Abstract
The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.
Highlights
Galloyl catechins, such as (À)-epicatechin gallate (ECg), (À)-epigallocatechin gallate (EGCg) and (À)-catechin gallate (Cg) are natural polyphenols, which constitute around 10% of the dry leaf weight of the green tea plant Camellia sinensis.[1]
Our previous synthesis of these compounds, which was developed by Chan,[11] introduced the desired stereochemistry using a Sharpless dihydroxylation followed by a four-step cyclisation (Scheme 1).[7,8]
Natural EGCg can be readily synthesised using a Mitsunobu cyclisation to form ring C to give the catechin followed by an oxidation and reduction to give the epicatechin.[12]
Summary
Galloyl catechins, such as (À)-epicatechin gallate (ECg), (À)-epigallocatechin gallate (EGCg) and (À)-catechin gallate (Cg) are natural polyphenols, which constitute around 10% of the dry leaf weight of the green tea plant Camellia sinensis.[1]. Dihydroxy B-ring 2 ECg analogues sensitized MRSA strains to the blactam antibiotic oxacillin to a comparable extent compared to the natural product, the complete deletion of all B-ring hydroxyl groups gave a compound 3 that displayed an enhanced capacity to reduce oxacillin resistance in EMRSA-16 (Fig. 1).[8] Complete deletion of A and B ring hydroxyl groups in either epicatechin 4 or catechin (À)-5 resulted in a reduction in b-lactam resistance-modifying potential and an increase in intrinsic anti-staphylococcal activity, with the catechin derivative (À)-5 showing an enhanced effect. We report an improved synthesis of these analogues, as well as the synthesis of the novel enantiomer of (À)-5 [(þ)-5], which we have used in further studies of our own[9] and we hope will be of use to others investigating the wide range of other biological effects exhibited by catechins in general.[10]
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