Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

Abstract

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N -alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

“…N -(2,4-Dimethoxybenzyl)-1-(4-nitrophenyl)methanimine ( 6 ), quantitative yield, yellow amorphous solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (s, 1H), 8.31–8.26 (m, 2H), 8.04–7.98 (m, 2H), 7.16 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 4.73 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H); Rf = 0.46 (EtOAc/Hexane = 1:1, v / v ) as reported [ 47 ].…”

“…N -(2,4-Dimethoxybenzyl)-1-(furan-2-yl)methanimine ( 10 ), quantitative yield, dark brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.49 (s, 1H), 7.21–7.16 (m, 1H), 6.73 (d, J = 3.4 Hz, 1H), 6.49–6.44 (m, 3H), 4.74 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H); Rf = 0.36 (EtOAc/Hexane = 1:1, v / v ) as reported [ 47 ].…”

A Diastereodivergent and Enantioselective Approach to syn- and anti-Diamines: Development of 2-Azatrienes for Cu-Catalyzed Reductive Couplings with Imines that Furnish Allylic Amines

“…Furthermore, the diamines were generated solely as the anti diastereomer in every case. [15] These examples highlight an often encountered situation in enantioselective reactions that afford more than one stereogenic center: the ability to access only one diastereoisomer. One strategy that addresses this shortcoming is a dual catalyst approach [16] wherein each catalyst acts cooperatively but independently to activate two reaction components individually, thereby enabling each to control stereochemistry at its respective fragment.…”

Synthesis of 1,2-Aminoalcohols through Enantioselective Aminoallylation of Ketones by Cu-Catalyzed Reductive Coupling

“…In the context of an umpolung route toward aminoalcohols 4 , aminoallylation of a carbonyl electrophile 2 by a nucleophilic amino-substituted allymetal reagent 1 represents a powerful technique for the generation of 1,2-aminoalcohol 3 containing alkene functionality that may be utilized in further synthetic manipulations. Indeed, carbonyl allylation chemistries have been extensively developed for the preparation of chiral homoallylic alcohols; however, the application of amino-substituted organometallic reagent 1 in analogous chemistry has been underdeveloped. ,− While Barrett originally reported an asymmetric process using the stoichiometric preparation of chiral boron reagents of 1 (M = B), only recently have catalytic asymmetric variants emerged to promote the catalytic generation of 1 . ,, For example, Krische (Figure B) recently disclosed an enantioselective Ir-catalyzed aminoallylation of aldehydes through hydrogen transfer from alcohol 5 to allenamide 6 generating the necessary α,γ-aminoanion nucleophile ( 1 , M = Ir) and the aldehyde electrophile. Additionally, our group recently reported an orthogonal method for the aminoallylation of ketone electrophiles enabled by Cu-catalyzed reductive coupling , (Figure C).…”

“…Additionally, our group recently reported an orthogonal method for the aminoallylation of ketone electrophiles enabled by Cu-catalyzed reductive coupling , (Figure C). Here, the readily available Evans-auxiliary derived chiral allenamide 9 was employed for stereochemical control affording high diastereoselectivies. , While this method is practical due to the low cost of the Evans auxiliary, we appreciated the fact that absolute stereochemical control by a chiral Cu-catalyst with an achiral allenamide would increase atom efficiency (Figure D). Significantly, enantioselective metal catalyzed aminoallylation of ketone electrophiles is unknown and can be more challenging than aldehydes due to the decreased reactivity and steric differentiation of ketones versus aldehydes.…”