Efficient Synthesis of Spirocyclic Nucleosides via Michael Addition-Initiated Intermolecular Cyclopropanation Reaction

Erjun Hao Qing Zhang Qiying Zhang Guirong Qu Xining Yang Haiming Guo

Citation:  Hao Erjun, Zhang Qing, Zhang Qiying, Qu Guirong, Yang Xining, Guo Haiming. Efficient Synthesis of Spirocyclic Nucleosides via Michael Addition-Initiated Intermolecular Cyclopropanation Reaction[J]. Chinese Journal of Organic Chemistry, 2019, 39(11): 3237-3243. doi: 10.6023/cjoc201904074 shu

通过Michael加成引发分子间的环丙烷化反应高效合成螺环嘧啶核苷

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

    河南省博士后科学基金 2015071

    高等学校学科创新引智计划 D17007

    国家自然科学基金(No.21602045, U1604283)、河南省博士后科学基金(No.2015071)和高等学校学科创新引智计划(111计划, No.D17007)资助项目

    国家自然科学基金 21602045

    高等学校学科创新引智计划 111计划

    国家自然科学基金 U1604283

摘要: 报道了一种简单高效的螺环核苷合成方法,以α-嘧啶取代的丙烯酸酯和α-氯代环烷酮为原料,KOtBu为碱,通过Michael加成引发的环丙烷化反应,高效合成一系列2'-螺环修饰的三元碳环嘧啶核苷.该反应底物适用范围较宽,非对映选择性较高(>20:1 dr),收率可高达85%.

English

  • Structurally modified nucleosides attract synthetic and biological interest because selective compounds are vulnerable to treat diseases where the normal state differs from the diseased state regarding the enzymes involved in the processing of nucleic acid.[1] The relevant enzymes possess strict conformational requirements of the furanose ring with respect to the geometry.[2] This prompted several research groups to prepare modified nucleosides that feature restrictions in conformational flexibility in order to obtain not only new but also improved antiviral drugs.[3] Thus, many spirocyclic nucleoside analogues with restricted conformation have been designed and synthesized.[4~8] For example, spirocyclic nucleoside (Figure 1) is a novel potent and selective inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRP), which is a clinically validated target for HCV treatment, [4~6] whereas nucleosides ~ display strong anti-HIV activities.[7] Moreover, spirocyclic nucleoside had also demonstrated strong inhibitory effect against human coronavirus.[8]

    Figure 1

    Figure 1.  Examples of biologically active spirocyclic nucleoside analogs

    Traditional routes to construct spirocyclic nucleoside have been based on either a linear approach or a convergent synthesis that requires multiple steps from an equivalent starting material.[9] Hence, development of efficient methods to synthetize various spirocyclic nucleoside is highly desirable. Recently, we developed a highly enantioselective synthesis of chiral cyclopropyl nucleosides via catalytic asymmetric intermolecular cyclopropanation reaction of α-purine acrylates with α-bromo-carboxylic esters.[10b] Inspired by this work, α-chloro-cyclopentone was selected to react with α-thymine acrylate in the presence of base. Interestingly, Michael addition first occurred in the presence of base to generate intermediate A, which subsequently underwent the nucleophilic substitution (SN2) to produce C(2')-spiro[2-oxocyclopentyl]cyclopropyl nucleoside. The excellent diastereoselectivity (dr > 20:1) was obtained due to the intramolecular SN2 reaction process (Scheme 1). Continuing from our previous works on nucleosides, [10] herein we report the intermolecular cyclopropanation reaction for the synthesis of a broad range of C(2')-spirocyclic modified cyclopropyl nucleosides, which could provide an easy access to various spirocyclic nucleosides with excellent diastereoselectivities and good yields.

    Scheme 1

    Scheme 1.  Our strategy to construct C(2')-spirocyclic modified cyclopropyl nucleoside analogs

    We conducted our studies with α-thymine acrylate 1a and 2-chloro-cyclopentone 2a as model substrates to optimize the reaction condition (Table 1). Initially, various bases were tested in CH3CN at room temperature (r.t.) (Table 1, Entries 1~6). Only trace amount of products were obtained when Na2CO3 and Et3N were used as bases, respectively (Table 1, Entries 1, 2). Interestingly, the desired products were obtained with 39%~56% yields when 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3 and Cs2CO3 were used as bases (Table 1, Entries 3~5). To our delight, the reaction proceeded well with KOtBu as base and 60% yield was achieved (Table 1, Entry 6). Thus, the KOtBu was selected as the best base to further screen solvents including CH2Cl2, MeOH, tetrahydrofuran (THF), toluene and dioxane. However, the obtained results were not further improved (Table 1, Entries 7~11). Therefore, CH3CN was used in subsequent studies. Up increasing temperature from room temperature to 35 ℃, the yield decreased (37% yield, Table 1, Entry 12). However, when the reaction was performed below room temperature, the optimal reaction temperature was -20 ℃ which afforded the desired product with up to 84% yield (Table 1, Entries 13~17). In addition, the effect of the base was also examined and the highest yield was obtained with 1.5 equiv. of KOtBu (Table 1, Entries 18, 19). Surprisingly, the yield did not obviously decrease when the reaction time was shortened to 0.5 h (83% yield, Table 1, Entry 21). Based on the above results, the optimal reaction conditions were KOtBu (1.5 equiv.) as base in CH3CN (1.0 mL) at -20 ℃ for 0.5 h.

    Table 1

    Table 1.  Screening of reaction conditionsa, b
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    Entry Base Solvent Temp. Yieldc/%
    1 Na2CO3 CH3CN r.t. Trace
    2 Et3N CH3CN r.t. Trace
    3 DBU CH3CN r.t. 39
    4 K2CO3 CH3CN r.t. 44
    5 Cs2CO3 CH3CN r.t. 56
    6 KOtBu CH3CN r.t. 60
    7 KOtBu CH2Cl2 r.t. 8
    8 KOtBu MeOH r.t. 51
    9 KOtBu THF r.t. 17
    10 KOtBu Toluene r.t. Trace
    11 KOtBu Dioxane r.t. 12
    12 KOtBu CH3CN 35 37
    13 KOtBu CH3CN 15 62
    14 KOtBu CH3CN 0 66
    15 KOtBu CH3CN -10 73
    16 KOtBu CH3CN -20 84
    17 KOtBu CH3CN -30 79
    18d KOtBu CH3CN -20 58
    19e KOtBu CH3CN -20 84
    20f KOtBu CH3CN -20 82
    21g KOtBu CH3CN -20 83
    a Unless otherwise noted, the reaction was performed with 1a (0.1 mmol), 2a (1.5 equiv.), base (1.5 equiv.) in solvent (1.0 mL) at air for 5 h. b > 20:1 dr. c Isolated yields. d KOtBu (1.2 equiv.). e KOtBu (2.0 equiv.). f 1 h. g 0.5 h.

    With the optimized reaction conditions in hand, the scope of the reaction was investigated and the results are presented in Table 2. In general, the reactions proceeded well and a series of C(2')-spirocyclic modified cyclopropyl nucleosides were obtained with up to 85% yield. The configuration of C(2')-spirocyclic modified cyclopropyl nucleosides was confirmed based on the X-ray analysis of 3fa. Several α-thymine substituted acrylates bearing different ester groups, such as CO2Me, CO2Et and CO2tBu groups were used and desired products were obtained with excellent yields (3aa~3ca, 83%~85% yields). When CO2Bn was used as ester group (1d), the cyclopropanation reaction proceeded smoothly and 65% yield was achieved (3da). Unfortunately, the yield marginally decreased when CO2Ph was used as ester group (3ea, 24% yield). Subsequently, α-thymine substituted acrylates 1f~1i bearing F, Cl, Br and I at C(5) of thymine skeleton were also examined and the desired products were produced in good yields (3fa~3ia, 63%~68% yields). Unfortunately, introducing CF3 at C(5) of thymine skeleton (1j) caused the yield to decrease to 31%. Acrylates 1k~1l bearing H or Et at C(5) of thymine skeleton were also evaluated and the desired products were produced with good yields (3ka~3la, 81%~84% yields). Acrylate 1m bearing MeO at C(5) of the thymine skeleton was investigated, and a satisfactory yield was obtained (3ma, 70% yield). Interestingly, varying the protecting groups at N(3) on thymine skeleton had no noticeable effect on the yields (3na~3pa, 70%~79% yields). When cytosine was used as nucleoside base, excellent yield was achieved (3qa, 84% yield). In addition, different 2-chloro-cycloalkanones were also probed. Good yield was obtained when 2-chloro-cyclo- hexanone 2b was used and reaction time was prolonged to 12 h (3ab, 66% yield). Similarly, when 2-chloro-cyclo- heptanone 2c was used as substrate, the reaction proceeded well with 72% yield.

    Table 2

    Table 2.  Scope of α-thymine acrylates and α-chloro-cycloalkanonesa, b, c
    下载: 导出CSV

    To further evaluate the potential application of this reaction for synthetizing diverse C(2')-spirocyclic modified cyclopropyl nucleosides, the reaction was carried out on 5.4 mmol scale. In the presence of 1.5 equiv. of KOtBu, 5.4 mmol of α-thymine substituted acrylate 1a reacted smoothly with 2-chloro-cyclopentone 2a, affording 1.54 g (72% yield) of the desired adduct 3aa (Scheme 2, a). Subsequently, further transformations were performed by using 3aa as substrate (Scheme 2, b). When NaBH4 was used as the reducing agent, only carbonyl group was reduced to hydroxy group, yielding hydroxyl-substituted spirocyclic nucleoside 4aa with excellent diastereoselectivity (> 20:1) and 60% yield. Lastly, Bz protecting group at N(3) position of 4aa could be removed, giving the corresponding product 5aa in 87% yield.

    Scheme 2

    Scheme 2.  Scale-up synthesis of 3aa and its further transformations

    In summary, an efficient synthetic route to produce C(2')-spirocyclic modified cyclopropyl nucleosides analogues via Michael addition-initiated intermolecular cyclopropanation reaction was developed. Using KOtBu as base, a series of C(2')-spirocyclic nucleoside analogues were obtained with excellent diastereoselectivities (> 20:1) and good yields (up to 85%). Moreover, through further transformations, other hydroxyl-substituted spirocyclic nucleosides were obtained.

    1H NMR spectra were recorded on Bruker Avance Ⅲ HD 600 or 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. IR absorption spectra were recorded on a PerkinElmer Spectrum 400F spectrometer. 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.

    To a mixture of α-thymine substituted acrylate 1a~1q (0.1 mmol) and KOtBu (16.8 mg, 0.15 mmol) in CH3CN (0.5 mL), the solution of α-chloro-cycloalkanones 2a~2c (0.15 mmol) in CH3CN (0.5 mL) was added. Then the mixture was stirred at -20 ℃ until the starting materials were consumed as indicated by thin layer chromatography (TLC) analysis. The reaction mixture was filtered, concentrated under reduced pressure. The residue was purified by flash column chromatography with pertroleum ether/ethyl acetate (V:V=2:1) as the eluant to afford product.

    Methyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3aa): White solid, 32.9 mg, 83% yield. m.p. 227.2~232.5 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.90~7.88 (d, J=8.0 Hz, 2H), 7.62 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.06 (d, J=3.2 Hz, 1H), 3.77 (s, 3H), 2.53~2.40 (m, 1H), 2.36~2.27 (m, 1H), 2.27~2.17 (m, 2H), 2.16~2.03 (m, 2H), 2.01~1.95 (m, 4H), 1.89 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.1, 167.7, 139.4, 135.0, 131.5, 130.7, 129.1, 111.5, 77.3, 53.6, 50.4, 42.6, 38.9, 28.5, 26.2, 20.2, 12.7; IR (KBr) ν: 1726, 1698, 1650, 1423, 1300, 1230, 776, 680, 754 cm-1; HRMS (ESI-TOF) calcd for C21H20N2NaO6 (M+Na)+ 419.1214, found 419.1206.

    Ethyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ba): Colorless oil, 34.9 mg, 85% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.97~7.83 (m, 2H), 7.61 (t, J=6.8 Hz 1H), 7.47 (t, J=7.6 Hz, 2H), 7.07 (d, J=1.2 Hz, 1H), 4.26~4.19 (m, 2H), 2.52~2.41 (m, 1H), 2.39~2.28 (m, 1H), 2.27~2.16 (m, 2H), 2.17~2.03 (m, 2H), 2.01~1.93 (m, 4H), 1.92~1.82 (m, 1H), 1.28~1.24 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 212.1, 167.1, 162.8, 139.5, 134.9, 131.5, 130.7, 129.1, 111.3, 77.3, 62.8, 50.5, 42.5, 38.9, 28.6, 26.0, 20.2, 14.2, 12.7; IR (KBr) ν: 1725, 1702, 1656, 1425, 1296, 1232, 777, 763, 685 cm-1; HRMS (ESI-TOF) calcd for C22H22N2NaO6 (M+Na)+ 433.1370, found 433.1370.

    tert-Butyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane1-carboxylate (3ca): Colorless oil, 36.4 mg, 83% yield. > 20:1 dr; 1H NMR (methanol-d4, 400 MHz) δ: 7.89~7.85 (m, 2H), 7.71 (t, J=7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.56~7.52 (m, 2H), 2.45~2.42 (m, 1H), 2.25~2.20 (m, 3H), 2.07~2.06 (m, 2H), 1.97~1.87 (m, 6H), 1.45 (s, 9H); 13C NMR (methanol-d4, 100 MHz) δ: 214.1, 169.7, 167.1, 142.9, 136.3, 132.7, 131.4, 130.3, 111.5, 84.8, 52.4, 43.8, 39.8, 29.9, 28.2, 26.9, 21.1, 12.2; IR (KBr) ν: 1724, 1703, 1651, 1423, 1297, 1246, 780, 764, 686 cm-1; HRMS (ESI-TOF) calcd for C24H26N2NaO6 (M+Na)+ 461.1683, found 461.1688.

    Benzyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3da): Colorless oil, 30.7 mg, 65% yield. > 20:1 dr; 1H NMR (CDCl3, 600 MHz) δ: 7.79 (d, J=6.0 Hz, 2H), 7.52 (t, J=7.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 2H), 7.30~7.18 (m, 6H), 7.00 (s, 1H), 5.13 (q, J=8.0 Hz, 2H), 2.35~2.31 (m, 2H), 2.17~2.09 (m, 2H), 2.04~2.02 (m, 2H), 1.90~1.86 (m, 4H), 1.81~1.77 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.0, 167.1, 162.8, 139.4, 134.9, 131.4, 130.6, 129.1, 128.8, 128.6, 127.7, 111.4, 68.2, 50.5, 42.7, 38.9, 28.5, 26.1, 20.2, 12.7; IR (KBr) ν: 1728, 1703, 1651, 1422, 1257, 1230, 798, 763, 685 cm-1; HRMS (ESI-TOF) calcd for C27H24N2NaO6 (M+Na)+ 495.1527, found 495.1519.

    Phenyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ea): Colorless oil, 11.0 mg, 24% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.89 (d, J=7.2 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.43~7.35 (m, 4H), 7.28~7.24 (m, 1H), 7.20 (s, 1H), 7.06~7.03 (m, 2H), 2.58~2.55 (m, 1H), 2.50~2.35 (m, 1H), 2.31~2.10 (m, 5H), 2.01 (s, 3H), 1.99~1.85 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 211.7, 166.0, 150.2, 139.1, 134.9, 131.3, 130.6, 129.6, 129.0, 126.5, 121.3, 111.6, 50.2, 43.0, 38.8, 28.5, 26.4, 20.1, 12.7; IR (KBr) ν: 1746, 1702, 1655, 1422, 1208, 1230, 778, 762, 685 cm-1; HRMS (ESI-TOF) calcd for C26H22N2NaO6 (M+Na)+ 481.1307, found 481.1366.

    Methyl 1-(3-benzoyl-5-fluoro-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3fa): White solid, 26.2 mg, 68% yield. m.p. 209.2~214.4 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.89~7.87 (m, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.51~7.47 (m, 3H), 3.78 (s, 3H), 2.46~2.40 (m, 1H), 2.30~2.20 (m, 3H), 2.13~2.08 (m, 2H), 1.97 (d, J=5.2 Hz, 1H), 1.92~1.87 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.1, 167.1, 167.1, 149.7, 140.5, 135.4, 130.9, 130.7, 129.2, 109.4, 53.8, 50.7, 42.6, 38.9, 28.5, 26.4, 20.1; IR (KBr) ν: 1728, 1707, 1668, 1413, 1296, 1235, 967, 752, 679 cm-1-; HRMS (ESI-TOF) calcd for C20H17FN2NaO6 (M+Na)+ 423.0963, found 423.0960.

    Methyl 1-(3-benzoyl-5-chloro-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ga): White solid, 27.0 mg, 65% yield. m.p. 202.5~207.3 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.89~7.87 (m, 2H), 7.64 (t, J=7.6 Hz 1H), 7.52~7.47 (m, 3H), 3.79 (s, 3H), 2.48~2.41 (m, 1H), 2.30~2.20 (m, 3H), 2.14~2.09 (m, 2H), 1.98 (d, J=5.2 Hz, 1H), 1.92~1.85 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 212.1, 149.7, 140.5, 135.4, 130.9, 130.8, 129.2, 109.5, 77.3, 53.8, 50.7, 42.6, 38.9, 28.5, 26.4, 20.2; IR (KBr) ν: 1728, 1710, 1668, 1412, 1238, 1212, 816, 778, 684 cm-1; HRMS (ESI-TOF) calcd for C20H17ClN2NaO6 (M+Na)+ 439.0667, found 439.0665.

    Methyl 1-(3-benzoyl-5-bromo-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ha): white solid, 29.0 mg, 63% yield. m.p. 194.0~199.4 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.88 (d, J=7.2 Hz, 2H), 7.65~7.59 (m, 2H), 7.49 (t, J=8.0 Hz, 2H), 3.79 (s, 3H), 2.45~2.40 (m, 1H), 2.30~2.20 (m, 3H), 2.11~2.08 (m, 2H), 1.98 (d, J=5.2 Hz, 1H), 1.92~1.87 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.1, 167.1, 167.1, 143.0, 135.3, 130.9, 130.7, 129.2, 97.2, 53.8, 50.7, 42.5, 38.9, 28.5, 26.4, 20.1; IR (KBr) ν: 1737, 1710, 1673, 1409, 1295, 1238, 962, 687, 649 cm-1; HRMS (ESI-TOF) calcd for C20H17BrN2NaO6 (M+Na)+ 483.0162, found 483.0167.

    Methyl 1-(3-benzoyl-5-iodo-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ia): Grey oil, 34.0 mg, 67% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.87 (d, J=7.6 Hz, 2H), 7.68~7.61 (m, 2H), 7.49 (t, J=7.6 Hz, 2H), 3.78 (s, 3H), 2.45~2.42 (m, 1H), 2.30~2.20 (m, 3H), 2.13~2.08 (m, 2H), 1.98~1.97 (m, 1H), 1.92~1.86 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.0, 167.2, 167.1, 150.3, 148.0, 135.3, 130.8, 130.7, 129.2, 68.7, 53.8, 50.5, 42.5, 38.9, 28.5, 26.5, 20.1; IR (KBr) ν: 1732, 1705, 1665, 1397, 1293, 1236, 757, 685, 648 cm-1; HRMS (ESI-TOF) calcd for C20H17IN2NaO6 (M+Na)+ 531.0024, found 531.0016.

    Methyl 1-(3-benzoyl-2, 4-dioxo-5-(trifluoromethyl)-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ja): Colorless oil, 14.0 mg, 31% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.88 (d, J=7.2 Hz 2H), 7.71~7.64 (m, 2H), 7.51 (t, J=7.6 Hz, 2H), 3.81 (s, 3H), 2.57~2.41 (m, 1H), 2.37~2.21 (m, 3H), 2.16~2.10 (m, 2H), 1.99~1.89 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 135.5, 130.7, 129.3, 77.4, 76.8, 53.9, 42.4, 38.9, 28.5, 26.5, 20.2; IR (KBr) ν: 1755, 1720, 1680, 1430, 1296, 1237, 778, 647, 637 cm-1; HRMS (ESI-TOF) calcd for C21H17F3N2NaO6 (M+Na)+ 473.0931, found 473.0923.

    Methyl 1-(3-benzoyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ka): White solid, 32.1 mg, 84% yield. m.p. 187.4~192.1 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.90~7.88 (m, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.26~7.23 (m, 1H), 5.84 (d, J=8.4 Hz, 1H), 3.77 (s, 3H), 2.46~2.43 (m, 1H), 2.28~2.19 (m, 3H), 2.12~2.08 (m, 2H), 1.95 (d, J=5.2 Hz, 1H), 1.89~1.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 212.0, 167.4, 161.9, 143.7, 135.1, 131.3, 130.6, 129.1, 102.9, 53.6, 50.5, 42.4, 38.9, 28.5, 26.3, 20.1; IR (KBr) ν: 1727, 1704, 1665, 1431, 1230, 1220, 801, 756, 680 cm-1; HRMS (ESI-TOF) calcd for C20H19N2O6 (M+H)+ 383.1238, found 383.1232.

    Methyl 1-(3-benzoyl-5-ethyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3la): Colorless oil, 33.2 mg, 81% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.88 (d, J=7.6 Hz, 2H), 7.61 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 6.98 (s, 1H), 3.77 (s, 3H), 2.47~2.37 (m, 3H), 2.35~2.18 (m, 3H), 2.14~2.08 (m, 2H), 1.96 (d, J=5.2 Hz, 1H), 1.90~1.85 (m, 1H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 212.1, 168.6, 167.7, 138.5, 135.0, 131.5, 130.6, 129.1, 117.1, 53.6, 50.5, 42.6, 38.9, 28.5, 26.2, 20.3, 20.1, 12.5; IR (KBr) ν: 1744, 1732, 1692, 1429, 1237, 1214, 954, 769, 687 cm-1; HRMS (ESI-TOF) calcd for C22H22N2NaO6 (M+Na)+ 433.1370, found 433.1365.

    Methyl 1-(3-benzoyl-5-methoxy-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3ma): Colorless oil, 28.8 mg, 70% yield. > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.88 (d, J=6.8 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 6.76 (s, 1H), 3.78~3.77 (m, 6H), 2.45~2.41 (m, 1H), 2.28~2.18 (m, 3H), 2.10~2.06 (m, 2H), 1.96 (d, J=5.2 Hz, 1H), 1.89 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 212.0, 167.6, 149.3, 136.6, 135.1, 131.2, 130.7, 129.1, 123.5, 57.9, 53.6, 50.8, 43.0, 38.9, 28.5, 26.2, 20.1; IR (KBr) ν: 1727, 1704, 1660, 1433, 1292, 1241, 763, 685, 644 cm-1; HRMS (ESI-TOF) calcd for C21H20N2NaO6 (M+Na)+ 435.1163, found 435.1161.

    tert-Butyl 3-(1-(methoxycarbonyl)-4-oxospiro[2.4]-heptan-1-yl)-5-methyl-2, 6-dioxo-3, 6-dihydropyrimidine-1(2H)-carboxylate (3na): White solid, 30.9 mg, 79% yield. m.p. 180.0~185.4 ℃; > 20:1 dr; 1H NMR (CDCl3, 600 MHz) δ: 6.94~6.92 (m, 1H), 3.74 (s, 3H), 2.65~2.44 (m, 2H), 2.33~2.18 (m, 3H), 2.03 (d, J=4.8 Hz, 1H), 1.93~1.92 (m, 3H), 1.89 (d, J=5.4 Hz, 1H), 1.68 (s, 1H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 211.2, 167.8, 147.7, 139.0, 111.1, 86.5, 53.6, 50.6, 42.4, 38.8, 28.6, 27.5, 26.3, 20.2, 12.7; IR (KBr) ν: 1775, 1739, 1714, 1652, 1302, 1250 cm-1; HRMS (ESI-TOF) calcd for C19H24-N2NaO7 (M+Na)+ 415.1476, found 415.1471.

    Methyl 1-(3-(4-chlorobenzoyl)-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3oa): White solid, 30.1 mg, 70% yield. m.p. 196.0~200.2 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.82 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.06 (s, 1H), 3.77 (s, 3H), 2.50~2.40 (m, 1H), 2.32~2.19 (m, 3H), 2.13~2.08 (m, 2H), 1.96~1.87 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ: 212.3, 167.6, 150.6, 141.7, 139.5, 132.0, 130.0, 129.5, 111.5, 53.6, 50.4, 42.6, 39.0, 28.6, 26.3, 20.2, 12.7; IR (KBr) ν: 1746, 1699, 1644, 1422, 1228, 1217, 854, 805, 768 cm-1; HRMS (ESI-TOF) calcd for C21H19ClN2NaO6 (M+Na)+ 453.0824, found 453.0825.

    Methyl 1-(3-(4-methoxybenzoyl)-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3pa): White solid, 31.9 mg, 75% yield. m.p. 205.1~210.3 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.84 (d, J=8.4 Hz, 2H), 7.05 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 2.46~2.43 (m, 1H), 2.24~1.80 (m, 10H); 13C NMR (CDCl3, 150 MHz) δ: 212.5, 167.7, 165.1, 139.3, 133.3, 124.2, 114.4, 111.4, 55.7, 53.6, 50.4, 42.6, 38.9, 28.5, 26.2, 20.2, 12.7; IR (KBr) ν: 1728, 1699, 1651, 1421, 1247, 1166, 783, 602 cm-1; HRMS (ESI-TOF) calcd for C22H22N2NaO7 (M+Na)+ 449.1319, found 449.1315.

    Methyl 1-(ditert-butyl-(1-allyl-2-oxo-1, 2-dihydropyrimidin-4-yl)-4-oxospiro[2.4]heptane-1-carboxylate (3qa): Colorless oil, 40.0 mg, 84% yield. > 20:1 dr; 1H NMR (600 MHz, CDCl3) δ: 7.47 (d, J=7.2 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 3.68 (s, 3H), 2.67~2.59 (m, 2H), 2.28~2.20 (m, 3H), 2.02 (d, J=4.8 Hz, 1H), 1.93 (d, J=5.4 Hz, 1H), 1.89~1.87 (m, 1H), 1.53 (s, 18H); 13C NMR (100 MHz, CDCl3) δ: 211.2, 167.9, 162.6, 149.5, 147.5, 96.8, 84.9, 53.4, 51.9, 41.9, 38.9, 28.6, 27.7, 26.6, 20.4; IR (KBr) ν: 1777, 1738, 1665, 1457, 1323, 1247, 788 cm-1; HRMS (ESI-TOF) calcd for C23H31N3NaO8 (M+Na)+ 500.2003, found 500.1998.

    Methyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.5]octane-1-carboxylate (3ab): white solid, 27.0 mg, 66% yield. m.p. 210.9~216.0 ℃; > 20:1 dr; 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=7.2 Hz, 2H), 7.62~7.60 (m, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.03 (s, 1H), 3.78 (s, 3H), 2.45~2.44 (m, 2H), 2.31~2.29 (m, 2H), 1.96 (d, J=1.3 Hz, 4H), 1.98~1.88 (m, 6H), 1.78 (d, J=5.2 Hz, 1H), 1.73~1.63 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 205.5, 168.4, 167.5, 139.6, 135.1, 131.5, 130.6, 129.2, 111.3, 53.7, 51.2, 42.9, 39.3, 27.4, 25.1, 23.5, 21.7, 12.7; IR (KBr) ν: 1774, 1696, 1648, 1420, 1310, 1260, 970, 762, 684 cm-1; HRMS (ESI-TOF) calcd for C22H22N2NaO6 (M+Na)+ 433.1370, found 433.1364.

    Methyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-oxospiro[2.6]nonane-1-carboxylate (3ac): white solid, 30.5 mg, 72% yield. m.p. 213.0~218.4 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.87 (d, J=8.0 Hz, 2H), 7.62 (t, J=7.2 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.04 (s, 1H), 3.76 (s, 3H), 2.82 (t, J=12.0 Hz, 1H), 2.34~2.29 (m, 1H), 2.21~2.15 (m, 3H), 2.00~1.73 (m, 8H), 1.38~1.25 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 207.6, 168.4, 167.6, 150.5, 139.7, 135.0, 131.5, 130.6, 129.1, 111.4, 53.7, 51.3, 46.1, 44.0, 30.6, 27.5, 27.1, 26.4, 25.6, 12.6; IR (KBr) ν: 1744, 1702, 1655, 1423, 1226, 1170, 762, 728, 683 cm-1; HRMS (ESI-TOF) calcd for C23H24N2NaO6 (M+Na)+ 447.1527, found 447.1532.

    Methyl 1-(3-benzoyl-5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)-4-hydroxyspiro[2.4]heptane-1-carboxylate (4aa): white solid, 23.8 mg, 60% yield. m.p. 175.5~180.1 ℃; > 20:1 dr; 1H NMR (CDCl3, 400 MHz) δ: 7.97~7.95 (m, 2H), 7.66~7.63 (m, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.13 (s, 1H), 3.74 (s, 3H), 3.54 (d, J=3.2 Hz, 1H), 2.30 (s, 1H), 2.13~2.02 (m, 1H), 1.99~1.94 (m, 3H), 1.90~1.70 (m, 6H), 1.34 (d, J=5.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ: 169.2, 167.8, 153.5, 139.8, 135.3, 131.2, 130.5, 129.3, 112.8, 77.4, 53.3, 49.8, 47.0, 32.9, 27.9, 26.6, 20.9, 12.6; IR (KBr) ν: 3414, 1741, 1647, 1423, 1300, 1258, 800, 775, 681 cm-1; HRMS (ESI-TOF) calcd for C21H22N2NaO6 (M+Na)+ 421.1370, found 421.1366.

    Methyl 4-hydroxy-1-(5-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-1(2H)-yl)spiro[2.4]heptane-1-carboxylate (5aa): white solid, 25.5 mg, 87% yield. m.p. 233.0~238.4 ℃; 1H NMR (CDCl3, 400 MHz) δ: 9.36 (s, 1H), 7.00 (s, 1H), 4.23 (s, 1H), 3.71 (s, 3H), 3.52 (d, J=3.2 Hz, 1H), 2.38 (s, 1H), 2.11 (s, 1H), 1.95~1.72 (m, 8H), 1.69 (d, J=5.3 Hz, 1H), 1.27 (d, J=5.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 169.4, 163.4, 154.3, 140.1, 112.7, 77.2, 53.3, 49.3, 47.0, 32.8, 27.9, 26.9, 20.9, 12.5; IR (KBr) ν: 3416, 1721, 1681, 1288, 1233 cm-1; HRMS (ESI-TOF) calcd for C14H18N2NaO5 (M+Na)+ 317.1108, found 317.1107.

    Supporting Information   The synthesis method of the starting materials, compound characterization data and X-ray data for compounds 3fa. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.


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  • Figure 1  Examples of biologically active spirocyclic nucleoside analogs

    Scheme 1  Our strategy to construct C(2')-spirocyclic modified cyclopropyl nucleoside analogs

    Scheme 2  Scale-up synthesis of 3aa and its further transformations

    Table 1.  Screening of reaction conditionsa, b

    Entry Base Solvent Temp. Yieldc/%
    1 Na2CO3 CH3CN r.t. Trace
    2 Et3N CH3CN r.t. Trace
    3 DBU CH3CN r.t. 39
    4 K2CO3 CH3CN r.t. 44
    5 Cs2CO3 CH3CN r.t. 56
    6 KOtBu CH3CN r.t. 60
    7 KOtBu CH2Cl2 r.t. 8
    8 KOtBu MeOH r.t. 51
    9 KOtBu THF r.t. 17
    10 KOtBu Toluene r.t. Trace
    11 KOtBu Dioxane r.t. 12
    12 KOtBu CH3CN 35 37
    13 KOtBu CH3CN 15 62
    14 KOtBu CH3CN 0 66
    15 KOtBu CH3CN -10 73
    16 KOtBu CH3CN -20 84
    17 KOtBu CH3CN -30 79
    18d KOtBu CH3CN -20 58
    19e KOtBu CH3CN -20 84
    20f KOtBu CH3CN -20 82
    21g KOtBu CH3CN -20 83
    a Unless otherwise noted, the reaction was performed with 1a (0.1 mmol), 2a (1.5 equiv.), base (1.5 equiv.) in solvent (1.0 mL) at air for 5 h. b > 20:1 dr. c Isolated yields. d KOtBu (1.2 equiv.). e KOtBu (2.0 equiv.). f 1 h. g 0.5 h.
    下载: 导出CSV

    Table 2.  Scope of α-thymine acrylates and α-chloro-cycloalkanonesa, b, c

    下载: 导出CSV
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  • 发布日期:  2019-11-25
  • 收稿日期:  2019-04-30
  • 修回日期:  2019-06-07
  • 网络出版日期:  2019-11-24
通讯作者: 陈斌, bchen63@163.com
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