A new approach towards the synthesis of bielschowskysin: Synthesis and photochemistry of an advanced macrocyclic enedione intermediate

Nešić, Marko; Kincanon, Maegen M; Ryffel, David B.; Šarlah, David

doi:10.1016/j.tet.2020.131318

Cited by 7 publications

(12 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A careful comparison of the NMR data for 31 to that obtained for 33 indicated the compounds were closely related but not identical. This analysis then strongly suggested that the two isomers differed only by their relative C1-isopropenyl stereochemistries, a result which stands in stark contrast with expectations based on previously reported NHK cyclizations of related systems. − Specifically, it appeared that the stereochemistry at C13 in our system is intimately tied to the stereochemical outcome of the NHK macrocyclization and dictates which of the two anti-homoallylic alcohols is produced ( 29 or 32 ). Notably, only the former of these ( 29 ) is useful for further advancement to ineleganolide ( 1 ) and sinulochmodin C ( 2 ).…”

Section: Resultscontrasting

confidence: 75%

“…Oxidation of 23 to skipped enal 24 was a remarkably sensitive operation due to the double bond’s proclivity for isomerizing into conjugation with the aldehyde (not shown). However, carefully controlling the oxidation with NaHCO 3 -buffered Dess–Martin periodinane and advancing without purification or delay allowed the effective use of 24 . , …”

Section: Resultsmentioning

confidence: 99%

“…However, carefully controlling the oxidation with NaHCO 3 -buffered Dess−Martin periodinane and advancing without purification or delay allowed the effective use of 24. 20,21 With 12 and 24 in hand, we investigated conditions for the aldol coupling (Scheme 5). In the event, the reaction was found to be best performed by brief exposure of lactone 12 to LiHMDS followed by quenching of the resultant lithium enolate with freshly prepared skipped enal 24 at low temperature.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The remote stereogenic isopropenyl moiety in 10 would be forged via a Nozaki–Hiyama–Kishi (NHK) macrocyclization . This would then necessitate the preparation of acyclic precursor 11 , which would be assembled via the aldol reaction of lactone 12 and a suitable aldehyde coupling partner. − Diastereoselective access to the bicyclic lactone present in 12 would be gained by employing a 5-exo-trig Ueno–Stork-type radical cyclization applied to an intermediate derived from two known fragments, chiral enone 13 and TIPS-protected furfuryl alcohol 14 …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Total Syntheses of (+)-Ineleganolide and (−)-Sinulochmodin C

Tuccinardi

Wood

2022

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Described herein are the first total syntheses of the nor-furanocembranoid natural products (+)-ineleganolide (1) and (−)-sinulochmodin C (2). The synthetic strategy is predicated on a transannular Michael reaction that provides both natural products from a common macrocyclic intermediate and leverages a diastereoselective radical cyclization to furnish a key bicyclic lactone. The latter is further advanced to a macrocyclic precursor via a Nozaki–Hiyama–Kishi cyclization and a one-pot furan oxidation/oxa-Michael cascade. Unexpected stereochemical nuances that guided the evolution and eventual completion of the total synthesis are discussed.

show abstract

Section: Resultscontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Total Syntheses of (+)-Ineleganolide and (−)-Sinulochmodin C

Tuccinardi

Wood

2022

J. Am. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…By taking advantage of the macrocyclic conformational bias at low temperature, we established a sequence of kinetic transformations with a pivotal regio- and stereoselective furan dearomatization triggered by an epoxide ring opening and a full control over the newly formed 3 S ,7 S ,8 S stereogenic centers (Figure ). Despite several elegant and innovative synthetic approaches toward bielschowskysin, only we and Nicolaou have been able to build the intricate tricyclo[9.3.0.0]tetradecane skeleton of the natural product. This study finally informs about the conformational dynamics of FBC-macrocycles and the role of intertwined strategical oxidations and chemoselective C–C bond-forming steps in the biosynthetic pathways of polycyclic FBCs.…”

Section: Introductionmentioning

confidence: 99%

Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin

2021

View full text Add to dashboard Cite

Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (e.g. plumarellide, verrillin, and bielschowskysin). These architecturally complex metabolites are thought to originate from site-selective oxidation of the macrocycle backbone and a series of intricate transannular reactions. Yet the development of a common biomimetic route has been hampered by a lack of synthetic methods for the pivotal furan dearomatization in a regio- and stereoselective manner. To address these shortcomings, a concise strategy of epoxidation followed by a kinetically controlled furan dearomatization is reported. The surprising switch of facial α:β-discrimination observed in the epoxidation of the most strained E-acerosolide versus E-deoxypukalide and E-bipinnatin J derived macrocycles has been rationalized by the variation of the 3D conformational landscape between macrocyclic scaffolds. A careful conformational analysis of these macrocycles by VT-NMR and NOESY experiments at low temperature was supported by DFT calculations to characterize these equilibrating macrocyclic conformers. The shift in conformational topology associated with a swing of the butenolide ring in E-deoxypukalide is in general agreement with the reversal of β-selectivity observed in the epoxidation. We also describe the downstream functionalization of FBC-macrocycles and how the C-7 epoxide configuration is retentively translated to the C-3 stereogenicity in dearomatized products under kinetic control to secure the requisite 3S,7S,8S configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a E-(Δ7,8)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.

show abstract