Enantioselective Lithiation–Substitution of Nitrogen‐Containing Heterocycles

Abstract

This review covers the enantioselective lithiation–substitution at the α‐position of nitrogen‐containing heterocycles mediated by strong organolithium bases and chiral ligands. The reactions occur by two main mechanistic pathways: asymmetric deprotonation and asymmetric substitution. For N ‐Boc heterocycles, asymmetric deprotonation is the predominant pathway, and s ‐BuLi, in combination with chiral diamines, such as (–)‐sparteine and the (+)‐sparteine surrogate, are used. This approach is highly successful with N ‐Boc pyrrolidines, piperidines, and piperazines. Substrates for asymmetric‐substitution‐mediated reactions include some N ‐Boc heterocycles, but other N ‐substituents, such as N ‐alkyl groups, N ‐alkyl‐BY 3 salts (Y = H, F) and N ‐thioamide groups are also used. With both mechanistic pathways, the lithiated heterocycle can be transmetalated to form an organocopper or organozinc species to widen the scope of the electrophile. The full scope and limitations of this approach to synthesize enantioenriched α‐substituted aziridines, azetidines, pyrrolidines, piperidines, piperazines, azepanes and other five‐/six‐membered‐ring heterocyles are summarized.

Kinetic Resolution of 2-Aryl-4-methylenepiperidines toward Enantioenriched Functionalizable Piperidine Fragments

“…This was subsequently reacted with p -bromobenzoyl chloride in the presence of triethylamine and DMAP, and the absolute configuration of the ester product was determined by single- crystal X-ray analysis (Figure ). This confirmed the cis -stereochemistry of 12 and that the piperidine 3a had the 2 S configuration, as expected based on the use of (+)-sparteine. , Alternatively, ozonolysis of the 4-methylene group in piperidine ( S )- 3a was carried out at −78 °C, and subsequent reductive workup using Me 2 S gave the enantioenriched 2-aryl-4-piperidone ( S )- 2a in high yield. This could be reacted with DAST to give difluoride ( S )- 14 without any loss in enantiopurity.…”

“…This confirmed the cis -stereochemistry of 12 and that the piperidine 3a had the 2 S configuration, as expected based on the use of (+)-sparteine. 16 , 17 Alternatively, ozonolysis of the 4-methylene group in piperidine ( S )- 3a was carried out at −78 °C, and subsequent reductive workup using Me 2 S gave the enantioenriched 2-aryl-4-piperidone ( S )- 2a in high yield. This could be reacted with DAST to give difluoride ( S )- 14 without any loss in enantiopurity.…”

Photocatalysis and Kinetic Resolution by Lithiation to Give Enantioenriched 2-Arylpiperazines

“…The 4-fluoro-, 4-chloro-, and 4-methyl-substituted piperazines 2c , 2f , and 2i were excellent substrates. The absolute configuration of the major enantiomer was assigned on the basis of the known preference for BuLi/(+)-sparteine to remove the pro-( R ) proton on the carbon atom attached to the N -Boc group, , and this aligns with all previous related examples . A model to illustrate the preference is shown (Figure ), in which the (+)-enantiomer of sparteine when coordinated to BuLi favors lithiation of the ( S ) enantiomer of the piperazines 2 .…”

Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine

“…1,2 In this context, there are a growing number of marketed pharmaceuticals that contain the αsubstituted pyrrolidine motif, including the anti-cancer and antiviral agents Larotrectinib, 3 Acalabrutinib 4 and Telaprevir 5 (Figure 1A). The lithiation-trapping of N-Boc heterocycles, first introduced by Beak in 1989 (using s-BuLi/TMEDA in Et 2 O at -78 °C), 6 is a useful route to α-substituted saturated nitrogen heterocycles 7 and continues to be exploited in the synthesis of potential drugs by medicinal and process chemists. 5,8,9 For example, lithiation-carboxylation of ~100 kg of a bicyclic N-Boc pyrrolidine was carried out by process chemists at Vertex in the synthesis of the hepatitis C drug Telaprevir.…”