Shashikumar K. Paknikar 1,2,* and Joydeep Bhattacharjee 1
1Department of Chemistry, Goa University, Goa, 403206, India and Prof. S.C. Bhattacharyya Organic
Synthesis Laboratory, VerGo Pharma, Research, Verna, Goa, 403722, India
Abstract- Lead tetraacetate oxidation of (+)-maaliol and (-)-guaiol has led to the production of one trinor-4,5-seco
eudesmane and two 4,5-secoeudesmane compounds from maaliol and 1,2-dehydroguaioxide from guaiol.
This paper is dedicated to the memory of Dr. Alan F. Thomas whose scientific goodwill and invaluable help in providing spectroscopic data, lively discussions, and supporting our research group in all possible ways.
Keywords: Lead tetraacetate oxidation, (+)-Maaliol, (-)-Guaiol, 4,5-Secoeudesmane, 1,2-Dehydroguaioxide.
Among natural products from terrestrial and marine origin, sesquiterpenes occupy a prime position due to a wide range of compounds having diverse carbon frame works and biosynthethetically derived through molecular rearrangements, fragmentation resulting in fission of sigma bonds and olefinic linkages. Whenever a new carbon frame work is derived via ring cleavage it is referred as seco (e.g. 4,5-secoeudesmane) and when the skeletal change is observed by loss of carbon atom the prefix nor is used (e.g. noreudesmane, norguaiane). Biosynthetic pathways, both hypothetical and proven for structure related natural products, can serve as more direct routes for their synthesis from a suitable natural product precursor with established absolute stereochemistry. The simplest representatives of 4,5 secoeudesmane and trinor guaiane are 4,5-diketo-11-hydroxy-eudesmane 1 and trinor guaidiene 2. [1-2] respectively (Figure 1).
Umbellifolide, 3 the extremely bitter diketo -γ-lact-one, represents the first well chracterized 4,5-secoeudesmane sesquiterpene, and was isolated from Artemisia umbelliformis Lam in 1983  . Its absolute stereochemistry has been established by x-ray crystall-ography. From the same source Garriboldi and co-workers  isolated the hydroperoxy eudesmanolides 4 and 5 and suggested they were precursors for 3, thus indicating the mode of cleavage of C4-C5 bond of the eudesmane skeleton. Several reports [4-6] have appeared describing new members of this group. Another small and rare group of compounds is formed by cleavage of the C7-C11 bond of the guaiane skeleton resulting in the loss of three carbon atoms and the resultant compounds are grouped under tri-norguaines [2,7-8]. This paper reports the synthesis of 4,5-seco eudesmane and tri-norguaine skeletons using the tertiary hydroxyl group of (+)-maaliol 6  and (-)-guaiol 7  as substrates and the results obtained
from lead tetra-acetate oxidation of 6 and 7 (Figure 2).
2. RESULTS AND DISCUSSION
2.1. Oxidation of (+)-Maaliol
Lead tetraacetate is well-known for its ability to oxid-ize monohydric alcohols and a variety of other func-tional groups. . Thomas and Ozainne  reported regiospecific fragmentation of patchouli alcohol 8(patchoulol) by lead tetra-acetate in benzene and characterized three oxidation products 9, 10 and 11 derived via β-cleavage. Based on their findings, it seemed attractive to subject (+)- maaliol 6 to lead tetraacetate oxidation to obtain products based on 4,5-secoeudesmanes in a one pot reaction.
It was of interest to determine the path of trans-formation, if it involved a cyclopropyl-carbinyl cation intermediate (Path a, Scheme 3) to give the oxidation products or not. Maaliol 6, on LTA oxidation in benzene followed by the usual workup yielded a brown oil, which on column chromatography over silica gel furnished two fractions. The GC-MS of the first fraction showed the presence of two compounds, one major compound A (92 %) and a minor compound-B (8 %). Compound A was obtained as a colourless oil using preparative GLC. The GC-MS of the second fraction also gave a mixture composed of compound-C (82 %) and unreact-ed maaliol (18 %). Compound C was also obtained by preparative GLC. The IR spectrum of compound A exhibited absorption bands at ν max 2950, 1716, 1642(terminal methylene), 1716 (CH3 CO-) and 741 (cis–11 disubstituted double bond) cm -1. The 1HNMR spectrum in CDCl3 showed three methyl singlets at δ 0.98 (H-15), 1.75 (H-12) and 2.15 (H-14). The olefinic methyl-enes were observed at δ 4.62 and 4.76 (brs, 1H each,H-13a and H-13b) and cis-disubstituted olefinic meth-ines at 5.48 and 5.49 ppm (d, 1-H each, J = 10.0 Hz ,H-5 and H-6 ) . The data imply three double bond equivalents Therefore the compound must be mono-cyclic. The tricyclic skeleton of 6 was converted into a monocyclic skeleton by the cleavage of the C4-C5 and 1C6-C11 bonds. The 1H NMR data of 12 when compared to those of maaliol 6 ( 1HNMR spectra (300MHz, CDCl3 , δ) 0.51 (1H,dd, J=5.1, 7.2 Hz, H-6),0.63(1H, dd, J=7.2, 7.2Hz, H-7), 0.87 (3H, s, H-12), 0.94 (3H, s, H-13), 1.05(3H, s, H-15),1.26 ( 3H, s, H- 14) shows the C-10 methyl of maaliol 6 has remained intact and cleavage of C4-C5 and C6-C11 resulted in 12. Comparable chemical shifts were reported  for a structurally similar compound p-mentha-5,8-diene-2-ol for olefinic hydrogens and isopropenyl methyl. Its EI mass spectrum showed the molecular ion at m/z 220 and the significant mass fragments are given in Scheme 1.
The minor component of fraction-1, compound B was not isolated in sufficient quantity for spectral characterization but could be identified as 13 by its characteristic mass spectral fragmentation pattern and +M = 194 corresponding to C12 H18 O2 . The major frag-ments are presented in Scheme 2.
A small amount of 13 was also observed in the proton spectrum of 12 with characteristic chemical shifts at δ H 1.14, s, 3H, H-15; 2.16, s, 3H, H-14; 5.87, d, 1H, J =10Hz, H-6 and 6.68, (d, 1H, J = 10Hz, H-5)ppm. The reported chemical shifts  of the tertiary methyls and olefinic protons of 4,4-dimethylcyclohex-2-ene-1-one were in agreement with those observed for 12.
The formation of 13 can be explained by the oxi-dation of the isopropylidine isomer of 12 (not isolated but expected) either as a result of further oxidation by LTA or by auto oxidation as shown in Scheme 3 and supported by literature reports [16-17].
The IR spectrum of compound C showed absorption-1 bands at νmax 1728 (broad) and 1257cm-1 due to an acetate group. The absence of an isopropenyl group 1 and the presence of five methyl singlets in its HNMR spectrum at δH 0.95(H-15), 1.38 (H-12), 1.4 (H-13), 1.97(H-17) and 2.13 (H-14) ppm suggested compound
C to have a molecular formula C17 H28 O3 . The chemical shifts of the olefinic protons were nearly identical and were observed at δH 5.48 (d, J=10 Hz, H-5) and 5.49(d,J=10 Hz, H-6) ppm while the chemical shifts of the methylene protons were observed between 2.35-2.46(m, H-7 H-3a and H-3b). Its mass spectrum did not show the molecular ion at m/z 280 but the base peak was observed at m/z 220 (M+. -CH3 COOH). The mass spectrum was identical with that of 10 thus confirming structure 14 for compound C. A rational mechanism for the formation of 12, 13 and 14 from maaliol 6 is pre-sented in Scheme 3. No product derived via a cyclo-propylcarbinyl cation rearrangement (CCR) [ 18] was
detected. The oxidation products 12, 13 and 14 were formed by a concerted mechanism (path b) without involvement of a cyclopropropyl carbinyl cation intermediate.
2.2. Oxidation of (-)-Guaiol, 7
Lead tetraacetate oxidation of (-)- guaiol 7 and the unambiguous characterization of 1,2-dehydroguaioxide 15 was reported by Ourisson and Ehret [19 ]. Besides the formation of 1,2-dehydroguaioxide there was no mention of the formation of products derived via β−cleavage. It was of interest to find out the relative reactivities of the 1,5-tetrasubstituted double bond and the tertiary hydroxyl group at C-11 towards LTA. The aim of this investigation, subjecting guaiol to lead tetraacetate oxidation, was to synthesise a tri-nor-guaiene 13 and related compounds by cleavage of the C7- C11 bond (Scheme 4) and secondly obtain NMR data for 1,2-dehydroguaioxide 15. Oxidation of guaiol with lead tetraacetate in benzene was therefore carriedout using the experimental conditions as for maaliol 4.
The crude oxidation product was obtained as a brown oil and was purified by careful chromatography over silica gel. The only product isolated in 20% yield was identified as 1,2-dehydroguaioxide 15. No product hav-ing trinor-guaiane skeleton was isolated. This clearly confirmed that a five membered oxide intermediate is the preferred pathway. In another report formation of α-agarofuran 17 was observed on LTA oxidation of 10-epi-γ-eudesmol 16 in anhydrous benzene . Trinor-eudesmane compounds resulting by β-cleavage were not found. This clearly shows that besides the solvent, the conformations play a very important role in the products formed. Both guaiol and 10-epi-γ-eudesmol have a common part structure, a tetra substituted γ-δ olefinic linkage with respect to hydroxy-isopropyl group.
The rigid conformations of guaiol shows the proxi-mity of the hydroxy isopropyl group and γ−δ double bond. Two mechanisms can account for the formation of 1,2-dehydroguaioxide 15 from guaiol 7. The pre-ferred mechanism (path A, Scheme 4) involves the initial attack of LTA with the 1,5 olefinic linkage of guaiol 7 followed by five member oxide ring formation and elimination of the lead intermediate to 1,2-dehydro-guaioxide 15 . In the suggested mechanistic path B,(Scheme 4) the initially formed lead ester gets convert-ed to guaioxide where fragmentation is totally suppress-ed which explains the absence of trinor-guaianes. The same sequence of steps may have led to the formation of α-agarofuran 17 from 10-epi-γ-eudesmol 16.
Isolation of (+)-maaliol: (+)-maaliol was isolated from Indian valerian root oil .The oil was fractionat-ed into three parts and the fraction ,b.p. 45-96 /5mm was dissolved in ether and separated into acidic and neutral fractions. The neutral fraction on standing in deep freeze deposited a crystalline solid which on fur-ther purification by sublimation under vacuum gave (+)o-maaliol ,m.p.104, [α]D + 21.7o(ethanol,c,5.0), It wasidentified by mixed m.p with an authentic sample(courtsey Dr. V.K. Sood) and comparison of spectral-1 data given in literature IR, νmax , (cm -1): 3496,2915,2855, 1457, 1383,1100.
Oxidation of (+)-maaliol with lead tetra-acetate: maaliol (2.22 g, 0.01 moles) was added to a mixture of lead tetraacetate (1.5 g ) in benzene (25 mL) and the mixture refluxed for 2h. Excess of LTA was decom-posed by careful addition of ethylene glycol. The mix-ture was cooledand the benzene layer was separated and washed with NaHCO 3 , water and brine. The red brown oil obtained by removal of benzene was chro-matographed on 60-80 mesh silica gel. The column was eluted with petroleum ether and polarity was increased using ethyl acetate. The separation was monitored by TLC and visualization of spots by alcoholic solution of phosphomolybdic acid. The GC of fraction1 showed it to be a mixture of two compounds 12 (92 %) and 13 (7 %). The major one 12 was purified by preparative GC on carbowax and obtained as a colourless oil. The mass spectrum for fraction 1 was taken by GC-MS coupling from a Supelcowax column. GC of fraction -2 showed it to be mixture of two substances, 14 (82%) and unreacted maaliol (14 %). Compound 14 was isolated by preparative GC on carbowax.
-1IR ν max , neat (cm-1) : 2950, 1716, 1642, 1452, 1369,1222, 1165, 891, 741.
1HNMR spectra (300 MHz, CDCl3 , δ) 0.98 (3H, s, H-15, ), 1.75 (3H, s, H-12, ), 2.15 (3H, s, H-14), 1.2 -1.38(m, 4H, H-1a, H-1b, H-9a, H-9 b),1.5 -1.62 ( m, 3H, H-2a, H-2 b, H-8b), 2.35-2.46 (m, 3H, H-8 a, H-3a and H-3b), 2.62 (t, 1H, H-7), 4.62 and 4.76 (bs, 1H each, H-13a and H-13b), 5.48 and 5.49 (d, 1-H each, J= 10.0 Hz).
EIMS, m/z(rel.Int.): 220(M+, )(2), 162(30), 147(12),135(97), 107(85), 93(95), 85(25), 79(75), 67(15), 55(25), 43(100).
EIMS, m/z (rel. Int.): 194(M+) (5), 179(8), 136(20),123(30), 109(52), 95(40), 79(50), 67(38), 53(20),43(100).
IR, ν max , neat (cm -1 ): 2950, 1728, 1462, 1367, 1257,1137, 1019, 941, 737.
1HNMR spectra (300 MHz, CDCl3 , δ ppm) 0.90( s,3H, H-14), 1.38 (s, 3H, H-12), 1.40 (s, 3H, H-13),1.97(s, 3H, H-17) and 2.13 (s, 3H, H-15),1.28-1.36 (m,4H), 1.5 -1.62 (m, 4H), 2.35-2.46 ( m, 3H, H-7, H-3a and H-3b), 5.48 (d, J = 10 Hz, H-5) and 5.49(d, J = 10
+Hz, H-6).EIMS, m/z (rel. Int.): 220 (M+ -CH3 COOH) (8),162 (28), 135 (97), 119 (18), 107 (50), 93 (15), 85 (15),
79 (50), 43 (100).
Isolation of (-)-guaiol: (-)-guaiol was isolated from Guaic wood oil, Paraguay (courtsey Merck, India). Theoil was stirred in hexane and left in the deep freeze forfew days. The solid obtained was crystallised from hex-oane, fine needles, 91-92 degree C, [α] D -28o (ethanol,c.5.0). It was identified by physical properties and comparison of spectral data given in literature . IR,-1 ν max , KBr(cm-1): 3400, 1460, 1385,1365,1150,920,881,1 821. HNMR spectra (300 MHz, CDCl 3 , δ) 0.95 (3H,d,J=7.0),0.98 (3H,d, J=7.0),1.17(3H,s),1.19 ( 3H,s).
Oxidation of (-)-guaiol: Guaiol (2.24 g, 0.01 mol)was added to a mixture of lead tetra acetate (1.5 g) and benzene (25 mL) and mixture was refluxed fo 2 h. Excess of LTA was decomposed by careful addition of ethylene glycol. The mixture was cooled, benzene layer was separated and washed with NaHCO 3 , water and brine. Concentration afforded an oil which was purified by column chromatography over silica gel using combination of petroleum ether and ethyl acetate as eluent. Colorless oil (0.43 g, 20 %) of 1,2-dehydroguai-oxide15.
1HNMR (300 MHz ,CDCl3 ,δ ppm): 1.12 d, 3H, J= 7Hz, H-14), 1.17 (d, 3H, J= 7Hz, H-15), 1.20 (s, 3H, H-12), 1.35 (s, 3H, H-13), 1.50 (m, 1H, H-8a), 1.50 (m, 1H, H-6a), 1.79( m, 1H, H-6b), 1.81(m, 1H, H-9a), 1.90(m, 1H, H-8b), 1.98(m, 1H, H-4), 2.00(m, 1H, H-7), 2.00(m, 1H, H-9b), 2.15(m, 1H, H-3a), 2.18(m,1H, H-3b), 2.30(m, 1H, H-10), 5.45(s, 1H, H-2).
13CMR (75 MHz, CDCl3 , δ ppm): 13.2 (q, C-15), 20.5 (q, C-14) , 23.6(q, C-12), 31.1(q, C-13), 31.4 (t, C-8), 33.3(d, C-10), 33.8 (t, C-6), 38.1(t, C-3), 38.4 (t, C-9), 42.5 (d, C-7), 45.1(d, C-4), 81.8(s, C-11), 93.5(s, C-5), 123.8 (d, C-2), 153.6(s, C-1).
Mass m/z (rel. int.): 220 (M+ ) (80), 205 (100), 187(25), 177 (15), 159 (32), 147 (62), 131 (25), 119 (45),105 (45), 91 (65), 79 (38), 69 (35), 55 (65), 43 (85).
We thank Dr. Kamlesh Pai Fondekar for his help in preparation of the manuscript, making critical com-ments and useful suggestions, Merck, Goa, for Guaicwood oil and Dr. Nitin Borkar, CEO, VerGo Pharma Research Laboratories Pvt. Ltd, Verna, Goa-403722,India for support.
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