First Construction of a Saricandin Analog Corresponding to Papulacandin D

Abstract

The first total synthesis of a saricandin analog corresponding to papulacandin D has been achieved via a highly convergent synthetic strategy. A readily accessible chiral building block 3 was designed and prepared in large scale via an enantioselective reduction with pinanyl-9-BBN. The adaptability of compound 3 toward structural modifications and the highly convergent nature of the approach is illustrated in the construction of the side chain present in saricandin by Pd-catalyzed cross-coupling of 2 and 3 and sequences that include triple bond reduction of fragment C(5-16) and generation of the double bond (C4-C5) using Horner-Emmons reaction. The assembly of the spirocyclic monoglycoside with saricandin side chain is described. A practical technique for isolating the final product 1 after deprotection with TBAF is discussed. Compound 1 was evaluated for its antifungal activity in enzyme assay and cell based assays. However, in contrast the activity reported by Traxler for papulacandin D, the presence of the galactose moiety together with the short fatty acid in natural saricandin seem to be essential for the antifungal activity.In 1977, Traxler and coworkers reported the isolation and characterization of a family of antifungal antibiotics named papulacandins A, B, C and D from Papularia sphaerospema. 1 The compounds displayed potent in vitro activity against Candida albicans and various other yeasts and have been shown to inhibit b-1,3-glucan synthase, an enzyme involved in fungal cell wall biosynthesis. However, little or no efficacy has been found in animal models. The papulacandins A, B and C contain a spirocyclic diglycoside and two unsaturated fatty acids, linked as esters to two hydroxyl groups of the diglycosides. Papulacandin D, a monosaccharide relative is the simplest member of the family. The antifungal properties of papulacandin D juxtaposed with lack of access to natural material and the synthetically challenging structural feature make this compound interesting synthetic target. 2 The first total synthesis and full stereochemical assignment of papulacandin D was reported by Barrett and coworkers 3 in 1996. Although there is no evidence for a biosynthetic pathway it is possible that papulacandin D, lacking the galactose residue and the short fatty acid chain (Figure 1), is formed as intermediate in the biosynthesis of papulacandins A, B and C.Recently, a new potent antifungal antibiotic produced by the fungal culture, AB 2202W-161, named saricandin was isolated and characterized. 4 Guided by the hypothesis that saricandin may be formed following an analogous biosynthetic pathway to the papulacandins, we postulated that compound 1 (Figure) may be an intermediate in the process. 5 Herein we wish to describe the first total synthesis of compound 1. By analogy with the relationship between papulacandin D and A, compound 1 would address the question of how the biological profile of saricandin is affected by the absence of the galactose moiety together with the short fatty acid. Furthermore, the signifi...

C-Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and Bioactivity Focused on Antidiabetic Potential

“…290 The same synthetic strategy was used for the study of the regioselective acylation of the glucose moiety, 291 but also for the further elaboration of this intermediate into saricandin analogues. 292 The lithiated glycal 252 was also engaged in a condensation with the quinone 253 to afford a C-glycosyl intermediate, which was further converted into the target papulacandin core. 293 More recently, the preparation of a glucal silanol 254 provided a rapid and efficient access to the spiro-bicyclic core of papulacandins through condensation with the iodo-arene 255 and to the total synthesis of papulacandin D. 219 A [2+2+2]-strategy 294 was also used through the condensation of gluconolactone 130 with (2trimethylsilyl)ethynyllithium and reaction of the lactol intermediate with trimethylsilylated propargylic alcohol to afford the bis-silylated intermediate 257.…”

“…217 An analogue of saricandin corresponding to papulacandin D (886-sar) had no antifungal effect on the in vitro and cellular assays. 292 Several 2glycosyl-benzimidazoles were screened as growth inhibitors against pathogenic yeasts, but none of them showed significant effect. 348 D-Galactosamine derivatives 887−890 were tested for their affinity for the asialoglycoprotein receptor (ASGPR), a galactosebinding receptor expressed on hepatocytes (Figure 10).…”

“…The synthesis started from the trimethylsilylated gluconolactone 133 , which was reacted with the lithiated anion of the bromo-aromatic derivative 251 to afford a lactol that was converted to the desired spiroketal under acidic catalysis in 45% yield . The same synthetic strategy was used for the study of the regioselective acylation of the glucose moiety, but also for the further elaboration of this intermediate into saricandin analogues . The lithiated glycal 252 was also engaged in a condensation with the quinone 253 to afford a C -glycosyl intermediate, which was further converted into the target papulacandin core .…”

Synthesis and antifungal properties of papulacandin derivatives

“…For the papulacandins it was shown that the substituted galactose is not essential for activity, since papulacandin D is still active, but it does increase the potency. Apparently, the situation is different for the related disaccharide saricandan carrying different acyl chains, for which the monosaccharide analogue was not active [ 29 ]. Removing the galactose acyl chain from papulacandin B results in material that can still inhibit the target (in a spheroplasts glucan synthesis assay) but cannot reach the target site of C. albicans [ 12 ].…”

Synthetic studies towards bistramide D

“…At the end of 2005, Crimmins reported an enantioselective synthesis of bistramide A, 28 which was the second stereoselective synthesis reported for this molecule. Crimmins started the THP fragment synthesis from a known aldehyde (1.70) 29 which on aldol reaction with the N-propionyl thiazolidinethione enolate (1.71) (Scheme 18), afforded the syn product (1.72) with excellent diastereoselectivity (98:2). Reductive cleavage of the chiral auxiliary followed by Wittig reaction gave the corresponding α,β-unsaturated ester (1.73) in 78 % yield in two steps.…”