Synlett 2016; 27(06): 919-923
DOI: 10.1055/s-0035-1561502
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Novel Amino Acids Containing Cubane

Joanna Wlochal*
a  Oncology, Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10, UK   Email: joannawlochal@gmail.com
,
Robert D. M. Davies
a  Oncology, Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10, UK   Email: joannawlochal@gmail.com
,
Jonathan Burton
b  Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
› Author Affiliations
Further Information

Publication History

Received: 22 October 2015

Accepted after revision: 23 November 2015

Publication Date:
28 December 2015 (online)


Abstract

The synthesis of four novel cubane-containing amino acids/protected amino acids is reported. Cubane glycine 5 was prepared, from readily available intermediate 9. Cubane alanine 6 was prepared after developing conditions for the hydrogenation of unsaturated precursor 16. Two further β-amino acids were prepared employing a ­Mitsunobu C–C bond-forming reaction and the addition of a lithium amide to an α,β-unsaturated ketone.

Supporting Information

 
  • References and Notes

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  • 41 Representative Experimental Procedures and Characterisation Data See Supporting Information for the characterisation data of other products. Methyl 2-Amino-2-(cuban-1-yl)acetate (12): To a solution of triphenylphosphine polymer bound (3 mmol/1 g of resin, 0.640 g, 1.93 mmol) in THF (6 mL) was added methyl 2-azido-2-(cuban-1-yl)acetate (11; 0.280 g, 1.29 mmol), and the reaction was stirred at r.t. for 2 h. To the resulting solution H2O (0.23 mL, 12.89 mmol) was added and the reaction was heated under reflux for 5 h. The reaction mixture was then filtered, the resin was washed with 10% MeOH in CH2Cl2 (100 mL) and the filtrate was evaporated to dryness to afford racemic methyl 2-amino-2-(cuban-1-yl)acetate (12; 0.227 g, 92%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 3.64 (s, 1 H), 3.71 (s, 3 H), 3.85–3.90 (m, 3 H), 3.91–3.95 (m, 3 H), 3.97–4.05 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ = 44.2, 47.1, 48.7, 51.8, 56.0, 59.2, 174.2. HRMS (ESI+): m/z [M + H]+ calcd for C11H14NO2: 192.1019; found: 192.1025. IR (neat): 3583, 3184, 2978, 1738, 1660 cm–1. 2-Amino-3-(cuban-1-yl)propanoic Acid (6): A solution of TFA (10% in CH2Cl2) (3.90 mL) was added to methyl 2-[(tert-butoxycarbonyl)amino]-3-(cuban-1-yl)propanoate (17; 0.120 g, 0.39 mmol) at r.t. The resulting solution was stirred at r.t. for 2 h. The reaction mixture was concentrated, then diluted with CH2Cl2 (5.0 mL) and washed sequentially with sat. NaHCO3 (5.0 mL), and sat. brine (5.0 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford racemic product methyl 2-amino-3-(cuban-1-yl)propanoate (0.080 g, 99%) as a white solid. 1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 2 H), 1.93 (dd, J = 7.0, 14.3 Hz, 1 H), 2.00 (dd, J = 6.9, 14.3 Hz, 1 H), 3.55 (t, J = 7.0 Hz, 1 H), 3.70 (s, 3 H), 3.74–3.79 (m, 3 H), 3.84–3.90 (m, 3 H), 3.97–4.04 (m, 1 H). To a solution of methyl 2-amino-3-(cuban-1-yl)propanoate (0.068 g, 0.33 mmol) in THF (1.5 mL) at 0 °C was added dropwise a solution of NaOH (2.0 M in MeOH, 0.18 mL, 0.36 mmol). The resulting mixture was stirred at r.t. overnight. The reaction mixture was evaporated to dryness, redissolved in H2O (5.0 mL), and extracted with CH2Cl2 (5.0 mL). The aqueous layer from the extraction was carefully acidified with 1 M HCl to pH ca. 4, the solvent was evaporated to dryness and the crude product was redissolved in CH2Cl2–MeOH. The filtrate was concentrated under reduced pressure to give racemic 2-amino-3-(cuban-1-yl)propanoic acid (6; 0.060 g, 95%) as a white powder; mp 160 °C (browned), >200 °C (dec.). 1H NMR (400 MHz, MeOD): δ = 2.09 (dd, J = 14.5, 8.1 Hz, 1 H), 2.13 (dd, J = 14.5, 6.2 Hz, 1 H), 3.86–3.94 (m, 6 H), 3.93–3.98 (m, 1 H), 3.99–4.07 (m, 1 H). 13C NMR (101 MHz, D2O, 30 °C): δ = 33.9, 44.1, 47.9, 48.5, 51.0, 54.9, 172.9. HRMS (ESI+): m/z [M + H]+ calcd for C11H14NO2: 192.1019; found: 192.10195. IR (neat): 3410, 2974, 2908, 1740 cm–1. Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(cuban-1-yl)propanoate (17): To a solution of (Z)-methyl 2-[(tert-butoxycarbonyl)amino]-3-(cuban-1-yl)acrylate (16; 0.100 g, 0.33 mmol) in 1 M NH3 in MeOH (6.0 mL) was added diisopropylethylamine (57.0 μL, 0.043 g, 0.33 mmol) and the reaction mixture was hydrogenated in the H-Cube hydrogenation cell at r.t., using a 30 mm RaNi cartridge and a flow rate of 0.3 mL/minute under 40 bar H2, (pressure regulator to 30), several cycles were performed over 24 h. The solution was concentrated, to provide crude product, that was purified by flash silica chromatography, elution gradient 0% to 20% EtOAc in heptane to afford racemic methyl 2-[(tert-butoxycarbonyl)amino]-3-(cuban-1-yl)propanoate (17; 0.080 g, 79%) as a white solid; mp 92.6–94.0 °C. 1H NMR (400 MHz, CDCl3): δ = 1.43 (s, 9 H), 1.96 (dd, J = 7.9, 14.4 Hz, 1 H), 2.05 (dd, J = 6.2, 14.4 Hz, 1 H), 3.72 (s, 3 H), 3.77 (dt, J = 2.2, 5.5 Hz, 3 H), 3.86 (q, J = 5.0 Hz, 3 H), 3.98 (tt, J = 2.4, 4.9 Hz, 1 H), 4.39 (q, J = 8.1 Hz, 1 H), 4.98 (d, J = 8.6 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 28.5, 36.4, 44.6, 48.2, 49.0, 51.2, 52.4, 56.5, 79.9, 155.0, 174.0. HRMS (ESI+): m/z [M + H]+ calcd for C17H24NO4: 306.1700; found: 306.1700. IR (neat): 3369, 2968, 2920, 1749, 1686 cm–1. Ethyl 3-Amino-2-(cuban-1-ylmethyl)propanoate (20): A solution of ethyl 3-(cuban-1-yl)-2-cyanopropanoate (19; 0.150 g, 0.65 mmol) in 1 M NH3 in EtOH (65.0 mL) at r.t. was hydrogenated in the H-Cube hydrogenation cell using a 30 mm RaNi cartridge, a flow rate of 0.2 mL/min, with the pressure regulator set to 20 bar and an effective H2 pressure of 30 bar. Two cycles were performed. The solution was then concentrated to provide the crude product, that was purified by flash silica chromatography, elution gradient 0% to 10% 1 M methanolic NH3 in CH2Cl2. Pure fractions were evaporated to dryness to afford ethyl 3-amino-2-(cuban-1-ylmethyl)propanoate (20; 80.0 mg, 53%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.75 (dd, J = 5.6, 14.3 Hz, 1 H), 1.94 (dd, J = 8.8, 14.3 Hz, 1 H), 2.48–2.57 (m, 1 H), 2.79 (dd, J = 4.7, 12.8 Hz, 1 H), 2.91 (dd, J = 8.7, 12.8 Hz, 1 H), 3.68–3.75 (m, 3 H), 3.81–3.88 (m, 3 H), 3.99–4.04 (m, 1 H), 4.10 (dq, J = 10.8, 7.1 Hz, 1 H), 4.16 (dq, J = 10.8, 7.1 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 14.3, 33.7, 44.3, 44.6, 45.8, 48.4, 48.9, 57.9, 60.5, 175.9. HRMS (ESI+): m/z [M + H]+ calcd for C14H20NO2: 234.1489; found: 234.1490. IR (neat): 3367, 3292, 2974, 1728 cm–1. tert-Butyl 3-(Benzylamino)-3-(cuban-1-yl)propanoate (8): To a solution of tert-butyl 3-(cuban-1-yl)-3-(dibenzylamino)propanoate (23; 0.100 g, 0.23 mmol) in CH2Cl2–H2O (4.4 mL, 10:1) at r.t. was added DDQ (0.064 g, 0.28 mmol) portionwise. The resulting solution was stirred at r.t. until consumption of starting material (TLC). The reaction mixture was poured onto sat. NaHCO3 (10 mL), extracted with CH2Cl2 (3 × 10 mL), the organic layer was dried (MgSO4), filtered and evaporated to afford a deep red residue. The crude product was purified by flash silica chromatography, elution gradient 0% to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 3-(benzylamino)-3-(cuban-1-yl)propanoate (8; 0.065 g, 82%) as a light pink oil. 1H NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.29 (dd, J = 7.6, 14.8 Hz, 1 H), 2.36 (dd, J = 5.0, 14.8 Hz, 1 H), 3.28 (dd, J = 5.0, 7.6 Hz, 1 H), 3.81 (s, 2 H), 3.86–3.96 (m, 6 H), 3.97–4.05 (m, 1 H), 7.20–7.26 (m, 1 H), 7.28–7.36 (m, 4 H). 13C NMR (101 MHz, CDCl3): δ = 28.3, 36.4, 44.4, 47.6, 48.4, 52.0, 55.5, 61.8, 80.5, 126.9, 128.2, 128.4, 141.1, 172.4. HRMS (ESI+): m/z [M + H]+ calcd for C22H28NO2: 338.2115; found: 338.2117. IR (neat): 3333, 2976, 1726, 1151 cm–1.