756
3
Chemical Glycosylation Reactions
rearrangement and transition metal-catalyzed reactions. Among these reactions, useful C-glycosylations with high stereoselectivities are reviewed in this chapter with an emphasis on the
reaction mechanisms.
Keywords
C-Glycosylation; Oxocarbenium cation; Anomeric radical; Anomeric anion; Stereoelectronic
effect
Abbreviations
HMPA hexamethylphosphoramide
MCPBA m-chloroperoxybenzoic acid
TIPS
triisopropylsilyl
TMSCN trimethylsilyl cyanide
1 Introduction
C-Glycosylation, a carbon–carbon bond-forming reaction at an anomeric center of carbohydrates and related compounds, has been the subject of great attention due to the importance of
C-glycoside-containing compounds such as C-glycoside mimics of glycolipids, oligosaccharides, and glycoproteins, and natural products in chemistry and biology.
In 1993, researchers of the Kirin Brewery Corporation, Japan, reported the isolation and
structure of agelasphines, novel anticancer sphingolipids isolated from an Okinawan marine
sponge, Agelas mauritianus ( > Fig. 1) [1]. Since these compounds are the first examples
of α-galactosyl ceramide found in nature, and a novel mode of action for their anticancer
activity was expected, development of an antitumor drug candidate based on agelasphines
led to KRN7000, a synthetic sphingolipid. Extensive studies regarding the mode of action
revealed that KRN7000 activated natural killer T-cells by binding CD1d, an antigen presentation protein, thus releasing cytokines including Interferon-γ (IFN-γ ) causing tumor rejection
and Interleukin-4 (IL-4) suppressing autoimmune diseases. Interestingly, OCH, a truncated
synthetic analog of KRN7000 induced a predominant production of IL-4 over IFN-γ , while
KRN7000 induced production of both cytokines. In 2003, Franck and co-workers reported
the synthesis of a C-glycoside analog of KRN7000, surprisingly, this compound exhibited
1000-fold more activity than KRN7000 in a mouse malaria assay as well as a 100-fold activity
increase in a mouse melanoma model. Significant efforts have been devoted towards the synthesis of C-glycoside that specifically releases one of these cytokines in order to yield compounds for chemotherapeutic application. This recent example demonstrates the importance
of C-glycoside analogs of biologically active glycoconjugates in biology and pharmacy. These
results are stimulating development of stereoselective and efficient methods for synthesizing
C-glycoside analogues of KRN7000 ( > Fig. 1).
The C-glycosidic linkage is also found in many biologically important natural products such
as marine natural toxins and antibiotics as shown in > Fig. 2. Since synthesis of these structurally complex natural products has been a major subject in modern organic synthesis, stere-
3
Chemical Glycosylation Reactions
rearrangement and transition metal-catalyzed reactions. Among these reactions, useful C-glycosylations with high stereoselectivities are reviewed in this chapter with an emphasis on the
reaction mechanisms.
Keywords
C-Glycosylation; Oxocarbenium cation; Anomeric radical; Anomeric anion; Stereoelectronic
effect
Abbreviations
HMPA hexamethylphosphoramide
MCPBA m-chloroperoxybenzoic acid
TIPS
triisopropylsilyl
TMSCN trimethylsilyl cyanide
1 Introduction
C-Glycosylation, a carbon–carbon bond-forming reaction at an anomeric center of carbohydrates and related compounds, has been the subject of great attention due to the importance of
C-glycoside-containing compounds such as C-glycoside mimics of glycolipids, oligosaccharides, and glycoproteins, and natural products in chemistry and biology.
In 1993, researchers of the Kirin Brewery Corporation, Japan, reported the isolation and
structure of agelasphines, novel anticancer sphingolipids isolated from an Okinawan marine
sponge, Agelas mauritianus ( > Fig. 1) [1]. Since these compounds are the first examples
of α-galactosyl ceramide found in nature, and a novel mode of action for their anticancer
activity was expected, development of an antitumor drug candidate based on agelasphines
led to KRN7000, a synthetic sphingolipid. Extensive studies regarding the mode of action
revealed that KRN7000 activated natural killer T-cells by binding CD1d, an antigen presentation protein, thus releasing cytokines including Interferon-γ (IFN-γ ) causing tumor rejection
and Interleukin-4 (IL-4) suppressing autoimmune diseases. Interestingly, OCH, a truncated
synthetic analog of KRN7000 induced a predominant production of IL-4 over IFN-γ , while
KRN7000 induced production of both cytokines. In 2003, Franck and co-workers reported
the synthesis of a C-glycoside analog of KRN7000, surprisingly, this compound exhibited
1000-fold more activity than KRN7000 in a mouse malaria assay as well as a 100-fold activity
increase in a mouse melanoma model. Significant efforts have been devoted towards the synthesis of C-glycoside that specifically releases one of these cytokines in order to yield compounds for chemotherapeutic application. This recent example demonstrates the importance
of C-glycoside analogs of biologically active glycoconjugates in biology and pharmacy. These
results are stimulating development of stereoselective and efficient methods for synthesizing
C-glycoside analogues of KRN7000 ( > Fig. 1).
The C-glycosidic linkage is also found in many biologically important natural products such
as marine natural toxins and antibiotics as shown in > Fig. 2. Since synthesis of these structurally complex natural products has been a major subject in modern organic synthesis, stere-