Asymmetric Guerbet Reaction to Access Chiral Alcohols

Abstract

The first example of an asymmetric Guerbet reaction has been developed. Using commercially available, classic Noyori RuII‐diamine‐diphosphine catalysts, well‐known in asymmetric hydrogenation, racemic secondary alcohols are shown to couple with primary alcohols in the presence of a base, affording new chiral alcohols with enantiomeric ratios of up to 99:1. Requiring no reducing agents, the protocol provides an easy, alternative route for the synthesis of chiral alcohols. Mechanistic studies reveal that the reaction proceeds via a Ru‐catalyzed asymmetric hydrogen autotransfer process in concert with a base‐promoted allylic alcohol isomerization.

Anti‐Markovnikov Hydroamination of Racemic Allylic Alcohols to Access Chiral γ‐Amino Alcohols

“…Based on our previous studies [10q, 12] and the literature, [11] the mechanism of this asymmetric hydroamination may be similar to that of the previously reported formal anti‐Markovnikov hydroamination of allylic alcohols [11–12] . As illustrated in Figure 1 d, the chiral Ru catalyst is likely to dehydrogenate the allylic alcohol to afford a Ru hydride complex and an α,β‐unsaturated ketone intermediate, which undergoes aza‐Michael addition to give a β‐amino ketone intermediate.…”

“…We recently showed the feasibility of formal anti‐Markovnikov hydroamination of allylic alcohols with an achiral iron catalyst via hydrogen borrowing [12] . Our further work using a similar approach has revealed that the Guerbet reaction can be made enantioselective with a chiral Ru‐diamine‐diphosphine catalyst, in which an intermediary ketone is reduced to a chiral alcohol product [10q] . We envisioned that such chiral Ru‐diamine‐diphosphine catalysts could be utilized for the formal hydroamination of racemic secondary allylic alcohols, which would produce chiral γ‐amino alcohols (Figure 1 d).…”

“…The initial results are indeed encouraging. With the Noyori catalyst [14] 3 a (1 mol %), which was used for the asymmetric cross coupling of alcohols in our previous study, [10q] the desired product 4 a was obtained in 97 % ee , albeit with a low yield of 10 %, in the presence of 0.5 equivalent of K 3 PO 4 in toluene at 30 °C for 12 h under Ar (Table 1, entry 1). Similar results were obtained with another Noyori catalyst 3 b [14] (Table 1, entry 2).…”

“…The absolute configuration of 4 a was determined to be S by X‐ray crystallography. The solid state structure indicates that there exists a hydrogen bonding interaction between the OH moiety and the γ‐N atom (The O−H⋅⋅⋅N distance is 2.080 Å), which, along with the enhanced steric bulkiness in the product, may explain why the reverse dehydrogenation of the product appears to be negligible, unlike the Guerbet reaction [10q] …”

Asymmetric Guerbet Reaction to Access Chiral Alcohols

“…[b] The enantiomeric ratio (er) was determined by HPLC analysis of pure isolated product, and the absolute configuration was determined by X-ray crystallography. [26] [c] R-4a was the major product.…”