Studies of Stereo-selective Cyclo-additions and Transformations of Substituted 2-cyclopenten-1-one with Chiral Anthracene Templates

The chiral (S)-9-(1-methoxyethyl), (R)-9-(1,2-dimethoxyethyl) and 9-(1R, 2R)-(1,2dimethoxypropyl) anthracenes were synthesised and used for the thermal Diels-Alder reaction with cyclopentene-3,5-dione. Unlike the maleic anhydride and N-substituted malemides, the cyclo-adducts were obtained with high regio-selectivity as a single diastereomer. The X-ray structure of the cyclo-adduct showed an enol form but the 13C NMR showed resonances for two cyclopentanone carbonyl groups suggesting the solution structure is in the diketone form. Stereocontrolled studies using organomagnesium additions to the carbonyl groups resulted in hydrolytic cleavage of the enol ether and elimination of water to give â-alkylketone anthracene adducts. These were unsuccessful in preparing chiral cyclopentenone core structures.


INTRODUCTION
The cyclopentenone skeleton has been reported in diverse biological active compounds.For example, prostanoids such as clavulone I and clavulone II 1 isolated from marine natural products and exhibiting strong cytotoxicity.Untenone A 2 isolated from the Okinawan marine sponge Plakortis sp. which inhibites cell proliferation of L1210 leukaemia (IC 50 = 0.4 µg/mg) and mammalian DNA polymerases (pol.α and β), and human terminal deoxynucleotidyl transferase (TdT). 3ecently, TEI-9826, 4 an antitumor agent in preclinical trials, has also been prepared.
The Diels-Alder reaction of cyclopentene-3,5-dione, a good dienophile, and anthracene has been reported to give a completely enolic anthracene adduct after refluxing in benzene for four days. 13Thus, it was considered that the reaction of cyclopentene-3,5-dione with our synthetic chiral anthracenes might provide single diastereomers of corresponding enolic anthracene adducts.The single diastereomer could be obtained as the hydrogen bond interaction between the enol oxygen and the anthracene C-9 hydrogen similar to the previous discussion in the cyclo-addition of chiral anthracene and maleic anhydride or N-methyl maleimide. 9The stereo-selective substitution from the less hindered face might provide asymmetric synthesis of cyclopentenone derivatives.

General Methods
Melting points were determined with a Stuart Scientific SMP 2 melting point apparatus and are uncorrected. 1H and 13 C NMR spectra were recorded in CDCl 3 with a Bruker Avance 300 spectrometer (300 MHz for 1 H, 75 MHz for 13 C) using TMS as an internal standard.Mass spectra were recorded with a POLARIS Q or HEWLETT PACKARD 5973 mass spectrometer.Reactions were monitored by TLC using aluminium or plastic sheets pre-coated with silica gel 60 F 254 .Column chromatography was performed with Kieselgel 60. 9-Vinylanthracene (1) was prepared as described previously 14 , (S)-9-(1-methoxyethyl) anthracene (6) was synthesised as described previously using Snyder's method 15 , and cyclopentene-3,5-dione (7) was commercially available.

RESULTS AND DISCUSSION
The synthesis of the chiral anthracene auxiliary started with vinyl anthracenes (1a-b) which was prepared according to the literature. 14symmetric dihydroxylation with AD-mix β was prepared using literature procedure 16 to afford compounds 2a-b in fair yields.Then methylation of 2a with CH 3 I and NaH in THF for 6 hours at room temperature gave the dimethoxy compound 3a in 52% yield and the mono-methylated product 4a in 36% yield.Methylation of 2b using the same conditions gave only the dimethylated product 3b in 18% yield.This low yield might be due to the steric strain of the methyl side chain of the propyl group.However, the methylated product yield was improved when the reaction time was increased.
The absolute stereochemistry of 2a was confirmed by comparing the spectroscopic data and optical rotation of the previous report. 17 due to the use of (-)-(S)-MTPA-acid reacted with steric alcohol 4a.The anthracene 6 was synthesised according to Snyder's method and the structure confirmation was compared to the literature. 15e Diels-Alder reactions of the chiral anthracene 3a-b and 6 with cyclopentene-3,5-dione (7) refluxing in xylenes for 12 h resulted in the ketone forms of 8a-c as single diastereomers (Scheme 2).The structures of the addition adducts were confirmed by NMR spectroscopy.The 13 C NMR spectra appeared to have peaks around 203 and 211 ppm which suggested the solution structures to be diketone carbonyl groups of 8a-c.However, the single crystal X-ray crystallography of adduct 8c were showed to be an enolic anthracene adduct (Fig. 2).These were supported the previous study 19 that cyclopentene-3,5-dione itself in refluxing benzene was present exclusively as the keto tautomer.The X-ray crystallography also showed the orientation of the methoxy group away from the approaching dienophile.These observations led to a proposition that in the transition state, the facial selectivity is controlled by minimisation of electrostatic repulsion between the methoxyl oxygen and the approaching dienophile.While the cyclo-addition completed, hydrogen bonding helped to stabilise the alternative product, giving rise to a single diastereomer as depicted in Scheme 2.
Prior to transformation of the carboxyl group of 8c, the hydroxyl group was converted to either an ether or ester derivative with good to poor regio-selectivity depending on the nature of the protection employed (Table 1).Transformation of 8c into enolate anions led to the breaking of the hydrogen bond, and consequently delocalisation of the enolate anion gave two regio-isomers (Scheme 3).The regio-selectivity obtained was due to the steric hindrance of substituents.The small steric group of the -CH 3 gave the methyl ether low selectivity and about a 2:3 ratio of adducts ( 9) and (10), respectively.Meanwhile, the -Ac group had high selectivity and gave exclusively adduct (10) (Table 1, entry 2).The HMBC analyses were used in assigning the regio-chemistry of the ether/ester adduct.In the regio-isomers (10), the HMBC spectra showed correlations between ether/ester carbons and proton at C 2 2.
Treatment of enol ethers ( 9) and (10) with Grignard reagents gave 1,2-addition and then hydrolysis of the resulted products gave the corresponding β-alkylketone anthracene adducts (11) and (12), respectively (Scheme 4 and 5).The organomagnesium compounds added to the carbonyl group subsequently caused hydrolytic cleavage of the enol ether and elimination of water 16 to give 11 and 12.In this approach, steric hindrance plays an important role as using bulky Grignard reagents gave only product (11) from the addition to the less hindered carbonyl ketone (9).While the hindered carbonyl ketone 10 was not attacked by the bulky Grignard reagents (Table 2).The 1 H NMR spectra of (11) indicated the absence of the methoxy protons and the presence of the alkyl protons in high fields and the 13 C NMR spectra showed the present of carbonyl group at around δ 207.4 ppm.The HMBC spectra showed the correlations between C-H proton of the alkyl groups and the C1′′, C2′′ and C4′′, correlations between H4′′ proton and the C 5 carbonyl group, and correlations between H1′′ proton and C 9 anthracene substituent.The COSY spectra showed the correlations between H1′′ and H2′′ and the long length coupling between C-H proton of the alkyl groups and H2′′ and H4′′ protons.Thus, these NMR experiments assigned the carbonyl group to be on the same side as the C 9 anthracene substituent.The COSY spectra of 12 showed the long length coupling between H1′′ and C-H proton of the alkyl group, but correlation between H2′′ and C-H proton of the alkyl group was not observed.

CONCLUSIONS
Chiral anthracene templates were synthesised prior to use in Diels-Alder reactions with cyclopentene-3,5-dione.The results showed that the cyclo-adducts were obtained with good regio-selectivity as a single diastereomer from completely enolic forms in crystal structure and diketone forms in the solution structures.However, the studies on the stereo-selectivity using organomagnesium addition to the methoxyenones resulted in the cleavage of enol ether and elimination of water.These could undergo hydrogenation of the enone double bond to give a chiral cyclopentenones .On the other hand, studies with other nucleophilic additions to the carbonyl group without loss of stereo-centre should be investigated.

13 C
Scheme 4: Preparation of adducts 9 via Grignard reagents and hydrolysis