β³-Tryptophans by Iron-Catalyzed Enantioselective Amination of 3-Indolepropionic Acids

Abstract

A straightforward and general strategy for the catalytic asymmetric synthesis of β³-tryptophans by carboxylic-acid-directed intermolecular C–H amination has been developed. The iron-catalyzed C–H amination of 3-indolepropionic acids with BocNHOMs (Boc, tert-butyloxycarbonyl; OMs, methylsulfonate) in the presence of the base piperidine provides N-Boc-protected β³-tryptophans in a single step with high enantiomeric excess (ee) of up to >99%. Mechanistic experiments and density functional theory calculations support a mechanism through carboxylate-directed iron-mediated C(sp³)–H nitrene insertion. The method incorporates two key sustainability criteria: the use of iron as an abundant, non-toxic, and environmentally benign metal, along with the achievement of streamlined enantioselective C–H functionalization.

β-Amino acids are important building blocks for the synthesis of pharmaceuticals, natural products, modified peptides, and modified proteins, among others.^1,2 β³-Amino acids, which are β-amino acids bearing a substituent in the β position, can often be synthesized from the corresponding α-amino acids via Arndt–Eistert homologation,³ and this method has been applied extensively for the synthesis of β³-amino acids with natural side chains. Catalytic asymmetric methods for the synthesis of β³-amino acids with unnatural side chains include the enantioselective hydrogenation of β-substituted β-aminoacrylates, the Mannich reaction of various imines with carbonyl compounds, and conjugate additions.² However, an economic catalytic enantioselective incorporation of the C–N bond by direct intermolecular C(sp³)–H amination⁴ has been elusive.

We recently reported a catalytic asymmetric α-amination of abundant carboxylic acid feedstock molecules, providing in a single step high-value non-racemic N-Boc-protected α-monosubstituted and α,α-disubstituted α-amino acids (Scheme 1a).⁵ The method integrates nitrene-mediated C(sp³)–H functionalization⁶ with targeted C(sp³)–H functionalization,⁷ eliminating the need for an intermediate cyclometalation. Following deprotonation, the carboxylic acid substrate binds to the iron center, acting as a directing group. An iron-bound nitrene species then enables a highly stereocontrolled nitrene-mediated C(sp³)–H amination⁸ via regioselective 1,5-hydrogen atom transfer (HAT) followed by C–N bond formation.

Scheme 1. Carboxylic-Acid-Directed Fe-Catalyzed Nitrene-Mediated C(sp³)–H Amination To Provide α- and β-Amino Acids.

We contemplated expanding the catalytic asymmetric α-amino acid synthesis to β-amino acids by favoring a 1,6-HAT (Scheme 1b) over a generally more common 1,5-HAT (Scheme 1a) in the key catalytic intermediate.⁹ In this context, we present here our advancements by unveiling a direct catalytic asymmetric amination of 3-indolepropionic acids. This approach features the first practical and general catalytic enantioselective synthesis of non-racemic N-Boc-protected β³-tryptophan derivatives. The sustainable method relies on a carboxylate-directed iron-catalyzed nitrene-mediated C(sp³)–H amination, yielding N-Boc-β³-tryptophans with enantioselectivities of up to >99% enantiomeric excess (ee).¹⁰⁻¹³

Initial experiments and optimization reactions are shown in Table 1. We recently reported an expedited synthesis of α-amino acids by stereocontrolled α-amination of carboxylic acids using the iron catalyst (R,R)-[FeCl₂(BIP)],¹⁴ with BIP¹⁵ being a bis-benzimidazole ligand with a chiral 2,2′-bipyrrolidine backbone [denoted in Table 1 as (R,R)-FeBIP], in combination with aminating reagent BocNHOMs⁵ (Ms = methylsulfonate) and base piperidine. We were wondering if we could steer the amination away from the α position toward the β position by activating the β-C–H bond with an arene substituent. We therefore initiated our study with 3-phenylpropionic acid (1a), which contains activated benzylic C–H in the β position of carboxylic acid. However, when we applied optimized amination conditions to this substrate, the conversion was very sluggish, and N-Boc-β³-phenylalanine (2a) was only obtained in 6% nuclear magnetic resonance (NMR) yield and almost racemic (6% ee, entry 1). Very small amounts of α-amination could also be observed. Interestingly, when the phenyl moiety was replaced with 3-indole, the results improved markedly. Accordingly, 3-indolepropionic acid (1b) in the presence of (R,R)-FeBIP (10 mol %), BocNHOMs (4 equiv), and piperidine (6 equiv) provided N-Boc-β³-tryptophan (2b) in 56% yield and the R enantiomer with 59% ee (entry 2). Encouraged by these results, we next opted for improving the yield and enantioselectivity by modifying the catalyst. (R)-Fe1, in which the chiral bipyrrolidine backbone is replaced with N-methylaminomethylpyrrole,¹⁶ provided compound 2b with a somewhat lower yield (51%) but an improved ee of 66% (entry 3). Fortuitously, much better results were achieved with this N-methylaminomethylpyrrole backbone when we added nitro substituents into the benzimidazole moieties [(R)-Fe2], affording the β-amination product 2b in 77% yield with 96% ee (entry 4). Finally, replacing the nitro groups with cyano groups [(R)-Fe3] afforded an even higher enantioselectivity. N-Boc-β³-tryptophan (2b) was isolated in 73% yield with 98% ee (entry 5). Using the optimal catalyst (R)-Fe3, the formation of N-Boc-β³-phenylalanine (2a) from 3-phenylpropionic acid (1a) was also somewhat improved (compare entries 1 and 6). With respect to optimal reaction conditions, CH₂Cl₂ turned out to be the solvent of choice (compare entry 5 to entries 7–9) and piperidine was the most suitable base (compare entry 5 to entries 10 and 11). It is also worth noting that a reduced reaction temperature (−23 °C) is required for this reaction due to the limited stability of BocNHOMs under the basic reaction conditions.⁵

Table 1. Initial Experiments and Optimization^a.

					yield (%)c
entry	catalyst	Ar	condition	conversionb (%)	2	3	ee (%)d
1	FeBIP	1a	standard	7	6b	1b	6
2	FeBIP	1b	standard	87	56	0	59
3	Fe1	1b	standard	100	51	0	66
4	Fe2	1b	standard	100	77	0	96
5	Fe3	1b	standard	100	73	0	98
6	Fe3	1a	standard	39	23	4	63
7	Fe3	1b	THF	91	47	0	86
8	Fe3	1b	DCE	83	58	0	93
9	Fe3	1b	CHCl3	100	65	0	96
10	Fe3	1b	Et3N	94	41	0	91
11	Fe3	1b	K2CO3	37	26	0	88

^aReaction conditions: compounds 1a and 1b (0.1 mmol), Fe catalyst (10.0 mol %), BocNHOMs (0.4 mmol), and piperidine (0.6 mmol) in CH₂Cl₂ (0.5 mL) were stirred at −23 °C for 17 h under a N₂ atmosphere.

^bDetermined by ¹H NMR using 1,1,2,2-tetrachloroethane as the internal standard.

^cIsolated yields.

^dThe ee of compound 2 was determined by high-performance liquid chromatography (HPLC) on a chiral stationary phase.

With satisfactory reaction conditions in hand (entry 5 in Table 1), we next investigated the scope of this reaction toward obtaining functionalized N-Boc-β³-tryptophans (Figure 1). 3-Indolepropionic acids with the indole moiety functionalized at the 5 position provided the N-Boc-β³-tryptophans 4–19 in 46–72% yields and from 94 to >99.5% ee. The results demonstrate that the method tolerates alkyl, alkenyl, alkynyl, aryl, heteroaryl, electron-withdrawing, and electron-donating substituents. Likewise, N-Boc-β³-tryptophans 20–23, bearing substituents in the 6 position of the indole moiety were synthesized in 53–62% yields and from 97 to >99.5% ee. A methyl scan revealed that methyl groups at the 4 position (24, 74% yield, 95% ee) or 7 position (25, 62% yield, 95% ee) are well-tolerated, while a methyl group at the 2 position provided respective N-Boc-β³-tryptophan 26 in only a 40% yield and with 51% ee. Interestingly, a methyl group at the α position of carboxylic acid does not affect the amination, affording N-Boc-β³-tryptophan 27 in 63% yield and with >99% ee as a 1:1 mixture of diastereomers when starting from the racemic substrate. Finally, indole alkylation reduces the enantiomeric excess of the product, as shown for N-Boc-β³-tryptophans 28–30.¹⁷ To summarize this part, these results demonstrate that this method provides general and convenient access to N-Boc-β³-tryptophans with high enantiomeric purity using iron catalysis. To the best of our knowledge, this is the first catalytic asymmetric synthesis of suitably N-protected β³-tryptophans. Beletskaya and co-workers recently reported an enantioselective copper(II)-catalyzed synthesis of β³-tryptophan derivatives via conjugate addition of indoles to diethyl phthalimidomethylenemalonate.¹⁸⁻²⁰ However, the resulting β³-tryptophans contain an N-phthalimido group that is very difficult to remove.

Figure 1.

Scope with 3-indolepropionic acid substrates. Reaction conditions: acid substrate (0.1 mmol), (R)-Fe3 (10.0 mol %), BocNHOMs (0.4 mmol), and piperidine (0.6 mmol) in CH₂Cl₂ (0.5 mL, 0.2 M) were stirred at −23 °C for 17 h under a N₂ atmosphere. ^aReacted for 38 h. ^bScale: 0.6 mmol. ^c(R)-Fe2 was used as the catalyst instead.

The reaction is anticipated to proceed through a pathway similar to our previously documented α-amination of carboxylic acids.⁵ However, a notable contrast lies in the amination of iron-coordinated carboxylate substrates occurring at the β position, resulting in the formation of β-amino acids as opposed to α-amino acids obtained previously through α-aminations. This proposed mechanism finds support in standard mechanistic experiments, detailed in the Supporting Information. Furthermore, we conducted density functional theory (DFT) studies to assess the reaction’s energetics (Figure 2). Our DFT calculations revealed that the reaction proceeds through a sequence of HAT and radical rebound on the quintet potential energy surface. Triplet and open-shell singlet states were both found to consistently lie >20 kcal/mol above the quintet state. After substrate coordination and activation steps as established in our previous mechanistic investigations,⁵ iron-bound nitrene species I is formed (Figure 2a). Complex I can undergo an intramolecular HAT at either the β-carbon position via TS-1 or the α position via TS-2. We found TS-1 to be 6.7 kcal/mol lower in energy than TS-2 (Figure 2b), and the post-HAT diradical structure II was calculated to be 12.2 kcal/mol lower than III. These results indicate that HAT at the β position is overwhelmingly more favorable than that at the α position both kinetically and thermodynamically. The radical rebound through TS-3 proceeds with a very low barrier of 2.6 kcal/mol and, thus, most likely occurs in a stereoretentive manner. To further investigate the role of the 3-indole substituent on the regioselectivity of the reaction, we also computed HAT transition states for 3-phenylpropionic acid (see the Supporting Information for details). While 3-phenylpropionic acid also shows a preference for the β-HAT pathway that is consistent with experimental observations (entry 1 in Table 1), the activation barrier difference is significantly lower at 3.3 kcal/mol. The much more pronounced β-HAT selectivity for the 3-indole substrate can be attributed to the fact that the resulting carbon radical is capable of delocalizing its unpaired electron α to indole nitrogen, which stabilizes both the diradical intermediate and the HAT transition state.

Figure 2.

(a) Calculated free energy diagram of the regioselective C(sp³)–H amination reaction of 3-indolepropionic acid catalyzed by (R,R)-FeBIP. All structures shown are in the quintet spin state. The tert-butyl group in Boc was truncated to methyl for the calculations. (b) Calculated structures of the HAT transition states. Energies are in kcal/mol, and interatomic distances are in Å.

Our remaining main objective was to ascertain the reason for the unexpectedly high enantiomeric excess values observed for the N-Boc-β³-tryptophan products. To address this, we examined conversion, yield, and ee values over varying reaction times for transformation 1b → 2b (Figure 3). Interestingly, these experiments unveiled a steady increase in the ee value of compound 2b with the reaction time, with the overall yield peaking at 17 h. For instance, after 5 min, the ee value reached 88% (29% yield), reaching 98% ee after 17 h (100% conversion and 73% yield) and exceeding 99% ee after 38 h (54% yield). These experiments imply that the inherent asymmetric induction of the β-amination of compound 1b is 88% ee, and the further increase in the ee value in the course of the reaction stems from the destruction of the minor enantiomer. Indeed, subjecting rac-2b to standard reaction conditions yielded compound 2b with 22% ee in a reduced yield of 51%. A byproduct, ketoacid 31, was isolated, presumably formed through double β-amination, followed by hydrolysis into a keto group. These experiments elucidate the overall moderate yields but exceptionally high enantioselectivities of isolated N-Boc-β³-tryptophans.

Figure 3.

Understanding the high enantiomeric excess. (a) Conversion, yield, and ee values for the reaction 1b → 2b under standard reaction conditions as a function of the reaction time. (b) Subjecting rac-2b to the standard reaction conditions.

With regard to synthetic utility, the β-amination of 3-indolepropionic acids introduces valuable N-Boc-β³-tryptophans in a single step. These compounds can be readily utilized for various applications, such as solution- and solid-phase peptide synthesis, or used as building blocks for further conversions.^1,2 For example, brominated N-Boc-β³-tryptophan 23 was converted to methyl ester 32 and methylamide 33, reduced to aminoalcohol 34, and converted to 2-imidazolidinone 35 in two steps (Scheme 2).

Scheme 2. Follow-Up Chemistry.

In conclusion, we reported here the first general and straightforward catalytic asymmetric synthesis of N-Boc-β³-tryptophans using an iron-catalyzed C(sp³)–H amination of 3-indolepropionic acids. 3-Indolepropionic acids are easily available by conjugate addition of indoles to methyl acrylate followed by ester hydrolysis. The disclosed iron-catalyzed C(sp³)–H amination provides N-Boc-β³-tryptophans typically with very high ee values and can therefore be directly utilized for many applications including the incorporation of modified β³-tryptophans into peptides or as valuable chiral synthetic building blocks. The method incorporates two key sustainability principles: utilizing iron as a plentiful, safe, and ecofriendly catalyst alongside achieving efficient enantioselective C(sp³)–H functionalization.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c03130.

• Experimental procedures, analytical data, NMR spectra, HPLC traces, and crystallographic data (PDF)

The authors declare no competing financial interest.