Synthesis of Novel Amino Acids Containing Cubane

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.

Key words

cubane - cubane glycine - cubane alanine - amino acids synthesis - medicinal chemistry - caged amino acids

• References and Notes

• 1 Kwon I, Lim SI. Macromol. Chem. Phys. 2013; 214: 1295
• 2 Chen S, Gopalakrishnan R, Schaer T, Marger F, Hovius R, Bertrand D, Pojer F, Heinis S. Nat. Chem. 2014; 6: 1009
• 3 Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han S.-P, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. J. Med. Chem. 2005; 48: 5025
• 4 Komarov IV, Grigorenko AO, Turov AV, Khilya VP. Russ. Chem. Rev. 2004; 73: 785
• 5 Kotha S, Goyal D, Chavan AS. J. Org. Chem. 2013; 78: 12288
• 6 Gibson SE, Guillo N, Jones JO, Buck IM, Kalindjian SB, Roberts S, Tozer MJ. Eur. J. Med. Chem. 2002; 37: 379
• 7 Mosberg HI, Lomize AL, Wang C, Kroona H, Heyl DL, Sobczyk-Kojiro K, Ma W, Mousigian C, Porreca F. J. Med. Chem. 1994; 37: 4371
• 8 Wlochal J, Davies RD, Burton J. Org. Lett. 2014; 16: 4094
• 9 Pellicciari R, Costantino G, Giovagnoni E, Mattoli L, Brabet I, Pin J.-P. Biorg. Med. Chem. Lett. 1998; 8: 1569
• 10 Curry K. PCT Int. Appl WO 2004024709 A2, 2004
• 11 Churches QI, Mulder RJ, White JM, Tsanaktsidis J, Duggan PJ. Aust. J. Chem. 2012; 65: 690
• 12 Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600
• 13 The amino acid 4 was incorporated into a dipeptide but it did not prove possible to hydrolyse the tert-butylsulfinamide to form the corresponding amine. Neither was it possible to hydrolyse the tert-butylsulfinamide in the ethyl ester corresponding to the amino acid 4 (see ref. 11).
• 14 For a very recent review on the synthesis and chemistry of cubane and its derivatives see: Biegasiewicz KF, Griffiths JR, Savage GP, Tsanaktsidis J, Priefer R. Chem. Rev. 2015; 115: 6719
• 15 Eaton PE. Angew. Chem. Int. Ed. 1992; 31: 1421
• 16 Lal B, Pramanik BN, Manhas MS, Bose AK. Tetrahedron Lett. 1977; 1977
• 17 The absolute configuration of the amino acids was assigned based on the VCD analysis performed by Marie Rydén Landergren, AZ Mölndal, Sweden.
• 18 Silverman RB, Zhou JP, Eaton PE. J. Am. Chem. Soc. 1993; 115: 8841
• 19 We investigated the Ellman,¹² Schöllkopf,³⁹ and Erlenmeyer^20,40 amino acid syntheses in the attempted preparation of cubane alanine 6.
• 20 Schmidt U, Griesser H, Leitenberger V, Lieberknecht A, Mangold R, Meyer R, Riedl B. Synthesis 1992; 487
• 21 The stereochemistry of 16 was assumed to be Z by analogy with the work of Duggan and co-workers (see ref. 11).
• 22 The enantiomers of 17 could only be partially separated by chiral HPLC.
• 23 Steer D, Lew R, Perlmutter P, Smith AI, Aguilar M.-I. Biochemistry 2002; 41: 10819
• 24 Seebach D, Matthews JL. Chem. Commun. 1997; 2015
• 25 Seebach D, Namoto K, Mahajan YR, Bindschädler P, Sustmann R, Kirsch M, Ryder NS, Weiss M, Sauer M, Roth C, Werner S, Beer H.-D, Munding C, Walde P, Voser M. Chem. Biodiver 2004; 1: 65
• 26 Giuliano MW, Horne WS, Gellman SH. J. Am. Chem. Soc. 2009; 131: 9860
• 27 Abraham E, Claridge TD. W, Davies SG, Odell B, Roberts PM, Russell AJ, Smith AD, Smith LJ, Storr HR, Sweet MJ, Thompson AL, Thomson JE, Tranter GE, Watkin DJ. Tetrahedron: Asymmetry 2011; 22: 69
• 28 Iverson BL. Nature (London) 1997; 385: 113
• 29 Wada M, Mitsunobu O. Tetrahedron Lett. 1972; 1279
• 30 Kurihara T, Sugizaki M, Kime I, Wada M, Mitsunobu O. Bull. Chem. Soc. Jpn. 1981; 54: 2107
• 31 Eaton PE, Yip YC. J. Am. Chem. Soc. 1991; 113: 7692
• 32 When the more basic azadicarboxylate reagent, 1,1′-(azodicarbonyl)dipiperidine was used, even at lower temperatures, significant decomposition of cubane alcohol 18 was observed. Under certain reaction conditions rearrangement of the cubane core was observed.
• 33 Rearrangement is sensitive to the reaction conditions. For example, treatment of cubylmethyl alcohol with CBr₄ and PPh₃ yields cubylmethyl bromide,³¹ whereas treatment of the same alcohol with I₂ and PPh₃ under reflux³⁸ gives the rearranged homocubyl iodide.
• 34 We have yet to find conditions for the complete separation of the enantiomers of 7 and 8 using chiral HPLC.
• 35 Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
• 36 Herrmann JL, Kieczykowski GR, Schlessinger RH. Tetrahedron Lett. 1973; 2433
• 37 Removal of the second benzyl group proved to be very challenging. Under standard oxidative deprotection conditions, the reaction did not progress, and when excess of the oxidant was used, complete decomposition of the starting material was observed.
• 38 Della EW, Head NJ, Janowski WK, Schiesser CH. J. Org. Chem. 1993; 58: 7876
• 39 Schollkopf U. Pure Appl. Chem. 1983; 55: 1799
• 40 Balducci D, Conway PA, Sapuppo G, Müller-Bunz H, Paradisi F. Tetrahedron 2012; 68: 7374
• 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.