Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ­ent-Sitagliptin

Abstract

The presence of nitrogen atoms in most chiral pharmaceutical drugs has motivated the development of numerous strategies for the synthesis of enantiomerically enriched amines. Current methods are based on multistep transformations of functionalized allylic electrophiles to form chiral allylic amines. The enantioselective allylic amination of nonactivated olefins would represent a more direct and more attractive strategy. We report the enantio­selective synthesis of ent-sitagliptin through an allylic amination of a nonactivated terminal olefin.

Key words

asymmetric catalysis - aminations - drugs - rearrangements - palladium

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• 13 N-[(1S)-1-Benzylprop-2-en-1-yl]-N-{[(phenylsulfonyl)amino]sulfanyl}benzenesulfonamide (11b); Typical Procedure A 0.5 M solution of diimide 8 (685 mg, 2 mmol) in Et₂O (4 mL) was cooled to 0 °C and treated with but-3-en-1-ylbenzene (6 mmol, 3 equiv), and the mixture was stirred at 4 °C for 12 h. The ene adduct 9, which formed as a white precipitate, was purified by vacuum filtration at r.t., washed with Et₂O (20–40 mL), and dried under vacuum. The ene adduct 9 was then suspended in DCE (5 mL) and the suspension was cooled to –20 °C then treated with a Pd–ligand complex in DCE (10 mL). The Pd–ligand complex was prepared by mixing Pd(TFA)₂ (10 mol%) and ligand 10b (20 mol%) in DCE (10 mL), and stirring for 30 min at 50 °C. The ene adduct-containing mixture was warmed to –15 °C and stirred for 7 d. Purification by flash chromatography [hexanes–EtOAc (20:1 to 5:1)] gave a clear oil; yield: 887 mg (94%, two steps); [α]_D ²³ = +93.0 (c 1.0, CH₂Cl₂). The enantiomeric excess of the product was determined to be 93% by comparison with a sample of the racemate. IR (thin film): 3234, 1447, 1352, 1165, 1088, 806 cm^–1. ¹H NMR (500 MHz, CDCl₃, 50 °C): δ = 7.90 (d, J = 7.5 Hz, 2 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 4 H), 7.37 (m, 2 H), 7.18–7.10 (m, 6 H), 6.95 (s, 1 H), 6.10 (br s, 1 H), 5.07 (m, 2 H), 4.80 (m, 1 H), 3.23 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃, 50 °C): δ = 140.9, 139.6, 137.8, 133.4, 133.3, 129.6, 129.4, 129.1, 28.6, 127.9, 127.3, 126.7, 118.9, 68.2, 39.9. HRMS (ESI): m/z [M + Na]⁺ calcd for [C₂₂H₂₂N₂O₄S₃Na]⁺: 497.0634; found: 497.0645.