Synthesis of Procyanidin Oligomers. Development and Application of Cross-Coupling Reactions using Novel C8-organometallic Derivatives.

Author: Eric Grant Dennis

Dennis, Eric Grant, 2010 Synthesis of Procyanidin Oligomers. Development and Application of Cross-Coupling Reactions using Novel C8-organometallic Derivatives., Flinders University, School of Chemical and Physical Sciences

Terms of Use: This electronic version is (or will be) made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. You may use this material for uses permitted under the Copyright Act 1968. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact with the details.


This thesis details the evolution of the iterative synthesis of 4-8 linked procyanidin (catechin) oligomers. This was achieved through the novel cross-coupling of a C4-electrophilc catechin species with a C8-organometallic catechin derivative. Chapter 1 details a short discussion of relevant aspects of flavan-3-ols (catechins) such as nomenclature, reactivity, importance to red wine sensory perception and biological properties. Included is a short review of recent methods in biomimetic-type syntheses of procyanidin oligomers, with particular focus on dimeric and trimeric species. A model cross-coupling system was developed and discussed in Chapter 2. In this chapter, a metallated 1,3,5-trimethoxybenzene derivative was employed as a C8-organometallic model. Coupling of a variety of metallated 1,3,5-trimethoxybenzenes to benzyl bromide revealed that 2,4,6-trimoxyphenylzinc chloride was readily coupled to this electrophile in moderate to good yields in the presence of numerous palladium catalysts. Following optimisation, the coupling product was obtained in very high yields using Pd(DPEPhos)Cl2 as a catalyst. This procedure was then extended to the coupling of the organozinc with a variety of substituted benzylic and aryl halides in good to high yields. The development of a Lewis acid-promoted coupling of a C4-ether with a C8-organometallic towards the synthesis of a 4-8 catechin-catechin dimer is outlined in Chapter 3. Once again, the metallated 1,3,5-trimethoxybenzene derivatives used in Chapter 2 were employed as a C8-organometallic model. The Lewis acid-promoted cross-coupling of a C4-ether with 2,4,6-trimethoxyphenylboronic acid afforded a model pseudo-4-8-dimer in excellent yield with the desired 3,4-trans stereochemistry obtained in excellent selectivity. Application of the model cross-coupling conditions using a C8-boronic acid-substituted catechin derivative provided a benzyl-protected catechin-4-8-dimer in consistent 90-95% yields. Debenzylation of the synthesised dimer provided catechin-4รก-8-catechin dimer, or natural procyanidin B3. This natural procyanidin dimer was produced in 6 linear steps from (+)-catechin in 54% overall yield. The synthesis of a boron-protected procyanidin dimer and trimer is presented in Chapter 4. The synthesis of these oligomers was achieved using a C8-boron-protected-C4-ether catechin derivative as a chain extension species. This species could be added to the C8-terminus of a growing oligomer chain in an iterative fashion using a coupling, boron-deprotection strategy. The C4-ether portion of this species selectively reacted with a free C8-boronic n-oligomer using the Lewis acid-promoted coupling method developed in Chapter 3 to provide an (n+1)-oligomer. Removal of the C8-boron protecting group furnished a free C8-boronic acid oligomer that could undergo further coupling to the chain extension species. The synthesis of C8-substituted catechin derivatives is discussed in Chapter 5. C8-phenyl substituted catechins were produced in good to excellent yields using Suzuki and Kumada cross-couplings of both C8-boronic acid and C8-iodide-substituted catechins using a variety of palladium catalysts. The synthesis of an 8-8 linked catechin-catechin dimer and C8-alkyl substituted catechin derivatives was attempted using both Suzuki and Kumada methods, but were not successful.

Keywords: procyanidin synthesis,catechin oligomers,boronic acids,C8-boronic acid catechin derivatives,C8-organometallic catechin derivatives,Negishi cross-couplings,Suzuki cross-couplings,procyanidin B3

Subject: Chemistry thesis

Thesis type: Doctor of Philosophy
Completed: 2010
School: School of Chemical and Physical Sciences
Supervisor: Mike Perkins