For a Correct Application of the CD Exciton Chirality Method: The Case of Laucysteinamide A

Abstract

The circular dichroism (CD) exciton chirality method (ECM) is a very popular approach for assigning the absolute configuration (AC) of natural products, thanks to its immediacy and ease of application. The sign of an exciton couplet (two electronic CD bands with opposite sign and similar intensity) can be directly correlated with the molecular stereochemistry, including the AC. However, a correct application of the ECM necessitates several prerequisites: knowledge of the molecular conformation; knowledge of transition moment direction; and preeminence of the exciton coupling mechanism with respect to other sources of CD signals. In recent years, by using quantum-chemical CD calculations, we have demonstrated that some previous applications of ECM were wrong or based on incorrect assumptions. In a recent publication of this journal (Mar. Drugs, 2017, 15(4), 121), the ECM was employed to assign the AC of a marine metabolite, laucysteinamide A. This is a further case of incorrect application of the method, where none of the aforementioned prerequisites is fully met. Using this example, we will discuss the criteria required for a correct application of the ECM.

ECD exciton chirality method today: a modern tool for determining absolute configurations

“…Adapted from ref. 55 sought to solve stereochemical problems in the most suitable way, also based on the ECM. 97 The important message from the case of acyclic 1,2and 1,3-diols is that, in the presence of flexible bis(chromophoric) compounds, one cannot infer the AC without knowing, or at least making a hypothesis, on the molecular conformation.…”

“…Because we considered the case of laucysteinamide A a very pertinent educational example to highlight the procedure for a correct application of the ECM, we run before a complete structural and electronic analysis by DFT and TD-DFT methods. 55 Here, we only briefly summarize the main results: F I G U R E 8 (A-C) Allylic benzoate method applied to a cholest-4-en-3β-ol benzoates (10). The shaded region in (B) is normally not accessible experimentally or obscured by other bands.…”

Isolation, stereochemical study, and racemization of (±)‐pratenone A, the first naturally occurring 3‐(1‐naphthyl)‐2‐benzofuran‐1(3H)‐one polyketide from a marine‐derived actinobacterium

“…For the ( R ) configuration, the two transition dipoles define a positive chirality (that is, a clockwise rotation is necessary to move the dipole in the front onto that in the back, shown in Figure ), which is in accord with the positive couplet found for (+)‐ 1 . It must be stressed that a correct application of the exciton chirality method necessitates various prerequisites to be met, the most important of which is, in the current case, an accurate knowledge of the transition moment directions. These latter (depicted in Figure ) were easily obtained by means of quick TDDFT calculations on the relevant chromophores (see details in Section 2.6).…”

“…Crystallographic data of 4: X-ray quality crystals were acquired by slow volatilization of a solvent mixture of MeOH and CH 2 Cl 2 . Crystal data for: C 21 Crystallographic data for compound 4 have been deposited in the Cambridge Crystallographic Data Centre with deposition number 1474260.…”

Induced axial chirality by a tight belt: naphthalene chromophores fixed in a 2,5-substituted cofacial para-phenylene–ethynylene framework

“…40,42 The transition dipole moment that is involved in the exciton coupling in 1 and 2 is the 1 L b transition, oriented along the long axis of the naphthalene. Since TDM orientation can differ in macromolecular structures and the ECM only reliably works with proper knowledge of its orientation, as has been shown by many corrections of reported assignments, 56,57 assignment by the ECM has to be considered with caution. In substituted naphthalenes it has been shown that the TDM is oriented along the substitution axis, which in the case of 1 and 2 is further supported by the conjugation to the central phenylene and adjacent naphthalene.…”