Natural product anticipation through synthesis

Abstract

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by the celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology "on the fly", or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. "Natural Product Anticipation". In this review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from Nature. The focus of our review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation occurred independently. Finally, we highlight cases where such a possibility has been suggested but not yet confirmed, inviting further collaborations between synthetic and natural product chemists. The total synthesis of natural products has always been a major factor in the development of organic chemistry. The reasons for pursuing it have evolved as the field has progressed. In its early history, total synthesis mostly served to confirm the constitution and configuration of readily available natural products. With the advent of X-ray crystallography, NMR spectroscopy, and mass spectrometry, this aspect has become less important, although numerous recent cases exist where the structure of a natural product was settled through total synthesis. [1,2] As a consequence, the emphasis has shifted more toward reaction development and the definition of efficient synthetic strategies. In some cases, the desire to achieve a particular transformation has led to the invention of new reactions or reagents that did not exist before. [3] If a total synthesis is sufficiently efficient, it can also be used to deliver a prized natural product on scale that can otherwise only be procured at great expense or by ignoring environmental concerns. [4] Many other motivations for total synthesis exist, ranging from its value as a training ground for medicinal chemists to the satisfaction that comes with solving the sheer intellectual challenge that it represents. [5,6] In this account, we wish to highlight yet another reason to pursue it: Natural Product Anticipation.In the early days of organic synthesis, there must have been many cases where a compound was prepared in the laboratory and considered "synthetic" that was subsequently identified as a natural product. For instance, Gabriel made aminoacetone (1) in 1893 using his eponymous method. [7,8]...

Bioinspired Asymmetric Total Synthesis of Emeriones A–C

“…This compound had NMR spectra that were identical with those reported for emerione C (Figure 3B, Table S3), strongly indicating that emerione C shares the same stereochemical backbone configuration as emerione A. To unambiguously clarify the chemical structures, we solved the structure of 50 by X-ray crystallography (Figure 3C), and found that it has the structure that was originally proposed for emerione C. We, therefore, reassign the structure of emerione C (49) as it is depicted in Scheme 2 and name compound 50, which we think is not unlikely to also be a natural product, (+)-emerione D. [23] In order to gain deeper insight into the stereochemical outcome of the 8/6 electrocyclization cascade, density functional theory (DFT) calculations were employed at the SMD(toluene)-M06-2X/Def2-TZVP//M06-2X/Def2-SVP level of theory. The calculations reveal that the two transition states (TS-1 and TS-2) leading from pentaene 9 to vinylcyclooctatrienes 47 and 48, respectively, are nearly isoenergetic as are 47 and 48 themselves (Figure 4, Figure S4).…”

Bioinspired Intramolecular Diels-Alder Cycloaddition for the Total Synthesis of Ophiorrhine A via Ophiorrhine G and Ophiorrhiside E

“…This remarkable bond reorganization delivers an original strictosidine-derived skeleton which is not a natural product or yet to be discovered from natural sources. 29 In order to form indolopyridone 52 and prevent the spontaneous Diels-Alder cycloaddition, the cyclodehydratation had to be performed at a lower temperature (80 °C) after which, removal of the four acetates with methanol and potassium carbonate led to ophiorrhiside E 6a in 30% over two steps (Scheme 5). At 80 °C, the conversion of (−)-50a into 52 is modest since 57% of ophiorrhine F 7a was also isolated.…”

Bioinspired Total Synthesis of Erectones A and B, and the Revised Structure of Hyperelodione D

“…Pleasingly, NMR data for 17 fully matched that for natural hyperelodione D, thus proving our structural reassignment of this complex meroterpenoid. The prenyl/geranyl substitution pattern of 17 and 26 was established by HMBC correlations and comparison to NMR data for erectones A and B. Alongside the Diels–Alder adducts 19 , 23 , 24 and 25 , it is also probable that tetracycle 26 occurs in nature, and our characterization of these compounds could aid their future discovery in Hypericum plants [24] . Finally, the Diels–Alder cascade between erectquione A and E ‐β‐ocimene was also conducted in 10 % aq.…”

“…The prenyl/geranyl substitution pattern of 17 and 26 was established by HMBC correlations and comparison to NMR data for erectones A and B. Alongside the Diels-Alder adducts 19, 23, 24 and 25, it is also probable that tetracycle 26 occurs in nature, and our characterization of these compounds could aid their future discovery in Hypericum plants. [24] Finally, the Diels-Alder cascade between erectquione A and E-β-ocimene was also conducted in 10 % aq. HCl at 50 °C to give erectones A and B in 40 % yield, alongside the Diels-Alder adducts.…”