Enantio‐ and Diastereoselective Synthesis of Homopropargyl Amines by Copper‐Catalyzed Coupling of Imines, 1,3‐Enynes, and Diborons

Abstract An efficient, enantio‐ and diastereoselective, copper‐catalyzed coupling of imines, 1,3‐enynes, and diborons is reported. The process shows broad substrate scope and delivers complex, chiral homopropargyl amines; useful building blocks on the way to biologically‐relevant compounds. In particular, functionalized homopropargyl amines bearing up to three contiguous stereocenters can be prepared in a single step.

Chiral homopropargyl amines are used in the synthesis of many natural products, and biologically and medicinally important molecules. [1][2][3] Most methods for homopropargyl amine synthesis involve the union of imines and propargylic or allenic substrates. These methods deliver racemic homopropargylic amines [4] and asymmetric variants selectively generate products with a stereocenter adjacent to the amino group (Scheme 1 A). In general, these methods use a transition metal catalyst and chiral ligand, or imines bearing a chiral auxiliary. [5] Constructing homopropargyl amines with more than one stereocenter, particularly if the stereocenters are adjacent, is a more challenging process (Scheme 1 B), few procedures address this goal and these require difficult-toaccess reagents and/or chiral auxiliaries. [6] Thus, a general preparation of chiral homopropargylic amines, bearing multiple stereocenters, from readily-accessible substrates, remains an important challenge.
Copper-catalyzed borylative transformations are a powerful method for uniting unsaturated hydrocarbons and electrophiles. [7] Importantly, these methods produce densely functionalized, chiral molecules from simple, achiral substrates, and use cheap and non-toxic transition metal catalysts. We and others have described efficient routes to amines through the multicomponent coupling of imines with hydrocarbon pro-nucleophiles and boron reagents. [8][9][10] Krische pioneered the use of enynes as hydrocarbon pro-nucleophiles in transition metal-catalyzed transformations, [11][12][13] however, in both reductive and borylative coupling, the asymmetric union of imines and enynes remains an unmet challenge. [14] We envisaged a new approach to homopropargyl amines involving the copper-catalyzed enantio-and diastereoselective multicomponent coupling of imines, enynes, and diboron reagents (Scheme 1 C). Furthermore, through routine oxidation of the carbon-boron bond, biologically relevant 1,3amino alcohols would be accessible. [15] Herein, we disclose an efficient method for obtaining functionalized chiral homopropargyl amines, bearing up to three stereocenters and various synthetic handles (amino, boron, alkynyl), using an inexpensive, non-toxic, and readily-available copper catalyst, and a commercial phosphine ligand.
We explored the copper-catalyzed coupling of imine 1 a, 1,3-enyne 2 a and bis(pinacolato)diboron (B 2 pin 2 ). Using CuCl and (S,S)-Ph-BPE (L1), the desired product 3 a' (PG = PMP) was obtained in 70 % yield and the major diastereoisomer was found to have an ee of 53 % (Table 1, entry 1). After screening reaction conditions with imine 1 a, we turned our attention to N-phosphinoylimine 1 b. With this imine, the enantioselectivity and diastereoselectivity of the reaction increased (89 % ee, > 95:5 dr), however, only 37 % yield of the desired product was obtained (entry 2). By screening the copper salt, base, and solvent, we found that the use of CuOAc, KOMe, and THF was optimal; 3 a was obtained in high yield, with excellent diastereoselectivity and enantioselectivity (entry 3). [16] X-ray crystallographic analysis of 3 d revealed the relative and absolute stereochemistry of the Scheme 1. Enantioselective transition metal-catalyzed nucleophilic addition to imines for the synthesis of homopropargyl amines. PG = protecting group; X = PG or chiral auxiliary; Pin = pinacolato.
The reaction tolerated electron-donating and electronwithdrawing substituents on the aryl ring of the aldimine; the desired products were obtained in high yield and with excellent enantio-and diastereoselectivity (Scheme 2). For example, electron-rich aldimines were well tolerated in the reaction and only a slight decrease in enantioselectivity was observed when an ortho-methoxy substituent was used (3 b). Similarly, imines bearing electron-withdrawing groups at the ortho-, meta-, and para-positions (3 e-3 j), including halogen (3 e-3 g, 3 i), ester (3 h), and trifluoromethyl (3 j) substituents, also performed well. The reaction also proceeded efficiently when heteroaryl-aldimines were used (3 l-3 o). The reaction could be executed on a gram scale without significant detriment to the yield or selectivity (3 a). Attempts to use an aliphatic aldimine in the process were unsuccessful (See Supporting Information).
Aryl-substituted 1,3-enynes bearing electron-donating groups delivered the corresponding products in good to excellent yield and with high enantioselectivities (Scheme 3, 4a-4d). Mixed results were obtained when using electrondeficient enynes; for example, whereas the bromo-substituted product 4e was prepared in good yield, with high selectivity, an ester substituent severely affected the efficiency of the coupling (4 f). The use of an alkyl substituted enyne gave 4h in low yield but with high enantiocontrol. Substitution at the terminal position of the alkene was investigated: E-enynes gave products 6b-6d in good to high yield, with good diastereoselectivity and excellent enantioselectivity. The structure of 6b was confirmed by X-ray crystallography. [16] The use of Z-enyne 5a-Z gave alternative diastereoisomeric product 6a. Thus, the process delivers amino alcohols bearing three contiguous stereocenters with essentially complete enantiocontrol. Amine 3 a was readily hydrogenated, to give the branched chain alkane 7 a, and the b-amino acid derivative 7 b was accessed by oxidation of 7 a (Scheme 4). Biologically-and medicinally-relevant N-containing heterocycles were also prepared, for example, azetidine 7 c, or 2,3-dihydropyrrole 7 d through p-activation of the alkyne bond using a Au-Ag catalyst system. [17] The phosphinoyl group could be removed to reveal the free amine 7 e, [9a] which was subjected to urethanation to give oxazinone 7 f.
Regioselective borocupration provides intermediate A (1), [12a, 13a] which is proposed to undergo propargyl-to-allenyl isomerization to B (2) (Scheme 5 A). [12d] We propose that intermediate B is the major allenyl-copper isomer in the reaction. [12d] Coupling of the allenyl-copper intermediate B with imine 1 b (C re , 3) gives chiral homopropargylic amine D and closes the catalytic cycle (4). [12b-d] Scheme 5 B provides an explanation for the anti-diastereoselectivity observed in the reaction. Coupling (3) between allenyl intermediate B and imine 1 b can occur from attack at either the re face (C re ) or the si face (C si ) of the imine. However, reaction at the si face (C si ) incurs unfavorable interactions between the N-phosphinoyl group and the -CH 2 Bpin group and is disfavored.
In conclusion, a highly enantio-and diastereoselective coupling of imines, 1,3-enynes, and diborons using an inexpensive copper catalyst and a commercial ligand, delivers chiral homopropargyl amines with up to three contiguous stereocenters. The products provide access to important targets, including b-amino acids and N-heterocycles.