Road Map Toward Computer-Guided Total Synthesis of Natural Products. The Dysiherbol A Case Study: What if Serendipity Hadn’t Intervened?

We present a computational study inspired by the story of dysiherbol A, a natural product whose putative structure was found incorrect through synthesis by a completely fortuitous event. While the carbon connectivity and chemical environment between both structures remain similar, the real dysiherbol A has a different molecular weight than that reported for the natural product. Had the synthesis groups not been favored by fortune, it could be speculated that a substantial amount of time and effort would have been required to solve the structural puzzle. Within the realm of computer-guided total synthesis of natural products, the question arose whether a synthesis group could have in silico reassigned the structure before embarking on the experimental adventure. To address this query, we evaluated some state-of-the-art computational procedures based on their computational demand and ease of implementation for nonexpert users with basic skills in computational chemistry (including HOSE, CASCADE, ANN-PRA, ML-J-DP4, DP4, and DP4+). While discussing the strengths and limitations of these methods, this case study provides a roadmap of what could be done before venturing into complex and time-demanding total synthesis projects

GIAO C–H COSY Simulations Merged with Artificial Neural Networks Pattern Recognition Analysis. Pushing the Structural Validation a Step Forward

The structural validation problem using quantum chemistry approaches (confirm or reject a candidate structure) has been tackled with artificial neural network (ANN) mediated multidimensional pattern recognition from experimental and calculated 2D C–H COSY. In order to identify subtle errors (such as regio- or stereochemical), more than 400 ANNs have been built and trained, and the most efficient in terms of classification ability were successfully validated in challenging real examples of natural product misassignments

Application of the Multi-standard Methodology for Calculating ¹H NMR Chemical Shifts

Gauge including atomic orbitals (GIAO) ¹H NMR chemical shift calculations have been performed for 66 organic compounds at 72 different levels of theory using the multi-standard approach (MSTD) previously developed for ¹³C NMR. This straightforward computational technique involves the combination of methanol and benzene as standards. The studied methodology has been shown to predict ¹H NMR chemical shifts efficiently at different levels of theory

Application of the Multi-standard Methodology for Calculating ¹H NMR Chemical Shifts

Gauge including atomic orbitals (GIAO) ¹H NMR chemical shift calculations have been performed for 66 organic compounds at 72 different levels of theory using the multi-standard approach (MSTD) previously developed for ¹³C NMR. This straightforward computational technique involves the combination of methanol and benzene as standards. The studied methodology has been shown to predict ¹H NMR chemical shifts efficiently at different levels of theory

Winged-Cone Conformation in Hexa-<i>p‑tert</i>-butylcalix[6]arene Driven by the Unusually Strong Guest Encapsulation

Hexa-<i>p</i>-<i>tert</i>-butylcalix­[6]­arene <b>(1)</b> is believed to adopt a winged conformation in a solution, featured by four phenyl rings perpendicular to the calix basis and two others at 1,4-positions lying down. However, there is some controversy on the occurrence of this conformation because it has never been found in the solid state of calix[6]­arenes, regardless of the substitution pattern at lower and upper rims. Here, we have observed the winged-cone conformation for the first time in a solvate form of <b>1</b> with dimethyl sulfoxide (DMSO), dimethylformamide, and pyridine. The DMSO molecule is strongly encapsulated into <b>1</b> through two OH···O hydrogen bonds with both flattened phenolic moieties, one lp_(S)···π and four CH···π interactions with the four perpendicular phenyl rings. This host–guest complex has energy lower by 23.4 kcal mol^–1 than the isolated species. In addition, another DMSO solvate form with 1,2,3-alternate conformation was also obtained in this study, and its structure is compared with that of the precedent one. A detailed density functional theory study has also been carried out to understand the energetic relationships among cone conformers, intramolecular hydrogen-bonding patterns, and DMSO encapsulation

1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with a Cellulose-Derived Chiral Enone. A Novel Route for Organocatalysts Development

Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based asymmetric Diels–Alder reactions

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through <i>retro</i>-aza-Michael//aza-Michael Isomerizations

The design and synthesis of biomass-derived triazoles and the <i>in vitro</i> evaluation as potential anticancer agents are described. The discovery of base-catalyzed <i>retro</i>-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through <i>retro</i>-aza-Michael//aza-Michael Isomerizations

The design and synthesis of biomass-derived triazoles and the <i>in vitro</i> evaluation as potential anticancer agents are described. The discovery of base-catalyzed <i>retro</i>-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through <i>retro</i>-aza-Michael//aza-Michael Isomerizations

The design and synthesis of biomass-derived triazoles and the <i>in vitro</i> evaluation as potential anticancer agents are described. The discovery of base-catalyzed <i>retro</i>-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through <i>retro</i>-aza-Michael//aza-Michael Isomerizations

The design and synthesis of biomass-derived triazoles and the <i>in vitro</i> evaluation as potential anticancer agents are described. The discovery of base-catalyzed <i>retro</i>-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues