Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

Abstract

The proposed diastereoisomers (1 a-d) together with their C8'-epimers (1 e-h) of amipurimycin, a unique antifungal peptidyl nucleoside antibiotic, have been synthesized for the first time. The synthetic approach is efficient and stereodivergent, and features a stereoselective aldol condensation to build the branched C9 sugar amino acid skeleton and a regio- and stereocontrolled gold(I)-catalyzed N-glycosylation to furnish the purine nucleoside. Analysis of the NMR data suggests that the previously assigned configuration of the tertiary C3' in amipurimycin should be of opposite configuration.

Amipurimycin: Total Synthesis of the Proposed Structures and Diastereoisomers

“…[15] In contrast, reduction of 8b with NaBH 4 led to the desired 7S-ol 9b (93 %, d.r. Thestructure of 10 a was confirmed by X-ray diffraction analysis of a p-bromobenzoyl derivative (S8 [22,23] ), thus indicating the correct stereochemistry established for C3 and C5. Subsequently,t he isopropylidene acetals in 9a/9b were cleaved (75 %H OAc, 60 8 8C) and the resultant primary 9-OH was protected with aTBDPS group, thus leading to the corresponding furanose hemiacetals.…”

The Miharamycins and Amipurimycin: their Structural Revision and the Total Synthesis of the Latter

“…[5] Although tremendous efforts have been dedicated to the chemical synthesis of amipurimycin [6] and miharamycin, [5,7] thesuccessful synthesis of the proposed amipurimycins (1a-d)w as only recently achieved by us. [8] However,a pparent discrepancies were found between the NMR spectroscopy data of the synthetic compounds and those recorded for the natural product, leading to aconclusion that the configuration of the tertiary C3' in the originally proposed structure of amipurimycin should be inverted. [8] Considering the possible biosynthetic relevance of amipurimycin and miharamycins,t he configuration of C3' in the latter should also be inverted.…”

“…[8] However,a pparent discrepancies were found between the NMR spectroscopy data of the synthetic compounds and those recorded for the natural product, leading to aconclusion that the configuration of the tertiary C3' in the originally proposed structure of amipurimycin should be inverted. [8] Considering the possible biosynthetic relevance of amipurimycin and miharamycins,t he configuration of C3' in the latter should also be inverted. Theinversion of the originally proposed configuration of C3' in miharamycins would lead to ac onformationally restricted trans-fused dioxabicyclo-[4.3.0]nonane sugar scaffold.…”

“…Herein, we report the final structural confirmation of amipurimycin and miharamycins. [9] Besides the necessary revision of the configuration at C3', acomparison of the NMR spectroscopy data of the synthetic amipurimycin (1a-d)a nd their 8'R antipodes (1e-h) [8] also led us to propose ar evision of the originally assigned S configuration at C8';t he H8' signals of 1a-d appear at d = 4.33-4.37 ppm, while those of the 8'R antipodes at d = 4.08-4.14 ppm are much closer to the reported d = 3.96 ppm for the natural amipurimycin. [10] Thesmaller Dd (À0.06 to 0.04 ppm) Figure 1.…”

“…[12] To our good fortune, conversion of furanoside 12 to fused pyranoside 13,c apable of adopting at wist-boat conformation, [6k,13] was realized following the previous procedure. [8] Thus,r emoval of the isopropylidene acetals in 12 (75 %H OAc, 60 8 8C), protection of the primary 9-OH with TBDPS,a nd treatment of the resulting furanose hemiacetal (B)w ith Hf(OTf) 4 (DTBMP, EtOAc,C aSO 4 ,6 08 8C) [8,14] afforded 13 in as atisfactory 51 % yield (for 3steps).…”