Synthesis of Macrocyclic Scaffolds from Natural Products and their Utilization for Solid-Phase Chemistry

Abstract

The versatile synthesis of natural product derived macrocyclic scaffolds suitable for solid- and for solution-phase chemistry is shown. The scaffolds are modified by solid-phase chemistry to yield macrocycles with two points of diversity.

Key words

combinatorial chemistry - natural products - solid-phase synthesis

References

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  Compound 1 was produced in-house by a fungal strain in a 3000 L fermentor containing 2500 L of culture broth with an average titer of 85 mg/L.

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9

(7S,11R,12R,13S)-11-Amino-4,12,13-trihydroxy-12-dimethoxy-7-methyl-8,9,11,12,13,14,15,16-octahydro-7H,10H-6-oxa-benzocyclotetradecen-5-one was obtained from 4 using p-TsOH·H₂O as acid catalyst. The crystallographic data (excluding structure factors) for the structure of this compound have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 262678. Copies of the data can be obtained free of charge on application to CCDC 12 Union Road Cambridge CB2 1 EZ UK [fax: [phone] or email: [e-mail]]

10

PS-Merrifield resin (crosslinked with 1% 14-divinyl­-benzene) diameter: 200 µm loading: 1.9 mmol/g.

11

The cleavage was performed with a mixture of TFA-DCE-MeOH-H₂O (5:84:10:1). The composition of 8 and 9 was determined by quantitative HPLC of the cleavage solution without prior evaporation. Under these conditions the TEOC group is stable.