Sequential Michael addition/biscyclization reactions leading to the formation of highly substituted polycyclic substrates: some preliminary studies

An intermolecular Michael addition reaction of a malonate or malononitrile to unsaturated carbonyl substrates Z2a , E2a and E2b followed by a palladium-mediated biscyclization reaction led to the formation of highly functionalised tricyclic compounds with, in general, a high level of selectivity . A preliminary study on the transformation of one of these resulting substrates into a tetracyclic compound is also presented.


Introduction
In recent years, transition metal-mediated tandem or cascade reactions have become a powerful method for the one-step synthesis of various carbo-and heterocyclic systems.Many groups have made important contributions to this area and the scope and limitation of such reactions have been the subject of recent reviews. 1 As a part of our ongoing effort to expand the synthetic utility of a new palladium-mediated cyclization reaction developed in our group, 2 we recently reported efficient strategies for the construction of tricyclic structures. 3In particular, we have demonstrated that the palladium-catalysed cyclization of linear compounds of type 1 (Z or E) proceeds with complete retention of the stereochemistry in a stereocontrolled mode since it involves attack of the carbon nucleophile onto the double bond electrophilically activated by the organopalladium species.Moreover, the regiochemistry of the cyclisation (5 exo versus 6 endo) can be controlled by the steric bulk of the nucleophile part (Scheme 1). 4  We now report further progress based on the use of an intermolecular Michael addition reaction coupled with this palladium mediated biscyclization reaction.The motivation of this study emanates from the view that this would permit suitable functionalisation of ring C and thereby provide potential intermediates for the synthesis of various tetracyclic compounds by way of several synthetic transformations (Scheme 2). 5 Another challenging aspect of this tandem reaction lies in the level of selectivity on this palladium biscyclization reaction with respect to the relative configuration of the three newly formed chiral centers.

Pd
The synthesis of E2a began with the addition of vinylmagnesium bromide to 3 which provided the allylic alcohol 4. To effect the Claisen rearrangement, this alcohol was placed in refluxing butyl vinyl ether, in the presence of mercuric acetate. 7To complete the sequence, the resulting aldehyde 5 was treated with carbomethoxymethylene triphenylphosphorane to afford E2a in 81% yield.In order to introduce another functional group for further transformation, we also prepared the unsaturated ketone E2b (82%) using a mild olefination procedure, 9 conventional methods giving poor results.The synthesis of the isomerically pure Z2a was realized through a three-step sequence.Wittig olefination of aldehyde 3 with the phosphorane derived from 4-bromobutyronitrile 8 proceeded smoothly at 0°C to provide olefin 6 in 90% yield.The nitrile function was then converted to the aldehyde 7 by reduction with diisobutylaluminium hydride.Introduction of the conjugated carboethoxy group was also carried out by a Wittig reaction.We initially attempted the sequential Michael addition / biscyclization reaction via a one pot procedure.We envisaged that Michael addition of active methylene compounds such as malonate and malononitrile to the α-β-unsaturated carbonyl compound such as Z2a would lead to the expected stabilised anionic intermediate Z9 by proton transfer.Addition of an appropriate palladium(0) complex to the reaction mixture would allow the biscyclization process to take place according to Scheme 2. 10 First of all, we studied the reaction of Z2a with the malonic enolate prepared from diethyl malonate and potassium hydride in THF as solvent.Although Michael addition of methylmalonate was nearly complete, as observed by GC, this solvent was not suitable for the biscyclization reaction.After addition of the palladium catalyst, no reaction occurred even after prolonged times at reflux of the solvent.Attempted modification of this standard method was unsuccessful in spite of variations of the solvent, the base, the temperature, the nature of the palladium catalyst and of the nucleophile (malononitrile in place of diethyl malonate).Consequently, we decided to overcome these problems by studying first the conjugate addition of active methylene compounds and secondly the biscyclization of the resulting adducts.
Michael addition of the sodium salt of diethylmalonate to Z2a in refluxing THF containing a catalytic amount of 18-crown-6 afforded adduct Z8 in 77% yield.Addition of malononitrile to the same substrate and to the trans analogue E2a required the use of -tBuOK as base instead of NaH, adducts Z9 and E10 were then obtained in respectively 84% and 80% yield.When these conditions were used for addition of malononitrile to the α,β-unsaturated ketone E2b, the yield of the adduct E11 was very low (25%).However, by employing the ruthenium(II) catalyzed conditions developed by Echavarren, the yield of E11 could be improved to 63%. 11A significant amount (23%) of the starting material was also recovered (Scheme 5) We next examined the palladium mediated biscyclization of these four cyclization precursors, aryl bromides Z8, Z9, E10 and E11.They were subjected to the conditions that had been determined optimum for the cyclization of the linear homologous substrates. 4The reaction was carried out by heating of a substrate in NMP at 60°C in the presence of 5%mole Pd(dppe), 1.1 equivalent of KH and 0.2 equivalent of 18-crown-6.Under these conditions, the less sterically demanding nucleophile Z9 underwent a clean regiospecific cyclization to afford a 2:1 mixture of C 2 epimeric perhydrophenanthrene substrates 12a and 12b in 73% total yield without formation of 5-exo-trig cyclization products.The structure of the cyclization products have been elucidated by analysis of the 1 H and 13 C NMR spectra in comparison with those of the linear analogues having no CH 2 CO 2 Et side chain whose structure had been confirmed by X-ray crystallography. 4As anticipated, a high degree of stereocontrol was observed during the cyclisation.The geometry of the newly formed ring junction is cis, this being in accord with the reaction mechanism proposed above.The major isomer could be isolated from the mixture by careful medium pressure liquid chromatography.Its structure has been deduced on the basis of NMR spectroscopic data.Indeed, 2D homo-and heteronuclear experiments allowed for identification of most of the hydrogens and carbons and in particular the small 1 H NMR coupling ( 3 J = 4.6 Hz) observed between the two adjacent ring methine protons(H 5 and H 14 ) confirmed the cis fused configuration.In the NOESY experiments, the presence of a cross peak between the two vicinal methine protons confirmed the cis ring fusion.The lack of signals between these two protons and the third methine C 2 proton and the presence of a cross peak between H 2 and one proton H 13 indicated that the side chain CH 2 CO 2 Et and the two vicinal methine protons were on the same face of the molecule.(Scheme 6) The palladium-catalysed cyclization of the bulkier nucleophile Z8, under the same conditions led to the exclusive formation of cyclopentanic compounds 13a and 13b with no selectivity at the C 2 center (1:1 mixture according to GC) (Scheme 6).The stereostructural assignments for these tricyclic compounds were based on the close resemblance of their 1 H and 13 C NMR to those of the linear homologue having no side chain. 4nder identical reaction conditions (60°C, 3h) the cyclization of E10 resulted in the formation of the tricyclic compound 14 as a single isomer as indicated by GC, 1 H and 13 C NMR.The structural and stereochemical assignments for this isomer were made on the basis of the HSQC, TOCSY and NOESY spectra.In particular, in the NOESY spectra, the presence of a cross peak between the two methine protons on both side of the carbon bearing the nitrile group allowed to assign the stereochemistry as shown in Scheme 7.

CN
It is noteworthy that the palladium-mediated cyclization reaction of linear alkenes (having no CH 2 CO 2 Et side chain) bearing a malononitrile were generally considerably slower (60h) than that of the corresponding malonates (5h). 4,12Concerning the cyclization of Z9 and E10, we observed a significantly faster biscyclisation of these two compounds compared to the linear dinitrile substrates (3.5h).This can be interpreted as a consequence of the Thorpe-Ingold effect.
When the same cyclisation reaction conditions were applied to the ketone E11, an intense degradation was observed and several by-products were formed along with the expected tricyclic compound 15 which could be isolated in only 14%.These failures seemed due to the presence of the keto group since performing this reaction on the corresponding protected ketone was successful and afforded a 3:1 mixture of C 2 epimeric compounds in 89% combined yield.The major isomer could be isolated by recrystallization from diethyl ether and mild acidic treatment liberated the ketone.The assigned structure of the resulting major isomer 15a has been elucidated from its NMR spectrum and by analogy to 14a.As mentioned in the introduction, the three highly functionalized perhydrophenanthrenes obtained in these two-step procedure may undergo further transformations to give tetracyclic substrates.As an example, we decided to prepare a tetracyclic lactam from the tricyclic nitrile ester 12a.Therefore, 12a was treated with concentrated H 2 SO 4 in absolute EtOH to provide the target compound as an inseparable 2:1 mixture of diastereomers 16 in 66 % combined yield.The assigned structure of these resulting tetracyclic products were corroborated by their IR, 1 H and 13 C NMR as well as their CI mass spectra.
Further extension of the scope of this Michael-addition/biscyclization reaction will be reported in due course.

Experimental Section
General Prpcedures.All reactions were carried out under a nitrogen atmosphere using standard syringe, cannula and septa techniques.All reactions were monitored by thin layer chromatography carried out on aluminium plates precoated with silica gel 60 F 254 (Merck) or by gas chromatography on a DB 1 capillary column 30 m. Column chromatographies were performed on silica gel SI 60 (40-60 µ, MERCK).Melting points (uncorrected) were determined on a Büchi Melting Point 510.IR spectra were recorded on a Perkin-Elmer 337 instrument.Nuclear Magnetic Resonance spectra were obtained on a Brucker ALS 300 spectrometer ( 1 H : 300 MHz or 13 C : 75 MHz) using TMS as an internal standard.Chemical shifts were expressed in ppm downfield from TMS and coupling constants (J) in Hertz.Microanalysis were performed by Service Central d'Analyse du CNRS, Solaize, France.THF was distilled from Na/benzophenone, N-methylpyrrolidone (NMP) and DMSO (dimethylsulfoxide) were distilled from CaH 2 , DMF was distilled from P 2 O 5 and Et 2 O was distilled from LAH prior to use.