Diastereoselective Synthesis of (1S,2S,3R)- and (1R,2R,3R)-2-Acetyl-5-(1,2,3,4-tetrahydroxybutyl)thiazole

Abstract

A diastereoselective synthesis of the (1S, 2S, 3R)-and (1R, 2R, 3R)-5-thiazole analogues of (1R, 2S, 3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole has been developed starting with 2,3-Oisopropylidene-D-erythrono-1,4-lactone.(1R, 2S, 3R)-2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI), a constituent of Caramel Colour III, has been found to depress blood lymphocyte counts in both mice and rats. 1 THI produces lymphopenia, apparently without toxic effects, in rats and mice and is able to affect the immune competence in the rat in quite small quantities (e.g. 1-50 ppm in drinking water). 2 THI has also been reported to prevent spontaneous and cyclophosphamide-induced diabetes in nonobese diabetic mice. 3 To investigate the structure-activity relationships of this structurally simple but biologically intriguing molecule we have developed a general and flexible synthesis of THI and its analogues. [4][5][6] We recently reported the synthesis of the 5-thiazole analogue 8, 7 using a double Sharpless asymmetric dihydroxylation of a 5-(1,3-butadienyl) thiazole derivative to introduce the tetrahydroxybutyl functionality in 8. This synthetic strategy, however, gave 8 in 78 % enantiomeric purity. We now report a short and diastereoselective synthesis of 8 from 2,3-Oisopropylidene-D-erythrono-1,4-lactone 2 and the synthesis of its (1R, 2R, 3R) diastereoisomer via an efficient epimerisation at the C-2 stereogenic centre.Treatment of the 5-lithio thiazole derivative 1 7 with 2,3-Oisopropylidene-D-erythrono-1,4-lactone 2 at -78 o C gave the lactol 3 in 69 % yield along with a small amount (< 10 %) of the C-2 epimerized ketone 4 (Scheme 1). The ratio of 3 : 4 changed to 2 : 1 when the above reaction mixture was warmed to 25 o C over 1 h prior to quenching with a saturated solution of ammonium chloride. The stereochemistry of lactol 3 was determined by single crystal X-ray structural analysis. 8,9 Treatment of 3 with sodium borohydride / methanol at -10 o C gave a 90 : 10 mixture of the diastereoisomeric diols 6 and 7 that could be readily separated by column chromatography. The stereochemistry of 6 and 7 was unequivocally determined by single crystal X-ray structural analysis 8,9 and is that expected from the Felkin-Anh transition state model A 10 or the γ-chelated transition state structure B 11 in which hydride attack would be expected to occur from the convex face of the bicyclo[5.3.0]decane ring system in B. Acid hydrolysis of the individual diastereoisomers 6 and 7 gave 8 and 9, respectively. 9 Compound 8 had identical spectral properties to that obtained for 8 from our previous synthesis, however, the specific rotation of 8 from this work, [α] D 25 +18.3 (c 0.6, H 2 O), was considerably higher than that obtained previously ([α] D 25 +7.7 (c 0.34, H 2 O)). 7In contrast to 3, the reduction of keto group of the 4-O-silylated cis-1,3-dioxolane 10, prepared from 6, was poorly diastereoselective (Scheme 2). This can be understood in terms of the transition state model C in which the OTBDMS group sterically hinders...

Synthesis of thiazole analogues of the immunosuppressive agent (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole

“…As part of an ongoing medicinal chemistry project [1][2][3][4][5][6][7] we required the synthesis of some 5-hexahydroxyhexylthiazole analogues, 4, of the known immunosuppressive agent, (1R, 2S, 3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) 1. [8][9][10] THI is a minor component of the common food additive Caramel Colour III.…”