From UK-2A to florylpicoxamid: Active learning to identify a mimic of a macrocyclic natural product.

Scaffold replacement as part of an optimization process that requires maintenance of potency, desirable biodistribution, metabolic stability, and considerations of synthesis at very large scale is a complex challenge. Here, we consider a set of over 1000 time-stamped compounds, beginning with a macrocyclic natural-product lead and ending with a broad-spectrum crop anti-fungal. We demonstrate the application of the QuanSA 3D-QSAR method employing an active learning procedure that combines two types of molecular selection. The first identifies compounds predicted to be most active of those most likely to be well-covered by the model. The second identifies compounds predicted to be most informative based on exhibiting low predicted activity but showing high 3D similarity to a highly active nearest-neighbor training molecule. Beginning with just 100 compounds, using a deterministic and automatic procedure, five rounds of 20-compound selection and model refinement identifies the binding metabolic form of florylpicoxamid. We show how iterative refinement broadens the domain of applicability of the successive models while also enhancing predictive accuracy. We also demonstrate how a simple method requiring very sparse data can be used to generate relevant ideas for synthetic candidates.

[2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes.

Aromatic ring isosteres and rigidified saturated hydrocarbons are important motifs to enable drug discovery. Herein we disclose [2]-ladderanes as a class of meta-substituted aromatic ring isosteres and rigidified cyclohexanes. A straightforward synthesis of the building blocks is presented along with representative derivatization. Preliminary studies reveal that the [2]-ladderanes offer similar metabolic and physicochemical properties thus establishing this class of molecules as interesting motifs.

Ladderane Natural Products: From the Ground Up.

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.

Lessons in Strain and Stability: Enantioselective Synthesis of (+)-[5]-Ladderanoic Acid.

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)-[5]-ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

Recent advances in the synthesis of gem-dimethylcyclobutane natural products.

Covering: January 2000 to July 2018 gem-Dimethylcyclobutanes are a common motif found in a multitude of natural products, and thus these structures have captivated synthetic chemists for years. However, until the turn of the century, most synthetic efforts relied upon the use of widely available terpenes, such as pinene or caryophyllene, that already contain the gem-dimethylcyclobutane motif. This approach limits the scope of molecules that can be accessed readily. This review highlights recent syntheses in which the gem-dimethylcyclobutane is assembled via de novo approaches. An outlook on the future of this research area is also provided.

Synthesis of ent-[3]-Ladderanol: Development and Application of Intramolecular Chirality Transfer [2+2] Cycloadditions of Allenic Ketones and Alkenes.

An enantioselective synthesis of ent-[3]-ladderanol is presented. The ladderanes are an interesting class of molecules for their unique structure of fused cyclobutane rings as well as their perceived biological function of organism protection. The route hinges on the development and application of a chirality transfer [2+2] cycloaddition of an allenic ketone and alkene. Further stereocontrolled transformations allowed for completion of the synthesis. The scope of the chirality transfer [2+2] cycloaddition is also presented.

Visible-light-mediated, nitrogen-centered radical amination of tertiary alkyl halides under metal-free conditions to form α-tertiary amines.

A mild and operationally convenient amino-functionalization of a range of tertiary alkyl halides by reaction with iminoiodinanes (PhI[double bond, length as m-dash]NNs) and I2 has been developed. According to the mechanistic experiments described within, the reaction is speculated to proceed through a light-promoted, N-centered radical pathway involving a N,N-diiodosulfonamide reactive species. This method of direct N-incorporation offers an attractive alternative to the production of α-tertiary amines, a synthetically challenging structural class found in a variety of bioactive molecules.