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Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

Fabio Tonin and Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483. https://doi.org/10.3762/bjoc.14.33

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Supporting Information features Figure S1 relative to the C7 dehydroxylation mechanism of hydroxysteroids and Figure S2 relative to the postulated biochemical pathway for the C12 dehydroxylation.

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Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

Fabio Tonin and Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483. https://doi.org/10.3762/bjoc.14.33

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Tonin, F.; Arends, I. W. C. E. Beilstein J. Org. Chem. 2018, 14, 470–483. doi:10.3762/bjoc.14.33

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TY  - JOUR
A1  - Tonin, Fabio
A1  - Arends, Isabel W. C. E.
T1  - Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review
JF  - Beilstein Journal of Organic Chemistry
PY  - 2018///
VL  - 14
SP  - 470
EP  - 483
SN  - 1860-5397
DO  - 10.3762/bjoc.14.33
PB  - Beilstein-Institut
JA  - Beilstein J. Org. Chem.
UR  - https://doi.org/10.3762/bjoc.14.33
KW  - bile acids
KW  - biotransformation
KW  - hydroxysteroid dehydrogenases
KW  - production process
KW  - UDCA
N2  - Ursodeoxycholic acid (UDCA) is a pharmaceutical ingredient widely used in clinics. As bile acid it solubilizes cholesterol gallstones and improves the liver function in case of cholestatic diseases. UDCA can be obtained from cholic acid (CA), which is the most abundant and least expensive bile acid available. The now available chemical routes for the obtainment of UDCA yield about 30% of final product. For these syntheses several protection and deprotection steps requiring toxic and dangerous reagents have to be performed, leading to the production of a series of waste products. In many cases the cholic acid itself first needs to be prepared from its taurinated and glycilated derivatives in the bile, thus adding to the complexity and multitude of steps involved of the synthetic process. For these reasons, several studies have been performed towards the development of microbial transformations or chemoenzymatic procedures for the synthesis of UDCA starting from CA or chenodeoxycholic acid (CDCA). This promising approach led several research groups to focus their attention on the development of biotransformations with non-pathogenic, easy-to-manage microorganisms, and their enzymes. In particular, the enzymatic reactions involved are selective hydrolysis, epimerization of the hydroxy functions (by oxidation and subsequent reduction) and the specific hydroxylation and dehydroxylation of suitable positions in the steroid rings. In this minireview, we critically analyze the state of the art of the production of UDCA by several chemical, chemoenzymatic and enzymatic routes reported, highlighting the bottlenecks of each production step. Particular attention is placed on the precursors availability as well as the substrate loading in the process. Potential new routes and recent developments are discussed, in particular on the employment of flow-reactors. The latter technology allows to develop processes with shorter reaction times and lower costs for the chemical and enzymatic reactions involved.
ER  -

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aromatic	the word “aromatic”
aromatic aldehyde	the word “aromatic” OR “aldehyde”
+aromatic +aldehyde	both words “aromatic” AND “aldehyde”
+aromatic -aldehyde	the word “aromatic” but NOT “aldehyde”
“aromatic aldehyde”	the exact phrase “aromatic aldehyde”
benz*	words which begin with “benz”, such as “benzene” or “benzyl”
benz*yl	words that begin with “benz” and end with “yl”, such as “benzyl” or “benzoyl”
benzyl~	words that are close to the word “benzyl”, such as “benzoyl” (i.e., fuzzy search)