Efficient Protocol for Accurately Calculating 13C Chemical Shifts of Conformationally Flexible Natural Products: Scope, Assessment, and Limitations.

An efficient protocol for calculating 13C NMR chemical shifts for natural products with multiple degrees of conformational freedom is described. This involves a multistep procedure starting from molecular mechanics and ending with a large basis set density functional model to obtain accurate Boltzmann conformer weights, followed by empirically corrected density functional NMR calculations for the individual conformers. The accuracy of the protocol (average rms <4 ppm) was determined by application to ∼925 diverse natural products, the structures of which have been confirmed either by X-ray crystallography or independent synthesis. The protocol was then applied to ∼ 2275 natural products, the structures of which were elucidated mainly by NMR and MS data. Five to ten percent of the latter compounds exhibited rms errors significantly in excess of 4 ppm, suggesting possible structural or signal assignment errors. Both data sets are available from an online browser ( NMR.wavefun.com ). The procedure can be and has been fully automated and is practical using present-generation personal computers, requiring a few hours or days depending on the size of the molecule and number of accessible conformers.

Revision of the Structure of Acremine P from a Marine-Derived Strain of Acremonium persicinum.

The previously published structure of the fungal metabolite acremine P is revised by re-evaluation of chemical shift values and NOESY data, and by DFT calculations.

Computation-Assisted Structural Elucidation of Epoxyroussoeone and Epoxyroussoedione Isolated from Roussoella japanensis KT1651.

The structures of epoxyroussoenone (1) and epoxyroussoedione (3) isolated from a culture broth of Roussoella japanensis KT1651 were determined. Although NMR spectra provided insufficient structural information, computation of the theoretical chemical shifts with DFT EDF2/6-31G* enabled us to elucidate not only the planar structure, but also the relative configuration. Their ECD (electric circular dichroism) spectra suggested the absolute configurations, which were confirmed with time-dependent DFT calculations employing BHandHLYP/TZVP. The ECD calculations for other stereoisomers yielded obviously different spectral profiles, thus confirming the relative structures of 1 and 3.

Dehydrative cyclocondensation mechanisms of hydrogen thioperoxide and of alkanesulfenic acids.

Structural features of hydrogen thioperoxide (oxadisulfane, H-S-O-H) and of alkanesulfenic acids (R-S-O-H; R = CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CCl3) and the mechanisms of their dehydrative cyclocondensation to the respective sulfinothioic acid (H-(S═O)-S-H) and alkyl alkanethiosulfinates (R-(S═O)-S-R) have been studied using coupled cluster theory with single and double and perturbative triple excitations [CCSD(T)] and quadratic configuration interaction with single and double and perturbative triple excitations [QCISD(T)] with the cc-pVDZ basis set and also using second-order Møller-Plesset perturbation theory (MP2) and the hybrid density functionals B3LYP, B3PW91, and PBE1PBE with the 6-311+G(d,p) basis set. The concerted cyclodehydration mechanisms include cyclic five-center transition states with relatively long distance sulfur-sulfur bonding interactions. Attractive and repulsive nonbonding interactions are predicted in the sulfenic acids, transition states, and thiosulfinates. In the alkyl alkanethiosulfinates attractive cyclic C-H----O═S nonbonding interactions are predicted. CCSD(T) and QCISD(T) predict similar values for the relative energies and CCSD(T) predicts the barrier to the cyclocondensation of H-S-O-H to sulfinothioic acid (H-(S═O)-S-H) to be 41.8 kcal/mol, and barriers in the range of 37.5 to 39.6 kcal/mol are predicted for the condensation of alkanesulfenic acids to alkyl alkanethiosulfinates.

The total synthesis of roquefortine C and a rationale for the thermodynamic stability of isoroquefortine C over roquefortine C.

The first total synthesis of roquefortine C is achieved by implementation of a novel elimination strategy to construct the thermodynamically unstable E-dehydrohistidine moiety. Molecular modeling studies are presented which explain the instability of the roquefortine C structure compared to that of isoroquefortine C.

Structure and biosynthesis of norneolambertellin produced by Lambertella sp. 1346.

Norneolambertellin (1) was isolated from a mycoparasite Lambertella sp. 1346. Combined analysis of the NMR spectra and chemical shift prediction based on molecular orbital calculation successfully revealed a novel pyrano[3,2-c]chromene-2,5-dione structure, which was further confirmed by X-ray crystallographic analysis. Isotopomer distribution analysis of the sample, prepared under labeling conditions, deduced its biosynthetic pathway.