Iridium‐Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols

Abstract

Undoubtedly, the catalytic asymmetric isomerization of allylic amines into enamines stands out as one of the most accomplished and well-studied reaction in asymmetric catalysis as illustrated by its industrial application. [1,2] In contrast, the related asymmetric isomerization of primary allylic alcohols to the corresponding aldehydes still constitutes a significant challenge in organic synthesis. [2] Successful examples of highly active and selective catalysts for this transformation remain rare and rely almost solely on the use of chiral rhodium complexes. [3] Furthermore, high catalyst loadings, elevated temperatures, long reaction times, poor catalyst accessibility, and limited substrate scope have prevented widespread use of this method. We have recently shown that the hydrogenation catalyst [Ir(PCy 3 )(pyridine)(cod)]BAr F 4 1 (Cy = cyclohexyl, cod = 1,5-cyclooctadiene, BAr F 4 = tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate) promoted exclusively the isomerization of primary allylic alcohols under appropriate experimental conditions (Scheme 1). [4] Very low loadings of this analogue of Crabtrees catalyst were used to quantitatively isomerize a wide range of substrates at room temperature with appreciable reaction rates. On one hand, the mild reaction conditions appeared well-suited for studying the asymmetric version of the reaction. On the other hand, any variation of the electronic and steric requirements of 1 induced a complete loss of catalytic activity, suggesting this might impose severe constraints on the design of related chiral complexes. Herein, we report the identification of a highly active and selective iridium catalyst for the asymmetric isomerization of primary allylic alcohols into the corresponding chiral aldehydes.Initial investigations began with a survey of known chiral (P,N) iridium complexes which have been shown to be highly active and selective catalysts in the asymmetric hydrogenation of olefins (2-6 a, Figure 1). [5][6] Reactions were carried out on the model substrate 7 in THF at room temperature for 18 hours using 5 mol % of the precatalyst (Table 1, entries 1-5). The iridium complexes were activated by slowly bubbling hydrogen directly through the solution for 5 minutes. To favor isomerization and to avoid competing hydrogenation, the substrate was added only after complete extrusion of excess hydrogen by degassing the solution. Whereas complexes 2-4 did not display any catalytic activity, the pyridyl/phosphinite catalyst 5 afforded 19 % of the aldehyde 8, albeit in a nearly Scheme 1. Iridium-catalyzed isomerization of primary allylic alcohols. Figure 1. Scope of iridium catalysts investigated. Cy = cyclohexyl, Ad = adamantyl.

Ruthenium‐Catalyzed Tandem‐Isomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols

“…Furthermore, several asymmetric isomerization protocols for the generation of enantiomerically enriched aldehydes and ketones have been developed, in which the stereogenic centers are in close proximity to the newly formed carbonyl functionality. [11][12][13][14][15][16][17] Transfer hydrogenations of unsaturated compounds are operationally simple and safe alternatives to reductions using ex-plosive molecular hydrogen or moisture-sensitive hydride reagents. [18][19][20] Asymmetric transfer hydrogenation (ATH) of prochiral ketones provides enantiomerically enriched products under relatively environmentally friendly conditions.…”

Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminium to β,γ‐Unsaturated α‐Ketoesters

“…To complement our previous work with a,b-unsaturated aldehydes, [19] we decided to apply a simple derivatization procedure to obtain the corresponding chiral b-substituted aldehyde. The groups of Feringa, [24] Hoveyda, [25] Palomo, [26] and Mazet [27] have already developed alternative methodologies to obtain this type of product but the yield, regio-and/or enantioselectivity left room for improvement. A two-step, reduction/ oxidation [28] procedure was applied to the synthesis of (S)-florhydral.…”

Ruthenium(IV)‐Catalyzed Isomerization of the CC Bond of O‐Allylic Substrates: A Theoretical and Experimental Study

“…Several metal complexes, mainly of Groups [8][9][10], that can promote this redox process have been described to date, [4] and the most recent advances are focused on the development of asymmetric versions, tandem processes, and its application in total syntheses. [5] In this sense, the metal-catalyzed isomerization of an allylic alcohol moiety, as a key step in the enantioselective synthesis of the naturally occurring pheromones muscone [5a] and (+)-iso-exo-brevicomin, [6a] and the marine alkaloid (À)-brevisamide, [6b] has already been reported in the literature. From a mechanistic point of view, the catalytic isomerization of allylic alcohols is based on the well-known ability of transition-metal complexes to assist the migration of carbon-carbon double bonds; [7] that is, the catalyst turns the allylic alcohol into an enol which readily tautomerizes to the corresponding carbonyl compound.…”