145455-05-6Relevant articles and documents
Mechanism and Stereochemistry of the Enzyme-catalysed Formation of a 2,2-Dimethylchromene Ring from a Prenylated Phenol: Conversion of Rot-2'-enonic Acid into Deguelin by Deguelin Cyclase
Bhandari, Prabha,Crombie, Leslie,Harper, Mark F.,Rossiter, John T.,Sanders, Mark,Whiting, Donald A.
, p. 1685 - 1698 (2007/10/02)
The stereochemistry of the enzymic conversion of rot-2'-enonic acid into deguelin, mediated by deguelin cyclase, has been studied.Using both an enzyme preparation and seedlings of Tephrosia vogellii, it is shown that (6aS,12aS,5'R/S)-5-hydroxy-4',5'-dihydrodeguelin is not an acceptable intermediate: no evidence for other oxygenated intermediates was found.The (pro-R)- and (pro-S)-6'-methyl groups of deguelin were identified by synthesis from rot-2'-enonic acid.Addition of benzeneselenenyl chloride gives two diastereoisomeric 5'-(phenylselenides) of 4',5'-dihydrodeguelin which are separated and their stereochemistry established by X-ray crystallography.Elimination of selenoxide from the (5'S)-stereoisomer then gives (6'R)-deguelin (δC 28.20): (6'S)-deguelin has δC 28.52.Although a chemical conversion of rot-2'-enonic acid into labelled deguelin produces a 1:1 distribution of label between the (pro-R)- and (pro-S)-6'-methyls, the enzyme-mediated conversion results unexpectedly in a 76percent incorporation into the (pro-R)- and 24percent into the (pro-S)-form.The stereochemistry of the removal of the key 1'-hydrogens in rot-2'-enonic acid was therefore examined.Addition of benzenesulfenyl chloride to deguelin gave a highly reactive chloro sulfide by syn-addition through attack from the less hindered β-face of the molecule.Treatment with sodium cyanoborohydride displaced the reactive chlorine with complete inversion to give (6aS,12aS,5'S)-5'-phenylthio-4',5'-dihydrodeguelin.Ring-E scission of the latter proceeded satisfactorily using sodium naphthalenide only after reduction of the 1,2-carbonyl to the alcohol: periodinane oxidation then produced rot-2'-enonic acid.Replacement of the unlabelled cyanoborohydride by cyanoborotritide gave the desired (6aS,12aS,1'S)-rot-2'-enonic acid.The (6aS,12aS,1'R)--counterpart was made by first preparing deguelin by syn-elimination from the sulfoxide formed from (6aS,12aS,4'R,5'S)-5'-phenylthio-4',5'-dihydro-deguelin.Addition of benzenesulfenyl chloride to the deguelin, followed by a sequence parallelling that above, using unlabelled sodium cyanoborohydride, gave the required (6aS,12aS,1'R)-rot-2'-enonic acid.Enzymic conversion of each -labelled rot-2'-enonic acid into deguelin along with a -labelled monitor, shows that a 73percent loss of (pro-4'S-H) in rot-2'-enonic acid correlates with a 76percent attainment of a (pro-6'R-Me) in deguelin, whilst a 27percent loss of (pro-4'R-H) in the former correlates with a 24percent attainment of a (pro-6'S-Me) in the latter.The possible enzymic mechanism of the reaction is discussed and related to a similar mechanism we have suggested for the enzymic formation of rotenone from rot-2'-enonic acid.
