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Boletín de la Sociedad Chilena de Química

versão impressa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.45 n.4 Concepción dez. 2000 



1Universidad Central de Venezuela, Facultad de Farmacia, Laboratorio de Productos
Naturales.  Apartado 40-190, Caracas 1040-A, Venezuela.
2School of Pharmacy and Pharmacal Sciences, Purdue University, West Lfayette, IN 47907,

(Received: August 23, 1999 - Accepted: January 27, 2000)


Xylopiacin 1, a cytotoxic mono-tetrahydrofuran Annonaceous acetogenin, hsa been isolated from the seeds of Xylopia aromatica (Lam.) Mart. (Annonaceae).  The absolute configuration of this compound was determined by its Mosher ester derivatives. The sterogenic carbinol centers of xylopiacin S-MTPA 2 and xylopiacin R-MTPA 3 have been determined by 1H-NMR and 2D-NMR experiments utilizing Mosher esters. The preferred conformation of xylopiacin 1 and its derivatives 2 and 3 sere determined using molecular mechanics and molecular dynamics calculations.

KEY WORDS: Acetogenins, absolute configuration, Mosher ester, molecular modeling.


Xylopiacin 1, una mono-tetrahidro acetogenina de las annonaceae, ha sido aislada de las semillas de la planta Xylopia aromatica (Lam.) Mart. (Annonaceae).  La configuración absoluta de este compueste fue determinada por sus derivados de tipo esteres de Mosher. Los centros estereogénicos tipo carbinol de xylopiacin S-MTPA 2 y R-MTPA 3 han sido determinados por experimentos de 1H-NMR y 2D-NMR, utilizando los esteres de Mosher.  La conformación preferida de Xylopiacin y sus derivados 2 y 3 fue determinada usando cálculos de mecánica molecular y de dinámica molecular.

PLABRAS CLAVES: Acetogenina, configuración absoluta, ester de Mosher, modelado molecular.


The Annonaceous Acetogenins are g-lactone derivatives of C-32 or C-34 long-chain fatty acids; these compounds have shown cytotoxic, T cell suppression, antimalarial, pesticidal, antiparasitic, and antimicrobial bioactivities1).  All of the acetogenins have multiple chiral (stereogenic) centers, and some are differentiated from each other only by their stereochemistries.  The stereochemistry, in many cases, influences the relative potencies and biological specificities.

Previously we reported the isolation of the cytotoxic acetogenin, xylopiacin 1, from the bark of Xylopia aromatica (Lam.) Mart. (Annonaceae)2, now we report the isolation from its seeds.

We have now determined the absolute configuration of the stereogenic carbinol centrs in xylopiacin 1(Figure 1) by 1H-NMR analysis of its Mosher ester derivatives.  The refined Mosher ester methodology analyzes differences between the proton chemical shifts of S- and R-MTPA esters (2-3) on both sides of the chiral carbinol center3,4).

We have also corried out a molecular modeling study of the preferred conformation of compound 1 and its Mosher ester derivatives, 2 and 3, using molecular mechanics and molecular dynamics calculations.


Xylopiacin 1 was isolated as a waxy solid, as previously described3).  The structure was determined on the basis of 1H. and 13C-NMR (Table I).  Determination of the relative stereochemistry around the THF ring moiety was determined by Borns's techniques as threo-trans-threo2,3).

The 1H-NMR data for the S-and R- per-MTPA esters of 1 are shown in Table I, the assignments were made based on 1H-1H COSY. Based on Mosher's arguments, C-15 and C-20 were assigned to the R absolute configuration, since the sign of DdH (dS-dR) is positive for the chain side, showing relatively less shielding for this side in the S-MTPA ester.  The sign of DdH (dS-dR) is negative for the methylene protons of the THF ring, showing high shielding for them in the S-MTPA; the signals appeared further upfield, while those in the aliphatic chain portion were less highly shielded.  As the relative stereochemistry from C-15 to C-20 of 1 is threo-trans.threo, the absolute configuration of C-15 (R), C-16 (R), C-19 (R) and C-20 (R) was, thus, readily concluded.  The configuration at C-4 was determjned to be R according to the Mosher ester data listed in Table I, since the sign of  H (dS-dR) is negative for the protons of the g-lactone-a,b-unsaturated moiety showing high shielding for them in the S-MTPA ester 2. Hoye et al.4) synthesized (+)-SS (like) and (+,-)-RS (unlike) model butenolides4) and permitted the assignments of the relative configurations between C-4 and C-36 in acetogenins by using the magnitudes of the Dd values for the 1H and 19F nuclei in their Mosher esters3,4).  The Dd 1H values for H-35, H-36, and H-37 in 2 and 3, at 0.28, 0.04 and 0.02 suggested that 1 has the 4R, 36S configuration, as is usual.  The absolute stereochemistry at C-8 was difficult to elucidate because the  DdH (dS-dR) values of the protons on both sides of carbinol center (C-8) could not be determined, i.e., confident assignments couldd not be made for protons H-7 and H-9. Thus, the structure and absolute configuration of xylopiacin 1 are proposed as illustrated in Figure 1.

To determine the energetically favored conformations of compounds 2-3 a computation for possible conformations was perfomed, using molecular dynamics6 (MD) and molecular mechanics7) (MM) methods.  We combine two series of MD simulations (at 900ºK) and then optimization of the structure using MM. For the S-MTPA ester 2, the minimum energy conformation 2a showed that the methylene protons of othe THF ring and the protons of the a,b-unsaturated g-lactone moiety of this molecule are in the shielding region of the aromatic rings and those in the aliphatic chain are not in the shieling region, as shown in Figure 3. The reverse was observed for the R-MTPA ester 3, in the most stable conformation 3a, as shown in Figure 2.




1H-NMR and 13C-NMR spectra were obtained on a Varian VXR-500S spectrometer. HPLC was carried out using a Dynamax software system and a Si gel (8 mm) column (250 x 21 mm) equipped with a Rainin UV-1 detector.

All computations were perfomed on a CAChe Scientific worksystem running Oxford Molecular Group, CAChe scientific propietary software, version 3.5.1.


Xylopiacin [1]: White waxy solid (10 mg), mp 91º; [a]25D + 24º (MeOH, c=0.006); UV (lmax, MeOH, nm) 220; FABMS (glycerol) m/z [MH]+ 625 (76%), [MH-H2O]+ 607 (12%), [MH-2H2O]+ 589 (11%), [MH-3H2O]+ 571 (14%), [MH-4H2O]+ 553 (27%); HRFABMS (glycerol) m/z 625.5024 (MH)+ (calcd. 625.5043 for C37H68O7), and 357.1915 for [C11H15O4(MTSi)2]+ (calcd. 357.1917); 1H-NMR (CDCl3, 500 MHz) see Table II, 13C-NMR (CDCl3; 125.75 MHz) see Table II; IR (film) cm-1 3626 (OH), 2920, 2847, 1737, 1314, 1071.


Molecular modeling

The three-dimensional models of compounds 2-3 were constructed using the molecular editor of the CAChe worstation. We made aminimization of each compound using Molecular Mechanics (MM). CAChe molecular mechanics uses Allinger's MM2 force field7,8).

Procedure of Molecular Dynamics (MD) calculations: CAChe dynamics uses the same force field of Molecular Mechanics calculations: the MD calculations were perfomed for equilibration at 900ºK for 10 ps. The simulation was made for 10 ps with the time step of 1.0 fs. Solvent molecules were not included in the calculations.  Several conformations were analyzed from the dynamics trajectory file, and a final MM optimization was done.  The same measurement was made for the conformations that differ in a maximun of 5 Kcal/mol. The minimal energy conformers (2q and 3a) are shown in Figure 2, for 2-3, respectively.


Base on Mosher's arguments, C-15 and C-20 were assigned the R absolute configuration.  As the relative streochemistry from C-15 to C-20 of 1 is threo-trans-threo, the absolute configuration of C-15 (R), C-16 (R), C-19 (R) and C-20 (R) was, thus, readily concluded.


This investigation was supported in part by Consejo Nacional de Investigaciones Científicas y Tecnológicas gran CONICIT S1-95000495, grant RO1 Nº CA30909 from the National Cancer Institute, National Institutes of Health, and Consejo Desarrollo Científico y Humanístico grants CDCH 06/03339/94 y CDCH 06/10/337/94.

*To whom correspondence should be addressed.


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7. N.L. Allinger. J.Amer. Chem. Soc., 108, 8153 (1977).         [ Links ]
8. CAChe Molecular Mechanics V 3.5 x setting: optimization by the Block Diagonal Newton Rapson Method; relaxation faactor + 1.00; energy value tolerance = 0.001 kcal/mol. Include terms bond stretch, bond angle, dihedral improper torsion, van deer Walls, electrostatics and hydrogen bonding, as augmented by Tecktronix.

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