Chiral 2-(2-hydroxyaryl)alcohols (HAROLs) with a 1,4-diol scaffold as a new family of ligands and organocatalysts
Introduction
Chiral compounds in enantiomerically pure form are intensely desired due to the fact that not only biological systems, in most cases, recognize a pair of enantiomers as different substances, but also enantiopure molecules offer new opportunities as functional materials.1, 2 Over the last three decades, catalytic asymmetric synthesis has proven to be the most efficient tool for providing pure enantiomers. Consequently, the development of novel chiral compounds, especially for catalytic applications, continues to be a most vibrant field of research.1 In this regard, enantiomerically pure diols, such as TADDOLs,3 hydrobenzoins4 as well as BINOLs,5 have played a significant role in enantioselective catalysis and materials science2, 4, 6 as chiral ligands, organocatalysts, chiral luminophores etc. Whereas the majority of works with chiral diols have dealt with their use as chiral ligands in combination with metals in asymmetric catalysis,3, 4, 5, 7 there have also been some reports in which chiral diols themselves serve as suitable hydrogen-bond donor (HBD) organocatalysts for certain asymmetric transformations.8, 9 For instance, chiral diols have been reported to perform in some reactions with a high degree of activity and enantioselectivity, such as the Morita-Baylis-Hillman reaction,9a,b epoxide ring-opening,9c,d hetero Diels-Alder reactions,9e-i aldol-type reactions,9k,l as well as some other transformations.9m,n As such, diols have become an appealing structural motif for organocatalysis in recent years.10, 11
Xu and his co-workers recently reported the synthesis of chiral Ar-BINMOLs (1,1′-binaphthalene-2-α-arylmethan-2′-ols) possessing both axial and sp3 point chirality (Fig. 1)12 which were shown to be efficient and highly enantioselective chiral ligands for the asymmetric 1,2-addition reactions of some organometallic compounds to aldehydes.13, 14, 15, 16, 17, 18 In some cases, up to >99% enantiomeric excesses were achieved for the 1,2-addition of organozinc,14 organolithium,15 organomagnesium,16 and organoaluminum17 reagents to aldehydes by employing a catalytic amount of ArBINMOLs (e.g. 5 mol%) and a super-stoichiometric amount of Ti(OiPr)4 (e.g. 2.50–6.00 equiv). Additionally, Xu and co-workers demonstrated that chiral ArBINMOLs can also act as supramolecular HBD organocatalysts for the enantioselective Michael addition of anthrone to (E)-β-nitrostyrene, furnishing the corresponding adduct in good yields, albeit moderate enantiomeric excesses were detected.14 Despite their utility as catalysts, ArBINMOL-type structures are rather limited to the 1,1′-binaphthalene-unit, due to the synthetic approach developed. On the other hand, a modular synthesis of targets is regarded as a very advantageous approach, because it leads to the generation of a library of compounds with structural diversity, thereby enhancing the hit rate of the purpose.19 Encouraged by the remarkable successes of ArBINMOLs as chiral ligands and by the potential catalytic applications of diols in general, we set out to prepare new chiral 1,4-diols possessing one phenolic and one alcohol hydroxyl (-OH) group. Herein, we report efficient and modular syntheses of structurally-diverse 2-(2-hydroxyaryl)alcohols (HAROLs) as well as their use as chiral ligands and organocatalysts (Fig. 1).
Section snippets
Results and discussion
In our previous work, we reported on the regioselective ring-opening of epoxides with ortho-lithioanisoles in the presence of BF3·OEt2 as the Lewis acid catalyst (Scheme 1).20 This method enabled us to prepare 2-(2-methoxyaryl)alcohols (5 and 6) in high yields and regioselectivities. It was also shown that the enantiomerically pure 2-(2-methoxyaryl)alcohols 5a and 6a could be obtained by employing (R)-(+)-styrene oxide (4a). Thus, the protected form of 2-(2-hydroxyaryl)alcohols (HAROLs) could
Conclusion
In summary, we have devised two efficient synthetic routes to chiral 2-(2-hydroxyaryl)alcohols (HAROLs), new 1,4-diols carrying a phenolic and an alcohol hydroxyl group: The first route is based on the regioselective ring-opening of enantiopure (R)-styrene oxide with ortho-lithioanisoles as the key transformation, whereas the second route comprises palladium-catalyzed α-arylation of ketones with ortho-bromoanisoles (Buchwald-Hartwig α-arylation) and the enantioselective reduction of the
General
All air-sensitive reactions were performed under an inert atmosphere of dry nitrogen (N2) using oven-dried glassware. All reagents and solvents were transferred using gas-tight syringe and cannula techniques under N2. Reactions were monitored by thin layer chromatography (TLC) on aluminum sheets that were pre-coated with silica gel SIL G/UV254 from MN GmbH & Co., in which the spots were visualized in UV-light (λ = 254 nm) and/or by staining with phosphomolybdic acid solution in EtOH (10%, w/v).
Acknowledgements
This work was financially supported by the Scientific and Technological Research Council of Turkey (TÜBITAK, project 111T597). We are indebted to Dr. Nilüfer Erdem and Gülçin Haykır for mass spectrometric measurements.
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