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 the 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 catalytic amounts 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.

GRAPHICAL ABSTRACT

KEYWORDS:

• Homocysteine
• LuxS
• S-ribosylhomocysteine
• ribonolactone
• C-substituted ribose

Disclosure statement

No potential conflict of interest was reported by the authors.

ORCID

Cesar Gonzalez http://orcid.org/0000-0003-0818-5671

Additional information

Funding

This work was partially supported by NIGMS/NCI [1SC1CA138176]. We thank the NIH MARC U*STAR (GM083688) program for the fellowship to DL and University of Wroclaw and EU social funds for supporting KSS and JN summer internship training at FIU.