Syntheses of 2,5‐Dialkylfuran and Tetrahydrofuran Carbinols and Their Cytotoxic Activity.

Abstract

.2,5-Dialkylfuran and tetrahydrofuran compounds as structural elements of Annonaceae acetogenins like Asitrocin were synthesized starting from furfural by Grignard reactions, lithiation of the furan ring and addition of aliphatic aldehydes. Hydrogenation of the furan rings over Pd-catalyst gave the corresponding tetrahydrofurans. All resulting compounds showed no or rather less antimicrobial activity against grampositive, gram-negative bacteria and fungi compared to tetracycline or clotrimazol but high cytotoxic activity against HL 60 cell line determined in the MTT assay. . So more simple compounds with the same or even higher potency are interesting for the development of new anticancer drugs. One of the discussed mechanisms of action is a complexation of mitochondrial iron by the dihydroxyalkyltetrahydrofuran core of the acetogenins [1]. So this partial structure of the natural compounds was the target of our synthesis. On the other hand some furancarbinols as 4-ipomeanol are well known cytotoxic compounds. 4-Ipomeanol is after bioactivation in lung tissue (clara cells) by cytochrom P 450 an alkylating agent [7]. It is tested in phase II studies against human lung cancer. So bisalkylfuran compounds might be interesting for the development of new anticancer drugs too. In addition, the products should also be tested for their antimicrobial activity (Scheme 1). Keywords Scheme 1. ChemistryCommercially available furan-2-carbaldehyde was reacted in a Grignard reaction with dodecylmagnesium bromide to give the alcohol 1 in good yield [3,4]. The furan ring of 1 was hydrogenated over Pd/C-catalyst under normal pressure to the tetrahydrofuran derivative 2 (mixture of diastereomers). On the other hand the furan ring of 1 was lithiated with n-BuLi, (a second equivalent of n-BuLi was consumed for deprotonation of the hydroxy group) and the resulting dianion was reacted with pent-4-enal to give the dialkylfuran 3 as an inseparable mixture of diastereomers (seperation was impossible by column chromatography). 3 was also hydrogenated with Pd/C in methanol to give the tetrahydrofuran 4 as a diastereomeric mixture. In the course of this hydrogenation the double bond was also reduced (Scheme 2).In the same manner homologues were prepared by reaction of furan-2-carbaldehyde with pent-4-enylmagnesiumbromide to the alcohol 5, followed by lithiation with two equivalents n-BuLi and addition of tridecanal.The diol 6 was obtained only in low yield. Hydrogenation of 6 gave the disubstituted tetrahydrofuran 7 (Scheme 3).It was impossible for us to separate the diastereomeric mixtures by flash column chromatography on silica gel or by preparative high-pressure liquid chromatography. Pharmacological results and discussionThe compounds described above were tested in the agar diffusion assay against E. coli, S. hominis, P. antimicrobia and the yeasts Y. lipolytica, C. glabrata and the filamentou fungi A. niger. All compounds showed only minor or no antimicrobial activity, only 2, 3, 4, 5 and 6 showed a moderate activity (Table 1). The cytot...

Synthesis by Ring Closing Metathesis and Cytotoxic Evaluation of Novel Thienylmacrolactones

“…Thiophene-2-carbaldehyde ( 1 ) was reacted in a Grignard reaction with pent-4-enyl-magnesium bromide to give alcohol 2 , following a methodology we had worked out earlier for furan derivatives [ 14 , 15 ]. Secondary alcohol 2 was esterified with undec-10-enoyl chloride to give the ester 3 .…”