Studies toward a library of tetrahydrofurans: Click and MCR products of mono- and bis-tetrahydrofurans

Abstract

Mono- and bis-tetrahydrofuran-based chemical libraries with diverse structural features have been prepared using the Sharpless azide-alkyne Click reaction and multi-component reactions (MCRs) such as Ugi and Biginelli reactions. Mono- and bis-tetrahydrofuran methyl azides, amines and ureas were key intermediates in these processes, and they were synthesized from the corresponding tetrahydrofuran methyl alcohols by mesylation followed by substitution with azide, reduction of the azide to the amine, and urea formation, as needed. Most mono- and tetrahydrofuran methyl alcohols were obtained by a Sharpless asymmetric dihydroxylation reaction. Alternatively, several mono-tetrahydrofurans were prepared by a cobalt(II) complex-catalyzed oxidative cyclization of bis-homoallylic alcohols, which were obtained by copper(I) iodide-catalyzed epoxide opening of 5,6-epoxyhex-1-ene with various alkyl and aryl Grignard reagents. These compounds are examples of an entirely new class of molecules in hitherto unknown chemical space, though their functions are yet to be determined presumably through random screening.

Introduction

Libraries of novel low molecular weight compounds with unique structural features and unknown properties have found a wide range of applications in ‘hit to lead’ screening and drug development programs. Hundreds of thousands of compounds are already available to screening centers in industry, and, more recently, in academia. Yet, new compounds with novel skeletons that could lead to new biological properties and expand the intellectual properties (IP) frontiers are always desirable. With this goal, we prepared a library of mono- and bis-tetrahydrofuran derivatives substituted with unusual fragments, such as I and II (Figure 1). These compounds, which can have as many as sixteen stereoisomers, feature a cyclic ether segment similar to the naturally occurring Annonaceous acetogenins,ⁱ such as solamin, 1, or asimicin, 2. The latter compounds are known for a wide range of biological activities, including anticancer properties. They are among the most powerful inhibitors of complex I (NADH/ubiquinone oxidoreductase) in the mitochondrial transport systems.^i,ii They also bind strongly to Ca^2+.iii The THF rings in these compounds are essential for high anticancer activities,^iv as well as complexation to Ca²⁺. Since intramitochondrial Ca²⁺ ions control both the rate of ATP production by oxidative phosphorylation and the induction of the mitochondrial permeability transition (MPT),^v both mono- and bis-THF compounds could modulate these processes.

Figure 1.

Mono-THF and bis-THF compounds based on the mono-THF and bis-THF acetogenins, solamin and asimicin, and their precursors. For the mono- and bis-THF diols 3 and 4: P = P′ = H, and for the mono-benzoate of compound 4: P = Bz and P′ = H.

We argued that the mono- and adjacent bis-THF acetogenins could be modified with unnatural side chains providing hybrid structures located in new chemical space. Such compounds could have functions that could be unknown and entirely different than a naturally occurring acetogenin, and could be determined using high-throughput screening (HTS). Thus, we focused on compounds having heterocyclic scaffolds that could be prepared readily using clickable processes, such as the Sharpless alkyne-azide Click reaction^vi and Ugi and Biginelli MCRs.^vii These reactions were previously found suitable for library synthesis. Before embarking on the synthesis of a large series of structurally and stereochemically diverse mono- and bis-THF compounds, we decided to carry out model studies by synthesizing a small library of THF compounds substituted with triazole, urea, dihydropyrimidine, and dipeptide fragments. These were prepared from several trans-mono-THF alcohols, and one each of the enantiomerically pure trans-mono-THF and cis,threo,cis-bis-THF diols (vide infra) by using the alkyne-azide coupling reaction and Ugi and Biginelli MCRs. In this communication, we describe the synthesis of both symmetrically and unsymmetrically disposed molecules as examples to highlight our initial studies.

Results and Discussion

As shown in Figure 1, a symmetrical mono-THF compound of the general structure Ia has three stereoisomers, two trans- and one cis-compound(s), analogous to the mono-THF diols 3, whereas a unsymmetrical mono-THF compound, Ib, has four stereoisomers, two trans- and two cis-compounds. Similarly, the symmetrical and unsymmetrical bis-THF derivatives IIa and IIb have ten and sixteen stereoisomeric structures, respectively. All of these target structures could be prepared using appropriately functionalized THF and bis-THF precursors. At first, we focused on the synthesis of the symmetrical mono- and bis-THF compounds Ia and IIa, substituted with triazole fragments. The latter were readily prepared by an azide-alkyne Click reaction, an easy and efficient way of increasing the diversity of a chemical library. This reaction is highly selective and takes place under mild conditions. It is orthogonal to most chemical and biochemical transformations, and therefore it has also found frequent applications in bio-conjugation.^viii We prepared trans-Ia and cis-threo-cis-IIa using the mono- and bis-THF diazides 5 and 6, respectively, and a series of alkynes (Figure 2). Thus, the diazides 5 and 6 were synthesized using the previously described mono- and bis-THF diols 3.1t and 4.3 in two steps,ⁱⁱ including mesylation of the diols using MsCl to give the dimesylates, followed by substitution with NaN₃. The reaction between the alkynes and azides was next conducted using CuSO₄•5H₂O and sodium ascorbate to give the mono- and bis-THF triazole hybrid molecules in unoptimized 15–85% yield.

Figure 2.

Synthesis of mono- and bis-THF triazole libraries via key bis-azides.

Next, we focused on the Ugi four-component MCR, which can afford a wide variety of compounds quickly in a single step from appropriately functionalized mono- or bis-THF amines (or aldehydes) and commercially available aldehydes (or amines), isocyanides and carboxylic acids. In this reaction, a protected dipeptide is formed through the initial formation of the imine intermediate by a reaction between an aldehyde and an amine, which is followed by a reaction with the isocyanide and the carboxylic acid. Presumably, MCR reactions could be conducted on both side chains of the THF rings in compounds 3 or 4 which would give symmetrical compounds; here, we focused on unsymmetrical compounds that could be obtained by performing these reactions on only one side chain of the molecules. While these two alternatives would increase the chemical space, we restricted our activity to unsymmetrical compounds since they are less complicated and obtained in higher yields than the symmetrical compounds. Thus, we carried out this process using a mono TBS-protected bis-THF-amino alcohol, 11, which was prepared from the bis-THF diol 4.3 via azide 10 (Figure 3). First, diol 4.3 was converted to azide 10 in three steps, including monoprotection of the diol using TBSCl, mesylation of the resulting mono TBS-protected bis-THF diol, followed by substitution of the mesylate using NaN₃, as used earlier for the conversion of 3.1t and 4.3 to 5 and 6. Subsequently, azide 10 was hydrogenated in the presence of 10% Pd/C to give amine 11 in 87% yield (crude) that was used in the Ugi reaction without further purification. As shown in Figure 1, amine 11 was reacted with tert-BuNC as the isonitrile component, and a series of aldehydes, 12, and carboxylic acids, 13, giving the Ugi products 14. TBS deprotection of compounds 14 afforded 15. In a typical reaction, aldehyde (1 eq.), acid (1 eq.) and tert-BuNC (1 eq.) were added sequentially to a solution of the amine 11 (1 eq) in methanol, and the reaction mixture was stirred at room temperature for 12–24 h. After completion of the reaction (monitored by TLC), the solvents were removed and work-up utilized water and EtOAC. Pure Ugi products, 14, were obtained after chromatography on SiO₂ in 23–54% yield. The TBS group in these compounds was deprotected using 60% AcOH in a 1:1 mixture of THF/water, giving the TBS-free Ugi products 15 in 35–93% yield (unoptimized). As shown in Figure 3, the diversity of the bis-THF library could be easily increased by using a wide array of isonitriles, aldehydes and acids, thereby enhancing the probability of a hit in the biological screens.

Figure 3.

Synthesis of Ugi products using bis-THF diol 4.3 via bis-THF amine 11.

For the THF-based Biginelli MCR products, we prepared urea derivatives using a series of readily available mono-THF amines 20, which were synthesized starting with 1,2-epoxyhexene via the bishomoallylic alcohols 16 and mono-THF alcohols 17 (Figure 4A). Thus, bis-homoallylic alcohols 16a–16d were readily obtained by the CuI-catalyzed opening of the epoxide using an appropriate alkyl- or arylmagnesium bromide, including n-nonyl-, 3-phenylpropyl-, 4-methoxyphenyl-, 1,4-biphenyl-, and 6-methoxy-2-naphthylmagnesium bromide, respectively, and converted to the mono-THF alcohols 17a–17d utilizing the Co(modp)₂-catalyzed oxidative cyclization (Co-OC) reaction.^ix We used alcohols 17c and 17d in subsequent reactions and converted them to amines 20c and 20d in three steps: the primary hydroxyl functions in 17c and 17d were mesylated, the resulting mesylate products 18c and 18d were reacted with NaN₃ to give azides 19c and 19d, and the latter products were hydrogenated in the presence of Pd-C to give the desired amines in 71% and 62%, respectively.

Figure 4.

Synthesis of the (A) mono-THF methylamines via Co(modp)₂-catalyzed oxidative cyclization (Co-OC) reaction, (B) urea derivatives for the Biginelli’s reaction, and (C) cyclic urea derivatives using the Biginelli reaction.

Amine 20c was reacted with several alkyl- or aryl isocyanates, such as n-octadecyl-, 4-phenylbutyl-,4-methoxy-phenyl-, and 4-bromophenyl-isocyanate, giving the unsymmetrical urea derivatives 21.2–21.5, respectively (Figure 4B). Both amines 20c and 20d were reacted with potassium isocyanate to produce compounds 21.1 and 21.6 in 34% and 41% yield (unoptimized), respectively, and these derivatives were used for the synthesis of numerous Biginelli products. All urea compounds were obtained as colorless solids after washing the crude products multiple times with CH₂Cl₂, and the yields refer to the solid materials.

In the Biginelli reaction,^x a β-keto ester and an aldehyde react with an urea to give the corresponding 3,4-dihydropyrimidin-2(1H)-one derivatives. Thus, compounds 21.1 and 21.6 were reacted with ethyl acetoacetate and a series of aldehydes under acidic conditions, affording the cyclic urea derivatives 22 (Figure 4C). Of course, all compounds were obtained as a mixture of the diastereomeric products at the newly-generated stereogenic center.

The azide-alkyne Click reaction and the Ugi and Biginelli MCRs offer rapid access to libraries of non-natural compounds that are highly complex and otherwise inaccessible or difficult to synthesize. While the azide-alkyne Click reaction provides the triazole derivatives in high yield, Ugi and Biginelli MCRs provide access to compounds that have higher orders of complexity. Here, by using mono- and bis-THF rings, as well as both symmetrical and unsymmetrical intermediates, as the next set of starting materials, one can increase not only the number of new chemical libraries, but also their complexities and overall shape, simply by changing the relative stereochemistry of the THF rings. For one set of compounds, there can be four sets of stereoisomeric products in a mono-THF library, and as many as sixteen sets for a bis-THF library.^xi Because the mono-THF and bis-THF compounds, as well as some nitrogen analogs and higher-order THF rings, can be readily obtained starting with the all-carbon skeletons, and using numerous oxidative processes, including the Re(VII),^xii Co(II), Os(VIII),^xiii and Ru(VIII)^xiv oxide-mediated/catalyzed OC reactions, this approach offers opportunities for the design and synthesis of an unprecedented set of non-natural compounds by the combination with Click and MCR reactions. Presumably, the THF-based chemical space can be further increased by introducing additional substitution on the THF rings and adding new synthetic transformations. Such isomeric compound libraries can demonstrate novel biological properties, which can be determined through high-throughput screening (HTS).

Conclusions

An efficient synthetic approach was developed for the construction of a new class of tetrahydrofuran-based hybrid molecules using the Sharpless azide-alkyne Click reaction and the Ugi and Biginelli MCRs as key transformations. Numerous mono- and bis- tetrahydrofuran triazoles, peptides, and acyclic and cyclic urea derivatives with diverse structural features were prepared in fair to good yields from the readily available mono- and bis-tetrahydrofuranyl azides and amines. Selected compounds have been submitted for evaluation under the MLSCN/MLPCN programs.^xv