Determination of the Absolute Stereochemistry of (−)-Galbonolide A

Abstract

The absolute stereochemistry of (-)-galbonolide A (1) was assigned by chemical methods. First, 1 was degraded to diol 3. After selective silylation of the primary alcohol, two independent methods were carried out to determine the chirality at C13. Both established its S-configuration. Using the methodology developed in the total synthesis of (-)-galbonolide B, diols 13(S,S) and 13(S,R) were prepared. Their (R)-MTPA esters, 14(S,S,R) and 14(S,R,R), were compared with the analogous (R)-MTPA ester of the degradation product 3, which subsequently established the S-chirality at C8. To determine the chirality at C4, two independent methods were carried out. One involved a comparison with the chirality of C4 of galbonolide B. The other involved a comparison of the degradation product of galbonolide A, 22, with its synthetic equivalents. Both methods confirmed the S-configuration at C4. Since three of the four chiral centers of galbonolides A and B have been confirmed to be identical and since the two galbonolides share very similar conformations as suggested by their (1)H NMR spectra, the configurations at C2 of these two compounds should also be the same.

Rustmicin, a Potent Antifungal Agent, Inhibits Sphingolipid Synthesis at Inositol Phosphoceramide Synthase

“…Isolation of the sphingolipid inhibitor and determination of its structure 3 resulted in the identification of the 14-membered macrolide known as rustmicin (19) or galbonolide A (20). The absolute stereochemistry was determined by chemical methods (27), and the structures of rustmicin and its degradation products are shown in Fig. 1.…”

Chemical Tools to Investigate Sphingolipid Metabolism and Functions

“…GbA (Rustmicin, Figure 17) was isolated as a fungal metabolite from Micromospora chalcea and from Streptomyces galbus , independently,120–123 and later identified, together with related macrolides, such as galbonolide B (GbB) and their 21‐hydroxy analogues (Figure 17) as the third class of IPC synthase inhibitors 124. In a previous work,125 the absolute stereochemistries of Gbs were determined by a combination of chemical modifications and total synthesis. GbA, GbB, and their 21‐hydroxy analogues126, 127 were effective antifungal agents against several Candida species and also in an in vivo mouse model of cryptococciosis.…”

Galbonolides from Streptomyces sp. SR107

“…Galbonolides A (rustmicin) and B [1], neorustmicins B-D [5] and galbonolides C-D [2] have been identified. Total synthesis of galbonolide B [6,7] and determination of its absolute stereochemistry have also been reported [8,9], and a series of galbonolide derivatives have been prepared [7,10]. Galbonolides E and F were also detected in small amounts in microbiological fermentations and may be the chemical conversion products of A at the enol ether group [2]; both have also been reported as synthesis products (in PCT WO02/059104A1, 2002/08/01).…”