C−H Insertion as a Key Step to Spiro‐Oxetanes, Scaffolds for Drug Discovery

Abstract

Abstract:A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro [3,5]nonane scaffold into a range of functionalized derivatives.Modern drug discovery programs drive an appetite for new, low molecular weight bioactive molecules. In support of the wellestablished drug discovery process, strategies such as diversity-oriented synthesis (DOS), lead-oriented synthesis (LOS), biologyoriented synthesis (BOS), and fragment based drug discovery (FBDD) have recently emerged as tools to accelerate the search for new drug candidates.[1] Nevertheless, access to compounds with desirable properties by chemical synthesis remains challenging. For example, the power of transition metal-catalyzed sp 2 -sp 2 cross coupling reactions has inadvertently led to large numbers of (hetero)aromatic-rich fragments, despite evidence that such compounds are susceptible to attrition in the later stages of drug development due to inappropriate physicochemical properties.[2] As a result, there is now a desire to develop robust synthetic methods that will provide ready access to diverse collections of lead-like, sp 3 -atom rich, low molecular weight and often densely functionalized molecules, ideally creating molecular complexity from simple starting materials in a few steps.One contemporary initiative, the European Lead Factory (ELF), [3] was established with the precise goal of identifying compound libraries that fulfil the above criteria. As part of our work under the ELF programme, [4] we were intrigued by the recent interest in spirooxetanes, [5] and identified the little known 1-oxa-7-azaspiro[3,5]nonane ring system (Figure 1) as an ideal scaffold for drug discovery.Spirocycles incorporating a small ring, such as an oxetane, have relatively rigid structures, and can be densely functionalized, with the substituent vectors clearly defined in their three-dimensional arrangement. Evidence that the 1-oxa-7-azaspiro[3,5]nonane scaffold does indeed allow access to lead-like properties came from analysis of a virtual library generated using the open access LLAMA tool (see Supporting Information for details).[ 6] When one functionalization was considered, 42% of the molecules in the virtual library fell within lead-like space (MW < 350, logP < 3) ( Figure S1), and all were compliant to Lipinski's 'rule of five'. In addition, current medicinal chemistry space is well populated with "disc-like" molecules. In contrast, the spiro-oxetanes occupy the "rod-like" area of molecular space (see Figure S2). Since the original report highlighting the potential of oxetanes in medicinal chemistry, [7] this small ring system has attracted considerable attention, not only due to its low steric bul...

Densely functionalised spirocyclic oxetane-piperidine scaffolds for drug discovery

“…In particular, spirocyclic oxetanes (Figure 2) represent an interesting alternative scaffold due to their intrinsic high degree of three-dimensional character, rigidity and well defined vectors. [7][8][9][10][11] Figure 2: Recent examples of spirocyclic oxetane scaffolds.…”

“…Oxetanes can be prepared using a variety of methods including the intramolecular Williamson ether synthesis, 10,12,13 the Paterno-Buchi reaction, 14 intramolecular alkylation, 15 or by gold catalysed rearrangement of propargylic alcohols. 16 In keeping with our aim to prepare sp 3 -atom rich scaffolds for drug discovery, as part of the European Lead Factory project, 10,[17][18][19] we identified the spirocyclic oxetane scaffold 5 for inclusion in the Joint European Compound Library (Figure 3).…”

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…Common methodologies for assembling spirocyclic scaffolds are mainly relaying on intramolecular S N 2 alkylation [9–19] and N‐acylation, [11,20,21] ring closing metathesis [20,22–24] of the appropriate precursors. Additionally, metal‐catalyzed [25–28] and hypervalent iodine mediated [29] dearmoatization reactions, Prins reaction [30–32] and cycloaddition reactions [23,33–35] should be mentioned.…”

Iridium-catalysed C–H borylation of β-aryl-aminopropionic acids

“…The innovative work of Hartwig and Miyaura, 15 and Smith and Maleczka 16 in iridium-catalysed aromatic C-H borylation offers a potentially powerful method for functionalisation given that the synthetic versatility of boronate groups is ever increasing. [17][18][19] Encouraged by previous examples of C-H borylation on simple phenylalanine 20 and tryptophan 21 derivatives we now report the substrate directed iridium borylation of β-3-aryl-aminopropionic acid precursors together with examples of "onepot" transformations to diversely functionalised 3,5-substi-tuted products and implementation of this methodology in the preparation of an integrin antagonist bearing a β-3,5-arylaminopropionic acid motif.…”