Enantioselective Synthesis of Flavan-3-ols Using a Mitsunobu Cyclization

Abstract

The synthesis of four flavan-3-ols with different substitution patterns and electron densities has been achieved in high stereo-and regioselectivity by a one-step Mitsunobu reaction from the corresponding diols, which were prepared by enantioselective Sharpless dihydroxylation of suitable olefins. The six-membered flavan-3-ols were the only cyclization products and the theoretically possible formation of five-membered rings during the Mitsunobu cyclization was not observed. The flavanols are important starting materials for the synthesis of dimers such as the procyanidins or other coupling products such as the flavan part of the potent DNA polymerase b inhibitor myristinin A. The enantioselectivities of both the Sharpless dihydroxylation and the Mitsunobu cyclization steps were monitored by chiral HPLC.Polyphenols are ingredients of agricultural products such as wine, tea, fruit, vegetables and herbal medicines, and play an important role due to their multitude of biological functions. 1 The specific interactions of polyphenols with biomolecules such as proteins have stimulated the search for new pharmaceutical entities derived from polyphenolic compounds. 2 Among them, flavanoids are considered to be particularly important secondary metabolites due to their antibacterial, 3 anticancer, 4 antioxidant 5 and antiviral 6 properties. Flavan-3-ols such as (+)-catechin (1) or their dimers such as procyanidin B3 (2; Figure 1) occur in fresh fruits, tea, cocoa and chocolate, 7 and have been shown to have beneficial effects on health. 8 Other kinds of bioactivity were recently discovered in the naturally occurring flavanoid myristinin A (3; Figure 1), which is a DNA polymerase b inhibitor capable of blocking the repair of DNA damage induced by clinically used damaging agents and thereby potentiates their cytotoxicity. [9][10][11][12][13] The key step in many syntheses of flavan-3-ols such as 13 is the Sharpless dihydroxylation 14 of diaryl propenes 10 to the diols 11. 12,15 In connection with an improvement of the myristinin A synthesis, 12 we now report on a new and shorter variation of the flavan-3-ol synthesis, using a Mitsunobu reaction for the one-step cyclization of phenolic diol precursors 12, as outlined in Scheme 1. In order to probe the generality of this one-step Mitsunobu cyclization, we conducted the reaction with four olefins 10a-d with different substitution patterns and electron densities, ranging from one to five oxygen substituents (Scheme 1). The flavan-3-ols thus prepared generally serve as precursors in procyanidin synthesis. 16 We started with the formation of chalcones 6a-d by Claisen-Schmidt condensation of 2-hydroxyacetophenones 4a-d with benzaldehydes 5a-d to afford chalcones 6a-d in nearly quantitative yields (Scheme 1). Deoxygenation of the ketones 6a-d to the olefins 7a-d was performed by employing ethyl chloroformate and sodium borohydride in a two-step sequence. 12,17 This procedure is shorter than the two-step hydrogenation-elimination procedure used by van Rensburg et al. 15 However, the ...

Monoamine oxidases inhibitors from Colvillea racemosa : Isolation, biological evaluation, and computational study

“…The 1 H and 13 C NMR spectroscopic data of 1 were similar to those of rhusopolyphenol E reported in the literature [25], but with different chiroptical data where the ECD spectrum of compound 1 exhibited negative Cotton effects at λ ( θ ) 219 (−2.36 × 10 3 ), 252 (−0.89 × 10 3 ), 271 (−0.62 × 10 3 ) nm. In order to determine the absolute configuration of 1 , it was converted to the corresponding flavanol using a Mitsunobu cyclization (Scheme 1) [26,27] which was identified as 3,7,4′-trihydroxyflavanone (garbanzol) by its NMR spectrum [28]. It has been reported previously that the six-membered flavan-3-ols were the only products of Mitsunobu cyclization and the theoretically possible formation of five-membered rings was not observed under the used conditions [27].…”

“…In order to determine the absolute configuration of 1 , it was converted to the corresponding flavanol using a Mitsunobu cyclization (Scheme 1) [26,27] which was identified as 3,7,4′-trihydroxyflavanone (garbanzol) by its NMR spectrum [28]. It has been reported previously that the six-membered flavan-3-ols were the only products of Mitsunobu cyclization and the theoretically possible formation of five-membered rings was not observed under the used conditions [27]. The assignment of the absolute configuration of garbanzol proceeded in two steps.…”

Improved synthesis of structural analogues of (−)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

“…The Mitsunobu cyclisation of requisite triols has been reported by Krohn to give (−)-catechin 18 . We repeated this reaction using both the known triols 8,18 synthesised using α-AD mix ® and β-AD mix ® to give cyclised compounds 12 and 13 19 .…”

Inhibitory and Activating Effects of Some Flavonoid Derivatives on Human Pyruvate Kinase Isoenzyme M2

“…In our study, the effect of 22 compounds including flavonoids and their building blocks on PKM2 enzyme activity was analyzed (Fig. ) . The results of the tested compounds are indicated in Table .…”