Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals

Laksmikanta Adak, Shintaro Kawamura, Gabriel Toma, Toshio Takenaka, Katsuhiro Isozaki, Hikaru Takaya, Akihiro Orita, Ho C. Li, Tony Kung Ming Shing, Masaharu Nakamura

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

Original languageEnglish
Pages (from-to)10693-10701
Number of pages9
JournalJournal of the American Chemical Society
Volume139
Issue number31
DOIs
Publication statusPublished - 2017 Aug 9
Externally publishedYes

Fingerprint

Glycosides
Iron
Cross Reactions
Carbon
Sodium-Glucose Transport Proteins
Metals
Medical problems
Bioactivity
Catalysis
Bromides
Pharmaceutical Preparations
Drug products
Functional groups
Density functional theory
Glucose
Chlorides
Ligands
Sodium
C-glycoside
Degradation

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars : Stereoselective Anomeric Arylation of Glycosyl Radicals. / Adak, Laksmikanta; Kawamura, Shintaro; Toma, Gabriel; Takenaka, Toshio; Isozaki, Katsuhiro; Takaya, Hikaru; Orita, Akihiro; Li, Ho C.; Shing, Tony Kung Ming; Nakamura, Masaharu.

In: Journal of the American Chemical Society, Vol. 139, No. 31, 09.08.2017, p. 10693-10701.

Research output: Contribution to journalArticle

Adak, L, Kawamura, S, Toma, G, Takenaka, T, Isozaki, K, Takaya, H, Orita, A, Li, HC, Shing, TKM & Nakamura, M 2017, 'Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals', Journal of the American Chemical Society, vol. 139, no. 31, pp. 10693-10701. https://doi.org/10.1021/jacs.7b03867
Adak, Laksmikanta ; Kawamura, Shintaro ; Toma, Gabriel ; Takenaka, Toshio ; Isozaki, Katsuhiro ; Takaya, Hikaru ; Orita, Akihiro ; Li, Ho C. ; Shing, Tony Kung Ming ; Nakamura, Masaharu. / Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars : Stereoselective Anomeric Arylation of Glycosyl Radicals. In: Journal of the American Chemical Society. 2017 ; Vol. 139, No. 31. pp. 10693-10701.
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abstract = "We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.",
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