Synthesis of macrocycles with one and more ent-beyerane skeletons based on the diterpenoid isosteviol

Abstract

Macrocycles with one and more ent-beyerane skeletons were prepared by the reaction of 16,19-dihydroxyent-beyerane with several dibasic carboxylic acid chlorides. The structures of the synthesized compounds, namely, the number of ent-beyerane skeletons in the macrocycle, depended on the length of the polymethylene chain in the acid chloride. The molecular structures of two of the synthesized macrocycles were established by x-ray crystal structures.The number of publications on the synthesis of macrocyclic compounds has risen dramatically in the last 20 years. The interest in them is due to their ability to act as host molecules, often exhibiting highly selective molecular recognition of guests (ions) [1-3]. Native macrocycles isolated from plants or marine organisms were also described in the literature [4][5][6][7]. However, these compounds have little practical value despite their biological activity because they are isolated in minimal quantities from natural sources. In this respect synthetic macrocycles obtained from biologically active metabolites isolated from natural sources in tangible quantities are much more promising. Several such compounds are known, for example, synthetic macrocycles based on bile acids [8] and mono-[9, 10] and diterpenoids [11][12][13][14]. It is noteworthy that the first macrocycles containing two diterpenoid skeletons were obtained as side products from the synthesis of compounds in which two isosteviol (16-oxo-ent-beyeran-19-oic acid) diterpenoid molecules (1) were joined by diester and anhydride spacers [14]. In order to synthesize macrocycles based on this diterpenoid, we used a more rational approach, the so-called acid-chloride approach, which consisted of the reaction of fully reduced isosteviol, diol 2, with dibasic carboxylic acid chlorides. As it turned out, the structures of the products depended on that of the starting acid chloride, namely, on the length of the hydrocarbon chain between the C(O)Cl groups.The reaction of 2 (16,19-dihydroxy-ent-beyerane) with malonic acid dichloride gave in 9% yield a product with a molecular ion that corresponded to the mass of macrocycle 3. According to PMR data this macrocycle was not a pure compound but a mixture of the head-to-head 3a and head-to-tail 3b isomers. This was indicated by the presence of not a single multiplet

Macrocyclic Derivatives of Diterpenoid Isosteviol with Hydrazide and Hydrazone Moieties

“…Macrocycles having such structures were obtained with the help of synthesis only. Thus macrocycles synthesized on the basis of monoterpenes (myrtenal, [8] 3-carene, [9,10] α-pinene [9,10] ), diterpenoids (isosteviol, [11][12][13][14] steviol, [15] paclitaxel [16,17] ), and bile acids [18,19] have been reported. In these compounds mono-or polycyclic terpene, or steroide skeletons are combined in macrocycle by various linkers.…”

“…Some of its derivatives were used as starting compounds: isosteviol oxo group was selectively reducted, or the carboxyl group was converted into the carbonyl chloride group, or into the hydroxymethyl group. [12,13] The synthetic potential of directly the C 16 =O group of isosteviol was not realized, though the involving this functionality in reactions with amines should lead to nitrogen containing macrocycles which could exhibit any biological activities. In addition, the course of a macrocyclization reaction of isosteviol derivative bearing the C 16 OH and the C 4 CH 2 OH groups with chloride-anhydrides of dicarboxylic acids appeared to be dependent on their length.…”

“…In addition, the course of a macrocyclization reaction of isosteviol derivative bearing the C 16 OH and the C 4 CH 2 OH groups with chloride-anhydrides of dicarboxylic acids appeared to be dependent on their length. Reactions with acid chlorides, in which the C(O)Cl groups are separated by polymethylene chain having n > 5, led to the formation of mononuclear macrocycles [12] (Scheme 1b), whereas reactions with acid chlorides, in which the C(O)Cl groups are separated by polymethylene chain having n < 5 (e.g. adipic and malonic), afforded the mixture of bi-and tetranuclear macrocycles [12] (Scheme 1c,d), each macrocycle existing as several isomers of head-to-head and head-to tail kinds.…”

“…Reactions with acid chlorides, in which the C(O)Cl groups are separated by polymethylene chain having n > 5, led to the formation of mononuclear macrocycles [12] (Scheme 1b), whereas reactions with acid chlorides, in which the C(O)Cl groups are separated by polymethylene chain having n < 5 (e.g. adipic and malonic), afforded the mixture of bi-and tetranuclear macrocycles [12] (Scheme 1c,d), each macrocycle existing as several isomers of head-to-head and head-to tail kinds. [12] The reason of the formation of such mixtures seems to be clear: the C(O)Cl groups of acid chlorides reacted with the C 16 OH and the C 4 CH 2 OH groups of two and more molecules of the reducted isosteviol derivative with equal probability.…”

“…adipic and malonic), afforded the mixture of bi-and tetranuclear macrocycles [12] (Scheme 1c,d), each macrocycle existing as several isomers of head-to-head and head-to tail kinds. [12] The reason of the formation of such mixtures seems to be clear: the C(O)Cl groups of acid chlorides reacted with the C 16 OH and the C 4 CH 2 OH groups of two and more molecules of the reducted isosteviol derivative with equal probability. To avoid the such situation, the macrocyclization of isosteviol and its isomer steviol carried out in several steps at a later time.…”