Synthetic Study on Telomerase Inhibitor, D8646-2-6: Synthesis of the Key Intermediate Using Sn(OTf)2 or Sc(OTf)3 Mediated Aldol-Type Reaction and Stille Coupling

Abstract

In 2002, the Mitsubishi Pharma group reported the isolation of a telomerse inhibitor, D8646-2-6 (1) from the culture broth of fungus Epicoccum purpurascens.1) The compound has a unique C 3 -pyranosyl 4-hydroxypyrone moiety 2) and conjugated polyene unit. [3][4][5][6][7] However the structure of 1 including the relative and absolute stereochemistry has not been fully elucidated yet. The potent biological activity and structural complexity of this compound prompted us to initiate synthetic studies toward 1. In our preceding paper, we have reported the construction of the C-glycosyl 4-hydroxy pyrone moiety of 1. Comparison of the NMR spectra of the C 3 -galactopyranosyl 4-hydroxy-2-pyrone moiety 2 with those of natural 1, demonstrated that the carbohydrate moiety of the latter compound to be C 3 -galactopyranoside (Fig. 1). 8)Our synthetic strategy toward the total synthesis of 1 is shown in Chart 1. Due to the labile nature of the polyeninc side chain, our synthestic strategy involved an initial aldol condensation of the pyrone moiety with the side chain unit (C8-C12), followed by the elongation of the remaining side chain unit. Since the stereochemistry at C21 and C23 was not determined, we envisaged that phosphonate 4 would serve as a versatile key intermediate for the synthesis of D8646-2-6 and its stereoisomeres. Horner-Wadsworth-Emmons reaction was successfully utilized by Cha and co-workers in the total synthesis of citreoviridin 9) which contains polyene conjugated with pyrone ring. Phosphonate 4 could be synthesized by Stille coupling 10) of triene 15 with vinyl stannane which contains phosphonate. 11) Although there have been some reports concerning the aldol-type reaction and alkylation of pyrones, 12-24) the application of this approach to a carbohydrate-containing compound is unprecedented. Since oxygenated functionalities of substrates might influence on the reactivity of carbanion, the reactivity of such carbohyrare-bearing pyrones as well as its synthetic utilities is quite interesting. Herein, we report the synthesis of the key intermediate 4 using aldol-type reaction of carbohydrate containing pyrone 7 followed by stepwise dehydration and Stille coupling with vinyl stannane 5 which contains phosphonate group.The feasibility of the key aldol-type reaction was evaluated through model systems. The aldol-type reaction of 7 [25][26][27] with (2E,4E)-hexa-2,4-dienal by the simple treatment with LiHMDS to give 8 in only 6% yield and 62% of 7 was recovered (Chart 2).However, the aldol-type reaction of 4-methoxy-6-methyl-2-pyrone 9 with (2E,4E)-hexa-2,4-dienal proceeded smoothly under the same conditions to afford the aldol product 10 in 87% yield. These results indicated that the carbohydrate moiety greatly influenced the aldol-type reaction. We reasoned that the highly oxygenated functional group of 7 might decrease the reactivity of the pyrone-stabilized carbanion through the coordination to the lithium ion or by steric The synthesis of the key intermediate (4) in the proposed route to D8646-2-6 is desc...

Polyunsaturated C‐Glycosidic 4‐Hydroxy‐2‐pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

“…Unfortunately,t his tantalizing question cannot be answered based on the literature data because their spectra had been recorded in different solvents ([D 6 ]DMSO versus [D 4 ]methanol). This formidable task was somewhat alleviated by the fact that the sugar contained in 2 is almost certainly galactose [2,3,5,8] and only the configuration of the chiral centers in the tail remains undefined. This formidable task was somewhat alleviated by the fact that the sugar contained in 2 is almost certainly galactose [2,3,5,8] and only the configuration of the chiral centers in the tail remains undefined.…”

“…[7,8] In view of five-plus-two basically unassigned chiral centers located in two separated clusters at the head and the tail region of 1,r espectively,o ne has to be prepared to make al ibrary of isomers to clarify this point. [7,8] In view of five-plus-two basically unassigned chiral centers located in two separated clusters at the head and the tail region of 1,r espectively,o ne has to be prepared to make al ibrary of isomers to clarify this point.…”

“…Thef ew studies previously directed towards these intricate targets had left the questions concerning constitution and stereostructure open. [7,8] In view of five-plus-two basically unassigned chiral centers located in two separated clusters at the head and the tail region of 1,r espectively,o ne has to be prepared to make al ibrary of isomers to clarify this point. Only ahighly convergent approach that assembles building blocks of unambiguous stereostructure may succeed.…”

Polyphasic Analysis of Intraspecific Diversity in Epicoccum nigrum Warrants Reclassification into Separate Species

“…Many studies have focused on the ability of this fungus to produce antimicrobial compounds such as epicorazins A–B [12], epicoccins A–D [13], epicoccarines A–B and epipyridone [14], flavipin [15] and epirodins [16]. The production of novel bioactive chemical compounds including siderophores [17], antioxidants [18], inhibitors of HIV-1 replication [19], [20], inhibitors of leucemic cells [21], inhibitors of protease [22], inhibitors of telomerase [23] and fluorescent compounds with biotechnological applications [24], [25] have also been described in Epicoccum isolates.…”

Dienals Derived from Pyridinium Salts and Their Subsequent Application in Natural Product Synthesis

“…43 In an extended aldol reaction, the lithium anion of carbohydrate-containing pyrone 59 was added to (2E,4E)-37b (Scheme 26). In order to expedite adduct formation, the presence of a Lewis acid such as Sn(OTf) 2 or Sc(OTf) 3 was needed.…”