Unified Total Synthesis of Polyoxins J, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions

Abstract

Polyoxins J(1a)a nd L(1b)a re important nucleoside antibiotics.T he complex and densely functionalized dipeptide structures of 1a and 1b contain thymine and uracil nucleobases,r espectively.H erein we report the unified total synthesis of 1a, 1b,a nd their artificial analogues 1c and 1d with trifluorothymine and fluorouracil structures.D ecarbonylative radical coupling between a-alkoxyacyl tellurides and achiral glyoxylic oxime ether led to chemo-and stereoselective construction of the ribonucleoside a-amino acid structures of 1a-d without damaging the preinstalled nucleobases.The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1a-d.The two amino acid fragments were connected and elaborated into 1a-d (longest linear sequence:1 1steps). Compounds 1a and 1b assembled in this way exhibited potent activity against true fungi, while only 1d was active against Gram-positive bacteria. Scheme 1. A) Structures of the four polyoxins 1a-d and synthetic plan. B) Decarbonylative radical reaction of 7 with achiral oxime 8 (Ref. [11]). Bn = benzyl, TBS = tert-butyldimethylsilyl. [*] H. Fujino, Dr.M.N agatomo,P rof. Dr.M .Inoue Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Enzymatic synthesis of fluorinated compounds

“…To overcome the poor water solubility and photostability of piperine, a threo -difluoropiperine analog was synthesized and showed higher potency and selectivity than piperine for the treatment of AD (Lizarme-Salas et al 2020 ). Similarly, fluorinated compounds are also the key building blocks of antibiotic, antimalarial, antiinflammatory, asthma, antagonists, migraine, and central nervous system drugs, such as 2,2-bis(6-fluoro-1H-indol-3-yl)ethan-1-amine, fluorinated steroidal, Trifluorothymidine and fluorouracil polytoxin, fluorinated cholesterol, fluorinated galegine, fluorinated bastimolide A, 6(R/S)-fluoropenibruguieramine, fluorinated cyclopropanecarboxylic acid derivatives, aryl-fluoro sulfates, 3-fluoro-4-aminopiperidine, and β-fluoramines (Adler et al 2019 ; Bakhotmah and Abdel-Rahman 2017 ; Campana et al 2020 ; Frank et al 2016 ; Fujino et al 2017 ; Gambini et al 2019 ; Liu et al 2018 ; Molinaro et al 2019 ; Munck Af Rosenschold et al 2019 ; Pupo et al 2019 ; Quintard et al 2018 ; Shao et al 2015 ; Wu et al 2020d ). Accordingly, fluorinated compounds will pay more and more attention to the research and development of new pharmaceutical intermediates.…”

Forging C(sp3)–C(sp3) Bonds with Carbon-Centered Radicals in the Synthesis of Complex Molecules

“…Radical fragment coupling reactions that unite two disubstituted carbon stereocenters are key steps in the total syntheses of polyoxins J and L reported by Inoue and coworkers in 2017 (Scheme 9). 28 These structurally complex and densely functionalized nucleoside antibiotics share ribofuranosyl α-amino acid and carbamoylated trihydroxynorvaline fragments and differ only in substitution at C-5 of the pyrimidine nucleobase. The coupling of α-alkoxyradicals, generated from α-alkoxyacyl tellurides upon exposure to O 2 and BEt 3 , 8e,15 with a camphorsultam-derived glyoxylic oxime ether 33 was employed to assemble two fragments of these natural product targets.…”

Photoredox-Catalyzed Deformylative 1,4-Addition of 2′-Deoxy-5′-O-phthalimidonucleosides for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates

“…1 H NMR (500 MHz, DMSO-d 6 ): (major isomer) δ 11.29 (s, 1H), 7.40 (d, J = 1.0 Hz, 1H), 6.12 (dd, J = 7.0, 7.0 Hz, 1H), 5.29 (d, J = 4.5 Hz, 1H), 4.10−4.06 (m, 1H), 4.04−3.93 (m, 4H), 3.66−3.63 (m, 1H), 2.22 (ddd, J = 13.5, 7.0, 7.0 Hz, 1H), 2.04 (ddd, J = 13.5, 6.5, 4.0 Hz, 1H), 1.87−1.68 (m, 4H), 1.79 (d, J = 1.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 6H). 1-[(3S,4R/4S)-6-(Dibenzyloxyphosphinyl)-2,5,6-trideoxy-β/αhexofuranosyl]uracil (6). Purification of the crude solution by flash column chromatography (CHCl 3 /MeOH = 20:1 to 5:1) afforded compound 6 as a white solid (49.6 mg, 51%, β:α = 6:1).…”

“…Very recently, Inoue and co-workers reported the generation of 4′-carbon radicals by radical decarbonylation from the 5′-acyl tellurides of 2′-O,3′-O-isopropylideneuridines and used it for the total synthesis of polyoxins J and L and their fluorinated analogs. 6 As such, a new generation method of 4′-carbon radicals of nucleosides will contribute to the development of useful nucleoside analogs.…”