Discovery, isolation, structure elucidation, and biosynthesis of U-106305, a cholesteryl ester transfer protein inhibitor from UC 11136

Abstract

During our screening of fermentation broths, culture UC 11136 was identified as producing potent inhibitor(s) of the in vitro cholesteryl ester transfer protein (CETP) reaction. Subsequent chemical isolation work identified two inhibitors of CETP produced by this culture. One of these inhibitors, U-106305, represented a novel CETP inhibitor as well as a structural class of compounds not previously reported from microbial fermentations. The structure of U-106305 was elucidated as V-isobutyl-tii(-rrtins-4,5:6,7:8,9:10,ll:12,13:16,17-hexamethylene-(£,£)-2,14-octadecadienamide by extensive NMR studies. Biogenetically, the backbone of U-106305 was found to derive from nine acetates linked in a head-to-tail fashion, while the cyclopropyl methylene carbons were derived from the methyl group of L-methionine. A biosynthetic pathway is proposed based on these findings.

Three-Membered-Ring-Based Molecular Architectures

“…35 To resolve these putative contradictions, which may be due to packing effects, an NMR study on the partially deuterated all-syn,trans-tercyclopropanedimethanol 28 in combination with quantum chemical calculations was undertaken. 41 The interunit dihedral angles were both found to be +40°causing the molecule to assume a helical conformation in accordance with the crystal structure published by Charette et al 35 All six diastereomeric unsubstituted quatercyclopropanes have been obtained by oxidative coupling of bicyclopropylidene (33) to give meso-(meso-34) and d,l-bis(bicyclopropylidenyl) (d,l-34), which subsequently were reduced either under Birch conditions with diimine or by catalytic hydrogenation to give quatercyclopropanes 30-32 and 35-37 (Scheme 4). 42 The geometrical parameters of 30 and 32 in the solid state could be determined by X-ray structure analyses.…”

“…33 The constitution of this natural product was established through NMR and mass spectrometric studies, suggesting all double bonds to be (E) and all cyclopropane rings to be trans configured. 33 However, because the absolute configuration had not been established for any of the stereogenic centers, there were 64 different isomers to be considered. The configuration of the natural product was established independently by Barrett et al., 34 who synthesized a product that was identical with the natural compound, and by Charette et al, 35 who prepared the enantiomer of the natural product.…”

“…38 The biosynthesis of U-103605 10 has been elucidated by feeding experiments. 33 After feeding 13 C-labeled S-adenosylmethionine, significantly enhanced NMR signals of the methylene carbons of all cyclopropane moieties were detected. The incorporation of labeled [1-13 C]-or [2-13 C]-acetate and the pattern of the labels within the backbone of the fatty acid side chain disclosed that a polyketide biosynthetic pathway must lead to an oligounsaturated precursor, which is subsequently cyclopropanated.…”

“…43 Other methods for the preparation of 38 rely on elimination reactions of appropiately substituted bicyclopropyls. Thus, Conia et al reported the dehydrohalogenation of 1-chloro-1-cyclopropylcyclopropane (43) with sodium amide to yield a mixture of the kinetically favored product 38 and the more stable isomer bicyclopropylidene (33), which arises from 38 by a basecatalyzed rearrangement (Scheme 5). 44 Finally, a Petersontype elimination of the 1-mesyloxy-2-trimethylsilylbicyclopropyl (46) gave 38 in preparatively useful yields (Scheme 5).…”

Identification of Cyclopropyl Fatty Acids in Walnut (Juglans Regia L.) Oil

“…An unusual fatty acid containing six cyclopropane rings was recently isolated from Streptomyces sp. 45,46 . Previously, dihydrosterculic acid (4) as well as sterculic acid (5) were found in Pachira aquatica seed oils 47 .…”