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Synlett 2012(2): 243-246  
DOI: 10.1055/s-0031-1290123
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Claudia Wuttkea, Rebecca Forda, Matthew Lilleya, Urszula Grabowskab, Daniel Wikteliusb, Richard F. W. Jackson*a
a Department of Chemistry, Dainton Building, The University of Sheffield, Sheffield S3 7HF, UK
Fax: +44(114)2229303; e-Mail: r.f.w.jackson@shef.ac.uk;
b Medivir AB, PO Box 1086, 14122 Huddinge, Sweden
Further Information

Publication History

Received 24 November 2011
Publication Date:
22 December 2011 (online)

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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.

Key words

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

    References and Notes

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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.

20

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.