Elucidation of the stereochemistry of diterpene derivatives obtained by palladium catalyzed oxidative coupling-oxidation of camphene

J. Braz. Chem. Soc., Vol. 14, No. 1, 83-89, 2003. Printed in Brazil - ©2003 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Elena V. Gusevskaya* and Marcio J. da Silva Departamento de Química, ICEx, Universidade Federal de Minas Gerais, CP 702, 31270-901 Belo Horizonte - MG, Brazil As estruturas dos derivados diterpénicos resultantes do acoplamento oxidativo - oxidação do canfeno catalisados por paládio, ou seja, bis(2,2-dimetil-biciclo[2.2.1]hepto-3-ilideno)etano e (4,4dimetilbiciclo[3.2.1]octo-2-on-3-il)(2,2-dimetilbiciclo[2.2.1]hepto-3-ilideno)metano, foram estudadas utilizando-se as técnicas de RMN de 1H e de 13C uni e bidimensionais. Sua estereoquímica foi determinada utilizando-se NOESY. The structures of diterpene derivatives resulting from the palladium catalyzed tandem oxidative coupling-oxidation of camphene, i.e., bis(2,2-dimethyl-bicyclo[2.2.1]hept-3-ylidene)ethane and (4,4dimethylbicyclo[3.2.1]oct-2-on-3-yl)(2,2-dimethylbicyclo[2.2.1]hept-3-ylidene)methane, were elucidated using one- and two-dimensional 1H and 13C NMR techniques. Their stereochemistry was determined unambiguously by NOESY experiments. Keywords: camphene oxidation, palladium catalyst, diterpene derivatives, NMR spectroscopy, NOESY Introduction Functionalization of inexpensive naturally occurring monoterpenes using transition metal homogeneous catalysis can provide various derivatives of interest to perfumery, flavor and pharmaceutical industries as well as useful synthetic intermediates and chiral building blocks.1,2 We have recently reported that allylic acetates, alcohols, aldehydes and esters can be obtained in good yields and in some cases with high stereoselectivity by catalytic oxidation or carbonylation of some monoterpenes, such as limonene, β-pinene, and camphene.3 The reactions of olefin oxidation by palladium salts may be incorporated into catalytic processes by use of reversible reoxidants, such as CuCl2 (the Wacker type catalyst). Although these processes have been developed into commercially important methods for the oxidation of olefins by dioxygen, the most abundant and cheapest oxidant, their applications to natural product synthesis are rather scarce. We previously reported a selective PdCl2/ CuCl2 catalyzed oxidation of limonene, however in the case of bicyclic monoterpenes, such as β-pinene and camphene, CuCl 2 promoted the extensive skeletal rearrangements of the substrates.3 Then, we developed a * e-mail: CuCl2-free system for selective oxidation of β-pinene and camphene into allylic and glycol derivatives, respectively, using H2O2 as the final oxidant and Pd(OAc)2 as catalyst.3 In a further study, we applied a Pd(II)/NO3- catalytic system, a valuable alternative to the Wacker catalyst,4 to the oxidation of camphene (1) by dioxygen. We found a new process consisting in oxidative coupling of camphene (C10) giving diene 2 (C20) and its further oxidation to β, γunsaturated ketone 3 (C20) (Figure 1). In order to fully characterize compounds 2 and 3, we used one- and two-dimensional 1 H and 13 C NMR techniques as well as gas chromatography-mass spectroscopy (GC-MS) and IR spectroscopy. In this paper, we report the results of the elucidation of the stereochemistry of these diterpene derivatives, mainly by nuclear Overhauser enhancement spectroscopy (NOESY). Experimental General Infrared spectra were recorded on a Mattson FTIR 3000/ Galaxy Series spectrometer. Mass spectra were obtained by GC-MS on a Hewlett-Packard MSD 5890/Series II instrument operating at 70 eV equipped with a HP Ultra 1 capillary column. The uncorrected melting point was Article Elucidation of the Stereochemistry of Diterpene Derivatives Obtained by Palladium Catalyzed Oxidative Coupling-Oxidation of Camphene 84 Gusevskaya and Silva J. Braz. Chem. Soc. Figure 1. Synthesis of bis(2,2-dimethyl-bicyclo[2.2.1]hept-3-ylidene)ethane (2) and (4,4-dimethylbicyclo[3.2.1]oct-2-on-3-yl)(2,2dimethylbicyclo[2.2.1]hept-3-ylidene)methane (3) by the palladium catalyzed tandem oxidative coupling-oxidation of camphene (1). determined on a Mettler FP82HT melting point apparatus. 1 H and 13C NMR spectra were obtained using a Bruker DRX-400 AVANCE spectrometer with a magnetic field induction of 9.4 T. in CDCl3 solutions (concentration of 30 mg mL-1). Analyses were performed at 298 K. Chemical shifts are referenced to tetramethylsilane as internal standard. Standard Bruker pulse sequences (given in parentheses) were used for NMR experiences and experimental conditions were as follows. For 1H NMR spectra (zg30): dwell time (DW) 146.400 µs, acquisition time (AQ) 4.131 s, number of transients (NS) 16, recycle delay (D1) 1.000 s. For 13C NMR spectra (zgpg30): DW 31.400 µs, AQ 2.058 s, NS 1024, D1 2.000 s, decoupling multiple resonance method Waltz-16. For DEPT 135 (dept135): DW 15.700 µs, AQ 1.029 s, NS 512, D1 2.000 s. For g-COSY (cosy45): DW 227.200 µs, AQ 0.233 s, NS 8, D1 2.000 s, data points (TD) 1024 (F2) and 256 (F1). For HMQC (inv4tp): DW 249.600 µs, AQ 0.233 s, NS 8, D1 2.000 s, TD 1024 (F2) and 512 (F1). For HMBC (inv4lplrnd): DW 62.400 µs, AQ 0.256 s, NS 16, D1 2.000 s, TD 2048 (F2) and 1024 (F1), delay for long-range coupling (D6) 0.07 s. For 2D NOESY (noesytp): DW 222.400 ms, AQ 0.446 s, NS 32, D1 2.000 s, mixing time 550 ms, time evolution 6.50 µs, TD 2048 (F2) and 512 (F1). The data were processed before Fourier transformation as follows. For 1 H NMR spectra: using Gaussian multiplication (line broadening -0.3 Hz, Gaussian broadening 0.2). For 13C NMR spectra: using exponential multiplication (line broadening 1.0 Hz). For DEPT 135: using exponential multiplication (line broadening 1.0 Hz). For g-COSY: using a sine-bell function in both dimensions. For HMQC: using a sine-bell function in the F1 dimension and a sine-bell squared window function in the F 2 dimension. For HMBC: using a sine-bell squared window function in both dimensions. For 2D NOESY: using a sinebell function in both dimensions. Oxidation of camphene: general procedure Reactions were carried out in a stirred glass reactor connected to a gas burette to monitor a dioxygen uptake and followed by GC using a Shimadzu 14B instrument fitted with a Carbowax 20 M capillary column and a flame ionization detector. The typical run conditions for the synthesis of compound 2 were as follows: Pd(OAc) (0.1 mmol), benzoquinone (0.5 mmol), camphene (5 mmol), acetic acid (10 mL), 60 oC, 1 bar of dioxygen, 6 h. Diene 2 was formed in stoichiometric amounts based on benzoquinone (96% selectivity at 22% conversion, which corresponded to a 21% GC yield, isolated yield was 14%). The typical run conditions for the synthesis of compound 3 were as follows: Pd(OAc) (0.1 mmol), LiNO3 (1.8 mmol), camphene (5 mmol), acetic acid (5 ml), 60 oC, 1 bar of dioxygen, 8.5 h. Enone 3 was formed with a 92% selectivity at 80% conversion of camphene (74% GC yield, 51% isolated yield). Compounds 2 and 3 were isolated from the reaction solutions as isomeric mixtures 2a/2b ( (...truncated)