Probing the Influence of an Allylic Methyl Group in Zearalenone Analogues on Binding to Hsp90

Abstract

By the replacement of an acetate with propionate by means of organic synthesis, a range of zearalenone analogues were prepared that feature an allylic methyl group. For the synthesis of the aliphatic region of the analogues, we used an asymmetric alkylation to yield pentenol derivatives 16 and ent-16. By means of hydroboration the corresponding aldehydes were secured. These were coupled with 2-pentynol derivate 23 by means of a Carreira acetylide addition. Further routine steps led to the sulfones 29 and 45, respectively. After merging them with 2-bromobenzaldehyde 9 in a Julia-Kocienski reaction, metalation, carboxylation, and protecting-group manipulations gave the seco acids 35 and 49. By means of lactonization under Mitsunobu (alcohol activation) or Trost-Kita conditions (carboxyl activation), all four possible macrocyclic ketone stereoisomers were accessible. In all, considering various protecting-group decorations, 16 analogues were obtained and tested for cytotoxicity (L929 mouse fibroblast cell line). Whereas most of the analogues were less active than zearalenone (IC(50)=9.4 μM), the resorcinol derivatives were comparable, with one stereoisomer (40 b) being slightly more active (IC(50)=6.6 μM). These results were also reflected in the binding assays to Hsp90 in which 40 b showed a dissociation constant (K(d)) value of 130 nM.

Biocatalytic Approach for the Total Synthesis of (–)‐Malyngolide and Its C(5)‐Epimer

“…Hydrogenation of the C=C bond in compound 3 using NiBH 4 (generated in situ from NiCl 2 · 6 H 2 O and NaBH 4 in MeOH) afforded the saturated ester 4 in 96% yield . Treatment of the saturated ester 4 with LiAlH 4 gave the mono‐benzyl alcohol 5 in 90% yield . Oxidation of the later under Swern conditions afforded the aldehyde, which was further treated with nonylmagnesium bromide (2.0 equiv., 1 m in Et 2 O) to give the alcohol 6 as a mixture of two diastereoisomers in 66% yield .…”

“…The combined org. extracts were dried (Na 2 SO 4 ), concentrated in vacuo , and purified by flash chromatography over SiO 2 (100 – 200 mesh) to afford 5 as colorless liquid (8.0 g, 90% yield). R f (30% AcOEt/PE) 0.35.…”

Stereoselective synthesis of marine macrolide Aspergillide D

“…The coupling of iodide 12 and the alkyne compound 3 was carried out in the presence of n-BuLi 24,25 in a THF-HMPA (2:1) mixture at -78 o C to obtain the desired compound 13 in 73% yield. The concomitant removal of the triple bond as well as the benzyl group was achieved via a Pd/C (10%) catalyzed hydrogenation in EtOAc to afford the saturated primary alcohol 29 14 in 90% yield.…”

Concise Total Synthesis of Curvulone B

“…Finally, demethylation of the methoxy group of 11 was successfully achieved under Maier's conditions (AlI 3 , TBAI, phloroglucinol) 15 in benzene at 0 °C to furnish curvulone B (2) in 91% yield. 16 The spectroscopic and analytical data for synthetic compound 2 were in good agreement with those reported for the natural product.…”