Regio- and stereoselective synthesis of new diaminocyclopentanols

Summary The optimal conditions for regio- and stereoselective epoxide ring opening of N,N-disubstituted 1,2-epoxy-3-aminocyclopentanes by different nucleophilic reagents have been developed. The substituents on the nitrogen atom in the epoxide precursor and the orientation of the oxirane ring are crucial for the reaction outcome. Thus, treatment of (1RS,2SR,3SR)-1,2-epoxy-3-(N,N-dibenzylamino)cyclopentane (3b) with amines gave a mixture of C1 and C2 regioadducts, while the use of (1RS,2SR,3SR)-1,2-epoxy-3-(N-benzyl-N-methylamino)cyclopentane (3a) led ultimately to C1 adducts. Base-catalyzed aminolysis of epoxides 6a,b afforded mainly C1 adducts 13a,b arising from trans-diaxal opening of the epoxide ring. Using a Lewis acid catalyst, epoxides 6a,b were transformed into diaminocyclopentanols 14a,b via an alternative pathway involving the formation of aziridinium intermediate 17.


Introduction
In recent years mimicry of aminoglycosides [1][2][3][4][5][6][7] and nucleosides [8][9][10] has become an important field in pharmaceutical research. Regio-and stereochemical diversities within a sugarlike moiety in those mimics may subtly influence their biological activity [11][12][13][14]. The functionalization of synthetic, unnatural aminocyclitols represents an attractive strategy towards the preparation of aminoglycoside and nucleoside mimics, and the development of common synthesis routes to various regio-and stereoisomeric aminocyclitol derivatives remains in demand. One of the optimal routes involves the stereoselective ring opening of epoxides by different nucleophiles in the presence of a variety of activators [15][16][17][18][19]. In this context, epoxidation of cyclic allylic amines and subsequent oxirane ring opening represent a viable approach for the development of new pharmaceutically relevant scaffolds.
As a part of our ongoing research in the development of new aminocyclitols, we exploited cyclopentane derivatives to mimic both the 2-deoxystreptamine ring, a core component in aminoglycosides [7], and nucleosides containing 9H-purin-6-amine as Scheme 1: Preparation of the starting materials. a nucleobase portion. High levels of stereoselectivity have been observed in substrate-controlled diastereoselective epoxidation of cyclic alkenes with Oand N-allylic directing groups [20,21]. Several 3-substituted diastereomeric epoxides have recently been synthesized via the ammonium-directed olefinic oxidation of cyclic allylic amines. It has been reported that functionalization of a range of allylic 3-(N,N-dibenzylamino)cycloalkenes with m-CPBA in the presence of trichloroacetic acid gave exclusively corresponding syn-epoxides [22]. Examples of stereoselective epoxide opening of these cyclic amine derivatives are limited to the preparation of the corresponding diols under acidic conditions [23]. Other reported strategies involve the formation of diaminocyclohexanols from epoxides under basic conditions [24] or by activating the epoxides with hydrogen bond donors [25]. Additionally, the synthesis of aminocyclitols from cyclitol epoxides has been described [26,27]. It has been shown that the reaction of cyclitol epoxides with nitrogen-containing nucleophiles in the presence of Lewis acids gave a mixture of C1 and C2 adducts. Both epoxide carbons can react with a nucleophile to produce regioisomeric aminocyclitols. Herein, we describe the regio-and stereoselective synthesis of diaminocyclopentanol derivatives from N-protected cyclopentanamine epoxides using nitrogencontaining nucleophiles.
The treatment of the corresponding acetates 4 with mesyl chloride and subsequent transesterification of mesylated substrates 5 resulted in the formation of 6a,b. Epoxides 3 and 6 were identi-fied by 1 H NMR data [28]. Morpholine (7a), 2-methyl-1Himidazole (7b), N-acetylpiperazine (7c) and 9H-purin-6-amine (7d) were used as nucleophiles ( Figure 1). Starting amines were selected based on the fact that these motifs are common structural features in drug molecules. Optimization of the epoxide ring opening reaction of 3a The opening of epoxides with nucleophiles in the presence of Lewis acid or base promoters is well documented [30][31][32][33][34]. We conducted a number of experiments to optimize the ring opening in 3a ( Table 1). The initial catalytic epoxide ringopening experiments of 3a in MeCN at 80 °C [35] were unsuccessful, since only starting material was recovered. A series of experiments was performed under solvent-free conditions at 100 °C. In case of morpholine (7a), the best catalytic effect was observed with LiClO 4 [36] and Zn(ClO 4 ) 2 ·6H 2 O [37] affording 56 and 76% yield of 8a after isolation and purification, therefore the absence of the solvent seems crucial for the reaction outcome (Table 1, entries 2 and 3).
In every experiment, 1,2-trans-2,3-cis-aminocyclopentanols, arising from opening of epoxide 3a at C1, were the only regioisomers isolated. The stereo-and regiochemistry of 8a and 8d were assigned by 2D NMR (HSQC-DEPT, 1  . Therefore, spectral data obtained for the compounds 8a-d are consistent with the acidcatalyzed trans-diaxial epoxide opening, proceeding via a latetransition state, and the N-benzyl-N-methylammonium moiety promotes the nucleophilic attack at the C1-oxirane carbon atom [29].

Synthesis of diaminocyclopentanols using epoxide 3b
Next, we explored the influence of the N,N-dibenzylamino group on the ring opening reaction using the optimized reaction conditions for 3b (Table 2). Surprisingly, the ring opening of N,N-dibenzyl derivative 4b displayed poor regioselectivity. In fact, a mixture of the separable regioisomers 9a-d and 10a-d were obtained, where the major products 9a-d were formed due to the attack of the nucleophile at the C1-oxirane carbon atom.
In case of aliphatic cyclic amines (morpholine (7a) and N-acetylpiperazine (7c)), the best regioisomeric ratio (2:1) was observed using Zn(ClO 4 ) 2 ·6H 2 O as a catalyst ( Table 2, entries 1 and 5). The use of LiClO 4 led to lower regioselectivity ( Table 2, entries 2 and 6). Apparently, the nature of the catalyst and the ability of the metal ion to coordinate with the oxirane oxygen have no significant influence on the regioisomeric ratio (rr). The reactions of 3b with 2-methyl-1H-imidazole (7b) and 9H-purin-6-amine (7d) in the presence of Cs 2 CO 3 in DMSO showed the same regioselectivity (Table 2, entries 4 and 7), indicating that the epoxide opening reactions are not directed by the amine nucleophilicity. Moreover, there was not much effect on the outcome of the reactions conducted either under solvent-free conditions or using DMSO as a solvent.
The regioisomers 9a-d and 10a-d were isolated through column chromatographic separation and fully characterized in order to avoid ambiguity. The stereochemistry of the major regioisomers 9a-d was deduced from the analysis of 1 H NMR and 2D NMR data as described for 8a-d. Assignments of CH proton resonances of 10a-d were established by 1 H, 13  In order to investigate the influence of different substituents on the nitrogen atom on the regioselective outcome, epoxides 3c and 3d were additionally synthesized, and the results are summarized in Table 3.
It has been proposed earlier that the coordination of the Lewis acid to both oxygen atoms in 2,3-epoxy alcohols and acids leads to the formation of the intermediate complex, for which nucleophiles attack preferably the C3 position [42,43]. The electron donating methyl group in 3a seems to improve the binding of the Lewis acid to the nitrogen atom, favoring the formation of the C1-adduct, and the lower basicity of the dibenzylamino moiety in 3b may lead to the diminished coordination of Lewis acid and hence the lower regioselectivity (Table 3, entries 1 and 2). Unexpectedly, using 3c, with an electron withdrawing phenyl group on the nitrogen atom, provided higher regioselectivity towards the C1-adduct (rr 5:1) in comparison with 3b (Table 3, entries 2 and 3). The structure of the major regioisomer 11 was established by the analysis of 1 H NMR and 1 H, 1 H COSY data (Supporting Information File 2). This fact can be explained by the suggestion that despite the induced binding of the Lewis acid to the nitrogen atom due to the negative inductive effect of the phenyl substituent, the intermediate complex is likely to be stabilized by the π electrons of the phenyl ring, which leads to the formation of 11 as a major product. However, the presence of electron withdrawing substituents on the nitrogen atom and, as a result, the diminished coordination of the Lewis acid required the longer reaction time (6 h), while in case of 3d bearing two phenyl groups no epoxide ring opening was observed (Table 3, entries 3 and 4).

Ring opening reactions for epoxides 6a,b
Ring opening of epoxides 6a,b was investigated by the reaction with 9H-purin-6-amine (7d) and morpholine (7a) as the nucleophiles under the above conditions ( Table 4). As it was expected, single regioisomers 13a,b with 1,2-anti-2,3-anti-configuration (Table 4, Table 4. The presence of C(2)H-C(5)H and C(1)H-NCH 3 NOEs were supportive of the assigned configuration of 13a (Supporting Information File 2). The ring opening reaction of epoxide 6b with 9H-purin-6-amine (7d) in the presence of Cs 2 CO 3 ( Table 4, entry 2) showed the higher level of regioselectivity in comparison with the regioselective outcome for epoxide 3b ( Table 2,  A bulky N,N-disubstituted amino group is prone to adopt a pseudoequatorial orientation. In basic conditions, the nucleophile (9H-purin-6-amine (7d)) attacks the oxirane carbon atom from the side of the carbocyclic ring where the N,N-disubstituted amino group is located, and this precludes the approach of the nucleophile to the C2 carbon atom because of sterical hindrance. Thus, C1 of 6a,b is the favoured site for the nucleophilic attack, which gives rise to the formation of products 13a,b with essentially complete regioselectivity (Table 4, entries 1 and 2). Surprisingly, aminolysis of substrates 6a,b under Lewis acid-catalyzed conditions resulted mostly in the formation of regioisomers 14a,b (Table 4, entries 3 and 4), while the target isomer 15 was obtained only from epoxide 6b, as the minor product in 6% yield (Table 4,  to C2 would be more favorable than that of the nucleophile (morpholine) to either oxirane carbon atoms. Therefore, the nucleophilic attack is subsequent to the formation of the aziridinium ring, which is consistent with our experimental results.

Conclusion
In summary, we have optimized the reaction conditions of epoxide ring opening of epoxides 3a,b and 6a,b with a variety of amines to give the corresponding diaminocyclopentanols in good yields. It has been shown that using Zn(ClO 4 ) 2 ·6H 2 O under solvent-free conditions and Cs 2 CO 3 in DMSO is preferable to the ring opening of di-N-protected cyclopentanamine epoxides. We have highlighted the influence of the nature of the N,N-disubstituted amino moiety and the orientation of the oxirane ring on the stereo-and regioselective outcomes. Aminolysis of epoxides 3a,b is mainly dictated by electronic bias to afford the corresponding C1 adducts for 3a and the mixture of C1 and C2 adducts in the ratio 2:1 for 3b. The treatment of epoxides 6a,b with 9H-purin-6-amine (7d) under basecatalyzed conditions gives C1 adducts as the sole products. Thus, the nucleophilic attack of the amine towards the C2 oxirane carbon atom can be controlled by steric constraints, and it is obvious that the bulky N,N-dibenzylamino moiety of epoxide 6b impedes the formation of the corresponding C2 adduct due to the steric hindrance. Application of Lewis acid as a catalyst for the ring opening reactions of 6a,b provides an alternative mechanism that involves the formation of aziridinium intermediate 17.
As a result, regioisomers 14a,b were obtained as the major products.

Supporting Information
Supporting Information File 1 Experimental and characterization data.

Supporting Information File 2
Copies of 1 H and 13 C NMR spectra.