Boc L Valine Synthesis Essay

4.1. Chemistry

NMR spectra were obtained on a Bruker Avance 400 at The Ohio State University College of Pharmacy (400 MHz for 1H and 100 MHz for 13C). Chemical shifts are reported in parts per million (ppm). The coupling constants are reported in Hertz (Hz). High Resolution-Electrospray Ionization (HR-ESI) mass spectra were recorded on a Micromass LCT Electrospray mass spectrometer at The Ohio State University Campus Chemical Instrumentation Center (OSU-CCIC). For all carborane-containing compounds, the mass of the most intensive peak of the isotopic pattern was reported for an 80% boron-11 to 20% boron-10 distribution. Compound visualization on Silica Gel 60 F254 precoated TLC plates (0.25 mm layer thickness) (Merck, Darmstadt, Germany) was attained by UV light and KMnO4 spray. Carborane-containing compounds were selectively visualized by spraying a solution of 0.06% PdCl2 /1% aqueous HCl on TLC plates and subsequent heating to ~ 120 °C. Reagent grade solvents were used for column chromatography using Silica gel 60, particle size 63–200 µm (Dynamic Adsorbents, Inc, Georgia). Standard reagent grade chemicals were obtained from commercial vendors and used as such. o-Carborane was purchased from Katchem, Ltd, Prague, Czech Republic. Valacyclovir was purchased from Toronto Research Chemicals, Inc. Canada. Solvents were dried prior to use following standard procedures. All chemical reactions were carried out under argon atmosphere. Bovine serum and phosphate buffered saline (PBS) were obtained from Sigma-Aldrich. Bovine cerebrospinal fluid (CSF) was obtained from Biochemed Services, Winchester (Virginia). Filters (Corning, Germany) used in the stability studies had 0.2 µm pore size. The colorimetric measurement of protein concentrations in Bovine serum and Bovine CSF was carried out by using a Spectramax Plus Spectrophotometer from Molecular Devices (Sunnyvale, California). The obtained data were analyzed using SoftMax Pro 3.1.2 software.

Preparative HPLC was performed on a Gemini 5µ C18 column (21.20 mm × 250 mm, 5 µm particle size) from Phenomenex Inc. CA, USA using a Hitachi HPLC system (L-2130) with a Windows based data acquisition and a Hitachi Diode array detector (L-2455). Purification was accomplished using a water (0.1% TFA)/methanol gradient at 7 mL/min flow rate (100:0 to 50:50 over 15 min then 50:50 to 15:85 [H2O:MeOH] over 70 min followed by 15:85 to 0:100 over 15 min).

Analytical HPLC for purity confirmation and stability analysis was carried out with a Gemini 5µ C18 110A Column (250 × 4.6 mm) from Phenomenex Inc. CA, USA using the HPLC system above. Two different solvent systems were used at 1 mL/min flow rate: A = water (0.1% TFA)/acetonitrile (0.1% TFA); B = water (0.1% TFA)/methanol (0.1% TFA). For each solvent system, different gradients were used for compound analysis (Table 3, A1-A4, B1-B3). For all Thd derivatives, a wavelength of 265 nm was used for detection, whereas valacyclovir/acyclovir were detected at 254 nm.

4.1.1. 5-{2-(tert.-Butyldimethylsilyl)-o-carboran-1-yl}pentyl 4-methylbenzenesulfonate (6)

To a solution of 5[24] (0.52 g, 2 mmol) in THF (50 mL) was added n-BuLi (0.9 mL, 2.36 mmol, 2.5 M solution in hexanes) at −78 °C over a period of 10 min. The solution was gradually warmed to rt and then stirred for 1 h. Subsequently, the reaction mixture was cooled to 0 °C and 1,5-pentandiol ditosylate (1.1 g, 2.6 mmol) was added dropwise. The mixture was refluxed at 80 °C for 5 h. Distilled water (20 mL) was added and excess THF was removed under reduced pressure. The residue was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with diluted HCl solution (2%, 30 mL) and brine (30 mL), and dried over anhydrous MgSO4. After filtration and evaporation, the residue was purified by silica gel column chromatography using hexanes/ dichloromethane, 8:2, as the eluent to give compound 6 (0.35 g, 36 %). Rf 0.70; 1H-NMR (CDCl3): δ 0.28 (s, 6H, (CH3)2Si), 1.01 (s, 9H, (CH3)3C), 1.18–1.30 (m, 2H, C2H4CH2), 1.36–1.46 (m, 2H, CH2CH2-Ccarborane), 1.56–1.64 (m, 2H, OCH2CH2), 2.09 (t, J = 7.7 Hz, 2H, CH2-Ccarborane), 2.42 (s, 3H, CH3), 3.96 (t, J = 6.1 Hz, 2H, OCH2), 7.32 (d, J = 7.9 Hz, 2H, Ph), 7.74 (d, J = 7.9 Hz, 2H, Ph); 13C-NMR (CDCl3): δ -1.53 ((CH3)2Si), 21.24 ((CH3)3C), 22.59 (CH3), 25.96 (C2H4CH2), 28.45 ((CH3)3C), 29.34 (CH2CH2-Ccarborane), 30.38 (OCH2CH2), 38.55 (CH2-Ccarborane), 70.82 (CH2O), 77.12, 82.10 (Ccarborane), 128.76, 130.83, 133.84, 145.38 (Ph); MS (HR-ESI) calcd for C20H42B10O3SSiNa (M+Na)+: 521.3525, found: 521.3434.

4.1.2. 3-(5-{2-[tert.-Butyldimethylsilyl]-o-carboran-1-yl}pentan-1-yl)thymidine (7)

To a solution of compound 6 (0.35 g, 0.71 mmol) in a mixture of DMF and acetone (30 mL, 1:1) were added Thd (0.86 g, 3.55 mmol) and potassium carbonate (0.59 g, 4,26 mmol) and stirred at 50 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/methanol, 20:1, as the eluent to give compound 7 (0.26 g, 65 %). Rf 0.5; 1H-NMR (CD3OD): δ 0.37 (s, 6H, Si(CH3)2), 1.09 (s, 9H, C(CH3)3), 1.27–1.37 (m, 2H, NC2H4CH2), 1.54–1.65 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.91 (s, 3H, CH3), 2.16–2.34 (m, 4H, CH2-Ccarborane, H-2" and H-2'), 3.75 (dd, J = 11.8, and 3.3 Hz, 1H, H-5"), 3.82 (dd, J = 11.8, and 3.3 Hz, 1H, H-5'), 3.87–3.96 (m, 3H, CH2N, and H-3'), 4.39–4.45 (m, 1H, H-4'), 6.31 (t, J = 6.8 Hz, 1H, H-1'), 7.85 (s, 1H, H-6), 13C-NMR (CD3OD): δ-2.94 (Si(CH3)2), 12.49 (CH3), 20.38 ((CH3)3C), 26.47 (NC2H4CH2), 27.25 ((CH3)3C), 30.14 (CH2CH2-Ccarborane, NCH2CH2), 38.01 (CH2-Ccarborane), 40.50 (CH2N), 41.02 (C-2'), 61.82 (C-5'), 71.15 (C-3'), 76.88, 82.24 (Ccarborane), 86.10 (C-1'), 87.87 (C-4'), 109.70 (C-5), 135.48 (C-6), 151.24 (C-2), 164.30 (C-4); MS (HR-ESI) calcd for C23H48B10N2O5SiNa (M+Na)+: 591.4233, found: 591.4304.

4.1.3. 3-(5-{o-Carboran-1-yl}pentan-1-yl)thymidine (1) [22–23]

To a solution of compound 7 (0.35 g, 0.62 mmol) in THF (30 mL) was added a 1 M solution of TBAF (1.0 mL, 1 mmol) in THF at −78 °C. The reaction mixture was stirred at rt for 0.5 h. Distilled water (10 mL) was added and excess THF was removed under reduced pressure. The residue was extracted with ethyl acetate (50 mL × 2), the combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. After filtration and evaporation, the residue was subjected to silica gel column chromatography using ethyl acetate/methanol, 20:1, as the eluent to give compound 1 (0.17 g, 58 %). Rf 0.6; 1H-NMR (CD3OD) δ 1.28–1.37 (m, 2H, NC2H4CH2), 1.49–1.66 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.17–2.33 (m, 4H, CH2-Ccarborane, H-2", and H-2'), 3.74 (dd, J = 11.8, and 3.3 Hz, 1H, H-5"), 3.81 (dd, J = 11.8, and 3.3 Hz, 1H, H-5'), 3.88–3.95 (m, 3H, CH2N, and H-3'), 4.39–4.44 (m, 1H, H-4'), 4.53 (s, 1H, carboranyl-CH), 6.31 (t, J = 6.4 Hz, 1H, H-1'), 7.85 (s, 1H, H-6); MS (HR-ESI) calcd for C17H34B10N2O5Na (M+Na)+: 477.3369, found: 477.3546.

4.1.4. 4-(2-{5-Iodopentyl}-o-carboran-1-yl)methyl-2,2-dimethyl-1,3-dioxolane (9)

To a solution of compound 8[25] (2.58 g, 10 mmol) in THF (50 mL) was added a solution of n-BuLi (4.8 mL, 12 mmol, 2.5 M solution in hexanes) at −78 °C. The reaction mixture was allowed to warm up to 0 °C and 1,5-diiodopentane (5.83 g, 18 mmol) was added dropwise in rapid fashion. The reaction mixture was refluxed at 80 °C for 6 h. Distilled water (30 mL) was added and excess THF was removed under reduced pressure. The residue was extracted with ethyl acetate (50 mL × 2), and the combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. After filtration and evaporation, the residue was purified by silica gel column chromatography using hexanes/dichloromethane, 7:4, as the eluent to give compound 9 (1.85 g, 41 %). Rf 0.3; 1H-NMR ((CD3)2CO): δ 1.31–1.45 (m, 8H, C(CH3)2, NC2H4CH2), 1.50–1.62 (m, 2H, CH2CH2-Ccarborane), 1.78–1.87 (m, 2H, ICH2CH2), 2.16–2.33 (m, 2H, CH2-Ccarborane), 2.39 (dd, J = 11.9, and 3.4 Hz, 1H, CHCH2-Ccarborane), 2.42 (dd, J = 11.9, and 3.4 Hz, 1H, CHCH2-Ccarborane), 3.17 (t, J = 6.8 Hz, 2H, ICH2), 3.55 (dd, J = 11.9 and 3.4 Hz, 1H, CH2O), 4.13 (dd, J = 11.9 and 3.6 Hz, 1H, CHCH2O), 4.21–4.30 (m, 1H, CH2CHO); 13C-NMR ((CD3)2CO): δ 6.92 (CH2I), 25.80 (CH3), 27.35 (CH3), 29.07 (C2H4CH2), 30.52 (CH2CH2-Ccarborane), 33.20 (ICH2CH2), 35.32 (CH2-Ccarborane), 39.92 (CH2-Ccarborane), 69.51 (CH2O), 74.87 (CHO),77.44, 80.22 (Ccarborane), 110.02 (C(CH3)2); MS (HR-ESI) calcd for C13H31B10IO2Na (M+Na)+: 477.2270, found: 477.2257.

4.1.5. 3-(5-{2-[(2,2-Dimethyl-1,3-dioxolane-4-yl)methyl]-o-carboran-1-yl}pentan-1-yl)thymidine (10).[25]

To a solution of compound 9 (1.67 g, 3.68 mmol) in a mixture of DMF and acetone (50 mL, 1:1) were added Thd (4.45 g, 18.4 mmol) and potassium carbonate (3.05 g, 22.1 mmol) and stirred at 50 °C overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/methanol, 20:1, as the eluent to give compound 10 (1.0 g, 48 %). Rf 0.29; 1H-NMR (CD3OD): δ 1.29–1.42 (m, 8H, (CH3)2C, NC2H4CH2), 1.57–1.69 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.17–2.40 (m, 4H, CH2-Ccarborane, H-2", and H-2'), 2.54 (dd, J = 11.9, and 3.4 Hz, 1H, CHCH2-Ccarborane), 2.61 (dd, J = 11.9, and 3.4 Hz, 1H, CHCH2-Ccarborane), 3.56 (t, J = 6.8 Hz, 1H, CH2O), 3.74 (dd, J = 11.9, and 3.4 Hz, 1H, H-5"), 3.82 (dd, J = 11.9, and 3.4 Hz, 1H, H-5'), 3.88–3.96 (m, 3H, CH2N, and H-3'), 4.06–4.14 (m, 1H, CH2O), 4.20–4.32 (m, 1H, CH2CHO), 4.38–4.44 (m, 1H, H-4'), 6.32 (t, J = 6.8 Hz, 1H, H-1'), 7.86 (s, 1H, H-6).

4.1.6.a. General procedure for the synthesis of the amino acid ester prodrugs of N5 (11–19) and the glycine ester prodrugs of N5-2OH (20–22)

Compound 1 (0.22 mmol) or 10 (0.18 mmol), N-Boc-amino acid (Boc-L-valine, Bocglycine, or Boc-L-glutamic acid α-tert-butyl ester) (0.44/0.36 mmol), DCC (0.44/0.36 mmol) and DMAP (0.044/0.036 mmol) were dissolved in 10 mL of anhydrous DMF. The reaction mixture was stirred at rt for 24 h. The progress of the reaction was monitored by TLC (ethyl acetate:hexanes, 8:5). The reaction yielded three products as determined by TLC. After 24 h, the reaction mixture was filtered and DMF was removed in vacuum. The residue was dissolved in ethyl acetate (30 mL) and washed with water (20 mL), 0.1 N HCl (20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried over anhydrous MgSO4. The three intermediates observed by TLC were separated and purified partially by column chromatography (ethyl acetate: hexane, 8:5, see supplementary material for 1H-NMR data and Rf values for Boc-protected intermediates). Individual Boc-substituted amino acid ester prodrugs were added to 10 mL of a mixture of trifluoroacetic acid (TFA) and dichloromethane (1:1) and stirred at rt for 2 h (Boc-L-glutamic acid 5-tert.-butyl esters were stirred for 4 h). The solvent was removed and the amino acid ester prodrugs were purified by preparative HPLC to give products 11–22 as wax-like compounds.

4.1.6.b. General procedure for the synthesis of the hydrochloride salts of the amino acid ester prodrugs 1113 and 1522

To a solution of the amino acid ester prodrug (1113 and 1522 [0.2 mmol]) in diethyl ether/THF (1/1, 2 mL) was added 1 mL of a 1 M solution of HCl gas in diethyl ether at 0 °C and stirred overnight at rt. The solvent was removed under reduced pressure and the oily residue was solidified by adding 5 mL of a 0.1 M solution of HCl gas in diethyl ether. The obtained solid was washed 3–4 times with a 0.1 M solution of HCl gas in diethyl ether to give product (1113HCl and 1522HCl) in 50% to 70% yield.

4.1.6.1. 3'-L-Valyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (11)

Yield: 6 mg, 5%; 1H-NMR (CD3OD): δ 1.11 (d, J = 4.6 Hz, 6H, CH(CH3)2), 1.28–1.38 (m, 2H, NC2H4CH2), 1.48–1.68 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.21–2.50 (m, 5H, CH2-Ccarborane, H-2", H-2', and CH(CH3)2), 3.82–3.85 (m, 2H, H-5", and H-5'), 3.90 (t, J = 6.8 Hz, 2H, CH2N), 4.09 (d, J = 4.6 Hz, 1H, CHNH2), 4.14–4.18 (m, 1H, H-4'), 4.52 (s, 1H, carboranyl-CH), 5.48–5.52 (m, 1H, H-3'), 6.34 (t, J = 6.8 Hz, 1H, H-1'), 7.86 (s, 1H, H-6); 13C-NMR (CD3OD): δ 12.69 (CH3), 17.87 (CH(CH3)2), 26.59 (NC2H4CH2), 27.39 (CH2CH2-Ccarborane), 29.42 (NCH2CH2), 30.54 (CH(CH3)2), 37.89 (CH2-Ccarborane), 38.04 (CH2N), 41.42 (C-2'), 58.81 (CHNH2), 62.29 (Ccarborane), 63.14 (C-5'), 76.75 (Ccarborane), 78.24 (C-3'), 85.78 (C-1'), 86.52 (C-4'), 110.69 (C-5), 135.56 (C-6), 151.86 (C-2), 164.76 (C-4), 169.20 (COO); MS (HR-ESI) calcd for C22H44B10N3O6 (M+H)+: 554.4233, found: 554.4145; 11HCl: Anal. (C22H44B10ClN3O6) C, H, N.

4.1.6.2. 5'-L-Valyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (12)

Yield: 12 mg, 10%; 1H-NMR (CD3OD): δ 1.04–1.09 (m, 6H, CH(CH3)2), 1.25–1.34 (m, 2H, NC2H4CH2), 1.46–1.63 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.91 (s, 3H, CH3), 2.23–2.36 (m, 5H, CH2-Ccarborane, H-2", H-2', and CH(CH3)2), 3.89 (t, J = 7.2 Hz, 2H, CH2N), 3.97 (d, J = 4.4 Hz, 1H, CHNH2), 4.06–4.13 (m, 1H, H-3'), 4.32–4.37 (m, 1H, H-4'), 4.41 (dd, J = 11.8, and 3.3 Hz, 1H, H-5"), 4.52 (s, 1H, carboranyl-CH), 4.56–4.64 (m, 1H, H-5'), 6.27 (t, J = 6.8 Hz, 1H, H-1'), 7.46 (s, 1H, H-6); 13C-NMR (CD3OD): δ 12.68 (CH3), 17.65, 17.76 (CH(CH3)2), 26.62 (NC2H4CH2), 27.41 (CH2CH2-Ccarborane), 29.44 (NCH2CH2), 30.55 (CH(CH3)2), 38.05 (CH2-Ccarborane), 39.59 (CH2N), 41.42 (C-2'), 58.86 (CHNH2), 63.16 (Ccarborane), 66.56 (C-5'), 71.61 (C-3'), 76.76 (Ccarborane), 84.64 (C-1'), 87.37 (C-4'), 110.58 (C-5), 135.92 (C-6), 151.66 (C-2), 164.75 (C-4), 169.55 (COO); MS (HR-ESI) calcd for C22H44B10N3O6 (M+H)+: 554.4233, found: 554.4227, calcd for C22H43B10N3O6Na (M+Na)+ 576.4053 (M+Na)+, found 576.4076; 12HCl: Anal. (C22H44B10ClN3O6) C, H, N.

4.1.6.3. 3',5'-Di-L-valyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (13)

Yield: 18 mg, 13%; 1H-NMR (CD3OD): δ 1.05 (d, J = 4.4 Hz, 6H, CH(CH3)2), 1.10 (d, J = 4.4 Hz, 6H, CH(CH3)2), 1.26–1.35 (m, 2H, NC2H4CH2), 1.47–1.63 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.23–2.38 (m, 4H, CH2-Ccarborane, H-2" and H-2'), 2.50–2.57 (m, 1H, CH(CH3)2), 2.61–2.70 (m, 1H, CH(CH3)2), 3.89 (t, J = 6.8 Hz, 2H, CH2N), 3.98 (d, J = 4.4 Hz, 1H, CHNH2), 4.02 (d, J = 4.4 Hz, 1H, CHNH2), 4.33–4.39 (m, 1H, H-4'), 4.45–4.55 (m, 2H, carboranyl-CH and H-5"), 4.68–4.74 (m, 1H, H-5'), 5.46–5.50 (m, 1H, H-3'), 6.23 (t, J = 6.8 Hz, 1H, H-1'), 7.47 (s, 1H, H-6); 13C-NMR (CD3OD) δ 12.16 (CH3), 17.17, 17.24, 17.36, 17.39 (2CH(CH3)2), 26.09 (NC2H4CH2), 26.89 (CH2CH2-Ccarborane), 28.91 (NCH2CH2), 30.04 (2CH(CH3)2), 35.96 (CH2-Ccarborane), 37.55 (CH2N), 40.91 (C-2'), 58.32 (2CHNH2), 62.69 (Ccarborane), 65.51 (C-5'), 72.28 (Ccarborane), 76.31 (C-3'), 81.89 (C-1'), 87.71 (C-4'), 110.32 (C-5), 135.72 (C-6), 151.14 (C-2), 164.13 (C-4), 168.83, 169.07 (2COO); MS (HR-ESI) calcd for C27H53B10N4O7 (M+H)+: 653.4917, found: 653.4932; 13HCl: Anal. (C27H54B10Cl2N4O7) C, H, N.

4.1.6.4. 3'-Glycinyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (14)

Yield: 1 mg, 1%; 1H-NMR (CD3OD): δ 1.22–1.34 (m, 2H, NC2H4CH2), 1.44–1.63 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.89 (s, 3H, CH3), 2.20–2.48 (m, 4H, CH2-Ccarborane, H-2" and H-2'), 3.87–3.94 (m, 6H, CH2N, CH2NH2, H-5" and H-5'), 4.12–4.17 (m, 1H, H-4'), 4.49 (s, 1H, carboranyl-CH, and), 5.45–5.55 (m, 1H, H-3'), 6.32 (t, J = 6.7 Hz, 1H, H-1'), 7.83 (s, 1H, H-6); 13C-NMR (CD3OD): δ 13.07 (CH3), 26.99 (NC2H4CH2), 27.78 (CH2CH2-Ccarborane), 29.82 (NCH2CH2), 38.27 (CH2-Ccarborane), 38.43 (NCH2), 41.02 (CH2NH2), 41.82 (C-2'), 62.71 (Ccarborane), 63.53 (C-5'), 77.13 (Ccarborane), 78.49 (C-3'), 86.22 (C-1'), 86.82 (C-4'), 111.08 (C-5), 135.92 (C-6), 152.25 (C-2), 165.13 (C-4), 168.17 (COO); MS (HR-ESI) calcd for C19H38B10N3O6 (M+H)+: 512.3764, found: 512.5839.

4.1.6.5. 5'-Glycinyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (15)

Yield: 8 mg, 7%; 1H-NMR (CD3OD): δ 1.25–1.35 (m, 2H, NC2H4CH2), 1.44–1.64 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.23–2.35 (m, 4H, CH2-Ccarborane, H-2" and H-2'), 3.84–3.95 (m, 4H, CH2N, and CH2NH2), 4.04–4.10 (m, 1H, H-3'), 4.36–4.40 (m, 1H, H-4'), 4.44 (dd, J = 11.7, and 3.6 Hz, 1H, H-5"), 4.48–4.55 (m, 2H, carboranyl-CH, and H-5'), 6.26 (t, J = 6.7 Hz, 1H, H-1'), 7.46 (s, 1H, H-6); 13C-NMR (CD3OD): 12.20 (CH3), 26.13 (NC2H4CH2), 26.92 (CH2CH2-Ccarborane), 28.94 (NCH2CH2), 37.56 (CH2-Ccarborane), 39.17 (NCH2), 39.96 (CH2NH2), 40.94 (C-2'), 62.65 (Ccarborane), 65.81 (C-5'), 71.05 (C-3'), 76.25 (Ccarborane), 84.12 (C-1'), 86.63 (C-4'), 110.11 (C-5), 135.34 (C-6), 151.19 (C-2), 164.27 (C-4), 167.47 (COO); MS (HR-ESI) calcd for C19H38B10N3O6 (M+H)+: 512.3764, found: 512.3798; 15HCl: Anal. (C19H38B10ClN3O6) C, H, N.

4.1.6.6. 3',5'-Di-glycinyl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (16)

Yield: 19 mg, 15%; 1H-NMR (CD3OD): δ 1.24–1.36 (m, 2H, NC2H4CH2), 1.48–1.64 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.26 (t, J=6.8 Hz, 2H, CH2-Ccarborane), 2.50–2.62 (m, 2H, H-2" and H-2'), 3.89–3.95 (m, 6H, CH2N, and 2CH2NH2), 4.32–4.38 (m, 1H, H-4'), 4.48–4.55 (m, 2H, carboranyl-CH, and, H-5"), 4.60 (dd, J = 11.7, and 3.6 Hz, 1H, H-5'), 5.46–5.49 (m, 1H, H-3'), 6.25 (t, J = 6.7 Hz, 1H, H-1'), 7.48 (s, 1H, H-6); 13C-NMR (CD3OD): δ 13.33 (CH3), 27.52 (NC2H4CH2), 28.04 (CH2CH2-Ccarborane), 30.08 (NCH2CH2), 37.17 (CH2-Ccarborane), 38.68 (NCH2), 41.11, 41.26 (2CH2NH2), 42.09 (C-2'), 63.80 (Ccarborane), 66.45 (C-5'), 77.39 (Ccarborane), 77.49 (C-3'), 82.93 (C-1'), 88.20 (C-4'), 111.45 (C-5), 136.52 (C-6), 152.28 (C-2), 165.33 (C-4), 168.52, 168.58 (2COO); MS (HR-ESI) calcd for C21H41B10N4O7 (M+H)+: 569.3978, found: 569.3975; 16HCl: Anal. (C21H42B10Cl2N4O7) C, H, N.

4.1.6.7. 3'-L-Glutam-5-yl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (17)

Yield: 3 mg, 2%; 1H-NMR (CD3OD): δ 1.28–1.35 (m, 2H, NC2H4CH2), 1.47–1.64 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.15–2.40 (m, 6H, CH2-Ccarborane, CH2CHNH2, H-2" and H-2'), 2.64–2.69 (m, 2H, CH2COO), 3.81–3.83 (m, 2H, H-5" and H-5'), 3.90 (t, J = 6.8 Hz, 2H, CH2N), 4.05 (t, J = 6.8 Hz, 1H, CHNH2), 4.10–4.13 (m, 1H, H-4'), 4.52 (s,1H, carboranyl-CH), 5.34–5.39 (m, 1H, H-3'), 6.31 (t, J = 6.8 Hz, 1H, H-1'), 7.86 (s, 1H, H-6); 13C-NMR (CD3OD): δ 12.19 (CH3), 25.45 (CH2CHNH2), 26.12 (NC2H4CH2), 26.91 (CH2CH2-Ccarborane), 28.94 (NCH2CH2), 29.50 (CH2COO), 37.51 (CH2-Ccarborane), 37.55 (NCH2), 40.94 (C-2'), 52.00 (CHNH2), 61.90 (C-5'), 62.66 (Ccarborane), 75.97 (C-3'), 77.50 (Ccarborane), 85.65 (C-1'), 85.98 (C-4'), 110.17 (C-5), 135.12 (C-6), 151.38 (C-2), 164.28 (C-4), 170.37 (COOCH2), 172.15 (COOH). MS (HR-ESI) calcd for C22H41B10N3O8Na (M+Na)+: 606.3795, found: 606.3813 (M+Na)+; 17HCl: Anal. (C22H42B10ClN3O8) calcd: C, 42.61; H, 6.83; N, 6.78, found: C, 41.95; H, 6.54; N, 6.62.

4.1.6.8. 5'-L-Glutam-5-yl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (18)

Yield: 17 mg, 13%; 1H-NMR (CD3OD): δ 1.28–1.35 (m, 2H, NC2H4CH2), 1.46–1.64 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.92 (s, 3H, CH3), 2.12–2.35 (m, 6H, CH2-Ccarborane, CH2CHNH2, H-2" and H-2'), 2.66 (t, J = 6.9 Hz, 2H, CH2COO), 3.89 (t, J = 6.9 Hz, 2H, CH2N), 4.01–4.11 (m, 2H, CHNH2, and H-3'), 4.30 (dd, J = 11.9, and 3.4 Hz, 1H, H-5"), 4.33–4.38 (m, 1H, H-4'), 4.41 (dd, J = 11.9, and 3.4 Hz, 1H, H-5'), 4.51 (s,1H, carboranyl-CH), 6.28 (t, J = 6.8 Hz, 1H, H-1'), 7.49 (s, 1H, H-6); 13C-NMR (CD3OD): δ 12.29 (CH3), 25.56 (CH2CHNH2), 26.13 (NC2H4CH2), 26.91 (CH2CH2-Ccarborane), 28.94 (NCH2CH2), 29.48 (CH2COO), 37.55 (CH2-Ccarborane), 39.57 (NCH2), 40.93 (C-2'), 51.99 (CHNH2), 62.64 (C-5'), 64.56 (Ccarborane), 71.22 (C-3'), 76.26 (Ccarborane), 84.65 (C-1'), 86.47 (C-4'), 110.00 (C-5), 135.00 (C-6), 151.18 (C-2), 164.28 (C-4), 170.29 (COOCH2), 172.32 (COOH); MS (HR-ESI) calcd for C22H41B10N3O8Na (M+Na)+ : 606.3795, found: 606.3793. 18HCl: Anal. (C22H42B10ClN3O8) calcd: C, 42.61; H, 6.83; N, 6.78, found: C, 42.12; H, 6.74; N, 6.74.

4.1.6.9. 3',5'-Di-L-glutam-5-yl-3-(5-{o-carboran-1-yl}pentan-1-yl)thymidine (19)

Yield: 48 mg; 1H-NMR (CD3OD): δ 1.28–1.35 (m, 2H, NC2H4CH2), 1.45–1.64 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.91 (s, 3H, CH3), 2.10–2.28 (m, 4H, CH2-Ccarborane, H-2", and H-2'), 2.35–2.50 (m, 4H, 2CH2CHNH2), 2.62–2.69 (m, 4H, 2CH2COO), 3.89 (t, J = 6.8 Hz, 2H, CH2N), 3.93–4.01 (m, 2H, 2CHNH2), 4.26–4.31 (m, 1H, H-4'), 4.34 (dd, J = 11.9, and 3.4 Hz, 1H, H-5"), 4.47 (dd, J = 11.9, and 3.4 Hz, 1H, H-5'), 4.51 (s,1H, carboranyl-CH), 5.29–5.33 (m, 1H, H-3'), 6.24 (t, J = 6.8 Hz, 1H, H-1'), 7.49 (s, 1H, H-6), 13C-NMR (CD3OD): δ 12.32 (CH3), 25.40, 25.54 (2CH2CHNH2), 26.12 (NC2H4CH2), 26.90 (CH2CH2-Ccarborane), 28.94 (NCH2CH2), 29.34, 29.52 (2CH2COO), 36.66 (CH2-Ccarborane), 37.55 (NCH2), 40.97 (C-2'), 52.00 (2CHNH2), 62.66 (C-5'), 64.36 (Ccarborane), 76.20 (C-3'), 77.25 (Ccarborane), 82.65 (C-1'), 86.59 (C-4'), 110.29 (C-5), 134.77 (C-6), 151.20 (C-2), 164.21 (C-4), 170.34, 170.38 (2COOCH2), 172.17, 172.31 (2COOH); MS (HR-ESI) calcd for C27H48B10N4O11Na, (M+Na)+, 735.4220, found: 735.4203; 19HCl: Anal. (C27H50B10Cl2N4O11) C, H, N.

4.1.6.10. 3'-Glycinyl-3-[5-(2-{2,3-dihydroxyprop-1-yl}-o-carboran-1-yl)pentan-1-yl]thymidine (20)

Yield: 4 mg, 4%; 1H-NMR (CD3OD): δ 1.28–1.38 (m, 2H, NC2H4CH2), 1.52–1.66 (m, 4H, NCH2CH2, and CH2CH2-Ccarborane), 1.89 (s, 3H, CH3), 2.17–2.58 (m, 6H, CH2-Ccarborane, CHCH2-Ccarborane, H-2" and H-2'), 3.33–3.49 (m, 2H, CH2OH), 3.71–3.96 (m, 7H, CH2N, CH2NH2, H-5", H-5' and CH2CHO), 4.12–4.17 (m, 1H, H-4'), 5.44–5.49 (m, 1H, H-3'), 6.31 (t, J = 6.7 Hz, 1H, H-1'), 7.83 (s, 1H, H-6), 13C-NMR (CD3OD): δ 13.37 (CH3), 27.38 (NC2H4CH2), 28.00 (CH2CH2-Ccarborane), 30.49 (NCH2CH2), 35.93 (CH2-Ccarborane), 38.55 (CH2-Ccarborane), 40.03 (NCH2), 41.32 (CH2NH2), 42.09 (C-2'), 62.98 (C-5'), 67.06 (CH2OH), 72.35 (CHOH), 78.75 (C-3'), 80.57 (Ccarborane), 82.00 (Ccarborane), 86.47 (C-1'), 87.08 (C-4'), 111.34 (C-5), 136.16 (C-6), 152.51 (C-2), 165.40 (C-4), 16.46 (COO); MS (HR-ESI) calcd for C22H44B10N3O8 (M+H)+: 586.4132, found: 586.4059; 20HCl: Anal. (C22H44B10ClN3O8) C, H, N.

4.1.6.11. 5'-Glycinyl-3-[5-(2-{2,3-dihydroxyprop-1-yl}-o-carboran-1-yl)pentan-1-yl]thymidine (21)

Yield: 23 mg, 22%; 1H-NMR (CD3OD): δ 1.24–1.37 (m, 2H, NC2H4CH2), 1.51–1.63 (m, 4H, NCH2CH2

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