Protection (and deprotection) of functional groups in organic synthesis by heterogeneous catalysis

Abstract

Fine chemicals are complex and multifunctional molecules, often characterized by low volatility and limited thermal stability, whose manufacture generally is based on multistep synthesis performed in the liquid phase and frequently involving protectiondeprotection steps. The use of blocking functions in organic synthesis, developed for nearly 100 years, makes more complex the entire synthetic plan since it requires at least two additional steps. At the same time, environmental and economic considerations have created interest, in both academic and industrial research, in designing synthetic procedures that are clean, selective, high-yielding, and manipulatively easy. In fact, as clearly recognized by Sheldon, “...traditional concepts of process efficiency are changing from an exclusive focus on chemical yield to one that assigns economic value to eliminating waste...”. An extensive application of heterogeneous catalysis in synthetic chemistry can help to achieve new selective reactions, to lower the waste production, and, finally, to render more attractive the synthetic process from both the environmental and also the economic point of view, in agreement with some parameters of the “ideal synthesis” recently presented by Wender. Indeed, solid catalysts can be easily separated from the reaction products by simple filtration and quantitatively recovered in the active form. They can be recycled, making less expensive the preparation of sophisticated fine chemicals and, at the same time, avoiding contamination of the products by trace amounts of metals. The heterogeneous catalysis that was originally studied and applied in bulk chemistry with particular interest to petrochemical industry was more recently extended to synthetic organic chemistry for production of fine chemicals and pharmaceuticals.3 Among the first reactions performed under heterogeneous catalysis are the hydrogenations and, in general, the redox processes which are extensively applied in synthetic organic chemistry. Acid-base heterogeneous catalysis was successively developed by exploiting the physicochemical properties of zeolites, clays, and metal oxides. However, many of these materials present some limitations when large reactants are involved, especially in liquid-phase systems, as frequently occur in the synthesis of fine chemicals. Attempts to improve the diffusion of reactants to catalytically active sites have so far focused on increasing the catalyst pore sizes, such as in the mesoporous MCM7 and ITQ8 type materials. Finally, application of catalysts to manufacting technologies, such as grafting and tethering combined with special copolymerization procedures, originally addressed to materials chemistry, made accessible a large number of (chiral) organic catalysts as well as (chiral) metal complexes covalently bound to the surface of both organic and inorganic supports. These materials are excellent catalysts for organic synthesis since they combine the properties of a stable organic or inorganic backbone with the flexibility of the organic derivatives; moreover, they are also characterized by higher thermal stability in comparison with their homogeneous counterparts. The application of all these large families of solid catalysts in liquid-phase synthetic chemistry has attracted a lot of interest. They also form the basis of some new industrial processes which have been developed to replace traditional problematic synthetic methods. As a consequence of the extensive application of heterogeneous catalysis in synthetic organic chemistry, a large number of articles describing the advantages of performing protection-deprotection reactions over solid catalysts have been published. However, these studies examined only marginally some crucial aspects of the heterogeneous catalysis, such as the quantitative and correct evaluation of catalyst efficiency in terms of the turnover number (TON) and turnover frequency (TOF) values; it is more frequently evaluated through the product yield as a function of each cycle. Similarly, direct and quantitative determination of the amount of recovered catalyst and leaching phenomena were scarcely taken into consideration. On the other hand, these articles were focused on synthetic organic chemistry, and their major goal was to point out the advantages of performing protection-deprotection reactions over heterogeneous catalysis, quantified as yield, easy workup, and, in particular, selectivity when multifunctional compounds are utilized. Due to the great interest in protecting group chemistry, many books and reviews have been published on this topic. Moreover, updated reviews are published yearly by Kocieriski and Spivey, describing selected important applications. Several reviews have also touched on more specialized fields, such as enzymatic protecting group techniques and protecting groups in solid-phase organic synthesis. However, until now, a full collection of the applications of heterogeneous catalysis to protecting group chemistry, highlighting the advantages related to the easier workup of the reaction mixture and purification of products as well as the high level of selectivity frequently achieved, has not been published. In this review we describe the application of heterogeneous catalysis in protecting group chemistry, focusing mainly on that developed during the past decade. The various reactions and procedures reported within this review are sorted into categories based on the functional group, according to Kocien´ ski’s typical classification. Significant examples for every class of compounds are collected in Tables 2-28, accompanied by the reference, the number of examples reported in the paper, the yield range, and information on the catalyst reusability. To provide the reader with rapid and easy information about the large number of catalysts described in the review, Table 1 summarizes the name (and/or the abbreviation) of every catalyst, accompanied by a short description of its availability. Some of the catalysts are commercially available (CA), such as many clays, zeolites, and metal oxides. In some instances, due to their insufficient acidity, prolonged reaction times or a large quantity of them are usually necessary, and, consequently, they are often modified by treatment with Lewis acids or protic acids (SA) to increase their catalytic activity. Similar procedures can be utilized to prepare catalysts displaying special redox properties. Unfortunately, the majority of the more attractive catalysts, such as many metal phosphates, polyoxometalates, and catalysts immobilized on solid supports, are not commercially available and must be prepared by tricky methodologies. In some cases, the catalysts are prepared in situ (ISP) by mixing convenient reagents (i.e., Lewis or protic acids with metal oxides) with the reaction mixture. Even though, in these circumstances, there are still many doubts about the effective heterogeneity of the catalysts, we report the application since the authors showed that use of these combinations affords cleaner and more efficient synthetic procedures. Similarly, rather sophisticated and useful catalysts are represented by active molecules immobilized through covalent bonds on the surface of polymeric supports. In spite of the exciting results frequently obtained by applying these catalysts to various areas of organic synthesis, further detailed information is needed to achieve their optimum performance in reproducible experiments and to better understand the interaction of the reactants and solvent molecules with the surface of the catalyst.