Synthesis of Highly Functionalised Enantiopure Bicyclo [ 3 . 2 . 1 ]-octane Systems from Carvone

The commercially available monoterpene carvone has been efficiently converted into the tricyclo[3.2.1.0]octane and bicyclo[3.2.1]octane systems characteristic of some biologically active compounds. The sequence used for this transformation involves as key features an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a cyclopropane ring opening.


Introduction
The bicyclo[3.2.1]octane ring system is the basic framework of many important biologically active natural compounds, particularly tri-and tetracyclic sesqui-and diterpenes [1].The widespread occurrence of this common structural motif in so many biologically active natural products has stimulated the preparation of simple non-natural structures containing the carbo-bicyclic system with variable functional diversity, many of which have also shown relevant biological activity.A logical consequence of the interest in this type of compounds has been the development of a plethora of synthetic methods for making bicyclo[3.2.1]octanes [2], in many cases appropriately functionalised to be useful intermediates in the synthesis of the more complex natural products containing this bicyclic subunit.Some of the more efficient methodologies developed for the preparation of the bicyclo[3.2.1]octane system are based in the selective fragmentation of different types of functionalised tricyclo[3.2.1.0 2.7 ]octane derivatives, whose tricyclic cores have been constructed basically using two methods, an intramolecular cyclopropanation of a double bond [2,3], or a bicycloannulation of cyclic dienolates with various Michael acceptors [2,4].

Scheme 1
It must be mentioned that although several intramolecular cycloadditions involving 5-vinyl-1,3cyclo-hexanedienes have been described in the literature [6], these types of Diels-Alder reactions have not been previously evaluated for their synthetic utility.Only recently, and while this work was in progress, Trauner described the preparation of several substituted tricyclo[3.2.1.0 2.7 ]oct-3-enes via IMDA reactions of 5-vinyl-1,3-cyclohexadienes.He has also called attention to the synthetic potential of this reaction in the synthesis of several polycyclic natural products and suggested the possible implication of such a reaction in their biosynthesis [7].

Results and Discussion
Carvone (4) was used as the starting chiral material with the objective of preparing the bicyclo[3.2.1]octane framework in enantiomerically pure form.This is a monoterpene, commercially available in both enantiomerically pure forms, (R)-(-)-and (S)-(+)-carvone, that has been widely used by us [8] and others [9] as a chiral starting material in the synthesis of numerous natural products.
The synthesis starts with the conversion of carvone (4) into the β-keto ester 5 using Mander´s methoxycarbonylation procedure [10].Thus, reaction of methyl cyanoformate with the kinetic lithium enolate of 4, generated by treatment with LDA in THF at low temperature, afforded the β-keto ester 5 in very high yield (Scheme 2).Although irrelevant from the synthetic point of view, compound 5 seems to exist basically in only one tautomeric form in which the methoxycarbonyl groups occupies the equatorial position, as suggested by the coupling constant pattern observed in the 1 H-NMR spectrum for H-1 (a singlet with J = 13 Hz).
It should be pointed out that the methoxycarbonyl group was introduced at the C-2 position of carvone with the dual purpose of installing a versatile functional group for further functionalization of the target bicyclic systems as well as to avoid diene isomerisation during the subsequent Diels-Alder step.In fact, attempts to directly elaborate the diene moiety from 4, e.g.compound 6, always afforded a mixture of isomeric cyclohexadienes under different experimental conditions.With the methoxycarbonyl group in place, the regioselective formation of the silyloxy diene moiety was readily accomplished by enolization of 5 by treatment with lithium bis(trimethyl)silylamide and capture of the enolate with tert-butyldimethylsilyl triflate.Conversion of (R)-carvone into the tert-butyldimethylsilyl enol ether 7 was thus accomplished in ca.82% overall yield.
The 5-vinyl-1,3-cyclohexadiene moiety of 7 underwent an intramolecular Diels-Alder reaction smoothly and efficiently upon heating a degassed anhydrous toluene solution of this compound and a small amount of propylene oxide in a sealed ampoule at 190 ºC for 48 h.Compound 8, containing the tricyclo[3.2.1.0 2.7 ]oct-3-ene system, was thus obtained in 80% of yield after purification by column chromatography.It must be mentioned that in the absence of propylene oxide as acid scavenger, both the starting tert-butyldimethylsilyl enol ether 7 and the Diels-Alder adduct 8 were partially hydrolyzed to the β-keto ester 5 and a mixture of epimeric tricyclo-ketones 9, respectively.The structure and stereochemistry of the adduct 8 were confirmed by its spectroscopic data, particularly the 1 H-and 13 C-NMR signals which were unambiguously assigned using HMQC and NOESY experiments [11].It is interesting to note that the intramolecular Diels-Alder reaction of the 5-vinyl-1,3-cyclohexadiene moiety is strongly preferred to other alternative intramolecular cycloadditions that were also attempted, in spite of the highly strained transition state presumably involved.Thus, when compound 13 (and also the corresponding dimethyl(vinyl)silyl analogue, 13 with R 2 = OSiMe 2 CH=CH 2 ), readily prepared from hydroxycarvone 10 as described in the Experimental section, was heated in toluene under the same conditions described above for 7, only the Diels-Alder adduct 14 was formed, without any appreciable amounts of the adduct resulting from the alternative intramolecular cycloaddition of the 1,3,10-undecatriene moiety being observed [12].

Reagents and conditions:
Having completed the construction of the tricyclo[3.2.1.0 2.7 ]octane framework, and prior to the opening of the cyclopropane ring, we decided to use the existing tert-butyldimethylsilyl enol ether moiety to incorporate an additional oxygenated function that could provide sites for further functionalization of the final bicyclo[3.2.1]octane system.In this regard, it was decided to transform the adduct 8 into the ketone 15 (Scheme 3).This transformation was accomplished in a single step by treatment of 8 with m-CPBA in methylene dichloride at -30 ºC.Under these conditions, epoxidation of the double bond took place from the less hindered β-face initially giving the corresponding β-epoxide, which directly rearranged with concomitant migration of the tert-butyldimethylsilyl group to give the ketone 15.The structure and relative stereochemistry of this compound were established by a detailed analysis of its NMR data.

Reagents and conditions:
In particular, protons H-8β and H-6α gave strong correlation signals with the tert-butyl protons and the methyl protons at C-4, respectively, unequivocally stabilising the spatial orientation of both groups at C-4.With the tricyclic system 15 at hand, we investigated the opening of the cyclopropane ring in order to elaborate the bicyclo[3.2.1]octane framework.In the literature, dissolving metal reductions with metal-ammonia systems has been the most frequently used method for the cleavage of cyclopropyl ketones [2].The electron transfer homogenous reagent samarium(II) iodide has been less often used for this purpose, although some examples of samarium(II)-mediated cyclopropane cleavage of rigid cyclopropyl ketones have been described [2,13].When applied to the opening of 15, a regioselective cleavage of the C 1 -C 2 bond of the cyclopropane ring took place to cleanly afford the bicyclo[3.2.1]octane ring system (Scheme 3).It was found that the best results were obtained by treatment of a cooled (-40 ºC) solution of 15 in a 9:1 mixture of THF and tert-butanol with a stock solution of samarium(II) diiodide in THF.An 80% yield of the β-keto ester 16 was obtained under these conditions, which both as a solid and in solution, basically exists in the enol tautomeric form.It is noticeable that elimination of the 4-silyloxy moiety was never observed, even when an excess of the reducing reagent was used.It is also interesting to note that when the samarium(II)-mediated cyclopropane cleavage was effected in the absence of a protic solvent, the reaction was not so clean and the compound 17 was the major product obtained.The formation of this compound is easily explained by formation of a radical intermediate at C-7 and subsequent hydrogen abstraction from the adjacent methyl group.The stereochemistry of 16 was unambiguously assigned on the basis of coupling constant and NOESY data.Particularly relevant was the presence of a strong NOESY correlation of methyl protons at C-7 to methyl protons of the ester moiety at C-2, which provided evidence of the (R)-configuration at C-7.
The carbobicyclic ring system formed in the above cyclopropane cleavage reaction not only constitutes the characteristic substructural fragment of some natural compounds that have been found to display important biological activity [14], but is also the basic core structure of carbo-tropanes, a group of synthetic compounds that are potent inhibitors of the dopamine transporter [15].Thus, the readily prepared enantiomerically pure compound 16 may be potentially used as an adequate scaffold from which to append "side chain" groups, thereby generating small libraries with functional and structural diversity that may be evaluated for biological activity.
In addition to the above radical opening of the cyclopropane ring of 15, we also evaluated the acid catalysed nucleophilic addition reaction to the cyclopropyl ketone moiety as an alternative procedure for the tricyclo[3.2.1.0 2.7 ]octane-to-bicyclo[3.2.1]octane interconversion.It was found that a rapid and efficient opening of the cyclopropane ring of 15 took place upon treatment with different nucleophilic reagents in the presence of an acid catalyst.Thus, treatment of 15 with methanol and catalytic p-toluenesulphonic acid (PTSA) or HCl at room temperature afforded a high yield of methyl ether 18, formed by acid initiated homoconjugate addition of methanol to the cyclopropyl ketone moiety.The addition of methanol takes place regio-and stereoselectively from the back of C-1, affording the bicyclo[3.2.1]oct-1-ene system stereoselectively functionalized at C-7.The stereochemistry of 18 was determined by comparison of its spectroscopic data with those of 16 and confirmed by a NOESY experiment.Thus, the H-8β proton gives a strong correlation signal with the protons of the methoxy group while the protons of the methyl group at C-7 give strong correlation signals with both the protons of the methoxycarbonyl group and the H-6β proton.
Similar results were obtained with other nucleophiles.Thus, benzyl ether 19, alcohol 20 and chloride 21 were readily formed by treatment of 15 with benzyl alcohol and catalytic PTSA in CH 2 Cl 2 (80% yield), water and catalytic HCl in THF (80% yield), and concentrated HCl in THF (86% yield), respectively.It should be mentioned that in the latter two cases, ie., compounds 20 and 21, partial reversion to the starting tricyclic compound 15 occurs on attempted chromatographic purification on silica gel.It is likely that this particularly easy interconversion is facilitated by the homoaromatic character of the carbocationic intermediate generated.

Conclusions
In brief, the results obtained show the viability of the synthetic approach based on the combination of an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a cyclopropane ring opening for the preparation of the bicyclo[3.2.1]octane framework.The application of this strategy, starting from carvone, has allowed us to prepare several enantiopure, highly functionalised, bicyclo[3.2.1]oct-1-ene derivatives.

General
Melting points were determined using a Buchi hot-stage apparatus.Optical rotations were determined using a 5 cm path length cell.[α] D values are given in units of 10 -1 deg cm 2 g -1 .All NMR spectra were recorded on a Bruker AVANCE 300 DRX spectrophotometer in CDCl 3 solutions (at 300 MHz for 1 H and 75 MHz for 13 C).Complete assignment of the NMR data for most of the compounds described in the experimental section was done on the basis of a combination of HMQC, HMBC and NOESY 2D experiments.Mass spectra were obtained by electron impact (EI) at 70 eV.IR spectra were measured as KBr pellets or liquid films.All reactions were carried out under an inert atmosphere of dry argon, using oven-dried glassware and freshly distilled and dried solvents.Column chromatography refers to flash chromatography and was performed on Merck silica gel 60, 230-400 mesh.