Sanctolide A, a 14-membered PK-NRP hybrid macrolide from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79)

Abstract

Sanctolide A (1), a 14-membered polyketide-nonribosomal peptide (PK-NRP) hybrid macrolide, was isolated from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). The planar structure was determined using various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The relative configuration was assigned by J-based configurational analysis in combination with NOE correlations. The absolute configuration was determined by Mosher ester and enantioselective HPLC analyses. The structure of sanctolide A (1) features a rare N-methyl enamide and a 2-hydroxyisovaleric acid, which are incorporated to form a 14-membered macrolide ring structure, comprising a new type of cyanobacterial macrolides derived from a PKS-NRPS hybrid biosynthetic pathway.

Figure 1

The structure of sanctolide A (1).

Figure 2

Key 2D NMR correlations used to determine the planar structure of 1.

Figure 3

Newman projections for A4: C5–C6 and B1: C6–C7. The DQF-COSY and GBIRD-HSQMBC spectra were used for the measurement of homo- and hetero-nuclear coupling constants. Labels in parentheses denote the predicted size of coupling constants: S-small, M-medium and L-large. No correlation observed in the HSQMBC spectrum was assigned as a coupling of 0 Hz. Observed nOe correlations are presented as arched arrows. A full list of rotamers can be found in Supplementary data.

Figure 4

Methanolysis and acid hydrolysis for the absolute configuration of 1 at C-5 and C-15; Δδ_S-R values (Δδ_S-R = δ_S − δ_R) for the MTPA esters 2S and 2R.

Figure 5

Proposed enamide hydrolysis of 1 in neutral pH that leads to ring-opening of the macrolide ring structure.