Background and Originality Content
Transition metal-catalysed isomerization of alkenyl alcohols has emerged as a powerful synthetic method, gaining widespread recognition and adoption over the past few decades.[1] This efficient process, relying on the isomerization of C=C bonds, offers several distinct advantages, including atom and step economy, as well as sustainability. Various catalytic systems have been developed to facilitate this efficient isomerization towards β-chiral carbonyl compounds (Scheme 1a).[2] However, accomplishing the asymmetric sequential isomerization/transformation tandem reaction in a one-pot fashion has remained a formidable challenge in the field of organic synthesis. Only a few successful examples have been documented, primarily focusing on the asymmetric isomerization/intermolecular transformation of allylic alcohols (Scheme 1b),[3]with no previous reports of intramolecular cases.
Chiral dihydrocoumarin backbones are commonly found in numerous natural products and pharmaceuticals, making them ubiquitous structural components.[4] In recent years, significant advancements have been made in the construction of chiral dihydrocoumarins.[5]Despite these advancements, considering the vital role played by these heterocyclic compounds in both natural products and synthetic chemistry, more efficient and direct methods for the enantioselective synthesis of these compounds are greatly desirable. Inspired by the progress in the asymmetric isomerization/transformation of allylic alcohols and motivated by our ongoing research endeavors,[6] we set out to explore the possibility of a new intramolecular tandem transformation. In our design, the combination of asymmetric isomerization of primary allylic alcohols and a subsequent intramolecular cross-coupling step within a single synthetic sequence presented a unique opportunity to efficiently construct valuable chiral dihydrocoumarin backbones.
Scheme 1 Isomerization of alkenyl alcohols.
The key to realizing this process lay in finding a suitable transition metal catalyst capable of achieving asymmetric redox isomerization to generate a chiral β-substituted aldehyde intermediate in situ, while also promoting the subsequent ester formation reaction to yield the final target product. Ruthenium, a promising transition metal, has demonstrated high activity and stereoselectivity in catalysing asymmetric isomerization reactions.[7]Additionally, it is well-suited for a variety of cross-coupling reactions, significantly expanding the accessible chemical structures. In this communication, we present a ruthenium-catalysed asymmetric isomerization/intramolecular coupling reaction of allylic alcohols, resulting in the efficient synthesis of various chiral dihydrocoumarins (Scheme 1c).
Results and Discussion
We initiated an exploration of the intramolecular tandem reaction using 2-(3-hydroxy-1-phenylprop-1-en-1-yl)-5-methoxyphenol 1a as the model substrate. In the presence of Ru(cod)Cl2 (5 mol%), 2,2,6,6-tetramethylpiperidine (TMP) (2.0 equiv.) as the base, and chiral diphosphine L1 (6 mol%) as the ligand, the isomerization/intramolecular esterification reaction can be achieved, and the desired lactone product 2a could be ultimately obtained in an impressive 83% yield, albeit with a low enantiomeric excess (ee) of 14% (Table 1, entry 1). Encouraged by this promising outcome, we expanded our investigation to encompass a range of commercially available chiral phosphine ligands, including phosphoramidites and bidentate phosphorus ligands. Gratifyingly, the application of the chiral phosphoramidite ligand L2 facilitated the smooth formation of 2a , affording a 58% yield with commendable enantioselectivity
Table 1 Summary of selected optimization of reaction conditions