Asymmetric Synthesis of 2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazoles

and, Matthew D. Cliff; Pyne, Stephen G.

doi:10.1021/jo961630f

Cited by 25 publications

(13 citation statements)

References 26 publications

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“…Treatment -4-(1,2,3,4,5-pentahydroxypentyl)-and 2-acetyl-5-(1,2,3,4 respectively, under standard conditions. 4 The stereochemistry of 24 and 27 was confirmed by single crystal X-ray analysis ( Fig. 7 and 8 ).…”

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confidence: 78%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…at C-1 and C-2. 4,6 Extension of this methodology to prepare the pentahydroxylpentyl 4-thiazole and 5-thiazole analogues was also efficient but the diastereoselectivity of the reductive ring-opening steps were poorly diastereoselective. Furthermore, this approach should be applicable to the diastereoselective synthesis of other polyhydroxylated bioactive molecules.…”

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confidence: 99%

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

Jeoffreys¹,

Ung²,

Pyne³

et al. 1999

J. Chem. Soc., Perkin Trans. 1

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confidence: 78%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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

Jeoffreys¹,

Ung²,

Pyne³

et al. 1999

J. Chem. Soc., Perkin Trans. 1

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“…DOP hydrochloride was obtained from Sigma. DOP 5 0 -phosphate (DOPP) and THI were synthesized with reference to previous reports [e.g., 23,24]. All other chemical reagents used in this paper were of analytical grade or equivalent.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency

et al. 2014

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Caramel food colorant 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) causes lymphopenia in animals through sphingosine 1-phosphate lyase (SPL) inhibition. However, this mechanism of action is partly still controversial because THI did not inhibit SPL in vitro either in cell-free or in cell-based systems. It is thought that the in vitro experimental conditions which have been used so far were not suitable for the evaluation of SPL inhibition, especially in case of cell-based experiments. We speculated that the key factor might be the coenzyme pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 (VB6), because media used in cell-based assays usually contain an excess amount of VB6 which leads to the activation of SPL. By the use of VB6-deficient culture medium, we could regulate apo- (without PLP) and holo- (with PLP) SPL enzyme in cultured cells, resulting in the successful detection of SPL inhibition by THI. Although the observed inhibitory effect was not as strong as that of 4-deoxypyridoxine (a VB6 analog SPL inhibitor), these findings may be useful for further understanding the mechanism of action of THI.

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“…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.…”

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confidence: 99%

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

Pyne¹,

Ung²

1998

Synlett

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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...

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Asymmetric Synthesis of 2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazoles

Cited by 25 publications

References 26 publications

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

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

Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency

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

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