Santonic acid: Zn–HCl–ether reduction and ceric ammonium nitrate oxidation

Reduction of santonic acid using Zn–HCl–ether yielded succinic anhydride derivatives via pinacolisation followed by rearrangement, whereas oxidation of santonic acid using ceric ammonium nitrate afforded five oxidative decarboxylation products. Dedicated to Prof. TBH McMurry.

(2 )-Santonic acid (2) appears to be a good precursor for bicyclic skeletons present among natural products.
An aim of this work was to seek entry into bicyclo[3.3.0]octane systems using Zn -HClether reduction (Toda et al. 1972) to obtain pinacol (3) (Figure 1) followed by acid-catalysed molecular rearrangement. Entry into bicyclo[4.3.0]nonane skeleton has been reported (Hortmann & Daniel 1972;Naik et al. 1987), and it was our interest to explore an alternate entry into this skeleton via oxidation of 2 with ceric ammonium nitrate (CAN).

Results and discussion
(2 )-Santonic acid (2) was subjected to reduction with the Zn -HCl -ether following reported conditions (Paquette et al. 1985), with the aim to obtain the previously prepared pinacol (3) (Hortmann & Daniel 1972) via intramolecular pinacolisation. However, under these conditions santonic acid (2) did not afford pinacol (3), but yielded a 60:40 mixture (GC -MS, 1 H NMR) of succinic anhydrides 4 and 5 ( Figure 2). The 13 C NMR (DEPT) spectrum indicated two sets of 15 signals confirming it to be a mixture of two C15 compounds. The IR spectrum of the product revealed characteristic twin bands at 1835 and 1780 cm 21 indicating the presence of substituted succinic anhydrides. It was found to be a 60:40 mixture of two isomers from its 1 H NMR spectrum. The major compound displayed a triplet at 1.0 (J ¼ 7.0 Hz) due to a CH 3 -CH 2 group, a singlet at d 1.20 and a doublet at d 1.35 (J ¼ 7.0 Hz). The olefinic proton was observed as a broad singlet at d 4.92. The complete spectroscopic analysis (Section 3) led to structure 4 for the major product. The 1 H NMR spectrum of the minor isomer (40%) exhibited a triplet at d 1.0 (J ¼ 7.0 Hz, CH 3 -CH 2 ), a singlet at d 1.18 and a doublet at d 1.35 (J ¼ 7.0 Hz). The vinyl  hydrogen was observed as a singlet at d 5.09. Structure 5 was, therefore, assigned to the minor isomer. It is clear that the reaction proceeds via pinacol (3), which under acidic conditions undergoes further rearrangement resulting in the cleavage of the C5ZC6 bond to yield succinic anhydrides 4 and 5. Thus, the action of zinc in ether saturated with dry hydrogen chloride on santonic acid (2) resulted in pinacolisation followed by cationic rearrangement to afford a mixture of 4 and 5 with rigid cis-bicyclo[3.3.0]octane skeletons in a single step.
CAN is another interesting oxidising agent (Ho 1973;Hwu & King 2001) which catalyses Baeyer -Villiger oxidation of carbonyl compounds (Goswami et al. 2004) and more interestingly regiospecific Baeyer -Villiger oxidation of conformationally constrained polycyclic ketones (Mehta et al. 1976). It was our interest to evaluate the reaction of CAN with santonic acid since we envisaged the insertion of oxygen between C5 and C6 if it undergoes regiospecific Baeyer -Villiger oxidation. However, oxidation of 2 with CAN yielded products derived exclusively by oxidative decarboxylation (Figure 3). Column chromatography and preparative TLC yielded 6, 7, an unseparated mixture of 8 þ 9 (60:40) and 10. All five products were characterised mainly by using NMR spectral analysis.
The most distinctive feature of the 1 H NMR spectrum of compound 6 is the 1:3:3:1 quartet (J ¼ 6.4 Hz) at d 5.29 due to C11 -H. This downfield shift is due to the replacement of the carboxyl group by an ZONO 2 group. The C13 protons were observed as a doublet (J ¼ 6.4 Hz) at d 1.45. The total proton count indicated 19 hydrogen atoms and confirmed the presence of 1 nitrogen atom giving molecular formula C 14 H 19 NO 5 (M þ 281). The chemical shifts and the splitting pattern of the protons indicated that the tricyclic skeleton and the two ketonic carbonyls remained intact. Based on these data, structure 6 is assigned to the first product.
Compound 7, the third product isolated from the column revealed 1 H NMR data very similar to 6 except the C11 -CH 3 doublet was at d 1.35 instead of d 1.45.
Compounds 6 and 7 are thus stereoisomeric, differing only in the configuration at C11. Examination of models suggested the structures of 6 and 7 to be as shown.
Although the second product isolated by column chromatography appeared as a single spot on TLC, the 1 H NMR spectrum indicated it to be a mixture of 8 and 9 (60:40) and revealed strong similarities to the spectrum of 6. Signals for only two methyl groups (C4 -CH 3 and C10 -CH 3 ) could be seen in the region d 1.0-2.0 ppm. The olefinic region contained a four-line pattern at d 5.70 (1H, dd, J ¼ 17.3 and 11.0 Hz) and the AB part of an ABX system at d 5.31 (1H, d, J ¼ 11.0 Hz) and d 5.42 (1H, d, J ¼ 17.3 Hz), characteristic of a vinyl group attached to a quaternary carbon. The ratio of the integration under the olefinic proton region and the methyl groups indicated that the major component (60%) contained a vinyl group and has structure 8. Structure 9 is assigned to the other component (40%) on the basis of a sharp signal at d 2.33 due to an acetyl group. Interestingly, 8 was obtained earlier by lead tetraacetate oxidation of santonic acid (Naik 1987). A sample prepared using the reported procedure displayed identical behaviour on TLC. Efforts to separate 8 and 9 using column chromatography were unsuccessful.
Compound 10 was obtained as a crystalline solid, mp. 1828C. The 1 H NMR spectrum displayed a sharp singlet at d 1.45 (3H, C10 -CH 3 ) and two methyls at d 1.27 (d, J ¼ 6.3 Hz, C11 -CH 3 ) and d 1.09 (d, J ¼ 6.8 Hz, C4 -CH 3 ). C 11 -H afforded a quartet at d 4.01 (J ¼ 6.3 Hz). The upfield shift of this methine compared with the corresponding methines of diketo-nitrates 6 and 7 can be accounted for if the hydroxyl group is attached to C11. Structure 10 was assigned to this product.
All the products are derived by Ce 4þ oxidation at the carboxyl group; the ketonic carbonyls of 2 were unaffected. Mechanisms which account for all five products formed in this reaction are presented in Figure 3. These proposed mechanisms are in agreement with the earlier observations of oxidative decarboxylations of substituted phenylacetic acids (Trahanovsky et al. 1974) which proceed via the radical generated by loss of CO 2 which undergoes oxidation with Ce 4þ to give a carbocation which reacts with nitrate and hydroxide ions or deprotonates to afford products such as 6-10.

General experimental procedures
Melting points are uncorrected. IR spectra (neat film/KBr) were recorded on a Perkin-Elmer IR 298 spectrometer (Perkin Elmer Corporation, USA). NMR spectra were recorded either on Bruker 360 MHz ( 1 H) or 90 MHz ( 13 C) for 4 and 5 (Bruker Corporation, USA). A Bruker 500 MHz ( 1 H NMR) was used for 6-10, and a Bruker 125 MHz ( 13 C) for 7 and Bruker 90 MHz ( 1 H) for the remaining compounds in CDCl 3 with TMS as an internal standard. HRMS were recorded on QSTAR XL MS/MS Applied Biosystem instrument (Applied Biosystem Instruments, USA). All yields refer to pure isolated products. Activation of zinc was performed by washing zinc dust with HCl (2%) followed by water, ethanol, acetone, dry ether and heating at 1008C for 5 min just before use.

Reaction of santonic acid (2) with Zn -HCl -ether
Santonic acid (2, 0.54 g, 0.002 moles) was added to dry ether saturated with dry HCl gas at 08C, followed by the addition of activated zinc powder (0.708 g, 0.01 moles) over 1 h. After stirring at 08C for 1 h, it was cooled to room temperature and stirred for additional 1 h. The reaction mixture was quenched on crushed ice, basified with sodium carbonate and extracted with ether. The combined organic extracts were washed with water, dried over sodium sulphate and concentrated to furnish a yellow liquid, which was distilled under reduced pressure to yield a mixture of 4 and 5 in the ratio 3:2 (GC -MS) as a colourless oil, 0.37 g (69%). IR l max (KBr) 2950, 1853, 1780, 1380, 1335, 1210, 930 cm 21 (Figures S1 and S2).

Conclusions
Santonic acid (2) on Zn -HCl -ether reduction resulted in the cleavage of the C5ZC6 bond to afford succinic anhydrides 4 and 5, whereas 2 with CAN underwent oxidative decarboxylation to yield products 6 -10.

Supplementary material
Supplementary material relating to this article is available online, alongside Figures S1 -S7.