A stereocontrolled first total synthesis of muraymycin D1 (1) has been achieved. The synthetic route is highly stereoselective, featuring 1) selective β-ribosylation of the C2-methylated amino ribose, 2) selective Strecker reaction, 3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (epi-capreomycidine). The acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc and tBu groups. Muraymycin D1 (1) and its amide derivatives (2 and 3) exhibited growth inhibitory activity against Mycobacterium tuberculosis (MIC50 1.56–6.25 μg/mL) and strong enzyme inhibitory activities against the bacterial phosphotransferases (MurX and WecA) (IC50 0.096−0.69 μM).

Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (5b), displayed remarkable effect on selective esterifications of primary alcohols. A wide range of carboxylic acids could be esterified with primary alcohols by using EDCI, NaHCO3, and Oxyma or an Oxyma derivative 5b in 5% H2O-CH3CN. An Oxyma derivative 5b is particularly useful since it could be removed after the reaction via a simple basic or an acidic aqueous work-up procedure.

Capuramycin and its congeners have been considered important lead molecules for the development of a new drug for multidrug-resistant (MDR) Mycobacterium tuberculosis infections. Extensive structure-activity relationship studies of capuramycin to improve the efficacy have been limited due to difficulty in selective chemical modifications of the desired position(s) of the natural product with biologically interesting functional groups. We have developed efficient syntheses of capuramycin and its analogs using new protecting groups, which are derived from the chiral (chloro-4-methoxyphenyl) (chlorophenyl) methanols, for the uridine ureido nitrogen and primary alcohol. The chiral non-racemic (2,6-dichloro-4-methoxyphenyl) (2,4-dichlorophenyl) methanol derivative is a useful reagent to resolve rac-3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, whose (S)-configuration isomer plays a significant role in improving the mycobactericidal activity of capuramycin.

One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2S,3S)-muraymycidine (or epi-capreomycidine). In order to diversify the structure of the oligo-peptide moiety of the muraymycins for thorough structure activity relationship studies, we have developed a highly stereoselective synthesis of ureido-muraymycidine derivatives with the lactone 4a.

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.