A general approach to the synthesis of enantiomerically pure spirocyclic alpha,beta-butenolides is presented where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone. Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology has been applied effectively. The availability of these building blocks makes possible in turn the acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25 and 31, as well as the targeted title compounds. Complementary reductions of the early intermediates provide the added advantage that the alpha- and beta-stereoisomeric carbinol series can be obtained on demand. These capabilities have been coordinated to allow the crafting of any member of the series in relatively few steps.
Tin tetrachloride-catalyzed glycosidation of persilylated nucleobases with acetate donor 6 in CH(2)Cl(2) solution followed by deprotection gave rise very predominantly to alpha-spironucleosides. These stereochemical assignments stem from the determination of NOE interactions and an X-ray crystallographic analysis of the latter product. Computational studies revealed that these results are consistent with the fact that the C5' substituent shields the beta-face of the oxonium ion involved in the coupling reaction while the C3' substituent is projected away from the alpha-underside. Attack from the more open direction is therefore kinetically favored. Entirely comparable calculations suggested that donor 19 should behave comparably. Experimentation involving this donor gave results consistent with this model although more equitable alpha/beta spironucleoside product ratios were seen when acetonitrile was employed as the reaction medium.
The concept of spirocyclic restriction, when generically applied to nucleoside mimics, allows for the preparation of diastereomeric pairs carrying either a syn- or anti-oriented hydroxyl at C-5'. Reported herein are convenient synthetic routes to enantiomerically pure 1-oxaspiro[4.4]nonanes featuring fully dihydroxylated end products as well as congeners having dideoxy and didehydrodideoxy substitution patterns. Notable use is made of the capacity for introducing unsaturation in the furanose sector via phenylsulfenylation and the incorporation of uracil and thymine by way of their silylated derivatives under catalysis with stannic chloride.
[reaction: see text] The potential benefits associated with the spirocyclic restriction of nucleosides are summarized. Following exploration of a pi-allylpalladium route to 5'-alpha- or syn-dideoxy examples, we evaluated MOM protection of the 5'-hydroxyl as being suited to the synthesis of the first member of this new class of nucleoside mimic.
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