Enantiospecific synthesis of functionalised bicyclo[3.3.1]nonanes from 10-bromocarvones via tandem intermolecular alkylation-intramolecular Michael addition sequence 1

A simple and convenient tandem methodology for the enantiospecific generation of functionalised bicyclo[3.3.1]nonanes 9 , 14 - 18 , via intermolecular alkylation of Michael donors with 10-bromocarvones 7 , 10 and 11 , followed by intramolecular Michael addition, is achieved. An unsuccessful attempt for the extension of the methodology for a possible short enantiospecific approach to AB-ring system 22 of taxanes via the allyl bromide 21 , is also described.


Introduction
Tandem reactions are among the most powerful building tools available in organic synthesis, since they rapidly increase the complexity of a substrate starting from simple precursors. 2 Stereocontrolled construction of various molecular frameworks with a high level of regio-, stereo-and enantioselectivity is one of the most challenging aspects in organic synthesis.Ready access to enantiomerically pure multifunctional compounds is highly desirable, as they can serve as chirons in the synthesis of complex products of biological significance.The bicyclo [3.3.1]nonane(1) system 3 is present in several natural products such as hyperforin, aristophenone A, guttiferone B, garsubellin A, papuaforin A, upial, trifarienols, etc. (Chart 1). 4 Biosynthetic pathway of many sesquiterpenoids and other naturally occurring materials involve formation and transformation of bicyclo [3.3.1]nonanes. 5In addition, bicyclo [3.3.1]nonanes have been utilised as synthons for the construction of various complex ring systems, enroute to natural products. 3,6This system has also received theoretical interest from the conformation point of view. 7In continuation of our interest in the enantiospecific synthesis of functionalised bi-and tricyclic carbocyclic systems from the readily and abundantly available monoterpene, (R)carvone, 8 we have developed a simple and convenient methodology for the construction of bicyclo [3.3.1]nonanesemploying a tandem intermolecular alkylation-intramolecular Michael addition reaction sequence. 9

Results and Discussion
It was anticipated that alkylation of a Michael donor such as dimethyl malonate with a 9bromocarvone derivative such as the bromoenone 2, 8b obtained by bromomethoxylation 10 of (R)carvone 3 [N-bromosuccinimide (NBS) in CH 3 OH-CH 2 Cl 2 ], would generate 4, which could undergo an intramolecular Michael addition leading to chiral bicyclo[3.3.1]nonane 5.Even though the bromoenone 2 was known to participate in the intramolecular alkylation reaction with potassium tertiary butoxide in tertiary butyl alcohol-THF leading to bicyclo[2.2.2]octenone 6, 8h contrary to our anticipation, it failed to undergo intermolecular alkylation with dimethyl malonate under a variety of basic conditions, and neither the alkylated product 4 nor the bicyclic product 5 were formed, perhaps due to the neopentylic nature of the electrophilic center.To overcome the steric crowding, the reaction was investigated with the allyl bromide 7. 8h Addition of NBS to a solution of carvone (3) and sodium acetate in methylene chloride and acetic acid at room temperature furnished a 3:2 mixture of 10-bromocarvone 7 and the bromoacetoxylation product 8, which were separated by silica gel column chromatography.Presence of a strong absorption band at 1715 cm -1 due to the ester carbonyl group and shift in the absorption band due to the ketone carbonyl group to 1700 cm -1 suggested the formation of the bicyclic product 9.The 1 H NMR spectrum exhibited characteristic resonances, in particular, two singlets at δ 4.79 and 4.72 due to the exomethylene protons, a singlet at 3.69 due to the two ester methyl groups, and a doublet at 1.02 ppm due to the secondary methyl group establishing the structure of the bicyclic ketone 9, which was further confirmed by the 15 lines 13 C NMR spectrum (see experimental section).The conformation and stereochemistry of 9 were deduced from the spectral data, in particular the various H-H coupling constants in the 400 MHz 1 H NMR spectrum.The twin chair conformation was assigned based on the 13 C NMR spectrum, as it was well established 11 that the resonance due to C-9 appear at δ 34.4,28.6, and 23.7 ppm for the twin chair, boat chair and twin boat conformations of the bicyclo [3.3.1]nonanes.The equitorial orientation of the methyl group at C-8 in 9 was assigned based on the quintet resonance for the C-8 axial proton at δ 2.73 (J 7.0 Hz), as the J 1,8eq is known to be less than 3 Hz. 12To establish the generality of this methodology, the reaction was also carried out with the allyl bromides 10 and 11 derived from 6-methylcarvone 12 and 6,6-dimethylcarvone 13, 13 respectively.Interestingly, treatment of 6,6-dimethylcarvone 13 with NBS in methylene chloride and methanol furnished, exclusively, the allyl bromide 11, in 84% yield, unlike the reaction with carvone, no product derived from bromomethoxylation reaction was observed probably due to the steric crowding.In a similar manner, reaction of trans-6-methylcarvone 12 with NBS in methanol and methylene chloride furnished the allyl bromide 10. 8l Paclitaxel (19, Taxol), 14 by virtue of its complex and densely functionalised structure, coupled with its novel mechanism of action, potent antitumor activity and its clinical use as a powerful anti-cancer drug has attracted the attention of many synthetic chemists. 15Indeed, only very few molecules in the last two decades have stirred as much imagination and activity among synthetic chemists as taxanes.While a few paid attentions to the total synthesis of taxol, a large number of research groups confined themselves to the development of methodologies toward various segments of taxol as well as analogues of taxanes. 16Assembling of the AB ring system of taxane, containing a bicyclo[5.3.1]undecane(20) framework and a bridgehead olefin, is proved to be one of the most difficult tasks in the construction of taxanes.Earlier, 17 we have developed an approach to functionalised A-ring of taxanes starting from (R)-carvone, wherein the C-5 and C-3 carbons of carvone were transformed into the C-1 and C-13 of taxanes (eqn.1).
In this context, after successful enantiospecific synthesis of the functionalised bicyclo[3.3.1]nonanes 9, 14-18, it was contemplated to explore the tandem intermolecular alkylation followed by intramolecular Michael addition methodology for a very short enantiospecific approach to the AB-ring system of the taxanes starting from 6,6-dimethylcarvone 13.In analogy to the synthesis of bicyclo[3.3.1]nonanes, it was anticipated that generation of the bromide 21 followed by tandem intermolecular alkylation with dimethyl malonate and intramolecular 1,6-conjugate addition leads to the AB-ring system of taxanes 22.A 1,3-enonetransposition methodology 18 was opted for the synthesis of the requisite vinyl enone 23.Thus, Grignard reaction of 6,6-dimethylcarvone 13 with vinylmagnesium bromide followed by oxidation of the resultant biallylic tertiary alcohol 24 with pyridinium chlorochromate (PCC) and silica gel in methylene chloride furnished In conclusion, we have developed a simple and convenient enantiospecific procedure for the construction of functionalised bicylo[3.3.1]nonanesemploying a tandem intermolecular alkylation of Michael donors with 10-bromocarvone derivatives followed by an intramolecular Michael addition reaction.

Experimental Section
General Procedures.Melting points are recorded using Tempo melting point apparatus in capillary tubes and are uncorrected.IR spectra were recorded on Perkin Elmer 781 spectrophotometer. 1 H (200, 300 and 400 MHz) and 13 C (22.5 and 75 MHz) NMR spectra were recorded on Brucker ACF-200 and AMX-400, and Jeol FX 90Q and JNM λ-300 spectrometers.The chemical shifts (δ ppm) and coupling constants (Hz) are reported in standard fashion with reference to either internal tetramethylsilane (for 1 H) or the central line (77.1 ppm) of CDCl 3 (for 13 C).In the 13 C NMR spectra, the nature of the carbons was determined by recording the offresonance spectra.Low and high-resolution mass measurements were carried out using Jeol JMS-DX 303 GCMS instrument using direct inlet mode.Relative intensities are given in parentheses.Elemental analyses were carried out using Carlo Erba 1106 CHN analyser.Optical rotations were measured using a Jasco DIP-370 digital polarimeter and [α] D values are given in units of 10 -1 deg cm 2 g -1 .Acme's silica gel (100-200 mesh) was used for column chromatography (approximately 15-20 g per 1 g of the crude product).Acetone was purified by distilling over potassium permanganate and storing over molecular sieves.6,6-Dimethylcarvone 13, 13 and the allyl bromides 7 8h and 10 8l were prepared as reported earlier.

16, 17 and 18, respectively. Structures of the products 14-18 were
Treatment of the allyl bromide 10 with dimethyl malonate and potassium carbonate in refluxing acetone furnished the bicyclo[3.3.1]nonane 14 in 82% yield.Reaction of the allyl bromide 11 with dimethyl malonate furnished the bicyclo[3.3.1]nonane 15, and with other Michael donors acetylacetone, ethyl acetoacetate and benzoylacetone furnished the bicyclic compounds established from their interrelated spectral data.Presence of an upfield shifted resonance due to the C-4 secondary methyl group at δ 0.66 ppm (shielded due to the equatorial aroyl group at the C-6 position) in the bicyclic compound 18 established the equatorial orientation of the benzoyl group.
4,4-dimethyl-3-vinylcarvone 23.Treatment of the vinyl enone 23 with one equivalent of NBS in a 3:2 mixture of methylene chloride and methanol furnished, exclusively, the bromoenone 21 in 85% yield, analogous to the reaction of dimethylcarvone, whose structure was established from its spectral data.However, contrary to our anticipation, treatment of the allyl bromide 21 with dimethyl malonate and potassium carbonate in refluxing acetone furnished only the alkylated product 25 in 85% yield.Presence of the molecular ion peak at m/z 334 (C 19 H 26 O 5 ) in the mass spectrum, presence of a strong absorption band at 1730 cm -1 due to ester carbonyl in the IR spectrum and absence of resonances due to bromomethyl group in the The diester 25 was treated with base once again.However, a variety of basic conditions failed to induce either the intramolecular 1,6-conjugate addition to generate AB ring system of the taxanes 22, or the intramolecular Michael addition to produce the bicyclo[3.3.1]nonane 26, perhaps due to the steric crowding generated because of the gemdimethyl group.
1H NMR spectrum indicated the formation of the compound 25.In the 1 H NMR spectrum presence of typical ABX pattern resonances for the vinyl group, a six protons singlet at δ 3.73 and a doublet of a doublet at 3.61 ppm due to the CH(COOMe) 2 group established the structure of the compound 25, which was further confirmed by the 17 lines 13 C NMR spectrum.