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The foregoing discussion of our results has revealed several important findings and fulfilled our main objective of providing a highly stereoselective novel rhodium (I)- catalysed tandem hydrosilylation-intramolecular aldol reaction as a general method for the preparation of substituted carbocycles of various ring sizes under very mild conditions. Furthermore, in many instances the required 6-oxo-2-hexenoate precursors can be easily prepared in a highly atom efficient way using a [3,3] sigmatropic rearrangement sequence. In addition, we have also demonstrated the applicability of our tandem methodology to the synthesis of the cyclopentanoid moiety of the antiviral carbocyclic nucleoside (-)-carbovir and its highly potent related analogue (-)-abacavir.

Thus, we have developed a simple atom efficient route to substituted 6-oxo-2- hexenoate derivatives by direct condensation of 2-hydroxy-3-butenoate esters and aldehydes. This Claisen based protocol was used to successfully prepare a range of aliphatic and aromatic 5,5-disubstituted 6-oxo-2-hexenoates in good yields and in a shorter and environmentally cleaner route to that existing in the literature for comparable substrates. This methodology proved to be compatible with the use of alternative electrophiles, such as enones and P-keto esters, permitting the incorporation of additional functionality for further elaboration. However, attempts to extend this methodology to the synthesis of 6-imino-2-hexenoate from N-p- toluenesulfonyl vinyl glycine via the related aza-Claisen rearrangement proved to be unsuccessful. Further research is therefore recommended in order to establish the feasibility of this transformation from a more nucleophilic glycine derivative such as N-acyl vinyl glycine 255 as it would provide a simple atom efficient approach to 6- imino-2-hexenoate derivatives. Moreover, if successful, the rhodium-catalysed tandem cyclisation of the resulting 6-imino-2-hexenoate 256 may provide an efficient synthesis of the potent antifungal agent Cispentacin^^^"^^ after deprotection of the amino group and acid hydrolysis of the ester as shown in Scheme 147.

COgMe Ac NH 255 H OEt p-TsOH, Toluene Soxhlet extractor CO„Me Ac 256 Rh(l) cyclisation Cispentacin Scheme 147 NHAc

The previous [3,3] sigmatropic rearrangement methodology could also be further extended to the synthesis of synthetically useful aliénés 257 from direct coupling of propargylic alcohols and aldehydes via a Saucy-Marbet type rearrangement (Scheme 148)/^^^^ The propargylic alcohol precursor 258 could be readily accessed by addition of differently substituted terminal acetylenes to ethyl glyoxylate mediated by zinc triflate or alternatively by the direct reaction of the corresponding acetylenic Grignard reagent with ethyl glyoxylate. In addition, chiral propargylic alcohols could be obtained from the same precursors by the Carreira procedure^^^^^ using zinc triflate and N-methyl ephedrine in order to obtain the corresponding chiral aliénés which are not only highly versatile intermediates in synthesis but also very resourceful substrates for potential tandem reactions.

EtO 258 0 R' H R" TsOH, Toluene Dean and Stark

r R R' R"-

r?,

On the other hand, the scope and limitations of the rhodium (I)-catalysed tandem hydrosilylation-aldol cyclisation have been established. A range of substituents in the substrate is tolerated, although aldehyde functionality proved to be crucial. However, as previously mentioned, it would be interesting to investigate whether replacement of the aldehyde by an imine may be compatible with our tandem sequence. Alternatively, the incorporation of heteroatoms into the substrate chain may also provide access to a range of substituted pyrrolidines, tetrahydrofurans or tetrahydrothiophenes (Scheme 149). COgMe O H COgMe Rh(l) EtgSiH Toluene As above R COoMe 0 SiEt3 X= O, NR, S Scheme 149

Replacing the a,p-unsaturated ester with alternative Michael acceptors such as nitrile, nitro or sulfonyl groups would lead to a more general synthesis of cyclopentanol s. In addition, 6-oxo-2-hexynoate 259 may cyclise to give the corresponding substituted cyclopentenol 260 (Scheme 150). This approach, if successful, could then be extended to the synthesis of the potent anti-cancer carbocyclic nucleoside Neplanocin A (Scheme 151).

259 Rh(i) EtgSiH Toluene COgMe 260 Scheme 150

HO NR. Rh(l) EtgSiH M e O g C ^ ^ HO NR ELSiO Toluene OH 2 1)TBAF 2)DIBAL NF^= Adenosine HO OH Neplanocin A NR, Scheme 151

The possibility of tandem cascade reactions as a means to fused carbocycles also requires investigation, but will require fine tuning of differentiated Michael acceptors (Scheme 152). O Rh(l) EtgSiH Toluene PSiEt, X= alkyl, aryl Scheme 152

The extension of our tandem sequence to the synthesis of larger ring sizes has also been investigated. From this study, it has been demonstrated that the rhodium (I)- catalysed tandem hydrosilylation-intramolecular aldol reaction is a suitable method for the construction of functionalised six- and seven-membered rings in good yields and with moderate selectivity.

We note parenthetically that the related tandem hydroboration-intramolecular aldol reaction was also investigated. However, when boranes are used as hydride donors, hydroboration of the aldehyde functionality becomes the dominant process. In addition, alternative catalytic systems containing a transition metal other than rhodium have also been evaluated. From this study, it was demonstrated that the combination of triethylsilane and a rhodium catalyst, either hydridotetrakis(triphenylphosphine) rhodium (I) or chlorotris(triphenylphosphine) rhodium (I), gave the best results in terms of yield, stereo- and chemo-selectivity.

The stereochemical outcome proved to be highly dependant on the catalyst precursor, with hydridotetrakis(triphenylphosphine) rhodium (I) giving the best results in terms of selectivity. As previously described, a number of asymmetric catalytic systems have been successfully employed in intramolecular hydroacylation chemistry to afford enantiomerically enriched cyclopentanones.^^"^^'^^^^ Screening of a number of chiral catalysts to probe the levels of enantioselectivity attainable on achiral substrates would also be of interest in the present case.

Finally, the constant demand for efficient synthetic routes to chiral carbocyclic nucleosides has prompted us to investigate the applicability of our methodology to the synthesis of biologically active carbocyclic nucleosides. In this context, we have successfully completed an asymmetric formal total synthesis of the potent antiviral agent (-)-carbovir and its related analogue (-)-abacavir in only 10 steps starting from D-ribose. Further applications of the rhodium (I)-catalysed tandem hydrosilylation- aldol chemistry to the synthesis of alternative carbocyclic nucleosides as well as more complex biologically active carbocyclic natural products can certainly be envisaged.