Synthesis of the C/D/E-ring core compound of maoecrystal V

Abstract Maoecrystal V is a highly oxidized and rearranged norterpenoid isolated from the Chinese herb, Isodon eriocalyx. A synthetic route for the C/D/E-ring core compound of maoecrystal V has been developed. Introduction of the C1 fragment to the D/E-ring compound was achieved by lithito dithiane attack, and the C-ring was formed by deprotective intramolecular hemiacetalization of the dithiane-alcohol precursor. GRAPHICAL ABSTRACT


Introduction
Maoecrystal V (1) is a highly oxidized and rearranged norterpenoid isolated from the Chinese herb, Isodon eriocalyx. [1] 1 was first reported to show strong cytotoxicity against HeLa cells (IC 50 ¼ 0.09 mg/ml); however, Baran's group reported that 1 has no cytotoxicity. [2] Due to its structural novelty and expectations as a lead for new anticancer agents, several synthetic studies have focused on 1 [2][3][4][5][6][7] and several groups achieved the total synthesis. Although most groups used Diels-Alder reaction to construct the bicyclic ring at a later stage, we devised a synthetic pathway that begins with the formation of the D/E bicyclic ring using an aldol reaction [3] similar to the approaches used by Trauner [4] and Sorensen.
[5] The current report shows our synthetic studies toward C/D/E-ring core compound 2 (Fig. 1).

Results and discussion
Our synthesis began with aldehyde 5, [4] prepared from cyclohex-2-en-1-one (3) via Kitahara's keto ester 4 [8] (Scheme 1). Acidic treatment of this keto-aldehyde 5 promoted an intramolecular aldol reaction and the newly formed hydroxy group attacked the ester carbonyl group to form tricyclic lactone 6 as a mixture of 5:2 endo/exo-diastereomers, which were separated by silica gel column chromatography. The stereochemistry of the reaction products was determined by the observation of NOE relationships. The preferential endo-isomer endo-6 was used for further studies, though the exo-isomer may also converge to 2 at the final stage. A carbon moiety was introduced using trimethylsilyl cyanide (Scheme 2). Treatment of endo-6 with TMSCN and ZnI 2 [9] afforded the corresponding cyanohydrin TMS ether 7 in moderate yield and good selectivity (dr 9:1, stereochemistry not determined). However, subsequent reduction using LiBH 4 did not give the desired diol 8; the use of a strong hydride reagent led to the decomposition of the cyanohydrin moiety. The isomer exo-6 also produced the corresponding cyanohydrin TMS ether 7 0 in 54% yield, but the selectivity decreased (dr 1.4:1) due to less crowded stereochemistry. In addition, a reduction of 7 0 also failed. 1,2-Dithiane was therefore selected as the C1 unit. The anion derived from 1,3-dithiane preferentially attacked from the less hindered side of the bicyclic ring to give 9 as a single diastereomer, though the yield was up to 15% (22% based on recovered starting material) due to a competing reaction with the lactone carbonyl group. Since our goal was to investigate the construction of the model lactone ring, we decided to proceed without improving this process. The lactone carbonyl group of 9 was reduced with LiAlH 4 to give triol 10, then oxidative deprotection of the dithiane group by [bis(trifluoroacetoxy)iodo]benzene (PIFA), [10] concomitant with intramolecular acetal formation, afforded 11 as a single diastereomer. The methyl acetal was quantitatively hydrolyzed, giving 12. Finally, the target lactone 2 was synthesized by selective oxidation of the hemiacetal and secondary hydroxy groups of 12, in 71% yield.

Conclusions
A synthetic route for the C/D/E-ring core compound of maoecrystal V (2) was successfully developed in this study. The key reaction is deprotective intramolecular hemiacetal formation of the dithiane-alcohol precursor. The total synthesis of maoecrystal V using this key reaction is now underway.

Disclosure statement
No potential conflict of interest was reported by the author(s).