Synthesis of Dimeric Terpenoyl Glycoside Side Chains from Cytotoxic Saponins

Abstract

Dedicated to Professor Axel Zeeck on the occasion of his 65th birthday Saponins are natural products from plants and marine organisms exhibiting a wide variety of biological activities, for example, anticancer properties.[1] Most saponins consist of a lipophilic steroid or triterpene core and hydrophilic oligosaccharide side chains. Despite their structural diversity, only few saponins contain an additional monoterpene glycoside side chain (A, Scheme 1) like that found in julibrosides, [2] elliptosides [3] and avicins.[4] These compounds selectively inhibit tumor cell growth by induction of apoptosis [4a,c] (IC 50 : 0.2 mg mL À1 for Jurkat cells) and prevent chemically induced carcinogenesis in mice.[4d,e] The occurrence of the terpenoyl glycoside side chain A appears to enhance the cytotoxic effect, [2a] which encouraged us to develop a synthetic path to this unique motif for subsequent bioactivity studies.Our initial approach to terpenoyl glycosides was to functionalize linalool 1 with a carboxylate followed by glycosylation (Scheme 2). The tertiary alcohol function of racemic linalool (AE )-1 was acetylated, and the more substituted double bond was selectively cleaved to give the aldehyde 2 by epoxidation with MCPBA, periodic-acidcatalyzed diol formation, and oxidative cleavage of the vicinal diol.[5] The volatile aldehyde 2 was extended to furnish the desired menthiafolic acid ethyl ester 4[6] in a Horner-Wadsworth-Emmons (HWE) reaction [7] using phosphonate 3.However, the tertiary alcohol could not be deprotected without undesired side reactions. In the presence of base in methanol, the free hydroxy group participated in an intramolecular 1,4-addition, resulting in a mixture of eight possible diastereomers of the tetrahydrofuran derivative 5. In addition transesterification to the methyl ester and hydrolysis to the free acid were observed. In order to circumvent the use of a protective group for the OH function, the tertiary alcohol was glycosylated prior to

Steroids: partial synthesis in medicinal chemistry

“…90 Methods for the attachment of glycosyl units at the C-3 of diosgenin have been examined. 91, 92 The synthesis of some spirostenols based on diosgenin which prevent b-amyloid induced neurotoxicity has been reported. 93 Cholesterol surrogates containing a benzophenone moiety have been synthesized 94 as potential photo-affinity labels for measuring cellular sterol efflux and HDL formation.…”