Total syntheses and structural validation of lincitol A, lincitol B, uvacalol I, uvacalol J, and uvacalol K

Abstract

Natural carbasugars are an important class of biologically active compounds. Due to their conformational freedom and the subtle difference in spectral characteristics between isomers, often their NMR-based structural assignments are erroneous. It is thus important to validate their structural identity through chemical synthesis. We report the first total syntheses and structural validation of five natural carbasugars, namely, lincitol A, lincitol B, uvacalol I, uvacalol J, and uvacalol K in their racemic forms, from a myo-inositol-derived common intermediate. This intermediate was synthesized by the vinylogous ring opening of myo-inositol orthoester cage under mild acidic conditions in six steps from myo-inositol. From this intermediate, we achieved the syntheses of (±)-lincitol A in six steps, (±)-lincitol B in seven steps, (±)-uvacalol I in five steps, (±)-uvacalol J in five steps, and (±)-uvacalol K in seven steps. The structure and relative stereochemistry of these natural products were confirmed by comparing the (1)H and (13)C NMR spectra of synthesised natural products with the reported data. These syntheses involved several unprecedented protecting-group manipulations and unexpected reactivities.

Concise Synthesis of (1R,2S,3R,6R)-6-Ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol, a Key Intermediate for the Synthesis of Uvacalols I and J

“…Finally, global deprotection of compound 24 with anhydrous FeCl 3 in CH 2 Cl 2 at room temperature gave the target compound 16, a key intermediate for the syntheses of uvacalol I (10) and uvacalol J (11) as well as the monobenzoate 14 and dibenzoate 15. 13 The physical and spectral data of 16 were in good agreement with the reported values. 13 Similarly, isomer 25 was treated with anhydrous FeCl 3 in CH 2 Cl 2 at room temperature for 30 minutes to afford compound 17, which can be used making other derivatives.…”

“…13 The physical and spectral data of 16 were in good agreement with the reported values. 13 Similarly, isomer 25 was treated with anhydrous FeCl 3 in CH 2 Cl 2 at room temperature for 30 minutes to afford compound 17, which can be used making other derivatives.…”

“…Earlier, uvacalols A-C, E, and G were synthesized from D-mannitol by Sureshan and co-workers, 4 who also reported a racemic synthesis of uvacalols I (10) and J (11), along with other two carbasugars 14 and 15, via the racemic key intermediate 16; their synthesis began from myoinositol and involved a selective benzoylation. 13 Our group has been involved in the synthesis of cyclitols (carbasugars) from carbohydrates for the last few years. 15 In this endeavor, we developed a Nozaki-Hiyama-Kishi (NHK) and ring-closing metathesis (RCM) approach for the conversion of carbohydrate into polyoxygenated cyclohexene compounds.…”

“…In continuation of this, we present an application of this method to a chiral synthesis of (1R,2S,3R,6R)-6ethoxy-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol ( 16), a key intermediate for the synthesis of uvacalol I (10) and uvacalol J (11), and of its epimer 17, starting from methyl Dglucopyranoside (18), a cheap and commercially available compound. The chiral key intermediates 16 and 17 have free hydroxy groups that can be utilized to prepare several derivatives for better therapeutic activity; moreover, compound 16 can also give two more carbasugars 14 and 15, 13 along with uvacalol I (10) and uvacalol J (11) in optically pure forms.…”

“…[9][10][11] They showed antitumor activities against some cancer cell lines (mammary carcinoma MCF-7 cell line and epidermoid carcinoma KB cell line) 12 and they are structurally similar to carbohydrates. 13 Characteristic structural features of uvacalols include the presence of a primary benzoate group on the C 7 cyclitol skeleton and the presence of…”