S-Ribosylhomocysteine analogs containing a [4-thio]ribose ring

Abstract

The [4-thio]-S-ribosylhomocysteine (SRH) analogs containing substitution of a sulfur atom for the endocyclic oxygen were synthesized by coupling of the 4-thioribose substrates with a thiolate generated from the protected homocysteine. Coupling of the protected 1-deoxy-5-O-mesyl-S-oxo-4-thio-D-ribofuranose with homocysteinate salt gave the C4 epimers of [4-thio]-SRH at the sulfoxide oxidation level lacking a hydroxyl group at anomeric carbon. Treatment of these sulfoxides with BF3⋅Et2O/NaI affected simultaneous reduction to sulfide and global deprotection affording 1-deoxy-4-thio-SRH analog. Treatment of the protected 1-deoxy-S-oxo-4-thio-D-ribofuranose sulfoxide with DAST/SbCl3 resulted in the fluoro-Pummerer rearrangement to give 4-thio-β-D-ribofuranosyl fluoride. Mesylation of the latter at 5-hydroxyl position followed by coupling with homocysteinate salt and subsequent global deprotection with trifluoroacetic acid afforded [4-thio]-SRH thiohemiacetal.

Keywords: Homocysteine; LuxS; S-Ribosylhomocysteine; Thioacetals; Thiosugars.

Figure 1

Biosynthetic pathway to AI-2. Enzymatic conversion of SRH to DPD by LuxS.

Figure 2

1-Deoxy and 4-aza analogues of S-ribosylhomocysteine.^,

Scheme 1

Reagents and conditions: (a) MCPBA/CH₂Cl₂/-78°C; (b) MsCl/Et₃N/CH₂Cl₂; (c) LDA/DMF; (d) BocNHCH(CHCHSH)CO₂t-Bu/LDA/DMF; (e) TFA/H₂O; (f) BF₃/Et₂O/NaI/CH₃CN.

Scheme 2

Reagents and conditions: (a) Ac₂O/DMAP; (b) MCPBA/CH₂Cl₂/-78°C; (c) DAST/SbCl₃/CH₂Cl₂/55°C; (d) NH₃/MeOH; (e) MsCl/Et₃N/CH₂Cl₂; (f) BocNHCH(CHCHSH)CO₂t-Bu/LDA/DMF; (g) H₂O/H⁺; (h) TFA/H₂O (9:1).

Scheme 3

Reagents and conditions: (a) Ac₂O/100 °C/6 h; (b) MCPBA/CH₂Cl₂/-78 °C; (c) MsCl/Et₃N/CH₂Cl₂; (d) NH₃/MeOH