Synthesis and photochemical reaction of tricyclo[7.2.2.0 2,8 ] tridecanes: a novel entry to the BCD carbon framework of phorbol

Synthesis of 10,10-dimethyltricyclo[7.2.2.0 2,8 ]tridec-12-ene-3,11-dione 5 via cycloaddition of a cyclohexa-2,4-dienone with cycloheptadiene and its photoreaction to tricyclic compound 3 containing BCD ring system of phorbol is presented.


Introduction
Recently, there has been an upsurge of interest [1][2][3][4][5] in the tigliane diterpene phorbol 1 and its esters since some derivatives such as 2 exhibit potent tumor promotor.The tumor promoting activity of phorbol esters related to their control on intracellular signal transduction through protein kinase C (PKC).Other phorbol derivatives and structurally related daphnane diterpenes also elicit a wide variety of biological responses and exhibit anitumor, anti HIV and analgesic properties.The complex structure and striking biological properties of phorbol and its derivatives have prompted to devise methodology for constructing the framework of phorbol esters.Efficient construction of the complex tetracyclic network of phorbol is one of the many problems in addition to other structural and stereochemical features associated with its synthesis.It appears that introduction of the cyclopropane ring having gem-dimethyl group to daphnane framework (ABC ring system) also poses considerable synthetic problem in addition to the other functionalities present in the molecule.Several approaches involving oxyallyl[4+3]cycloaddition, 1a tandem anioinic cyclization-Claisen, 1c reductive coupling, 1d intramolecular oxido-pyrylium-alkene cycloaddition, 2 transannular cyclization, 3 intramolecular nitrile oxide cycloaddition, 4 Diels-Alder reaction, 5 carbonyl ylide cyclization, 6 and and others have been employed to generate various rings of phorbol.The intramolecular oxido-pyryliumalkene cycloaddition methodology 2 and oxyallyl cycloaddition 1b has led to synthesis of phorbol.
In continuation of our studies towards development of new synthetic methods employing photoreaction of β,γ-enones 7 and the interest in phorbol, we considered it possible to generate a tricyclic system of type 3 having the BCD carbon framework of phorbol, via decarbonylation of an annulated bicyclo[2.2.2]octenone 5 on singlet excitation, either directly, or through the 1,3acyl shift product 4.We wish to report an efficient synthesis of the dione 5 and its photoreaction leading to the tricyclic compound 3 having the D, C and B rings of phorbol. 8

Scheme 1
Treatment of 8 with aqueous KOH in chloroform readily gave the ketoepoxide 9 in quantitative manner. 8The oxirane ring in 9 was transformed into geminal dimethyl group as shown in the scheme 1.Thus, the keto-epoxide 9 was subjected to reduction with zinc-NH 4 Cl in dry dioxane 7c which gave the monomethyl ketone 10 (as a mixture of syn: anti isomers) as a major product.Alkylation of 10 with methyl iodide in the presence of NaH-THF afforded the methylated ketone 11 in excellent yield whose structure was deduced from the following data.The IR spectrum of 11 showed an absorption band at 1720 cm -1 for the carbonyl group.The 1 H NMR (300 MHz) spectrum displayed characteristic resonances at δ 6.48 (superimposed dd, J 1 =J 2 = ~7.5 Hz, 1H) and 6.12 (superimposed dd, J 1 =J 2 =8.5 Hz, 1H) for γand β-protons of the β,γ-enone moiety, respectively.The olefinic protons were observed at δ 5.57 (m, 1H) and 5.22 (d with structure, J=~10 Hz, 1H).The signals due to other methine, methylene and methyl protons were observed at δ 3. 13  Regioselective epoxidation of 11 with m-chloroperbenzoic acid in CH 2 Cl 2 at ambient temperature (~30 o C) gave the epoxyketone 12 whose structure was discerned from the following data (Scheme 2).The 1 H NMR (300 MHz) spectrum exhibited only two signals at δ 6.59 (superimposed dd with structure, J 1 =J 2 ~7.5 Hz, 1H) and 6.21 (superimposed dd with structure, J 1 =J 2 =7.5 Hz, 1H) corresponding to the olefinic protons of the β,γ-enone moiety.It also showed resonances at δ 3.39 (d with structure, J=~7.5 Hz, 1H) and 2.48 (m of d, J=7.5 Hz, 1H) due to bridgehead protons at C1 and C9 respectively.Furthermore, signals were observed at δ 2.94 (m, 1H), 2.74 (superimposed dd, J=4 Hz, 1H) corresponding to the protons at C4 and C3 respectively, in addition to resonances for methine, methylene and methyl protons.These assignments were confirmed with the help of a COSY spectrum which showed the following characteristic correlations.The resonance at δ 3.39 exhibited a strong correlation with the signal due to β-proton at δ 6.21 and a very weak correlation with the signal at δ 6.59 assigned to the γproton of the β,γ-enone moiety.On the other hand, the signal at δ 2.48 (assigned to the bridgehead proton at C9) showed a strong correlation with signal at δ 6.59 (assigned to the γproton of the β,γ enone moiety) and only a very weak correlation with the signal due to β-proton of the β,γ-enone group.Moreover, the signal at δ 2.74 (assigned to the proton at C3) exhibited COSY with the resonance at δ 2.94 (assigned to the proton at C4) and one of the signals at δ 2.28 (partly overlapped with another signal) due to methine proton.Similarly, the signal at δ 2.94 (assigned to the C4 proton) showed a strong COSY with the signals at δ 2.74 (assigned to the proton at C3) and δ 2.17 (dd of d, one of the methylene protons presumably at C5).These relationships between the protons and comparison of the spectral features with that of the precursor 11 clearly suggested that the olefinic linkage present in the seven membered ring of 11 had undergone a selective epoxidation.The observed selectivity is a manifestation of the homoconjugation of the olefinic moiety present in the bicyclo[2.2.2]octane framework.The exo orientation of the oxirane ring was suggested on the basis of the attack of the peracid from more accessible exo π-face.The 13 C NMR spectrum of the epoxide 12 also corroborated its formulation since it showed a signal at δ 215.65

Scheme 2
At this juncture, rearrangement of the oxirane moiety to carbonyl group was attempted.Of the several reagents such as BF 3 .OEt 2 , LiClO 4 , HClO 4 which are known to affect this transformation, we opted for BF 3 .OEt 2 for the rearrangement of 12. Thus, a solution of the epoxy-ketone 12 in dry benzene was treated with BF 3 .OEt 2 at ~5 0 C for about 2 hours (Scheme 2).Usual work-up and chromatography gave a dione to which the structure 5 was assigned on the basis of the following data.The presence of two carbonyl groups was clearly revealed from its 13 C NMR (75 MHz) spectrum that showed signals at δ 215.93 and 214.04 along with other resonances.The 1 H NMR (300 MHz) spectrum displayed characteristic signals at δ 6.39 (superimposed dd, J 1 =J 2 =7 Hz, 1H), 6.18 (d of superimposed dd, J 1 =J 2 = 7 Hz, J 3 =1.5 Hz, 1H) due to γ-and β-protons of β,γ-enone moiety, respectively.It also showed signals at δ 3.60 (d with structure, J=7 Hz, 1H) for the bridgehead proton at C1.Further signals were observed at δ 2.82 (m, 1H, partly overlapped with another multiplet) and 2.58 (d with structure, J ~7Hz, 1H) for the ring junction proton at C2 and the bridgehead proton at C9 respectively, in addition to the signals for other methine, methylene and methyl protons.These assignments were confirmed with the help of a COSY spectrum which revealed correlation between the signals at δ 6.39, 6.18 and 2.58.Similarly, the olefinic signal at δ 6.18, assigned to the β-proton of the β,γ-enone moiety, showed a correlation with resonances at δ 6.39 and 3.60.The signal at δ 2.82 (partly merged with another multiplet) was assigned to the ring junction proton at C2 since it showed correlation with the signal at δ 3.60 assigned to the bridgehead proton at C1 (which in turn, correlated with β-proton of the β,γ-enone moiety).The relationships between the various protons were further confirmed through NOESY spectrum.The signal at δ 6.39 exhibited NOESY with signals at δ 6.18, 2.58.The signal at δ 2.58 showed NOESY with signals at δ 2.90, 1.92 and the signal hidden under methyl groups.Furthermore, the signal at δ 2.90 showed NOESY with the signals at δ 2.82 in addition to other signals.The chemical shift and the relationship of the proton at C2 with other protons as revealed by COSY and NOESY spectra suggested the structure 5 for the above compound.
Though the mechanism of the epoxide rearrangement and the factors governing the regioselectivity are not very clear, it appears that the 1,3-steric interactions between protons at C1 and C3 may be responsible for the preferential migration of the hydrogen from C3 to C4.
Rigid carbocyclic systems containing a β,γ-enone chromophore undergo two unique reactions upon excitation.1][12] The direct excitation (S1) of β,γ-unsaturated ketones containing the homo-conjugated carbonyl group in ethano bridge leads to the formation of cyclobutanone derivative as a result of 1,3-shift.In some cases decarbonylation is also observed. 13,14We considered it possible to induce photodecarbonylation in 5 on direct irradiation in appropriate conditions.
Thus, a solution of the dione 5 in dry benzene was irradiated with a mercury vapour lamp (400 W, Applied photophysics) for 2h, in a Pyrex immersion well.Removal of the solvent followed by chromatography gave the tricyclic compound 3 in good yield (42%) as a result of decarbonylation, whose structure was clearly revealed from its spectral data (Scheme 3).The mechanism of formation of the decarbonylated product during the above photoreaction is difficult to suggest at this moment.Apparently, it proceeds through initial α-cleavage leading to the biradical 13 which cyclizes to give the 1,3-acyl shift product 4 that on subsequent decarbonylation gives the final product (Scheme 4). .

Scheme 4
This contention is based on the preliminary observation that 1,3-acyl shift product is formed (tlc, IR) during initial stages of the photoreaction that disappears after continued irradiation and the formation of the final product is observed.In this context it may be noted that cyclobutanones are known to undergo photo-decarbonylation upon excitation.However, the possibility of decarbonylation in biradicals 13 or 14 followed by ring closure can not be ruled out.
In summary, we have described a novel route to bicyclo[2.2.2]octenone annulated with a seven membered ring and its photochemical reaction directly leading to the tricyclic BCD framework of phorbol in a single stereoselective sequence.

Experimental Section
General Procedures.IR spectra were recorded on Nicolet Impact 400 FT-IR Instrument.UV spectra were recorded on Schimadzu 260 instrument. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) were recorded on Varian VXR 300 instrument.Most of the samples were dilute solutions in CDCl 3 with SiMe 4 as internal standard.Mass spectra were recorded on HP GCD 1800A mass spectrometer.Microanalyses were done on a CEST 1106 instrument.Melting points were determined on a veego apparatus of Buchi type and are uncorrected.All the organic extracts were dried over anhydrous sodium sulphate.Reactions were monitored with thin layer chromatography and spots were visualized with iodine vapour.Column chromatography was performed using Acme/SRL silica gel (60-120 and 100-200 mesh).The elution was done with petroleum ether (60-80 0 C) and ethyl acetate mixtures.The fractions eluted from column were concentrated at reduced pressure on a Buchi-RE 111 rotary evaporator.