Crystal Structure of 14-((1-(Benzyloxycarbonyl-Amino

Z. Kristallogr. NCS 2016; 231(2): 465–467

Open Access

Ruofeng Shang*, Yunpeng Yi and Jianping Liang Crystal structure of 14-((1-(benzyloxycarbonyl- amino)-2-methylpropan-2-yl)sulfanyl)acetate Mutilin, C34H49NO6S

Table 2: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2).

Atom Site x y z Uiso H(1) 2a 1.0821 0.2214 0.1214 0.103 H(1A) 2a 0.8359 0.5181 0.2733 0.046 H(22A) 2a 0.7419 0.5952 0.5253 0.069 H(22B) 2a 0.7084 0.4445 0.5340 0.069 H(3) 2a 0.4974 0.8183 0.7040 0.077 H(0AA) 2a 0.9052 0.3101 0.3753 0.056 H(0AB) 2a 1.0269 0.3655 0.3681 0.056 DOI 10.1515/ncrs-2015-0142 H(4) 2a 1.0827 0.3656 0.2178 0.060 H(5) 2a 0.8762 0.4919 0.1504 0.056 Received July 3, 2015; accepted January 13, 2016; available H(8) 2a 1.1106 0.5115 0.3021 0.053 online February 16, 2016 H(9) 2a 0.9875 0.8276 0.3289 0.058 H(10A) 2a 0.8123 0.6965 0.1914 0.071 Abstract H(10B) 2a 0.8400 0.8495 0.1905 0.071 H(11A) 2a 1.0243 0.8055 0.1647 0.071 C H NO S, monoclinic, P21 (no. 4), a = 11.7112(8) Å, 34 49 6 a 3 H(11B) 2 0.9278 0.7361 0.0858 0.071 b = 10.0135(5) Å, c = 14.6411(10) Å, V = 1664.4 Å , Z = 2, H(12A) 2a 1.0724 0.1535 0.3052 0.117 2 a Rgt(F) = 0.0659, wRref(F ) = 0.1269, T = 293 K. H(12B) 2 0.9803 0.0845 0.2228 0.117 H(12C) 2a 0.9516 0.1043 0.3211 0.117 CCDC no.: 1446995 H(13) 2a 0.7533 0.3146 0.2189 0.082 H(14A) 2a 0.8005 0.1386 0.0960 0.193 H(14B) 2a 0.6740 0.1943 0.1032 0.193 Table 1: Data collection and handling. H(15A) 2a 0.9991 0.4629 0.0087 0.103 H(15B) 2a 0.8943 0.5626 0.0028 0.103 a Crystal: Colorless block, H(15C) 2 0.8721 0.4082 0.0029 0.103 H(16A) 2a 1.1741 0.5117 0.1416 0.086 size 0.25×0.34×0.37 mm H(16B) 2a 1.1329 0.6415 0.0819 0.086 K Wavelength: Mo α radiation (0.71073 Å) H(17A) 2a 1.3093 0.6395 0.2335 0.114 µ −1 : 1.40 cm H(17B) 2a 1.2444 0.7718 0.1905 0.114 Diractometer, scan mode: SuperNova (Dual, Cu at zero, Eos) H(19A) 2a 0.7633 0.7441 0.3470 0.115 ω scans H(19B) 2a 0.8089 0.8918 0.3521 0.115 2θmax: 52.04° H(19C) 2a 0.8626 0.7915 0.4335 0.115 N(hkl)measured, N(hkl)unique: 6782, 5443 H(20A) 2a 1.0017 0.6420 0.4892 0.096 a N(param)rened: 386 H(20B) 2 1.1134 0.6957 0.4601 0.096 Programs: OLEX2 [6], SHELXS [7] H(20C) 2a 1.0945 0.5416 0.4680 0.096 H(26A) 2a 0.5129 0.4074 0.6250 0.125 H(26B) 2a 0.5386 0.5070 0.7102 0.125 H(26C) 2a 0.6386 0.4703 0.6604 0.125 *Corresponding author: Ruofeng Shang, Lanzhou Institute of H(24A) 2a 0.3653 0.7061 0.5276 0.148 Husbandry and Pharmaceutical Sciences of CAAS - Key Laboratory H(24B) 2a 0.3654 0.6360 0.6234 0.148 of New Animal Drug Project of Gansu Province; and Key Laboratory H(24C) 2a 0.3454 0.5515 0.5306 0.148 a of Veterinary Pharmaceutical Development, Ministry of Agriculture, H(25A) 2 0.6706 0.7117 0.6313 0.071 H(25B) 2a 0.5677 0.7994 0.5727 0.071 No. 335, Qilihe District, lanzhou, Gansu Province 730050, H(28A) 2a 0.6806 0.9449 0.9691 0.101 e-mail: [email protected] H(28B) 2a 0.7515 0.8176 0.9530 0.101 Yunpeng Yi and Jianping Liang: Lanzhou Institute of Husbandry and H(30) 2a 0.5727 0.9368 1.0821 0.098 Pharmaceutical Sciences of CAAS - Key Laboratory of New Animal H(31) 2a 0.5025 0.8169 1.1949 0.115 Drug Project of Gansu Province; and Key Laboratory of Veterinary H(32) 2a 0.5095 0.5889 1.1949 0.110 a Pharmaceutical Development, Ministry of Agriculture Lanzhou, H(33) 2 0.5860 0.4777 1.0871 0.111 H(34) 2a 0.6541 0.5944 0.9766 0.097 Gansu China

Table 3: Atomic displacement parameters (Å2).

Atom Site x y z U11 U22 U33 U12 U13 U23

S(1) 2a 0.5416(2) 0.5663(2) 0.4665(1) 0.056(1) 0.069(1) 0.060(1) 0.008(1) 0.016(1) −0.009(1) O(1) 2a 1.0162(5) 0.2549(5) 0.1069(4) 0.089(4) 0.064(3) 0.058(3) 0.013(3) 0.027(3) −0.016(3) O(2) 2a 1.2135(5) 0.7759(6) 0.3619(4) 0.089(5) 0.103(4) 0.084(5) −0.049(4) 0.028(4) −0.025(4) O(3) 2a 0.8428(4) 0.5179(4) 0.4134(3) 0.050(3) 0.054(3) 0.037(3) −0.006(2) 0.016(2) −0.008(2) O(4) 2a 0.6660(5) 0.4461(5) 0.3312(4) 0.057(3) 0.091(4) 0.047(3) −0.027(3) 0.017(3) −0.018(3) O(5) 2a 0.7335(5) 0.7133(6) 0.8062(4) 0.047(3) 0.112(5) 0.087(4) 0.018(4) 0.011(3) 0.009(4) O(6) 2a 0.5985(5) 0.8391(6) 0.8549(4) 0.066(4) 0.143(5) 0.050(4) 0.013(4) 0.015(3) −0.014(4) C(1) 2a 0.8962(6) 0.5045(6) 0.3322(4) 0.041(4) 0.042(4) 0.039(4) −0.006(3) 0.020(3) −0.006(3) C(22) 2a 0.6945(6) 0.5220(7) 0.4930(5) 0.054(5) 0.077(5) 0.049(5) 0.006(4) 0.027(4) −0.003(4) N(3) 2a 0.5642(5) 0.7806(6) 0.7067(4) 0.055(4) 0.086(4) 0.049(4) 0.026(4) 0.009(3) −0.006(3) C(0AA) 2a 0.9441(6) 0.3617(6) 0.3357(4) 0.057(5) 0.041(4) 0.043(4) −0.004(4) 0.017(4) 0.002(3) C(3) 2a 0.9345(6) 0.2806(6) 0.2439(5) 0.061(5) 0.038(4) 0.054(5) −0.003(4) 0.017(4) −0.003(3) C(4) 2a 1.0034(7) 0.3468(6) 0.1791(5) 0.069(5) 0.045(4) 0.039(4) −0.003(4) 0.021(4) −0.010(3) C(5) 2a 0.9521(6) 0.4799(6) 0.1346(4) 0.057(5) 0.046(4) 0.039(4) −0.006(4) 0.014(4) −0.004(3) C(6) 2a 1.0294(6) 0.6013(6) 0.1760(5) 0.051(4) 0.050(4) 0.040(4) −0.005(4) 0.020(3) −0.002(3) C(8) 2a 1.0764(6) 0.6003(6) 0.2857(5) 0.044(4) 0.041(4) 0.048(4) −0.010(3) 0.013(3) 0.000(3) C(7) 2a 0.9884(6) 0.6217(6) 0.3470(5) 0.047(4) 0.040(4) 0.038(4) −0.012(3) 0.013(3) −0.007(3) C(9) 2a 0.9260(6) 0.7590(6) 0.3147(5) 0.052(4) 0.044(4) 0.050(5) −0.005(4) 0.013(4) −0.003(3) C(10) 2a 0.8746(7) 0.7624(7) 0.2081(5) 0.073(6) 0.040(4) 0.067(6) 0.005(4) 0.021(5) 0.001(4) C(11) 2a 0.9662(7) 0.7345(7) 0.1526(5) 0.082(6) 0.049(4) 0.048(5) −0.008(4) 0.020(4) 0.008(4) C(12) 2a 0.9900(8) 0.1426(6) 0.2764(6) 0.122(8) 0.042(4) 0.079(6) 0.019(5) 0.042(6) 0.005(4) C(13) 2a 0.8046(8) 0.2635(7) 0.1939(6) 0.077(6) 0.057(5) 0.072(6) −0.020(5) 0.019(5) −0.021(4) C(14) 2a 0.756(1) 0.193(1) 0.1252(9) 0.12(1) 0.16(1) 0.20(2) −0.011(9) 0.01(1) −0.10(1) C(15) 2a 0.9271(7) 0.4782(8) 0.0273(5) 0.090(6) 0.073(5) 0.043(5) 0.003(5) 0.018(4) 0.006(4) C(16) 2a 1.1453(7) 0.6021(8) 0.1440(5) 0.074(6) 0.085(6) 0.068(6) −0.023(5) 0.041(5) −0.003(5) C(17) 2a 1.2337(8) 0.684(1) 0.2157(7) 0.074(6) 0.112(8) 0.114(9) −0.035(6) 0.050(6) −0.026(6) C(18) 2a 1.1802(7) 0.6960(9) 0.2980(6) 0.062(5) 0.075(6) 0.070(6) −0.021(5) 0.024(5) −0.006(5) C(19) 2a 0.8312(7) 0.8005(7) 0.3668(6) 0.089(7) 0.056(5) 0.091(7) 0.008(5) 0.034(6) −0.016(4) C(20) 2a 1.0558(6) 0.6256(8) 0.4508(4) 0.063(5) 0.081(5) 0.042(5) −0.017(5) 0.003(4) −0.007(4) C(21) 2a 0.7289(7) 0.4909(7) 0.4018(5) 0.056(5) 0.051(4) 0.051(5) −0.003(4) 0.028(4) −0.003(4) C(23) 2a 0.5184(7) 0.6038(7) 0.5824(5) 0.049(5) 0.062(5) 0.063(5) 0.017(4) 0.025(4) 0.008(4) C(26) 2a 0.5556(8) 0.4860(8) 0.6510(6) 0.115(8) 0.066(5) 0.089(7) 0.010(6) 0.059(6) 0.012(5) C(24) 2a 0.3865(7) 0.626(1) 0.5643(7) 0.060(6) 0.132(8) 0.113(8) 0.007(6) 0.037(6) −0.035(7) C(25) 2a 0.5870(7) 0.7302(7) 0.6204(5) 0.071(5) 0.055(4) 0.054(5) 0.008(4) 0.020(4) 0.006(4) C(27) 2a 0.6414(7) 0.7718(9) 0.7909(6) 0.052(5) 0.089(6) 0.052(5) 0.009(5) 0.013(4) −0.008(5) C(28) 2a 0.6733(8) 0.852(1) 0.9511(6) 0.079(7) 0.116(7) 0.054(6) −0.026(6) 0.007(5) −0.013(5) C(29) 2a 0.6222(7) 0.7756(9) 1.0187(6) 0.059(5) 0.080(6) 0.046(5) −0.016(5) 0.009(4) −0.002(4) C(30) 2a 0.5759(8) 0.8440(9) 1.0832(7) 0.091(8) 0.075(6) 0.079(7) 0.007(5) 0.020(6) 0.002(5) C(31) 2a 0.5333(9) 0.772(1) 1.1507(7) 0.092(8) 0.114(9) 0.090(8) 0.009(7) 0.040(6) 0.003(7) C(32) 2a 0.5377(9) 0.637(1) 1.1506(7) 0.081(8) 0.111(9) 0.086(8) −0.007(7) 0.026(6) 0.007(7) C(33) 2a 0.5830(8) 0.571(1) 1.0864(8) 0.069(6) 0.079(6) 0.114(9) −0.009(6) −0.004(6) 0.009(7) C(34) 2a 0.6242(8) 0.641(1) 1.0207(7) 0.060(6) 0.077(7) 0.100(8) −0.004(5) 0.009(5) −0.005(6)

The crystal structure is shown in the gure. Tables 1–3 contain with anhydrous Na2SO4 overnight. The solvent was evapo- details of the measurement method and a list of the atoms rated in vacuum and the residue was chromatographed on including atomic coordinates and displacement parameters. silica gel (petroleum ether : ethyl acetate 2:1 v/v) to aord a pure product (1.40 g, yield: 78°; m.p. 60–63 °C). The crystals Source of material were obtained by slow evaporation from an dichloromethane Benzyl carbonochloridate (0.56 g, 3.3 mmol) was added drop- solution at room temperature. wise to a solution of 14-O-[(1-amino-2-methylpropane-2-yl) thioacetyl] mutilin (1.39 g, 3. mmol) and triethylamine (0.81 g, Discussion 8 mmol) in dichloromethane (60 mL) and was stirred at 0 °C The title compound was synthesized to be used as an or room temperature for 4.5 h. Then the reaction mixture was antibiotic candidate against some Gram-positive bacteria washed with saturated aqueous NH4Cl and water and dried and mycoplasmas. The starting material was pleuromutilin Shang et al.: C34H49NO6S Ë 467 which was rst isolated in a crystalline form from cul- Scientic Research Institutions (No. 1610322014003) and The tures of two species of basidiomycetes, Pleurotus mutilus and Agricultural Science and Technology Innovation Program P. passeckerianus in 1951 [1]. The pleuromutilin class has a (CAAS-ASTIP-2014-LIHPS-04). unique mode of action, which involve inhibition of protein synthesis by primarily inhibiting ribosomal peptidyl trans- References ferase center (PTC) [2], and thus display high antibacterial 1. Kavanagh, F.; Hervey, A.; Robbins, W. J.: Antibiotic substances activities with no target-specic cross-resistance to other an- from basidiomycetes. VIII. Pleurotus multilus (Fr.) Sacc. and tibiotics [3]. The molecular modications of pleuromutilin Pleuotus passeckerianus Pilat. Proc. Natl. Acad. Sci. 37 (1951) led to three drugs: tiamulin, valnemulin, and retapamulin. 570–574. The rst two drugs were used as veterinary medicines [4]. 2. Schlunzen, F.; Pyetan, E.; Fucini, P.; Yonath, A.; Harms, J. M.: The retapamulin became the rst pleuromutilin approved for Inhibition of peptide bond formation by pleuromutilins: the human use in 2007 [5]. structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin. Mol. Microbiol. 54 (2004) The crystal structure of the title compound is built up 1287–1294. of C33H48N2O6S molecules containing a 5-6-8 tricyclic carbon 3. Shang, R. F.; Wang, J. T.; Guo, W. Z.; Liang, J. P.: Ecient skeleton and a phenyl group, in which all bond lengths are antibacterial agents: A review of the synthesis, biological in normal ranges. The ve-membered ring (C6—C16—C17— evaluation and mechanism of pleuromutilin derivatives. Curr. C18—C8) is not planar and the six-membered ring (C6—C11— Top. Med. Chem. 13 (2013) 3013–3025. 4. Tang, Y. Z.; Liu, Y. H.; Chen, J. X.: Pleuromutilin and its C10—C9—C7—C8) exhibits a chair conformation. The eight- derivatives. The lead compounds for novel antibiotics. Mini Rev. membered ring (from C1 to C8) exhibits a boat conforma- Med. Chem. 12 (2012) 53–61. tion. The synthesized side chain of pleuromutilin exhibits 5. Moody, M. N.; Morrison, L. K.; Tyring, S. K.: Retapamulin: what is zig-zag conformation. The torsion angles are 67.54°, 172.51°, the role of this topical antimicrobial in the treatment of bacterial 107.39° and −112.90° for C22—S1—C23—C25, S1—C23—C25— infections in atopic dermatitis? Skin Ther. Lett. 15 (2010) 1–4. N3, C23—C25—N3—C27 and C27—O6—C28—C29, respectively. 6. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H.: OLEX2 : a complete structure solution, Weak NH··· O and OH··· O hydrogen bonds are present. renement and analysis program J. Appl. Cryst. 42 (2009) 339–341. Acknowledgements: This work was supported by grants 7. Sheldrick, G. M.: A short history of SHELX. Acta Crystallogr. A 64 from Basic Scientic Research Funds in Central Agricultural (2008) 112–122.