Dynamic Kinetic Transformation of Sulfinyl Chlorides:  Synthesis of Enantiomerically Pure C₂-Symmetric Bis-Sulfoxides

Abstract

Two modular and highly convergent approaches for the synthesis of both isomers of a large number of optically pure C(2)-symmetric bis-sulfoxides have been developed, and their scope and limitations have been assessed. The first one uses as intermediate diastereomerically pure C(2)-symmetric bis-sulfinate esters 6(S(S),S(S)) and 6(R(S),R(S)), obtained by dynamic kinetic resolution of ethane-1,2-bis-sulfinyl chloride 5. A single inducer of chirality, the glucose-derived DAG (diacetone-D-glucose) 1 is used for the enantioselective synthesis of both diastereomerically pure C(2)-symmetric bis-sulfinate esters, thanks to the opposite stereodirecting effect of pyridine and (i)Pr(2)NEt used to catalyze the reaction. The second approach is based on the copper-catalyzed oxidative coupling of optically pure lithiomethyl sulfoxides. Both isomers of a large number of methyl sulfoxides can be obtained in a convergent manner using (R(S))- and (S(S))-DAG methanesulfinate esters 8R(S) and 8S(S). Methanesulfinates 8R(S) and 8S(S) are also obtained in an enantioselective way by a dynamic kinetic resolution of methane sulfinyl chloride 24. The final bis-sulfoxides are obtained with enhanced enantioselectivities compared to the corresponding monomers, as a result of the Horeau effect which is operating in both approaches. A model based on the formation of pentacoordinated sulfur intermediate is proposed. This model can explain the dynamic kinetic resolution observed via Berry pseudorotations, without the commonly accepted in situ racemization of the starting material. The usefulness of the approaches is demonstrated by the preparation of complexes of Pd(II) and Ru(II) bearing bidentated chiral sulfoxides as ligands.

Titanium‐Catalyzed Tandem Sulfoxidation‐Kinetic Resolution Process: A Convenient Method for Higher Enantioselectivities and Yields of Chiral Sulfoxide

“…Recently, it has been shown that nucleophilic displacement of diastereomeric sulfinates, via dynamic kinetic resolution using DAGOH technology, [7] or stereochemically differentiating oxathiazolidine-2-oxide [8] with organometallic reagents provides highly enantiopure sulfoxides. Chiral oxaziridine derivatives with a camphor skeleton have also been used as chiral oxidants to afford sulfoxides in up to 96% ee.…”

How does the Achiral Base Decide the Stereochemical Outcome in the Dynamic Kinetic Resolution of Sulfinyl Chlorides? A Computational Study

“…[11][12][13] This interesting feature was found when the DAG method was initially tested in the synthesis of methanesulfinate esters [11] (see Table 1). Good yields and diastereoselectivities, up to 90 % and 96 % de, were obtained and the subsequent addition of Grignard reagents led to the formation of chiral sulfoxides with very high enantioselectivities (> 98 % ee).…”

“…The by-product of the DAGOH addition is HCl, which is neutralized with stoichiometric amounts of an organic base, like pyridine or triethylamine. The DAG method has been successfully used in the synthesis of C 2 -symmetric bissulfoxides [12,13] that have been applied as chiral ligands in asymmetric synthesis. [15,16] Other compounds with pharmacological and synthetic [17] interest have been obtained by means of this method as well.…”

“…Two relevant examples of this methodology are the Cinchona-assisted DKR [8][9][10] and the DAG synthetic method. [11][12][13] In the DAG method (see Scheme 1), a racemate of a sulfinyl chloride is transformed into a chiral sulfi- …”

Serial Ligand Catalysis: A Highly Selective Allylic C—H Oxidation.

“…When stoichiometric mixtures of 1-undecene, Pd(OAc) 2 , and 2 were heated and monitored by 1 H NMR, dimeric π-allylpalladium acetate complex A was observed in ca. 59% yield (eq 1).…”