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Boc Protection of Aminoglycosides; Hexa-NBoc Neomycin

SyntheticPage 564
DOI: 10.1039/SP564
Submitted Jul 13, 2012, published Jul 15, 2012
Brandon Findlay (brandon.findlay@zoho.com)


			Reaction Scheme: <IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif">Boc Protection of Aminoglycosides<IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif"><IMG src="/images/empty.gif">

Chemicals Used

Neomycin (Bought as a 85:15 mixture of neomycin B and neomycin C)
Boc anhydride
Triethylamine
Water
Methanol

Procedure

The amine of interest is dissolved in a 10/10/7 solution of water, methanol and triethylamine.  As the solution is stirred Boc2O(s) (1.6eq) is slowly added, with a small amount of methanol used to rinse the weigh boat/paper.  The solution is then heated to 55°C for 16hr (overnight), during which time the production of t-butanol will result in a thick slurry.

Following the reaction the solution is allowed to cool to room temperature and the stir bar is removed (if possible).  The slurry is evaporated to dryness on a combined high vacuum/rotary evaporator setup, using dry ice as a coolant.  The resulting white solid is then left under high vacuum for a minimum of 72hr, during which time residual Boc2O will sublimate into the dry ice trap.  The product may then be used without further purification, extracted if the aminoglycoside was provided as a salt, or columned to separate out isomers (ie. neomycin B from neomycin C).

Author's Comments

This reaction has been successfully applied to the protection of Neomycin B, Neamine, Nebramine, Tobramycin and Amikacin.  It failed during an attempted protection of Streptomycin, likely due to the guanidine.

In this reaction, the starting material is a 85:15 mixture of neomycin B and neomycin C, which seems to be a fairly constant ratio among chemical suppliers. At the end of the reaction it is possible to isolate Boc-protected neomycin B via column chromatography (3:2 DCM:acetone).  Yields for NBoc-neomycin B were ~60%, due to poor separation between the closely moving spots, but yields with tobramycin approached 97%.

Data

1H NMR (300 MHz, MeOD) δ 5.38 – 5.12 (m, 2H), 4.92 (s, 1H), 4.21 (s, 2H), 4.10 – 3.06 (m, 20H), 2.05 – 1.88 (m, 1H), 1.71 – 1.19 (m, 55H).


Lead Reference

Quader S, Boyd SE, Jenkins ID, & Houston TA (2007). Multisite modification of neomycin B: combined Mitsunobu and click chemistry approach. The Journal of organic chemistry, 72 (6), 1962-79. PMID: 17298096

Supplementary Information

1H NMR spectra attached.
1H NMR Spectra for Neomycin B (NBoc Neomycin B Spectra.png)

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Keywords: amines, carbamates, carbocyclic compounds, carbohydrates and sugars, heterocyclic compounds, protection

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