General Synthesis of 3‐Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres**

Abstract

A general approach to 3‐azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties.

A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues

“…With a streamlined method to access 2-azabicyclo[3.2.0]­heptanes, we wanted to understand if these motifs could function as potential bioisosteres for other N-heterocycles commonly found in MedChem libraries. Typically, new bioisostere identification has taken a targeted approach, in which specific bond vectors of novel chemotypes are compared with the ones of few selected parent compounds. − We decided to utilize a different approach where the bicyclic cores were compared with a virtual database of >250 potentially interesting N-heterocycles with two vectors appended. , This strategy would allow an expansive area of chemical space to be efficiently surveyed, including unreported species. To map the chemical space to the goal of bioisostere identification, we decided to create a high-dimensional data set of relevant descriptors , where the chemical space could then be visualized and interpreted by a principal component analysis (PCA). , Such a data set would also offer the opportunity to apply unsupervised learning algorithms, to identify machine-guided relationship. − Therefore, we envisioned that applying methods such as the relatively straightforward k -Medoids clustering − would provide an unbiased insight into bioisostere identification.…”

Synthesis of Heterocycle-Substituted Bicyclo[3.1.1]heptanes and Aza-bicyclo[3.1.1]heptanes via Photocatalytic Minisci Reaction

“…BCHeps with ester-functionalized bridgehead positions can be readily prepared by double alkylation of cyclohexane 1,3-diesters with diiodomethane, and we questioned whether these convenient building blocks, which obviate the need for [3.1.1]­propellane, could be converted to RAEs ( 2 , Figure c) and then functionalized via the Sherwood–Minisci reaction ( 3 ). Here we report the realization of this goal, which increases the repertoire of strategies for the synthesis of BCHep-containing structures by introducing a new route toward heterocycle-functionalized BCHeps and aza-BCHeps …”

“…Here we report the realization of this goal, which increases the repertoire of strategies for the synthesis of BCHep-containing structures by introducing a new route toward heterocycle-functionalized BCHeps and aza-BCHeps. 12 …”

“…With heterocycles successfully introduced onto the carbocyclic BCHep bridgehead, we questioned whether aza-bicyclo[3.1.1]heptanes, which have recently emerged as potential bioisosteres for 3,5-disubstituted pyridines, 12 would also be compatible with this chemistry ( Figure 3 ). To our delight, the aza-BCHep RAE 6a underwent a successful Minisci reaction with several heterocycle acceptors, affording the corresponding bis-heterocyclic products 7a – 7c in good yields (a small amount of double addition was observed using 7c ).…”

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

“…Recently, the unusual and sterically constrained non-natural amino acid, seco -1-azacubane-2-carboxylic acid ( 1 ), was the focus of a comparative chemical analysis to the natural amino acid proline (e.g., comparing carbonyl-carbonyl interatomic distances and dihedral angles between 2 and 3 ) (Figure ). , Although structural similarities and differences were clearly identified, biological assessment was lacking, which could greatly assist in understanding whether 1 has potential to act as either a proline mimic, pyridine bioisostere, , general (bio)­motif, or amino acid scaffold.…”