A biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids

• Published in: Nature communications Vol. 10; no. 1; pp. 3378 - 9
• Main Authors: Wang, Junlin, Zhang, Yanan, Liu, Huanhuan, Shang, Yong, Zhou, Linjun, Wei, Penglin, Yin, Wen-Bing, Deng, Zixin, Qu, Xudong, Zhou, Qianghui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-07-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 38/77; 631/92/603; 639/638/549/977; 639/638/92/349/977; 82/80; Androstenedione; Androstenedione - chemistry; Androstenedione - metabolism; Biocatalysis; Chemical synthesis; Cloning; Cortodoxone - chemistry; Cortodoxone - metabolism; Enzymes; Fermentation; Genetic engineering; Humanities and Social Sciences; Hydroxylation; Intermediates; Laboratories; Models, Chemical; Molecular Structure; multidisciplinary; Optimization; Organic chemistry; Pregnanes - chemistry; Pregnanes - metabolism; Science; Science (multidisciplinary); Steroid hormones; Steroids; Steroids - chemical synthesis; Steroids - chemistry; Steroids - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11344-0

Steroidal C19-hydroxylation is pivotal to the synthesis of naturally occurring bioactive C19-OH steroids and 19-norsteroidal pharmaceuticals. However, realizing this transformation is proved to be challenging through either chemical or biological synthesis. Herein, we report a highly efficient method to synthesize 19-OH-cortexolone in 80% efficiency at the multi-gram scale. The obtained C
19
-OH-cortexolone can be readily transformed to various synthetically useful intermediates including the industrially valuable 19-OH-androstenedione, which can serve as a basis for synthesis of C19-functionalized steroids as well as 19-nor steroidal drugs. Using this biocatalytic C19-hydroxylation method, the unified synthesis of six C19-hydroxylated pregnanes is achieved in just 4 to 9 steps. In addition, the structure of sclerosteroid B is revised on the basis of our synthesis.
C19 hydroxylation is a unique feature of some bioactive steroids. Here, the authors developed a direct C19 hydroxylation approach to scalably access 19-OH-cortexolone in the host
T. cucumeris
and then converted the product into various pharmaceutically useful products via chemical synthesis.