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