Recent Applications of the Diels–Alder Reaction in the Synthesis of Natural Products (2017–2020)

Abstract

The Diels-Alder reaction has long established its high rank in the toolbox of any natural product chemist. The tremendous toleration of building blocks of various complexity and derivatization degree, as well as the enablement of furnishing six-membered rings with well-defined stereochemistry represents its main features and advantages. In recent years, many total syntheses of natural products relied at some point on the use of a [4+2]-cycloaddition step. Among classic approaches, several modifications of the Diels-Alder reaction, such as hetero-Diels-Alder reactions, dehydro-Diels-Alder reactions or domino-Diels-Alder reactions have been employed to extend the scope in the synthesis of natural products. Our review covers the application of the Diels-Alder reaction in natural product syntheses from 2017 to 2020, as well as selected methodologies which were inspired by, or could be used to access natural products.

Efficient and Accurate Description of Diels‐Alder Reactions Using Density Functional Theory**

“…It is therefore not surprising that its applications in synthesis are numerous, going from the access to small, highly functionalized building blocks to the construction of complex natural products or polymers. [1,2] The possibility of describing these reactions via chemical simulations is thus of crucial importance. For example, it allows to understand (and predict) solvation effects or to model the role of pressure in tuning stereo-selectivity.…”

“…This two‐bond‐forming pericyclic combination of a 1,3‐diene (4 π component) with a dienophile (2 π component) allows the formation of six‐membered rings with well‐defined regio‐ and stereo‐chemistries and tolerates a large variety of functionalities. It is therefore not surprising that its applications in synthesis are numerous, going from the access to small, highly functionalized building blocks to the construction of complex natural products or polymers [1,2] …”

Carbohydrate‐Derived Dienes as Building Blocks for Pharmaceutically Relevant Molecules

“…Herein, we will discuss the applications of the two main classes: 1) conjugated 1,3-dienes (Section 2.1); and 2) non-conjugated 1,6dienes (Section 2.2). A number of different strategies have been described to prepare carbohydrate-based dienes, such as Wittig olefination of α-carbonylfunctionalized glycals, [19] enyne metathesis, [20][21][22] coupling reactions [23] and elimination reactions, [24] and will not be described further within the scope of this review.…”

Chasing Polycyclic Natural Products: 5/6/5‐ or 5/6/6‐Carbotricyclic Scaffold Construction via Stereodivergent Diels‐Alder Reaction of Chiral Hydrindanes and Their Boron Complexes

“…It should be noted that despite the wealth of information (including mechanistic studies) [48,49] on Diels‐Alder reactions in natural product synthesis [50] surprisingly little work has been carried out regarding indanones as dienophiles. For example, in the total synthesis of hamigerane B Lau utilized ketene acetals to overcome the poor [4+2] reactivity of an indanone [51] .…”