Structure Determination of Monomeric Phloroglucinol Derivatives with a Cinnamoyl Group Isolated from Propolis of the Stingless Bee, Tetragonula carbonaria

Abstract

Tetragocarbones A and B were isolated from the propolis of an Australian stingless bee, Tetragonula carbonaria. These largely planar structures were proposed as a result of NMR analysis as well as comparison of their NMR data with those of related monomeric phloroglucinol derivatives. To elucidate relative and absolute stereochemistry of tetragocarbone A, the synthesis of the proposed structure of tetragocarbone A was performed. As a result, the synthetic compound bearing stereogenic centers 1R*,3R*,6S* was identical with naturally occurring tetragocarbone A. The absolute stereochemistry of tetragocarbone A was established to be 1R,3R,6S by chiral HPLC separation and X-ray analysis. Comparison of the NMR data of tetragocarbone A with that of tetragocarbone B indicated that tetragocarbone B would be a natural congener of tetragocarbone A.Stingless bees are a large group of social honey bees and live in tropical and subtropical areas.[1] Stingless bees produce propolis as their hive material. The propolis of stingless bees has been use in traditional medicines and health supplements worldwide. Because of their pharmacological utility, the propolis of stingless bees has attracted much attention as a rich source of biologically active natural products. [2,3] Many efforts have been devoted to analyzing and identifying biologically active natural products in the propolis. [2,3] However, to the best of our knowledge, novel natural products have not been isolated from the propolis of stingless bees. Herein, we report the isolation and structure determination of monomeric phloroglucinol derivatives [4] tetragocarbone A (1 a) and B (1 b, Figure 1) isolated from the propolis of the Australian social stingless bee, Tetragonula carbonaria (= Trigona carbonaria). Tetragocarbone A and B are the first examples of tetramethylated monomeric phloroglucinol derivatives bearing a cinnamoyl group. The relative and absolute stereochemistry of 1 a was unambiguously determined by its total synthesis and X-ray crystal analysis. Comparison of the NMR data of tetragocarbone B (1 b) with that of 1 a provides a proposed structure of 1 b that would be a natural congener of 1 a. Hexane extracts of the propolis of T. carbonaria were purified by repeated normal phase silica gel chromatography, normal phase HPLC, and chiral normal phase HPLC to give 1 a and 1 b (Scheme S1 in the supporting information). Tetragocarbone A (1 a) and B (1 b) were obtained as yellow oil. These optical rotations were found to be levorotatory (1 a: [a] = À13.6 (c = 0.28, CHCl 3 ), 1 b: [a] = À17.1 (c = 0.14, CHCl 3 )). The molecular formulas of 1 a and 1 b were putatively assigned as C 26 The planar structures of 1 a and 1 b were proposed as a result of NMR analysis and comparison of their NMR data with those of monomeric phloroglucinols 2 a, 2 b, and 3 [a] Dr.

Lessons from Exploring Chemical Space and Chemical Diversity of Propolis Components

“…Only seven countries, including Brazil ( Melipona interrupta [ 126 ], M. quadrifasciata anthidioides [ 43 ], M. seminigra [ 126 ], M. scutellaris [ 139 ], M. subnitida [ 122 ], and Tetragonula (Trigona) spinipes [ 88 ] bees), Indonesia ( Tetragonula aff. biroi [ 42 ], T. sapiens [ 160 ], and T. incisa [ 136 ] bees), Malaysia ( Heterotrigona itama [ 149 ] bee), Philippines ( Tetragonula biroi [ 137 ] bee), Thailand ( Tetragonula laeviceps [ 138 ], T. pagdeni [ 151 ], and Tetrigona melanoleuca [ 138 ] bees), Vietnam ( Lisotrigona cacciae [ 157 ], L. furva [ 153 ], and Tetragonula minor [ 146 , 152 ] bees), and Australia ( Tetragonula carbonaria [ 131 , 140 ] bee) have published their SBP studies ( Figure 5 D). Vietnam is leading the numbers of compounds isolated from SBP, with 34 compounds, followed by Brazil (29 compounds) and Thailand (19 compounds).…”

Improved total synthesis of (±)-Tetragocarbone A

“…On the other hand, switching to LiAlH4 afforded a 10:3 mixture of (1R*,3R*)-8 and (1R*,3S*)-17. 1 Reduction of acetate 16 with NaBH4 in MeOH gave (1R*,5S*)-15 as a single isomer. The stereochemistry of 15 was unambiguously determined by the total synthesis of 1 from 15.…”

“…Spectroscopic data of the synthetic 1 were identical with those of the authentic data. 1 Scheme 6. Total synthesis of (±)-tetragocarbone A (1).…”

“…Tetragocarbone A (1) was isolated from the propolis of an Australian stingless bee, Tetragonula carbonara. 1 Among several highly substituted cyclic polyketides that have been isolated, such as 2~5, 1 features a highly complex cyclohexanone skeleton with eight substituents and a cinnamic acid ester (Figure 1). 2,3 The relative structure of 1 was proposed by NMR analysis and the first total synthesis of 1.…”

“…The first total synthesis of 1 was achieved in 13 steps starting from phloroglucinol (6) in 1.9 % overall yield (Scheme 1). 1 Although the first synthesis contributed to the structure elucidation, it suffered from low stereoselectivities in the following steps: (i) LiAlH4 reduction of 7 (dr = 10:3), (ii) esterification of diol 8 to give a mixture of mono-and diesters, and (iii) dihydroxylation of 10 to give 11 (dr = 1:1). These results suggested that the above intermolecular reactions would not be suitable for the practical synthesis of 1.…”