Chiral amines represent an important structural motif present in many natural products and pharmaceuticals that bear important biological properties and medicinal value. In particular, α-tertiary amines (ATA) are a useful subset of this class and are defined as an organic amine having a nitrogen atom bound to a sp3-hybridized carbon that bears three additional carbon–carbon bonds1,2 (Fig. 1a). The asymmetric synthesis of chiral ATAs is a significant challenge, requiring either the formation of a C–C bond through the stereoselective addition of a carbon-based nucleophile to a ketimine3,4 or formation of a C–N bond by stereoselective substitution at a tertiary carbon-centre5. Potential methods for asymmetric C-nucleophile additions to ketimines are complicated by the fact that ketimines can exist as E- or Z-stereoisomers, where one diastereomer may be more selective than the other, and separation of the E/Z-isomers is typically not straightforward. As a result, diastereoselective synthesis of the ketimine is often required and limited to certain substrate classes having sterically differentiated R-groups on the ketimine to ensure high E/Z-selectivities. In contrast, enantioselective substitution at a tertiary carbon-centre with an amine nucleophile can be challenging due to competitive elimination processes from the basicity of the amine nucleophile and due to the similar steric size of three carbon-based substituents at the reacting carbon-atom. However, this can be somewhat circumvented through metal-catalysed asymmetric allylic alkylation reactions using amine nucleophiles to access α-chiral α-tertiary allylic amines6.

Fig. 1: Asymmetric Cu-catalysed propargylic amination (ACPA) enables stereoselective synthesis of chiral α-tertiary amines.
figure 1

a, Structural features of α-tertiary amines (ATA). R1, R2, R3 = C-aryl or C-alkyl. b, The developed ACPA process using modified pybox ligands. c, Small selection of results from the developed ACPA process. Boc, butyloxycarbonyl.

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Now, writing in Nature Chemistry, Feng Zhou, Xin Wang, Jian Zhou and co-workers7 report the development of an asymmetric Cu-catalysed propargylic amination (ACPA) of racemic tertiary propargylic electrophiles to access chiral α-tertiary propargylic amines in excellent enantioselectivities (Fig. 1b,c). The process can be characterized as a dynamic kinetic asymmetric transformation8 for the deracemization of easily prepared tert-butylcarbonyloxy-activated propargylic alcohols to propargyl ATAs. Furthermore, because the alkyne functional group represents a powerful synthetic archetype that can be reacted in many different chemical processes9, subsequent transformations of the products are demonstrated, giving access to a variety of useful chiral α-tertiary amine-containing synthons and heterocycles that are not easily accessible in a stereocontrolled way through other means.

While the ACPA reaction10 is a well-established method for the convenient and efficient synthesis of chiral propargylic amines having α-secondary stereogenic carbon-atoms, the analogous process to prepare ATAs is underdeveloped and has typically relied on specific electrophile classes to provide good enantioselectivities11,12. In an effort to make a more generalized ACPA system to access propargylic ATAs, F. Zhou, Wang, J. Zhou and co-workers focused on utilizing the pyridinebisoxazoline (pybox) scaffold (L1, L2, Fig. 1b) as the chiral ligand due to its ease of modification, allowing catalyst optimization to improve stereocontrol7. The pybox ligand required substitution at the oxygen-substituted carbon atom of the oxazoline ring to improve enantiocontrol through a presumed relaying effect, where this group can alter the orientation of the substituent at the nitrogen-substituted carbon atom of the oxazoline ring, making a more defined chiral pocket at the copper centre. However, more remote substitution at the para-position of the pyridine ring of the pybox ligand was also necessary, and the nature of this group had a dramatic impact on the enantioselectivity of the ACPA reaction. Ligands lacking substitution at this position provided poor enantiocontrol, but modulation of the N-donating ability of the pyridine group of the pybox showed that electron-donating alkoxy groups enhanced enantioselectivities. Finally, steric effects and possibly π-stacking of this remote substituent also seem to play a role in improving enantioinduction, with substituted benzyloxy groups as observed in L1 and L2 being optimal.

The scope of this ACPA system to prepare chiral propargylic ATAs was demonstrated through a large number of impressive examples (Fig. 1c). While propargylic electrophile coupling partners with substituents that are significantly sterically differentiated by size (for example, Ar versus Me-groups) unsurprisingly performed well in the process, the system provided excellent enantiocontrol for substituents that were also similar in size. For example, the catalyst could efficiently distinguish between ArCH2CH2 groups versus straight chain alkyls (that is, Et, n-propyl, and n-butyl). However, it should be noted that one straight chain alkyl group does require the presence of an unsaturated substituent in order to achieve good enantioselectivities, implying the importance of π-stacking effects in the enantiodiscrimination process of the chiral catalyst, which is believed to be dimeric in nature. While the amine nucleophile utilized in these reactions was often aniline or a substituted derivative, a variety of heterocyclic anilines were also studied along with a few simple cyclic benzylic amines.

The propargylic ATAs prepared in this study are further notable due to the high synthetic value of the present alkyne motif9. The alkyne group can function as a ‘chemical chameleon’13 through orthogonal functionalization of both π-systems and can also be used as either a nucleophile by deprotonation or as an electrophile through various metal-catalysed activation processes9. F. Zhou, Wang, J. Zhou and co-workers demonstrate this synthetic potential by conversion of the ACPA products to 5- and 6-membered heterocyclic ATAs, including the synthesis of a BACE-1 inhibitor target, and enabling several diversity-oriented synthesis applications to complex heterocycles and diamines.

The ACPA system developed represents a powerful synthetic technique to access enantioenriched ATAs of high diversity, as shown by the impressive substrate scope and demonstration of subsequent chemical modification of the alkyne motif. Extension of this system to other nucleophiles beyond nitrogen, including an O-based (oxime) and a C-based (1,3-ketoester) nucleophile, was briefly demonstrated and shows promise that this system can be optimized to these other classes. It is expected that these methodologies will aid researchers in the efficient asymmetric synthesis of complex chiral compounds important for biological activity studies and pharmaceutical development.