Review pubs.acs.org/CR
Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities Erick M. Carreira*,† and Thomas C. Fessard*,†,‡ †
Laboratorium für Organische Chemie, and ‡SpiroChem AG, ETH-Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland 4.3. Spiro[3.5]nonane Ring Systems 4.3.1. Oxetane−Tetrahydropyran Systems 4.3.2. Oxetane−Tetrahydrothiopyran Systems 4.3.3. Oxetane−Piperidine Systems 4.3.4. Oxetane−Cyclohexane Systems 4.3.5. Thietane−Tetrahydropyran Systems 4.3.6. Thietane−Tetrahydrothiopyran Systems 4.3.7. Thietane−Piperidine Systems 4.3.8. Thietane−Cyclohexane Systems 4.3.9. Azetidine−Tetrahydropyran Systems 4.3.10. Azetidine−Tetrahydrothiopyran Systems 4.3.11. Azetidine−Piperidine Systems 4.3.12. Azetidine−Cyclohexane Systems 4.3.13. Cyclobutane−Tetrahydropyran Systems 4.3.14. Cyclobutane−Tetrahydrothiopyran Systems 4.3.15. Cyclobutane−Piperidine Systems 4.4. Spiro[3.n]alkane Ring Systems with n = 3, 4, 5 4.4.1. Spiro[3.3]heptane 4.4.2. Spiro[3.4]octane 4.4.3. Spiro[3.5]nonane 4.5. Other Spiro[3.5]nonanes 4.5.1. 5,8-Dioxaspiro[3.5]nonane 4.5.2. 5-Oxa-8-azaspiro[3.5]nonane 4.5.3. 5-Oxa-2,8-diazaspiro[3.5]nonane 4.5.4. 2,5-Dioxa-8-azaspiro[3.5]nonane 4.5.5. 5-Thia-8-azaspiro[3.5]nonane 4.5.6. 2-Oxa-5-thia-8-azaspiro[3.5]nonane 4.5.7. 8-Oxa-5-azaspiro[3.5]nonane 4.5.8. 2,5,8-Triazaspiro[3.5]nonane 4.5.9. 5,8-Diazaspiro[3.5]nonane 5. Current Chemical Space of Spirocyclic Systems and the Eldorado of Unexplored Classes 5.1. Why Spirocycles? 6. Conclusion Author Information Corresponding Authors Notes Biographies References
CONTENTS 1. Introduction 2. Methodology for Data Mining 2.1. Applied Filters for the Selection of Examples 2.2. Scope 3. General Methods for the Formation of Small Rings 4. Synthetic Strategies toward the Synthesis of Spiro[3.n]alkanes 4.1. Spiro[3.3]heptane Ring Systems 4.1.1. Oxetane−Oxetane Systems 4.1.2. Oxetane−Thietane Systems 4.1.3. Oxetane−Azetidine Systems 4.1.4. Oxetane−Cyclobutane Systems 4.1.5. Thietane−Thietane Systems 4.1.6. Thietane−Azetidine Systems 4.1.7. Thietane−Cyclobutane Systems 4.1.8. Azetidine−Azetidine Systems 4.1.9. Azetidine−Cyclobutane Systems 4.2. Spiro[3.4]octane Ring Systems 4.2.1. Oxetane−Tetrahydrofuran Systems 4.2.2. Oxetane−Tetrahydrothiophene Systems 4.2.3. Oxetane−Pyrrolidine Systems 4.2.4. Oxetane−Cyclopentane Systems 4.2.5. Thietane−Tetrahydrofuran Systems 4.2.6. Thietane−Tetrahydrothiophene Systems 4.2.7. Thietane−Pyrrolidine Systems 4.2.8. Thietane−Cyclopentane Systems 4.2.9. Azetidine−Tetrahydrofuran 4.2.10. Azetidine−Tetrahydrothiophene 4.2.11. Azetidine−Pyrrolidine Systems 4.2.12. Azetidine−Cyclopentane Systems 4.2.13. Cyclobutane−Tetrahydrofuran Systems 4.2.14. Cyclobutane−Tetrahydrothiophene Systems 4.2.15. Cyclobutane−Pyrrolidine Systems
© 2014 American Chemical Society
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8285 Special Issue: 2014 Small Heterocycles in Synthesis
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Received: March 3, 2014 Published: July 8, 2014 8257
dx.doi.org/10.1021/cr500127b | Chem. Rev. 2014, 114, 8257−8322
Chemical Reviews
Review
1. INTRODUCTION Four-membered rings are witnessing significant prominence in medicinal chemistry discovery programs. For example, a search of the chemical databases shows exponential increase in their representation, which is found principally in the patent literature as a consequence of the stakeholders involved. The various reports that have documented the benefits accompanying their use in discovery candidates are driving the increased visibility. The range of advantages includes structural novelty along with improved physicochemical and pharmaco-kinetic properties. This has led the scientific community to redesign, improve, or invent strategies for their synthesis, and tactics enabling their incorporation into complex structures. A particular class of structures that is of interest to discovery chemists at present is the spirocyclic modules incorporating a four-membered ring. The advantages of these in particular are clear, as they constitute poorly explored regions of chemical space. Their use affords opportunities for the design of new classes of lead candidates that do not impinge on, infringe, or overlap with the dense regions of intellectual property space that have been intensively populated over the last 5 decades. The crowded structural space that has been mined in the context of work emanating from medicinal chemistry programs relies on a widely used portfolio of fragments, including heterocycles, hetarenes, and arenes. It has been pointed out that the impressive advances of modern medicinal chemistry in the last few decades have been fueled by parallel developments in synthetic chemistry and proteomics, in which metal-mediated coupling reactions hand-in-hand with molecular docking have driven the science. However, with the generalization of screening libraries and database tools, pharmaceutical scientists currently face the challenge of identifying and developing new molecules that may include the same toolbox as their colleagues and competitors, thereby limiting the opportunities for creating truly new entities. The identification of novel building blocks, such as spirocyclic modules, opens new avenues, especially when the search for new structures is intimately coupled to assessment of the attendant molecular properties. The new chemical space generated opens new vistas by offering an expanded toolbox to improve, alter, and modulate physicochemical properties, such as the lipophilicity, the acidity or basicity of embedded groups, aqueous solubility, and stability against metabolic degradation. The use of spirocycles furnishes access to denser, more rigid substructures, especially when these incorporate small rings, such as cyclobutanes, oxetanes, azetidines, and thietanes. This engenders new sets of scaffolds wherein the attendant exit vectors are rigorously well-defined in their spatial disposition. Comparison of these with the structures that have been at the center of drug discovery over the last three decades reveals some interesting contrasts. The typical aromatic or heteroaromatic structures from the traditional “flatland” of chemical space require linking of several modules to fully address the third dimension.1 By contrast, the nature of a spirocycle is such that the exit vectors of a single spirocycle populate the third dimension (Figure 1). This results in a vastly expanded set of accessible vectorizations. When combined with other strategies, such as timed or targeted delivery, the scientist can employ a larger range of pharmacopeia’s multidimensional opportunities.
Figure 1. Schematic comparison of a simple biaryl and spiro[3.4]octane.
2. METHODOLOGY FOR DATA MINING This Review aims to provide an up-to-date survey of spirocyclic structures with at least one four-membered ring. A broad search for reported spirocyclic structures in spiro[3.3]-, spiro[3.4]-, and spiro[3.5]-alkane classes produces results that exceed 2 million.2 The structures are equally divided in each of the three categories illustrated in Table 1. However, this entry-level Table 1. Number of Spirocyclic Structures [3.n] Having a CAS Numbera
a
●: Any atom except H.
literature research is naı̈ve as it includes a number of species, such as, among others, organometallic complexes, which are not obviously relevant to drug or agrochemicals discovery. Consequently, it is not representative of the true extent of structures that would be deemed actionable. It is primarily in medicinal chemistry literature (scientific articles and patents) that the synthesis and use of spirocyclic structures have been described and are witnessing exponential growth in their use. Spirocyclic building blocks have been utilized in two very different modes, as an integral part of fundamental scaffolding or as peripheral add-on fragments. Accordingly, we have opted to introduce a number of filters to limit the scope of this Review to molecules that are relevant, which include only fourmembered ring-containing spiro(carbo- and hetero)cycles. 2.1. Applied Filters for the Selection of Examples
A spirocyclic structure is defined as an assembly of heavy atoms composed of at least two rings in which these are linked by only one heavy atom belonging to both rings. In gathering the structural data that form the basis of this Review, the following filters were implemented in the literature searches: 8258
dx.doi.org/10.1021/cr500127b | Chem. Rev. 2014, 114, 8257−8322
Chemical Reviews
Review
Figure 2. Incidence of spirocyclic structures in the literature over a period of 50 years (1964−2013). Legend: blue ■, total number of references (scientific articles and patents); red ◆, patents only; ●, any atom except H; ×, any atom except C or H. Filter: MW of molecules
