Stereochemical Elucidation of Natural Products from Residual Chemical Shift Anisotropies in a Liquid Crystalline Phase

Abstract

Determination of the stereochemistry of organic molecules still represents one of the major obstacles in the structure elucidation procedure in drug discovery. Although the application of residual dipolar couplings (RDCs) has revolutionized this field, residual chemical shift anisotropies (RCSAs) which contain valuable structural information for nonprotonated carbons have only been scarcely employed so far. In this study, we present a simple but highly effective solution to extract RCSAs of the analytes in a liquid crystalline phase formed by AAKLVFF oligopeptides. This method does not require any special instruments, devices, or correction during postacquisition data analysis and thus can be easily applied in any chemistry laboratory. To illustrate the potential of this method, the relative configurations of four known natural products (1−4) belonging to different structural classes were confirmed. Moreover, we unambiguously elucidated the stereochemistry of spiroepicoccin A (5), a rare thiodiketopiperazine marine natural product whose configuration could not be assigned based on conventional NMR methods.

Measurement of Residual Dipolar Couplings of Organic Molecules in Multiple Solvent Systems Using a Liquid‐Crystalline‐Based Medium

“…[14] Relying on the intramolecular non-covalent interactions,this bottom-up approach evades the challenging synthesis for polymers.Inthis respect, oligopeptides have been considered as promising candidates because of their structural diversity and strong tendencytoform self-assemblies in solution. In our previous study,w ep roposed two types of oligopeptides as aligning media that are compatible with D 2 O [15] and CD 3 OD, [16] respectively.N otably,u sing AAKLVFF as alignment medium, the relative configuration of as eries of challenging novel natural products including spiroepicoccin A, [17] sarcomililate A, [18] xylarichalasin A, [19] herpotrichones Aa nd B, [20] polyoxygenated sesquiterpenoid, [21] and curtachalasins [22] have been elucidated based on the RDC and residual chemical-shift anisotropy (RCSA) analysis.D espite these encouraging results,s ome challenges still exist. First, until now,t here has been no DMSO-bearing medium based on molecular self-assembly.S econd, the formation of selfassembly in organic solvents usually takes several hours or even days to complete.Third, residual background signals and broad linewidths frequently hinder an accurate measurement of the dipolar couplings.F inally,d espite the feasible solidphase peptide-synthesis (SPPS) technique,t he time-consuming peptide-purification step quite often prohibits the largescale production of peptide-based media.…”

Cytotoxic Thiodiketopiperazine Derivatives from the Deep Sea-Derived Fungus Epicoccum nigrum SD-388

“…In continuation of our research aimed at discovery of bioactive metabolites from marine-derived microorganisms [10][11][12], a fungal strain of Epicoccum nigrum SD-388 was isolated from a deep-sea sediment sample collected at a depth of 4500 m. Chemical investigation of the fungus resulted in the isolation of spiroepicoccin A, an unusual spiro-TDKP derivative, whose stereochemistry could not be elucidated by conventional NMR methods and was solved based on residual chemical shift anisotropies [12]. This result encouraged us to perform a further study of the fungus and has led to the isolation of four new TDKPs including 5'-hydroxy-6'-ene-epicoccin G (1), 7-methoxy-7'-hydroxyepicoccin G (2), 8'-acetoxyepicoccin D (3), and 7'-demethoxyrostratin C (4), as well as a pair of new enantiomeric diketopiperazines (DKPs), (±)-5-hydroxydiphenylalazine A ((±)-5), together with five known analogues including diphenylalazine A (6) [4], emeheterone (7) [13], epicoccins E (8) and G (9) [4], and rostratin C (10) [7] (Figure 1).…”

Antibacterial Alkaloids and Polyketide Derivatives from the Deep Sea-Derived Fungus Penicillium cyclopium SD-413

“…In our continuing excavation to identify new bioactive metabolites from deep sea-derived fungi [7][8][9][10][11][12], the fungus Penicillium cyclopium SD-413, which was obtained from a sediment sample collected from the East China Sea, was screened out for chemical investigations. As a result, two new polyketide derivatives, 9-dehydroxysargassopenilline A (4) and 1,2-didehydropeaurantiogriseol E (5), along with seven known related metabolites (1-3 and 6-9) (Figure 1), were isolated and identified from the culture extract of the fungus.…”