反应详情

The synthesis shown in FIG. 1 started with commercially available 2,3-O-isopropylidene-D-erythronolactone (105), which was reduced with DIBAL-H to provide 2,3-O-isopropylidene-D-erythrose (106) according to published methods. Gao et al., J. Amer. Chem. Soc. 1983, 105, 3661-3672. This lactol underwent Wittig olefination with the corresponding methylenetriphenylphosphine ylid to afford the ring-opened alcohol 107 in 60% yield. At this stage, a Swern oxidation protocol was chosen among several methods tested to oxidize 107 to the corresponding aldehyde 108. The resulting aldehyde was found to be unstable and therefore it was utilized immediately for the next reaction. Oxidation of the aldehyde to the acid 109 with sodium chlorite, followed by Dieckmann condensation of the activated acid with ethyl 2-lithioacetate, afforded the desired β-ketoester 110 (59%) plus an unwanted epimerized derivative 111 (9%) as a mixture of separable diastereoisomers. This epimerization problem was surmounted by treating aldehyde 4a directly with ethyl diazoacetate in the presence of tin (II) chloride to provide the keto ester 110 as the sole product in 36% overall yield from alcohol 107. Using a standard protocol, the unsaturated keto ester 110 was converted to the diazo compound 112, which underwent a thermally-induced intramolecular cyclopropanation to give the bicyclo[3.1.0]hexan-2-one derivatives 113 and 114 in a combined 48% yield with a favorable diastereoisomeric ratio (3:1) for the desired isomer 113. The bicyclo derivative 113 was isolated chromatographically and reduced stereospecifically with NaBH4 to give alcohol 115 as a single product in 72% yield. The structure of 115 was confirmed by X-ray analysis, which unambiguously validated the suitability of our synthetic approach to construct (N)-methanocarba carbocyclic nucleosides.