Synthetic studies towards the tunicamycins and analogues based on diazo chemistry. Total synthesis of tunicaminyl uracil

Abstract

A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were prepared efficiently from commercially available D-galactal and uridine, respectively. After a high yielding coupling reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative 17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-hydroxy tunicaminyl uracil analogs 33a and 33b.

Oxidative Deamination ofN-Acetyl Neuraminic Acid: Substituent Effects and Mechanism

“…Alternatively, the incorporation of deuterium (Scheme ) can be accommodated by the intermediacy of the carbene 59 , or its stabilized equivalent, the ylid 62 . Other carbohydrate-based diazoalkanes generated from N -nitroacetamides have been previously shown to participate in typical carbene-type intermolecular C–H insertions. , The very high levels of overall retention of configuration typically seen in these reactions, both past ,,,, and present (Table , entries 1–6), argue against the formation of the substitution product 35 directly from the carbenium ion 58 or the carbene 59 , although it remains possible that the elimination products 64 and 65 are formed from 58 and 59 by deprotonation or C–H insertion, respectively. Rather, it is likely that the origin of stereoselectivity lies with the intermediacy of one or other of the level 3 intermediates formed either directly from the level 1 intermediates 56 and 57 in a concerted manner or via the transient level 2 intermediates 58 and 59 .…”

A Modular Approach to Phosphoglycosyltransferase Inhibitors Inspired by Nucleoside Antibiotics

“…This is exemplified by the large differencesi ni nhibition properties of mureidomycin Aa nd tunicamycin ( Figure 1). Furthermore, the complexity of the natural product structures makes it very challenging to repurpose the structures of the natural products, by synthesis [14][15][16] or semisynthesis, [17][18][19][20][21][22] to target alternative PGTsw ith different substrate specificities.T his challenge is furthere xacerbated when working with PGTs belongingt os tructural classes other than the wellstudied MraY and WecA-type integral membrane proteins, which feature 10 and 11 predicted TMHs, respectively.F or example,r ecent bioinformaticsa nd biochemical analysish as revealed thousands of homologous small bacterial PGTsw ith only as ingle TMH and as oluble globulard omain within a2 0-25 kDa protein. [23] While these PGTsc atalyze comparable biochemicalp rocesses and also play important roles at the initiation of diverse glycoconjugate biosynthetic pathways,t here are currently no small molecule inhibitors that can be used to inform on the biology and essentiality of particularp athways and which may ultimately representn ovel targets for therapeutic intervention.…”

“…This is exemplified by the large differences in inhibition properties of mureidomycin A and tunicamycin (Figure ). Furthermore, the complexity of the natural product structures makes it very challenging to repurpose the structures of the natural products, by synthesis or semisynthesis, to target alternative PGTs with different substrate specificities. This challenge is further exacerbated when working with PGTs belonging to structural classes other than the well‐studied MraY and WecA‐type integral membrane proteins, which feature 10 and 11 predicted TMHs, respectively.…”

A Modular Approach to the Total Synthesis of Tunicamycins

“…[5] To conduct structure-activity relationship (SAR) studies and to develop aspecific inhibitor (especially of clinical usefulness), as ynthetic method that provides access to pure samples of as ingle tunicamycin and modified analogues is required. [8] Indeed, tremendous efforts have been devoted towards the chemical synthesis of tunicamycins; [9][10][11][12][13][14][15] however,only two successful total syntheses have been described. [9,10] Suami et al applied aHenry condensation to form the C5'ÀC6' bond and aK oenigs-Knorr-type glycosylation to construct the C11'ÀOÀC1'' linkage,b ut both the elaboration of the 5'hydroxy group from the nitroaldol adduct and the formation of the b,a-11',1''-trehalose were non-stereoselective and lowyielding.…”