Total Synthesis of Cercidinin A

Abstract

An ellagitannin, cercidinin A, was synthesized through both intramolecular coupling of gallates on a glucose moiety and double esterification of protected hexahydroxydiphenic acid to a diol. The total synthesis confirmed the revised structure of cercidinin A as 1,2,6‐tri‐O‐galloyl‐3,4‐(R)‐hexahydroxydiphenoyl (HHDP) β‐D‐glucose. This is the first synthesis of 3,4‐HHDP‐bridged ellagitannins and was achieved after overcoming two challenges: (1) full galloylation of β‐glucose hindered the formation of the 3,4‐HHDP group, and (2) the fully benzylated galloyl group, which is a routine component in ellagitannin synthesis, was not always appropriate. The solutions to these problems can be used to form a strategy for the synthesis of complex ellagitannins.

Non‐Enzymatic Oxidation of a Pentagalloylglucose Analogue into Members of the Ellagitannin Family

“…In particular,production of the axial-rich ellagitannins from 1 is still at the suppositional level. Fora xial chirality of the HHDP group,i ts eems that synthetic work has verified the hypothesis by showing that the couplings at the 1,6-, [15] 2,3-, [16,17] 3,4-, [18] 3,6-, [19,20] and 4,6-positions [21][22][23][24] almost reflect the axial chirality in natural products.H owever,t he verification is deficient because all reactants used in the reported work are partly galloylated glucose,w hich cannot mimic the reaction of the fully galloylated 1.A lthough as imple chemical reaction cannot reflect the biosynthesis where enzymes may take charge of the transformations,i ti si mportant to understand behaviors in non-enzymatic oxidation of 1 in the process of clarifying the biosyntheses of ellagitannins because the galloyl group can also couple non-enzymatically.However,simple oxidation of unprotected galloyl groups produces various types of reaction products,t hus making an analysis focused on the oxidation products difficult. In this study,w ei nvestigated non-enzymatic oxidation of 5 (Figure 1), an analogue of 1,and thereby reveal which 4-O-benzylated galloyl groups tended to couple…”

“…[20] This coupling reaction was suitable for as tudy aimed at understanding the non-enzymatic oxidation of the b-PGG analogue because 1) the reaction proceeds effectively at room temperature,w hen thermal conditions are similar to those of the biosynthesis,2 )the spatial proximity of the groups to each other make coupling possible,a nd 3) the reaction has been applied in syntheses of natural ellagitannins for coupling of the galloyl groups at various positions of glucose. [15,18,[24][25][26][27][28] Theo xidation of 5 with CuCl 2 and n BuNH 2 provided ac omplicated mixture of products ( Figure 2). We conducted the reaction, after optimization to completely consume 5, because residual reactant would make separation of the products increasingly difficult.…”

Non‐Enzymatic Oxidation of a Pentagalloylglucose Analogue into Members of the Ellagitannin Family

“…In particular, production of the axial‐rich ellagitannins from 1 is still at the suppositional level. For axial chirality of the HHDP group, it seems that synthetic work has verified the hypothesis by showing that the couplings at the 1,6‐, 2,3‐, 3,4‐, 3,6‐, and 4,6‐positions almost reflect the axial chirality in natural products. However, the verification is deficient because all reactants used in the reported work are partly galloylated glucose, which cannot mimic the reaction of the fully galloylated 1 .…”

“…For the coupling of the galloyl groups of 5 , we adopted a reaction induced by CuCl 2 ‐ n BuNH 2 (Figure ) . This coupling reaction was suitable for a study aimed at understanding the non‐enzymatic oxidation of the β‐PGG analogue because 1) the reaction proceeds effectively at room temperature, when thermal conditions are similar to those of the biosynthesis, 2) the spatial proximity of the groups to each other make coupling possible, and 3) the reaction has been applied in syntheses of natural ellagitannins for coupling of the galloyl groups at various positions of glucose …”

Total Syntheses of Laevigatins A and E

“…Although a wide variety of biological activities have been reported for the ellagitannins, [1,2,9] the elucidation of their structure-activity relationships has been a problem due to the difficulty of obtaining a complete collection of systematically related analogues from nature. Fortunately, the synthesis of monomeric ellagitannins and their artificial analogues has progressed significantly, and much knowledge has been accumulated, [11][12][13][14][15][16][17][18][19][20][21][22][23][24] although the amounts of the compounds synthesized have been small in many cases. A considerable number of characterized compounds, which could be isolated only in trace amounts, have been left unexplored.…”