Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, we introduce a novel [Cp*Ru(MeCN)3]PF6/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions. The approach is demonstrated for a broad scope of tertiary electrophiles as well as ester enolates and accomplishes stereoretentive substitution with excellent conservation of ee (89–99%) and branched/linear regioselectivities (up to 40:1).

T ransition metal-catalyzed allylic and related allenylic substitution reactions have found widespread application in enantioselective synthesis for a broad range of settings.These reactions have been deployed for the stereocontrolled construction of carbon−heteroatom (−N, −O, −S) as well as carbon−carbon bonds, 1 with some methods providing access to quaternary centers. 2 The stereocontrolled synthesis of fragments that incorporate vicinal quaternary centers remains a significant challenge both for the general field of asymmetric synthesis 3 and also, specifically, in transition metal-mediated allylic substitution reactions. 4In general, the field has been dominated by catalysts derived from Pd, 5 Ir, 6 and Rh. 7 Herein, we present the first enantiospecific Ru-catalyzed substitution of tert-butyl allyl carbonates with lithium ester enolates.The use of this underrepresented class of nucleophiles provides access to products that feature vicinal quaternary centers (Scheme 1).A novel feature of our approach is the direct use of ester enolates in combination with Ru catalysis in allylic substitution reactions.The catalyst is conveniently generated in situ from [Cp*Ru(MeCN) 3 ]PF 6 and phenoxythiazoline L1. 8 The enantiospecific transformation delivers optically active adducts for a broad range of α,α-disubstituted ester enolates and tertiary allylic electrophiles.
The stereocontrolled synthesis of quaternary centers continues to challenge organic chemists, especially for the construction of complex scaffolds as encountered in many natural products and bioactive molecules. 9This challenge is further compounded for targets featuring vicinal quaternary centers, 3 as exemplified by lingzhiol, 10 cuparenone, 11 and trichodiene. 12Although asymmetric allylic substitutions have been broadly applied to the synthesis of methine and quaternary centers, 2 access to vicinal quaternary centers is limited (Scheme 2).In the field, the synthesis of acyclic vicinal quaternary centers has been perceived as a particular challenge. 13Asymmetric allylic substitutions based on Pd and Ir catalysts have been utilized for the synthesis of acyclic-cyclic vicinal quaternary centers.4a−d,g Two reports have demonstrated the synthesis of products incorporating acyclic-acyclic vicinal quaternary centers.In a study of the regiochemistry of Ru-catalyzed allylic substitutions of secondary allylic esters and carbonates, Kawatsura and Itoh included as a singular example a reaction that gave acyclic vicinal quaternary centers with a malonate as nucleophile.4h In 2018, Stoltz reported the first enantioselective allylic substitution reaction leading to acyclic vicinal quaternary centers using an Ir catalyst with malononitriles and substituted cinnamyl carbonates.4e Additionally, Ircatalyzed asymmetric synthesis has been demonstrated for related allenylic systems from silyl ketene acetals 14 and racemic allenylic alcohols. 15ransition metal-catalyzed allylic substitutions are effected predominantly with nucleophiles such as malonates, malononitriles, and β-ketoesters. 16By contrast, there are few reports on the direct use of less stabilized enolates, such as ester enolates. 17Our long-standing interest in Ir-catalyzed allylic substitutions has compelled us to explore alternative metals.We reasoned that the use of new catalyst systems could expand the scope of nucleophiles, electrophiles (nonbenzylic), and thereby products.We were particularly attracted to Ru because it is relatively underexplored in enantioselective allylic substitutions compared to Pd and Ir.1c,18 Furthermore, we wanted to investigate the application of nonstabilized ester enolates and tertiary allylic electrophiles as the latter are also underrepresented in asymmetric allylic substitutions.
Thioethers are known ligands for transition metal catalysts such as Ru which they often bind irreversibly. 29Accordingly, we were curious whether thioether 1e would also be compatible with the catalyst.We subjected thioether 1e to the reaction conditions.The corresponding coupling product 4e was formed in 54% yield, 3:1 b/l, and excellent >99% ee.Frequently encountered bulky protecting groups such as the TIPS ether in 1f were compatible with the method.Tertiary benzylic substrate 1g was very well tolerated and provided 4g in 92% yield, 40:1 b/l, and 98% ee.Commonly found terpenoid linalool-derived 1h and diterpenoid sclareol-derived 1i were successfully coupled with ester enolate 2a.This afforded product 4h in 76% yield and 89% ee as well as 4i in 76% yield as a single diastereomer.We were able to extend the Ru-catalyzed allylic substitution to cyclic electrophiles.Tertiary carbonate 1j provided cyclopentene 4j featuring cyclic-acyclic vicinal quaternary centers.Heterocyclic and highly polar theobromine derivative 1k was compatible and provided product in 62% yield and 40:1 b/l.
It is generally accepted 4h,26,30 that Ru-mediated allylic substitution reactions proceed in analogy to the double inversion mechanism described for Pd 31 and Ir. 32To the best of our knowledge, the stereochemical features of the oxidative addition of Ru II to allylic electrophiles have not been studied.With that in mind, we set out to investigate the reaction of cyclic, diastereomeric carbonates 1l and 1m.Interestingly, the two diastereomers exhibited strikingly different reactivities (Scheme 5).Carbonate 1l was unreactive under the standard conditions (−20 °C), however, conducting the reaction with 1l at room temperature led to the formation of 4l in 51% yield as a single diastereomer.Remarkably, 1m did not react at all, even at 40 °C, and the starting material was fully recovered.This observation suggests that for 1m, formation of an allyl complex is not possible under the reaction conditions.We hypothesize that stereoinvertive oxidative addition to the pseudoaxially oriented 33 C−O bond proceeds for half-chair 1l but is blocked by the adjacent isopropenyl group in half-chair 1m.Hence, the differential reactivity of 1l and 1m further supports a double inversion mechanism to be operative, which accounts for the stereochemical net retention observed in Ru-catalyzed allylic substitution reactions.
In conclusion, we have developed a novel catalyst based on the combination of [Cp*Ru(MeCN) 3 ]PF 6 and phenoxythiazoline ligand L1 for the enantiospecific coupling of lithium ester enolates and tertiary allylic carbonates.The approach provides products featuring vicinal quaternary centers (acyclic-acyclic) in high yields, excellent ee (89−99%), and b/l ratios up to 40:1.Because the method is not limited to benzylic electrophiles as starting materials, a wide spectrum of highly congested products can be accessed.Finally, the results we describe provide fresh opportunities for the development of asymmetric allylation reactions that go beyond the traditional metals employed in the area to include ruthenium.■ ASSOCIATED CONTENT Scheme 5. Allylic Substitution Reaction of Cyclic, Diastereomeric Electrophiles a Allylic carbonate 1l-1m (0.2 mmol), [Cp*Ru(MeCN) 3 ]PF 6 (5 mol %), phenoxythiazoline L1 (15 mol %), lithium ester enolate 2a (3 equiv, 0.9 M in 1.5:1 hexane−THF), CH 2 Cl 2 (0.2 M), −20 °C.After 1 h at −20 °C, the reaction was warmed to 23 °C, additional 2 equiv of 2a were added, and stirring was continued for 20 h.For 1m, the reaction was further warmed to 40 °C and stirred for 3 h.Isolated yields are provided.b 4l was formed as a single diastereomer.

Scheme 3 .
Scheme 3. Scope of Lithium Ester Enolates for the Ru-Catalyzed Allylic Substitution Reaction a

Scheme 4 .a
Scheme 4. Scope of Enantioenriched Electrophiles for the Ru-Catalyzed Allylic Substitution Reaction a