Intermolecular -Photocycloaddition as the Key Step

The fact that all approaches employing the intermolecular photocycloaddition key step used the same precursor for the construction of the four-membered ring renders enone 6 the key intermediate of the different synthetic strategies. It is therefore sensible to compare first the different strategies to synthesize precursor 6. Afterwards, the different ways to complete the syntheses of kelsoene will be discussed. 

6-dihydroxybicyclo[3.3.0]octane (rac-12). Oxidation of the two hydroxy groups followed by selective monomethylenation and catalytic hydrogenation furnished the cndo-methyl diastereoisomer rac-13 as the major product (dr=80/20). The observed diastereoselectivity was explained by the fact that the catalytic hydrogenation proceeded preferentially from the more easily accessible convex face of the diquinane framework [7]. 

Ketone rac-13 was transformed into the corresponding silylenolether and by Pd(II)-mediated Saegusa oxidation [14] into a, -unsaturated ketone rac-14. By alkylative enone transposition comprising methyl lithium addition and pyridinium chlorochromate (PCC) oxidation [15], rac-14 was finally converted into the racemic photo cycloaddition precursor rac-6. In conclusion, the bicyclic irradiation precursor rac-6 was synthesized in a straightforward manner from simple 1,5-cyclooctadiene (11) in nine steps and with an overall yield of 21%. 

Continuing the synthesis of rac-6 with enantiomerically pure diols 12 and ent-l2 (after saponification of 15 with KOH), both enantiomers 6 and ent-6 were accessible. This allowed for an enantioselective synthesis of natural kel-soene (1) and its enantiomer (ent-l) (see below) with only one additional step as compared to the synthesis of the racemate (rac-l). 

The photocycloaddition precursor ent-6 was obtained from 19 by transformation into the corresponding acid chloride and AlCl3-mediated intramolecular acylation of the double bond. While the conciseness of this strategy is appealing, drawbacks are the low yields achieved in the individual reaction steps giving ent-6 in an overall yield of only 5%. 

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In conclusion, the three groups which applied the intermolecular photocycloaddition as the key step in their approach to kelsoene (1) reported different strategies to synthesize the irradiation precursor 6 in racemic or enantiomerically pure form. After the photocycloaddition step the syntheses of kelsoene were completed in different ways. The next section describes the different strategies employed in the second half of the way to kelsoene. 

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