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. 2011 Dec;3(12):969-73.
doi: 10.1038/nchem.1178.

Remodelling of the natural product fumagillol employing a reaction discovery approach

Bradley R Balthaser  1 , Meghan C Maloney, Aaron B Beeler, John A Porco Jr, John K Snyder
Affiliations

Remodelling of the natural product fumagillol employing a reaction discovery approach

Bradley R Balthaser et al. Nat Chem. 2011 Dec.

Abstract

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.

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Conflict of interest statement

Additional information

The authors declare no competing financial interests. Supplementary information and chemical compound information accompany this paper at www.nature.com/naturechemistry. Reprints and permission information is available online at http://npg.nature.com/reprintsandpermissions/. Correspondence and requests for materials should be addressed to J.A.P., Jr.

Figures

Figure 1
Figure 1. Natural Product Remodeling using Fumagillol
a, Fumagillol can be transformed into multiple chemotypes through a panel of related reaction conditions. Fumagillol was obtained by hydrolysis of crude fumagillin isolated from the fermentation broth of Aspergillus fumigatus. b, a) M(OTf)n (10 mol%), p-anisidine (1.1 equiv.), DTBMP (60 mol%), toluene, 60 °C, 20 h; DTBMP = 2,6-di-tert-butyl-4-methylpyridine.
Figure 2
Figure 2. Mechanistic Studies
a, Metals of different sizes preferentially coordinate to the C-6 hydroxyl and C-5 methyl ether of fumagillol by 13C NMR. b, Epoxide opening of TMS-protected fumagillol shows an inversion of regioselectivity; a) amine (1.1 equiv.), M(OTf)n (10 mol%), DTBMP (60 mol%), toluene, 60 °C; b) TMSCl, imdazole, DMAP, CH2Cl2, 83%; c) isolated yields; d) ratio by 1H NMR. c, A working model demonstrating the role of the C-6 hydroxyl toward regioselectivity; DMAP = 4-dimethylaminopyridine, DTBMP = 2,6-di-tert-butyl-4-methylpyridine, TMS = trimethylsilyl.
Figure 3
Figure 3. Use of amino acid esters as reaction partners
a, Selective formation of perhydroisoindoles, perhydroisoquinolines, or morpholinones with phenylalanine; a) amine (2.0 equiv.), M(OTf)n (50 mol%), DTBMP (1.5 equiv.), toluene, 60 °C; b) NaOH (2.0 M), THF, rt, 6 h; DTBMP = 2,6-di-tert-butyl-4-methylpyridine, Phe = phenylalanine. b, Molecular models of the phenylalanine-derived morpholinones 18 and 21.
Figure 4
Figure 4. Reaction with 2-ethynylaniline
a, Selective formation of a perhydroisoindole, perhydroisoquinoline, or 4,1-benzoxazepine; DTBMP = 2,6-di-tert-butyl-4-methylpyridine. b, A novel cascade process to form a 4,1-benzoxazepine.
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