Natural Products with Anti‐Bredt and Bridgehead Double Bonds

Mak, Jeffrey Y. W.; Pouwer, Rebecca H.; Williams, Craig M.

doi:10.1002/anie.201400932

Cited by 97 publications

(80 citation statements)

References 269 publications

(214 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4a). Notably, unique architectures of bioactive natural products such as medium-sized rings33 ( E , F , I and K ), bridge-head bicyclic structures34 ( J and P ) and β-lactam rings3536 ( G ) were successfully incorporated into the pyrimidine-containing core skeletons. When we overlaid the energy-minimized conformers of each scaffold in 3D space by aligning the pyrimidine substructure, we clearly demonstrated the skeletal diversity and structural complexity of the resulting polyheterocycles (Fig.…”

Section: Resultsmentioning

confidence: 99%

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

et al. 2016

View full text Add to dashboard Cite

Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

show abstract

Section: Resultsmentioning

confidence: 99%

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

et al. 2016

View full text Add to dashboard Cite

show abstract

“…[3,5] However,the relevance of these studies,which focused on small synthetic parent systems,t ot he stabilities of complex natural products (NPs) is unclear. [7,8] This problem is reflected in anumber of literature reports that have proposed NP structures in obvious violation of Bredts rule. [7,8] This problem is reflected in anumber of literature reports that have proposed NP structures in obvious violation of Bredts rule.…”

mentioning

confidence: 99%

“…[5,7].B ottom:Schleyer's classification of bridgehead alkenes (olefins) as "isolable"," observable", or "unstable" based on olefin strain (OS) energy. [5,7].B ottom:Schleyer's classification of bridgehead alkenes (olefins) as "isolable"," observable", or "unstable" based on olefin strain (OS) energy.…”

mentioning

confidence: 99%

Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Krenske

Williams

2015

Angew Chem Int Ed

Self Cite

View full text Add to dashboard Cite

Bredts rule holds as pecial place in the realm of physical organic chemistry,b ut its application to natural products chemistry-the field in which the rule was originally formulated-is not well defined. Herein, the use of olefin strain (OS) energy as areadily calculated predictor of the stability of natural products containing abridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products,u sing contemporary forcefield methods,u nequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus,w hen one assigns the structure of ap utative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is ared flag for error.

show abstract

“…The optimal conjugation of the nitrogen lone pair electrons with the carbonyl function in the planar amide group leads to the usual stability and lack of reactivity of amides towards nucleophiles. In the twisted amides A and B,i nw hich the amide group is located at ab ridgehead, such ideal electron delocalisation is Bredt's rule-forbidden, [9] strongly influencing their reactivity by decreasing their stability and inertness towards nucleophilic attack. [6][7][8] As an example of reactivity inducedb ys train duet os terically demanding groups, we have recently reported that the in-troduction of two methyl groups in the hydrazone C [10] markedly enhances its reactivity towards the dynamic covalent exchange of the hydrazine component as ar esult of the distortion from planarity of the C=NÀNÀMe group that decreases the conjugation between the nitrogen CÀNÀMe electronic lone pair and the C=Nd ouble bond.…”

Section: Introductionmentioning

confidence: 99%

Strain‐Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines

Ratjen

Vantomme

Lehn

2015

Chemistry A European J

View full text Add to dashboard Cite

The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state. Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+2]-macrocyclic resting state. The process can be monitored by (1) H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree-Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.

show abstract

Natural Products with Anti‐Bredt and Bridgehead Double Bonds

Cited by 97 publications

References 269 publications

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Do Anti‐Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Strain‐Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines

Contact Info

Product

Resources

About