Synthesis of 4‐Octuloses. Part 6. 4‐Octulose Derivatives, Prepared from L‐Sorbose, as Key Intermediates in the Stereoselective Synthesis of C‐Glycoside and Polyhydroxyindolizidine Analogues.
Reactions of 1 and 12 with p-toluenesulfonyl chloride in pyridine gave the corresponding 1-O-p-toluenesulfonyl derivatives 2 and 13 in yields of 91% and 60%, respectively. Compound 12 was also transformed into 14 by treatment with I2/ Ph3P/imidazole in anhydrous dichloromethane. Treatment of compounds 12 and 13/14 with NaN3 in DMF furnished the respective 1-azido-1-deoxy derivatives 3 and 15, which were then deacetonated to give the free 4-octuloses 4 and 16. These were subsequently hydrogenated in the presence of 10% Pd/C to afford the expected polyhydroxylated branched-chain pyrrolidines 5 and 17. Attempted OH R
4‐Octulose Derivatives, Prepared from L‐Sorbose, as Key Intermediates in the Stereoselective Synthesis of C‐Glycoside and Polyhydroxyindolizidine Analogues
Reactions of 1 and 12 with p-toluenesulfonyl chloride in pyridine gave the corresponding 1-O-p-toluenesulfonyl derivatives 2 and 13 in yields of 91% and 60%, respectively. Compound 12 was also transformed into 14 by treatment with I2/Ph3P/imidazole in anhydrous dichloromethane. Treatment of compounds 12 and 13/14 with NaN3 in DMF furnished the respective 1-azido-1-deoxy derivatives 3 and 15, which were then deacetonated to give the free 4-octuloses 4 and 16. These were subsequently hydrogenated in the presence of 10% Pd/C to afford the expected polyhydroxylated branched-chain pyrrolidines 5 and 17. Attempted OH OMes transformation at C-8 in the N−Cbz-protected pyrrolidines 7 and 19 was unsuccessful and an internal anhydration process took place to yield the corresponding C-glycoside-like furanoses 9 and 20. On the other hand, 23 was transformed into the D-ribo analogue 25 through reduction of the intermediate 4,6-diulose 24. Finally, deprotection of 25 in acid medium to give the free 4-ulose 26, followed by hydrogenation of the latter in the presence of 10% Pd/C in methanol, allowed the preparation of (6S,7S,8S,8aS)-6,7,8-trihydroxy-8a-methoxyindolizidin-3-one (27).
Synthesis of 2-deoxy-4-octulose derivatives by highly diastereoselective alkylations of protected hexuloses
Reformatsky reaction of 2,3:4,5-di-O-isopropylidene-β-d-arabino-hexos-2-ulopyranose1 with methyl bromoacetate proceeded with high diastereoselectivity to give methyl 2-deoxy-4,5:6,7-di-O-isopropylidene-β-d-manno-oct-4-ulo-4,8-pyranosonate2 and its -d-gluco isomer 3, in an ∼-10:1 ratio. Configurations of the new stereogenic centres (C-3) in 2 and 3 were determined by reduction of their ester groups to the related 2-deoxy-4,5:6,7-di-O-isopropylidene-β-d-manno-4 and -d-gluco-oct-4-ulo-4,8-pyranose5, respectively. When alkylation at C-1 of 1 was carried out with 2-lithio tert-butyl acetate, the corresponding tert-butyl ester of 2 (6) and 3 (7) were formed in an ∼-5.4:1 ratio. The stereochemistry of 6 and 7 was established by their respective reductions to 4 and 5. On the other hand, reaction of 1 with methyl methoxycarbonylmethylenedimethylsulfurane gave only methyl 2,3-anhydro-4,5:6,7-di-O-isopropylidene-β-d-glycerso-d-galacto-oct-4-ulo-4,8-pyranosonate8, whose stereochemistry was demonstrated by its transformation to 4. On the other hand, Reformatsky reaction of 2,3:4,6-di-O-isopropylidene-α-l-xylo-hexos-2-ulofuranose10 with methyl bromoacetate proceeded with moderate diastereoselectivity to give methyl 2-deoxy-4,5:6,8-di-O-isopropyliddene-α-l-gulo-oct-4-ulo-4,7-furanosonate11 and its -l-ido isomer 12, in an ∼-3.5:1 ratio. Configuration of the new stereogenic centre (C-3) in 11, and hence in 12, was determined by degradation to the known dimethyl d-methoxymalate (+)-13.