Bis(oxiranes) Containing Cyclooctane Core: Synthesis and Reactivity towards NaN3

Reactions of oxirane ring opening provide a powerful tool for regio- and stereoselective synthesis of polyfunctional and heterocyclic compounds, widely used in organic chemistry and drug design. Cyclooctane, alongside other medium-sized rings, is of interest as a novel molecular platform for the construction of target-oriented leads. Additionally, cyclooctane derivatives are well known to be prone to transannular reactions, which makes them a promising object in the search for novel approaches to polycyclic structures. In the present work, a series of cyclooctanediones was studied in Corey-Chaykovsky reactions, and novel spirocyclic bis(oxiranes) containing cyclooctane core, namely, 1,5-dioxadispiro[2.0.2.6]dodecane and 1,8-dioxadispiro[2.3.2.3]dodecane, were synthesized. Ring opening of the obtained bis(oxiranes) upon treatment with sodium azide was investigated, and it was found that the reaction path is determined by the reciprocal orientation of oxygen atoms in the oxirane moieties. Diastereomers of the bis(oxiranes) with cis-orientation underwent independent ring opening, supplying corresponding diazidodiols, while in the case of stereoisomers with trans-orientation, domino-like reactions occurred, including intramolecular nucleophilic attack and the formation of a novel three- or six-membered O-containing ring. Summarily, a straightforward approach to polyfunctional compounds containing cyclooctane or oxabicyclo[3.3.1]nonane cores, employing bis(oxiranes), was elaborated.


Introduction
Transformations of strained electron-deficient oxirane rings represent a powerful tool in drug design and organic synthesis. Oxirane rings occur in a number of medicinal drugs and bioactive natural compounds ( Figure 1) and are widely used for the construction of novel drug candidates, particularly as an alkylating agent [1][2][3][4][5]. Synthetic approaches towards such drugs as atazanavir (HYV protease inhibitor), linezolid (antibiotic), diltiazem (antihypertensive drug), and a number of others include transformations of oxirane moiety [6]. Reactions of oxirane ring opening are widely used as a regio-and stereoselective approach to polyfunctional and heterocyclic compounds, and novel reactions and synthetic procedures employing oxiranes are still being developed [7][8][9][10][11][12][13][14]. The presence of two or more oxirane moieties in a molecule creates the opportunity for a straightforward synthesis of polyfunctional compounds, and for the use of such a molecule as a linker in the construction of multivalent ligands.
Cyclooctane, alongside other medium rings, is characterized by an optimal balance of conformational rigidity and flexibility and is of interest as a novel molecular platform for the design of target-oriented leads [15][16][17][18]. On the other hand, the synthetic application of ring-closure reactions to medium rings is often limited because of the entropy factor disfavoring ring closure. Therefore, the search for simple preparative approaches to the functionalization of already existing cyclooctane moiety poses an important problem [19,20]. Cyclooctane, alongside other medium rings, is characterized by an optimal balance of conformational rigidity and flexibility and is of interest as a novel molecular platform for the design of target-oriented leads [15][16][17][18]. On the other hand, the synthetic application of ring-closure reactions to medium rings is often limited because of the entropy factor disfavoring ring closure. Therefore, the search for simple preparative approaches to the functionalization of already existing cyclooctane moiety poses an important problem [19,20]. Additionally, a number of transannular reactions can proceed due to cyclooctane conformational transitions, including those starting from oxirane ring-opening processes [21,22].
This work is therefore aimed at the synthesis of novel bis(oxiranes) A, containing cyclooctane core, the investigation of the reactions with azide anion, and the preparation of polyfunctional compounds B starting from the bis(oxiranes) (Scheme 1).

Synthesis of Bis(oxiranes) via Corey-Chaykovsky Reaction of Cyclooctanediones
In order to obtain previously unknown bis(oxiranes), cyclooctanediones 1-5 were investigated in a Corey-Chaykovsky reaction using sulfur ylide derived from trimethylsulfonium iodide and potassium tert-butoxide (Scheme 2). This work is therefore aimed at the synthesis of novel bis(oxiranes) A, containing cyclooctane core, the investigation of the reactions with azide anion, and the preparation of polyfunctional compounds B starting from the bis(oxiranes) (Scheme 1).  Figure 1. Examples of marketed drugs and bioactive compounds containing oxirane or cyclooctane rings.
Cyclooctane, alongside other medium rings, is characterized by an optimal balance of conformational rigidity and flexibility and is of interest as a novel molecular platform for the design of target-oriented leads [15][16][17][18]. On the other hand, the synthetic application of ring-closure reactions to medium rings is often limited because of the entropy factor disfavoring ring closure. Therefore, the search for simple preparative approaches to the functionalization of already existing cyclooctane moiety poses an important problem [19,20]. Additionally, a number of transannular reactions can proceed due to cyclooctane conformational transitions, including those starting from oxirane ring-opening processes [21,22].
This work is therefore aimed at the synthesis of novel bis(oxiranes) A, containing cyclooctane core, the investigation of the reactions with azide anion, and the preparation of polyfunctional compounds B starting from the bis(oxiranes) (Scheme 1).
The interaction of cyclooctane-1,3-dione (2) and sulfur ylide produced no bis(oxirane), which is probably due to the tendency of 1,3-diketone to produce enolate under basic conditions. As such, 1,3-diketone 3, containing a spirocyclopropane moiety between the carbonyl groups, was employed in a Corey-Chaykovsky reaction, yielding bis(oxirane) 7 as a mixture of meso form 7a and racemate 7b in ratio 3:1 (Scheme 2). The reaction proceeded in low yield and a decrease in the reaction time down to 1 h was required in order to prevent the decomposition of the products. The lability of compounds 7a,b prevented their isolation via column chromatography, and full description of NMR spectra could be accomplished only for the isomer 7a prevailing in the reaction mixture.
The relative configuration of compounds 6a,b was determined using a calculation of 13 C NMR chemical shifts. The assignments of configuration for 7a,b and 9a,b were made on the basis of NMR spectra, taking into account differences in the symmetry of molecules (see Supplementary Materials for details). Bis(oxirane) 6 was obtained from cyclooctane-1,2-dione (1) as a mixture of diastereomers in good yield (Scheme 2). In order to study the difference in the reactivity of stereomers of compound 6, individual diastereomer 6a (meso form) and 6b (as racemate) were isolated via preparative column chromatography.
The interaction of cyclooctane-1,3-dione (2) and sulfur ylide produced no bis(oxirane), which is probably due to the tendency of 1,3-diketone to produce enolate under basic conditions. As such, 1,3-diketone 3, containing a spirocyclopropane moiety between the carbonyl groups, was employed in a Corey-Chaykovsky reaction, yielding bis(oxirane) 7 as a mixture of meso form 7a and racemate 7b in ratio 3:1 (Scheme 2). The reaction proceeded in low yield and a decrease in the reaction time down to 1 h was required in order to prevent the decomposition of the products. The lability of compounds 7a,b prevented their isolation via column chromatography, and full description of NMR spectra could be accomplished only for the isomer 7a prevailing in the reaction mixture.
The relative configuration of compounds 6a,b was determined using a calculation of 13 С NMR chemical shifts. The assignments of configuration for 7a,b and 9a,b were made on the basis of NMR spectra, taking into account differences in the symmetry of molecules (see Supplementary Materials for details).

Ring Opening of Bis(oxiranes) with Sodium Azide
In order to compare the reactivity of bis(oxiranes) with different reciprocal positions of three-membered rings, compounds 6a,b and 9a,b were investigated by the treatment Scheme 2. Investigation of diketones 1-5 in Corey-Chaykovsky reaction.

Ring Opening of Bis(oxiranes) with Sodium Azide
In order to compare the reactivity of bis(oxiranes) with different reciprocal positions of three-membered rings, compounds 6a,b and 9a,b were investigated by the treatment with a well-known nucleophile: sodium azide. It should be mentioned that organic azides are of the utmost interest as versatile intermediates in organic synthesis and can be found in a variety of pharmaceuticals and biologically active compounds, such as Zidovudine, Azidamfenicol, Azidocillin, and others [25][26][27][28].
The conditions of the ring opening of oxiranes containing spriroannelated cyclooctane moiety were probed for model oxaspirodecane 10. It was found that the reaction of compound 10, with a four-fold excess of sodium azide in water under reflux, produces azidoalcohol 11 as a sole product (Scheme 3).
Molecules 2022, 27, x FOR PEER REVIEW 4 of 10 with a well-known nucleophile: sodium azide. It should be mentioned that organic azides are of the utmost interest as versatile intermediates in organic synthesis and can be found in a variety of pharmaceuticals and biologically active compounds, such as Zidovudine, Azidamfenicol, Azidocillin, and others [25][26][27][28]. The conditions of the ring opening of oxiranes containing spriroannelated cyclooctane moiety were probed for model oxaspirodecane 10. It was found that the reaction of compound 10, with a four-fold excess of sodium azide in water under reflux, produces azidoalcohol 11 as a sole product (Scheme 3). Under the same conditions, compound 6a interacted with sodium azide, producing predominantly product 12, resulting from the opening of one of two oxirane rings, which was obtained as a poorly separable mixture with diazidodiol 13 (see section 3. Under the same conditions, compound 6a interacted with sodium azide, producing predominantly product 12, resulting from the opening of one of two oxirane rings, which was obtained as a poorly separable mixture with diazidodiol 13 (see Section 3.3 and Supplementary Materials). To obtain diazidodiol 13 as the sole product, an additional optimization of reaction conditions was conducted (see Supplementary Materials). Varying solvents, reaction times and reagents ratios demonstrated that for the full conversion of compound 6a into diazidodiol 13, 16-fold excess of nucleophilic agent and reflux in water for 30 h are required (Scheme 4).
predominantly product 12, resulting from the opening of one of two oxirane rings, which was obtained as a poorly separable mixture with diazidodiol 13 (see section 3.3 and Supplementary Materials). To obtain diazidodiol 13 as the sole product, an additional optimization of reaction conditions was conducted (see Supplementary Materials). Varying solvents, reaction times and reagents ratios demonstrated that for the full conversion of compound 6a into diazidodiol 13, 16- Bis(oxirane) 6b, on the contrary, smoothly reacted with sodium azide, producing oxirane 14 as a sole product and no products of independent ring opening similar to compounds 12 or 13 were observed (Scheme 4). Thus, in the reaction of 6b with nucleophile, a fairly rare reaction pathway, described for bis(oxiranes) containing neighboring oxirane moieties [29,30], was observed. In this case, anion I, formed after the opening of first oxirane ring, underwent intramolecular nucleophilic attack of the oxygen atom to form a new oxirane moiety. Such reaction is highly improbable for diastereomer 6a because in the case of oxirane 12 (or corresponding anion), a nucleophilic attack of oxygen must proceed "from the front".
The presence of a hydroxyl group in compound 14 was additionally confirmed via the methylation reaction. Treatment of oxirane 14 with an excess of methyl iodide in the presence of NaH produced methyl ether 15 as the sole product (Scheme 4).
The interaction of two diastereomers of bis(oxirane) 9 with sodium azide also proceeded via two different pathways. It was found that the ring opening of both oxirane moieties in compound 9a occurs upon treatment with eight-fold excess of nucleophile under reflux for 3 h, producing diazidodiol 17 as the only product in high yield (Scheme 5). Bis(oxirane) 6b, on the contrary, smoothly reacted with sodium azide, producing oxirane 14 as a sole product and no products of independent ring opening similar to compounds 12 or 13 were observed (Scheme 4). Thus, in the reaction of 6b with nucleophile, a fairly rare reaction pathway, described for bis(oxiranes) containing neighboring oxirane moieties [29,30], was observed. In this case, anion I, formed after the opening of first oxirane ring, underwent intramolecular nucleophilic attack of the oxygen atom to form a new oxirane moiety. Such reaction is highly improbable for diastereomer 6a because in the case of oxirane 12 (or corresponding anion), a nucleophilic attack of oxygen must proceed "from the front".
The presence of a hydroxyl group in compound 14 was additionally confirmed via the methylation reaction. Treatment of oxirane 14 with an excess of methyl iodide in the presence of NaH produced methyl ether 15 as the sole product (Scheme 4).
The interaction of two diastereomers of bis(oxirane) 9 with sodium azide also proceeded via two different pathways. It was found that the ring opening of both oxirane moieties in compound 9a occurs upon treatment with eight-fold excess of nucleophile under reflux for 3 h, producing diazidodiol 17 as the only product in high yield (Scheme 5). When the reaction time was shorter, a mixture of compounds 16 and 17 was obtained, with diazidodiol 17 prevailing (see Section 3.3 and Supplementary Materials).  The reaction of bis(oxirane) 9b, containing trans-oriented oxygen atoms, with sodium azide required shorter time (2 h) and lower excess of nucleophile (4 eq), and again proceeded in an unexpected way, producing oxabicyclononane 18 in good yield (Scheme 5). The formation of oxabicyclononane 18 presumably resulted from the ring opening of an oxirane moiety, producing anion II, and subsequent intramolecular nucleophilic attack of oxygen on the second oxirane ring. It should be noted that no examples of the formation of tetrahydropyran moiety via domino ring opening of bis(oxiranes) has been found in earlier research. This reaction opens the way to hardly accessible oxabicyclononane derivatives, which, like bicyclononanes [31,32] and azabicyclononanes [33], represent promising 3D scaffolds for drug design.
Thus, it was demonstrated that diastereomers of bis(oxiranes) with cyclooctane cores possess different reactivity towards azide anion. Compounds 6a and 9a, containing cisoriented oxygen atoms, are less reactive and undergo independent ring opening of The reaction of bis(oxirane) 9b, containing trans-oriented oxygen atoms, with sodium azide required shorter time (2 h) and lower excess of nucleophile (4 eq), and again proceeded in an unexpected way, producing oxabicyclononane 18 in good yield (Scheme 5). The formation of oxabicyclononane 18 presumably resulted from the ring opening of an oxirane moiety, producing anion II, and subsequent intramolecular nucleophilic attack of oxygen on the second oxirane ring. It should be noted that no examples of the formation of tetrahydropyran moiety via domino ring opening of bis(oxiranes) has been found in earlier research. This reaction opens the way to hardly accessible oxabicyclononane derivatives, which, like bicyclononanes [31,32] and azabicyclononanes [33], represent promising 3D scaffolds for drug design.
Thus, it was demonstrated that diastereomers of bis(oxiranes) with cyclooctane cores possess different reactivity towards azide anion. Compounds 6a and 9a, containing cisoriented oxygen atoms, are less reactive and undergo independent ring opening of oxirane moieties, whereas compounds 6b and 9b, containing oxygen atoms in trans-position, undergo relatively fast domino-type ring opening of oxirane rings and generate products of intramolecular nucleophilic attack 14,18.

Synthesis of Bis(oxiranes) (General Method)
To the solution of trimethylsulfonium iodide (6.6 g, 32.4 mmol) in 60 mL of dry DMSO, the solution of corresponding cyclooctanedione (1.4 g, 10 mmol) in 5 mL of dry DMSO was added dropwise at stirring under argon. Then the solution of potassium tert-butoxide (3.36 g, 30 mmol) in 40 mL of dry DMSO was added dropwise. The reaction mixture was stirred for 16 h at r.t., then it was poured into icy water (60 mL) and extracted with pentane (3 × 20 mL). Combined organic layers were quickly dried over MgSO 4 ; the solvent was evaporated under reduced pressure. The products were isolated via preparative column chromatography (SiO 2 ).

Ring Opening of Oxiranes upon Treatment with Sodium Azide (General Method)
To the solution of sodium azide (2-32 mmol) in water (2 mL), the corresponding oxirane (1 mmol) was added. The reaction mixture was stirred under reflux for 2-30 h, cooled down to r.t. and extracted with ethyl acetate (3 × 3 mL). The organic layers were combined; the solvent was evaporated under reduced pressure. The products were isolated via preparative column chromatography (SiO 2 ).

Conclusions
To summarize, novel bis(oxiranes), containing cyclooctane core, were synthesized and investigated upon treatment with sodium azide. Configuration of bis(oxiranes) was found to drastically influence on their reactivity towards azide anion. A novel pathway of the reaction of 1,3-bis(oxiranes) with a nucleophile, producing oxabicyclononane moiety, was found. Preparative approaches towards a series of novel cyclooctane and oxabicyclononane derivatives, containing azido and hydroxy groups, starting from spirocyclic oxiranes and employing simple and convenient methods, were realized.