New Routes to Lipophilic Amino Acids: Synthesis of Alkynyl and Fluoro-Containing Alanine Derivatives

Abstract

Branched α-amino acids incorporating an alkynyl group have been prepared by copper-catalysed reaction of a serine-derived organozinc reagent with bromoallenes. Substantial improvements to our previously reported Negishi cross-coupling of the serine-­derived organozinc reagent with cycloalkenyl triflates are possible using a combination of LiCl and SPhos as ligand. Finally, we report a preliminary example of addition of HF to cycloalkenyl alanine ­derivatives, leading to the corresponding tertiary fluoride.

amino acids - alkynes - cross-coupling - fluorine - zinc

References and Notes

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18

General Method for the Preparation of Alkynes 4:
The organozinc reagent 1 was prepared from protected iodoalanine 9 (329 mg, 1 mmol) as a ca. 1 M solution in DMF according to our previously reported method.^¹¹ CuBr˙DMS (20.6 mg, 0.1 mmol) was gently heated under vacuum in a dry flask until the powder turned light green, and was then allowed to cool under nitrogen. DMF (0.6 mL) and the bromoallene 8 (1.1 mmol) were added. The reaction mixture was cooled to -10 ˚C. After 2 min stirring at -10 ˚C, a solution of the organozinc reagent 1 (1 mL of a 1 M solution in DMF, 1 mmol) was added dropwise via syringe over 10 min. The reaction mixture was stirred for the time indicated at either -10 ˚C or 0 ˚C. The reaction mixture was applied directly to a silica gel column, which was eluted (5% Et₂O in toluene) to give the alkynes 4 ^¹9-²¹ and the allenes 10 as light yellow oils.
General Method for the Preparation of Alkenes 12: The cycloalken-1-yl triflate 3 (1.3 mmol, 1.3 equiv), Pd₂(dba)₃ (22 mg, 2.5 mol%), SPhos (21 mg, 5 mol%) and LiCl (1.8 mmol, 1.8 equiv), if required, were added at r.t. to the organozinc reagent 1 (1 mL of a ca. 1 M solution in DMF). The reaction mixture was stirred at r.t. overnight under a positive pressure of nitrogen, and then applied directly to a silica gel column, which was eluted (10% EtOAc in petroleum ether) to give the cross-coupled product 12.
( R )-2-Amino-3-(1-fluorocyclopentyl)propionic Acid Methyl Ester (5): Alkene ent-12a (492 mg, 1.83 mmol) was dissolved in toluene (4 mL) in a Teflon bottle, cooled to 0 ˚C and stirred vigorously. HF-pyridine (70% HF, 3.2 mL, CAUTION: very toxic) was added and the bottle was sealed. After 2 h, the reaction mixture was carefully transferred into a slurry of CaCO₃ (12.8 g) in H₂O (50 mL) and CH₂Cl₂ (35 mL) cooled to 0 ˚C. The mixture was stirred while the pH was adjusted to ca. 10 by addition of sat. aq Na₂CO₃, followed by stirring for a further 30 min. Celite (6.4 g) was washed with Na₂CO₃ solution, H₂O, EtOH, EtOAc and CH₂Cl₂ in sequence and added to the slurry. The suspension was filtered and the filter cake was washed with CH₂Cl₂ (50 mL in portions) and H₂O (25 mL). The phases were separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic phases were washed with sat. aq NaHCO₃ (20 mL) and evaporated. The crude mixture of amino esters (0.253 g) was dissolved in 1,4-dioxane (4 mL), aq sat. NaHCO₃ (6 mL) was added and the mixture was cooled to 0 ˚C with stirring. Boc₂O (0.323 g, 1.48 mmol) in 1,4-dioxane (4 mL) was added to the reaction mixture. The reaction mixture was allowed to reach r.t. and stirred for 1 h. The reaction mixture was diluted with Et₂O (10 mL) and H₂O (10 mL) and the layers were separated. The aqueous phase was extracted with Et₂O (2 × 10 mL). The combined organic phases were washed with H₂O and brine (10 mL each) and evaporated. The product was purified by gradient column chromatography [Column 40 mm i.d. × 82 mm, loaded with 50 g Biotage KP-Sil (silica gel) 2-17% EtOAc in iso-hexane] to give 5 ^²² (158 mg, 30% over two steps) and recovered ent-12a (160 mg, 32%).

19

Characterisation data for alkyne 4a: [α]_D ^²¹ +9.8 (c = 1.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 1.26 (s, 3 H), 1.27 (s, 3 H), 1.42 (s, 9 H), 1.74 (dd, J = 9.1, 14.0 Hz, 1 H), 1.90 (dd, J = 4.3, 14.2 Hz, 1 H), 2.15 (s, 1 H), 3.71 (s, 3 H), 4.43-4.48 (m, 1 H), 5.17 (d, J = 7.7 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 28.4, 28.9, 29.8, 29.8, 44.3, 51.8, 52.2, 69.2, 79.9, 90.5, 155.2, 173.5. IR (ATR): 3293, 2973, 1744, 1705, 1508, 1436, 1391, 1366, 1279, 1246, 1209, 1160, 1048, 1028, 868, 779, 629 cm^-¹. HRMS (ES): m/z [M + H⁺] calcd for C₁₄H₂₄NO₄: 270.1705; found: 270.1716.

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Characterisation data for alkyne 4b: [α]_D ^²¹ +2.9 (c = 10.2, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 1.42 (s, 9 H), 1.45-1.54 (m, 2 H), 1.55-1.72 (m, 2 H), 1.73-1.89 (m, 3 H), 1.90-2.00 (m, 2 H), 2.04 (dd, J = 4.3, 14.2 Hz, 1 H), 2.18 (s, 1 H), 3.71 (s, 3 H), 4.43-4.56 (m, 1 H), 5.18 (d, J = 7.7 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 23.4, 23.8, 28.4, 40.2, 40.5, 41.1, 41.9, 52.2, 52.5, 70.1, 79.8, 89.8, 155.2, 173.5. IR (ATR): 3294, 2954, 2874, 1709, 1507, 1437, 1391, 1366, 1248, 1214, 1162, 1049, 1019, 868, 778, 630 cm^-¹. HRMS (ES): m/z [M + H⁺] calcd for C₁₆H₂₆NO₄: 296.1862; found: 296.1864.

21

Characterisation data for alkyne 4c: mp 56-57 ˚C; [α]_D ^²¹ +2.0 (c = 7.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 1.04-1.27 (m, 3 H), 1.42 (s, 9 H), 1.56-1.70 (m, 5 H), 1.70-1.85 (m, 3 H), 1.89 (dd, J = 4.1, 14.1 Hz, 1 H), 2.33 (s, 1 H), 3.70 (s, 3 H), 4.45-4.51 (m, 1 H), 5.21 (d, J = 7.6 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 22.5, 22.6, 25.8, 28.4, 35.2, 37.0, 38.0, 44.3, 51.2, 52.2, 71.9, 79.8, 88.5, 155.2, 173.7. IR (ATR): 3306, 2930, 2857, 2360, 1744, 1712, 1506, 1449, 1391, 1366, 1252, 1206, 1165, 1048, 1023, 866, 776, 632 cm^-¹. HRMS (ES): m/z [M + H⁺] calcd for C₁₇H₂₈NO₄: 310.2018; found: 310.2017.

22

Characterisation data for 5: mp 47-51 ˚C; [α]_D ^²¹ -5.2 (c = 1.0, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 1.43 (s, 9 H), 1.50-1.70 (m, 4 H), 1.73-1.85 (m, 2 H), 1.93-2.07 (m, 2 H), 2.10-2.32 (m, 2 H), 3.72 (s, 3 H), 4.40-4.50 (m, 1 H), 5.21 (br d, J = 7.0 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 23.5, 23.6, 28.3, 37.65 (d, J = 13 Hz), 37.8 (d, J = 13 Hz), 39.9 (d, J = 23 Hz), 51.3, 52.3, 79.9, 105.9 (d, J = 172 Hz), 155.2, 173.1. ^¹9F NMR (376 MHz, CDCl₃): δ = -142.7.
IR (ATR): 3364, 2974, 1750, 1718, 1508, 1367, 1167 cm^-¹. HRMS (ES): m/z [M + H⁺] calcd for C₁₄H₂₅NO₄F: 290.1768 (base peak is 579 [M₂H⁺]); found: 290.1769.