Total Synthesis Of 4-Acetylmananthoside B

The investigation aimed at the total synthesis of 4″-acetylmananthoside B is described. Retrosynthetic analysis for 4″-acetylmananthoside B gave rise to two fragments, the disaccharide fragmentâ… and the aromatic fragment diphyllin. The synthesis ofâ… has been accomplished in 15 steps and in an overall yield of 12%, and the synthesis of diphyllin has also been achieved in 7 steps and in an overall yield of 38%.The synthesis of the disaccharide fragmentâ… , p-methoxyphenyl 2,3,4-tri-O-benzyl-β-L-arabinopyranosyl-(1→6)-2-0-benzyl-3,4-di-O-acetyl-β-D-galactopyranos ide, has been achieved so far in 15 steps from L-arabinose and D-galactose. L-Arabinose underwent successively a-methylation, benzylation, demethylation, acetylation and phenylthiolation to yield donor 1 in an overall yield of 64% (5 steps), with a-methylation being the key step to establish the six-membered pyranoside framework, and D-galactose underwent in order peracetylation,α-bromination, substitution by sodium p-methoxyphenolate, deacetylation, isopropylidenation, benzylation, acetylation and selective debenzylation to produce acceptor 2 in an overall yield of 24% (9 steps), with selective debenzylation as key step. The donor 1 and acceptor 2 were dissolved in dried dichloromethane and treated with NBS to deliver the disaccharide fragmentâ… in 79% yield.The synthesis of diphyllin was accomplished according to a modified earlier procedure. Vanillin 58 was used as starting material, which underwent methylation, bromination, acetalization, lithiation followed by nucleophlic addition to aldehyde, Diels-Alder reaction, selective reduction and lactonization to produce diphyllin in an overall yield of 38% (7 steps). The key steps included Diels-Alder reaction to establish the molecular skeletion of diphyllin and the selective reduction. Several new synthetic strategies were also attempted; however, none of them furnished the desired diphyllin ultimately since some reactions did not proceed in the originally envisioned manners or did not proceed at all.One synthetic strategy started fromγ-butyrolactone 38, from which a cyclohexadiene intermediate 30 was prepared in an overall yield of 44% in a 7-step procedure after y-butyrolactone underwent a-bromination, dehydrobromination, Diels-Alder reaction, aminolysis, benzylation, bromination and dehydrobromination, with the key step being the Diels-Alder reaction under harsh condition. However, when this intermediate was treated with ozone, only one C=C double bond was cleaved and the other one could not be ozonolyzed under a variety of conditions, making us reject this synthetic strategy ultimately.The second synthetic strategy commenced from butane-1,4-diol 50, which underwent monobenzylation, Swern oxidation, enolization followed by acetylation and debenzylation to yield an intermediate 46 in an overall yield of 54% in a 4-step procedure. Compound 46 was subsequently subjected to Swern oxidation to furnish a complex mixture, instead of the desired corresponding aldehyde. Other similar oxidants also failed to effect this conversion. As a sequence, this synthetic strategy was also rejected finally. A few synthetic strategies were also attempted, and none of them were successful.A new catalyst, I₂/TsOH, for the isopropylidenation of the vicinal hydroxyl groups in carbohydrate chemistry and a novel reaction to build arylnaphthalene in a one-pot procedure were found during the course of total synthesis.The new isopropylidenating catalyst, combination of I₂ and TsOH, was found during the synthesis of the disaccharide fragment I. A few selected substrates were efficiently isopropylidenated in 20 minutes by stirring their solution or suspension in acetone in the presence of this catalyst at 45℃. A variety of structurally different carbohydrate substrates, including commonly encountered monosaccharides and derivatives thereof, could be converted to their acetonides, demonstrating the generality of this catalyst in the carbohydrate chemistry; however, commonly encountered monosaccharides could only be isopropylidenated under more vigorous condition than that aforementioned presumably due to their poor solubilities in acetone. Thus, D-glucose and D-galactose were smoothly converted to their acetonides in 3 hours, respectively, when they were suspended in acetone and refluxed in the presence of catalyst in question. The novel reaction to create 6,7-dimethoxy-1-(3,4-dimethoxyphenyl)-4-hydroxy-naphthalene 83 in one-pot procedure was found during the synthesis of diphyllin, which started from catechol dimethylether and succinic anhydride and involved heating the molten mixture of the two reactants in the presence of polyphosphoric acid at 140℃. The structure of the isolated compound was elucidated from ¹H NMR, ¹³C NMR, IR and ESI-MS and further confirmed by X-ray crystallographic analysis. This reaction is likely to be expended to prepare other arylnaphthalene compounds, in particular the electron-rich ones. Two mechanisms for the formation of the product were proposed, but neither one has been experimentally verified up to now.However, the coupling of disaccharide I with the aromatic fragment diphyllin to complete the total synthesis of 4″-acetylmananthoside B has not been carried out mainly due to the time limitation.