Synthesis and Stereochemical Revision of the Aromatic Polyketide NFAT-133

Abstract

NFAT-133, isolated from Streptomyces sp., is an immunosuppressive, antidiabetic, and antitrypanosomal aromatic polyketide with three contiguous stereocenters. The first enantioselective total synthesis of the proposed structure of NFAT-133 [(10R,11R,12S)-1] and its C10 epimer [(10S,11R,12S)-1] was achieved from a known aromatic ester (5) by a 10-step sequence that featured chiral auxiliary-directed asymmetric alkylation and the Evans asymmetric aldol reaction as the chirality-inducing steps. The 1H and 13C NMR data as well as the specific rotation value of natural NFAT-133 were not identical to those of the proposed structure, but were in good agreement with those of its C10 epimer. This led us to conclude that the absolute configuration of NFAT-133 should be revised to 10S, 11R, and 12S.

Antidiabetic profiling of veramycins, polyketides accessible by biosynthesis, chemical synthesis and precursor-directed modification

“…These findings were in line with the configurations observed for the structurally related isochromans panowamycin A and B. 14 Veramycin D (19) was isolated as a white powder. Its molecular formula was determined as C 22 H 26 O 4 by HR-ESI-MS.…”

“…17 The synthesis and stereochemical revision of 1 was disclosed while our own studies on the total synthesis of NFAT-133 and the Veraymcins were already in progress. 19 In line with the initial proposal for 1 17 relying upon on JBCA for 1,2-hydroxymethyl dimethine systems 21,22 and own initial analyses of 3 J H-H and 2,3 J C-H coupling constants between H-10/H11, H-11/C-10 and H-10/C-12, the configurations of the three stereogenic centers of 13 and 17 were thus at first tentatively assigned as 10R, 11R and 12S, too (Scheme 1, epi-13 and epi-17). We realized, however, that the configurational analyses based on standard JBCA parameters led to controversial results with regard to the open-chain congeners 1, 13, 17, 20 and 21 on the one hand and the cyclic derivatives 18, 19 and 22 on the other hand.…”

“…These findings were confirmed by the report of the total synthesis and structural revision of NFAT-133 published during the course of our work. 19 The corresponding building block for the syn,syn stereotriad series with the absolute 10S,11R,12S configurations required (S)-aldehyde 28 for the subsequent key aldol addition. Aldehyde 28 was prepared essentially the same way as its (R) enantiomer epi-28.…”

“…18 The first total synthesis of NFAT-133, however, led to the revised configuration of 10S, 11R and 12S, representing a syn,syn (threo,threo) stereotriad. 19 During our ongoing screening program for antibacterial compounds, we have isolated and characterized NFAT-133 from the crude extract of Streptomyces sp. ST157608 from Sanofi's microbial strain collection.…”

Identification and Biological Activity of NFAT-133 Congeners from Streptomyces pactum

“…[12][13][14]16 While the absolute stereoconfiguration of 1 was initially reported to be 10R, 11R, 12S, 16 a more recent study by Ogura and co-workers concluded that the absolute stereoconfiguration is 10S, 11R, 12S. 17 In addition to NFAT-133, a number of its analogues have also been isolated from several species of Streptomyces. Those include benwamycins from Streptomyces sp.…”