Organometallics 2009, 28, 2927–2930
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Notes Novel Synthesis and Crystal Structure Analysis of rac-β-(Trimethylsilyl)alanine Steffen Falgner, David Schmidt, Ruediger Bertermann, Christian Burschka, and Reinhold Tacke* UniVersita¨t Wu¨rzburg, Institut fu¨r Anorganische Chemie, Am Hubland, D-97074 Wu¨rzburg, Germany ReceiVed February 18, 2009 Summary: A new efficient, conVenient, and cost-saVing multistep synthesis of rac-2-amino-3-(trimethylsilyl)propanoic acid (racβ-(trimethylsilyl)alanine, rac-4) has been deVeloped, starting from diethyl malonate (total yield 25%). In addition, rac-4 has been structurally characterized by single-crystal X-ray diffraction.
Scheme 1
Nonproteinogenic amino acids play an increasingly important role in medicinal chemistry.1 They are challenging precursors and building blocks for the synthesis of novel peptidic and nonpeptidic drugs. In this context, silicon-containing amino acids are of great interest. Already in 1956, the first synthesis of a silicon-containing R-amino acid, 2-amino-3-(trimethylsilyl)propanoic acid (β-(trimethylsilyl)alanine, 4), was reported in the literature and since that time attracts lively interest from both academia and industry.2-12 Various methods for the preparation of rac-4,2,3 (R)-4,4-11 and (S)-45,7-10 have been developed, and (R)-4 and (S)-4 have been successfully used as building blocks for the synthesis of biologically active decapeptides (GnRH antagonist).8,10 In addition, a series of compounds derived from rac-4 and (R)-4 have recently been claimed to exhibit cathepsin inhibitory activity.12 In search for an alternative, efficient, convenient, and cost-saving synthesis of rac-4, we have * To whom correspondence should be addressed. Phone: +49-931-8885250. Fax: +49-931-888-4609. E-mail:
[email protected]. (1) (a) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc., Perkin Trans. 1 2000, 4197–4212. (b) Pojitkov, A. E.; Efremenko, E. N.; Varfolomeev, S. D. J. Mol. Catal. B: Enzymatic 2000, 10, 47–55. (c) Xie, J.; Schultz, P. G. Nat. ReV. Mol. Cell Biol. 2006, 7, 775–782. (d) Liao, J. Biotechnol. Prog. 2007, 23, 28–31. (e) Liu, C. C.; Mack, A. V.; Tsao, M.-L.; Mills, J. H.; Lee, H. S.; Choe, H.; Farzan, M.; Schultz, P. G.; Smider, V. V. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17688–17693. (f) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241–1251. (g) Hassan, Q. ACS Chem. Biol. 2008, 9, 524–526. (2) Birkofer, L.; Ritter, A. Angew. Chem. 1956, 68, 461–462. (3) Porter, T. H.; Shive, W. J. Med. Chem. 1968, 11, 402–403. (4) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277–5292. (5) Weidmann, B. Chimia 1992, 46, 312–313. (6) Walkup, R. D.; Cole, D. C.; Whittlesey, B. R. J. Org. Chem. 1995, 60, 2630–2634. (7) Yamanaka, H.; Fukui, T.; Kawamoto, T.; Tanaka, A. Appl. Microbiol. Biotechnol. 1996, 45, 51–55. (8) Tacke, R.; Merget, M.; Bertermann, R.; Bernd, M.; Beckers, T.; Reissmann, T. Organometallics 2000, 19, 3486–3497. (9) Pietzsch, M.; Waniek, T.; Smith, R. J.; Svetoslav, B.; Bienz, S.; Syldatk, C. Monatsh. Chem. 2000, 131, 645–653. (10) Merget, M.; Gu¨nther, K.; Bernd, M.; Gu¨nther, E.; Tacke, R. J. Organomet. Chem. 2001, 628, 183–194. (11) Kenworthy, M. N.; Kilburn, J. P.; Taylor, R. J. K. Org. Lett. 2004, 6, 19–22. (12) Link, J. O.; Graupe, M. (Inventors), Axys Pharmaceuticals Inc., PCT Int. Pat. Appl. WO 2005/074904 A2 (August 18, 2005).
developed a new method for synthesizing this compound, starting from diethyl malonate. In addition, rac-4 has been structurally characterized by single-crystal X-ray diffraction. Interestingly, no crystal structure of 4 has ever been published, probably due to the common problems in collecting X-ray diffraction data from crystals built up by water-soluble hydrophobic R-amino acids.13 We report here on a novel synthesis of rac-4 and the first crystal structure analysis of this compound. Compound rac-4 was synthesized according to Scheme 1, starting from diethyl malonate. Thus, reaction of diethyl malonate with sodium ethoxide in ethanol, followed by treatment with (chloromethyl)trimethylsilane, afforded diethyl [(trimethylsilyl)methyl]malonate (1, 87% yield). Treatment of 1 with an ethanolic solution of potassium hydroxide and subsequent reprotonation with concentrated hydrochloric acid yielded rac3-ethoxy-3-oxo-2-[(trimethylsilyl)methyl]propanoic acid (rac2, 84% yield). Reaction of rac-2 with thionyl chloride, treatment (13) Weissbuch, I.; Frolow, F.; Addadi, L.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1990, 112, 7718–7724.
10.1021/om900130j CCC: $40.75 2009 American Chemical Society Publication on Web 04/15/2009
2928 Organometallics, Vol. 28, No. 9, 2009
Notes
Table 1. Crystal Data and Experimental Parameters for the Crystal Structure Analyses of rac-4 empirical formula formula mass, g mol-1 collection T, K λ(Mo KR), Å cryst syst space group (No.) a, Å b, Å c, Å β, deg V, Å3 Z D(calcd), g cm-3 µ, mm-1 F(000) cryst dimens, mm 2θ range, deg index ranges no. of collected reflns no. of indep reflns Rint no. of reflns used no. of restraints no. of params Sa weight params a/bb R1c [I > 2σ(I)] wR2d (all data) max./min. residual electron density, e Å-3
C6H15NO2Si 161.28 100(2) 0.71073 monoclinic P21/c (14) 13.6597(5) 7.0086(3) 9.7599(4) 103.003(2) 910.41(6) 4 1.177 0.208 352 0.50 × 0.23 × 0.23 3.06-61.20 -19 e h e 19, -10 e k e 9, -13 e l e 13 25 516 2787 0.0388 2787 3 108 1.126 0.0362/0.3124 0.0288 0.0838 +0.569/-0.155
Figure 1. Molecular structure of (R)-4 in the crystal of rac-4 (probability level of displacement ellipsoids 50%). Selected bond distances (Å) and angles (deg): Si-C1 1.8730(10), Si-C2 1.8656(11), Si-C3 1.8674(11), Si-C4 1.8877(10), O1-C6 1.2496(11), O2-C6 1.2625(11), N-C5 1.4906(11), C4-C5 1.5329(12), C5-C6 1.5334(12), C1-Si-C2109.07(5),C1-Si-C3109.62(5), C1-Si-C4 106.19(5), C2-Si-C3 112.25(5), C2-Si-C4 110.05(5), C3-Si-C4 109.48(5), Si-C4-C5 118.50(6), C4-C5-C6 112.02(7), N-C5-C4 108.81(7),N-C5-C6108.01(7),O1-C6-O2125.16(8),O1-C6-C5 117.75(8), O2-C6-C5 117.08(8).
a S ) {∑[w(Fo2 - Fc2)2]/(n - p)}0.5; n ) no. of reflections; p ) no. of parameters. b w-1 ) σ2(Fo2) + (aP)2 + bP, with P ) [max(Fo2,0) + 2Fc2]/3. c R1 ) ∑|Fo| - |Fc|/∑|Fo|. d wR2 ) {∑[w(Fo2 - Fc2)2]/ ∑[w(Fo2)2]}0.5.
of the resulting ethyl rac-3-chloro-3-oxo-2-[(trimethylsilyl)methyl]propanoate (rac-3) with sodium azide, heating of the resulting carboxylic acid azide (Curtius rearrangement), and treatment of the resulting isocyanate with hydrochloric acid gave rac-β-(trimethylsilyl)alanine hydrochloride (rac-4 · HCl), which upon treatment with an aqueous solution of sodium hydroxide finally afforded rac-4 (34% yield). To make this multistep synthesis of rac-4 as efficient as possible, the intermediate rac-3 and all the intermediates formed in the transformation rac-3 f rac-4 were used as crude products without any further purification. Using this procedure, compound rac-4 was obtained with a total yield of 25%, starting from diethyl malonate. Compound rac-4 was isolated as a colorless crystalline solid, whereas 1 and rac-2 were obtained as colorless liquids. The identities of 1, rac-2, and rac-4 were established by elemental analyses (C, H, N) and solution NMR studies (1H, 13C, 15N, 29 Si). In addition, compound rac-4 was structurally characterized by single-crystal X-ray diffraction (Table 1, Figures 1 and 2). As can be seen from Figure 1, the molecules of rac-4 adopt a zwitterionic structure in the crystal. All bond lengths and angles are in the expected ranges, except for the Si-C4-C5 angle (118.50(6)°), which differs significantly from the ideal tetrahedral angle. It is not clear if this is an intrinsic structural feature of the molecule or the result of intermolecular interactions in the crystal. As shown in Figure 2, all three NH groups of the ammonium moiety act as hydrogen donors, and both oxygen atoms of the carboxylate group act as hydrogen acceptors to form an infinite two-dimensional network along the shorter basis vectors [0 0 1] and [0 1 0]. Adjacent molecules are associated by N-H1 · · · O1a and N-H2 · · · O2b hydrogen bonds and a bifurcate N-H3 · · · O1c/O2c hydrogen bond, thus (14) The hydrogen-bonding system was analyzed by using the program system PLATON: Spek, A. L. PLATON; University of Utrecht: Utrecht, The Netherlands, 1998.
Figure 2. Hydrogen-bonding system of rac-4 in the crystal.14 Bond lengths (Å) and angles (deg): N-H1 0.887(12), O1a · · · H1 1.898(12), N · · · O1a 2.7465(11), N–H1 · · · O1a 159.6(12), N-H2 0.891(13), O2b · · · H2 1.952(13), N · · · O2b 2.7987(11), N-H2 · · · O2b 158.2(12), N-H3 0.891(13), O1c · · · H3 2.380(13), O2c · · · H3 2.009(13), N · · · O1c 3.0580(11), N · · · O2c 2.8786(11), N–H3 · · · O1c 133.0(10), N-H3 · · · O2c 165.0(12), O1c · · · H3 · · · O2c 60.4(3).
forming layers of connected ammonium and carboxylate groups. The nonpolar (trimethylsilyl)methyl groups are sticking out on either side of these polar layers (direction of the longest basis vector [1 0 0]), thus forming infinite two-dimensional nonpolar areas dominated by van der Waals interactions. As an overall result, the crystals of rac-4 are built up by a layered lamellar structure. In conclusion, we have succeeded in developing a novel multistep synthesis of rac-β-(trimethylsilyl)alanine (rac-4) and in establishing its crystal structure. The synthesis of rac-4 is efficient and convenient, starting from diethyl malonate and using inexpensive reagents in all steps (total yield 25%). In
Notes
Organometallics, Vol. 28, No. 9, 2009 2929
principle, this method is suitable for the synthesis of rac-4 on a larger scale. Starting from rac-4, the pure enantiomers (R)-4 and (S)-4 can be obtained by biotransformations7,9 or chromatographic resolution methods.10
Experimental Section General Procedures. All syntheses in organic solvents were carried out under dry nitrogen. The organic solvents used were dried and purified according to standard procedures and stored under dry nitrogen. The 1H, 13C, 15N, and 29Si NMR spectra were recorded at 23 °C on a Bruker DRX-300 (15N, 30.4 MHz) or Bruker Avance 500 NMR spectrometer (1H, 500.1 MHz; 13C, 125.8 MHz; 29Si, 99.4 MHz), using DMSO-d6, C6D6, or D2O as the solvent. Chemical shifts (ppm) were determined relative to internal DMSO-d5 (1H, δ 2.49), internal C6HD5 (1H, δ 7.28), internal DHO (1H, δ 4.70), internal DMSO-d6 (13C, δ 39.5), internal C6D6 (13C, δ 128.0), external TMS (13C, 29Si, δ 0), or external H2NC(O)H (15N, 90% in DMSO-d6, δ -268.0). Assignment of the 1H NMR data was supported by 1H,1H COSY, 13C,1H, and 15N,1H correlation experiments, and the spin systems were analyzed by using the WIN-DAISY software package (version 4.05, Bruker).15 Assignment of the 15N NMR data was performed by 15N,1H correlation experiments, and assignment of the 13C NMR data was supported by DEPT 135 and 13 1 C, H correlation experiments. Coupling constants are given as their absolute values. Melting points were determined with a Mettler Toledo DSC 823e apparatus. Preparation of Diethyl [(Trimethylsilyl)methyl]malonate (1). Diethyl malonate (160.2 g, 1.00 mol) was added dropwise at 20 °C within 30 min to a stirred freshly prepared solution of sodium ethoxide in ethanol (prepared from sodium (23.0 g, 1.00 mol) and ethanol (400 mL)). The mixture was heated under reflux for 2 h, (chloromethyl)trimethylsilane (123.0 g, 1.00 mmol) was added dropwise at reflux temperature within 30 min, and the mixture was then heated under reflux for 24 h. Subsequently, the mixture was allowed to cool to 20 °C and was then neutralized with a few drops of concentrated hydrochloric acid. The solid formed was separated by filtration and discarded, the solvent of the filtrate was removed under reduced pressure, water (500 mL) was added to the residue, the aqueous phase was extracted with diethyl ether (3 × 150 mL), and the combined organic solutions were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by distillation in vacuo (Vigreux column) to afford 1 in 87% yield as a colorless liquid (213.1 g, 865 mmol); bp 112 °C/12 mbar. 1H NMR (500.1 MHz, C6D6): δ 0.11 (s, 9 H, SiCH3), 1.06 (δX), 4.08 (δA), and 4.10 (δB) (OCHAHBC(HX)3, 10 H, 2JAB ) 10.8 Hz, 3JAX ) 7.0 Hz, 3JBX ) 7.2 Hz), 1.47 (d, 3JHH ) 7.8 Hz, 2 H, SiCH2CH), 3.62 (t, 3JHH ) 7.8 Hz, 1 H, SiCH2CH). 13C NMR (125.8 MHz, C6D6): δ -1.5 (SiCH3), 14.0 (OCH2CH3), 16.3 (SiCH2CH), 48.3 (SiCH2CH), 61.1 (OCH2CH3), 170.4 (C(O)OCH2CH3). 29Si NMR (99.4 MHz, C6D6): δ 1.6. Anal. Calcd for C11H22O4Si: C, 53.63; H, 9.00. Found: C, 53.72; H, 9.11. Preparation of rac-3-Ethoxy-3-oxo-2-[(trimethylsilyl)methyl]propanoic Acid (rac-2). Potassium hydroxide (2.78 g, 49.5 mmol) was added in a single portion at 20 °C to a stirred solution of 1 (12.3 g, 49.9 mmol) in ethanol (100 mL). The mixture was heated under reflux for 2 h and was then allowed to cool to 20 °C. Another portion of potassium hydroxide (570 mg, 10.2 mmol) was added in a single portion at 20 °C, and the mixture was heated under reflux for 4 h and was then allowed to cool to 20 °C. The solvent was removed under reduced pressure, water (400 mL) was added, the aqueous phase was extracted continuously with diethyl ether (700 mL) over a period of 6 h using a perforator, and the extract (15) (a) WIN-DAISY 4.05; Bruker-Franzen GmbH: Bremen, Germany, 1998. (b) Weber, U.; Germanus, A.; Thiele, H. Fresenius J. Anal. Chem. 1997, 359, 46–49.
was discarded. The remaining aqueous solution was acidified with concentrated hydrochloric acid (7 mL) and was then extracted continuously with diethyl ether (700 mL) over a period of 2 h using a perforator. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by bulb-to-bulb distillation (130 °C, 0.02 mbar) to afford rac-2 in 84% yield as a colorless liquid (9.18 g, 42.0 mmol). 1H NMR (500.1 MHz, DMSO-d6): δ -0.03 (s, 9 H, SiCH3), 1.01 (δA), 1.02 (δB), and 3.27 (δX) (SiCHAHBCHX, 3 H, 2JAB ) 14.7 Hz, 3JAX ) 8.2 Hz, 3JBX ) 7.3 Hz), 1.17 (δX), 4.07 (δA), and 4.08 (δB) (OCHAHBC(HX)3, 5 H, 2JAB ) 10.8 Hz, 3JAX ) 3JBX ) 7.1 Hz), 12.71 (s, 1 H, C(O)OH). 13C NMR (125.8 MHz, DMSOd6): δ -1.5 (SiCH3), 13.9 (OCH2CH3), 15.6 (SiCH2CH), 47.3 (SiCH2CH), 60.7 (OCH2CH3), 170.4 (C(O)OCH2CH3), 171.5 (C(O)OH). 29Si NMR (99.4 MHz, DMSO-d6): δ 1.7. Anal. Calcd for C9H18O4Si: C, 49.51; H, 8.31. Found: C, 49.18; H, 8.19. Preparation of rac-2-Amino-3-(trimethylsilyl)propanoic Acid (rac-β-(Trimethylsilyl)alanine, rac-4). A solution of thionyl chloride (6.54 g, 55.0 mmol) in dichloromethane (40 mL) was added dropwise at 0 °C within 20 min to a stirred solution of rac-2 (10.0 g, 45.8 mmol) in a mixture of dichloromethane (60 mL) and DMF (100 µL). The resulting mixture was allowed to warm to 20 °C and was then stirred at this temperature for 4 days. The solvent and the excess thionyl chloride were removed under reduced pressure (20 °C, 0.02 mbar) to give the intermediate ethyl rac-3chloro-3-oxo-2-[(trimethylsilyl)methyl]propanoate (rac-3) as a colorless liquid (1H NMR (500.1 MHz, C6D6): δ 0.01 (s, 9 H, SiCH3), 0.99 (δX), 3.98 (δA), and 4.00 (δB) (OCHAHBC(HX)3, 5 H, 2JAB ) 10.8 Hz, 3JAX ) 7.1 Hz, 3JBX ) 7.2 Hz), 1.16 (δA), 1.35 (δB), and 3.77 (δX) (SiCHAHBCHX, 3 H, 2JAB ) 14.8 Hz, 3JAX ) 6.3 Hz, 3 JBX ) 9.2 Hz); 13C NMR (125.8 MHz, C6D6): δ 0.0 (SiCH3), 15.4 (OCH2CH3), 18.5 (SiCH2CH), 61.3 (SiCH2CH), 63.8 (OCH2CH3), 169.3 (C(O)OCH2CH3), 172.9 (C(O)Cl); 29Si NMR (99.4 MHz, C6D6): δ 1.7). The intermediate rac-3 (crude product, not further purified) was dissolved in acetone (40 mL), and the resulting solution was added dropwise at 0 °C within 20 min to a stirred suspension of sodium azide (3.28 g, 50.5 mmol) in acetone (60 mL). The mixture was allowed to warm to 20 °C and was then stirred at this temperature for 2 days. The resulting precipitate was separated by suction filtration, washed with acetone (3 × 20 mL), and discarded. The filtrate (including the wash solutions) was then heated under reflux for 4 h, the mixture was allowed to cool to 20 °C, and the solvent was removed under reduced pressure. Subsequently, hydrochloric acid (6 M, 300 mL) was added to the residue in a single portion at 20 °C, and the resulting mixture was heated under reflux for 6 h. The solid formed was separated by filtration and discarded, the solvent of the filtrate was removed under reduced pressure, and the solid residue was dissolved in water (200 mL). The resulting aqueous solution was extracted with diethyl ether (3 × 50 mL), and the aqueous phase was freeze-dried to afford a colorless powder (rac-4 · HCl; the NMR data of the product (solvent, D2O) were identical with those obtained for rac-4), which was dissolved in a mixture of methanol (25 mL) and an aqueous sodium hydroxide solution (1 M, 20.9 mL).16 The solution was kept undisturbed at 20 °C for 6 h, and the resulting precipitate was separated by suction filtration and washed with diethyl ether (3 × 30 mL) to afford rac-4 in 34% yield as a colorless crystalline solid (2.52 g, 15.6 mmol); mp 271 °C (dec). 1H NMR (500.1 MHz, D2O): δ 0.00 (s, 9 H, SiCH3), 1.11 (δA), 1.15 (δB), and 3.99 (δX) (SiCHAHBCHX, 3 H, 2JAB ) 14.2 Hz, 3JAX ) 5.0 Hz, 3JBX ) 11.1 Hz), OH and NH not detected (H/D exchange). 13C NMR (125.8 MHz, D2O): δ 0.0 (SiCH3), 21.5 (SiCH2CH), 53.6 (SiCH2CH), 175.4 (CO). 29Si NMR (99.4 MHz, D2O): δ 0.1. 15N NMR (30.4 MHz, D2O): δ -336.2. Anal. Calcd for C6H15NO2Si: C, 44.68; H, 9.37; N, 8.68. Found: C, 44.51; H, 9.50; N, 8.70. (16) The molar ratio takes into account the amount of rac-4 · HCl formed in the former step.
2930 Organometallics, Vol. 28, No. 9, 2009 Crystal Structure Analysis. A suitable single crystal of rac-4 was obtained directly via the preparation procedure described above. The crystal was mounted in inert oil (perfluoropolyalkyl ether, ABCR) on a glass fiber and then transferred to the cold nitrogen gas stream of the diffractometer (Bruker Nonius Kappa APEX II CCD system with Goebel mirror, Mo KR radiation (λ ) 0.71073 Å)). The structure was solved by direct methods.17 All nonhydrogen atoms were refined anisotropically.18 A riding model was employed in the refinement of the CH hydrogen atoms. Crystallographic data (excluding structure factors) for the structure reported in this paper has been deposited with the (17) (a) Sheldrick, G. M. SHELXS-97; University of Go¨ttingen: Go¨ttingen, Germany, 1997. (b) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467–473. (18) Sheldrick, G. M. SHELXL-97; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
Notes Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-724810. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223/336033; e-mail:
[email protected]).
Acknowledgment. We appreciate the expert technical assistance of Martina Amend. Supporting Information Available: Crystal and structure refinement data, tables of atomic coordinates and equivalent isotropic displacement parameters, experimental details of the X-ray diffraction studies, and bond lengths and angles for rac4. This material is available free of charge via the Internet at http://pubs.acs.org. OM900130J
