Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-L-bulgecinine from D-glucuronolactone and of L-DNJ, L-DMDP, and (3S)-3-hydroxy-D-bulgecinine from L-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas L-DMDP is a potent and specific inhibitor of α-glucosidases

被引:55
作者
Best, Daniel [1 ]
Wang, Chen [1 ]
Weymouth-Wilson, Alexander C. [2 ]
Clarkson, Robert A. [2 ]
Wilson, Francis X. [5 ]
Nash, Robert J. [4 ]
Miyauchi, Saori [3 ]
Kato, Atsushi [3 ]
Fleet, George W. J. [1 ]
机构
[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England
[2] Dextra Labs Ltd, Ctr Sci & Technol, Reading RG6 6BZ, Berks, England
[3] Toyama Univ, Dept Hosp Pharm, Toyama 9300194, Japan
[4] Phytoquest Ltd, IBERS, Aberystwyth SY23 3EB, Ceredigion, Wales
[5] Summit PLC, Abingdon OX14 4RY, Oxon, England
关键词
LARGE-SCALE SYNTHESIS; GLYCOGEN-PHOSPHORYLASE; N-BUTYLDEOXYNOJIRIMYCIN; 2,5-DIDEOXY-2,5-IMINO-D-MANNITOL DMDP; ENANTIOSPECIFIC SYNTHESES; PRACTICAL SYNTHESIS; 2S; 3R; 4R; 5S-TRIHYDROXYPIPECOLIC ACID; 2R; 4S; 5S-DIHYDROXYPIPECOLIC ACID; POLYHYDROXYLATED PYRROLIDINE;
D O I
10.1016/j.tetasy.2010.01.017
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from D-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-alpha-D-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP (2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-L-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-L-proline]. L-Glucuronolactone, a readily available L-sugar chiron, may similarly be used to access the enantiomers L-DNJ, L-DMDP, and (3S)-3-hydroxy-D-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of beta-glucosidases and beta-galactosidases) and L-DMDP (a potent and specific alpha-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-L-bulgecinine show weak inhibition of glycogen phosphorylase. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:311 / 319
页数:9
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