A Diels-Alder cycloaddition approach to the sweroside aglycone intermediate of iridoids was explored using silylated butenolides and levoglucosenone as dienophiles under both Lewis acid and thermal conditions. Results of this study reveal no evidence that using less sterically demanding derivatives compromise the diastereofacial selectivity of the cycloaddition using silylated butenolides. Further chemistry performed on cycloadducts concentrated on the identification and management of methodologies suitable for its conversion into sweroside aglycone. During the course of these studies, a dehydrative cyclisation onto a preformed tetrahydrofuran ring to a bis-tetrahydrofuranoid moiety was unravelled. In addition studies on levoglucosenone-derived cycloadducts provide extensive insight into the conformational behaviour and reactivity. Further, the X-ray crystal structure of an alcohol intermediate from one-carbon homologation studies provided the first structural evidence confirming the diastereoselectivity of the cycloaddition procedure.
In the course of synthetic studies towards the development of diastereoselective routes to secoiridoid aglycones, cis-1,2,4,6-tetrahydrophthalic anhydride was transformed into the corresponding lactone cis-3a,4,7,7a-tetrahydro-3H-isobenzofuran-1-one, which served as a key precursor for a variety of chemoselective synthetic manipulations. Unsuccessful formylation of an ester intermediate resulted in a (E/Z) mixture of vinyl alcohols which were protected as acetates and as a single p-methoxybenzyl (PMB) ether (E) isomer. Dihydroxylation of the cyclohexene motif using OsO(4) led to the unexpected deprotection of the PMB ether. On the other hand, successful formylation of a suitably silyl protected lactonised intermediate was achieved using tert-butoxybis(dimethylamino)methane, or Bredereck's reagent. Tetrabutylammonium fluoride (TBAF) deprotection of a methoxyethoxymethyl (MEM)-ether intermediate serendipitously afforded an approximately 1 : 1 mixture of pyrano-pyranones, which are products of a seldom encountered intramolecular Michael addition, using an oxygen donor, to the terminus of an alpha,beta-unsaturated system, followed by beta-elimination of the MEM moiety.
Chemoselective deprotection of a tert-butyldimethyl (TBS) silyl ether group in the presence of an acetal moiety within an advanced iridoid precursor using scandium trifluoromethanesulfonate at 25°C unexpectedly leads to internal acetal formation in high yield (70%). The same reaction at 0°C resulted in spontaneous lactonisation of the diol intermediate, which was further elaborated to an iridoid glycosidation precursor.
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