Examination of the Reactivity of Hydroxy Groups in Multioxygenated Cyclohexanoids: Synthetic Study toward Cytotoxic Pericosine B

Abstract

As a part of our ongoing search for new antitumor metabolites from marine microorganisms, we have previously isolated pericosin B (1) as a metabolite of Periconia byssoides originally separated from sea hare (Fig. 1).1) So far only a total synthesis of 1 has been achieved by Donohoe et al.2) We have been interested in an alternative route for the synthesis of pericosin B and related compounds. As a basic study of synthesis of pericosin B, the reactivity for O-methylation or O-acylation of hydroxy groups in diols derived from methyl 3,4-O-isopropylidene-6-epishikimate (2) was examined. Interesting differences in reactivity among those compounds were observed. Results and DissccusionThe Diels-Alder product between furan and methyl acrylate was converted to racemic methyl 3,4-O-isoporpylidene-6-epishikimate (2) using the reported method, 3) and then 2 was converted to silyl ether (3) quantitatively. Compound 3 was dihydroxylated with catalytic amounts of osmium tetroxide and trimethylamine N-oxide to a single diol (4) 4) in 94% yield. The newly generated two hydroxy groups and 3,4-Oisopropylidene moiety had the trans configuration. This stereoselection in oxidation is explained by Kishi's rule. 5)Diol (4) was converted to hydroxyketone (5) by Swern oxidation in 62% yield, then reduced to diol (6) with NaBH 4 in 75% yield with 100% diastereoselectivity. The newly generated hydroxy group at C-2 and 3,4-O-isopropylidene moiety had the cis configuration, and the relative stereochemistry in 6 is suitable for the synthesis of pericosine B (1). The evidence of the stereochemistry will be described later. Treatment with tetrabutylammonium fluoride of 6 led to spontaneous cyclization to afford lactone (7) in 49% yield (Chart 1). In this preparation, the reaction mixture was directly concentrated, then the resulting residue was applied to silica gel chromatography for purification. A reduction in chemical yield (Ͻ30%) was observed when the reaction mixture was treated in the usual way (extraction with ethyl acetate) and even the 1 H-NMR spectrum of crude product indicated the formation of nearly pure 7.O-Methylation or O-acylation were examined in these three diols (4, 6, 7). The results are summarized in Table 1 The reactivity of two hydroxy groups in some multioxygenated cyclohexanoids was examined for basic study of the synthesis of the cytotoxic marine natural product pericosine B and related compounds. Differences in reactivity for O-methylation or O-acylation among substrates were observed.

Synthesis of the Epimer of Pericosine B from (-)-Quinic Acid

“…Compound 6 was treated with a catalytic amount of osmium tetroxide and trimethylamine N-oxide to give a mixture of diols (8: 30% and 9: 10%) with recovery of 6 (33%) (Chart 1). The prolonged reaction time and the stereoselectivity 7) of this dihydroxylation should be affected by the steric a-tert-butyldimethylsilyloxy group at C-3. Changing the cooxidant to morpholin N-oxide 10) gave a similar result.…”

“…5) So far only the total synthesis of 1 has been reported by Donohoe and coworkers. 6) We have been interested in the synthesis of pericosins and related compounds 7) because they are thought to be a class of carbasugars. In this paper we report the stereoselective synthesis of the epimer of pericosine B (2) from commercially available (Ϫ)-quinic acid (3).…”

First Total Synthesis of (-)-Pericosine A from (-)-Shikimic Acid: Structure Revision and Determination of the Absolute Configuration of Antitumor Natural Product Pericosine A

“…The basic protocol of the transformations is the same as that of our previous reports. 4,5 The key reaction is the introduction of a chloro atom at C-6 with retention of the stereochemistry of alcohol 14. Shikimic acid (4), which can be synthesized from (-)-quinic acid, 8 was transformed into known alcohol 5 with a known method.…”

Synthesis of Marine-Derived Carbasugar Pericosines

“…Problems associated with this synthesis included poor stereoselectivity in the crucial step, and the need to use a stoichiometric amount of highly toxic OsO 4 . This was the only report of the successful synthesis of natural pericosine up until 2006, in spite of the efforts made by several research groups, including our own [71][72][73][74].…”

“…As mentioned above, our early efforts toward the synthesis of pericosine B were not successful [73], so, as an alternative, we attempted the synthesis of the epimer of pericosine B (3) [75]. Synthesis of 3 is illustrated in Scheme 2.…”