Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling
Résumé
In the presence of a chiral iridium complex, commercially available 3-chloro-2-chloromethyl-1-propene (1) was selectively activated for various reductive couplings. Depending on the reaction conditions it allows a selective mono-or bidirectional condensation with one or two external aldehydes with excellent enantiocontrol (>90% ee). This approach occurring simply under mild conditions and avoiding premetalated reagents constructs rapidly chiral homoallylic alcohols, key precursors of important molecular fragments such as furans, pyrans, ketodiols, or 1,3,5-polyols. A ssembling simple building blocks into elaborate complex chiral chemical architectures with good stereocontrol while limiting waste generation represents a priority for modern organic synthesis. 1 Notably, the discovery of greener and easy to use enantioselective catalytic methods should enhance the application potential of organic transformations facilitating their transposition in the synthesis of elaborated drugs or materials. Among crucial synthetic building blocks necessary for the construction of divers chemical architectures, homoallylic alcohols 3 and 4 stand out (Scheme 1.a). They constitute privileged precursors for the synthesis of molecular patterns found in a number of natural products and drugs. For example, 3 provides a direct access to furans and pyrans while preparation of 4 constitutes a straightforward route to keto-diols, 1,3,5-polyols or spiroketals (Scheme 1b). 2 As a result of this pivotal synthetic interest, numerous methods have been developed for their stereoselective preparation 3 mainly relying on stoichiometric metal activation and chiral additives. 4 The only chiral Lewis-acid-catalyzed strategy to access alcohols 3 from 1 involved allylic stannanes obtained after initial Cl−Li exchange. 5 Access to parent ketodiols A can also be based on bidirectional aldolization by condensing two molecules of aldehydes with a ketone equivalent, however the direct enantioselective variant on aliphatic aldehydes still represents a challenge. 6 As a result, it is clear that the development of a modular enantioselective catalytic synthesis of 3 and 4 starting f rom aliphatic aldehydes, occurring without the use of stoichiometric prematallated reagents and under mild conditions is highly desirable. To circumvent waste and hazards associated with the use of stoichiometric premetalated nucleophiles, the group of Krische has proposed a wide array of coupling reactions based on the concept of alcohol mediated carbonyl addition. 7,8 In a typical reaction, dehydrogenation of an alcohol by a catalytic metal complex (Ru or Ir) generates a carbonyl and a metal hydride. The formed metal hydride then inserts in the allyl pronucleophile, forming a reactive metal−allyl complex able to stereoselectively add to an electrophilic carbonyl generating the desired chiral alcohol. This type of reductive coupling is illustrated in Scheme 1c where two allyl donors 5 are condensed to a pivotal 1,3-diol 6, providing enantioenriched diols 7. 9 Interestingly, this reductive coupling chemistry can be performed by starting from an alcohol or from an aldehyde. In the latter case, addition of an environmentally friendly reductant such as 2-propanol initiates the formation of the required catalytic metal-hydride. Continuing with our interest on bidirectional condensations, we hypothesized that 2-propanol might be used to activate commercially available 3-chloro-2-(chloromethyl)-1-propene (1)
Domaines
Chimie organique
Origine : Fichiers produits par l'(les) auteur(s)
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