A reliable Pd-mediated hydrogenolytic deprotection of BOM group of uridine ureido nitrogen

Abstract

The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-natural products. The BOM group is also one of few choices to protect uridine ureido nitrongen. However, hydrogenolytic cleavage of the BOM group of uridine derivatives has been unrealizably performed via heterogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated hydrogenation conditions is the over-reduced product of which the C5–C6 double bond of the uracil moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized that the addition of water to the iPrOH-based hydrogenation conditions can suppress the formation of over-reduced uridine derivatives and the addition of HCO2H (0.5%) dramatically improve the reaction rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections of a wide range of uridine derivatives.

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

“…The generated white precipitate was collected through filtration and dried in vacuo . The intermediate (0.17 g, 0.74 mmol), 28 (0.26 g, 0.79 mmol), EDC HCl (0.29 g, 1.5 mmol) and 4-dimethylaminopyridine (DMAP) (9.1 mg, 7.4 μmol) were dissolved in DCM (30 mL), and the reaction mixture was stirred at room temperature for overnight to afford BOM protected intermediate, which was deprotected with Pd/C (10%), H 2 and HCOOH (0.5%) in i-propanol/H 2 O (10/1 mL) [ 30 ] to give 26 (eluent system: 5% MeOH in DCM, 45 mg, 0.11 mmol, 13% yield). 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.54–1.83 (m, 7 H, 5-CH 3 , piperdyl-3-yl, piperidyl-5-yl), 2.53–2.67 (m, 1 H, piperidyl-2/6-yl), 3.07 (t, J = 10.8 Hz, 1 H, piperidyl-2/6-yl), 3.59–3.85 (m, 2 H, COCH 2 ), 4.05 (d, J = 13.5 Hz, 1 H, piperidyl-2/6-yl), 4.43–4.56 (m, 2 H, piperidyl-4-yl, piperidyl-2/6-yl), 6.82–6.91 (m, 2 H, Ph), 6.95–7.03 (m, 3 H, Ph), 7.08–7.15 (m, 1 H, Ph), 7.31 (t, J = 7.8 Hz, 1 H, Ph), 7.34–7.41 (m, 2 H, Ph), 7.53 (d, J = 0.9 Hz, 1 H, H-6), 11.20 (s, 1 H, NH).…”

“…Amide 26 was obtained via N-(3-dimethylaminopropyl)-N -ethylcarbodiimide (EDC)-mediated coupling of 28 with 2-(3-phenoxyphenyl)acetic acid, which was obtained by hydrolysis of the corresponding methyl ester. The BOM group in the resulting amide intermediate was removed by catalytic hydrogenation with Pd/C [30].…”

Improved Synthesis of Capuramycin and Its Analogues

“…Hydrogenolytic cleavage of the benzyloxymethyl (BOM) group of the uridine ureido nitrogen via heterogeneous conditions often yields the over-reduced product of which the C5–C6 double bond of the uracil moiety was saturated. [19] Recently, we identified a new capuramycin analog UT-01309 ( 2 ) possessing ( S )-3-amino-1,4-benzodiazepine-2-one [( S )- 13 ], which showed an improved antimycobacterial activity (2.5 μg/mL vs 12.0 μg/mL for 1 against M. tuberculosis ). [20] Significantly, UT-01309 is active against drug-resistant M. tuberculosis and did not exhibit cytotoxicity against Vero monkey kidney cells and HepG2 human hepatoblastoma cells even at 250 μg/mL concentrations ( vide infra ).…”

“…Selective deacetylation at the 6′′‐position of 7 a has to be stopped at around 30–70 % conversion to avoid the over‐reactions and the recovered starting material is recycled to perform the same reaction multiple times. Hydrogenolytic cleavage of the benzyloxymethyl (BOM) group of the uridine ureido nitrogen under heterogeneous conditions often yields the over‐reduced product in which the C5C6 double bond of the uracil moiety is saturated 19. Recently, we identified a new capuramycin analogue, UT‐01309 ( 2 ), containing ( S )‐3‐amino‐1,4‐benzodiazepine‐2‐one [( S )‐ 13 ], which showed improved antimycobacterial activity (2.5 vs. 12.0 μg mL −1 for 1 against M. tuberculosis ) 20.…”

Selective Esterifications of Primary Alcohols in a Water-Containing Solvent

“…1 We have recently reported an efficient synthesis of the ureido-muraymycidine derivatives (the partial structure highlighted in a box in Figure 1). 1b In the synthesis of muraymycin A 1 selective acetylation of the primary alcohol is necessary to accomplish an efficient synthesis of the left half of 1 . We have screened reported esterification conditions for 4a to form the mono-acetate 3a .…”