English

• 1.   Introduction

  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 Ⅰ (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 Ⅱ~Ⅳ display strong anti-HIV activities.^[7] Moreover, spirocyclic nucleoside Ⅴ had also demonstrated strong inhibitory effect against human coronavirus.^[8]

  Figure 1

  

  Figure 1.  Examples of biologically active spirocyclic nucleoside analogs

  下载: 全尺寸图片 幻灯片

  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 (S_N2) to produce C(2')-spiro[2-oxocyclopentyl]cyclopropyl nucleoside. The excellent diastereoselectivity (dr > 20:1) was obtained due to the intramolecular S_N2 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

  下载: 全尺寸图片 幻灯片

  2.   Results and discussion

  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 KO^tBu as base and 60% yield was achieved (Table 1, Entry 6). Thus, the KO^tBu 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 KO^tBu (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 KO^tBu (1.5 equiv.) as base in CH₃CN (1.0 mL) at －20 ℃ for 0.5 h.

  Table 1

  

  Table 1.  Screening of reaction conditions^{a, b}

  下载: 导出CSV

  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 CO₂^tBu 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-cycloalkanones^{a, 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 KO^tBu, 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

  下载: 全尺寸图片 幻灯片

  3.   Conclusions

  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 KO^tBu 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.

  4.   Experimental section

  4.1   Instrument and reagent

  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.

  4.2   General procedure for cyclopropanation reaction

  To a mixture of α-thymine substituted acrylate 1a~1q (0.1 mmol) and KO^tBu (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.

  
  
• 1. [1]

     (a) Paquette, L. A.; Owen, D. R.; Bibart, R. T.; Seekamp, C. K. Org. Lett. 2001, 3, 4043.
     (b) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L. Org. Lett. 2001, 3, 4039.
     (c) Tang, Y. B.; Li, Z. R. Chin. J. Biochem. Pharm. 2004, 25, 44 (in Chinese).
     (汤雁波, 李卓荣, 中国生化药物杂志, 2004, 25, 44.)
     (d) Rungta, P.; Mangla, P.; Maikhuri, V. K.; Singh, S. K.; Prasad. A. K. ChemistrySelect 2017, 2, 7808.
     

  2. [2]

     (a) Prota, A.; Vogt, J.; Pilger, B.; Perozzo, R.; Wurth, C.; Marquez, V. E.; Russ, P.; Schulz, G. E.; Folkers, G.; Scapozza, L. Biochemistry 2000, 39, 9597.
     (b) Jacobson, K. A.; Ji, X.; Li, A.; Melman, N.; Siddiqui, M. A.; Shin, K. J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem. 2000, 43, 2196.
     (c) Nandanan, E.; Jang, S.-Y.; Moro, S.; Kim, H. O.; Siddiqui, M. A.; Russ, P.; Marquez, V. E.; Busson, R.; Herdewijn, P.; Harden, T. K.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2000, 43, 829.
     

  3. [3]

     (a) Lemaire, S.; Diène, C.; Gavryushin, A.; Jourdin, X. M. D.; Paolini, L.; Jusseau, X.; Knochel, P.; Farina, V. J. Org. Chem. 2019, 84, 4910.
     (b) Kumar, R.; Kumar, M.; Singh, A.; Singh, N.; Maity, J.; Prasad, A. K. Carbohydr. Res. 2017, 445, 88.
     (c) Cobb, A. J. A.; Del'Isola, A.; Abdulsattar, B. O.; McLachlan, M. M. W.; Neuman, B. W.; Müller, C.; Shankland, K.; Al-Mulla, H. M. N.; Binks, A. W. D.; Elvidgeb, W. New J. Chem. 2018, 42, 18363.
     (d) Lebreton, J.; Escudier, J.-M.; Arzel, L.; Len, C. Chem. Rev. 2010, 110, 3371.
     

  4. [4]

     Li, H.; Yoo, J. C.; Hong, J. H. Bull. Korean Chem. Soc. 2011, 32, 1146. doi: 10.5012/bkcs.2011.32.4.1146
     

  5. [5]

     Zeng, D.; Zhang, R.; Nie, Q.; Cao, L.; Shang, L.; Yin, Z. ACS Med. Chem. Lett. 2016, 7, 1197. doi: 10.1021/acsmedchemlett.6b00270
     

  6. [6]

     Jonckers, T. H. M.; Lin, T.; Buyck, C.; Lachau-Durand S.; Vandyck, K.; Hoof, S. V.; Vandekerckhove, L. A. M.; Hu, L.; Berke, J. M.; Vijgen, L.; Dillen, L. L. A.; Cummings, M. D.; de Kock, H.; Nilsson, M.; Sund, C.; Rydegård, C.; Samuelsson, B.; Rosenquist, Å.; Fanning, G.; Emelen, K. V.; Simmen, K.; Raboisson, P. J. Med. Chem. 2010, 53, 8150. doi: 10.1021/jm101050a
     

  7. [7]

     de Castro, S.; Lozano, A.; Jimeno, M.-L.; Pérez-Pérez, M.-J.; San-Félix, A.; Camarasa, M.-J.; Velázquez, S. J. Org. Chem. 2006, 71, 1407. doi: 10.1021/jo0520588
     

  8. [8]

     Paquette, L. A.; Seekamp, C. K.; Kahane, A. L. J. Org. Chem. 2003, 68, 8614. doi: 10.1021/jo0301954
     

  9. [9]

     (a) Dang, S.; Sun, J.; Xu, X.; Wang, P.; Wu, J. Chem. Res. Chin. Univ. 2008, 24, 473.
     (b) Wu, W. M.S. Thesis, Jilin University, Changchun, 2014 (in Chinese).
     (吴为, 硕士论文, 吉林大学, 长春, 2014.)
     

  10. [10]

      Selected examples: (a) Xie, M.-S.; Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2016, 18, 4344.
      (b) Li, J.-P.; Zhao, G.-F.; Wang, H.-X.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2017, 19, 6494.
      (c) Huang, K.-X.; Xie, M.-S.; Zhang, Q.-Y.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2018, 20, 5398.
      (d) Guo, Z.; Xie, M.; Han, R.; Qu, G.; Guo, H. Chin. J. Org. Chem. 2018, 38, 112 (in Chinese).
      (郭真, 谢明胜, 韩瑞杰, 渠桂荣, 郭海明, 有机化学, 2018, 38, 112.)
      (e) Zhang, Y.-M.; Zhang, Q.-Y.; Wang, D.-C.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2019, 21, 2998.
      

• 

  Figure 1  Examples of biologically active spirocyclic nucleoside analogs

  下载: 全尺寸图片 幻灯片
  

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

  下载: 全尺寸图片 幻灯片
  

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

  下载: 全尺寸图片 幻灯片

  Table 1.  Screening of reaction conditions^{a, 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-cycloalkanones^{a, b, c}

  下载: 导出CSV
•