Visible-light photoredox synthesis of unnatural chiral α-amino acids

Unnatural chiral α-amino acids are widely used in fields of organic chemistry, biochemistry and medicinal chemistry, and their synthesis has attracted extensive attention. Although the asymmetric synthesis provides some efficient protocols, noble and elaborate catalysts, ligands and additives are usually required which leads to high cost. Distinctly, it is attractive to make unnatural chiral α-amino acids from readily available natural α-amino acids through keeping of the existing chiral α-carbon. However, it is a great challenge to construct them under mild conditions. In this paper, 83 unnatural chiral α-amino acids were prepared at room temperature under visible-light assistance. The protocol uses two readily available genetically coded proteinogenic amino acids, L-aspartic acid and glutamic acid derivatives as the chiral sources and radical precursors, olefins, alkynyl and alkenyl sulfones, and 2-isocyanobiphenyl as the radical acceptors, and various unnatural chiral α-amino acids were prepared in good to excellent yields. The simple protocol, mild conditions, fast reactions, and high efficiency make the method an important strategy for synthesis of diverse unnatural chiral α-amino acids.


Results and Discussion
Synthesis of compounds 3a-bm. At first, N-Bis(Boc)-Asp(OPht)-OMe (1a) was applied as the chiral source and radical precursor, 1-phenylprop-2-en-1-one (2a) as the radical receptor to optimize reaction conditions including photocatalysts, solvents, atmosphere, and time (see Supplementary Materials for the details), and the results showed that the optimal conditions for the decarboxylative coupling are as follows: 1 mol% [Ru(bpy) 3 ]Cl 2 as the photocatalyst, dichloromethane (DCM) as the solvent in the presence of diisopropylethylamine (DIPEA) and Hantzsch ester (HE) under vacuum and irradiation of visible light at room temperature. With the optimized photoredox conditions in hand, we next evaluated the scope of olefins as the radical acceptors, including α,β-unsaturated ketones, esters, amides and a sulfone (using N-Bis(Boc)-Asp(OPht)-OMe (1a) as the chiral source and radical precursor) (Fig. 2). For α,β-unsaturated ketones with aryl, the substrates containing electron-donating groups on the aryl rings provided higher yields than those containing electron-withdrawing groups (see 3a-l in Fig. 2). The α,β-unsaturated ketones with aliphatic alkyls also exhibited good reactivity (see 3m-o in Fig. 2), but the internal alkene was slightly weaker than terminal alkenes (compare 3n and 3o in Fig. 2). Three α,β-unsaturated esters were employed as the radical acceptors (see 3p-r in Fig. 2), and the substrate with α-phenyl provided the highest yield (see 3r in Fig. 2). Furthermore, α,β-unsaturated amides were also suitable radical acceptors (see 3s-af in Fig. 2). For the substrates made from primary arylamines, affect of the substituents on the aryl rings was not evident (see 3s-ad in Fig. 2). The substrates from aliphatic amines displayed slightly weaker reactivity (see 3ae and 3af in Fig. 2). We attempted a α,β-unsaturated sulfone, and it afforded the corresponding target product in 72% yield (see 3ag in Fig. 2). The visible-light photoredox decarboxylative couplings exhibited excellent tolerance of functional groups including amides, esters, ethers, C-F, C-Cl, C-Br bonds and cyan in the substrates. Further, we investigated N-Bis(Boc)-Glu(OPht)-OMe (1b) as the chiral source and radical precursor using the same olefins (Fig. 3). To our pleasure, the dacarboxylative couplings exhibited similar results to the reactions from N-Bis(Boc)-Asp(OPht)-OMe (1a). Therefore, the present method showed effective commonality which provides opportunity for construction of diverse chiral amino acids.
We investigated whether the dacarboxylative couplings above led to racemization of unnatural α -amino acid derivatives (3a-bm). At first, three racemates, Rac-3a, Rac-3s and Rac-3w, were prepared, and then the three racemates, 3a, 3s and 3w in Fig. 2 were determined by HPLC with ID-H chiral column using n-hexane/isopropanol (90:10) as the mobile phase (column pressure = 42 bar, flow rate = 1 ml/min), and the results exhibited that no racemization was observed in the synthesis of unnatural chiral α -amino acids (see Supplementary Information for the details).
Synthesis of compounds 5a-n. Inspired by the excellent results above, we continued synthesis of diverse unnatural chiral α -AAs. As shown in Fig. 4a, decarboxylative alkynylation of aspartic acid and glutamic acid derivatives with alkynyl sulfones was investigated. The corresponding α-AAs (5a-n) containing alkynyls were prepared in good yields, and the substrates with electron-donating groups on the aryl rings displayed slightly higher reactivity than those with electron-withdrawing groups. The method showed tolerance of functional groups Synthesis of compounds 7a, 7b, 9a and 9b. Furthermore, we extended reactions of aspartic acid and glutamic acid derivatives (1). As shown in Fig. 4b, coupling of 1 with alkenyl sulfone 6 afforded the corresponding chiral α -AAs (7a and 7b) containing alkene in 70% and 71% yields, respectively. When 2-isocyanobiphenyl 8 was used as the partner, chiral α-AAs (9a and 9b) with phenanthridine were obtained in good yields (Fig. 4c). The results above exhibit that the present strategy using aspartic acid and glutamic acid derivatives as the chiral sources and radical precursors can provide diverse unnatural chiral α -AAs for various fields at a lower cost.
A plausible mechanism on the visible-light photoredox decarboxylative couplings of aspartic acid and glutamic acid derivatives is suggested in Fig. 5 according to the results above and the previous references 18  radical E, and reaction of E with A gives product 3 freeing F. On the other hand, reaction of D with alkynyl sulfone (4) donates radical intermediate G, 28 and dissociation of radical H from G affords product 5.
In conclusion, we have developed novel and efficient approaches to unnatural chiral α -amino acids at room temperature under visible-light assistance, in which 83 unnatural chiral α -amino acids containing ketones, esters, amides, alkynes, alkene and phenanthridine on the side chains were prepared in good to excellent yields. The protocol uses two readily available genetically coded proteinogenic amino acids, L-aspartic acid and glutamic acid derivatives, as the chiral sources and radical precursors, olefins, alkynyl and alkenyl sulfones, and 2-isocyanobiphenyl as the radical acceptors, and the reactions exhibited excellent tolerance of functional groups. The strategy of keeping chiral α -carbon configuration great decreases cost, improves efficiency and declines waste. Therefore, the present researches pave the way for future synthesis of biological and pharmaceutical molecules containing amino acid and peptide fragments, and we believe that the present strategy will find wide applications in various fields.

Methods
General procedure for synthesis of compounds 3a-bm. To a 25-mL Schlenk tube equipped with a Teflon septum and magnetic stir bar were added [Ru(bpy) 3 ]Cl 2 (1.0 μ mol, 0.78 mg), N-Bis(Boc)-Glu(OPht)-OMe (1b) (0.10-0.15 mmol) (using 1b as the substrate), olefins (2) (0.10-0.15 mmol, if solid) (see Fig. 3 for amount of 1b and 2) and Hantzsch ester (HE) (0.15 mmol, 38 mg). The tube was evacuated and back-filled with nitrogen for three cycles and then sealed under an atmosphere of nitrogen. N-Bis(Boc)-Asp(OPht)-OMe (1a) (0.10-0.15 mmol) (using 1a as the substrate), olefins (2) (0.10-0.15 mmol, if liquid) (see Fig. 2 for amount of 1a and 2) and DIPEA (0.25 mmol, 42 μ L, 32.3 mg) were dissolved in 1.0 mL of dichloromethane (DCM), and then the solution was added to the tube by syringe. The resulting solution was freezed with liquid nitrogen, and the tube was degassed by alternating vacuum evacuation then allowing it to warm to room temperature for three cycles. The tube was irradiated with a 40 W fluorescent lamp at room temperature (approximately 2 cm away from the light source). After the complete conversion of the substrates (monitored by TLC), the reaction mixture was diluted with 20 mL of EtOAc, and the solution was filtered by flash chromatography. The filtrate was evaporated by rotary evaporator, and the residue was purified by silica gel column chromatography or preparative thin layer chromatography (pTLC) to give the desired product (3a-bm). General procedure for synthesis of compounds 5a-n and 7a,b. To a 25-mL Schlenk tube equipped with a Teflon septum and magnetic stir bar were added [Ru(bpy) 3 ]Cl 2 (1.0 μ mol, 0.78 mg), N-Bis(Boc)-Glu(OPht)-OMe (1b) (0.10-0.15 mmol) (using 1b as the substrate, see Fig. 4 for amount of 1b), alkynyl sulfone (4) (0.10 mmol) or alkenyl sulfone (6) (0.15 mmol, 48 mg) and Hantzsch ester (HE) (0.15 mmol, 38 mg). The tube was evacuated and back-filled with nitrogen for three cycles and then sealed under an atmosphere of nitrogen. N-Bis(Boc)-Asp(OPht)-OMe (1a) (0.10-0.15 mmol) (using 1a as the substrate, see Fig. 4 for amount of 1a) and DIPEA (0.25 mmol, 42 μ L, 32.3 mg) were dissolved in 1.0 mL of dichloromethane (DCM), and then the solution was added to the tube by syringe. The resulting solution was freezed with liquid nitrogen, and the tube was degassed by alternating vacuum evacuation then allowing it to warm to room temperature for three cycles. The tube was irradiated with a 40 W fluorescent lamp at room temperature (approximately 2 cm away from the light source). After the complete conversion of the substrates (monitored by TLC), the reaction mixture was diluted with 20 mL of EtOAc, and the solution was filtered by flash chromatography. The filtrate was evaporated by rotary evaporator, and the residue was purified by silica gel column chromatography or preparative thin layer chromatography (pTLC) to give the desired product (5a-n or 7a,b).
General procedure for synthesis of compounds 9a,b. To a 25-mL Schlenk tube equipped with a Teflon septum and magnetic stir bar were added [Ru(bpy) 3 ]Cl 2 (1.0 μ mol, 0.78 mg) and N-Bis(Boc)-Glu(OPht)-OMe (1b) (0.15 mmol) (using 1b as the substrate). The tube was evacuated and back-filled with nitrogen for three cycles and then sealed under an atmosphere of nitrogen. N-Bis(Boc)-Asp(OPht)-OMe (1a) (0.15 mmol) (using 1a as the substrate), 2-isocyanobiphenyl (8) (0.10 mmol, 19.3 mg) and DIPEA (0.25 mmol, 42 μ L, 32.3 mg) were dissolved in 1.0 mL of dichloromethane (DCM), and then the solution was added to the tube by syringe. The resulting solution was freezed with liquid nitrogen, and the tube was degassed by alternating vacuum evacuation then allowing it to warm to room temperature for three cycles. The tube was irradiated with a 40 W fluorescent lamp at room temperature (approximately 2 cm away from the light source). Some suspended solids appeared during the reaction. After the complete conversion of the substrates (monitored by TLC), the reaction mixture was diluted with 20 mL of EtOAc, and the solution was filtered by flash chromatography. The filtrate was evaporated by rotary evaporator, and the residue was purified by silica gel column chromatography or preparative thin layer chromatography (pTLC) to give the desired product (9).