SYNTHESIS OF NEW DI- AND TRI-NORLABDANE COMPOUNDS WITH 2-AMINO-1,3-THIAZOLE UNITS

The present paper reports the synthesis of new hybrid terpeno-heterocyclic compounds belonging to diand tri-norlabdane series. Starting from natural labdane diterpenoide (-)-sclareol, via its intermediates 8α-hydroxy-15,16-dinorlabd-13-one and sclareolide, two di-norlabdane and three tri-norlabdane, previously unreported compounds possessing 2-amino-1,3-thiazole structural units were obtained in three and four steps, respectively, with acceptable to good overall yields. The structures of newly obtained compounds were confirmed by means of spectral IR, H and C NMR analyses. It can be assumed that the synthesized compounds possess potential biological activity due to the presence of the heterocyclic unit. Additionally, the mechanism of 2-amino-1,3-thiazole ring formation is proposed.


Introduction
Terpenoids represent one of the most numerous and important classes of natural compounds from both, theoretical and practical points of view. Terpenic compounds possess a strong biological activity and influence vital processes in vegetal and animal worlds [1][2][3][4].
From the diversity of terpenic compounds, labdanes, belonging to the bicyclic diterpenoids group, have been found as secondary metabolites in tissues of fungi, insects, marine organisms, and in essential oils, resins and tissues of higher plants. Diterpenes of labdane type reportedly showed a broad spectrum of biological activities such as cytotoxic, antifungal, anti-inflammatory, antiparasitic, analgesic activities, etc. [5][6][7][8][9][10][11]. In recent years, a special attention was drawn to the isolation of biologically active compounds with terpenic and heterocyclic structural units from various natural sources [12][13][14][15].
Thiazoles are the most important class of heterocyclic compounds. According to published data, these compounds are highlighted by a broad spectrum of pharmacological properties such as anticancer, antitubercular, antimicrobial, anti-inflammatory, analgesic and anticonvulsant activities [16,17]. Based on these data, a remarkable progress has been made lately in the development of new thiazole compounds. Moreover, much interest has also been focused on the antihelmitic, diuretic, and antimalarial activities displayed by compounds incorporating this heterocyclic system [18,19].
In the scientific literature, there are just a few mentions related to the syntheses of hybrid compounds with terpenic and heterocyclic skeleton. According to some authors, such compounds possess a potent biological activity [12][13][14][15]. Therefore, the use of terpenic derivatives as chiral synthones in condensation reactions with heterocycles is expected to give some new biologically active compounds containing both terpenic and heterocyclic units.
The main goal of the research presented here was the synthesis of new di-and trinorlabdane compounds containing 1,3-thiazole structural units. The key strengths of this research are: accessible starting material, a natural labdane diterpenoide (-)-sclareol, extracted from renewable resources, and high probability of biological activities combined with low toxicity of the mentioned compounds, due to their natural origin.

Generalities
Optical rotations were measured on a Jasco DIP 370 polarimeter with a 1 dm microcell, in CHCl3. The IR spectra were registered on a Spectrum-100FT-IR spectrometer (Perkin-Elmer) by the ATR technique. 1 H and 13 C NMR spectra were acquired on a Bruker Avance DRX 400 spectrometer (400, 100 MHz). CDCl3 was used as solvent. The following abbreviations were used to designate chemical shift multiplicities: s= singlet, d= doublet, t= triplet, q= quartet, m= multiplet. All chemical shifts are quoted on the δ-scale in ppm and referred to residual CHCl3 (δH at 7.26 ppm) and as CDCl3 (δC 77.00 ppm). The coupling constants (J) are given in Hz. The twodimensional H, H-COSY; H, C-HSQC and H, C-HMBC experiments were recorded using standard pulse sequences, in the version with z-gradients, as delivered by the Bruker Corporation. Carbon substitution degrees were established by the DEPT pulse sequence. For the analytical TLC, Merck silica gel plates 60G in 0.25 mm layers were used. Visualization of the plates was achieved using UV lamp (max= 254 or 365 nm) and/or by spraying with acidic aqueous cerium(III) sulphate solution, or 20% KMnO4 solution. The column chromatography was carried out on the Acros Organics silica gel (60-200 mesh) using dichloromethane and the gradient mixture of CH2Cl2 and MeOH.
All solvents were purified and dried by standard techniques before use. Solutions in organic solvents were dried over anhydrous Na2SO4, then filtered and evaporated under reduced pressure.
The condensation-cyclization reaction of unsaturated ketones 9 and 10, under the same conditions, led to tetra-substituted 12 and tri-substituted 13 thiazoles, with 82% and 80% overall yields, respectively.
The structures of all synthesized compounds were confirmed by IR, 1 H and 13 C NMR data. The spectroscopic data of the new compounds are given in the experimental section and are fully consistent with the suggested structures. The IR spectra of compounds 5, 6 and 11-13 had strong absorption maxima characteristic for the N=C group around 1620-1610 cm -1 and comparative absorptions at 3308-3116 cm -1 , which were assigned to the amino group bounded to the thiazole fragment. The 1 H NMR spectra of the compounds 5, 6 and 11-13 fully confirm their structures by the presence of singlet signals belonging to C-17, C-18, C-19 and C-20 methyl groups of the terpenic fragment in the 1.81-0.76 ppm region, a broad singlet of protons related to the amine group of the thiazole fragment at 5.41-5.05 ppm, and a singlet of the proton from the thiazole fragment at 6.15-5.92 ppm (Figure 1). The 13 C NMR spectra of the obtained compounds 5, 6, and 11-13 clearly confirmed their structures by the presence of the chemical shift for C-2ʹ form the thiazole ring that was assigned to 167 ppm, while the signals of C-4ʹ and C-5ʹ from the thiazole ring appeared around 152-155 ppm and 102 ppm, respectively ( Figure 2).
A proposed mechanism for the synthesis of di-and tri-norlabdane compounds with 2-amino-1,3-thiazole fragment is given in

Conclusions
The present paper describes a short and efficient synthesis of novel hybrid terpenoheterocyclic compounds. Starting from natural labdane diterpenoide (-)-sclareol 1, via its intermediate 8α-hydroxy-15,16-dinorlabd-13-one 2, di-norlabdanes 5 and 6 containing 2-amino-1,3thiazole unit were synthesized in ~30.0-70% overall yields. The synthetic route via sclareolide 7 leaded to tri-norlabdanes 11-13 bearing the 2-amino-1,3-thiazole unit that were obtained in 6.5-31.5% overall yields. In contrast to pure isomers 3,4 and 9,10, the use of hydroxyketones 2 and 8, offered some disadvantages because of the formation of the mixture of 2-amino-1,3-thiazole compounds. The formation of these mixtures can be explained by the suggested reaction mechanism which proves that the presence of molecular iodine encourages dehydration of hydroxy group in the mentioned compounds. The spectral analysis (IR, 1 H and 13 C NMR) of newly synthesized compounds fully confirmed their structure and the presence of the 2-amino-1,3thiazole unit.