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Total synthesis of carbocyclic nucleoside (+)-neplanocin A
Tetrahedron xxx (2015) 1e6
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Total synthesis of carbocyclic nucleoside (þ)-neplanocin A Young Hoon Jung *, Seung In Kim, Yeon Ju Hong, Sook Jin Park, Kyung Tae Kang, So Yeon Kim, In Su Kim School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 October 2014 Received in revised form 26 December 2014 Accepted 27 December 2014 Available online xxx
Asymmetric total synthesis of (þ)-neplanocin A was concisely achieved from readily available D-galactose via the regioselective and diastereoselective amination of carbocyclic polybenzyl ether using chlorosulfonyl isocyanate and intramolecular olefin metathesis using second-generation Grubbs catalyst. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Amination Chlorosulfonyl isocyanate Metathesis Neplanocin Nucleoside
1. Introduction Carbocyclic nucleosides, in which an oxygen atom in a furanose ring of ribonucleosides is replaced by a methylene group, are among the most interesting discoveries in the field of natural products.1 Due to the absence of a true glycosidic bond, carbocyclic nucleosides are more chemically stable and not involved in the action of the enzymes that cleave the N-glycosidic linkage in conventional nucleosides.2 Thus carbocyclic nucleosides have been the focus of much attention in the development of new therapeutic agents.3 ()-Neplanocin A (1),4 an unsaturated analogue of ()-aristeromycin (2),5 is a naturally occurring carbocyclic nucleoside isolated from the culture filtrate of the soil fungus Ampullariella regularis in 1981 (Fig. 1). The absolute structures of 1 and 2 were established by X-ray analysis.6 Other natural neplanocin analogs, e.g., ()-neplanocin B (3), ()-neplanocin C (4), ()-neplanocin D (5), and ()-neplanocin F (6), were also identified.7 Among neplanocin family, ()-neplanocin A has received great attention due to its interesting biological properties such as potent antiviral and antitumor activities.4 ()-Neplanocin A efficiently inhibits cellular S-adenosylmethionine hydrolase in cells, which results in the accumulation of S-adenosylhomocysteine, thus inhibiting cell and viral methyltransferases involved in messenger RNA maturation and the synthesis of other macromolecules.8
* Corresponding author. Tel.: þ82 31 290 7711; fax: þ82 31 290 7773; e-mail address: [email protected] (Y.H. Jung).
Fig. 1. Structure of neplanocin family.
The protected tetrol 7 has been widely used as a convenient precursor wherein a Mitsunobu inversion of a secondary hydroxyl group with adenine followed by deprotection of hydroxyl groups provided ()-neplanocin A (Scheme 1). The formation of 7 and its enantiomer is achieved from optically active ribonolactone derivatives via the palladium-catalyzed rearrangement of the acetate moiety,9 construction of a carbocyclic ring by intramolecular HornereWadswortheEmmons or Wittig reactions,10 intramolecular aldol reaction,11 CeH insertion reaction of alkylidenecarbenes,12 and ring-closing metathesis reaction using Grubbs catalysts.13 Another approach for the preparation of 1 includes
http://dx.doi.org/10.1016/j.tet.2014.12.093 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
Scheme 1. Synthetic approach for the formation of neplanocin A.
a palladium-catalyzed desymmetrization of cyclopentenes with 6chloropurine,14 chemoenzymatic desymmetrization of bicyclic DielseAlder adducts,15 intramolecular nitrone cycloaddition,16 zirconocene-mediated ring construction,17 and intramolecular BayliseHillman reaction.18 As part of an ongoing research program aimed at developing asymmetric total synthesis of biologically active compounds through a chlorosulfonyl isocyanate-mediated stereoselective amination,19 we herein describe the asymmetric total synthesis of (þ)-neplanocin A (ent-1) starting from commercially available D-galactose via the highly regioselective and diastereoselective allylic amination of cyclic polybenzyl ethers using chlorosulfonyl isocyanate (CSI) and intramolecular olefin metathesis as the key steps. 2. Results and discussion Our initial investigation focused on the efficient construction of carbocyclic polybenzyl ether 12, which can be subjected to our amination methodology to give the protected amino alcohol 13. Thus, the total synthesis of (þ)-neplanocin A began with the protected lactol 8 derived from D-galactose according to the reported
literature (Scheme 2).20 Wittig reaction of 8 and subsequent Swern oxidation of a secondary alcohol afforded the ketone 10 in high yields. Second Wittig reaction of 10 was subjected under NaHMDS as a base to give the diene 11, which was treated with secondgeneration Grubbs catalyst in refluxing CH2Cl2 to provide the carbocyclic polybenzyl ether 12 in 90% yield. Next, after the screening of various reaction conditions for the coupling between 12 and CSI, we found that the reaction in methylene chloride at 0 C gave the desired product 13 with an excellent level of diastereoselectivity (anti/syn¼50:1) in 91% yield. The origin of stereochemistry can be explained by competition between SNi mechanism and SN1 mechanism.19c In general, SNi mechanism leads to retention of stereochemistry via a four-centered transition state by the formation of a tight ion pair. Another plausible SN1 mechanism may cause the generation of a carbocation intermediate, which can provide the racemization of products. However, in the case of anti-dibenzyl ether 12, anti-amino alcohol 13 can be exclusively obtained due to the facile approach of NCO2Bn species to the less sterically hindered face in a carbocation intermediate. To obtain an essential precursor 14 for the formation of (þ)-neplanocin A, we then screened a chemoselective removal of the Cbz protection of 13 under various reaction conditions. After
Scheme 2.
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several failed attempts such as BF3$OEt2/SMe2,21 BBr3,22 40% KOH/ MeOH,23 and Pd(OAc)2/Et3SiH/Et3N,24 the chemoselective removal of the Cbz protection of 13 was successfully achieved under basic hydrolysis conditions (LiOH$H2O, 1,4-dioxane/water (3:1), 120 C, 48 h) to give the primary amine 14 in high yield (89%). To construct the remaining adenine heterocycle, compound 14 was subjected to the three-step sequence as reported in the literature (Scheme 3).15a The condensation of 14 with 5-amino-4,6dichloropyrimidine in n-butyl alcohol at 120 C afforded our desired product 15 in low yield (20%) (Table 1, entry 1). The yield of 15 was improved to 61% when DMF was employed (Table 1, entry 4), however, the reaction required 48 h to go to completion. The best result was realized when 14 was exposed to 5-amino-4,6dichloropyrimidine in isoamyl alcohol, which produced the pyrimidine compound 15 in high yield (89%) within 24 h (Table 1, entry 5). Intramolecular ring formation of 15 and subsequent amination reaction using methanolic ammonia afforded the adenine 17 in high yields. Finally, debenzylation of 17 under the standard reaction condition (BCl3 in anhydrous CH2Cl2) proceeded cleanly to afford (þ)-neplanocin A (ent-1) with specific rotation and spectral data (1H and 13C NMR) identical to those reported in the literature.10c
3
4. Experimental 4.1. General Commercially available reagents were used without additional purification, unless otherwise stated. All reactions were performed under an inert atmosphere of nitrogen or argon. Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded on a Bruker Unity 300 MHz and Varian Unit 500 MHz spectrometer for CDCl3 solutions, and chemical shifts are reported as parts per million (ppm) relative to, respectively, residual CHCl3 dH (7.26 ppm) and CDCl3 dC (77.0 ppm) as internal standards. Resonance patterns are reported with the notations s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). In addition, the notation br is used to indicate a broad signal. Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Bruker Infrared spectrophotometer and are reported as cm1. Optical rotations were measured with a Jasco P1020 polarimeter. Thin layer chromatography was carried out using plates coated with Kieselgel 60F254 (Merck). For flash column chromatography, E. Merck Kieselgel 60 (230e400 mesh) was used. LC/mass spectra (LC/MS) were recorded on a Waters 2767 LCMS system. High-
Scheme 3.
Table 1 Selected optimization for the coupling of 14 and 5-amino-4,6-dichloropyrimidine.a Entry
Solvent
Temperature ( C)
Time (h)
Yieldb (%)
1 2 3 4 5
n-BuOH EtOH 1,4-Dioxane DMF Isoamyl alcohol
120 120 120 150 130
24 48 48 48 24
20 20 N.R. 61 89
a
Reaction conditions: (i) 13 (1 equiv), 5-amino-4,6-dichloropyrimidine (5 equiv), Et3N (3 equiv), solvent (0.1 M). b Isolated yield by flash column chromatography.
3. Conclusion We described a concise total synthesis of (þ)-neplanocin A starting from readily available D-galactose via the highly regioselective and diastereoselective amination of carbocyclic polybenzylic ether with retention of stereochemistry using chlorosulfonyl isocyanate and intramolecular olefin metathesis. It is believed that this synthetic strategy can be applied to the preparation of a broad range of biologically active compounds containing a chiral amine moiety.
resolution mass spectra (HRMS) were recorded on a JEOL JMS600 spectrometer. 4.2. (2R,3S,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-ol (9) To a stirred solution of MePPh3Br (17.6 g, 49.3 mmol) in THF (54 mL) was carefully added n-BuLi (37.1 mL, 59.4 mmol in 1.6 M solution) at 0 C under N2 atmosphere. The reaction mixture was stirred for 2 h at room temperature to generate ylide. To a reaction mixture was added a solution of 8 (6.78 g, 12.5 mmol) in THF (7.5 mL) at 78 C. The resulting mixture was warmed to room temperature and further stirred for 4 h. The reaction was quenched with water (30 mL) and the aqueous layer was extracted with EtOAc (100 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼5:1) to afford 5.07 g (9.41 mmol, 75%) of 9 as yellow syrup. Rf¼0.30 (nhexane/EtOAc¼5:1); [a]25 D 3.4 (c 0.5, CHCl3); IR (neat) n 3030, 2867, 1497, 1454, 1210, 1095, 1067, 1028, 736, 698, 477, 419 cm1; 1H NMR (500 MHz, CDCl3) d 7.37e7.16 (m, 20H), 5.87 (ddd, J¼17.5, 10.0, 8.0 Hz, 1H), 5.36e5.30 (m, 2H), 4.76 (d, J¼12.0 Hz, 2H), 4.65 (d,
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J¼12.0 Hz, 1H), 4.50e4.34 (m, 5H), 4.13e4.06 (m, 2H), 3.82e3.78 (m, 2H), 3.50 (dd, J¼9.5, 6.0 Hz, 2H), 3.02 (d, J¼5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 138.5, 138.4, 138.4, 138.3, 136.0, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 119.5, 82.3, 81.0, 76.8, 75.5, 73.4, 71.4, 70.5, 69.9; HRMS (CI) calcd for C35H39O5 [MþH]þ 539.2791, found 539.2792. 4.3. (3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-one (10) To a stirred solution of oxalic chloride (0.32 mL, 3.7 mmol) in CH2Cl2 (9 mL) were added dimethyl sulfoxide (0.53 mL, 7.4 mmol) and 9 (1.33 g, 2.5 mmol) at 78 C. After stirring for 1 h at same temperature, Et3N (1.74 mL, 12.1 mmol) was added. The reaction mixture was further stirred for 4 h at 78 C. The resulting mixture was carefully quenched with water (10 mL) and the aqueous layer was extracted with CH2Cl2 (20 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼4:1) to afford 1.17 g (2.2 mmol, 88%) of 10 as yellow syrup. Rf¼0.57 (n-hexane/EtOAc¼4:1); [a]25 D þ2.9 (c 6.5, CHCl3); IR (neat) n 2869, 1728, 1497, 1454, 1273, 1103, 740, 699, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.35e7.15 (m, 20H), 5.85 (ddd, J¼17.7, 10.5, 7.8 Hz, 1H), 5.40e5.24 (m, 2H), 4.72 (d, J¼11.4 Hz, 1H), 4.63e4.51 (m, 2H), 4.51e4.18 (m, 7H), 4.17 (d, J¼4.2 Hz, 1H), 4.10 (dd, J¼13.8, 6.0 Hz, 1H), 3.89 (dd, J¼5.9, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 207.6, 138.4, 138.2, 137.7, 137.3, 135.4, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 119.9, 83.0, 82.3, 80.9, 75.0, 74.7, 73.3, 72.9, 70.9; HRMS (CI) calcd for C35H37O5 [MþH]þ 537.2647, found 537.2646. 4.4. ((3S,4R,5S)-2-Methylenehept-6-ene-1,3,4,5-tetrayl)tetrakis(oxy)tetrakis(methylene)tetrabenzene (11) To a stirred solution of MePPh3Br (2.39 g, 6.7 mmol) in THF (11 mL) was slowly added NaHMDS (6.7 mL, 6.7 mmol) at 0 C under N2 atmosphere. The reaction mixture was stirred for 2 h at room temperature, and a solution of 10 (1.44 g, 2.7 mmol) in THF (2.4 mL) was added at 0 C. The reaction mixture was stirred for 1 h at 0 C. The resulting mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (30 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼5:1) to afford 1.22 g (2.3 mmol, 85%) of 11 as yellow syrup. Rf¼0.64 (n-hexane/ EtOAc¼6:1); [a]25 D þ22.4 (c 1.7, CHCl3); IR (neat) n 3031, 2863, 1496, 1454, 1391, 1208, 1092, 1071, 1028, 923, 736, 698, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.35e7.12 (m, 20H), 5.94e5.73 (m, 1H), 5.58e5.09 (m, 5H), 4.84e4.79 (m, 1H), 4.66 (s, 1H), 4.62 (d, J¼11.0 Hz, 2H), 4.54 (d, J¼11.0 Hz, 2H), 4.50 (d, J¼2.5 Hz, 1H), 4.40 (d, J¼2.5 Hz, 1H), 4.29 (d, J¼11.9 Hz, 1H), 4.18e4.04 (m, 4H), 3.57 (dd, J¼7.9, 3.5 Hz 1H); 13C NMR (125 MHz, CDCl3) d 138.7, 138.6, 138.5, 136.5, 128.6, 128.5, 128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 118.4, 115.7, 83.8, 80.4, 79.8, 75.1, 72.8, 70.8, 70.7, 70.5; HRMS (CI) calcd for C36H39O4 [MþH]þ 535.2851, found 535.2848. 4.5. ((1S,2R,3S)-4-(Benzyloxymethyl)cyclopent-4-ene-1,2,3triyl)tris(oxy)tris(methylene)tribenzene (12) To a stirred solution of 11 (1.11 g, 2.08 mmol) in CH2Cl2 (21 mL) was added second-generation Grubbs catalyst (0.35 g, 0.41 mmol). The reaction mixture was refluxed for 8 h. The solution was evaporated to dryness and the residue was purified by flash column chromatography (n-hexane/EtOAc¼8:1) to afford 1.01 g (1.99 mmol, 95%) of 12 as brown syrup. Rf¼0.25 (n-hexane/EtOAc¼8:1); [a]25 D þ61.6 (c 1.0, CHCl3); IR (neat) n 3031, 2864, 1723, 1602, 1496,
1453, 1357, 1271, 1094, 1027, 737, 699, 604, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.39e7.16 (m, 20H), 5.99 (d, J¼1.5 Hz, 1H), 4.80e4.75 (m, 1H), 4.73 (d, J¼11.8 Hz, 1H), 4.65 (d, J¼2.7 Hz, 1H), 4.62e4.60 (m, 4H), 4.53 (d, J¼1.8 Hz, 1H), 4.49 (d, J¼3.9 Hz, 2H), 4.07 (s, 2H), 4.00 (d, J¼6, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 142.5, 138.9, 138.6, 138.5, 138.3, 130.5, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.2, 86.7, 84,6, 79.1, 72.9, 72.5, 72.1, 71.7, 67.5; HRMS (EI) calcd for C34H34O4 [M]þ 506.2457, found 506.2456. 4.6. Benzyl (1S,4S,5R)-4,5-bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enylcarbamate (13) To a stirred solution of 12 (0.13 g, 0.26 mmol) in anhydrous CH2Cl2 (2.6 mL) were added Na2CO3 (0.25 g, 2.3 mmol) and chlorosulfonyl isocyanate (0.18 mL, 2.0 mmol) at 0 C under N2 atmosphere. The reaction mixture was stirred for 24 h at 0 C and quenched with water (1.3 mL). The aqueous layer was extracted with EtOAc (10 mL2). The organic layer was added to a solution of aqueous 25% Na2SO3 (5 mL), and the reaction mixture was further stirred for 24 h at room temperature. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (nhexane/EtOAc¼5:1) to afford 0.13 g (0.236 mmol, 91%) of 13 as white solid. Rf¼0.24 (n-hexane/EtOAc¼4:1); mp¼107e113 C; [a]25 D þ29.3 (c 4.0, CHCl3); IR (neat) n 3309, 3031, 2857, 1690, 1544, 1454, 1336, 1281, 1251, 1138, 1095, 734, 696, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.37e7.24 (m, 20H), 5.81 (s, 1H), 5.17e5.12 (m, 2H), 4.87 (br s, 1H), 4.73 (s, 2H), 4.65 (d, J¼11.4 Hz, 2H), 4.55 (d, J¼5.0 Hz, 1H), 4.53e4.48 (m, 3H), 4.08 (s, 2H), 3.77 (d, J¼4.5 Hz, 1H); 13 C NMR (125 MHz, CDCl3) d 143.4, 138.7, 138.2, 129.7, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 83.0, 73.2, 71.9, 67.2, 67.0, 60.5; HRMS (EI) calcd for C35H35NO5 [M]þ 549.2515, found 549.2516. 4.7. (1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enamine (14) To a stirred solution of 13 (0.16 g, 0.28 mmol) in 1,4-dioxane (5.4 mL) was added LiOH$H2O (0.14 g, 3.4 mmol) in water (1.8 mL) at room temperature. The reaction mixture was stirred at 120 C for 48 h, and then cooled to room temperature. The resulting mixture was evaporated to dryness, and the residue was partitioned between water (20 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL2). The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/ MeOH¼20:1) to afford 0.103 g (0.248 mmol, 89%) of 14 as yellow syrup. Rf¼0.37 (CH2Cl2/MeOH¼15:1); [a]25 D þ91.6 (c 2.4, CHCl3); IR (neat) n 3030, 2856, 1724, 1662, 1496, 1453, 1360, 1209, 1095, 1027, 737, 698, 604, 477, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.40e7.21 (m, 15H), 5.80 (d, J¼1.5 Hz, 1H), 4.78 (d, J¼11.7 Hz, 1H), 4.64e4.49 (m, 7H), 4.06 (s, 2H), 4.10 (s, 2H), 3.54 (dd, J¼11.1, 5.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 140.0, 139.0, 138.6, 138.4, 135.4, 128.7, 128.6, 128.3, 128.1, 128.0, 127.9, 127.8, 88.3, 79.3, 73.0, 72.7, 71.5, 67.6, 61.0; HRMS (CI) calcd for C27H30NO3 [MþH]þ 416.2226, found 416.2227. 4.8. N4-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl) cyclopent-2-enyl)-6-chloropyrimidine-4,5-diamine (15) To a stirred solution of 14 (0.57 g, 1.37 mmol) in isoamyl alcohol (13.7 mL) were added 5-amino-4,6-dichloropyrimidine (1.12 g, 6.8 mmol) and triethylamine (0.58 mL, 4.17 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 130 C for 24 h. The resulting mixture was cooled to room
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temperature and evaporated to dryness. The residue was purified by flash column chromatography (n-hexane/EtOAc¼3:1) to afford 0.66 g (1.22 mmol, 89%) of 15 as yellow syrup. Rf¼0.50 (n-hexane/ EtOAc¼1:1); [a]25 D þ32.9 (c 0.4, CHCl3); IR (neat) n 3357, 3030, 2858, 1576, 1496, 1455, 1420, 1360, 1210, 1097, 749, 698, 746, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.12 (s, 1H), 7.36e7.27 (m, 15H), 5.91 (d, J¼1.5 Hz, 1H), 5.32 (dd, J¼3.5, 1.5 Hz 1H), 4.86 (d, J¼12.0 Hz, 1H), 4.72 (d, J¼12.5 Hz, 1H), 4.66 (d, J¼12.0 Hz, 1H), 4.47 (d, J¼11.5 Hz, 1H), 4.59e4.51 (m, 4H), 4.13 (s, 2H), 3.88 (dd, J¼4.5, 4.4 Hz, 1H), 3.21 (s, 2H); 13C NMR (125 MHz, CDCl3) d 154.8, 150.0, 144.1, 143.9, 138.6, 138.4, 138.2, 129.5, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 121.9, 82.6, 79.3, 73.4, 72.0, 71.7, 67.3, 60.3; HRMS (CI) calcd for C31H32ClN4O3 [MþH]þ 543.2163, found 543.2163. 4.9. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyl)-6-chloro-9H-purine (16)
5
ion-exchange resin DOWEX 50WX8-100 using aqueous 0.5 M NH4OH to afford 0.044 g (0.167 mmol, 72%) of ent-1 as white solid. Rf¼0.53 (CH2Cl2/MeOH/EtOH/NH4OH 5:2:1:1); [a]25 D þ8.2 (c 0.9, MeOH); IR (neat) n 3383, 2948, 2834, 1652, 1453, 1032, 657, 419 cm1; 1H NMR (300 MHz, DMSO/D2O) d 8.14 (s, 1H), 8.11 (s, 1H), 5.71 (d, J¼3.6 Hz, 1H), 5.36 (br s, 1H), 4.43 (d, J¼5.7 Hz, 1H), 4.26 (t, J¼5.7 Hz, 1H), 4.12 (s, 2H); 13C NMR (125 MHz, DMSO/D2O) d 155.8, 152.3, 150.2, 149.9, 140.8, 124.3, 119.4, 77.2, 72.6, 65.0, 59.0; HRMS (EI) calcd for C11H13N5O3 [M]þ 263.1018, found 263.1019. Acknowledgements This work was supported by the National Research Foundation of Korea (NRF-2012-002506) funded by the Ministry of Education, Science and Technology. Supplementary data
To a stirred solution of 15 (0.542 g, 0.998 mmol) in isoamyl alcohol (25 mL) was added triethyl orthoformate (1.1 mL, 6.61 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 120 C for 12 h. The resulting mixture was evaporated to dryness and the residue was purified by flash column chromatography (n-hexane/EtOAc¼3:1) to afford 0.496 g (0.897 mmol, 90%) of 16 as yellow syrup. Rf¼0.43 (n-hexane/EtOAc¼1:1); [a]25 D þ72.0 (c 1.4, CHCl3); IR (neat) n 3030, 2864, 1592, 1559, 1495, 1454, 1402, 1338, 1200, 1125, 1028, 938, 948, 747, 699, 638, 476, 458, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.65 (s, 1H), 7.92 (s, 1H), 7.35e7.30 (m, 10H), 7.13e7.05 (m, 3H), 7.01e6.97 (m, 2H), 5.95 (d, J¼1.5 Hz, 1H), 5.74 (dd, J¼4.5, 1.5 Hz, 1H), 4.79 (d, J¼11.5 Hz, 1H), 4.68 (d, J¼5.5 Hz, 1H), 4.56 (d, J¼12.0 Hz, 1H), 4.61 (d, J¼¼11.6 Hz, 1H), 4.58e4.54 (m, 2H), 4.38 (d, J¼12.5 Hz, 1H), 4.30 (dd, J¼11.5, 5.5 Hz, 1H), 4.20e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3) d 151.9, 151.7, 151.2, 145.9, 144.2, 138.3, 137.9, 137.0, 132.3, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 126.7, 82.7, 76.9, 73.2, 72.8, 72.7, 67.1, 64.4; HRMS (CI) calcd for C32H30ClN4O3 [MþH]þ 553.2006, found 553.1996. 4.10. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyl)-9H-purin-6-amine (17) A solution of 16 (0.16 g, 0.29 mmol) dissolved in ammonia solution (3 mL, 2 M in MeOH) was stirred at 80 C for 24 h in a sealed tube. The solution was evaporated to dryness and the residue was purified by flash column chromatography (CH2Cl2/MeOH¼15:1) to afford 0.124 g (0.232 mmol, 80%) of 17 as yellow syrup. Rf¼0.23 (CH2Cl2/MeOH¼15:1); [a]25 D þ61.1 (c 0.9, CHCl3); IR (neat) n 3166, 2865, 1644, 1598, 1474, 1416, 1365, 1329, 1252, 1207, 1127, 746, 699, 477, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.33 (s, 1H), 7.63 (s, 1H), 7.37e7.28 (m, 10H), 7.21e7.12 (m, 3H), 7.10e7.07 (m, 2H), 5.97 (d, J¼1.5 Hz, 1H), 5.72 (dd, J¼4.0, 1.5 Hz, 1H), 5.55 (s, 2H), 4.76 (d, J¼11.0 Hz, 1H), 4.58 (d, J¼11.0 Hz, 1H), 4.69 (d, J¼5.0 Hz, 1H), 4.65 (d, J¼12.0 Hz, 1H), 4.52 (d, J¼12.0 Hz, 1H), 4.60e4.54 (m, 2H), 4.30 (dd, J¼11.0, 5.0 Hz, 1H), 4.21e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3) d 155.4, 153.1, 150.2, 145.3, 139.5, 138.4, 138.0, 137.4, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.4, 120.3, 82.9, 78.7, 73.1, 72.4, 67.1, 63.8; HRMS (CI) calcd for C32H32N5O3 [MþH]þ 534.2505, found 534.2501. 4.11. (D)-Neplanocin A (ent-1) To a stirred solution of 17 (0.13 g, 0.23 mmol) in CH2Cl2 (1.2 mL) was added BCl3 (4.93 mL, 4.93 mmol, 1 M in CH2Cl2) at 78 C. The reaction mixture was stirred for 24 h at 78 C and then quenched with MeOH (4.6 mL). The resulting mixture was warmed to room temperature and evaporated to dryness. The residue was dissolved in MeOH (10 mL) and then evaporated. The residue was purified by
1
H NMR and 13C NMR copies of all compounds. Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2014.12.093. References and notes 1. (a) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-nucleosides; Kluwer Academic: Dordrecht, The Netherlands, 1998; (b) Crimmins, M. T. Tetrahedron 1998, 54, 9229; (c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611; (d) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. 2. Montgomery, J. A. Med. Res. Rev. 1982, 2, 271. 3. (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1; (b) Saunders, J.; Cameron, J. M. Med. Res. Rev. 1995, 15, 497; (c) Roberts, S.; Biggadike, K.; Borthwick, A. D.; Kirk, B. In Topics in Medicinal Chemistry; Leeming, P. R., Ed.; Royal Society of Chemistry: London, UK, 1998; (d) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985. 4. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. J. Antibiot. 1981, 34, 359. 5. Kusuka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.; Mizuno, K. J. Antibiot. 1968, 21, 255. 6. Hayashi, M.; Yaginuma, S.; Yoshioka, H.; Nakatsu, K. J. Antibiot. 1981, 34, 675. 7. For selected reviews on neplanocin family, see: (a) Isono, K. J. Antibiot. 1988, 41, 1711; (b) Herdewijin, P. Modified Nucleosides: In Biochemistry, Biotechnology and Medicine; Wiley-VCH: Weinheim, 2008. 8. (a) Borchardt, R.; Keller, B. T.; Patel-Thomvre, U. J. Biol. Chem. 1984, 259, 4353; (b) Wolfson, G.; Chisholm, J.; Tashjian, A. H., Jr.; Fish, S.; Abeles, R. H. J. Biol. Chem. 1986, 261, 4492. 9. Medich, J. R.; Kunnen, K. B.; Johnson, C. R. Tetrahedron Lett. 1987, 28, 4131. 10. (a) Lim, M.-I.; Marquez, V. E. Tetrahedron Lett. 1983, 24, 5559; (b) Tseng, C. K. H.; Marquez, V. E. Tetrahedron Lett. 1985, 26, 3669; (c) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest, M. A.; Khan, M. S.; Kaskar, B. J. Org. Chem. 1988, 53, 5709; (d) Bestmann, H. J.; Roth, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 99; (e) Wolfe, M. S.; Anderson, B. L.; Borcherding, D. R.; Borchardt, R. T. J. Org. Chem. 1990, 55, 4712; (f) Hill, J. M.; Hutchinson, E. J.; Le Grand, D. M.; Roberts, S. M.; Thorpe, A. J.; Turner, N. J. J. Chem. Soc. , Perkin Trans. 1 1994, 1483; (g) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K. J. Org. Chem. 1999, 64, 4173; (h) Hegedus, L. S.; Geisler, L. J. Org. Chem. 2000, 65, 4200; (i) Michel, B. Y.; Strazewski, P. Tetrahedron 2007, 63, 9836. 11. Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.; Tomioka, K. J. Org. Chem. 2001, 66, 8199. 12. (a) Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995, 36, 1537; (b) Niizuma, S.; Shuto, S.; Matsuda, A. Tetrahedron 1997, 53, 13621. 13. Cho, J. H.; Bernard, D. L.; Sidwell, R. W.; Kern, E. R.; Chu, C. K. J. Med. Chem. 2006, 49, 1140. 14. (a) Trost, B. M.; Madsen, R.; Guile, S. D. Tetrahedron Lett. 1997, 38, 1707; (b) Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122, 5947. 15. (a) Arita, M.; Adachi, K.; Ito, Y.; Sakai, H.; Ohno, M. J. Am. Chem. Soc. 1983, 105, 4049; (b) Hutchinson, E. J.; Roberts, S. M.; Thorpe, A. J. J. Chem. Soc., Perkin Trans. 1 1992, 2245; (c) Yoshida, N.; Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677. 16. Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis, A. E. J. Org. Chem. 2005, 70, 6884. 17. Paquette, L. A.; Tian, Z.; Seekamp, C. K.; Wang, T. Helv. Chim. Acta 2005, 88, 1185. 18. Tan, Y. X.; Santhanakrishnan, S.; Yang, H. Y.; Chai, C. L. L.; Tam, E. K. W. J. Org. Chem. 2014, 79, 8059. 19. (a) Kim, I. S.; Li, Q. R.; Dong, G. R.; Kim, Y. C.; Hong, Y. J.; Lee, M.; Chi, K.-W.; Oh, J. S.; Jung, Y. H. Eur. J. Org. Chem. 2010, 1569; (b) Kim, I. S.; Jung, Y. H. Heterocycles 2011, 83, 2489; (c) Lee, S. H.; Kim, I. S.; Li, Q. R.; Dong, G. R.; Jeong, L. S.; Jung, Y. H. J. Org. Chem. 2011, 76, 10011; (d) Dong, G. R.; Hong, S.; Kim, S. I.; Kim, I. S.;
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6 Jung, Y. H. Eur. J. Org. Chem. 2012, 4200; (e) Kim, S. J.; Jeon, T. H.; Min, I. S.; Kim, I. S.; Jung, Y. H. Tetrahedron Lett. 2012, 53, 3680; (f) Li, Q. R.; Dong, G. R.; Park, S. J.; Hong, Y. R.; Kim, I. S.; Jung, Y. H. Eur. J. Org. Chem. 2013, 4427; (g) Min, I. S.; Kim, S. I.; Hong, S.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 3901; (h) Lee, S. H.; Park, S. J.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 1877; (i) Li, Q. R.; Kim, S. I.; Park, S. J.; Hong, Y. R.; Yang, H. R.; Baek, A. R.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 10384.
20. Dasari, B.; Jogula, S.; Borhade, R.; Balasubramanian, S.; Chandrasekar, G.; Kitambi, S. S.; Arya, P. Org. Lett. 2013, 15, 432. pez, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J. J. Am. Chem. Soc. 21. S anchez, I. H.; Lo 1983, 105, 7640. 22. Pless, P.; Bauer, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 147. 23. Angel, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515. 24. Sakatani, M.; Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1986, 27, 3753.
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Total synthesis of carbocyclic nucleoside (þ)-neplanocin A Young Hoon Jung *, Seung In Kim, Yeon Ju Hong, Sook Jin Park, Kyung Tae Kang, So Yeon Kim, In Su Kim School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 October 2014 Received in revised form 26 December 2014 Accepted 27 December 2014 Available online xxx
Asymmetric total synthesis of (þ)-neplanocin A was concisely achieved from readily available D-galactose via the regioselective and diastereoselective amination of carbocyclic polybenzyl ether using chlorosulfonyl isocyanate and intramolecular olefin metathesis using second-generation Grubbs catalyst. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Amination Chlorosulfonyl isocyanate Metathesis Neplanocin Nucleoside
1. Introduction Carbocyclic nucleosides, in which an oxygen atom in a furanose ring of ribonucleosides is replaced by a methylene group, are among the most interesting discoveries in the field of natural products.1 Due to the absence of a true glycosidic bond, carbocyclic nucleosides are more chemically stable and not involved in the action of the enzymes that cleave the N-glycosidic linkage in conventional nucleosides.2 Thus carbocyclic nucleosides have been the focus of much attention in the development of new therapeutic agents.3 ()-Neplanocin A (1),4 an unsaturated analogue of ()-aristeromycin (2),5 is a naturally occurring carbocyclic nucleoside isolated from the culture filtrate of the soil fungus Ampullariella regularis in 1981 (Fig. 1). The absolute structures of 1 and 2 were established by X-ray analysis.6 Other natural neplanocin analogs, e.g., ()-neplanocin B (3), ()-neplanocin C (4), ()-neplanocin D (5), and ()-neplanocin F (6), were also identified.7 Among neplanocin family, ()-neplanocin A has received great attention due to its interesting biological properties such as potent antiviral and antitumor activities.4 ()-Neplanocin A efficiently inhibits cellular S-adenosylmethionine hydrolase in cells, which results in the accumulation of S-adenosylhomocysteine, thus inhibiting cell and viral methyltransferases involved in messenger RNA maturation and the synthesis of other macromolecules.8
* Corresponding author. Tel.: þ82 31 290 7711; fax: þ82 31 290 7773; e-mail address: [email protected] (Y.H. Jung).
Fig. 1. Structure of neplanocin family.
The protected tetrol 7 has been widely used as a convenient precursor wherein a Mitsunobu inversion of a secondary hydroxyl group with adenine followed by deprotection of hydroxyl groups provided ()-neplanocin A (Scheme 1). The formation of 7 and its enantiomer is achieved from optically active ribonolactone derivatives via the palladium-catalyzed rearrangement of the acetate moiety,9 construction of a carbocyclic ring by intramolecular HornereWadswortheEmmons or Wittig reactions,10 intramolecular aldol reaction,11 CeH insertion reaction of alkylidenecarbenes,12 and ring-closing metathesis reaction using Grubbs catalysts.13 Another approach for the preparation of 1 includes
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
Scheme 1. Synthetic approach for the formation of neplanocin A.
a palladium-catalyzed desymmetrization of cyclopentenes with 6chloropurine,14 chemoenzymatic desymmetrization of bicyclic DielseAlder adducts,15 intramolecular nitrone cycloaddition,16 zirconocene-mediated ring construction,17 and intramolecular BayliseHillman reaction.18 As part of an ongoing research program aimed at developing asymmetric total synthesis of biologically active compounds through a chlorosulfonyl isocyanate-mediated stereoselective amination,19 we herein describe the asymmetric total synthesis of (þ)-neplanocin A (ent-1) starting from commercially available D-galactose via the highly regioselective and diastereoselective allylic amination of cyclic polybenzyl ethers using chlorosulfonyl isocyanate (CSI) and intramolecular olefin metathesis as the key steps. 2. Results and discussion Our initial investigation focused on the efficient construction of carbocyclic polybenzyl ether 12, which can be subjected to our amination methodology to give the protected amino alcohol 13. Thus, the total synthesis of (þ)-neplanocin A began with the protected lactol 8 derived from D-galactose according to the reported
literature (Scheme 2).20 Wittig reaction of 8 and subsequent Swern oxidation of a secondary alcohol afforded the ketone 10 in high yields. Second Wittig reaction of 10 was subjected under NaHMDS as a base to give the diene 11, which was treated with secondgeneration Grubbs catalyst in refluxing CH2Cl2 to provide the carbocyclic polybenzyl ether 12 in 90% yield. Next, after the screening of various reaction conditions for the coupling between 12 and CSI, we found that the reaction in methylene chloride at 0 C gave the desired product 13 with an excellent level of diastereoselectivity (anti/syn¼50:1) in 91% yield. The origin of stereochemistry can be explained by competition between SNi mechanism and SN1 mechanism.19c In general, SNi mechanism leads to retention of stereochemistry via a four-centered transition state by the formation of a tight ion pair. Another plausible SN1 mechanism may cause the generation of a carbocation intermediate, which can provide the racemization of products. However, in the case of anti-dibenzyl ether 12, anti-amino alcohol 13 can be exclusively obtained due to the facile approach of NCO2Bn species to the less sterically hindered face in a carbocation intermediate. To obtain an essential precursor 14 for the formation of (þ)-neplanocin A, we then screened a chemoselective removal of the Cbz protection of 13 under various reaction conditions. After
Scheme 2.
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
several failed attempts such as BF3$OEt2/SMe2,21 BBr3,22 40% KOH/ MeOH,23 and Pd(OAc)2/Et3SiH/Et3N,24 the chemoselective removal of the Cbz protection of 13 was successfully achieved under basic hydrolysis conditions (LiOH$H2O, 1,4-dioxane/water (3:1), 120 C, 48 h) to give the primary amine 14 in high yield (89%). To construct the remaining adenine heterocycle, compound 14 was subjected to the three-step sequence as reported in the literature (Scheme 3).15a The condensation of 14 with 5-amino-4,6dichloropyrimidine in n-butyl alcohol at 120 C afforded our desired product 15 in low yield (20%) (Table 1, entry 1). The yield of 15 was improved to 61% when DMF was employed (Table 1, entry 4), however, the reaction required 48 h to go to completion. The best result was realized when 14 was exposed to 5-amino-4,6dichloropyrimidine in isoamyl alcohol, which produced the pyrimidine compound 15 in high yield (89%) within 24 h (Table 1, entry 5). Intramolecular ring formation of 15 and subsequent amination reaction using methanolic ammonia afforded the adenine 17 in high yields. Finally, debenzylation of 17 under the standard reaction condition (BCl3 in anhydrous CH2Cl2) proceeded cleanly to afford (þ)-neplanocin A (ent-1) with specific rotation and spectral data (1H and 13C NMR) identical to those reported in the literature.10c
3
4. Experimental 4.1. General Commercially available reagents were used without additional purification, unless otherwise stated. All reactions were performed under an inert atmosphere of nitrogen or argon. Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded on a Bruker Unity 300 MHz and Varian Unit 500 MHz spectrometer for CDCl3 solutions, and chemical shifts are reported as parts per million (ppm) relative to, respectively, residual CHCl3 dH (7.26 ppm) and CDCl3 dC (77.0 ppm) as internal standards. Resonance patterns are reported with the notations s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). In addition, the notation br is used to indicate a broad signal. Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Bruker Infrared spectrophotometer and are reported as cm1. Optical rotations were measured with a Jasco P1020 polarimeter. Thin layer chromatography was carried out using plates coated with Kieselgel 60F254 (Merck). For flash column chromatography, E. Merck Kieselgel 60 (230e400 mesh) was used. LC/mass spectra (LC/MS) were recorded on a Waters 2767 LCMS system. High-
Scheme 3.
Table 1 Selected optimization for the coupling of 14 and 5-amino-4,6-dichloropyrimidine.a Entry
Solvent
Temperature ( C)
Time (h)
Yieldb (%)
1 2 3 4 5
n-BuOH EtOH 1,4-Dioxane DMF Isoamyl alcohol
120 120 120 150 130
24 48 48 48 24
20 20 N.R. 61 89
a
Reaction conditions: (i) 13 (1 equiv), 5-amino-4,6-dichloropyrimidine (5 equiv), Et3N (3 equiv), solvent (0.1 M). b Isolated yield by flash column chromatography.
3. Conclusion We described a concise total synthesis of (þ)-neplanocin A starting from readily available D-galactose via the highly regioselective and diastereoselective amination of carbocyclic polybenzylic ether with retention of stereochemistry using chlorosulfonyl isocyanate and intramolecular olefin metathesis. It is believed that this synthetic strategy can be applied to the preparation of a broad range of biologically active compounds containing a chiral amine moiety.
resolution mass spectra (HRMS) were recorded on a JEOL JMS600 spectrometer. 4.2. (2R,3S,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-ol (9) To a stirred solution of MePPh3Br (17.6 g, 49.3 mmol) in THF (54 mL) was carefully added n-BuLi (37.1 mL, 59.4 mmol in 1.6 M solution) at 0 C under N2 atmosphere. The reaction mixture was stirred for 2 h at room temperature to generate ylide. To a reaction mixture was added a solution of 8 (6.78 g, 12.5 mmol) in THF (7.5 mL) at 78 C. The resulting mixture was warmed to room temperature and further stirred for 4 h. The reaction was quenched with water (30 mL) and the aqueous layer was extracted with EtOAc (100 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼5:1) to afford 5.07 g (9.41 mmol, 75%) of 9 as yellow syrup. Rf¼0.30 (nhexane/EtOAc¼5:1); [a]25 D 3.4 (c 0.5, CHCl3); IR (neat) n 3030, 2867, 1497, 1454, 1210, 1095, 1067, 1028, 736, 698, 477, 419 cm1; 1H NMR (500 MHz, CDCl3) d 7.37e7.16 (m, 20H), 5.87 (ddd, J¼17.5, 10.0, 8.0 Hz, 1H), 5.36e5.30 (m, 2H), 4.76 (d, J¼12.0 Hz, 2H), 4.65 (d,
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J¼12.0 Hz, 1H), 4.50e4.34 (m, 5H), 4.13e4.06 (m, 2H), 3.82e3.78 (m, 2H), 3.50 (dd, J¼9.5, 6.0 Hz, 2H), 3.02 (d, J¼5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 138.5, 138.4, 138.4, 138.3, 136.0, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9, 119.5, 82.3, 81.0, 76.8, 75.5, 73.4, 71.4, 70.5, 69.9; HRMS (CI) calcd for C35H39O5 [MþH]þ 539.2791, found 539.2792. 4.3. (3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-one (10) To a stirred solution of oxalic chloride (0.32 mL, 3.7 mmol) in CH2Cl2 (9 mL) were added dimethyl sulfoxide (0.53 mL, 7.4 mmol) and 9 (1.33 g, 2.5 mmol) at 78 C. After stirring for 1 h at same temperature, Et3N (1.74 mL, 12.1 mmol) was added. The reaction mixture was further stirred for 4 h at 78 C. The resulting mixture was carefully quenched with water (10 mL) and the aqueous layer was extracted with CH2Cl2 (20 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼4:1) to afford 1.17 g (2.2 mmol, 88%) of 10 as yellow syrup. Rf¼0.57 (n-hexane/EtOAc¼4:1); [a]25 D þ2.9 (c 6.5, CHCl3); IR (neat) n 2869, 1728, 1497, 1454, 1273, 1103, 740, 699, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.35e7.15 (m, 20H), 5.85 (ddd, J¼17.7, 10.5, 7.8 Hz, 1H), 5.40e5.24 (m, 2H), 4.72 (d, J¼11.4 Hz, 1H), 4.63e4.51 (m, 2H), 4.51e4.18 (m, 7H), 4.17 (d, J¼4.2 Hz, 1H), 4.10 (dd, J¼13.8, 6.0 Hz, 1H), 3.89 (dd, J¼5.9, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 207.6, 138.4, 138.2, 137.7, 137.3, 135.4, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 119.9, 83.0, 82.3, 80.9, 75.0, 74.7, 73.3, 72.9, 70.9; HRMS (CI) calcd for C35H37O5 [MþH]þ 537.2647, found 537.2646. 4.4. ((3S,4R,5S)-2-Methylenehept-6-ene-1,3,4,5-tetrayl)tetrakis(oxy)tetrakis(methylene)tetrabenzene (11) To a stirred solution of MePPh3Br (2.39 g, 6.7 mmol) in THF (11 mL) was slowly added NaHMDS (6.7 mL, 6.7 mmol) at 0 C under N2 atmosphere. The reaction mixture was stirred for 2 h at room temperature, and a solution of 10 (1.44 g, 2.7 mmol) in THF (2.4 mL) was added at 0 C. The reaction mixture was stirred for 1 h at 0 C. The resulting mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (30 mL2). The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc¼5:1) to afford 1.22 g (2.3 mmol, 85%) of 11 as yellow syrup. Rf¼0.64 (n-hexane/ EtOAc¼6:1); [a]25 D þ22.4 (c 1.7, CHCl3); IR (neat) n 3031, 2863, 1496, 1454, 1391, 1208, 1092, 1071, 1028, 923, 736, 698, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.35e7.12 (m, 20H), 5.94e5.73 (m, 1H), 5.58e5.09 (m, 5H), 4.84e4.79 (m, 1H), 4.66 (s, 1H), 4.62 (d, J¼11.0 Hz, 2H), 4.54 (d, J¼11.0 Hz, 2H), 4.50 (d, J¼2.5 Hz, 1H), 4.40 (d, J¼2.5 Hz, 1H), 4.29 (d, J¼11.9 Hz, 1H), 4.18e4.04 (m, 4H), 3.57 (dd, J¼7.9, 3.5 Hz 1H); 13C NMR (125 MHz, CDCl3) d 138.7, 138.6, 138.5, 136.5, 128.6, 128.5, 128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 118.4, 115.7, 83.8, 80.4, 79.8, 75.1, 72.8, 70.8, 70.7, 70.5; HRMS (CI) calcd for C36H39O4 [MþH]þ 535.2851, found 535.2848. 4.5. ((1S,2R,3S)-4-(Benzyloxymethyl)cyclopent-4-ene-1,2,3triyl)tris(oxy)tris(methylene)tribenzene (12) To a stirred solution of 11 (1.11 g, 2.08 mmol) in CH2Cl2 (21 mL) was added second-generation Grubbs catalyst (0.35 g, 0.41 mmol). The reaction mixture was refluxed for 8 h. The solution was evaporated to dryness and the residue was purified by flash column chromatography (n-hexane/EtOAc¼8:1) to afford 1.01 g (1.99 mmol, 95%) of 12 as brown syrup. Rf¼0.25 (n-hexane/EtOAc¼8:1); [a]25 D þ61.6 (c 1.0, CHCl3); IR (neat) n 3031, 2864, 1723, 1602, 1496,
1453, 1357, 1271, 1094, 1027, 737, 699, 604, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.39e7.16 (m, 20H), 5.99 (d, J¼1.5 Hz, 1H), 4.80e4.75 (m, 1H), 4.73 (d, J¼11.8 Hz, 1H), 4.65 (d, J¼2.7 Hz, 1H), 4.62e4.60 (m, 4H), 4.53 (d, J¼1.8 Hz, 1H), 4.49 (d, J¼3.9 Hz, 2H), 4.07 (s, 2H), 4.00 (d, J¼6, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 142.5, 138.9, 138.6, 138.5, 138.3, 130.5, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.2, 86.7, 84,6, 79.1, 72.9, 72.5, 72.1, 71.7, 67.5; HRMS (EI) calcd for C34H34O4 [M]þ 506.2457, found 506.2456. 4.6. Benzyl (1S,4S,5R)-4,5-bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enylcarbamate (13) To a stirred solution of 12 (0.13 g, 0.26 mmol) in anhydrous CH2Cl2 (2.6 mL) were added Na2CO3 (0.25 g, 2.3 mmol) and chlorosulfonyl isocyanate (0.18 mL, 2.0 mmol) at 0 C under N2 atmosphere. The reaction mixture was stirred for 24 h at 0 C and quenched with water (1.3 mL). The aqueous layer was extracted with EtOAc (10 mL2). The organic layer was added to a solution of aqueous 25% Na2SO3 (5 mL), and the reaction mixture was further stirred for 24 h at room temperature. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (nhexane/EtOAc¼5:1) to afford 0.13 g (0.236 mmol, 91%) of 13 as white solid. Rf¼0.24 (n-hexane/EtOAc¼4:1); mp¼107e113 C; [a]25 D þ29.3 (c 4.0, CHCl3); IR (neat) n 3309, 3031, 2857, 1690, 1544, 1454, 1336, 1281, 1251, 1138, 1095, 734, 696, 476, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.37e7.24 (m, 20H), 5.81 (s, 1H), 5.17e5.12 (m, 2H), 4.87 (br s, 1H), 4.73 (s, 2H), 4.65 (d, J¼11.4 Hz, 2H), 4.55 (d, J¼5.0 Hz, 1H), 4.53e4.48 (m, 3H), 4.08 (s, 2H), 3.77 (d, J¼4.5 Hz, 1H); 13 C NMR (125 MHz, CDCl3) d 143.4, 138.7, 138.2, 129.7, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 83.0, 73.2, 71.9, 67.2, 67.0, 60.5; HRMS (EI) calcd for C35H35NO5 [M]þ 549.2515, found 549.2516. 4.7. (1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enamine (14) To a stirred solution of 13 (0.16 g, 0.28 mmol) in 1,4-dioxane (5.4 mL) was added LiOH$H2O (0.14 g, 3.4 mmol) in water (1.8 mL) at room temperature. The reaction mixture was stirred at 120 C for 48 h, and then cooled to room temperature. The resulting mixture was evaporated to dryness, and the residue was partitioned between water (20 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL2). The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (CH2Cl2/ MeOH¼20:1) to afford 0.103 g (0.248 mmol, 89%) of 14 as yellow syrup. Rf¼0.37 (CH2Cl2/MeOH¼15:1); [a]25 D þ91.6 (c 2.4, CHCl3); IR (neat) n 3030, 2856, 1724, 1662, 1496, 1453, 1360, 1209, 1095, 1027, 737, 698, 604, 477, 419 cm1; 1H NMR (300 MHz, CDCl3) d 7.40e7.21 (m, 15H), 5.80 (d, J¼1.5 Hz, 1H), 4.78 (d, J¼11.7 Hz, 1H), 4.64e4.49 (m, 7H), 4.06 (s, 2H), 4.10 (s, 2H), 3.54 (dd, J¼11.1, 5.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 140.0, 139.0, 138.6, 138.4, 135.4, 128.7, 128.6, 128.3, 128.1, 128.0, 127.9, 127.8, 88.3, 79.3, 73.0, 72.7, 71.5, 67.6, 61.0; HRMS (CI) calcd for C27H30NO3 [MþH]þ 416.2226, found 416.2227. 4.8. N4-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl) cyclopent-2-enyl)-6-chloropyrimidine-4,5-diamine (15) To a stirred solution of 14 (0.57 g, 1.37 mmol) in isoamyl alcohol (13.7 mL) were added 5-amino-4,6-dichloropyrimidine (1.12 g, 6.8 mmol) and triethylamine (0.58 mL, 4.17 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 130 C for 24 h. The resulting mixture was cooled to room
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
temperature and evaporated to dryness. The residue was purified by flash column chromatography (n-hexane/EtOAc¼3:1) to afford 0.66 g (1.22 mmol, 89%) of 15 as yellow syrup. Rf¼0.50 (n-hexane/ EtOAc¼1:1); [a]25 D þ32.9 (c 0.4, CHCl3); IR (neat) n 3357, 3030, 2858, 1576, 1496, 1455, 1420, 1360, 1210, 1097, 749, 698, 746, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.12 (s, 1H), 7.36e7.27 (m, 15H), 5.91 (d, J¼1.5 Hz, 1H), 5.32 (dd, J¼3.5, 1.5 Hz 1H), 4.86 (d, J¼12.0 Hz, 1H), 4.72 (d, J¼12.5 Hz, 1H), 4.66 (d, J¼12.0 Hz, 1H), 4.47 (d, J¼11.5 Hz, 1H), 4.59e4.51 (m, 4H), 4.13 (s, 2H), 3.88 (dd, J¼4.5, 4.4 Hz, 1H), 3.21 (s, 2H); 13C NMR (125 MHz, CDCl3) d 154.8, 150.0, 144.1, 143.9, 138.6, 138.4, 138.2, 129.5, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 121.9, 82.6, 79.3, 73.4, 72.0, 71.7, 67.3, 60.3; HRMS (CI) calcd for C31H32ClN4O3 [MþH]þ 543.2163, found 543.2163. 4.9. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyl)-6-chloro-9H-purine (16)
5
ion-exchange resin DOWEX 50WX8-100 using aqueous 0.5 M NH4OH to afford 0.044 g (0.167 mmol, 72%) of ent-1 as white solid. Rf¼0.53 (CH2Cl2/MeOH/EtOH/NH4OH 5:2:1:1); [a]25 D þ8.2 (c 0.9, MeOH); IR (neat) n 3383, 2948, 2834, 1652, 1453, 1032, 657, 419 cm1; 1H NMR (300 MHz, DMSO/D2O) d 8.14 (s, 1H), 8.11 (s, 1H), 5.71 (d, J¼3.6 Hz, 1H), 5.36 (br s, 1H), 4.43 (d, J¼5.7 Hz, 1H), 4.26 (t, J¼5.7 Hz, 1H), 4.12 (s, 2H); 13C NMR (125 MHz, DMSO/D2O) d 155.8, 152.3, 150.2, 149.9, 140.8, 124.3, 119.4, 77.2, 72.6, 65.0, 59.0; HRMS (EI) calcd for C11H13N5O3 [M]þ 263.1018, found 263.1019. Acknowledgements This work was supported by the National Research Foundation of Korea (NRF-2012-002506) funded by the Ministry of Education, Science and Technology. Supplementary data
To a stirred solution of 15 (0.542 g, 0.998 mmol) in isoamyl alcohol (25 mL) was added triethyl orthoformate (1.1 mL, 6.61 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 120 C for 12 h. The resulting mixture was evaporated to dryness and the residue was purified by flash column chromatography (n-hexane/EtOAc¼3:1) to afford 0.496 g (0.897 mmol, 90%) of 16 as yellow syrup. Rf¼0.43 (n-hexane/EtOAc¼1:1); [a]25 D þ72.0 (c 1.4, CHCl3); IR (neat) n 3030, 2864, 1592, 1559, 1495, 1454, 1402, 1338, 1200, 1125, 1028, 938, 948, 747, 699, 638, 476, 458, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.65 (s, 1H), 7.92 (s, 1H), 7.35e7.30 (m, 10H), 7.13e7.05 (m, 3H), 7.01e6.97 (m, 2H), 5.95 (d, J¼1.5 Hz, 1H), 5.74 (dd, J¼4.5, 1.5 Hz, 1H), 4.79 (d, J¼11.5 Hz, 1H), 4.68 (d, J¼5.5 Hz, 1H), 4.56 (d, J¼12.0 Hz, 1H), 4.61 (d, J¼¼11.6 Hz, 1H), 4.58e4.54 (m, 2H), 4.38 (d, J¼12.5 Hz, 1H), 4.30 (dd, J¼11.5, 5.5 Hz, 1H), 4.20e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3) d 151.9, 151.7, 151.2, 145.9, 144.2, 138.3, 137.9, 137.0, 132.3, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 126.7, 82.7, 76.9, 73.2, 72.8, 72.7, 67.1, 64.4; HRMS (CI) calcd for C32H30ClN4O3 [MþH]þ 553.2006, found 553.1996. 4.10. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclopent-2-enyl)-9H-purin-6-amine (17) A solution of 16 (0.16 g, 0.29 mmol) dissolved in ammonia solution (3 mL, 2 M in MeOH) was stirred at 80 C for 24 h in a sealed tube. The solution was evaporated to dryness and the residue was purified by flash column chromatography (CH2Cl2/MeOH¼15:1) to afford 0.124 g (0.232 mmol, 80%) of 17 as yellow syrup. Rf¼0.23 (CH2Cl2/MeOH¼15:1); [a]25 D þ61.1 (c 0.9, CHCl3); IR (neat) n 3166, 2865, 1644, 1598, 1474, 1416, 1365, 1329, 1252, 1207, 1127, 746, 699, 477, 419 cm1; 1H NMR (500 MHz, CDCl3) d 8.33 (s, 1H), 7.63 (s, 1H), 7.37e7.28 (m, 10H), 7.21e7.12 (m, 3H), 7.10e7.07 (m, 2H), 5.97 (d, J¼1.5 Hz, 1H), 5.72 (dd, J¼4.0, 1.5 Hz, 1H), 5.55 (s, 2H), 4.76 (d, J¼11.0 Hz, 1H), 4.58 (d, J¼11.0 Hz, 1H), 4.69 (d, J¼5.0 Hz, 1H), 4.65 (d, J¼12.0 Hz, 1H), 4.52 (d, J¼12.0 Hz, 1H), 4.60e4.54 (m, 2H), 4.30 (dd, J¼11.0, 5.0 Hz, 1H), 4.21e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3) d 155.4, 153.1, 150.2, 145.3, 139.5, 138.4, 138.0, 137.4, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.4, 120.3, 82.9, 78.7, 73.1, 72.4, 67.1, 63.8; HRMS (CI) calcd for C32H32N5O3 [MþH]þ 534.2505, found 534.2501. 4.11. (D)-Neplanocin A (ent-1) To a stirred solution of 17 (0.13 g, 0.23 mmol) in CH2Cl2 (1.2 mL) was added BCl3 (4.93 mL, 4.93 mmol, 1 M in CH2Cl2) at 78 C. The reaction mixture was stirred for 24 h at 78 C and then quenched with MeOH (4.6 mL). The resulting mixture was warmed to room temperature and evaporated to dryness. The residue was dissolved in MeOH (10 mL) and then evaporated. The residue was purified by
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6 Jung, Y. H. Eur. J. Org. Chem. 2012, 4200; (e) Kim, S. J.; Jeon, T. H.; Min, I. S.; Kim, I. S.; Jung, Y. H. Tetrahedron Lett. 2012, 53, 3680; (f) Li, Q. R.; Dong, G. R.; Park, S. J.; Hong, Y. R.; Kim, I. S.; Jung, Y. H. Eur. J. Org. Chem. 2013, 4427; (g) Min, I. S.; Kim, S. I.; Hong, S.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 3901; (h) Lee, S. H.; Park, S. J.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 1877; (i) Li, Q. R.; Kim, S. I.; Park, S. J.; Hong, Y. R.; Yang, H. R.; Baek, A. R.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 10384.
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