 mg, 95% yield, 99.9% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=25:75, flow rate=0.3 mL/min, λ=250 nm, retention time: 15.524 min. White solid, m.p. 230.5~234.9 ℃; [α]D20-72.89 (c 0.58, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.14 (s, 1H), 7.59 (s, 1H), 4.86 (dt, J=11.4, 5.4 Hz, 1H), 4.70 (d, J=5.4 Hz, 1H), 3.54 (s, 3H), 3.26 (s, 3H), 2.39~2.31 (m, 1H), 2.27~2.21 (m, 1H), 2.09~2.02 (mm, 2H), 1.95~1.90 (m, 1H), 1.72~1.64 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 152.5, 152.1, 150.4, 140.3, 119.7, 70.1, 63.7, 39.7, 38.0, 32.8, 26.6, 20.5; IR (KBr) ν: 3172, 2919, 1603, 1415, 1162, 1096, 774, 656 cm-1; HRMS (ESI-TOF) calcd for C12H18N5O [M+H]+ 248.1506, found 248.1507.

    (1R, 2S)-2-(6-(pyrrolidin-1-yl)-3H-purin-3-yl)cyclopen-tan-1-ol (2c): 24.6 mg, 90% yield, 99.9% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=90:10, flow rate=0.8 mL/min, λ=256 nm, retention time: 26.353 min. White solid, m.p. 105.4~110.1 ℃; [α]D20-198.60 (c 0.29, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.59 (s, 1H), 4.89~4.84 (m, 1H), 4.73~4.69 (m, 1H), 4.01~3.95 (m, 1H), 3.80~3.73 (m, 1H), 3.66~3.54 (m, 2H), 2.40~2.20 (m, 2H), 2.15~1.89 (m, 7H), 1.73~1.61 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 152.6, 150.5, 149.9, 140.6, 119.8, 69.9, 63.6, 48.8, 48.2, 32.7, 26.6, 26.3, 24.4, 20.5; IR (KBr) ν: 3396, 2956, 1606, 1402, 1183, 1047, 771, 649 cm-1; HRMS (ESI-TOF) calcd for C14H20N5O [M+H]+ 274.1662, found 274.1661.

    (1R, 2S)-2-(6-(piperidin-1-yl)-3H-purin-3-yl)cyclo-pentan-1-ol (2d): 26.7 mg, 93% yield, 95% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=25:75, flow rate=0.3 mL/min, λ=250 nm, retention time: 14.556, 18.992 min. White oil; [α]D20-108.91 (c 0.17, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.12 (s, 1H), 7.64 (s, 1H), 4.87~4.84 (m, 1H), 4.70~4.62 (m, 2H), 4.30 (s, 1H), 4.02 (s, 1H), 3.70~3.58 (m, 1H), 2.39~3.32 (m, 1H), 2.22~2.16 (m, 1H), 2.08~2.02 (m, 2H), 1.94~1.89 (m, 1H), 1.72~1.57 (m, 7H); 13C NMR (150 MHz, CDCl3) δ: 151.5, 151.3, 150.8, 140.5, 119.5, 70.4, 63.7, 48.2, 45.7, 32.8, 26.8, 26.3, 24.6, 20.4; IR (KBr) ν: 3184, 2920, 1600, 1417, 1182, 1021, 774, 655 cm-1; HRMS (ESI-TOF) calcd for C15H22N5O [M+H]+ 288.1819, found 288.1819.

    (1R, 2S)-2-(6-Morpholino-3H-purin-3-yl)cyclopentan-1-ol (2e): 26.3 mg, 91% yield, 96% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=80:20, flow rate=0.7 mL/min, λ=250 nm, retention time: 10.246, 11.684 min. White solid, m.p. 177.2~181.3 ℃; [α]D20-110.98 (c 0.17, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.17 (s, 1H), 7.64 (s, 1H), 4.92~4.88 (m, 1H), 4.63~4.58 (m, 1H), 4.25~4.22 (m, 2H), 3.81~3.71 (m, 6H), 2.38~2.31 (m, 1H), 2.23~2.15 (m, 1H), 2.14~2.03 (m, 2H), 1.93~1.88 (m, 1H), 1.75~1.65 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 152.1, 151.3, 151.1, 140.6, 119.7, 70.3, 66.9, 63.8, 45.9, 32.9, 26.9, 20.4; IR (KBr) ν: 3079, 2865, 1598, 1420, 1180, 1113, 769, 653 cm-1; HRMS (ESI-TOF) calcd for C14H20N5O2 [M+H]+ 290.1612, found 290.1612.

    (1R, 2S)-2-(6-(azepan-1-yl)-3H-purin-3-yl)cyclopentan-1-ol (2f): 26.2 mg, 87% yield, 96% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=25:75, flow rate=0.3 mL/min, λ=250 nm, retention time: 16.223, 21.363 min. White solid, m.p. 119.3~123.1 ℃; [α]D20-89.50 (c 0.11, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.67 (s, 1H), 4.91~4.85 (m, 1H), 4.67~4.64 (m, 1H), 4.57~4.51 (m, 1H), 4.28~4.22 (m, 1H), 3.90~3.84 (m, 1H), 3.52~3.45 (m, 1H), 2.43~2.33 (m, 1H), 2.24~2.17 (m, 1H), 2.10~2.03 (m, 2H), 1.95~1.88 (m, 1H), 1.86~1.74 (m, 4H), 1.73~1.65 (m, 1H), 1.61~1.39 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 152.3, 151.9, 150.5, 140.6, 119.9, 70.7, 63.8, 50.3, 48.9, 32.9, 28.5, 27.6, 27.2, 26.7, 26.5, 20.4; IR (KBr) ν: 3188, 2920, 1599, 1416, 1182, 775, 656 cm-1; HRMS (ESI-TOF) calcd for C16H24- N5O [M+H]+ 302.1975, found 302.1975.

    (1R, 2S)-2-(6-Ethoxy-3H-purin-3-yl)cyclopentan-1-ol(2g): 23.3 mg, 94% yield, 95% ee. White solid, m.p. 215.0~218.9 ℃; [α]D20-133.66 (c 0.15, CH2Cl2); 1H NMR (600 MHz, CD3OD)δ: 8.75 (s, 1H), 8.08 (s, 1H), 5.24~5.20 (m, 1H), 4.79~4.75 (m, 2H), 4.47~4.46 (m, 1H), 2.56~2.49 (m, 1H), 2.30~2.25 (m, 1H), 2.23~2.17 (m, 1H), 2.15~2.09 (m, 1H), 1.93~1.80 (m, 2H), 1.52 (t, J=7.2 Hz, 3H); 13C NMR (150 MHz, CD3OD)δ: 161.2, 155.7, 155.4, 143.9, 123.8, 71.5, 65.7, 65.6, 33.7, 27.5, 21.1, 14.9; IR (KBr) ν: 3094, 2924, 1631, 1382, 1179, 1017, 779, 648 cm-1; HRMS (ESI-TOF) calcd for C12H17N4O2 [M+H]+ 249.1346, found 249.1345.

    6-Ethoxy-3-((1S, 2R)-2-((trimethylsilyl)oxy)cyclo-pentyl)-3H-purine (2g'): 29.8 mg, 93% yield, 95% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propa- nol)=90:10, flow rate=0.8 mL/min, λ=256 nm, retention time: 9.483 min, 12.333 min. White solid, m.p. 219.0~222.6 ℃; [α]D20-66.13 (c 0.19, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.42 (s, 1H), 8.19 (s, 1H), 5.41~5.37 (m, 1H), 4.83~4.79 (m, 2H), 4.45 (t, J=4.8 Hz, 1H), 2.42~2.35 (m, 1H), 2.27~2.22 (m, 1H), 2.15~2.08 (m, 2H), 1.86~1.78 (m, 2H), 1.53 (t, J=6.6 Hz, 3H), -0.27 (s, 9H); 13C NMR (150 MHz, CDCl3) δ: 159.6, 156.5, 155.1, 140.9, 123.5, 71.6, 65.1, 63.4, 33.7, 27.2, 20.5, 14.8, -0.5; HRMS (ESI-TOF) calcd for C15H25N4O2Si [M+ H]+ 321.1741, found 321.1745.

    (1R, 2S)-2-(6-(Propylthio)-3H-purin-3-yl)cyclopentan-1-ol (2h): 26.4 mg, 95% yield, 94% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=80:20, flow rate=0.7 mL/min, λ=250 nm, retention time: 8.400, 9.659 min. White solid, m.p. 176.9~182.6 ℃; [α]D20-189.29 (c 0.28, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.46 (s, 1H), 7.77 (s, 1H), 5.03 (dt, J=12.0, 5.4 Hz, 1H), 4.86 (t, J=5.4 Hz, 1H), 3.43 (dt, J=13.2, 6.6 Hz, 1H), 3.09 (dt, J=13.2, 6.6 Hz, 1H), 2.46 (p, J=10.2 Hz, 1H), 2.32~2.26 (m, 1H), 2.17~2.10 (m, 4H), 1.80~1.69 (m, 3H), 1.04 (t, J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ: 160.0, 157.4, 149.4, 139.6, 133.6, 69.5, 64.8, 32.9, 31.4, 26.9, 22.9, 20.7, 13.6; IR (KBr) ν: 3218, 2925, 1594, 1426, 1148, 986, 655 cm-1; HRMS (ESI-TOF) calcd for C13H19- N4OS [M+H]+ 279.1274, found 279.1272.

    (1R, 2S)-2-(6-(Diethylamino)-3H-purin-3-yl)cyclohexan-1-ol (2i): 26.3 mg, 91% yield, 99.9% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=90:10, flow rate=0.4 mL/min, λ=250 nm, retention time: 15.290 min. White solid, m.p. 172.2~175.7 ℃; [α]D20-36.68 (c 0.18, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 8.12 (s, 1H), 7.90 (s, 1H), 4.68~4.66 (m, 1H), 4.36~4.32 (m, 3H), 3.79~3.75 (m, 2H), 2.53 (q, J=12.6 Hz, 1H), 1.98~1.96 (m, 2H), 1.85~1.78 (m, 1H), 1.74~1.69 (m, 2H), 1.56~1.47 (m, 2H), 1.35~1.24 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 152.3, 151.4, 149.9, 141.0, 121.0, 67.5, 64.0, 44.3, 43.1, 33.2, 25.9, 25.5, 18.9, 14.2, 13.2; IR (KBr) ν: 3100, 2921, 1601, 1410, 1190, 776, 657 cm-1; HRMS (ESI-TOF) calcd for C15H24N5O [M+H]+ 290.1975, found 290.1978.

    3-Benzoyl-1-((1S, 2R)-2-hydroxycyclopentyl)pyrimi-dine-2, 4(1H, 3H)-dione (4a): 28.8 mg, 96% yield, 97% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propa- nol)=80:20, flow rate=0.8 mL/min, λ=250 nm, retention time: 24.179, 36.556 min. White oil. [α]D20-49.40 (c 0.25, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 7.97~7.84 (m, 2H), 7.67~7.61 (m, 2H), 7.52~7.48 (m, 2H), 5.76 (d, J=8.4 Hz, 1H), 4.74~4.68 (m, 1H), 4.34~4.31 (m, 1H), 2.04~1.97 (m, 4H), 1.77~1.63 (m, 2H); 13C NMR (150 MHz, CDCl3) δ: 169.3, 162.5, 150.7, 143.5, 135.2, 131.6, 130.7, 129.3, 100.8, 71.6, 59.4, 33.3, 26.6, 20.2; IR (KBr) ν: 3188, 2919, 1632, 1449, 1239, 975, 682 cm-1; HRMS (ESI-TOF) calcd for C16H17N2O4 [M+H]+ 301.1183, found 301.1174.

    3-Benzoyl-1-((1S, 2R)-2-hydroxycyclopentyl)-5-methyl-pyrimidine-2, 4(1H, 3H)-dione (4b): 28.9 mg, 92% yield, 96% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=80:20, flow rate=0.8 mL/min, λ=250 nm, retention time: 20.420, 24.577 min. White solid, m.p. 86.1~90.7 ℃; [α]D20-73.98 (c 0.25, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.93 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.2 Hz, 1H), 7.50~7.44 (m, 3H), 4.68 (d, J=11.4 Hz, 1H), 4.32 (s, 1H), 2.20~2.17 (m, 1H), 2.07~1.94 (m, 6H), 1.74~1.63 (m, 2H); 13C NMR (150 MHz, CDCl3) δ: 169.5, 163.1, 150.8, 139.4, 135.1, 131.8, 130.6, 129.3, 109.3, 71.8, 59.3, 33.3, 26.5, 20.2, 12.8; IR (KBr) ν: 3461, 2956, 1742, 1632, 1439, 1254, 982, 763, 685cm-1; HRMS (ESI-TOF) calcd for C17H19N2O4 (M+H)+ 315.1339, found 315.1330.

    3-Benzoyl-5-ethyl-1-((1S, 2R)-2-hydroxycyclopentyl)-pyrimidine-2, 4(1H, 3H)-dione (4c): 30.5 mg, 93% yield, 95% ee. HPLC CHIRALCEL ASH, V(n-hexane):V(2- propanol)=70:30, flow rate=0.8 mL/min, λ=256 nm, retention time: 7.970, 12.263 min. White solid, m.p. 154.3~156.3 ℃; [α]D20-38.33 (c 0.42, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.94~7.92 (m, 2H), 7.64~7.61 (m, 1H), 7.49~7.47 (m, 2H), 7.40~7.39 (m, 1H), 4.70~4.66 (m, 1H), 4.32~4.29 (m, 1H), 2.39~2.35 (m, 2H), 2.09~2.04 (m, 1H), 2.02~1.95 (m, 3H), 1.74~1.62 (m, 2H), 1.14 (t, J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ: 169.6, 162.7, 150.7, 138.7, 135.1, 131.8, 130.6, 129.2, 114.9, 71.8, 59.4, 33.3, 26.5, 20.3, 20.2, 12.9; IR (KBr) ν: 3395, 2921, 1739, 1628, 1441, 1255, 1180, 985, 759, 684 cm-1; HRMS (ESI-TOF) calcd for C18H21N2O4 [M+H]+ 329.1496, found 329.1487.

    1-((1S, 2R)-2-Hydroxycyclopentyl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (4d): 19.3 mg, 92% yield, 97% ee. HPLC CHIRALCEL IE, V(n-hexane):V(2-propanol)=40:60, flow rate=0.8 mL/min, λ=250 nm, retention time: 14.717 min, 31.463 min. White solid, m.p. 202.1~204.5 ℃; [α]D20-37.74 (c 0.24, CH2Cl2); 1H NMR (600 MHz, CD3OD)δ: 7.54 (s, 1H), 4.65~4.61 (m, 1H), 4.23~4.21 (m, 1H), 2.10~1.99 (m, 2H), 1.98~1.91 (m, 2H), 1.89 (s, 3H), 1.75~1.63 (m, 2H); 13C NMR (150 MHz, CD3OD)δ: 166.6, 153.6, 141.6, 109.5, 71.8, 60.6, 33.7, 27.1, 21.1, 12.4; IR (KBr) ν: 3173, 2920, 1644, 1469, 1275, 1050, 1013, 590 cm-1; HRMS (ESI-TOF) calcd for C10H15N2O3 [M+H]+ 211.1077, found 211.1073.

    3-(4-Chlorobenzoyl)-1-((1S, 2R)-2-hydroxycyclopentyl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (4e): 31.7 mg, 91% yield, 95% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=90:10, flow rate=0.9 mL/min, λ=250 nm, retention time: 17.014 min, 21.647 min. White oil.[α]D20-45.71 (c 0.21, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.88~7.86 (m, 2H), 7.47~7.44 (m, 3H), 4.70~4.66 (m, 1H), 4.34~4.32 (m, 1H), 2.08~1.99 (m, 4H), 1.96~1.94 (m, 3H), 1.77~1.71 (m, 1H), 1.69~1.63 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 168.7, 162.9, 150.7, 141.8, 139.4, 131.9, 130.3, 129.7, 109.3, 71.8, 59.3, 33.4, 26.5, 20.2, 12.8; IR (KBr) ν: 3393, 2921, 1743, 1634, 1438, 1251, 1091, 984, 766, 564 cm-1; HRMS (ESI-TOF) calcd for C17H18ClN2O4 [M+H]+ 349.0950, found 349.0947.

    3-Benzoyl-1-((1S, 2R)-2-hydroxycyclohexyl)-5-methyl-pyrimidine-2, 4(1H, 3H)-dione (4f): 29.8 mg, 91% yield, 97% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=80:20, flow rate=0.8 mL/min, λ=250 nm, retention time: 16.242, 21.449 min. White oil. [α]D20-36.51 (c 0.15, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.92 (d, J=7.8 Hz, 2H), 7.63 (t, J=6.6 Hz, 1H), 7.49~7.47 (m, 3H), 4.53~4.50 (m, 1H), 4.17 (s, 1H), 2.15~2.08 (m, 1H), 1.96 (s, 3H), 1.94~1.92 (m, 1H), 1.86~1.84 (m, 1H), 1.66~1.62 (m, 3H), 1.54~1.52 (m, 1H), 1.49~1.42 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 169.5, 163.0, 150.4, 139.2, 135.0, 131.9, 130.5, 129.2, 109.2, 68.2, 57.2, 33.3, 25.7, 24.9, 18.8, 12.7; IR (KBr) ν: 2922, 2850, 1744, 1632, 1435, 1275, 977, 765, 685 cm-1; HRMS (ESI-TOF) calcd for C18H21N2O4 [M+H]+ 329.1496, found 329.1488.

    3-Benzoyl-1-((1S, 2R)-2-hydroxycycloheptyl)-5-methyl-pyrimidine-2, 4(1H, 3H)-dione (4g): 25.7 mg, 75% yield, 99% ee. HPLC CHIRALCEL OD-H, n-hexane/2-propa- nol=80/20, flow rate=0.8 mL/min, λ=250 nm, retention time: 15.426, 25.394 min. White oil. [α]D20-27.37 (c 0.13, CH2Cl2); 1H NMR (400 MHz, CD3OD)δ: 7.99~7.93 (m, 2H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J=7.2 Hz, 2H), 4.58~4.50 (m, 1H), 4.08~4.01 (m, 1H), 2.32~2.21 (m, 1H), 1.94 (s, 3H), 1.91~1.77 (m, 3H), 1.76~1.55 (m, 5H), 1.50~1.41 (m, 1H); 13C NMR (100 MHz, CD3OD) δ: 170.6, 164.9, 151.4, 142.1, 136.3, 133.0, 131.5, 130.4, 110.0, 71.0, 61.5, 35.2, 28.8, 27.8, 26.9, 21.9, 12.4; IR (KBr) ν: 2921, 2851, 1744, 1632, 1438, 1254, 979, 763, 686 cm-1; HRMS (ESI-TOF) calcd for C19H23- N2O4 [M+H]+ 343.1652, found 343.1645.

    3-Benzoyl-1-((1R, 2S)-1-hydroxy-2, 3-dihydro-1H-inden-2-yl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (4h): 30.0 mg, 83% yield, 94% ee. HPLC CHIRALCEL IA, V(n-he- xane):V(2-propanol)=80:20, flow rate=0.6 mL/min, λ=250 nm, retention time: 16.745, 19.076 min. White oil.[α]D20+60.09 (c 0.22, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.96~7.94 (m, 2H), 7.66~7.63 (m, 1H), 7.51~7.48 (m, 2H), 7.44~7.43 (m, 1H), 7.37~7.31 (m, 3H), 7.14 (s, 1H), 5.39~5.35 (m, 1H), 5.29~5.28 (m, 1H), 3.37~3.28 (m, 2H), 1.85 (d, J=1.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ: 169.3, 162.9, 151.1, 141.5, 139.1, 138.7, 135.2, 131.7, 130.6, 129.7, 129.3, 128.2, 125.5, 124.9, 110.0, 74.7, 57.9, 34.6, 12.8; IR (KBr) ν: 2921, 2850, 1743, 1633, 1440, 1229, 1178, 977, 755, 684 cm-1; HRMS (ESI-TOF) calcd for C21H19N2O4 [M+H]+ 363.1339, found 363.1331.

    3-Benzoyl-1-((1S, 2S)-2-fluorocyclopentyl)-5-methyl-pyrimidine-2, 4(1H, 3H)-dione (5b): 16.1 mg, 51% yield, 93% ee. HPLC CHIRALCEL ID, V(n-hexane):V(2- ropa- nol)=70:30, flow rate=0.8 mL/min, λ=256 nm, retention time: 21.400, 22.387 min. White oil. [α]D20+9.02 (c 0.51, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.93~7.91 (m, 2H), 7.65 (t, J=7.2 Hz, 1H), 7.50 (t, J=7.8 Hz, 2H), 7.07 (s, 1H), 5.40~5.29 (m, 1H), 4.43~4.35 (m, 1H), 2.22~2.08 (m, 2H), 2.00~1.97 (m, 5H), 1.91~1.80 (m, 2H); 13C NMR (150 MHz, CDCl3) δ: 169.0, 162.9, 149.6, 139.7, 135.3, 131.6, 130.6, 129.3, 111.2, 97.5 (J=179.7 Hz), 68.8 (J=25.5 Hz), 31.9 (J=22.5 Hz), 29.2 (J=4.5 Hz), 22.4, 12.6; IR (KBr) ν: 2921, 2850, 1743, 1643, 1438, 1256, 1178, 977, 761, 685 cm-1; HRMS (ESI-TOF) calcd for C17H18FN2O3 [M+H]+ 317.1296, found 317.1291.

    (1R, 2S)-2-(3-Benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydro-pyrimidin-1(2H)-yl)cyclopentyl methanesulfonate (6b): 184 mg, 94% yield, 95% ee. HPLC CHIRALCEL IA, V(n-hexane):V(2-propanol)=15:85, flow rate=0.3 mL/min, λ=250 nm, retention time: 18.571 min, 19.698 min. White solid, m.p. 140.4~142.5 ℃; [α]D20-57.58 (c 0.26, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ: 7.94 (d, J=7.8 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 2H), 7.20 (s, 1H), 5.11 (t, J=4.8 Hz, 1H), 4.71~4.67 (m, 1H), 2.89 (s, 3H), 2.15~1.97 (m, 5H), 1.91 (s, 3H), 1.72~1.66 (m, 1H); 13C NMR (150 MHz, CDCl3) δ: 169.3, 162.8, 150.6, 137.2, 135.2 131.5, 130.9, 129.2, 110.3, 81.5, 58.6, 38.2, 30.7, 25.6, 19.9, 12.8; IR (KBr) ν: 2936, 1746, 1644, 1439, 1351, 1231, 1178, 970, 905, 797, 696 cm-1; HRMS (ESI-TOF) calcd for C18H21N2O6S [M+H]+ 393.1115, found 393.1108.

    S-((1S, 2S)-2-(3-Benzoyl-5-methyl-2, 4-dioxo-3, 4-dihy-dropyrimidin-1(2H)-yl)cyclopentyl) ethanethioate (7b): 21.2 mg, 57% yield, 93% ee. HPLC CHIRALCEL OD-H, V(n-hexane):V(2-propanol)=70:30, flow rate=0.8 mL/min, λ=256 nm, retention time: 11.637, 16.467 min. Yellow oil.[α]D20-17.34 (c 0.37, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 7.99~7.96 (m, 2H), 7.65~7.61 (m, 1H), 7.50~7.46 (m, 2H), 7.11~7.10 (m, 1H), 4.71 (s, 1H), 3.95 (q, J=9.2 Hz, 1H), 2.31 (s, 3H), 2.28~2.14 (m, 2H), 1.98 (d, J=1.2 Hz, 3H), 1.95~1.82 (m, 3H), 1.73~1.65 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 195.8, 169.3, 162.9, 150.2, 137.2, 135.0, 131.8, 130.7, 129.2, 111.3, 45.6, 31.1, 30.7, 29.9, 22.8, 12.8; IR (KBr) ν: 2921, 1743, 1643, 1439, 1228, 1112, 988, 762, 685, 630 cm-1; HRMS (ESI-TOF) calcd for C19H21N2O4S [M+H]+373.1217, found 373.1209.

    1-((1S, 2S)-2-Azidocyclopentyl)-5-methylpyrimidine-2, 4(1H, 3H)-dione (8b): 53.6 mg, 76% yield, 93% ee. HPLC CHIRALCEL ID, V(n-hexane):V(2-propanol)=70:30, flow rate=0.8 mL/min, λ=256 nm, retention time: 24.443, 26.077 min. Yellow solid, m.p. 158.4~165.3 ℃; [α]D20+10.92 (c 0.20, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ: 8.53 (s, 1H), 6.94~6.93 (m, 1H), 4.35 (q, J=7.6 Hz, 1H), 4.14 (q, J=7.6 Hz, 1H), 2.24~2.11 (m, 2H), 1.99~1.89 (m, 5H), 1.88~1.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 163.5, 150.7, 138.3, 111.5, 64.9, 64.5, 29.9, 28.1, 21.3, 12.7; IR (KBr) ν: 2919, 2848, 2094, 1644, 1351, 1263, 1125, 903, 760, 595 cm-1; HRMS (ESI- TOF) calcd for C10H14N5O2 [M+H]+ 236.1142, found 236.1151.

    Supporting Information  Experimental procedures, the synthesis method of the starting materials, and compound characterization data (PDF), X-ray data for compounds 2a (CIF), 2b (CIF), and 6b (CIF). The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.


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      (a) Zhang, Y.-M.; Zhang, Q.-Y.; Wang, D.-C.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2019, 21, 2998.
      (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.

    12. [12]

      (a) Chan, A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem. Soc. 1980, 102, 5952.
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  • Figure 1  Examples of chiral carbocyclic N3-purine nucleosides

    Scheme 1  Our strategy for the synthesis of chiral carbocyclic N3-purine nucleosides

    Scheme 2  The proposed transition state models

    Scheme 3  Gram-scale reaction of 1a and the further transformations of 4b

    Table 1.  Screening of reaction conditionsa, b

    Entry Catalyst (mol%) Solvent Temp./℃ Yieldc/% eed/%
    1 (R, R)-A(2) Dioxane 27 91 85
    2 (R, R)-B(2) Dioxane 27 92 80
    3 (R, R)-C(2) Dioxane 27 26 81
    4 (R, R)-D(2) Dioxane 27 93 96
    5 (R, R)-D(2) CHCl3 27 91 94
    6 (R, R)-D(2) EtOAc 27 93 94
    7 (R, R)-D(2) DCM 27 92 73
    8 (R, R)-D(2) THF 27 95 93
    9 (R, R)-D(2) CH3OH 27 92 69
    10 (R, R)-D(2) Acetone 27 73 88
    11 (R, R)-D(2) CH3CN 27 93 91
    12e (R, R)-D(2) Dioxane 27 91 96
    13f (R, R)-D(2) Dioxane 27 45 91
    14 (R, R)-D(1) Dioxane 27 93 97
    15 (R, R)-D(0.5) Dioxane 27 85 97
    a Unless otherwise noted, the reaction was performed with rac-α-(purin-3- yl)cyclopentone 1a (0.1 mmol), 70 μL of FA/TEA (molar ratio is 1:1) in solvent (1.0 mL) for 24 h. b > 20:1 dr. c Isolated yields. d Determined by chiral HPLC analysis. e FA/TEA (molar ratio is 2.5:1) was used. f FA/TEA (molar ratio is 0.2:1) was used.
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    Table 2.  Substrate scopea

    下载: 导出CSV

    Table 3.  Substrate scopea

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  • 发布日期:  2020-02-25
  • 收稿日期:  2019-07-30
  • 修回日期:  2019-09-30
  • 网络出版日期:  2019-02-25
通讯作者: 陈斌, bchen63@163.com
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