Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis

Abstract

Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition-metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium-catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π-σ-π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between β-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched-linear >99:1, up to 99% enantiomeric excess).

Figure 1.

Bioactive molecules containing α-trisubstituted α-tertiary amines.

Figure 2.

(A) Regioselective synthesis of linear α-tertiary amines and asymmetric synthesis of α-disubstituted-α-tertiary amines. (B) Asymmetric synthesis of α-trisubstituted-α-tertiary amines.

Figure 3.

(a) Transition-metal-catalyzed enantioselective synthesis of α-disubstituted-α-tertiary amines. (b) Challenges associated with enantioselective synthesis of α-trisubstituted-α-tertiary amines. (c) Reaction design and development.

Figure 4.

Experimental mechanistic studies (a–c) and (d) proposed the mechanism of Rh-catalyzed asymmetric synthesis of α-trisubstituted-αtertiary amine.

Figure 5.

Substitution of enantioenriched deuterium-labeled trichloroacetimidate substrates.

Figure 6.

Possible modes of rhodium coordination to allylic trichloroacetimidate and formation of π-allyl complexes.

Figure 7.

Energy profile for the asymmetric synthesis of α-trisubstituted-α-allylic amine. Free energies (kcal/mol) were computed using PBE1PBE/6–311+G(d,p) (diethyl ether).

Figure 8.

(A) Transition state for major branched (S)-7 and linear product. (B) Transition state for minor branched (R)-7 and linear product.

Figure 9.

Relative energies of amine addition to the γ-oxygen-substituted substrate. Free energies (kcal/mol) were computed using PBE1PBE/6–311+G(d,p) (diethyl ether)

Scheme 1.

Investigation of Reactions of Allylic Substrates 5 and 1a with Aniline 6

Scheme 2.

Rhodium-Catalyzed Asymmetric Amination with γ-Oxygen-Substituted Tertiary Allylic Trichloroacetimidate