Field of Science

Synthesis of Hygromycin A

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 sugar is synthesised by standard reactions but with triisopropyl protected alcohols at C2 and C3, the aim of which is to force the β-anomeric configuration and to protect the epimerisation of C4 by hindering the vulnerable proton. A strategy that eventually paid off. The sugar was then attached to B by a selective mitsonobu reaction  (slow addition of DIAD, tiphenyphosphine, toluene at 60 deg C) which on optimisation gave 9:1 ratio for the β-anomer with excellent yield.

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

1 comment:

  1. We use hygromycin to assess cell wall integrity. Although the target is the translational machinery and mutations affecting translation can confer resistance/sensitivity, mutations affecting the fungal cell wall also confer resistance/sensitivity because they alter uptake of the drug. Cool compound.


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