Journal of the Chinese Chemical Society, 2007, 54, 1313-1320 1313 NMR Studies of a Series of Shikimic Acid Derivatives Ping Zhang ( ), Jian Huang ( ) and Fen-Er Chen* ( ) Department of Chemistry, Fudan University, Shanghai 200433, P. R. China The investigations of the 1 Hand 13 C resonances of a series of 9 shikimic acid derivatives were carried out using one- and two-dimensional methods. 1 Hand 13 C spectral data were assigned by DEPT, 1 H- 1 H COSY, HSQC, HMBC, and the stereo configuration was confirmed by 1D selective NOESY experiments. Keywords: NMR; 1 H NMR; 13 C NMR; 1D NOE; Shikimic acid derivatives. INTRODUCTION During the course of our research in total synthesis of l-reserpine, 1 the octahydrobenzofuran derivative 9 is a key chiral building block. By employing (-)-shikimic acid as chiron, 2 we synthesized 9 successfully via a series of shikimic acid analogues which possessed the interesting polyoxygenated cyclohexene skeleton and several contiguous stereocenters (Fig. 1). Among the compounds obtained, 1, 3 2, 3a 5 4 and 6 4 have been described in the literature and 1 H and 13 C NMR data have already been reported, but their complete spectral assignment and configuration elucidation had not yet been presented. Due to the stereochemical complexity of the nine derivatives, we decided to perform the complete assignment of the 1 H and 13 C NMR spectra of these substances and elucidate the absolute configuration of them in order to provide several sets of data that might serve as reference for future assignments of other structurally related compounds. H-2 at about 6.60~6.84 and methylene H-6 at about 2.00~ 2.60 by COSY DEPT and HSQC. From the shapes and integration information of the 1 H NMR spectra, OCH 3 and OTBS signals can be easily obtained. For compound 9,itis easier to start from the CH 2 group from DEPT135; again COSY and HSQC reveal all signals from six-membered ring atoms. RESULTS AND DISCUSSION The structures and numbering system for compounds 1-9 are presented in Fig. 1. For the assignment of the 1 H and 13 C NMR spectra of 1-9 (Tables 1, 2 and 3, respectively), a combination of two-dimensional COSY, HSQC and HMBC 5 experiments was carried out, together with 1D NOE 6 spectra for establishing the absolute stereochemistry and conformations of these chiral intermediates. For compounds 1-8, the assignment of the proton and carbon signals is easiest to start from cyclohexene olefin Fig. 1. Structures and numbering of the compounds investigated.
1314 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 Zhang et al.
NMR Studies of a Series of Shikimic Acid Derivatives J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1315
1316 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 Zhang et al. Table 3. Proton 1 Hand 13 C NMR Chemical shifts (ä, ppm), multiplicity and coupling constants (Hz) for compound 9 Compound 9 1 H 13 C 1 - - 2 5.11(d; 5.2) 102.87 3 1.85,1.68, overlap 33.30 4 2.73(ddd; 13.6,5.2,4.4) 38.42 4a 2.93(ddd; 12.8,12.8,6.4) 37.69 5 1.80, overlap 29.63 5 1.64, overlap 29.63 6 3.35, overlap 72.15 7 2.79(dd; 9.2,7.6) 87.41 7a 4.00(dd; 7.6,7.6) 83.31 8 3.52(s) 60.66 9 3.71(q; 7.2),3.39,overlap 62.69 10 1.14(t; 7.2) 15.14 11-173.41 12 3.64(s) 53.34 13 0.04(s),0.02(s) -4.59,-4.65 14 0.85(s) 25.76 15-18.01 Compound 1 has been previously reported by Meier, Tamm, et al. in 1991. 3a However, the endo-oh in C(3)/ C(4) positions and exo-oh in C(5) position were not assigned. The stereochemistry of H-3, H-4 and H-5 were confirmed by the NOE effect observed for H-4 at = 3.57 and H-3 at = 4.22 in 1D NOESY spectra [Fig. 2(b)]. When compared to compound 1, many similarities were observed in the 1 H NMR and 1D NOESY spectra of compounds 2-4. Furthermore, the signals for substituents in C(3), C(4) and C(5) positions can be observed from 1 H and 13 C NMR spectra. Compound 5 is the oxidated derivative of compound 4, as was evidenced by the vanish of the H-3 (at 4.50) in its 1 H NMR spectra. In addition, the irradiation of H-5 resulted in no NOE enhancement [Fig. 3(b)], suggesting the OCH 3 at C-4 is endo-configured. The assignments of 1 H- and 13 C-NMR data of 6 (Table 2) determined on the basis of high-resolution NMR experiments, were in good agreement with those of 5 except for the appearance of an exo-otbs moiety in the C-5 position. The assignment of all proton and carbon signals of 7 is rather straightforward and similar to that of compound 6 except for an exo-oh at C-4, which can be confirmed by 1D NOESY spectra, a similar configuration at C-3, C-4 and C-5 as in compound 8. Unequivocal assignments of compound 8 could not be made with conventional DEPT, COSY and HSQC experiments. However, by using 1D selective NOESY exper- Fig. 2. (a) 1 H NMR spectra of 1 in CDCl 3 ; (b) 1D Selective NOESY spectra; arrows indicate irradiated peaks.
NMR Studies of a Series of Shikimic Acid Derivatives J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1317 iment in combination with a gradient HMBC experiment, it was possible to identify the absolute stereochemistry of 8. Long-range HMBC correlations of 8 [Fig. 5] through three bonds ( 3 J) between H-2 ( 6.67) and C-4 ( C 86.13, 85.34), C-6 ( C 33.86, 33.99), C-7 ( C 166.47) unambiguously confirmed the COOCH 3 group in the C-1 position. The contour plots of the HMBC spectra of 8 displayed three-bond cross peaks between H-4 ( 3.18) and C-6 ( C 33.86, 33.99), C-10 ( C 61.32, 61.17), suggesting the presence of endo- OCH 3. The H-12 ( 4.92, 4.87) showing long range coupled with C-3 ( C 78.00, 76.05) and C-14 ( C 62.33, 62.40), unambiguously confirmed the side chain in the C-3 position. Next, we started to determine the absolute configuration of substituents in C-3, C-4 and C-5 positions, and the 1D NOESY spectra was measured. Irradiation of the H-3 resonance at = 4.17 and = 4.22 produced strong NOE enhancements in the signals of H-2 (at = 6.67), H-5 (at = 3.73) and H-12 (at =4.92and = 4.87) [Fig. 4(b)]. This indicates that the substituents at positions 3 and 5 are cis. Fig. 3. (a) 1 H NMR spectra of 5 in CDCl 3 ; (b) 1D Selective NOESY spectra; arrows indicate irradiated peaks. Fig. 4. (a) 1 H NMR spectra of 8 in CDCl 3 ; (b) 1D Selective NOESY spectra; arrows indicate irradiated peaks.
1318 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 Zhang et al. It is interesting to note the NOE correlations of cyclized product 9, which has five contiguous chiralcenters on the six-membered ring. In the 1 H NMR spectra of 9 recorded in CDCl 3 solution, the H-2 resonance appears in a relatively low frequency region at = 2.93 compared with H-7a ( = 4.00). The 2-OCH 2 CH 3 and the substituents in C-4/4a/6/7a positions were determined to be the exo-configuration, which were supported by a sequence of 1D selective NOESY experiments. Irradiation of the H-7a resonance at = 4.00 resulted in NOE enhancements for protons H-4, H-4a and H-6, and on irradiation at 2.93 (H-4a), the signals of H-2 and H-7a were enhanced [Fig. 6]. Key NOE correlations of compound 9 are presented in Fig. 7. CONCLUSIONS Fig. 5. HMBC spectra of compound 8 in CDCl 3 at 400 MHz. In conclusion, a complete set of spectral parameters Fig. 6. (a) 1 H NMR spectra of 9 in CDCl 3 ; (b) and (c) 1D Selective NOESY spectra; arrows indicate irradiated peaks.
NMR Studies of a Series of Shikimic Acid Derivatives J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1319 Fig. 7. Key NOE correlations of compound 9. and stereochemistry for nine shikimic acid derivatives were unambiguously assigned by one- and two-dimensional homo- and heteronuclear shift correlation spectroscopy. Especially, 1D selective NOESY experiment provided a less tedious and a more efficient method for assignment of stereochemistry. This study showed the importance of NMR spectroscopy for structrural elucidation of chiral intermediates formed in the total synthesis of l-reserpine. EXPERIMENTAL One- and two-dimensional NMR spectra ( 1 H, 13 C, DEPT, 1D Selective NOESY, 1 H- 1 H COSY, HSQC and HMBC) were recorded using a Bruker Avance 400 spectrometer (equipped with BBO-5 mm-zgrad probe) without spinning in 5 mm NMR tubes at 305 K. Chemical shifts ( ) are expressed in ppm from the residual signal of solvent as an internal standard. 1 H NMR spectra were acquired using 8 khz spectral width with 32 k data points and observed at 400.13 MHz (13.5 µs for 90 pulse width, 30 flip angle, and 0.244 Hz/ point digital resolution). The acquisition time was 2.045 s and the relaxation delay was 1.0 s. 13 C NMR proton-decoupled (decoupled sequence: WALTZ16) spectra were acquired using 24 khz spectral width with 65 k data points and observed at 100.62 MHz (9 µs for 90 pulse width, 16 s for decoupling pulse, 30 flip angle and 0.367 Hz/point digital resolution). The acquisition time was 1.363 s and the relaxation delay was 2.0 s. DEPT spectra were acquired with a 1.363 s acquisition time, a 24 khz spectral width, a 2.0 s relaxation delay (9 s for 90 pulse width, 16 s for decoupling pulse, 135 flip angle for DEPT135, 90 flip angle for DEPT90 and 0.367 Hz/point digital resolution). 1D Selective NOESY, homonuclear 2D spectra COSY and heteronuclear 2D spectra HSQC were obtained using gradient pulses. They were performed by standard Bruker pulse programs [selnogp (1D NOE), cosygpqf ( 1 H- 1 H COSY), hsqcetgp (HSQC), hmbcgpnd (HMBC)]. 1 H- 1 H COSY spectra were acquired with a spectral width of 3 khz in the F1 and F2 dimensions, a 0.32 s acquisition time, a 1.487 s relaxation delay, digital resolution 25.008/1.563 Hz (F1/F2), and matrix size 128 2048 (F1 F2). HSQC spectra were acquired with a spectral width of 24 khz in f1 and 3 khz in f2 dimensions a 0.16 s acquisition time, a 1.50 s relaxation delay, digital resolution 98.147/ 3.126 (F1/F2), and matrix size 256 1024 (F1 F2). HMBC spectra were acquired with a spectral width of 22 khz in f1 and 3.6 khz in f2 dimensions, a 0.14 s acquisition time, a 1.50 s relaxation delay, digital resolution 87.191/3.513 (F1/F2), and matrix size 256 1024 (F1 F2). Received December 28, 2006. REFERENCES 1. (a) For a review on total synthesis of reserpine, see: Chen, F. E.; Huang, J. Chem. Rev. 2005, 105, 4671. (b) Huang, J.; Chen, F. E. Helv. Chim. Acta 2007, in press. 2. (a) Barco, A.; Benetti, S.; Risi, C. D.; Marchetti, P.; Pollini, G.-P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515. (b) Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H. J.; Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Gockel, V.; Gotzo, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Rockel- Stabler, O.; Trussardi, R.; Zwahlen, A.-G. Org. Process Res. Dev. 1999, 3, 266. 3. (a) Meier, R. M.; Tamm, C. Helv. Chim. Acta 1991, 74, 807. (b) Liu, A.; Liu, Z. Z.; Zou, Z. M.; Chen, S. Z.; Xu, L. Z.; Yang, S. L. Tetrahedron 2004, 60, 3689. 4. Hanessian, S.; Pan, J. W.; Carnell, A.; Bouchard, H.; Lesage, L. J. Org. Chem. 1997, 62, 465. 5. (a) Wu, T.-S.; Leu, Y. L.; Tsai, Y. L.; Lin, F. W.; Chan, Y. Y.; Chiang, C. Y. J. Chin. Chem. Soc. 2001, 48, 109. (b) Liao, J. C.; Zhu, Q. X.; Yang, X. P.; Jia, Z. J. J. Chin. Chem. Soc. 2002, 49, 129.
1320 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 Zhang et al. 6. (a) MacDougall, J. M.; Turnbull, P.; Verma, S. K.; Moore, H. W. J. Org. Chem. 1997, 62, 3792. (b) Katritzky, A. R.; Akhmedov, N. G.; Wang, M.; Rostek, C. J.; Steel, P. J. Magn. Reson. Chem. 2004, 42, 648. (c) Katritzky, A. R.; Akhmedov, N. G.; Wang, M.; Rostek, C. J.; Steel, P. J. Magn. Reson. Chem. 2004, 42, 999. (d) Rijo, P.; Simoes, M. F.; Rodriguez, B. Magn. Reson. Chem. 2005, 43, 595.