Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non‐UV‐active compounds. A new variation of the shake‐flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.
Decoupling the roles
of the farnesoid X nuclear receptor and Takeda
G-protein-coupled bile acid receptor 5 is essential for the development
of novel bile acid therapeutics targeting metabolic and neurodegenerative
diseases. Herein, we describe the synthesis of 12β-methyl-18-nor-bile acids which may serve as probes in the search for
new bile acid analogues with clinical applicability. A Nametkin-type
rearrangement was applied to protected cholic acid derivatives, giving
rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12β-methyl-18-nor-bile
acid intermediates (24a and 25a). Subsequent
catalytic hydrogenation and deprotection yielded 12β-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction
products. Optimization of the synthetic sequence enabled a chromatography-free
route to prepare these bile acids at a multi-gram scale. In addition,
the first cis-C-D ring-junctured bile acid and a
new 14(13 → 12)-abeo-bile acid are described.
Furthermore, deuteration experiments were performed to provide mechanistic
insights into the formation of the formal anti-hydrogenation product
12β-methyl-18-nor-chenodeoxycholic acid (27a).
The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase.
The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.
A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.
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