Terpenoid‐Alkaloids: Their Biosynthetic Twist of Fate and Total Synthesis

Abstract

Terpenes and alkaloids are ever-growing classes of natural products that provide new molecular structures which inspire chemists and possess a broad range of biological activity. Terpenoid-alkaloids originate from the same prenyl units that construct terpene skeletons. However, during biosynthesis, a nitrogen atom (or atoms) is introduced in the form of β-aminoethanol, ethylamine, or methylamine. Nitrogen incorporation can occur either before, during, or after the cyclase phase. The outcome of this unique biosynthesis is the formation of natural products containing unprecedented structures. These complex structural motifs expose current limitations in organic chemistry, thus providing opportunities for invention. This review focuses on total syntheses of terpenoid-alkaloids and unique issues presented by this class of natural products. More specifically, it examines how these syntheses relate to the way terpenoid-alkaloids are made in Nature. Developments in chemistry that have facilitated these syntheses are emphasized, as well as chemical technology needed to conquer those that evade synthesis.

Intermolecular Ritter-Type C–H Amination of Unactivated sp3 Carbons

“…14 In a continuing effort to use such logic for the synthesis of terpenoidalkaloids, 15 a C sp3 –H amination was pursued, inspired by the unexpected finding by Banks et al . of the formation of dihydrooxazinium salt 2 derived from menthol ( 1 , Figure 1B).…”

Development of a Terpenoid Alkaloid‐like Compound Library Based on the Humulene Skeleton

“…In particular, monoterpene indole alkaloids are very important resources in drug discovery. [6] The production of terpenoid alkaloids that are not involvedi nn atural biosynthetic pathways and that contain varioust ypes of terpenoid moieties may be useful for constructing chemically diversec ompound libraries for drugd iscovery. [6] The production of terpenoid alkaloids that are not involvedi nn atural biosynthetic pathways and that contain varioust ypes of terpenoid moieties may be useful for constructing chemically diversec ompound libraries for drugd iscovery.…”

Lessons and revelations from biomimetic syntheses

“…Similarly, reaction cascades are highlighted in the biomimetic synthesis of the endiandric acids 12,13 and in the conversion of squalene-type precursors into members of the Daphniphyllum alkaloid family (Fig. 1d) 14,15 . An important contribution to the field was the elucidation of the biosynthesis of the penicillins, which was determined through a series of biological and chemical studies 16 .…”

“…(a) The retrosynthetic pyramid places the highest-oxidized target (eudesmantetraol, 21) at the apex, and the level 1, low-oxidation-state targets at the base. dihydrojunenol(15) was chosen as the most logical starting point to ascend the pyramid owing to its potential to access both level 2 eudesmanes without wasteful functional-group manipulation. Selective c-H oxidations are required to reach advanced levels of the pyramid.…”