Synthesis 2009(22): 3880-3896  
DOI: 10.1055/s-0029-1218154
© Georg Thieme Verlag Stuttgart ˙ New York

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

Xianbin Su, Gemma L. Thomas, Warren R. J. D. Galloway, David S. Surry, Richard J. Spandl, David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44(1223)336362; e-Mail: [email protected];
Further Information

Publication History

Received 11 August 2009
Publication Date:
07 October 2009 (online)


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.

1 Introduction

2 Results and Discussion

2.1 Total Synthesis of Sanguiin H-5

2.2 Studies towards the Total Synthesis of Elaeocarpusin

2.2.1 Towards Elaeocarpusin: Organocuprate Oxidation

2.2.2 Towards Elaeocarpusin: A Double Esterification Approach

3 Conclusions


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It is not entirely obvious why the oxidative coupling of organocuprates should be so effective at forming medium-ring biaryl systems, especially given the difficulties associated with the use of more conventional palladium-mediated methods. It has been postulated that the approximately linear geometry of the [R-Cu-R] bond of the organocuprate intermediate may be the key (Scheme  [¹] ). Such an arrangement may keep groups that could otherwise suffer destabilising transannular interactions well separated from each other. However, it is not immediately apparent how such a system may progress to a configuration in which reductive elimination could occur whilst still minimising transannular interactions.


Feldman K. S. Personal communication. See also ref. 12d.


Sanguiin H-5 was found to be hydrolytically unstable on silica and alumina, making further purification problematic. Chromatography using reversed-phase (C-18) silica could be used if required; however, the filtered, concentrated reaction mixture gave material of ˜95% purity.


Conformational analysis of the 11-membered medium-ring in 33 reveals that it does not have a low-energy conformation where both esters’ groups are capable of obtaining their preferred U-shape (s-cis) simultaneously (unlike the northern-hemisphere 12-membered ring). The crystal structure of geraniin (31) shows that the strain in the
11-membered ring is relieved somewhat, since both esters’ groups can form a lower energy s-trans conformation. We hypothesize that the internal strain inherent in this medium-ring may make this system more susceptible to oxidation, and be the reason why the 2,4-bridging biaryl group has never been observed as such in ellagitannin natural products (see ref. 11b).


Attempts to protect the 3-hydroxyl group of 35 with the silane protecting groups TBS and TMS were unsuccessful. In addition, attempts to protect this hydroxyl group with a benzoyl group (by reaction with benzoyl chloride) also met with failure.


Treatment of laevoglucosan (35) with allyl bromide or iodide in the presence of sodium hydride generated fully alkylated product rather than the desired 2,4-allyl protected derivative. Silver triflate was found to be essential for the generation of 42 from 41.