The Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling

Abstract

Interest in unnatural α-amino acids has increased rapidly in recent years in areas ranging from protein design to medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their enantioselective synthesis is an important objective in reaction development. In this report, we establish that a chiral catalyst based on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a wide variety of alkylzinc reagents (1:1.1 ratio) to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling, which proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups, complements earlier approaches to the catalytic asymmetric synthesis of this valuable family of molecules. We have applied our new method to the generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in the synthesis of bioactive compounds.

Graphical Abstract

The development of effective and straightforward methods to access enantioenriched unnatural (non-canonical) α-amino acids is a highly important objective, as they are finding widespread use in fields such as biology, biochemistry, pharmaceutical science, and materials science;^1-5 furthermore, they can readily be transformed into other useful families of chiral molecules, including β-amino alcohols (Figure 1).^6,7 Catalytic asymmetric routes to unnatural α-amino acids are especially attractive,^5,8,9 and numerous approaches have been described, such as hydrogenations of olefins and imines,^10,11 electrophilic aminations of enolates,¹² electrophilic alkylations of glycine derivatives,¹³ and nucleophilic additions to α-imino esters.¹⁴

Figure 1.

Diverse applications of unnatural α-amino acids.

The development of radical-based methods in organic synthesis, which may complement polar/heterolytic processes, has expanded dramatically in recent years,^15,16 but to our knowledge no such methods have been described for the catalytic asymmetric synthesis of unnatural α-amino acids. We envisioned that nickel-catalyzed enantioconvergent cross-couplings of alkyl electrophiles, which are emerging as a powerful tool in asymmetric synthesis and typically proceed through radical intermediates,^17-23 might provide a straightforward route to protected α-amino acids from readily available coupling partners. In this report we describe the realization of this objective, specifically, that a chiral nickel/pybox catalyst can achieve the coupling of an array of organozinc reagents with racemic α-haloglycine derivatives, enabling ready access to a wide variety of protected α-amino acids (eq 1), including several that have been applied to the synthesis of bioactive target molecules.

(1)

To our knowledge, α-halo-α-amino acid derivatives have not been employed as electrophiles in metal-catalyzed asymmetric cross-coupling reactions,^24-27 although they have been utilized as precursors to iminium ions in two organocatalytic processes (nucleophiles: enolates of 1,3-dicarbonyl compounds and allylmetal reagents).^28-30 By following a procedure reported by Roche,³¹ Cbz-protected α-chloroglycine ester A can be obtained in a single step on a multigram scale, and it can be stored at 0 °C for at least six months without degradation. When this racemic electrophile is treated with an alkylzinc reagent (1:1.1 ratio, despite a potentially labile N-bound proton) in the presence of a chiral nickel/pybox catalyst, alkyl–alkyl coupling proceeds to generate the desired protected α-amino acid in good yield and enantioselectivity (84% yield and 97% ee; entries 1 and 2 of Table 1).

Table 1.

Catalytic Enantioconvergent Synthesis of a Protected α-Amino Acid: Effect of Reaction Parameters.

entry	variation from the standard conditions	yield (%) a	ee (%) b
1	none	84	97
2	30 min, instead of 4 h	86	97
3	no NiBr2 • glyme	10	<1
4	no L1	40	-
5	L2, instead of L1	60	96
6	L3, instead of L1	71	80
7	L4, instead of L1	67	15
8	L5, instead of L1	47	41
9	5.0 mol% NiBr2 • glyme, 6.0 mol% L1	82	96
10	2.5 mol% NiBr2 • glyme, 3.0 mol% L1, 24 h	61	92
11	r.t., instead of 0 °C	80	95
12	0.5 equiv H2O added	80	96
13	1.0 equiv H2O added	53	93
14	under air in a closed vial	77	96

All data are the average of two experiments.

^aDetermined through LC–MS analysis using an internal standard.

^bDetermined through SFC analysis.

In the absence of NiBr₂•glyme or of ligand L1, only a small amount of product is observed (racemic; entries 3 and 4 of Table 1). Although a variety of other chiral ligands are less effective than ligand L1 (entries 5–8), it is worth noting that commercially available pybox ligand L2 affords a reasonable yield and high enantioselectivity (entry 5). A lower catalyst loading can be used (entries 9 and 10), and the method performs well at room temperature (entry 11). The coupling process is robust, only modestly inhibited by small amounts of water (entries 12 and 13; carbon–carbon bond formation is faster than protonation of the organozinc reagent and hydrolysis of the electrophile) or by air (entry 14).

This straightforward method for the catalytic enantioconvergent synthesis of protected unnatural α-amino acids is compatible with an array of substituents on the nitrogen (R¹; Figure 2, products 1–5) and on the oxygen (R²; products 1 and 6) of the electrophile, providing a range of products with good yield and high ee. The scope of the coupling is also broad with respect to the nucleophile. For example, the R substituent can range in size from methyl to isobutyl (products 7–11; the use of a secondary alkylzinc reagent leads to little product under our standard conditions). Furthermore, a wide variety of functional groups are compatible with the method, including a silyl ether, ether, nitrile, imide, alkyne, unactivated primary alkyl fluoride / chloride, alkene, carbonate, and acetal (products 12–33; we have also established that an aldehyde, aryl iodide, benzofuran, benzonitrile, benzothiophene, epoxide, α-ketoester, ketone, nitroarene, unactivated secondary alkyl bromide, and thioether are compatible: see the Supporting Information). In the case of several nucleophiles that bear one or more stereocenters, the stereochemistry of the catalyst, rather than that of the nucleophile, predominantly controls the stereochemistry of the product (products 22–33). On a gram scale (1.48 g of product), the coupling to generate product 1 proceeds in identical yield and ee as for a reaction conducted on a 0.6-mmol scale (83% yield, 97% ee).^32,33

Figure 2.

Catalytic enantioconvergent synthesis of protected unnatural α-amino acids: Scope. All couplings were conducted on a 0.6-mmol scale (unless otherwise noted), and all yields are of purified products.

Because the α-haloglycinate coupling partner can generally be prepared in one step, this nickel-catalyzed enantioconvergent alkyl–alkyl coupling provides an unusually versatile and efficient method for the generation of a wide array of unnatural α-amino acid derivatives, which are common building blocks in the synthesis of bioactive compounds. For example, Boc-protected α-amino acid 34 (Figure 3), which serves as an intermediate in the synthesis of a histone deacetylase (HDAC) inhibitor, has previously been generated in four steps via an enzymatic kinetic resolution.³⁴ Alternatively, a nickel-catalyzed enantioconvergent cross-coupling affords α-amino acid 34 in two steps in good yield and ee (70% overall yield, 95% ee).

Figure 3.

Catalytic enantioconvergent synthesis of protected unnatural α-amino acids: Applications to the synthesis of bioactive compounds. All data are the average of two experiments, and all yields are of purified products.

Similarly, protected unnatural α-amino acid 35 (Figure 3), which has been employed as an intermediate in the synthesis of a calpain-1 inhibitor, was originally produced in four steps from a derivative of pyroglutamic acid.³⁵ Through the nickel-catalyzed asymmetric coupling method described herein, target 35 can be generated in two steps in 65% overall yield and with high enantioselectivity (97% ee).

Furthermore, ketone-bearing α-amino acid 37, an intermediate in the synthesis of cyclic peptide apicidin A, which exhibits anti-malarial activity, can be produced in three steps via an enantioconvergent alkyl–alkyl cross-coupling (prior route: six steps from glutamic acid).³⁶ Finally, our method provides protected unnatural α-amino acid 38 (Figure 3), bearing a cyano substituent, in two steps; compound 38 has previously been generated in six steps from lysine en route to L-indospicine, a component in tropical legumes in the genus Indigofera.³⁷

In conclusion, we have developed a straightforward, versatile method for the asymmetric synthesis of protected unnatural α-amino acids, an important family of target molecules, via nickel-catalyzed enantioconvergent cross-couplings of readily available racemic alkyl halides with alkylzinc reagents (1:1.1 ratio). These couplings can be achieved under mild, convenient conditions and are tolerant of air, moisture, and a wide variety of functional groups, including alkenes and alkynes (cf. asymmetric hydrogenation). The usefulness of the new method has been demonstrated by its application to the efficient synthesis of unnatural α-amino acid derivatives that have previously been employed as intermediates en route to bioactive compounds. The development of additional catalytic asymmetric processes based on nickel, an earth-abundant metal, is underway.