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

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 amines⁴ 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-to-access 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 1,3-amino 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 (B₂pin₂). 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 product.¹⁶ Other diboron reagents are applicable in the reaction; the use of bis(neopentyl glycolato)diboron (B₂neo₂) gave 3 a in moderate yield but with high diastereo- and enantiocontrol (entry 11).

Table 1. Screening of reaction conditions^[a]

Entry	Imine	Ligand	CuI/base	dr	3 Yield/ee[b] [%]
1	1 a	L1	CuCl/NaOtBu	87:13	70/53[c]
2	1 b	L1	CuOAc/NaOtBu	>95:5	37/89
3	1 b	L1	CuOAc/KOMe	>95:5	92/99
4	1 b	L2	CuOAc/KOMe	–	–
5	1 b	L3	CuOAc/KOMe	–	–
6	1 b	L4	CuOAc/KOMe	–	–
7	1 b	L5	CuOAc/KOMe	>95:5	56/34
8	1 b	L6	CuOAc/KOMe	–	–
9	1 b	L7	CuOAc/KOMe	88:12	37/16
10	1 b	L8	CuOAc/KOMe	>95:5	88/96[d]
11	1 b	L1	CuOAc/KOMe	90:10	56/92[e]

• [a] Reaction conditions: 1 (0.2 mmol), 2 a (0.3 mmol), B₂pin₂ (0.3 mmol), base (0.3 mmol), Cu^I (10 mol %), ligand (12 mol %) in THF (2.0 mL) at RT for 16 h under nitrogen. The diastereoselectivity was determined by ¹H NMR analysis of the crude product mixtures. NMR yields are given. [b] The ee values were determined by chiral HPLC after oxidation. [c] The ee values were measured by chiral HPLC analysis of the boron-containing product. [d] The enantiomer of 3 a was formed. [e] B₂neo₂ (0.3 mmol) was used. THF=tetrahydrofuran. PMP=4-methoxyphenyl; Neo=neopentyl glycolato.

The reaction tolerated electron-donating and electron-withdrawing 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, 4 a–4 d). Mixed results were obtained when using electron-deficient enynes; for example, whereas the bromo-substituted product 4 e 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 4 h in low yield but with high enantiocontrol. Substitution at the terminal position of the alkene was investigated: E-enynes gave products 6 b–6 d in good to high yield, with good diastereoselectivity and excellent enantioselectivity. The structure of 6 b was confirmed by X-ray crystallography.¹⁶ The use of Z-enyne 5 a-Z gave alternative diastereoisomeric product 6 a. 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 β-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 π-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–^12d 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 -CH₂Bpin 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 β-amino acids and N-heterocycles.