Questions in natural products synthesis research that can (and cannot) be answered using computational chemistry

Abstract

Questions of relevance to those working in the field of natural products synthesis that can be answered, at least in part, using computational chemistry approaches are described. Illustrative examples are provided, as are descriptions of limitations.

From Decades to Minutes: Steps Toward the Structure of Strychnine 1910–1948 and the Application of Today's Technology

“…Myriad examples have now been published using chemical shifts, computed with modern theoretical methods (generally density functional theory, DFT) to support or refute structure assignments. [53][54][55][56] The application of this type of approach to such complex molecules only became feasible in recent decades, due in large part to the continued development of DFT methods. Here we apply an expedient approach to explore how such technology could be used to rapidly rule out many quickly-proposed, perhaps simply brainstormed structures.…”

“…However, because of the multiple condensed ring systems of the various proposed structures for strychnine (see Table 1), reasonably unstrained diastereomers are few (except for 2 and the position of the methyl group in several others). While quantum chemical computations for chemical shifts are certainly reliable enough to distinguish among diastereomers, [53][54][55][56][57] we plunge ahead here in the spirit of determining connectivity and postponing the determination of relative configuration. The assumption here is that chemical shift differences associated with configuration changes again would not change our conclusions about connectivity within the very complex multi-ring systems.…”

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

“…Computational chemistry is now widely applied to modeling reactions of biosynthetic relevance . Detailed descriptions of computational methods can be found elsewhere, but it is important that practitioners generating and interpreting results, along with nonpractitioners who consume, interpret, and synthesize those results, keep the following distinctions in mind.…”

On the Structural Assignments Underlying R. B. Woodward's Most Personal Data That Led to the Woodward–Hoffmann Rules: Subramania Ranganathan's Key Role and Related Research by E. J. Corey and A. G. Hortmann

“…Is it reasonable that the relative configurations of Ranganathan's compounds 3 and 4 could have been assigned with confidence,g iven the 1 HNMR spectra available at the time (Figure 9)?T hese spectra are obviously low resolution by today's standards,a nd many 1 Hp eaks are not resolved. But might there be enough information present to allow one to make correct as well as confidenta ssignments?T oe xamine this matter,w ep redictedt he 1 Hc hemical shifts for 3 and 4 using aw ell-precedented quantum chemical approach: [53][54][55][56] (SMD(chloroform)-GIAO-mPW1PW91/6-311+ +G(2d,p), scaled; [57,58] scaling factorsw ere obtained from:c heshirenmr.info). Using these 1 Hc hemical shift predictions,w et hen evaluated the validity of Woodward'sa nd Ranganathan's assignments.…”

“…But might there be enough information present to allow one to make correct as well as confident assignments? To examine this matter, we predicted the 1 H chemical shifts for 3 and 4 using a well‐precedented quantum chemical approach: [53–56] (SMD(chloroform)‐GIAO‐mPW1PW91/6–311+G(2d,p), scaled; [57, 58] scaling factors were obtained from: cheshirenmr.info). Using these 1 H chemical shift predictions, we then evaluated the validity of Woodward's and Ranganathan's assignments.…”