Efficient synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol

Cyclooctene endoperoxide was used as the key compound for the synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol. Reduction of the cyclooctene endoperoxide, prepared by photooxygenation of cis,cis-1,3-cyclooctadiene, with zinc gave a cyclooctenediol and then benzylation of the hydroxy group yielded dibenzylated cyclooctene. Oxidation of the latter compound by OsO4/NMO followed by mesylation of the hydroxy group provided bis(benzyloxy)cyclooctane-1,2-diyl dimethanesulfonate. Reaction of the bis(benzyloxy)cyclooctane-1,2-diyl dimethanesulfonate with NaN3 gave 2-azido-3,8-bis(benzyloxy)cyclooctyl methanesulfonate. Reduction of the azide group and debenzylation to give an amine provided the new 3-aminocyclooctanetriol. Treatment of the 2-azido-3,8-bis(benzyloxy)cyclooctyl methanesulfonate with Zn/NH4Cl and debenzylation resulted in the target aziridinecyclooctanediol.


Introduction
Aziridines are the smallest nitrogen-containing heterocycles and they are important building blocks in the synthesis as well as substructures of a number of biologically active natural and unnatural products [1][2][3][4][5][6][7][8]. Aziridines are valuable synthetic intermediates for the preparation of structurally complex molecules because of their versatility in numerous regio-and stereoselective ring opening and/or expansion reactions, as well as rearrangements [5]. The aziridine structural motif is present in natural products such as mitomycins and azinomycins ( Figure 1) [1,5], which exhibit potent biological activities such as antitumor and antibiotic activities.
Therefore, synthetic methodologies for the preparation of the aziridinyl system have attracted attention in recent decades. Opening of the aziridine ring by using different nucleophiles gives the corresponding amino alcohols, amino esters, azido amines, amines, and other derivatives [9]. Furthermore, aziridine derivatives are valuable precursors for the synthesis of aminocyclitols, which can be found in nature in several families of natural and clinically important antibiotics [10].

Results and Discussion
The synthesis of the diol 5, which was prepared by reduction of the endoperoxide 4 with zinc was carried out as described in the literature [18]. Treatment of the diol 5 with benzyl bromide and NaH in DMF gave the corresponding (dibenzyloxy)cyclooctene 6 in 70% yield (Scheme 1). Oxidation of the dibenzylated compound 6 with OsO 4 /NMO provided the corresponding diol 7 in 90% yield. The exact configuration of 7 was confirmed by 1 H and 2D NMR spectroscopic data. Next, mesylation of the hydroxy groups in 7 with MsCl in pyridine yielded Scheme 2: Synthesis of aminocyclooctanetriol 13. dimesylate 8 in 90% yield. Thus, the dimesylate 8, which is one of the most relevant precursors for the synthesis of aminocyclitols, was synthesized from the diol 7. The structure of compound 8 was assigned on the basis of NMR spectroscopy. In the 1 H NMR spectrum, we observed that methyl signals of the mesylate groups in 8 gave a multiplet, although compound 8 is symmetrical. To determine the existence of a dynamic process in the molecule 8, the NMR spectra of 8 were recorded at different temperatures. With an increase in the temperature, only one signal for the mesylate groups was observed in the spectrum. This difference is due to the occurrence of dynamic balance when the system is heated.
A general and versatile method for the synthesis of azides involves the reaction of a mesylate with sodium azide. Therefore, the dimesylate 8 was first reacted with an excess of sodium azide in DMF at 105 °C to give the diazide 9 (Scheme 2). However, the product was determined to be the azidomesylate 10 instead of the expected diazide 9 based on NMR spectroscopy. The position of the azide functionality in 10 was determined from its COSY spectrum. The diagonal peak at 3.97 ppm has cross peaks with the protons resonating at 3.84 and 4.92 ppm. Analysis of these cross peaks shows that the cross peak at 4.92 ppm is strong. This strong correlation supports the trans relation of the protons H-2 and H-1.
Next, in the preparation of the azidomesylate 10 from dimesylate 8, when the amount of 8 was increased (from milligrams to grams), the azido alcohol 11 was obtained during purification of the crude product from DMF. When the crude product 10 remains on the silica gel column with EtOAc/n-hexane 2:8 followed by methanol as the eluent for 48 hours to remove DMF, we determined from the NMR spectra that the mesylate group in compound 10 was converted to the corresponding alcohol 11 as the sole isomer via S N 2 substitution by hydrolysis. In the azidolysis reaction of compound 8, we propose that because the azide group is bulkier than the water molecule, it could not substitute the second mesylate group, and therefore the diazide 9 could not form. The configuration of the hydroxy group in 11 was determined by the cross peak between the proton H-2 and the protons H-1 and H-3 in the COSY spectrum. Moreover, the fact that the proton H-1 gives a positive NOE clearly indicates that it should have a cis configuration relative to the proton H-2. For the synthesis of the aminocyclooctanetriol 13, hydrogenation of the azido alcohol 11 gave amine 12 in 95% yield (Scheme 2). Subsequent, benzyl deprotection with BCl 3 of 12 resulted in the target compound 13 in 85% yield. The structures of compounds 12 and 13 are completely in agreement with our NMR spectral findings.
We then turned our attention to the synthesis of an aziridinefused cyclooctane derivative from azidomesylate 10. Treatment

Conclusion
In summary, we have achieved the synthesis of 3-aminocyclooctanetriol 13 and aziridinecyclooctanediol 16 starting from cis,cis-1,3-cyclooctadiene. The nitrogen functionalities were introduced by the substitution with NaN 3 of the corresponding mesylate. Reduction of the azido functionalities gave monoaminocyclitol and aziridine-fused derivatives.

Supporting Information
Supporting Information File 1 Experimental section, 1 H and 13 C NMR spectra for all new compounds, as well as selected 2D NMR spectra are provided.