|Retrosynthetic analysis of Hygromycin by Donohoe et. al.|
Shown to be a broad-spectrum antibiotic which also exhibits immunosuppressant activity, Hygromycin A has an intriguing structure and yet has only been synthesised once before (Ogawa et. al. 24 linear steps and 1% yield). Donohoe's retroysynthesis aims at addressing two key issues in the the sugar moiety: epimerisation at C4 and glycosylation of β-anomer. The route also aims at making use of the group's methodology, the tethered aminohydroxylation (TA) reaction in synthesising the inositol portion.
|The TA-reaction at work|
The inositol portion was synthesised using the key TA step which had an superb yield of 74% on using (only) 1 mol% catalyst loading, giving the desired diastereomer exclusively. This step has been improved upon the previously reported result (61% yield at 4 mol% catalyst loading). The attacment of the inositol portion to the B+C part was achieved using standard coupling reagents and on deprotection yielded Hygromycin A in 17 linear steps and 10% overall yield a great improvement over the previous synthesis.
Donohoe, T., Flores, A., Bataille, C., & Churruca, F. (2009). Synthesis of (−)-Hygromycin A: Application of Mitsunobu Glycosylation and Tethered Aminohydroxylation Angewandte Chemie International Edition, 48 (35), 6507-6510 DOI: 10.1002/anie.200902840