Expedient Synthesis of Norbenzomorphan Library via Multicomponent Assembly Process Coupled with Ring-Closing Reactions

Abstract

A 124 member norbenzomorphan library has been prepared utilizing a novel multicomponent assembly process (MCAP) followed by a variety of ring-closing reactions to generate norbenzomorphan scaffolds that were readily derivatized via a series of aryl halide cross-coupling and nitrogen functionalization reactions. Biological screening has revealed some novel activities that have not been previously associated with this class of compounds.

Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification

“…31,32 A straightforward modification of this methodology using dihalo aldehydes 88 and 89 83 as inputs together with allylamine, benzyl chloroformate, and allylzinc bromide afforded the dienes 90 and 91 , respectively (Scheme 13). 84,85 Cyclizations of these compounds via RCM to give the corresponding tetrahydropyridines 92 and 93 were induced using Grubbs II catalyst.…”

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

“…Similarly, peptide isosteres such as the angiotensin receptor 1 antagonists, the sartans, or the HIV protease inhibitors (the vast majority of which are isosteres of the natural hexapeptide substrate) are not revealed in such analyses. The recent paper by Sahn and Martin, 5 however, demonstrates what can be done if like Nicolaou (see Section 21.3), one starts with a known series of bioactive agents, in this particular case, the morphine alkaloids, which are now known to be peptide isosteres of the endorphins, the endogenous substrates for the opioid receptors in man. By taking the base tricyclic structure of the benzomorphan and removing one carbon in the central ring system, a 6.5.6 tricyclic motif with one nitrogen atom was generated (the norbenzomorphans; see Figure 21 By utilizing as the starting materials, substituted benzaldehydes, a 124-member library was constructed that is currently being tested in a variety of biological screens, with current activities ranging from identification of an inhibitor of the topoisomerase I of Yersinia pestis to an antagonist of the human M 1 muscarinic receptor.…”

Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype‐Selective Ligands

“…In a series of investigations directed toward discovering biologically active small molecules, we developed a general platform for the rapid synthesis of small collections of functionalized heterocyclic scaffolds that can be further diversified by cross-coupling reactions and refunctionalizations [1,2]. One class of heterocycles that piqued our interest is the substituted norbenzomorphan ring system (Fig.…”

“…One class of heterocycles that piqued our interest is the substituted norbenzomorphan ring system (Fig. 1, red highlight in 1 – 4 ) [2], which has drug-like features, including low molecular weight and conformational rigidity [3,4]. Investigational compounds embodying this framework include 1 , which induces antinociception in an animal pain model [5] and 2 , which inhibits acetylcholinesterase in vivo [6].…”

“…Screening novel norbenzomorphans prepared in our lab led to the discovery of hit compounds with potentially useful medicinal properties. For example, amide 3 is an inhibitor of striatal-enriched protein tyrosine phosphatase (STEP) [2b], an enzyme that is overactive in Alzheimer’s disease (AD) [7], whereas benzylamine 4 is an antagonist of dopamine-3 [8], a target currently being evaluated for treating addiction [9]. …”