Synthesis of β-anti-Substituted α-Amino Acids through Iridium-Catalyzed Alkylation/Chelation-Controlled Nucleophilic Addition

Abstract

An Ir/Ag dual-catalysis method has been developed for the synthesis of β-anti-substituted α-amino acids in high yields and with good enantioselectivities through a ligand/chelation-control strategy. By using this chiral-ligand-control strategy, a natural product for the regulation of a plant-growth hormone was synthesized on a gram scale in three steps.

Key words

iridium catalysis - allylic carbonates - asymmetric catalysis - natural products - dual catalysis - amino acids

Publication History

Received: 21 January 2022

Accepted after revision: 11 February 2022

Article published online:
08 March 2022

• References and Notes

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• 13 tert-Butyl (2S,3S)-2-Amino-3-{[(4-methoxybenzyl)oxy] methyl}pent-4-enoate (4a); Typical Procedure [Ir(cod)Cl]₂ (4.0 mg, 0.006 mmol, 0.03 equiv), ligand (S,S,S)-L (6.4 mg, 0.012 mmol, 0.06 equiv), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD; 2.8 mg, 0.02 mmol, 0.1 equiv) were dissolved in THF (0.5 mL) under N₂, and the mixture was vigorously stirred at 50 °C for 30 min. The resulting dark-red solution was added to a mixture of 1a (88.5 mg, 0.30 mmol, 1.5 equiv), Ag₂CO₃ (5.5 mg, 0.02 mmol, 0.1 equiv), and DABCO (22.5 mg, 0.24 mmol, 1.2 equiv) in a screw-capped glass vial, affording a yellow solution. To this solution was added a solution of the allylic carbonate ester 2a (53 mg, 0.2 mmol, 1.0 equiv) in THF (0.5 mL). The vessel was purged with N₂ and the resulting solution was stirred at r.t. for 8–12 h. The ¹H NMR spectrum of the crude mixture was recorded to determine the diastereomeric ratio of the product. The mixture was then purified by flash chromatography to afford product 3a. The product diastereomers were not separable under these conditions. A 0.1 M solution of 3a (0.2 mmol) in 1:1 THF–H₂O at r.t. was treated with 15% aq citric acid (5.0 mL), and the resulting mixture was stirred at r.t. until the starting material was completely consumed (TLC). The reaction was then quenched by addition of sat. aq NaHCO₃, and the mixture was diluted with EtOAc. The organic phases were separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried (Na₂SO₄), filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 10%~20% EtOAc/hexans) to give a colorless oil; yield: 62.9 mg (98%); ee 99%. SFC: AD-H column (5.0% i-PrOH–hexanes, 1 mL/min, λ = 200 nm, 25 °C); R_t = 11.48 min (major), 12.48 min (minor). ¹H NMR (400 MHz, CDCl₃): δ = 7.27 (d, J = 8.4 Hz, 2 H), 6.90–6.85 (m, 2 H), 5.73–5.61 (m, 1 H), 5.19–5.08 (m, 2 H), 4.52–4.41 (m, 2 H), 3.80 (s, 3 H), 3.65–3.57 (m, 2 H), 3.49 (dd, J = 9.3, 5.8 Hz, 1 H), 2.86 (tt, J = 8.7, 4.6 Hz, 1 H), 1.44 (s, 9 H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 174.3, 159.2, 133.8, 130.3, 129.3, 118.6, 113.8, 81.0, 72.8, 70.1, 55.2, 54.9, 46.9, 28.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₈NO₄: 322.2013; found: 322.2012.