Synthesis of Biaryl-Containing Medium-Ring Systems by Organocuprate Oxidation: Applications in the Total Synthesis of Ellagitannin Natural Products

Abstract

In this feature article we discuss the construction of biaryl-containing medium-sized rings by organocuprate oxidation and the application of this chemistry in the synthesis of members of the ellagitannin family of natural products. A concise and efficient total synthesis of the ellagitannin sanguiin H-5 is highlighted. Studies towards the synthesis of elaeocarpusin are also presented.

Synthesis of ellagitannin natural products

“…On the one hand, Spring and co-workers developed an organocuprate oxidation protocol to construct biaryl-containing medium-ring systems, and successfully applied it to the concise and efficient total synthesis of the 4 C 1 -glucopyranose-based 2,3-(S)-HHDP-containing ellagitannin sanguiin H-5 (70) via an intermediate of type 31 [with X ¼ I or Br, P 4 ¼ P 5 ¼ P 6 ¼ Bn] (see Section 4.2, Scheme 10). 56,57 On the other hand, Yamada and co-workers reconsidered their initial Ullmann coupling approach 58 to set up a successful alternative based on a CuCl 2 $amine complex-mediated oxidative coupling of a symmetrically protected 4-O-benzylgallic acid derivative [i.e., 31 with X ¼ H, P 4 ¼ P 6 ¼ H, P 5 ¼ Bn] that led them to achieve the total synthesis of the 1 C 4 -glucopyranose-based 3,6-(R)-HHDP-containing ellagitannin corilagin (103) (see Section 5.3, Scheme 16). 59 The alternative route B relies on a double esterification of a Dglucose diol derivative such as 33 with a preformed, and suitably protected, hexahydroxydiphenoic acid 34, used either in its enantiopure form or in its racemic version (Scheme 2).…”

Synthesis, characterization, and crystal structure of 2-iodo-3,4,5-trimethoxybenzoic acid

“…The I 2 AAgTFA couple is usually used in cases of using electron-poor arenes (such as haloarenes) and benzoic acid. Commonly, the reaction conditions are dependent on the chemical reactivity of the arene; e.g., the benzoic acid is been iodinated in nitrobenzene at 150°C with 84% yield [15], the methyl ester of 3,4,5-trimethoxybenzoic acid in chloroform at room temperature with 45% yield [23], and 3,4,5-trimethoxybenzoic acid in chloroform with 99% yield [21]. Although, in most cases, the authors have not provided a detailed description of the preparative procedure, it is reasonable to expect that the iodination of aromatic hydrocarbons should be quantitative when using freshly prepared AgTFA, rigorously anhydrous conditions and inert atmosphere.…”

Fundamental Methods in Ellagitannin Synthesis

“…On the other hand, strict anhydrous reaction conditions are necessary for the sequence. With the method, Spring and co-workers have achieved two total syntheses of ellagitannins [33,36,37].…”