HETEROCYCLES

Short Paper | Special issue | Vol. 86, No. 1, 2012, pp. 697-704
Received, 24th May, 2012, Accepted, 21st June, 2012, Published online, 29th June, 2012.
DOI: 10.3987/COM-12-S(N)20

■ A CONVENIENT SYNTHESIS OF THE L-LIKE ENANTIOMER OF 4'-METHYL-3-dEAZAARISTEROMYCIN

Chun Chen, Wei Ye, and Stewart W. Schneller*

Department of Chemistry and Biochemistry, Auburn University, 179 Chemistry Building, Auburn, AL 36849-5312, U.S.A.

Abstract

As an entry into L-like 3-deazaaristeromycins, synthesis of the enantiomer of D-like 4'-methyl-3-deazaaristeromycin is described in 11 steps from a readily accessible cyclopentenone that, in turn, is prepared from D-ribose.

The therapeutic prominence of abacavir (1)1 and entecavir (2)2 has placed carbocyclic nucleosides3 at the forefront of drug discovery. The successes with 1 and 2 can be traced to the beginning of carbocyclic nucleoside research with the preparation of aristeromycin (3)4 and its subsequent isolation from natural sources5 that stimulated numerous investigations in carbocyclic nucleosides.3 With the D-like structure of 3, it is not surprising that most structural variation development drew attention to this configuration.
It was not until sometime later that reports of the L-like enantiomer of 3 (4) began to appear.6-8 The first non-enzymatic total synthesis of L-like adenine derived carbocyclic nucleosides (and other heterocyclic base variations) was from the Chu laboratories.9 At the same time, we reported the anti-HBV activity of L-like 5'-noraristeromycin (5) with no similar activity with the D-like analog.10 This was followed by our laboratory describing the anti-trypanosomal activity for L-like 7-deaza-5'-noraristeromycin (6) and 8-aza-7-deaza-5'-noraristeromycin (7) with no corresponding properties for the D-like enantiomer.11,12

Our laboratory has recently returned to L-aristeromycin built around the 3-deazapurine base. This was prompted by the significant antiviral potential of 3-deazaaristeromycin13 that has never been extended to the L-like series. In that direction, we sought a convenient way into the 4'-alkyl derivatives as represented here with the L-like 3-deazaaristeromycin possessing a C-4' methyl group (8).
As shown in Scheme 1, the preparation of 8 began with treatment of the cyclopentenone 914 with methyllithium in THF at -78 °C to yield the tertiary allylic alcohol 10 in 85% yield. Subjecting 10 to the oxidative rearrangement of tertiary allylic alcohols by pyridinium dichromate (PDC)15 in the presence of acetic anhydride16,17 afforded 11. This was followed by the conjugate 1,4-addition reaction of vinylmagnesium bromide to 11 in the presence of CuBr·Me2S as catalyst and TMSCl and hexamethylphosphoramide (HMPA) added18 to result in ketone 12. Luche reduction of 12 with sodium borohydride and cerium(Ш) chloride heptahydrate (CeCl3·7H2O) gave the alcohol 13. The high diastereoselectivity of this latter 1,2-reduction19,20 was confirmed by X-ray crystallography of the eventual target 8 (Figure 2).
The alcohol 13 was converted to its triflate 14 with trifluoromethanesulfonic anhydride. A subsequent SN2 substitution reaction of the triflate 14 with the sodium salt of 6-chloro-3-deazapurine21 in the presence of catalytic amount of 18-crown-6 in DMF afforded carbocyclic nucleoside 15. Transformation of the vinyl group of 15 to a hydroxyl group occurred, first, by oxidative cleavage (OsO4/NaIO4) followed by sodium borohydride reduction to obtain 16 in 66% yield. Deprotection of 16 with hydrochloric acid afforded triol 17. Amination of 17 with hydrazine and subsequent reduction of 18 with Raney nickel produced the desired 4'-methyl-3-deazaaristeromycin (8) (30% yield, last two steps).22
In addition to NMR data, the structure of 4′-methyl-3-deazaaristeromycin (8) was confirmed by X-ray crystallography (Figure 2).23
In conclusion, we have established a general method into the L-like 4'-alkyl-3-deaazristeromycin series that can be varied with the selection of the alkyllithium reagent employed in the first step of Scheme 1.

EXPERIMENTAL
1H and 13C NMR spectra were measured on a Bruker AV-400 spectrometer or Bruker AC-250 spectrometer. 1H chemical shifts are reported relative to CDCl3 at δ 7.27 ppm (or MeOD at δ 3.51 ppm or DMSO-d6 at δ 2.51 ppm) and tetramethylsilane as an internal standard. 13C chemical shifts are reported in relative to CDCl3/MeOD/ DMSO-d6. The spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), and m (multiplet). Elemental analyses were performed by Atlantic Microlabs, Atlanta, Georgia. The mass spectral data were obtained using a Waters Micromass QTOF Premier mass spectrometer. Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm E. Merck silica gel 60-F254 precoated silica gel plates with visualization by irradiation with a Mineral light UVGL-25 lamp or exposure to iodine vapor. Column chromatography was performed on Whatman silica gel (average particle size 5–25 mm, 60 Å) and elution with the indicated solvent system. Yields refer to chromatographically and spectroscopically (1H and 13C NMR) homogeneous materials. The reactions were generally carried out in an N2 atmosphere under anhydrous conditions.
(3aR,4S,6aR)-4-Methyl-4,6a-dihydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1’-cyclopentan]-4-ol (10). Methyl lithium (31.2 mL, 1.6 M, 49.9 mmol) was added, dropwise, to a solution of 914 (5.0 g, 27.7 mmol) in dry THF (50 mL) at -78 °C. After stirring at -78 °C for 30 min, the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched by the addition of aqueous NH4Cl (50 mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 × 50 mL), and the combined organic layers dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to give 10 (4.63 g, 85%) as a white solid: mp 43-44 °C; 1H NMR (400 MHz, CDCl3): δ 5.81 (d, J = 9.2 Hz, 1H), 5.74 (d, J = 9.2 Hz, 1H), 5.04-5.07 (m, 1H), 4.24 (d, J = 9.2 Hz, 1H), 3.09 (s, 1H), 1.79-1.84 (m, 4H), 1.61-1.70 (m, 4H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ142.3, 131.7, 114.8, 84.9, 81.9, 80.3, 78.9, 39.3, 37.9, 20.3, 20.1. Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.18; H, 8.13.
(3aS,6aS)-6-Methyl-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1’-cyclopentan]-4(6aH)-one (11). A mixture of 10 (3.43 g, 17.6 mmol), PDC (13.26 g, 35.3 mmol), 4 Å molecular sieves (3 g), and Ac2O (7.84 mL, 141 mmol) in CH2Cl2 (100 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous Na2CO3 (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2 (2 × 100 mL) and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc = 10:1) to afford 11 (1.87 g, 54.8%) as a white solid: mp 80-81 °C; 1H NMR (400 MHz, CDCl3) δ 5.99 (s, 1H), 4.96 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 5.6 Hz, 1H), 2.2 (s, 3H), 1.68-1.86 (m, 4H), 1.62-1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 202.8, 184.3, 174.8, 130.0, 116.0, 80.7, 37.3, 35.9, 24.9, 20.5, 20.1. Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 68.18; H, 7.26.
(3aS,4S,6aS)-4-Methyl-4-vinyldihydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1’-cyclopentan]-6(6aH)-one (12). Vinylmagnesium bromide (10.95 mL, 10.95 mmol, 1.0 M in THF) and HMPA (3.2 mL, 18.25 mmol) were added to a suspension of CuBr·Me2S (150 mg, 0.73 mmol) in dry THF (20 mL) at -78 °C over 10 min. After stirring at -78 °C for 15 min, a solution of 11 (1.42 g, 7.3 mmol) and TMSCl (1.94 mL, 15.33 mmol) in dry THF (20 mL) was added dropwise over 30 min. The reaction mixture was stirred at -78 °C for 2 h, and then quenched by the addition of saturated aqueous NH4Cl (10 mL). The reaction mixture was extracted with EtOAc (3 × 40 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc = 10:1) to give 12 (1.13 g, 69.8%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.66-5.73 (m, 1H), 4.99-5.04 (m, 2H), 4.4-4.43 (d, J = 5.6 Hz, 1H), 4.11-4.22 (d, J = 5.6 Hz, 1H), 1.94 (d, J = 7 Hz, 2H), 1.68-1.86 (m, 4H), 1.62-1.67 (m, 4H), 1.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 213.6, 142.9, 114.4, 113.3, 82.8, 79.2, 44.5, 41.6, 36.7, 34.6, 25.0, 21.9, 21.7. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.11; H, 8.09.
(3aS,4S,6R,6aR)-4-Methyl-4-vinyltetrahydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1’-cyclopentan]-6-ol (13). Cerium chloride heptahydrate (1.43 g, 4.95 mmol) was added to a solution of 12 (1 g, 4.5 mmol) in MeOH (10 mL) at -30 °C. After stirring for 15 min at -30 °C, NaBH4 (340 mg, 9.0 mmol) was added, carefully, and the reaction mixture was warmed to room temperature for 30 min. The mixture was neutralized with conc. aqueous HCl. The volume was reduced in vacuo to 2/3, extracted with brine and Et2O. The organic layers were combined, dried (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc = 5:1) to give 13 (866 mg, 85.8%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.66-5.73 (m, 1H), 4.99-5.03 (m, 2H), 4.37 (t, J = 6.0 Hz, 1H), 4.22 (d, J = 5.5 Hz, 1H), 3.99-4.03 (m, 1H), 2.41 (d, J = 10.0 Hz, 1H), 1.94-1.98 (m, 5H), 1.52-1.72 (m, 5H), 1.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 112.9, 111.2, 84.7, 78.5, 70.8, 44.2, 41.9, 35.9, 33.9, 25.2, 21.3, 20.99. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.73; H, 8.82.
4-Chloro-1-((3aS,4S,6S,6aR)-4-methyl-4-vinyltetrahydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1’-cyclopentane]-6-yl)-1H-imidazo[4,5-c]pyridine (15). Triflic anhydride (1.5 mL, 8.92 mmol) was added to a solution of 13 (1 g, 4.46 mmol) and pyridine (1.44 mL, 17.83 mmol) in dry CH2Cl2 (10 mL) at 0 °C. After stirring for 50 min at 0 °C, cold CH2Cl2 (10 mL) and ice-H2O (20 mL) were added. The aqueous layer was washed with cold CH2Cl2 (15 mL) and the combined organic phases were dried (MgSO4), filtered, and concentrated to give the crude triflate 14, which was dried in vacuo at 0 °C for 1 h. A solution of 6-chloro-3-deazapurine21 (1.3 g, 8.47 mmol), NaH (357 mg, 8.92 mmol, 60% dispersion in mineral oil), and 18-crown-6 (2.36 g, 8.92 mmol) in DMF (15 mL) was heated at 70 °C for 4 h and then cooled to 0 °C. To this mixture was added the solution of previously prepared triflate in DMF (5 mL). This reaction mixture was allowed to stir at 0 °C for 12 h and then at room temperature for 2 days. The DMF was removed in vacuo and the residue purified by silica gel column chromatography (hexane:EtOAc = 5:1) to give 15 (882 mg, 55%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 5.95-6.01 (m, 1H), 5.06-5.14 (m, 3H), 4.98-5.02 (m, 1H), 4.69 (d, J = 6.5 Hz, 1H), 2.64-2.69 (m, 1H), 2.26- 2.3 (m, 1H), 1.80-1.82 (m, 2H), 1.64-1.69 (m 2H), 1.48-1.59 (m, 4H), 1.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ149.8, 139.7, 137.2, 136.7, 132.3, 122.6, 114.8, 113.0, 108.1, 84.9, 83.9, 61.5, 46.3, 42.8, 36.1, 34.2, 25.1, 21.9, 21.7; HRMS calcd for C19H22ClN3O2 359.1488, found 359.1438.
((3aR,4S,6S,6aS)-4-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)-6-methyltetrahydro-3aH-spiro[cyclo-penta[d][1,3]dioxole-2,1’-cyclopentane]-6-yl)methanol (16). Compound 15 (882 mg, 2.45 mmol) was dissolved in MeOH (8 mL). To this H2O (8.3 mL) and NaIO4 (1.15 g, 5.39 mmol) were added. This mixture was cooled to 0 °C and OsO4 (31 mg, 0.12 mmol, 5% mol) was added. The mixture was stirred at 0 °C for 2 h. The mixture was filtered and the MeOH removed under reduced pressure. The residue was extracted with CH2Cl2 (3×10 mL) and the organic layer washed with brine, dried (Na2SO4), and concentrated. The residue was dissolved in MeOH (10 mL) and to this NaBH4 (232 mg, 6.13 mmol) was added, portionwise, at 0 °C. The mixture as then stirred at 0 °C for 1 h and saturated aqueous NH4Cl solution (10 mL) added. The mixture was filtered through celite and the solvent was removed with reduced pressure. The residue was extracted with EtOAc (3 ×10 mL). The combined organic layers were dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc = 3:1) to provide 16 as a white foam (587 mg, 65.8%); 1H NMR (400 MHz, CDCl3), δ 8.27 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 4.74-4.78 (m, 1H), 4.63-4.65 (m, 1H), 4.46-4.48 (d, J = 6.4 Hz, 1H), 3.61 (d, J=5.6 Hz, 2H), 2.62-2.68 (m, 1H), 2.31-2.37 (m, 1H), 1.65-1.8 (m, 8H), 1.2 (s, 3H); 13C NMR (100 MHz, CDCl3) δ149.9, 139.6, 137.1, 132.2, 122.7, 113.2, 108.2, 84.7, 83.9, 67.5, 61.5, 46.2, 42.6, 36.2, 34.3, 25.2, 21.9, 21.7; Calcd HRMS for C18H22ClN3O3: 363.1377. Found: 363.1367.
(1R,2S,3S,5S)-5-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-methylcyclopentane- 1,2-diol (17). Compound 16 (587 mg, 1.61 mmol) was dissolved in 2 N HCl (1 mL) in MeOH at 0 °C and this solution was stirred at 25 °C overnight. Sodium bicarbonate was added to neutralize the solution until it no longer bubbled. The mixture was filtered. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc:MeOH = 2:1) to provide 17 as a white solid (287 mg, 59.7%): mp 184-186 °; 1H NMR (400 MHz, DMSO-d6), δ 8.56 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 4.82-4.92 (m, 1H), 4.53-4.57 (m, 1H), 3.9-3.93 (m, 1H), 3.51 (d, J = 5.6 Hz, 1H), 3.44 (d, J = 5.6 Hz, 1H), 3.29 (s, 1H), 2.09-2.18 (m, 1H), 2.01-2.07 (m, 1H), 1.12 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 149.3, 138.4, 136.8, 132.1, 119.2, 108.4, 75.7, 74.5, 69.4, 60.4, 44.4, 36.7, 18.4; Calcd HRMS for C13H16ClN3O3: 297.0965. Found: 297.0961.
(1R,2S,3S,5S)-5-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-methylcyclopentane-1,2-diol (8). To a mixture of anhydrous hydrazine (99%, 1 mL) and 1-propanol (3 mL) was added 17 (287 mg, 1.87 mmol). The solution was brought to reflux for 8 h. The reaction was cooled to room temperature and the residual hydrazine and 1-propanol was evaporated under reduced pressure. Water (5 mL) was added to dissolve the residue and then Raney nickel (0.8 g) was added portionwise. The mixture was heated to reflux for 1 h. The reaction mixture was then filtered through a celite pad. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc:MeOH:NH4OH = 20:2:1) to provide 8 as a white solid (76 mg, 30.3%): mp 208-209 °C; 1H NMR (400 MHz, MeOD), δ 8.21 (s, 1H), 7.64 (d, J = 6 Hz, 1H), 7.0 (d, J = 6 Hz, 1H), 4.56-4.78 (m, 1H), 4.53-4.57 (m, 1H), 3.94 (d, J = 6 Hz, 1H), 3.51 (d, J = 5.6 Hz, 1H), 3.48 (d, J = 5.6 Hz, 1H), 2.08-2.13 (m, 1H), 1.98-2.05 (m, 1H), 1.13 (s, 3H); 13C NMR (100 MHz, MeOD) δ 176.5, 153.3, 142.3, 140.4, 128.2, 99.7, 77.5, ,76.0, 70.6, 62.7, 45.7, 37.7, 20.1; Calcd HRMS for C13H18N4O3: 279.1469. Found: 279.1457.

ACKONWLEDGMENTS
A small portion of this research has been supported by funds from the Department of Health and Human Services (Al 56540), which is appreciated. Also, support from the Molette Fund and Auburn University is appreciated. We are grateful for the assistance of Dr. John Gorden at Auburn University in providing the X-ray structural analysis of 8.

References

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