Beyond optical rotation: what's left is not always right in total synthesis

Abstract

Longstanding debate on the absolute configuration of frondosin B was definitively solved using circular dichroism spectroscopy.

Direct regioisomer analysis of crude reaction mixtures via molecular rotational resonance (MRR) spectroscopy

“…The compounds in this sample did present additional conformational flexibility, due to the fused cyclohexene and cycloheptadiene rings that can obtain several energetically favorable conformations; these were previously described in greater detail. 35 Additionally, the methyl ether group can adopt two configurations that are planar with the phenyl ring it is connected to. Crucially for the MRR analysis, one of these two configurations of OMe-frondosin B 5 results in a strong molecular dipole moment (>2 Debye), while the other has very low dipole moment (<0.3 Debye).…”

“…As the regioisomeric byproduct 6 contains two chiral centers, in the previous study of this reaction 35 the relative stereochemistry was determined on the basis of 1 H ROESY 2-D NMR experiments on an isolated sample with comparison to chemical shifts predicted using DFT. Just as for regioisomers, MRR is extremely precise in distinguishing between diastereomers on the basis of their differences in moments of inertia.…”

“…The second reaction was part of an investigation into the absolute configuration of a natural product, frondosin B. 35 As part of this study, previously reported syntheses of frondosin B were re-examined to determine the cause of a reversal in the sign of the optical rotation. While a stereochemical inversion was initially expected, it was discovered that near the end of the synthesis a two-step gem -dimethylation of ketone 4 produced a significant amount of regioisomeric impurity 6 ( Scheme 1b ).…”

Enantiomeric Mixtures in Natural Product Chemistry: Separation and Absolute Configuration Assignment

“…The differences in OR obtained for products of distinct synthetic routes had been attributed to an unexpected inversion of the C-8 stereogenic center. However, a recent report by Joyce et al [ 33 ] demonstrated that the presence of a minor impurity (ca. 7%), that appears in a key step late in the synthesis, was responsible for measured OR values of opposite signs for the synthetic products with the same AC.…”

“…7%), that appears in a key step late in the synthesis, was responsible for measured OR values of opposite signs for the synthetic products with the same AC. As a result, the assignment of the absolute stereochemistry of the natural product was also compromised [ 33 ]. The authors finally state that the reported inversions of the AC assigned at C-8 came “ only from differences observed in the measurements of a small optical rotation conducted on minute quantities of material, often of unknown chemical or enantiopurity ”.…”