An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)‐Norcembrene 5

Breunig, Michael; Yuan, Philip F.; Gaich, Tanja

doi:10.1002/anie.201912613

Cited by 17 publications

(11 citation statements)

References 45 publications

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“…after reflux in benzene (Scheme 6). 9 A similar reactivity was observed by Pattenden during the attempted total synthesis of plumareillide, in this case postulating the transannular Diels Alder reaction as part of the biosynthetic pathway to this secondary metabolite. 10…”

Section: Accepted Manuscriptsupporting

confidence: 71%

“…This is the case of the attempt to access the norcembrenolide diterpenic scaffold in which a furane-containing macrocycle underwent this transannular process converted slowly upon standing into a complex polycyclic highly oxygenated adduct or in 80 minutes after reflux in benzene (Scheme 6). 9 A similar reactivity was observed by Pattenden during the attempted total synthesis of plumareillide, in this case postulating the transannular Diels-Alder reaction as part of the biosynthetic pathway to this secondary metabolite. 10 Scheme 6 Transannular Diels-Alder reaction employed to build the decaline core of verongidolide In fact, it has been demonstrated that a 'Diels-Alderase' enzyme is involved in the acceleration of a transannular [4+2] cycloaddition during the biosynthesis of natural product spynosyn A (Scheme 7).…”

Section: Scheme 5 Transannular Diels-alder Reaction Employed To Build...supporting

confidence: 70%

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Recent Developments in Transannular Reactions

Reyes¹,

Prieto²,

Carrillo³

et al. 2022

Synthesis

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Transannular reactions have shown a remarkable performance for the construction of polycyclic scaffolds from medium- or large sized cyclic molecules in an unconventional manner. Recent examples of transannular reactions reported from 2011 have been reviewed, emphasizing the excellent performance of this approach when accessing the target compounds. This review also highlights how this methodology provides an alternative approach to other commonly used methodologies for the construction of cyclic entities such as cyclization or cycloaddition reactions

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Section: Accepted Manuscriptsupporting

confidence: 71%

Section: Scheme 5 Transannular Diels-alder Reaction Employed To Build...supporting

confidence: 70%

Recent Developments in Transannular Reactions

Reyes¹,

Prieto²,

Carrillo³

et al. 2022

Synthesis

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“…a | iso-epicolactone (92) [75,76] , (+)brevianamide Y (93), [77][78][79] (±)-desoxyisobruceol (94) [80][81][82][83] , and (-)-prehalenaquinone (95) [84] are additional examples for molecules that were synthesized in the laboratory prior to their isolation. b | Cases of anticipated natural products that await isolation from natural sources: 8-epi-isoaplydactone (96), [85] dia-angiopterlactone B (97), [86] biyouyanagin C (98), [87] epi-pycnanthuquinone C (99), [88] 8-epi-homodimericin A (100), [89] intricarene side-product (101), [90] protected dia-millingtonine (102) [91] , diaincargranine B aglycone (103) [92] , diastereomer towards neonectrolides (104) [93] , preuisolactone precursor (105) [94] , nuphar alkaloid isomer (106) [95] , side-product towards (+)-norcembrene 5 (107) [96] , monolomaiviticin A (108) [97] , 2-epilankacyclinol (109) [98] , 3,7-epi-massadine (110) [99] , santarubin S (111) [100] , epiguajadial B (112) [101] , Δ 23,24 -perovskone (113) [102] , epi-pungiolide A (114) [103] , and iso-aspergilasine A (115) [104] . This review cannot be comprehensive since it relies mostly on our own experience in the field of biomimetic natural product synthesis and is limited by difficulties in finding diffuse information in the vast chemical literature.…”

Section: Discussionmentioning

confidence: 99%

Natural product anticipation through synthesis

2022

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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]...

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“…Whileas, Gaich's team presented the first total synthesis of (+)‐Norcembrene 5 532 (Scheme 80), a diterpenoid with 14‐membered cembrane framework where the RCM was employed as one of the decisive step to construct the 14‐membered macrocyclic ring system [261] . Herewith, Wittig olefination of aldehyde 529 with MePPh 3 Br and LiHMDS afforded a diene 530 , which fruitfully endured to the ring closing metathesis with G‐II catalyst 2 and delivered a macrocyclic compound 531 .…”

Section: Ring‐closing Metathesis (Rcm)mentioning

confidence: 99%

“…Whileas, Gaich's team presented the first total synthesis of (+)-Norcembrene 5 532 (Scheme 80), a diterpenoid with 14membered cembrane framework where the RCM was employed as one of the decisive step to construct the 14-membered macrocyclic ring system. [261] Herewith, Wittig olefination of tides with a 12-membered macrolactone linked to a long alkyl chain, isolated from the endophytic actinomycete Actinoallomurus fulvus MK10-036 and possess a strong profile against Trypanosoma protozoan parasites. [262] In this synthetic strategy, they employed an RCM protocol as the key transformation to construct the 12-membered macrolactone.…”

Section: Total Synthesis Of Natural Products Based On Rcmmentioning

confidence: 99%

Metathesis Reactions in Natural Product Fragments and Total Syntheses

et al. 2022

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The passion of total‐ and fragments syntheses of natural products always remained one of the top priorities among the synthetic chemists worldwide. Due their curiosity toward the complexity of molecules of living nature and their endeavour to imitate them in laboratory; limitless arrays of natural products have been extracted, architecturally‐elucidated, synthesized, and chronicled by utilizing various synthetic methodologies in different fashions. Frequently, the synthesis of complex natural products proceed with inscrutable synthetic challenges, which can be circumvented either by modification of previously developed synthetic methods or by formulating a new one. In this way, a myriad of powerful synthetic reactions have been developed since the genesis of the logic of chemical synthesis. Amongst them, metathesis tactics discovered unexpectedly in the 1950s (Nobel Prize in 2005), have incredibly influenced and changed the landscape of the art of the total and formal synthesis in the last three A. H. Hoveyda, A. R. Zhugralin, me abruptly as compared to other developed transformations or their modified forms. In this particular review article, we envisioned to report a comprehensive detail of the metathetic tools involved in both total and fragments synthesis of natural products in the years 2018 and 2019 along with an overview of 2017.

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An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)‐Norcembrene 5

Cited by 17 publications

References 45 publications

Recent Developments in Transannular Reactions

Recent Developments in Transannular Reactions

Natural product anticipation through synthesis

Metathesis Reactions in Natural Product Fragments and Total Syntheses

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