A novel route for the preparation of betamethasone from 9α-hydroxyandrost-4-ene-3,17-dione (9αOH-AD) by chemical synthesis and fermentation

Tang, Jie; Liu, Xirong; Zeng, Chunlin; Meng, Hao; Tian, Mi; Guo, Can‐Cheng

doi:10.3184/174751917x14925986241025

“…Our synthesis commenced with the preparation of Δ 4,9 (11) diene propargylic alcohol 8 from commercially available 9α-OH-AD (9) as shown in Scheme 2. Dehydration of 9 under slightly modified Guo conditions [20] (glacial AcOH, 70 % aq. H 2 SO 4 , DCE, 60 °C, 6 h) resulted in the formation of Δ 4,9 (11) -AD 10 in 95 % isolated yield.…”

Section: Resultsmentioning

confidence: 99%

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

Wei,

Zhang,

Liu

et al. 2023

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Abstract16β‐Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β‐methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability‐oriented strategy toward the unified stereoselective synthesis of 16β‐methylcorticoids in 12.6–14.0 % overall yield from commercially available 9α‐hydroxyandrost‐4‐ene‐3,17‐dione (9α‐OH‐AD). In this approach, the chiral C16β‐Me and C17α‐OH groups of the corticosteroid D ring were installed via a substrate‐controlled diastereo‐ and enantioselective Mn‐catalyzed oxidation‐reduction hydration of Δ4,9(11),16‐triene‐3,20‐dione. The C1−C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3‐ketosteroid‐Δ1‐dehydrogenase (MK4‐KstD)‐catalyzed regioselective Δ1‐dehydrogenation of Δ4,9(11)‐diene‐3,21‐dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

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“…One important enzyme involved in this process is 3‐ketosteroid Δ1‐dehydrogenase (KstD) [26a–b] . Arthrobacter simplex , which is known for its efficient bioconversion capabilities, has been widely used in the industry [26c–g] . Recently, Tang and co‐workers developed a novel and efficient synthesis of betamethasone ( 40 ) using readily available 9α OH−AD ( 39 ) as the starting material, giving 40 in 11 steps with a 22.9 % overall yield.…”

Section: δ1‐3‐ketosteroid Dehydrogenase‐mediated Chemoenzymatic Synth...mentioning

confidence: 99%

“…The authors utilize a similar strategy for the production of fluocinolone acetonide ( 41 ) in 9 steps with 38.5 % yield (Scheme 7). [26e–g] …”

Section: δ1‐3‐ketosteroid Dehydrogenase‐mediated Chemoenzymatic Synth...mentioning

confidence: 99%

Chemoenzymatic Synthesis of Steroidal Products: Recent Advances

Zheng,

Lin,

Lin

et al. 2024

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The synthesis of steroidal products has garnered sustained interest due to their versatile bioactivities and physicochemical properties in pharmaceutics. However, the complicated structure of steroids, especially their highly oxygenated skeleton, has presented significant challenges. Benefitted from recent advancements in bioinformatics, genetics, and enzyme engineering, chemoenzymatic strategy combines the flexibility of chemical synthesis with the high regio‐ and stereo‐selectivity of biocatalysis, being an effective approach for the concise synthesis of natural products. In this concept, we review and discuss the recent advances in chemoenzymatic approaches for efficient synthesis of steroids and their analogs, as well as future research opportunities and challenges.

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Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

Wei,

Zhang,

Liu

et al. 2023

Angewandte Chemie

0

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Abstract16β‐Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β‐methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability‐oriented strategy toward the unified stereoselective synthesis of 16β‐methylcorticoids in 12.6–14.0 % overall yield from commercially available 9α‐hydroxyandrost‐4‐ene‐3,17‐dione (9α‐OH‐AD). In this approach, the chiral C16β‐Me and C17α‐OH groups of the corticosteroid D ring were installed via a substrate‐controlled diastereo‐ and enantioselective Mn‐catalyzed oxidation‐reduction hydration of Δ4,9(11),16‐triene‐3,20‐dione. The C1−C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3‐ketosteroid‐Δ1‐dehydrogenase (MK4‐KstD)‐catalyzed regioselective Δ1‐dehydrogenation of Δ4,9(11)‐diene‐3,21‐dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

show abstract

A novel route for the preparation of betamethasone from 9α-hydroxyandrost-4-ene-3,17-dione (9αOH-AD) by chemical synthesis and fermentation

Cited by 7 publications

References 19 publications

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

Chemoenzymatic Synthesis of Steroidal Products: Recent Advances

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

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