Crystal structure of 14-((1-(benzyloxycarbonyl-amino)-2-methylpropan-2-yl)sulfanyl)acetate Mutilin, C34H49NO6S

Ruofeng Shang; Yunpeng Yi; Jianping Liang

doi:10.1515/ncrs-2015-0142

Open Access Published by De Gruyter (O) February 16, 2016

Crystal structure of 14-((1-(benzyloxycarbonyl-amino)-2-methylpropan-2-yl)sulfanyl)acetate Mutilin, C₃₄H₄₉NO₆S

Ruofeng Shang , Yunpeng Yi and Jianping Liang

From the journal Zeitschrift für Kristallographie - New Crystal Structures

https://doi.org/10.1515/ncrs-2015-0142

Abstract

C₃₄H₄₉NO₆S, monoclinic, P2₁ (no. 4), a = 11.7112(8) Å, b = 10.0135(5) Å, c = 14.6411(10) Å, V = 1664.4 Å³, Z = 2, R_gt(F) = 0.0659, wR_ref(F²) = 0.1269, T = 293 K.

CCDC no.:: 1446995

The crystal structure is shown in the figure. Tables 1–3 contain details of the measurement method and a list of the atoms including atomic coordinates and displacement parameters.

Table 1

Data collection and handling.

Crystal:	Colorless block, size 0.25×0.34×0.37 mm
Wavelength:	Mo K_α radiation (0.71073 Å)
μ:	1.40 cm⁻¹
Diffractometer, scan mode:	SuperNova (Dual, Cu at zero, Eos) ω scans
2θ_max:	52.04°
N(hkl)_measured, N(hkl)_unique:	6782, 5443
N(param)_refined:	386
Programs:	OLEX2 [6], SHELXS [7]

Table 2

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

Atom	Site	x	y	z	U_iso
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
H(4)	2a	1.0827	0.3656	0.2178	0.060
H(5)	2a	0.8762	0.4919	0.1504	0.056
H(8)	2a	1.1106	0.5115	0.3021	0.053
H(9)	2a	0.9875	0.8276	0.3289	0.058
H(10A)	2a	0.8123	0.6965	0.1914	0.071
H(10B)	2a	0.8400	0.8495	0.1905	0.071
H(11A)	2a	1.0243	0.8055	0.1647	0.071
H(11B)	2a	0.9278	0.7361	0.0858	0.071
H(12A)	2a	1.0724	0.1535	0.3052	0.117
H(12B)	2a	0.9803	0.0845	0.2228	0.117
H(12C)	2a	0.9516	0.1043	0.3211	0.117
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
H(15A)	2a	0.9991	0.4629	0.0087	0.103
H(15B)	2a	0.8943	0.5626	0.0028	0.103
H(15C)	2a	0.8721	0.4082	0.0029	0.103
H(16A)	2a	1.1741	0.5117	0.1416	0.086
H(16B)	2a	1.1329	0.6415	0.0819	0.086
H(17A)	2a	1.3093	0.6395	0.2335	0.114
H(17B)	2a	1.2444	0.7718	0.1905	0.114
H(19A)	2a	0.7633	0.7441	0.3470	0.115
H(19B)	2a	0.8089	0.8918	0.3521	0.115
H(19C)	2a	0.8626	0.7915	0.4335	0.115
H(20A)	2a	1.0017	0.6420	0.4892	0.096
H(20B)	2a	1.1134	0.6957	0.4601	0.096
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
H(24A)	2a	0.3653	0.7061	0.5276	0.148
H(24B)	2a	0.3654	0.6360	0.6234	0.148
H(24C)	2a	0.3454	0.5515	0.5306	0.148
H(25A)	2a	0.6706	0.7117	0.6313	0.071
H(25B)	2a	0.5677	0.7994	0.5727	0.071
H(28A)	2a	0.6806	0.9449	0.9691	0.101
H(28B)	2a	0.7515	0.8176	0.9530	0.101
H(30)	2a	0.5727	0.9368	1.0821	0.098
H(31)	2a	0.5025	0.8169	1.1949	0.115
H(32)	2a	0.5095	0.5889	1.1949	0.110
H(33)	2a	0.5860	0.4777	1.0871	0.111
H(34)	2a	0.6541	0.5944	0.9766	0.097

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)

Source of material

Benzyl carbonochloridate (0.56 g, 3.3 mmol) was added dropwise to a solution of 14-O-[(1-amino-2-methylpropane-2-yl) thioacetyl] mutilin (1.39 g, 3. mmol) and triethylamine (0.81 g, 8 mmol) in dichloromethane (60 mL) and was stirred at 0 °C or room temperature for 4.5 h. Then the reaction mixture was washed with saturated aqueous NH₄Cl and water and dried with anhydrous Na₂SO₄ overnight. The solvent was evaporated in vacuum and the residue was chromatographed on silica gel (petroleum ether : ethyl acetate 2:1 v/v) to afford a pure product (1.40 g, yield: 78°; m.p. 60–63 °C). The crystals were obtained by slow evaporation from an dichloromethane solution at room temperature.

Discussion

The title compound was synthesized to be used as an antibiotic candidate against some Gram-positive bacteria and mycoplasmas. The starting material was pleuromutilin which was first isolated in a crystalline form from cultures of two species of basidiomycetes, Pleurotus mutilus and P. passeckerianus in 1951 [1]. The pleuromutilin class has a unique mode of action, which involve inhibition of protein synthesis by primarily inhibiting ribosomal peptidyl transferase center (PTC) [2], and thus display high antibacterial activities with no target-specific cross-resistance to other antibiotics [3]. The molecular modifications of pleuromutilin led to three drugs: tiamulin, valnemulin, and retapamulin. The first two drugs were used as veterinary medicines [4]. The retapamulin became the first pleuromutilin approved for human use in 2007 [5].

The crystal structure of the title compound is built up of C₃₃H₄₈N₂O₆S molecules containing a 5-6-8 tricyclic carbon skeleton and a phenyl group, in which all bond lengths are in normal ranges. The five-membered ring (C6—C16—C17—C18—C8) is not planar and the six-membered ring (C6—C11—C10—C9—C7—C8) exhibits a chair conformation. The eight-membered ring (from C1 to C8) exhibits a boat conformation. The synthesized side chain of pleuromutilin exhibits zig-zag conformation. The torsion angles are 67.54°, 172.51°, 107.39° and −112.90° for C22—S1—C23—C25, S1—C23—C25—N3, C23—C25—N3—C27 and C27—O6—C28—C29, respectively. Weak NH⋯O and OH⋯O hydrogen bonds are present.

Corresponding author: Ruofeng Shang, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS - Key Laboratory of New Animal Drug Project of Gansu Province; and Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, No. 335, Qilihe District, lanzhou, Gansu Province 730050, e-mail:

Acknowledgements:

This work was supported by grants from Basic Scientific Research Funds in Central Agricultural Scientific Research Institutions (No. 1610322014003) and The Agricultural Science and Technology Innovation Program (CAAS-ASTIP-2014-LIHPS-04).

References

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Received: 2015-7-3

Accepted: 2016-1-13

Published Online: 2016-2-16

Published in Print: 2016-6-1

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