CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications

Abstract

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis, but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of product. A stereochemical model is provided to explain the high diastereo-and enantioselectivity of this process. Finally, this method was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

Engaging Aldehydes in CuH‐Catalyzed Reductive Coupling Reactions: Stereoselective Allylation with Unactivated 1,3‐Diene Pronucleophiles

“…By analogy to other copper‐catalyzed reductive olefin–ketone and olefin–imine coupling reactions, we proposed that the current reaction proceeds through the mechanism illustrated in Figure C. Previous computational and experimental investigations of related transformations have revealed, in intricate detail, the sequence of events and controlling factors that dictate the regio‐, diastereo‐, and enantioselectivity observed in these transformations . However, we were interested in several questions pertaining to the mechanism and selectivity that are particular to this aldehyde allylation.…”

“…We initiated our study by examining reactions of p ‐anisaldehyde ( 1 a ) and 2‐phenyl‐1,3‐butadiene ( 1 b ) under reaction conditions previously described for CuH‐catalyzed ketone allylation (Table ) . With ( S , S )‐QuinoxP*( L1 ) as the ligand, the desired product 1 was obtained in 48 % yield, with exclusive branched‐selectivity and excellent preference for the indicated diastereomer (11:1 dr; entry 1).…”

“…No desired homoallylic alcohol 1 was obtained when ( R )‐DTBM‐SEGPHOS ( L2 ) was used as the ligand: complete reduction of the aldehyde was observed instead (entry 2). JosiPhos derivative SL‐J011‐1 ( L3 ), a ligand which had been employed with good results in ketone allylation, was also examined. The corresponding test reaction provided 1 in moderate (57 %) yield, with 8:1 dr and 85:15 er (entry 3).…”

“…Based on previous mechanistic studies, we envisioned that our proposed transformation would proceed through hydrocupration of a diene to generate a mixture of allylcopper complexes represented by II (Figure C). One or more of these species could engage an aldehyde coupling partner in a stereoselective migratory insertion process to form the copper alkoxide III , from which metathesis with a hydrosilane ( IV ) would regenerate LCuH ( I ) and the desired product ( V ) in silyl‐protected form.…”

Switch in Selectivity for Formal Hydroalkylation of 1,3‐Dienes and Enynes with Simple Hydrazones

“…[12] In other words,a tl east six different regioisomers can be potentially formed during the addition of NuÀHacross aterminal diene,and the selectivity of the newly formed bonds depends on either the Markovnikov or anti-Markovnikov selectivity for internal addition, terminal 1,2addition, or conjugate 1,4-addition (Scheme 1a). [13][14][15][16] Recently our group [17] and that of Zhou [18] independently communicated an ickel-catalyzed 1,2-Markovnikov hydroalkylation [19] of 1,3-dienes with umpolung carbonyls to generate branched allylic compounds (Scheme 1b). In these reactions,anickel hydride species is generated and reacts with the diene to generate an electrophilic nickel-p-allyl intermediate (hydride adds preferentially to the less sterically hindered terminal olefinic carbon center;S cheme 1c,l eft).…”