Chiral 1-tetrahydronaphthamides are ubiquitous in natural products and synthetic intermediates in organic chemistry, and their reduction products chiral tetrahydronaphthalen-1-ylmethylamines are core functional units of many bioactive molecules. For example, a series of potent KDM4 inhibitors with a chiral tetrahydronaphthalen-1-ylmethylamine fragment have been found to be cell permeable and antiproliferative in cancer cell models. Many molecules with this fragment have been demonstrated to be active on the α2-adrenoceptor and the 5-HT receptor, such as A-80426, which has potential to be developed into an antidepressant medication, and Landipirdine, which has already entered a phase II clinical trial as a drug for treating Parkinson’s disease. However, the synthesis of chiral 1-tetrahydronaphthamides remains a challenge. Traditionally, chiral 1-tetrahydronaphthamides are obtained through two synthetic pathways. One starts from 1-tetralone, through cyanation with TMSCN and hydrolysis with concentrated sulfuric acid, followed by asymmetric hydrogenation and N-alkylation. The other one is synthesis by dehydration condensation between amines and chiral carboxylic acids which are prepared via chiral separation. Practical methods for the highly enantioselective synthesis of chiral 1-tetrahydronaphthamides are lacking. Therefore, the development of an efficient and enantioselective method for the preparation of chiral 1-tetrahydronaphthamides under mild conditions is desired for both academia and industry.

Recently, Qi-Lin Zhou’s group have established a new strategy for the enantioselective reduction of 1-naphthamides to chiral 1-tetrahydronaphthamides by electrochemical reduction and ruthenium-catalyzed asymmetric hydrogenation in tandem. This strategy takes advantage of the high efficiency of electrochemical reduction of the aromatic ring and high enantioselectivity of transition-metal-catalyzed asymmetric hydrogenation of olefins. By this method, a variety of chiral 1-tetrahydronaphthamides and related intermediates of bioactive molecules have been synthesized with good yields and high enantioselectivities from readily available 1-naphthamides. They believe that this synthesis strategy has the potential to be applied to the transformation of a wide variety of aromatic substrates, thereby broadening the horizon of enantioselective transformation of aromatic compounds. Relevant achievements were published in J. Am. Chem. Soc., 2025. DOI: 10.1021/jacs.4c18009.