Synthetic Studies of 1,6-C-Linked Disaccharide Analogues Based on Direct Radical Coupling

PS2 Poster session 2 Even numbers
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:45 to 17:15

Noriaki Kiya1, Yu Hidaka1, Makoto Yoritate1, Kazuteru Usui1, Go Hirai1

1Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Carbohydrates exist as glycol-conjugates and interact with various biomolecules in cells. However, the exact functions of carbohydrates remain poorly understood, because they are known to readily undergo hydrolytic cleavage by metabolic enzymes. C-glycoside analogues have been of particular interest as carbohydrate mimics, because the replacement of the oxygen atom by a methylene group renders them stable against metabolic enzymes [1]. C-glycoside analogues have been shown to adopt similar conformations to native O-glycosides and also to exhibit similar or even more potent biological activities [2]. However, it is generally complicated to synthesize these analogues because of the highly oxidized structure and the dense sp³ carbon centers. To supply a variety of biologically useful C-glycosides, efficient synthetic method was required. 

In this study, we aimed to synthesize the typical (1,6)-CH₂-glycoside analogues. We thought that “direct coupling” between a C1-sp³-donor and an acceptor with additional carbon atom at C6 would be the one of the powerful method [3,4]. This time, we focused on the atom-transfer radical coupling reaction [5] between the xanthate donor 1 and the acceptor 2 with a terminal olefin (Scheme 1). The glycosyl radical species 3 generated from stable donor 1 by treatment with a peroxide reagent added to alkene 2. Following xanthates transfer from donor 1 to transient secondary radical on the 6-position of the acceptor resulted in C-glycoside 4. The xanthate group of 4 was easily removed by means of a simple reduction process to give CH₂-linked (1,6)-disaccharide 5. The radical coupling reaction proceeded to form the α-isomer exclusively, when we employed the glycosyl donor 1 with appropriate protecting group in order to restrict it ⁴C₁ conformation. This methodology was successfully applicable to synthesize the CH₂-linked isomaltose analogue 6 by employing the appropriate glucose acceptor. Details of the synthesis of both donor 1 and acceptor 2, and their radical coupling reaction will be disclosed in this presentation [6].

Scheme 1. Radical coupling with xanthate donor 1 and acceptor 2

  1. Yang, Y.; Yu, B. Chem. Rev. 2017, 117, 12281.
  2. (a) Franck, R. W. et al. Angew. Chemie - Int. Ed. 2004, 43, 3818. (b) Hirai, G. Sodeoka, M. et al. J. Am. Chem. Soc. 2007, 129, 15420.
  3. (a) Beau, J. et al. Angew. Chemie - Int. Ed. 2000, 39, 4111. (b) Walczak, M. A. et al. ACS Cent. Sci. 2018, 4, 1652.
  4. Representative synthesis of a variety of CH₂-linked disaccharides with C1-sp² hybridized donor; Werz, D. B. et al. Angew. Chemie - Int. Ed. 2013, 52, 2985.
  5. Zard, S. Z. Angew. Chemie - Int. Ed. 1997, 36, 672.
  6. Kiya, N.; Hidaka, Y.; Usui, K.; Hirai, G. Org. Lett. 2019, 21, 1588.