Direct assembly of multiply oxygenated carbon chains by decarbonylative radical–radical coupling reactions

Abstract

Pentoses and hexoses contain more than three oxygen-bearing stereocentres and are ideal starting materials for the synthesis of multiply oxygenated natural products such as sagittamide D, maitotoxin and hikizimycin. Here we demonstrate new radical-radical homocoupling reactions of sugar derivatives with minimal perturbation of their chiral centres. The radical exchange procedure using EtB/O converted sugar-derived α-alkoxyacyl tellurides into α-alkoxy radicals via decarbonylation and rapidly dimerized the monomeric radicals. The robustness of this process was demonstrated by a single-step preparation of 12 stereochemically diverse dimers with 6-10 secondary hydroxy groups, including the C5-C10 stereohexad of sagittamide D and the enantiomer of the C51-C60 stereodecad of maitotoxin. Furthermore, the optimally convergent radical-radical cross-coupling reaction achieved a one-step assembly of the protected C1-C11 oxygenated carbon chain of the anthelmintic hikizimycin. These exceptionally efficient homo- and heterocoupling methods together provide a powerful strategy for the expedited total synthesis of contiguously hydroxylated natural products.

Convergent Total Synthesis of Asimicin via Decarbonylative Radical Dimerization

“…Namely, upon treatment of α‐alkoxy acyl telluride 12 a with Et 3 B (5 equiv) in CH 2 Cl 2 (0.2 m ) under air at room temperature for 20 min, 12 a sequentially underwent C−Te bond homolysis, CO‐ejection from the acyl radical, and a radical–radical coupling reaction of the resultant F , affording the desired C 2 ‐symmetric dimer 3‐ SS and its stereoisomer 3‐ SR in 27 and 25 % yields, respectively. The reaction displayed the desired SS ‐stereoselectivity ( 3‐ SS / SR / RR =52:48:0) compared with the statistical ratio (25:50:25), presumably due to the preferred C−C bond formation from the opposite face of the bulky acetonide group of α‐alkoxy radical F . Most importantly, the single‐step installation of the two new C19,20‐stereocenters of 3‐ SS under mild conditions clearly showed the exceptional efficacy of the present method for assembling the bridged bis‐THF structures.…”

“…We recently reported the direct construction of bis‐THF structures via decarbonylative homo‐radical‐radical coupling reactions of monosaccharide derivatives (Scheme B) . For instance, when d ‐ribose‐derived α‐alkoxyacyl telluride A was treated with Et 3 B and O 2 at room temperature, three dimeric structures, B‐ RR , B‐ RS , and B‐ SS , with eight contiguous stereocenters were produced in 68 % combined yield.…”

“…Despite the stability of intermediates 12 a and 12 b against air,l ight, and silica gel, both of the compounds underwent homo-coupling by the action of Et 3 Ba nd O 2 .N amely,u pon treatment of a-alkoxya cyl telluride 12 a with Et 3 B( 5equiv) in CH 2 Cl 2 (0.2 m)u nder air at room temperature for 20 min, 12 a sequentially underwent CÀTe bond homolysis, CO-ejection from the acyl radical, and ar adical-radical coupling reaction of the resultant F,a ffording the desired C 2 -symmetric dimer 3-SS and its stereoisomer 3-SR in 27 and 25 %y ields, respectively. The reaction displayed the desired SS-stereoselectivity (3-SS/ SR/RR = 52:48:0) compared with the statistical ratio (25:50:25), presumably due to the preferred CÀCb ond formationf rom the oppositef ace of the bulky acetonide group of a-alkoxy radical F. [9,20] Most importantly, the single-step installation of the two new C19,20-stereocenters of 3-SS under mild conditions clearly showedt he exceptional efficacy of the present methodf or assembling the bridged bis-THFs tructures.I nc ontrast, C19-epimeric 12 b was an inferiorr adical precursor:t reatment of 12 b under the same conditions resulted in the formation of 3-SS and 3-SR in as imilar ratio, but in lower yields (15 and 11 %, respectively). Since both 12 a and 12 b lost their C19stereochemistry and went through the same a-alkoxy radical F upon dimerization, the better yield from 12 a was attributed to higher efficiency of the formation of F from the C19'a-isomer 12 a than from the C19'b-isomer 12 b.…”

“…[6c,g,h] We recently reported the direct construction of bis-THF structures via decarbonylative homo-radical-radicalc oupling reactions of monosaccharide derivatives (Scheme 1B). [9] For instance, when d-ribose-derived a-alkoxyacylt elluride A was treated with Et 3 Ba nd O 2 at room temperature, three dimeric structures, B-RR, B-RS,a nd B-SS,w ith eight contiguous stereocenters werep roduced in 68 %c ombined yield. In this reaction, the ethyl radicalg enerated from Et 3 B/O 2 [10] homolytically cleaves the weak CÀTe bond of A to form acyl radical C.R apid decarbonylation of C proceeds to give a-alkoxyc arbon radical D, [11] and subsequent radical-radicalc oupling leads to B-RR/ RS/SS.…”

Et3B/Et2AlCl/O2‐Mediated Radical Coupling Reaction between α‐Alkoxyacyl Tellurides and 2‐Hydroxybenzaldehyde Derivatives

“…Despite the broad scope of the method for assembling saturated polyol systems, benzaldehyde ( 4 ) did not function as a radical acceptor, presumably due to the lower electrophilicity of the carbonyl group in the conjugated system (Scheme 1A). Namely, treatment of 1 c and 4 with Et 3 B/O 2 failed to produce coupling adduct 5 and only provided 6 though dimerization of the resultant α‐alkoxy radical [7c] . Herein, we report that a new reagent combination comprising Et 3 B, Et 2 AlCl, and O 2 allowed the coupling of α‐alkoxyacyl tellurides with variously substituted 2‐hydroxybenzaldehydes.…”