Enantioselective Synthesis of β-Amino Acid Derivatives Enabled by Ligand-Controlled Reversal of Hydrocupration Regiochemistry

Abstract

A Cu-catalyzed enantioselective hydroamination of α,β-unsaturated carbonyl compounds for the synthesis of β-amino acid derivatives was achieved through ligand-controlled reversal of the hydrocupration regioselectivity. While the hydrocupration of α,β-unsaturated carbonyl compounds to form α-cuprated species has been extensively investigated, we report herein that, in the presence of an appropriate ancillary chiral ligand, the alternative regiochemistry can be observed for cinnamic acid derivatives, leading to delivery of the copper to the β-position. This copper can react with an electrophilic aminating reagent, 1,2-benzisoxazole, to provide enantioenriched β-amino acid derivatives, which are important building blocks for the synthesis of natural products and bioactive small molecules.

Synthetic organic chemists have had a long-standing interest in general methods for the synthesis of chiral β-amino acid derivatives, which are fundamental building blocks for the preparation of biologically active peptides and small molecule pharmaceuticals.^[1] Commonly used direct catalytic asymmetric synthetic strategies include the hydrogenation of enamines,^[2] addition of nucleophiles to imines,^[3] conjugate addition^[4] and biocatalytic processes.^{[1a, 5]} Catalytic enantioselective conjugate addition reactions are among the most important methods to access the chiral β-amino acid derivatives because of the readily available α,β-unsaturated carbonyl compound starting materials.^[6] Lewis-acid-catalyzed asymmetric conjugate addition methods usually require substrates containing achiral heterocyclic templates, such as an oxazolidinone or pyrrolidinone.^{[5a, 7]} Recently reported Bronsted-acid-catalyzed asymmetric aza-Michael addition reactions can employ less reactive Michael acceptors, such as α,β-unsaturated esters and carboxylic acids.^[8] However, as they require the use of secondary amines or O-alkylhydroxylamines, the development of a complementary method for the direct synthesis of unprotected, primary amines is important. Moreover, although some enzyme-catalyzed reactions can be used to prepare enantiopure aromatic β-amino acids by the additional of ammonia to cinnamic acid, a mixture of α- and β-amino acids is often obtained.^[5]

We report a CuH-catalyzed hydroamination protocol for enantioselective synthesis of β-amino acid derivatives. This method employs readily available α,β-unsaturated carbonyl compounds with commercially available 1,2-benzisoxazole as an electrophilic primary aminating reagent^[9] (Scheme 1A). In addition, the reaction proceeds through the hydrocupration of α,β-unsaturated carbonyl compounds with the opposite regioselectivity than would be expected based on previous research on CuH-catalyzed hydrofunctionalization reactions.^[10] The copper hydride transfers its hydride to the β-position of an α,β-unsaturated system to form a copper enolate, which can then react with various electrophiles to construct a new C–H^[11] or C–C bond^[12] (Scheme 1B). Since Stryker’s reagent was first applied to conjugate reduction of α,β-unsaturated carbonyl compounds in 1988,^[10] the regioselectivity of this transformation has been considered to be predominantly dictated by the intrinsic preference of the hydride to transfer to the carbon β to the carbonyl, due to the electron-withdrawing nature of the carbonyl group. We show here that, with both the appropriate choice of ligand for copper and β-aryl substituent as an activating group, the hydrocupration of α,β-unsaturated carbonyl compounds shows a reversal in regioselectivity, favoring the β-organocopper product (I, Scheme 1C). The resulting species I could undergo the further amination reaction to provide the desired chiral β-amino acid derivatives.

Scheme 1.

Catalytic Hydrocupration and β-Selective Hydroamination.

We began our studies by examining the reaction of tert-butyl cinnamate (1a) under previously reported conditions for asymmetric synthesis of primary amines.^[9] Initially, we expected that the copper enolate generated from the α-selective hydrocupration of tert-butyl cinnamate (1a) could react with 1,2-benzisoxazole to afford the α-amino acid derivative 3a’. However, we found that reactions using several bisphosphine ligands, L1-L4, furnished the reduced alkene 3a” as the major product (blue pathway, Table 1, Entries 1–4). In particular, the (S)-BINAP-ligated CuH catalyst, which is known to undergo α-selective hydrocupration to form copper enolate with high efficiency,^{[10b, 13]} gave 3a” in 99% yield. In no case did we see evidence for the formation of the α-amination product, 3a’ or products derived from it. We reasoned that rather than undergoing C–N bond formation, the copper enolate intermediate was rapidly converted into a silyl enol ether, which was later protonated by an internal proton source.^{[9, 14]} On the other hand, when L2-L4 were used, a certain amount of the β-amination product 3a could also be observed, presumably formed via the amination of a β-copper species through the red pathway (Table 1). Thus, the ratio of 3a to 3a” could provide an approximate indication of the α/β-regioselectivity of the hydrocupration. When we attempted the same reaction using (S,S)-Ph-BPE (L6) as the supporting ligand, the reaction provided the β-amination product 3a, instead of the anticipated α-amination product 3a’ in high yield and enantioselectivity (Table 1, Entry 6). The identity of the aminated product implied that the regioselectivity of the hydrocupration had been reversed relative to the conventional α-selective hydrocupration. Further experimentation indicated that CPME and CyH were excellent solvents for the amination reaction, both providing 3a in 87% yield and >99:1 er. For subsequent experiments, we chose CPME as the solvent since it can dissolve a wider range of polar and nonpolar compounds.^[15] In addition, β-alkyl α,β-unsaturated esters were also examined under our standard reaction conditions. However, the hydroamination of these substrates only provided the reduction products in quantitative yield. (See Supporting Information 3.4)

Table 1.

Reaction Development.

^[a]Cu(OAc)₂ (2.0 mol%), Ligand (2.2 mol%), 1a (1.0 mmol), Me(MeO)₂SiH (3.2 equiv), 1.5 equiv of 2 was added via syringe pump (75 μL/h), cyclohexane (1.0 mL), rt, 3 h. Yields were determined by ¹H-NMR analysis of the crude reaction mixtures. (S,S)-Ph-BPE = 1,2-bis((2S,5S)-2,5-diphenylphospholano) ethane.

^[b]cyclopentyl methyl ether (CPME).

^[c]THF.

Using the optimized conditions, we evaluated the scope of the reaction with respect to the carbonyl group. A series of cinnamate derivatives, including esters, an acid, an amide and an imide, were examined under our reaction conditions (Table 2). Tert-butyl cinnamate underwent the hydroamination very efficiently to afford the Schiff base S. This intermediate could be desilylated by treatment with NaHCO₃ (aq) to afford the Schiff base product 3a, which was easily purified and could be quantitatively converted to a primary amine in a step-wise approach without erosion of enantiomeric purity.^[9] Intermediate S could also be directly converted to β-amino ester 4a in a one-pot procedure. Additionally, under the same reaction conditions, ethyl cinnamate was converted into primary amine 4b in good yield with excellent enantioselectivity. Interestingly, an unprotected cinnamic acid also underwent the hydroamination reaction to afford the hydrochloride salt (4c) in high yield and enantioselectivity via a three-step, one-pot sequence involving the in situ silylation of carboxylic acid,^[16] the hydroamination with 2, and the hydrolysis of Schiff base. Finally, 1d and 1e were examined as substrates. While the hydroamination of 1d only gave ~11% yield (¹H NMR) of the corresponding Schiff base product and ~90% reduction, a good yield of desired product was realized in the hydroamination of imide 1e.

Table 2.

Scope of Carbonyl Substituent

^[a]1.5 equiv of 2 was added via syringe pump (75 μL/h). Yield refers to isolated yield of purified product (1.0 mmol scale, average of two runs), and the er was determined on the Schiff base product.

^[b]Cu(OAc)₂ (1.0 mol%), (S,S)-Ph-BPE (1.1 mol%), Me(MeO)₂SiH (4.0 equiv), THF (1 mL), 1.5 equiv of 2 was added via syringe pump (37.5 μL/h).

^[c]Yield was determined by ¹H-NMR analysis of crude reaction mixture.

Since tert-butyl esters performed well in this reaction, and the β-amino esters can be conveniently deprotected to yield the corresponding β-amino acids,^[17] we further explored the scope of the hydroamination reaction with respect to various tert-butyl cinnamate derivatives (Table 3). Substrates with substituents on the ortho (3f, 3g, 3h), meta (3i, 3j), and para positions (3m, 3n, 3o, 3p) of the arene, as well as doubly substituted arenes (3k, 3l), underwent selective hydroamination to give the corresponding Schiff base product in medium-to-good yield and high enantioselectivity (>98:2 er). Substrates containing electron-withdrawing (3g, 3k) and electron-donating (3f) substituents were converted to product with good efficiency. Due to the mild reaction conditions, a wide range of functional groups, including halides, fluoride (3g) and bromide (3i), trifluoromethyl (3m), trifluoromethoxy (3k), dioxolane (3l), and silyl groups (3o) were well tolerated. In addition, nitrogen-containing heterocycles, such as indole (3j), pyrrole (3p), and pyridine (3q) were all readily accommodated.

Table 3.

Scope of Arene Substitution

^[a]Condition A: 1.5 equiv of 2 was added via syringe pump (75 μL/h). Yield refers to isolated yield of purified product (1.0 mmol scale, average of two runs), and the er was determined on the Schiff base product.

^[b]Condition B: Cu(OAc)₂ (2.0 mol%), (S,S)-Ph-BPE (2.2 mol%), THF (1 mL), 1.5 equiv of 2 was added via syringe pump (37.5 μL/h) at 45 °C.

To demonstrate the scalability of this method, we performed the one-pot synthesis of chiral primary amine 4k from 1k on a 5 mmol scale. This gram-scale reaction provided the desired β-amino ester in high yield and enantioselectivity using 1.0 mol% of catalyst (Scheme 2A). This one-pot protocol can also be used in the hydroamination of a para-silyl tert-butyl cinnamate to afford the primary amine product 4r, which can be converted to a building block for the solid-phase synthesis of β-amino acid-containing polypeptides (Scheme 2B).^[18] In addition, we found that Bn₂NOPiv also can also be used to afford the β-tertiary amino ester 5a (Scheme 2C). This result indicates that a variety of other amine electrophiles developed previous CuH-catalyzed hydroamination reactions could be used under these reaction conditions for the synthesis of chiral β-tertiary amino acid derivatives.^[19]

Scheme 2.

Extensions and Applications

To gain mechanistic understanding of the hydroamination reaction, deuterated methanol was used as an electrophile to probe the predominant organocopper species generated from the ligand-controlled hydrocupration (Scheme 3A). We found that Re1,^[20] consistent with deuteration of copper enolate S1, was the predominant product in the presence of (S)-BINAP. However, Re2, resulting from the deuteration of S2, was the major product when (S,S)-Ph-BPE was used. Furthermore, when Ph₂SiD₂ was used in the hydroamination of tert-butyl cinnamate, enantioenriched monodeuterated product 3s was produced in high yield (Scheme 3B). By comparison with spectral data for the primary amine, the relative configuration was determined to be syn.^[21] These results indicate that the β-amination product was generated from syn addition of CuH to the alkene followed by amination with 1,2-benzisoxazole. These mechanistic experiments, together with the observed product regioselectivity, strongly suggest that L6 enables the β-selective hydrocupration of cinnamate-derived olefins. Moreover, from a synthetic perspective, the protocol (Scheme 3B) also represents a potentially useful strategy for the synthesis of stereoselectively deuterium-labeled β-amino acid derivatives, which are valuable tools for the investigation of protein structure at the atomic level.^[22]

Scheme 3.

Mechanism Study

In conclusion, we have demonstrated that the regioselectivity of hydrocupration of cinnamate derivatives can be controlled by the choice of ligand. The ability to achieve high β-selectivity was employed in the mild, enantioselective preparation of important β-amino acids. Although extensive calculations in hopes of explaining the origin of this ligand effect were carried out, no model or hypothetical mechanism has been able to reproduce the observed regioselectivity so far. We hope that further theoretical and experimental studies will uncover the origin of this unusual regiochemical outcome. Overall, an improved fundamental understanding of ligand effects on the regioselectivity of this and related transformations may aid in the discovery of previously inaccessible hydrofunctionalization reactions.