93 Synthesis of L-Biotin

Faculty Mentor: Andrew Roberts (Chemistry, University of Utah)

Introduction

Vitamin B7, more commonly known as Biotin, is part of a group of essential micronutrients. Present in every living cell, it has a strong interaction with the synthetic protein streptavidin. The non-covalent interaction complex resists denaturing from detergents, proteolytic enzymes, and organic solvents. In nature, Biotin exists in the D conformation, with the unnatural L-Biotin only accessed synthetically (Fig. 1). Herein, this research focuses on the total synthesis of L-Biotin, motivated by the synthetic route from the Seki group. In collaboration with the Kay Laboratory at University of Utah Biochemistry, this research hopes to introduce new therapeutic applications.

Background

Structurally, Biotin is a heterocyclic molecule containing a carboxylic side chain, thiophene ring fused to a carbamate ring. Typically, D-biotin is synthesized racemic starting from L-cysteine and chirally resolved late stage. While the starting cysteine is commercially available and relatively inexpensive, a late-stage chiral resolution decreases the total yield afforded, not making this ideal on commercial scale. The carboxylic side chain offers a carbon dioxide carrier in metabolic carboxylation reactions. In 2004, the Seki group demonstrated their synthetic route for D-Biotin(1), utilizing key intermediates via Moffatt Oxidation and a Fukuyama coupling reaction. Motivated by promising new therapeutic techniques and the Seki synthetic route, we envisioned synthetic access to L-Biotin from D-cysteine with a few central changes.

RESULTS

Starting from the D-cysteine HCl salt, a cyclization with phenyl chloroformate was achieved and yielded 2 in good yield (Fig 2). Next, a benzyl protection of the nitrogen was afforded in 74% yield. Sequential reduction to the alcohol and oxidation to the aldehyde followed in high yield of 5. With aldehyde 5 in hand, a Strecker reaction was optimized with a bisulfite adduct to avoid the highly toxic TMSCN. This change in reaction conditions allowed for the use of a more stable cyanide source, NaCN. The stereoselectivity of this reaction gave 28:1 syn:anti and was carried through to the amidation yield the major syn product 7. Next, an N,S-carbonyl migration was implored to form free thiol 8. Ring closing thiolactonization followed by epimerization afforded 9.

A Fukuyama coupling with the thiolactone was next investigated. Currently, challenges have been met with alkene formation. This is likely due to the hemi-thioacetal formation being favored versus the elimination. For better mechanistic insight, a stepwise approach is being taken, subjecting the hemi-thioacetal to a broad scope of elimination conditions. With the alkene formation optimized, D-Biotin will be accessed in 2 steps via reduction and global deprotection. The total synthesis is 15 steps, and 13 of them have been completed successfully and optimized to yield the best results.

CONCLUSION

Unnatural L-Biotin shows promise toward new therapeutic techniques. Our collaboration with the Kay group hopes to provide insights into these new applications. Following the Seki synthetic route of D-Biotin, changes in reactions, condition development, and optimization was utilized for the total synthesis of L-Biotin. Efforts toward the final two steps are ongoing but are anticipated to yield L-Biotin without disappointment.

Bibliography

Seki, M.; Hatsuda, M.; Mori, Y.; Yoshida, S.; Yamada, S.; Shimizu, T. A Practical Synthesis of (+)‐Biotin from L‐Cysteine. Chemistry – A European Journal 2004, 10 (23), 6102–6110.

Zhang, Dong; Chen, Ming; Yuan, Fuping; Jin, Aimin; Qi, Gaofei., Preparation of thiazolidone derivatives. CN 115181075 A. 2022.10.14