S-Ribosylhomocysteine analogues modified at the ribosyl C-4 position

Abstract

4-C-Alkyl/aryl-S-ribosylhomocysteine (SRH) analogues were prepared by coupling of homocysteine with 4-substituted ribofuranose derivatives. The diastereoselective incorporation of the methyl substituent into the 4 position of the ribose ring was accomplished by addition of methylmagnesium bromide to the protected ribitol-4-ulose yielding the 4-C-methylribitol in 85% yield as single 4R diastereomer. The 4-C hexyl, octyl, vinyl, and aryl ribitols were prepared analogously. Chelation controlled addition of a carbanion to ketones from the (Si-face) was responsible for the observed stereochemical outcome. Oxidation of the primary alcohol of the 4-C ribitols with the catalytic amount of tetrapropylammonium perruthenate in the presence of N-methylmorpholine N-oxide produced 4-C-alkylribono-1,4-lactones in high yields. Mesylation of the latter compounds at the 5-hydroxyl position and treatment with a protected homocysteine thiolate afforded protected 4-C-alkyl/aryl-SRH analogues as the lactones. Reduction with lithium triethylborohydride and successive global deprotections with TFA afforded 4-C-alkyl/aryl SRH analogues. These analogues might impede the S-ribosylhomocysteinase(LuxS)-catalyzed reaction by preventing β-elimination of a homocysteine molecule, and thus depleting the production of quorum sensing signaling molecule AI-2.

Interference With Quorum-Sensing Signal Biosynthesis as a Promising Therapeutic Strategy Against Multidrug-Resistant Pathogens

“…In the inhibitor S-homoribosyl-L-cysteine, the carbon (C5)-sulfur bond was replaced by a C5-C6 carbon-carbon bond, which interferes with the cleavage of the carbon-sulfur bond (Alfaro et al, 2004; Figure 2, compound 3). Recently, Chbib et al (2016) synthesized 4-C-Alkyl/aryl-SRH analogs that potentially could inhibit LuxS at the β-elimination step. The substitution of the hydrogen atom at C4 position by alkyl/aryl groups should prevent the abstraction of the C4-proton, which is important for the β-elimination step (Chbib et al, 2016).…”

“…Recently, Chbib et al (2016) synthesized 4-C-Alkyl/aryl-SRH analogs that potentially could inhibit LuxS at the β-elimination step. The substitution of the hydrogen atom at C4 position by alkyl/aryl groups should prevent the abstraction of the C4-proton, which is important for the β-elimination step (Chbib et al, 2016). Interestingly, these authors suggested that the 4-C-Alkyl/aryl-SRH analogs also could inhibit LuxS by interfering with the dimerization of the enzyme.…”

Reduction of sugar lactones to hemiacetals with lithium triethylborohydride

“…In our program on developing novel inhibitors of S -ribosylhomocysteine (SRH) hydrolase (LuxS; EC 4.4.1.21), which mediates the interspecies quorum sensing among bacteria, 17, 18 we recently applied lithium triethylborohydride (LTBH, Super-Hydride ® ) 19, 20 for the reduction of lactam and lactone analogues of SRH to the corresponding azahemiacetals ( N,O -acetals) 21 or lactols ( O,O -acetals). 22 Although application of LTBH for the reduction of lactams to cyclic hemiaminals (azahemiacetals) is documented, 23, 24 the reduction of lactones to the hemiacetals with LTBH is underdeveloped. In his landmark paper from 1980, 25 Brown reported that LTBH, when used in excess (2 equiv.…”

Synthesis of Gemcitabine Analogues with Silicon-Fluoride Acceptors for 18F Labeling

“…97,98 Figure 12. Silicon-fluoride acceptors in octreotate 96 32 and thymidine derivatives 99 109 has been utilized for the reduction of lactam (Scheme 10) and lactone analogues of SRH to the corresponding azahemiacetals (N,O-acetals) 110,111 or lactols (O,Oacetals) 112 , a method not extensively explored. Below, the commonly used reducing agents for this type of transformation will be reviewed.…”

“…121,122 Although the application of LTBH in organic synthesis is well documented, [140][141][142][143] including the reduction of lactams to cyclic hemiaminals (azahemiacetals), including in sugar lactams, 110 the reduction of lactones to the lactols with LTBH is underdeveloped. In the synthesis of 4-C-alkyl/aryl-substituted Sribosylhomocysteine (SRH) analogues, 112 which were prepared by coupling of homocysteine with 4-substituted ribonolactone derivatives, a project that I was involved in, LTBH was used to reduce a series 4-C-alkyl/aryl-modified lactones to their corresponding hemiacetals (Scheme 27). These hemiacetals were then coupled to homocysteine to yield 4C-SRH analogues.…”