Facile synthesis of cleistetroside-2, a partially acetylated oligorhamnoside from Cleistopholis glauca and patens

Abstract

(cleistetroside-2), was synthesized via '2+2' convergent strategy. Annonaceae is a family of large trees that grow in the rain forests of Africa. Extracts from the stem bark of this species are used to treat stomach pain, bronchial diseases and hepatitis. The root is believed to be a vermifuge, and the leaves are commonly employed for the treatment of fever.1,2 From the stem bark of Cleistopholis glauca and the leaves of Cleistopholis patens (Annonaceae), a number of partially acetylated oligorhamnoside derivatives were isolated.1-4 Among these -rhamnopyranoside] was found to show significant in vitro antibacterial activity against Gram-positive bacteria. 4 For investigation of the oligosaccharide's structure-bioactivity relationships in respect to antibacterial activities, 5 we have prepared a series of L L-rhamnose oligosaccharides. 6 Here we would like to report a facile synthesis of cleistetroside-2, a partially acetylated oligorhamnoside isolated from the stem bark of Cleistopholis glauca and the leaves of Cleistopholis patens (Annonaceae).As outlined in Scheme 1, fully acetylated L L-rhamopyranose 1 was converted into dodecanyl 2,3-O-isopropylidene-a-L L-rhamnopyranoside (2) by a method similar to that of reported. 7 Similarly, compound 1 was transformed into isopropyl 2,3,4-tri-O-acetyl-1-thio-a-L Lrhamnopyranoside (3) under modified Helferich reaction conditions. 8 Deacetylation of 3 with NaOMe in methanol gave the acceptor, isopropyl 1-thio-a-L Lrhamnopyranoside (4). 2,3-O-Isopropylidenation of 4 with Me 2 C(OMe) 2 in the presence of TsOH in acetone, and acetylation with Ac 2 O in pyridine, afforded isopropyl 2,3-O-isopropylidene-1-thio-a-L L-rhamnopyranoside (5) in 85.5% yield over three steps. Cleavage of the isopropylidene group from 5 using aq 80% AcOH at 55°C gave isopropyl 4-O-acetyl-1-thio-a-L L-rhamnopyranoside (6), which was then silylated with TBSCl and imidazol in DMF at 50°C to give the building block, isopropyl 4-O-acetyl-2,3-di-O-tert-butyldimethylsilyl-1-thio-a-L L-rhamnopyranoside (7) in 89% yield. Glycosyl donor 4-O-acetyl-2,3-O-isopropylidene-a-L L-rhamnopyranosyl trichloroacetimidate (8) was obtained from 5 0008-6215/$ -see front matter Ó

Synthesis of Several Cleistrioside and Cleistetroside Natural Products via a Divergent De Novo Asymmetric Approach

“…For instance, cleistrioside- 5 ( 1 ) and cleistetroside- 2 ( 3 ) have shown significant antimicrobial activity against several methicillin-resistant Staphylococcus aureus (e.g., ATCC 33592 0.5 μg/mL for 3 and 8 μg/mL for 1 ). Due to limited supplies of the isolated materials, only two members ( 1 and 3 ) of this class of natural products have been extensively studied for biological activity and only cleistetroside- 2 ( 3 ) has succumbed to total synthesis . However, some related acylated rhamnoside natural products have possessed anticancer activity …”

Structure–Activity Relationship Study of the Cleistriosides and Cleistetrosides for Antibacterial/Anticancer Activity

“…As part of a high-throughput-based search for new natural products with unique structures and interesting biological activity, two partially acetylated trisaccharides (cleistrioside-5/-6, 1 and 2 ) and six partially acetylated tetrasaccharides (cleistetroside-2/-3/-4/-5/-6/-7, 3 – 8 ) natural products were discovered (Figure ) from the leaves and bark of trees with a folk medicinal tradition. − These dodecanyl tri- and tetrarhamnoside structures with various degrees of acylation were isolated from Cleistopholis patens and glauca . , The structures of the cleistriosides and cleistetrosides were assigned by detailed NMR analysis and later confirmed by total synthesis. The absolute and relative stereochemistry for one member of the cleistetrosides ( 3 ) was confirmed by two total synthetic efforts by Zhang and Chen in 2007 via a traditional carbohydrate approach. In 2010, we reported a divergent de novo asymmetric synthesis of both cleistriosides ( 1 and 2 ) as well as the six cleistetrosides ( 3 – 8 ), thus confirming the structures of the remaining members …”

“…1,2 The structures of the cleistriosides and cleistetrosides were assigned by detailed NMR analysis and later confirmed by total synthesis. The absolute and relative stereochemistry for one member of the cleistetrosides ( 3 ) was confirmed by two total synthetic efforts by Zhang 4 and Chen 5 in 2007 via a traditional carbohydrate approach. In 2010, we reported a divergent de novo asymmetric synthesis of both cleistriosides ( 1 and 2 ) as well as the six cleistetrosides ( 3–8 ), thus confirming the structures of the remaining members.…”

“…8,9 Accordingly, the structurally novel cleistrioside and cleistetroside potential antibiotics inspired us to develop a divergent de novo asymmeric approach, which resulted in a reasonably efficient approach to eight of the members of these two classes of natural products (Scheme 1). While our de novo route to any particular member was not notably more efficient than the two traditional carbohydrate approaches to cleistetroside-2 (3), 4,5 the approach allows for the divergent synthesis of all eight oligo-rhamnosides (1−8) with the minimal use of protecting groups. The overall efficiency of the route is best exemplified by the fact that it affords sufficient quantities of material for detailed biological investigations.…”

De novoasymmetric Achmatowicz approach to oligosaccharide natural products

“…Our first synthetic foray into this class of oligosaccharides was the synthesis of the partially acylated cleistrioside and cleistetroside class of natural product oligosaccharides. 50 This effort led to the successful synthesis of 2 members of the cleistriosides and 9 members of the cleistetrosides 51,52 For space reasons we have chosen to limit this discussion to the synthesis of cleistetroside- 2 (Scheme 8). Key to the practicality of this approach will be its reliance on the minimal use of protecting groups ( i.e.…”