Kinetic Resolution of α‐Substituted Alkanoic Acids Promoted by Homobenzotetramisole

Abstract

A new method for catalytic nonenzymatic kinetic resolution of α-substituted alkanoic acids has been developed, which relies on their activation with DCC followed by enantioselective alcoholysis of the intermediate symm-anhydrides in the presence of the amidine-based catalyst homobenzotetramisole (HBTM). Moderate to excellent selectivity factors (s=5-96) have been obtained in the case of several classes of substrates, namely, α-aryl-, α-aryloxy/alkoxy-, α-halo-, α-azido-, and α-phthalimido-alkanoic acids. Under similar conditions, α-(arylthio/alkylthio)-alkanoic acids undergo dynamic kinetic resolution providing corresponding esters in up to 92% ee and up to 93% yield.

Manifestation of Felkin–Anh Control in Enantioselective Acyl Transfer Catalysis: Kinetic Resolution of Carboxylic Acids

“…(4a) and (4b)], then the energy differences between the diastereomeric transition states may lead to alternative modes of diastereoselectivity, as illustrated in Scheme . Computational studies reported herein, combined with our recent experimental results,4a,c,d demonstrate that stereoelectronic effects indeed play a key role in controlling the enantioselectivity of catalytic, asymmetric alcoholysis of α‐substituted acyclic anhydrides. Although the venerable Felkin–Anh model has been the subject of many theoretical investigations,5 to the best of our knowledge, this is the first one extending its scope to stereochemical analysis of nucleophilic acyl substitution.…”

“…M06‐2X18 single‐point calculations indicated that 7 a ‐TS1 is favored over 7 b ‐TS1 by 3.2 kcal mol −1 , which is consistent with our experimental observation that the ( S ) ‐ enantiomer of α‐chloropropionic acid reacts faster than the ( R )‐enantiomer in the presence of ( S )‐HBTM. In a similar manner, we examined the two analogous diastereomeric transition states 8 a ‐TS1 and 8 b ‐TS1 derived from ( R )‐BTM (Figure 2) and obtained almost the same results, which is in accord with essentially the same enantioselectivities obtained with BTM and HBTM in the KR of α‐chloropropionic acid (selectivity factors 23 and 21, respectively, were obtained using di(1‐naphthyl)methanol) 4d. 19…”

“…Replacing diphenylmethanol with benzyl alcohol in transition states 7 a ‐TS1 and 7 b ‐TS1 and re‐optimization of the geometry resulted in a slightly decreased activation free energy difference (ΔΔ G ≠ ; 3.0 vs. 3.2 kcal mol −1 ), in accord with the lower enantioselectivities obtained using the less bulky alcohol. Analogous calculations using di(1‐naphthyl)methanol produced a larger free energy difference (4.4 kcal mol −1 ), which is consistent with its superior performance in kinetic resolution 4d. 20…”

“…reported that benzotetramisole (BTM) 1 6d is effective in promoting kinetic resolution (KR)9 of α‐arylpropionic acids. Subsequently, we demonstrated that a variety of heteroatom‐substituted carboxylic acids can be resolved with homobenzotetramisole (HBTM) 2 6h using the protocol illustrated in Scheme 4a,c,d. BTM 1 was also competent in most cases studied, albeit usually less active and enantioselective 10…”

“…Finally, we examined the origin of an additional general trend we had observed in our KR experiments: increasing the size of the R 1 group on the α‐carbon atom resulted in progressively lower enantioselectivities 4d. 21 It was difficult to predict a priori whether the fast‐ or the slow‐reacting diastereomer of the transition state would suffer greater destabilization by a bulkier R 1 group.…”