MOLECULAR REARRANGEMENTS OF HIGHLY FUNCTIONALIZED TERPENES . AN UNIQUE REACTIVITY OF BICYCLIC FRAMEWORK AND POLIENIC CHAIN INHIBITION UNDER SUPERACIDIC TREATMENT

Synthesis of polyfunctional triterpene derivative [8(27),13E,17E,21E]-15-phenylsulfonyl-16-oxobicyclofarnesylfarnesol benzyl ether (8) from commercially available monoterpene geraniol and diterpene manool has been accomplished in 73% yield and its chemical transformation in superacid medium has been investigated. An unexpected rearrangement of 8 occurred, which involved methyl migration in the bicyclic fragment and total inhibition of the lateral polienic chain. A new bicyclic triterpene product [5(10),13E,17E,21E]-15-phenylsulfonyl16-oxo-30(10→9)-abeo-bicyclofarnesylfarnesol benzyl ether (9), with rearranged new carbon skeleton has been obtained. Its bicyclic moiety is analogous to this of a natural triterpene neopolypodatetraene.


Introduction
Triterpenes is a group of terpenes with a high structural diversity, which includes natural products with more than 100 types of skeleton [1][2][3].Reviews related to biological activities of triterpenes appear regularly and are focused on their anti-infl ammatory [4], antitumor [5], anti-HIV [6,7] and insecticidal [8] activities, and also their use in treatment of metabolic and vascular diseases [9].

Results and discussions
The aim of the present work is development of the method for synthesis of bicyclic polyfunctional triterpenes with a new carbon skeletons and study of their conversion in superacid medium.
Synthesis of the bicyclic triterpenoids containing two structural blocks, fragment A (monoterpene -aliphatic) and fragment B (diterpene -bicyclic) has been drawn, in order to achieve the proposed goal.
Fragment A has been obtained from commercially available monoterpene -geraniol (1) in three steps (Scheme 1).Treatment of geraniol (1) with benzyl chloride in dichloromethane and sodium hydride led to the corresponding benzyl ether.Its spectral data and physico-chemical constants are in accordance with the reported ones [10].Compound 2 has been subjected to oxidation with selenium dioxide in ethanol furnishing the α,ω-bifunctionalized derivative 3 in a modest 45% yield.Finally, the monoterpene alcohol 3 has been oxidized with pyridinium chlorochromate (PCC) into the corresponding aldehyde 4 [11] (fragment A) in a 72% yield, its overall yield is ~32%.
Synthesis of fragment B has been achieved starting from commercially available manool (5).It was transformed into new diterpenic phenylsulfone 6 in a two-step sequence, according to the reported method [12].It should be mentioned that from reaction product by column chromatography also the 13Z-izomer of diterpenyl-phenylsulfone 6 was obtained in ~20% yield.
The structures of coupling reaction 7 and oxidation reaction 8 products have been established on the basis of their spectral data (see Experimental part).
The 1 H NMR spectrum of compound 9 also contains the signals of two phenyl groups: one belonging to benzyl moiety, for which strong signal overlapping has been noted, at δ Η 7.26-7.35(m, 4H, H-3'-7') and another one, identifying phenylsulfone fragment at δ Η 7.50 (bt, J = 8.0 Hz, H-3", 5" and 8.09 (dm, J = 8.0 Hz, H-2", 6").The clear substructures H-18 -H-19 -H-20; H-14 -H-26; H-22 -H-23 -H-24 -H-20 and, in contrast to the precursor 8-H-2"-H-3", H-4", H-5"are evident in 1 H/ 1 H COSY spectrum, the accurate description of all methylene protons being diffi cult because of severe signal overlapping (see: Table 1).The 13 C NMR data exhibited thirty nine carbon signals, which were assigned by a DEPT experiment as seven methyls, eleven sp 3 methylenes, one sp 3 and nine sp 2 methines, two sp 3 and ten sp 2 quaternary carbons.The presence of α,β-unsaturated carbonyl moiety has been corroborated in the molecules of precursor 8, by the 1 H and 13  N. Ungur   The rearranged triterpene derivative 9 has been thereby obtained as a result of selective reactivity of the bicyclic part under superacidic treatment.Its plausible formation from compound 8 is depicted in Scheme 2. Due to the presence of oxygenated groups in side chain at C-16 and C-17 that can be easily protonated the bication A, which blocks the carbocyclisation in acid medium, is formed.In such a manner only the migration of proton from C-9 to C-8 takes place, producing the carbocation B. The latter is subjected to ulterior conversion into the carbocation C, as a result of methyl group migration from C-10 to C-9.While "quenching" the carbocation C the separation of at C-5 occurs and the fi nal product 9 is obtained.
It should be noted that the polyfunctional triterpene derivative 9 can be considered a congener of natural triterpenoid neopolypodatetraene (10), especially on considering the similarity in the bicyclic fragment (Figure 2).The latter has been isolated from a squalene hopene cyclase mutant of the prokaryotic bacterium Alicyclobacillus acidocaldarius F365A [18].studied.Mentioned bicyclic triterpene product with rearranged carbon framework, which is a structural analogous of the natural triterpene neopolypodatetraene, has been obtained for the fi rst time.

Experimental
General.Melting points (mp) were determined on a Boetius hot stage.IR Spectra were recorded on a Spectrum-100 FT-IR spectrophotometer (Perkin-Elmer), with the universal ATR sampling accessory (υ in cm -1 ). 1 H-and 13 C-NMR spectra were recorded in CDCl 3 on Bruker 400 Avance III spectrometer (400.13 and 100.61MHz); chemical shift are given in ppm and are referenced to measured in chloroform (CHCl 3 ) as internal standard (δ = 7.26 ppm for proton and δ = 77.0 for carbon).Optical rotations were measures in chloroform on a Jasco DIP 370 polarimeter, using 5 cm cell.Commercial Merck Si gel 60 (70-230 mesh ASTM) was used for fl ash chromatography, and Merck pre-coated SiO 2 plates were used for TLC.The chromatograms were sprayed with 0.1% solution of cerium (IV) in 2N sulfuric acid and heated at 80°C for 5 min to detect the spots.GC/MS analysis were recorded on Agilent 7890A chromatograph, equipped with quadrupole MS detector MSD 5975C and HP-5 ms capillary column (30 m/0.25 mm).Treatment of reaction mixtures in organic solvents included the extraction by Et 2 O, washing of the extract with H 2 O up to neutral reaction, drying over anhydrous Na 2 SO 4 , and solvent removal in vacuum.