Ozone-free synthesis of ozonides: Assembling bicyclic structures from

Article Cite This: J. Org. Chem. 2018, 83, 4402−4426

pubs.acs.org/joc

Ozone-Free Synthesis of Ozonides: Assembling Bicyclic Structures from 1,5-Diketones and Hydrogen Peroxide Ivan A. Yaremenko,†,‡,§,○ Gabriel dos Passos Gomes,∥,○ Peter S. Radulov,†,§ Yulia Yu. Belyakova,†,‡ Anatoliy E. Vilikotskiy,†,‡ Vera A. Vil’,†,‡,§ Alexander A. Korlyukov,⊥,# Gennady I. Nikishin,† Igor V. Alabugin,*,∥ and Alexander O. Terent’ev*,†,‡,§ †

Russian Academy of Sciences, N. D. Zelinsky Institute of Organic Chemistry Russian, 47 Leninsky Prospect, Moscow 119991, Russian Federation ‡ D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, Moscow 125047, Russian Federation § All-Russian Research Institute for Phytopathology, B. Vyazyomy, Moscow 143050, Russian Federation ∥ Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32313, United States ⊥ Russian Academy of Sciences, A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, Moscow 119991, Russian Federation # Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997, Russian Federation S Supporting Information *

ABSTRACT: Reactions of 1,5-diketones with H2O2 open an ozone-free approach to ozonides. Bridged ozonides are formed readily at room temperature in the presence of strong Brønsted or Lewis acids such as H2SO4, p-TsOH, HBF4, or BF3·Et2O. The expected bridged tetraoxanes, the products of double H2O2 addition, were not detected. This procedure is readily scalable to produce gram quantities of the ozonides. Bridged ozonides are stable and can be useful as building blocks for bioconjugation and further synthetic transformations. Although less stabilized by anomeric interactions than bis-peroxides, ozonides have an intrinsic advantage of having only one weak O−O bond. The role of the synergetic framework of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. Consequently, the cyclization selectivity is determined by the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in a [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the threecarbon bridge.

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INTRODUCTION

amounts and are broadly used as radical initiators for the preparation of polymers.8 The synthesis of organic peroxides is mainly based on the reaction of ketones and aldehydes with hydrogen peroxide and organic hydroperoxides. This approach to the preparation of peroxides benefits from the broad availability of such starting materials and from the great reactivity of nucleophilic peroxide oxygen toward carbonyl compounds. These reactions opened synthetic access to many important classes of peroxides, such as geminal bis-hydroperoxides,9 geminal bis-peroxides,10 tetraoxanes,11 cyclic triperoxides,12 and tricyclic monoperoxides.13 However, peroxides containing the 1,2,4-trioxolane moiety (i.e.,

In the past decade, the progress of chemistry of organic peroxides was catalyzed by numerous reports of their antimalarial,1 anthelmintic,2 antitumor,3 growth regulation,4 and antitubercular activity.5 The importance of these studies is illustrated by the 2015 Nobel Prize in Medicine awarded to Youyou Tu for the discovery and development of artemisinin, a natural peroxide antimalarial drug.6 The greatest progress in the development of medicinal agents on the base of synthetic peroxides is associated with compounds that contain an ozonide moiety. Recently, the first commercial antimalarial agent was developed by combining synthetic ozonide arterolane with piperaquine.7 Organic peroxides derived from ketones are produced in the multiton © 2018 American Chemical Society

Received: January 16, 2018 Published: March 13, 2018 4402

DOI: 10.1021/acs.joc.8b00130 J. Org. Chem. 2018, 83, 4402−4426

Article

The Journal of Organic Chemistry

Peroxidation of 1,5-diketones 1a−v can be accomplished with a variety of H2O2 sources such as aqueous H2O2, ethereal H2O2, and urea/H2O2 complex using acid promoters such as BF3·Et2O, 98% H2SO4, p-TsOH·H2O, and 50% aq HBF4. In every case, the reaction provided ozonides as either a mixture of stereoisomers (2a−s and 3a−s) or as individual compounds (2t−v, Scheme 1).

secondary ozonides) have been traditionally obtained using ozone. Numerous papers reported the synthesis of ozonides via the reaction of ozone with alkenes.14 The first example of ozonolysis of ethylene goes back to 1855.15 Interesting variations of this process were developed over time, such as the 1997 approach to the preparation of ozonides via ozonolysis of O-methyl oximes in the presence of acyclic or cyclic ketones (Griesbaum coozonolysis).16 However, ozone is significantly inferior to H2O2 due to a combination of factors that include cost, convenience, and toxicity. Therefore, the development of synthetic approaches to ozonides that utilize hydrogen peroxides represents an important fundamental and practical challenge. In this context, it is noteworthy that the direct approach to secondary ozonides via the reaction of 1,5-diketones and H2O2 has been described in only a few scattered reports. The 1953 two-step formation of an ozonide from 2,6-heptanedione in the overall 51% yield from the consecutive reactions with H2O2 and P2O5 by Criegee and Lohaus17 remained the only example of such transformation for ∼20 years until reports of ozonide preparation from 2,2′-methylene-bis(cyclohexanone) and H2O2 using V2O5 as a catalyst.18 More recently, diketones of the oleanane family were transformed into ozonides using the CH3COOOH/H2O2 system.19 There is a report of ozonide formation in a low yield from 2,6-heptanedione and H2O2 in the gas phase at 10−2 Torr.20 Finally, a recent literature report5b described the transformation of hidden 1,5-dicarbonyl functionality of Artemisinin into a mixed ketoacetal, subsequently converted into a pair of stereoisomeric ozonides via a HCl-catalyzed reaction with H2O2. In our earlier work, we found that the acid-catalyzed reaction of branched β′,δtriketones with H2O2 yields ozonides, bridged tetraoxanes, and tricyclic monoperoxides.21 We have recently reported that substrates containing the 1,5diketone fragment can produce ozonides in a one-step general reaction with H2O2 without the formation of other peroxides and oxidized byproducts. We also provided stereoelectronic reasons for the high efficiency and selectivity of this process.22 In this work, we disclose full experimental details, investigate the scope of the new transformation, and complement it with an extended computational analysis. We also carried out transformations of ozonides in order to study the stability of the ozonide cycle and create hybrid molecules of interest for biological testing on the antiparasitic activity against malaria and schistosomiasis, fungicidal activity against phytopathogenic and human fungi, as well as cytotoxic activity against cancer cells.

Scheme 1. Synthesis of Stereoisomeric Ozonides 2a−v and 3a−s via Peroxidation of 1,5-Diketones 1a−v by H2O2

Peroxidation of ethyl 2-acetyl-2-(4-nitrobenzyl)-5-oxohexanoate 1p was used to study the effect of the nature and the amount of the promoter (BF3·Et2O, 98% H2SO4, p-TsOH· H2O, and 50% aq HBF4), reaction time, and variations in the nature of H2O2 (aqueous solution, ethereal solution, and complex with urea) at the yield of stereoisomeric ozonides 2p and 3p, Table 1. We chose acetonitrile as the preferred reaction solvent because it dissolves all starting 1,5-diketones and is also miscible with water and diethyl ether. A typical procedure for peroxidation of 1,5-diketone 1p was as follows: to a solution of the diketone 1p (0.350 g; 1.044 mmol) in MeCN (5 mL) at 20−25 °C, H2O2 was added, followed by the promoter. The reaction mixture was then stirred at 20−25 °C. The yield of stereoisomeric ozonides 2p and 3p was determined by NMR. The stereochemical assignment is based upon X-ray crystallography (vide infra) and NMR analysis with 2D correlation spectroscopic techniques (COSY, NOESY, editing-HSQC, and HMBC). For ozonide 2p, the characteristic peaks in the 1H NMR spectrum include singlets at 1.48 ppm (s, 3H, CH3CCH2) and 1.79 ppm (s, 3H, CH3CC), whereas for ozonide 3p they include singlets at 1.56 ppm (s, 3H, CH3CCH2) and 1.66 ppm (s, 3H, CH3CC). Ozonides 2p and 3p turned out to be white crystalline substances, which melted without decomposition at 97−98 and 143−144 °C, respectively.

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RESULTS AND DISCUSSION Peroxidation of 1,5-Diketones with the Formation of Ozonides. Most of the starting 1,5-diketones 1a−v can be easily prepared from the commercially available reagents on a >10 g scale. In particular, 1,5-diketones 1a−r can be easily synthesized by the Michael reaction of the respective αsubstituted ketoesters and methyl vinyl ketone;22,23 whereas diketone 1s can be easily synthesized from enamine and paraformaldehyde.24 Diketones 1t,u25 and ketoaldehyde 1v22,26 can be prepared by oxidation of 4-substituted hept-6-en-2-ones. However, the synthesis of 1,5-diketones 1t,u requires PdCl2, which is not very convenient for a large scale synthesis at the gram scale, whereas the synthesis of ketoaldehyde 1v requires toxic ozone. 4403


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(experiment 5) changes in favor of ozonide 2p when an additional amount of BF3·Et2O is used (experiments 8−10). One can suggest that this change is associated with the BF3· Et2O-promoted equilibration of the initially formed ozonide 3p with 2p. We plan to investigate the further details of acidmediated equilibrium between the two diastereomers in the future work. The use of 1 equiv of H2O2 led to incomplete conversion of the diketone (experiment 6), whereas the use of 3 equiv of H2O2 also decreases the yield of the target ozonide (experiments 7 and 14), likely due to the further oxidation. In both cases, the overall yield of ozonides was decreased. Lower yields of ozonides were obtained when the urea/H2O2 complex was used (entry 11). Overall, the ozonides 2p and 3p are obtained in good yields in experiments 15 and 21 in the presence of H2SO4 or p-TsOH·H2O, as long as the acids were used in a sufficiently large excess. This is a very interesting fact: in the Nojima’s studies, we can see that, in the presence of 10 mol % of SbSl5 in CH2Cl2 or 10 mol % ClSO3H in CH2Cl2 or AcOH, bridged ozonides undergo intramolecular rearrangement with the subsequent formation of decomposition products.27 It is important to note that, upon the increase in the amount of the promoter, e.g., BF3·Et2O and H2SO4, the yield of ozonides 2p and 3p goes through a maximum. For H2SO4, the maximum yield of compounds 2p and 3p is achieved under conditions described in entries 15 and 18. For BF3·Et2O, the optimal conditions correspond to experiments 4, 5, and 9 (Table 1). An increase in the molar excess of hydrogen peroxide (experiments 7 and 14) did not lead to the formation of tetraoxanes, the product that is generally observed upon peroxidation of 1,3-diketones. In exploring the scope of the new method, we have used the best peroxidation conditions identified in experiment 5. Under these conditions, the lowest loading of the BF3·Et2O catalyst (0.5 equiv relative to diketone 1p) provides a high yield of the ozonides (95%) along with the highest selectivity (2p/3p = 1.6:1.0). Under the above conditions, we can synthesize ozonides 2a− c and 3a−c from 1,5-diketones 1a−c that have a single substituent at one of the internal carbons (Table 2). In particular, the ozonides can be assembled from diketones 1a and 1c in a good total isolated yield (68% and 61%, respectively). In contrast, the presence of an “external” bulky isobutyl group at one of the carbonyl carbons of 1,5-diketone 1b dramatically decreased the isolated yield of ozonides 2b and 3b (23%). The bulky substituent is likely to hinder the nucleophilic attack at the carbonyl carbon. Unfortunately, formation of the ozonide is not observed from 2,5heptanedione. In the case of 4-methylheptane-2,6-dione, the desired ozonide was detected only in trace amounts by NMR data. Peroxidation of 4,4-dimethylheptane-2,6-dione resulted in the formation of the target ozonide in a yield of 75% by NMR. However, the product was unstable, and we could not isolate it from the reaction mixture. The efficiency of assembly of the ozonides from 1,5diketones and hydrogen peroxide is facilitated greatly by a bulky substituent at the tether between the two carbonyl groups, suggesting the important role of the Thorpe−Ingold effect on the ring closure.28 To test these expectations, we investigated 1,5-diketones 1d−q with two substituents at the internal α-carbon of the 1,5diketone moiety. One of the substituents (ethoxycarbonyl) was

Table 1. Synthesis of Ozonides 2p and 3p from Diketone 1p and H2O2

equiv of H2O2 vs 1p/ type of H2O2 entry 1 2 3 4 5

12 13 14 15 16 17 18 19 20

1.5; 35% aq 1.5; 35% aq 1.5; 35% aq 1.5; 35% aq 1.5; 3.7 M ethereal 1.0; 3.7 M ethereal 3.0; 3.7 M ethereal 1.5; 3.7 M ethereal 1.5; 3.7 M ethereal 1.5; 3.7 M ethereal 1.5; H2O2/ urea 1.5; 35% aq 1.5; 35% aq 3.0; 35% aq 1.5; 35% aq 1.5; 35% aq 1.5; 35% aq 1.5; 35% aq 1.5;35% aq 1.5; 35% aq

21

1.5; 35% aq

22

1.5; 35% aq

23

1.5; 35% aq

6 7 8 9 10 11

acid (mol of acid/mol of 1p) BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O

NMR yield of 2p and time, h 3p, %

ratio of 2p/3p

(1.0) (2.0) (4.0) (6.0) (0.5)

1 1 1 1 1

58 90 95 98 95

1.4:1.0 2.7:1.0 4.5:1.0 5.7:1.0 1.6:1.0

BF3·Et2O (0.5)

1

84

1.6:1.0

BF3·Et2O (0.5)

1

42

1.1:1.0

BF3·Et2O (1.0)

1

93

2.6:1.0

BF3·Et2O (2.0)

1

95

5.2:1.0

BF3·Et2O (4.0)

1

95

5.2:1.0

BF3·Et2O (0.5)

1

11

1.75:1.0

H2SO4 (1.0) H2SO4 (3.0) H2SO4 (3.0) H2SO4 (5.0) H2SO4 (11.0) H2SO4 (1.0) H2SO4 (3.0) H2SO4 (5.0) p-TsOH·H2O (8.0) p-TsOH·H2O (10.0) 50% aq HBF4 (12.0) 50% aq HBF4 (8.0)

1 1 1 1 1 5 5 5 1

30 81 50 84 73 69 86 61 85

1.0:1.0 1.6:1.0 1.0:1.0 3.9:1.0 4.5:1.0 1.2:1.0 3.5:1.0 4.4:1.0 1.9:1.0

1

88

2.2:1.0

1

62

1.8:1.0

5

64

2.5:1.0

Among the tested promoters, BF3·Et2O, 98% H2SO4, pTsOH·H2O, and 50% aq HBF4, the best results were obtained with BF3·Et2O. The combination of 35% aq H2O2 (1.5 equiv of H2O2 vs 1p in most cases) and 6-fold molar excess of BF3·Et2O relative to the diketone 1p (experiment 4) yielded the stereoisomeric ozonides in the combined yield of 98% (2p/ 3p = 5.7:1.0). The use of a 3.7 M solution of H2O2 in ether instead of aqueous H2O2 maintains the high yield (95% overall, 2p/3p = 1.6:1.0) while allowing substoichiometric (0.5 equiv) amounts of BF3·Et2O relative to the diketone 1p (experiment 5). The equally high overall yield is obtained when a 2-fold excess of BF3·Et2O was used (95% overall, 2p/3p = 5.2:1.0, experiment 9). The significant decrease in the required catalyst amount is likely to be connected with the hydrolysis of BF3 by the aqueous H2O2 solution into the less efficient catalysts, fluoroboric and boric acids. Indeed, in the presence of 50% aq HBF4, the overall yield of ozonides 2p and 3p was only 64% (2p/3p = 2.5:1.0, entry 23). Interestingly, the ratio of 2p/3p (1.6:1.0) observed in the presence of 0.5 equiv of BF3·Et2O 4404


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Table 2. Structures and Isolated Yields of the Individual Isomers and the Isomeric Mixtures of Ozonides 2a−c and 3a−c Synthesized from 1,5-Diketones 1a−ca

The general reaction conditions are in Table 1. A 3.7 M ethereal solution of H2O2 and BF3·Et2O were successively added to a stirred solution of 1,5diketone 1a−c (0.350 g) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. Molar ratio of H2O2/BF3·Et2O/ diketone = 1.5:0.5:1.0. bThe ratio of stereoisomers of ozonides was determined by the 1H NMR spectroscopic data from their mixture separated from the residual diketone reactant by column chromatography on SiO2. cScaled to 1.0 g of 1,5-diketones 1a in the conditions of experiment 9 (Table 1). a

stereoisomers with good yields based on isolated product (62% and 85%, respectively) (Table 4). Based on the previously discussed difficulties for the peroxidative cyclizations of diketones with substituents at the central carbon (4-methylheptane-2,6-dione and 4,4-dimethylheptane-2,6-dione), the synthesis of ozonides from the diketones with substituents at the central carbon appears problematic. However, the addition of an isopropyl substituent at the central carbon of 1,5-diketone 1u allowed preparation of a stable ozonide 2u in a good isolated yield (71%). Furthermore, diketone 1t and ketoaldehyde 1v with a phenyl substituent at the central carbon furnished ozonides 2t,v in good yields (Table 5). These results indicated that a variety of ozonides can be obtained from diketones with bulky substituents at the central carbon, as long as the starting diketones are synthetically accessible. On the basis of these results, it is clear that the reaction of 1,5-dicarbonyl compounds with H2O2 provides a convenient synthetic route to ozonides. In every case, the tetraoxane products that contain two peroxide bridges were not detected. This approach is applicable to ozonides with pendant alkene and alkyne functionalities that are useful as potential functional handles for bioconjugation and further synthetic transformations but incompatible with the classic ozonolysis route. Structure Determination by X-ray Crystallography. The structure of ozonides 2p, 2v, 3a, 3p, 4, and 5 was unambiguously established by X-ray crystallographic analysis (Figure 1). X-ray data for 2p, 2p, and 5 was provided in our previous communication.22 A more detailed description of Xray data for 2v, 3a, and 4 is provided in the Supporting Information. NMR analysis was facilitated by 2D correlation spectroscopic techniques (COSY, NOESY, editing-HSQC, and HMBC) that were helpful in providing the reference NMR chemical shifts for ozonides.

common for all substrates, whereas the second substituent included a variety of functional groups separated from the branching point by a methylene group. The yields for the mixtures of ozonides 2d−q and 3d−q under the optimal conditions, as well as the isolated yields of the individual isomers 2d−q and 3d−q, are shown in Table 3. As illustrated by the results summarized in Table 3, peroxidation of the 1,5-diketones 1d−q leads, in every case, to the formation of stereoisomeric ozonides in yields ranging from moderate (49% for diketone 1i) to high (90% for diketones 1n,p). Stereoisomeric ozonides 2a−q and 3a−q (Tables 2 and 3) can be readily separated by the ordinary column chromatography. 1H and 13C NMR spectroscopy with using 2D correlation spectroscopic techniques (COSY, NOESY, editing-HSQC, and HMBC) can reliably distinguish 2 from 3. Our approach makes possible preparation of ozonides with a variety of substituents including ester, nitrile, alkene, and alkyne functional groups. The ozonides are obtained in high yields with both electron-donating and electron-withdrawing groups. Interestingly, the alkene function remains unchanged under the reaction conditions, and the possible products of epoxidation were not detected. The isolated yields of ozonides remained high when the amount of starting diketones were increased to the gram quantities. In particular, under conditions of entry 5 in Table 1, ozonides 2d and 3d were obtained in a 74% isolated yield (reaction with 1 g of diketone 1d). Peroxidation of 3 g of diketone 1g provided 66% of isolated ozonides 2g and 3g. Under conditions 9 of Table 1, peroxidation of a 1 g amount of 1,5-diketones 1a,j,p led to ozonides 2a and 3a, 2j and 3j, as well as 2p and 3p in the isolated yields of 58, 77, and 91%, respectively. Peroxidation of diketones with a fusion of additional cycles 1r and 1s ozonides produced an inseparable mixture of 4405


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Table 3. Structures and Isolated Yields of the Individual Isomers and the Isomeric Mixtures of Ozonides 2d−q and 3d−q Synthesized from Diketones 1d−qa

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The Journal of Organic Chemistry Table 3. continued

a A 3.7 M ethereal solution of H2O2 and BF3·Et2O were successively added to a stirred solution of 1,5-diketone 1d−q (0.350 g) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. Molar ratio of H2O2/BF3·Et2O/diketone = 1.5:0.5:1.0. bThe ratio of stereoisomers of ozonides was determined by the 1H NMR spectroscopic data from their mixture separated from the residual diketone reactant by column chromatography on SiO2. cScaled to 1.0 g of 1,5-diketones 1a,j,p in the conditions of experiment 9 (Table 1). dScaled to 1.0 g of 1,5-diketone 1d in the conditions of experiment 5 (Table 1). eScaled to 3.0 g of 1,5-diketone 1g in the conditions of experiment 5 (Table 1).

The six-membered ring on the bicyclic framework (Figure 1) adopts a distorted chair conformation where both exocyclic C− O bonds to the peroxide moiety are pseudoaxial. This conformation satisfies the stereoelectronic requirements of the endoanomeric effect.29 Further, we decided to compare the obtained X-ray data of ozonides synthesized in this study with the X-ray data of known ozonides in the literature. A selection of ozonide and peroxide structures, for which crystal structures have been reported, along with selected structural data (bond length, angle, and dihedral) are reported in Table 6 including several molecules that contain a 6,7,8-trioxabicyclo[3.2.1]-

octane moiety substituted by functional groups of different natures.30−35 The 6,7,8-trioxabicyclo[3.2.1]octane moiety receives some stabilization from donation of peroxide lone pairs to the σ*C4−O3 orbitals shared with the six-membered rings, analogously to the exoanomeric effect in oxacyclohexanes (with O5−C4-O3−O2 dihedral of ∼30°) (Figure 2). On the other hand, the COOC subunit of the five-membered ring is much closer to planarity (C1−O2-O3−C4 angles of 0− 7°) than the same subunit in acyclic peroxides (91.3° in 4407


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compounds, which is consistent with the NBO interactions (3.4 vs 9.1 kcal/mol for the nO → σ*C−O interactions, vide infra). This is the same, but a slightly more pronounced trend, than in compounds B−D. Curiously, it is reversed in comparison to the relative C−O bond lengths in the parent ozonide (calculated by DFT, Supporting Information). This reversal is likely to be one of the stereoelectronic consequences of the bicyclic constraints. Comparison of bicyclic ozonides prepared in this work with the earlier reported ozonides A−C indicates that the effect of the additional bridge at the O−O bond length is relatively small (an increase from 1.46 to 1.47 Å). According to Cambridge Data Base, for O−O single bonds, where each O atom is flanked by a C atom, the mean O−O bond length is 1.474 Å, with an esd of 0.031 Å, which matches our data well. Unfortunately, the X-ray data on ozonides still remain limited. Because these data are difficult to obtain, not all literature data are accurate. For example, ozonides H−J have much shorter reported O−O bonds (as short as 1.38−1.39 Å for H and J).36 Strikingly, the O−O bonds in ozonides H−J are even shorter than a few of the C−O bonds in the same molecules. This discrepancy is due to the limitation of supramolecular crystallography (including the crystal sponge method) that deals with hundreds of atoms in a very large unit cell used to obtain the structures of those ozonides. Note that all ring bond lengths for H−J are distinctly different from such parameters for the other reported ozonides. Stability and Reactivity of Bicyclic Ozonides. Ozonides, listed in Tables 2−5, are stable compounds. We have stored them for about a year in a refrigerator at −10 °C without decomposition. Remarkably, the crystalline ozonides melt without decomposition. Ozonides 2p and 3p can be selectively reduced by triphenyl phosphine with the recovery of the starting diketone 1p (Scheme 2). After 8 h after the addition of triphenyl phosphine to the solution of ozonide 2p or 3p in an NMR tube with CDCl3 as a solvent, only signals of the starting diketone 1p were observed in the NMR spectra. On the other hand, the ozonide cycle is stable toward LiAlH4 at −78 °C, bases, amines, and ethyl chloroformate. Bicyclic ozonides can be opened at the higher temperatures under LiAlH4 with the formation of 1,5-diols.38 This finding allowed us to prepare acids 4 and 5 (74 and 80% yields, respectively), amides 6−9 (44−75% yields), azido-ozonides 13 and 17 (62 and 63% yields, respectively), tetraoxaneozonide 15 (60% yield), and triazolozonide 18 (95% yield, Schemes 3 and 4). Due to its sufficient stability under the range of conditions, the ozonide cycle can be used as a protecting group for the biscarbonyl functionality. For example, the direct synthesis of acid 10 from ester 1j is impossible. In this case, a complex mixture of products without a target compound is formed. However, the transformation of 1j to 10 is possible if 1j is transformed into the ozonide. In the latter compound, the ester group can be cleanly hydrolyzed and/or converted into the other functionalities. At the end of these transformations, the biscarbonyl can be unmasked by treatment with triphenyl phosphine (Scheme 3). Earlier, reduction of monocyclic39 and bicyclic40 ozonides with triphenylphosphine was used for the preparation of dicarbonyl compounds from alkenes. It is surprising that the ozonide cycle is stable toward such a strong reducing agent as LiAlH4. The reduction of the ester group to the hydroxyl group opens the door for a number of ozonide transformations. These transformations are potentially interesting for the development of a wide range of biologically

Table 4. Structures and Isolated Yields of Ozonides 2r,s and 3r,s from Diketones 1r and 1sa

A 3.7 M ethereal solution of H2O2 and BF3·Et2O were successively added to a stirred solution of 1,5-diketone 1r,s (0.350 g) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. Molar ratio of H2O2/BF3·Et2O/diketone = 1.5:0.5:1.0. bThe ratio of stereoisomers of ozonides was determined by the 1H NMR spectroscopic data from their mixture separated from the residual diketone reactant by column chromatography on SiO2. a

Table 5. Structures and Isolated Yields of Individual Forms of Ozonides 2t−v from Diketones 1t,u and Ketoaldehyde 1va

A 3.7 M ethereal solution of H2O2 and BF3·Et2O were successively added to a stirred solution of 1,5-diketone 1a−v (0.350 g) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. Molar ratio of H2O2/BF3·Et2O/diketone = 1.5:0.5:1.0.

a

benzoyl peroxide). This structural feature further deactivates the already weak anomeric effect in the peroxide moiety.37 The endocyclic orbital interactions (e.g., nO3 → σ*C4O5) are relatively inefficient, and the involved bonds remain relatively long; e.g., the C1−O2 bond is in the range 1.44−1.45 Å. The presence of an endocyclic acceptor can have a larger structural effect; e.g., a Cl atom in C leads to the C1−O2 bond shortening to 1.39 Å. Interestingly, the C1−O2 (C4−O3) bonds are always longer (∼1.44 Å) than C1−O5 (C4−O5) bonds (∼1.41 Å) in our 4408


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Figure 1. Molecular structures of 2p,v, 3a, 3p, 4, and 5. Atoms are presented as atomic displacement parameters (ADP) ellipsoids (50% probability).

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COMPUTATIONAL ANALYSIS To gain deeper insight into the origin of observed selectivities, we have evaluated the relative thermodynamic stabilities of the ozonides and the bis-peroxides using the meta-hybrid M06-2X functional. The M06-2X functional has demonstrated good thermodynamic data for organic reactions. For more details, see ref 45, with solvation corrections when necessary (SMD46 = MeCN or H2O). We employed the double-hybrid B2PLYP-D2 functional47 for the conformational analysis of selected ozonides and bis-peroxides. The latter method was also used for the natural bond orbital (NBO)48 analysis of stereoelectronic interactions. The 6-311++G(d,p) basis set was employed for all systems. Gaussian 09 was used for all DFT calculations. Three-dimensional structures and orbital plots were produced with CYLView 1.0.149 and Chemcraft 1.8.50 In order to compare the contributions of different basic sites in these multifunctional molecules, we employed the (“Geometry, Frequency, Noncovalent, eXtended Tight Binding”) GFN-xTB method by Grimme and co-workers51 for an automated search and energy-ranking of protomers.52 GFNxTB is a semiempirical (TB) method for the calculation of structures, vibrational frequencies, and noncovalent interactions of large molecular systemstakes. After placing a proton on each heteroatom, each geometry was optimized by GFN-xTB and ranked by energies within a threshold of 50 kcal/mol. These calculations took implicit solvation into account using GBSA (Generative Born Surface Area)53 for acetonitrile. The lowest energy protomers were then fully optimized by at the (SMD = MeCN)/M06-2X/6-311++G(d,p) level of theory. General Comments on Reactions of Ketones and H2O2. We have started our analysis by evaluating the general thermodynamic landscape of the reaction of ketones with H2O2. Several findings are of general interest. For example, the intermolecular addition of hydrogen peroxide to a carbonyl is more favorable than the addition of water. In particular, the reaction of acetone with H2O2 is close to being thermoneutral,

active ozonides (Scheme 4). To date, there have been no published synthesis of azido-ozonides in an individual form. The present work reports the azido-ozonides 13 and 17, the first members of this family. These compounds, obtained from ozonide 2k, readily participate in the click reaction with an electronically activated twisted cyclodecyne reported by Harris et al.41 The ozonide cycle was so stable that it was possible to append a secondary amino group to the same molecule, even though peroxides are well-known to decay under the action of amines.42 However, the presence of the amine may account for the partial decomposition of the ozonide cycle that can explain the moderate 29% yield of aminoperoxide 14. On the other hand, the hybrid tris-peroxide 15 that contains both a tetraoxane and an ozonide in the same molecule was obtained in a good yield (60%). Such remarkable oxygen-rich hybrid molecules can be of interest in the search of new compounds with an antiparasitic activity against malaria and schistosomiasis, fungicidal activity against phytopathogenic and human fungi, and cytotoxic activity against cancer cells.43 The combination of an ozone-free synthesis of ozonides and the unique stability of the ozonide cycle make it possible to carry out the ozonolysis of alkenyl substituted ozonide 2h with the formation of aldehyde 19 (Scheme 5). This synthetic sequence showcases the dramatically different stability and reactivity of “normal” and bicyclic ozonides, whereas ozonides derived from the terminal alkene readily undergo fragmentation in the presence of Et3N; the bicyclic ozonide remains intact. The reactivity of ozonides toward the reductive ring opening is also strongly increased when one of the bridgehead carbons does not have an alkyl substituent.44 Compound 19 with a free aldehyde function can serve as a building block for the synthesis of biologically active ozonides in the future. 4409


a

4410

° ° ° ° °

4

3

(C −O -C −O ) (C4−O5-C1−O2) (O5−C1-O2−O3) (O5−C4-O3−O2) (C1−O2-O3−C4)

5

A30

−14.5 −13.3 33.9 34.8 −42.2 1.465 1.393 1.396 1.391 1.390

Bond lengths in Å; dihedrals in °.

dihedral, dihedral, dihedral, dihedral, dihedral, O2−O3 C1−O5 C4−O5 C1−O2 C4−O3

1

−15.6 −13.1 35.8 37.5 −45.6 1.462 1.427 1.427 1.437 1.431

B31 −8.9 −21.1 42.1 34.4 −47.5 1.474 1.429 1.441 1.436 1.456

C31 −44.5 47.5 −31.2 24.5 4.2 1.478 1.414 1.408 1.435 1.445

D32 −43.0 42.4 −25.1 26.1 −0.7 1.471 1.414 1.418 1.449 1.448

E33 13.9 13.6 −35.1 −35.3 44.7 1.475 1.521 1.517 1.420 1.420

F34

−91.3 1.450

G35 −45.7 47.3 −29.6 27.0 1.4 1.480 1.416 1.422 1.438 1.446

2v

Table 6. Selected Structural Parameters of Ozonides and Other Peroxides from Their X-ray Structuresa

−43.7 43.8 −26.2 26.6 −0.4 1.479 1.417 1.426 1.444 1.451

3a

−45.4 41.0 −20.7 31.4 −6.8 1.478 1.407 1.422 1.445 1.440

4

−43.6 40.9 −22.2 28.6 −4.1 1.479 1.409 1.421 1.451 1.449

5

56.8 −51.2 29.9 −39.3 5.2 1.381 1.399 1.377 1.329 1.347

H36

11.2 12.8 −31.3 −29.0 40.1 1.437 1.415 1.452 1.359 1.321

I36

−44.6 46.9 −29.8 23.2 4.3 1.386 1.398 1.406 1.397 1.396

J36

The Journal of Organic Chemistry Article


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Scheme 3. Reactions of Ozonides 2j and 3j That Preserve the Ozonide Cycle

Figure 2. Highlighted dihedral angles for the 6,7,8trioxabicyclo[3.2.1]octane moiety and their implications for anomeric orbital interactions.

Scheme 2. Reduction of Ozonides 2p and 3p

whereas the addition of water to acetone is endergonic by >6 kcal/mol at the same level of theory. Furthermore, substitution of the remaining OH group to an OOH moiety in the reaction with H2O2 is >4 kcal/mol exergonic, rendering double “peroxidation” of acetone thermodynamically favorable and suggesting that the bis-hydroperoxide should be a dominant acyclic structure in the precyclization equilibrium of monocarbonyl compounds (Scheme 6). For the equilibrating systems of species derived from acetone, the bis-peroxide is clearly more favorable than the ozonide. The ∼12 kcal/mol greater exergonicity of its formation in comparison to that for the ozonide clearly indicates that the bis-peroxide is greatly favored under the thermodynamic control conditions. Bridge Length Effect on the Cyclizations. In the next step, we investigated thermodynamics of the ozonide formation in bis-carbonyl systems with a varying degree of separation between the two ketone groups (Scheme 7). Computational results reveal significant effects of bicyclic constraints on the relative stabilities of ozonides and bis-peroxides. As stated above, the bis-peroxides are clearly more favorable in monocyclic systems, without the effect of an additional bridge. A small, one-carbon, bridge accentuates this effect, and the differences between the [2.2.1] ozonides and [2.2.2] bisperoxides favors the bis-peroxide structure even more: the dramatic ∼31 kcal/mol preference. However, the large bridges (two- and three-carbons) have the opposite effect. In particular, the competition between the [3.2.1]/[3.2.2] possible products is shifted toward ozonides. For the parent systems, our DFT calculations suggest that the ozonide is 2−4 kcal/mol more stable than the peroxide. Importance of Stereolectronics on the Ozonide/Bisperoxide Competition. In order to understand why the introduction of two additional bridge atoms affect the relative stability of the trioxa and tetraoxa bicyclic structures so significantly, we have quantified the key interactions in the two bicyclic families with NBO analysis. We have shown before that stereoelectronic factors can strongly affect the stability of cyclic peroxides.54 In particular, reactivation of anomeric nO → σC−O * interactions provides significant stabilization to monocyclic bis-

peroxides with two peroxide units separated by a one-carbon methylene bridge.54a The additional bridge in bicyclic structures perturbs this orbital interaction in a manner that depends on the length of the bridge. In particular, the three-carbon bridge imposes a nonsymmetric twist on the boat conformations of the heterocyclohexane subunits of bicyclic cores. These structural distortions have a direct effect on the number and magnitude of stabilizing nO → σC−O * anomeric interactions in these systems. In particular, the geometric constraints imposed by the [3.2.2] frame deactivate two of the four nO → σ*C−O interactions in the bicyclic tetraoxane (Scheme 8). The full discussion of these stereoelectronic features can be found in the earlier communication and will not be repeated here.22 The six-membered ring in the bicyclic ozonides has two possible conformations: chair and boat. We evaluated how the differences in geometric constraints change the magnitude of anomeric interactions. The boat conformer has a single strong nO → σ*C−O donation from the peroxide moiety that amounts to 7.7 kcal/mol, while the chair conformer displays two nO → σC−O * interactions of 3.4 kcal/mol each (total 6.8 kcal/mol). Given that the chair conformation is ∼4 kcal/mol more stable 4411


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The Journal of Organic Chemistry Scheme 4. Reactions of Ozonide 2k That Preserve the Ozonide Cycle

Scheme 5. Ozonolysis of Ozonide 2h

Scheme 6. General Thermodynamic Landscape for the Reaction of Acetone with H2O2 and Water

(Supporting Information), the conformational analyses discussed below focus on the chair conformers. The geometry of the chair conformer defines the dihedral angles that correlate well with the magnitude of anomeric interactions (Figure 3). Indeed, the C1O5C4O3 = 46° corresponds to moderate endoanomeric interactions of 9.1 kcal/mol each, as expected from our observations in Scheme 8A. Weaker exoanomeric interactions (3.4 kcal/mol each) are observed at the O5C4O3O2 = 28°, and finally, complete deactivation of anomeric interactions with the σO−C * bonds was found in a good agreement with the 0° C1O2O3C4 dihedral. Adding the anomeric donations from the ether bridge to the σ* orbitals directed to the peroxide oxygens gives a total of ∼25 kcal/mol in hyperconjugative stabilizations for both boat and chair conformers. Hence, the difference is their total energies are not associated directly with the primary anomeric interactions. As the above discussion illustrates, ozonides are less stabilized by anomeric interactions than bis-peroxides. How-

ever, one should not forget that the ozonides have an intrinsic advantage over bis-peroxides by having only one weak O−O bond (bis-peroxides, of course, have two). The role of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. When the anomeric 4412


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The Journal of Organic Chemistry Scheme 8a

Scheme 7. Relative Energies of Ozonides and Bis-peroxides As a Function of Tether Length

stabilization wanes, ozonides win thermodynamic competition under the acidic equilibration conditions. Scheme 9 illustrates how the bridge size affects ozonides and bis-peroxides. The addition of one methylene bridge increases the total nO → σC−O * interactions for both functionalities by enforcing a more favorable orbital overlap. The increase is larger in the ozonide due to the very small magnitude of such interactions in the parent, nearly planar, ozonide ring taken as the reference point. Note, of course, that this increase is offset by parallel destabilizing effects (e.g., change from chair to boat in bis-peroxides, formation of a four-membered cycle in ozonides, etc.). As the bridge size increases, structural distortions start to weaken the anomeric interactions. Interestingly, this weakening is more pronounced in bisperoxides as illustrated by the reduction of the difference of stabilization energies between ozonides and bis-peroxides. In short, an increase of the bridge size is more deleterious for bisperoxides than for ozonides. Additional substituents at the bicyclic skeleton can further modify the relative stability in the ozonide/bis-peroxide pairs. For example, the bulky isopropyl group (Scheme 10) additionally favors the ozonide by ∼1 kcal/mol. Protomers Evaluation. Finally, we have considered the possible role of acidic components of the reaction mixture in shifting the equilibrium toward ozonides. The proton transfer from hydronium ion to hydrogen peroxide is highly unfavorable. (The calculated literature pKa of H3O2+ is −5.21,55 and the experimental pKa of H2O2 is 11.0.56) However, both ozonides and bis-peroxides are much more basic and should be readily protonated under the reaction conditions. Thus, we evaluated the role of protonation on the ozonide/bis-peroxide equilibrium by comparing the relative stability of the respective protonated species. The calculated thermodynamics of proton transfer between hydronium ion and the key organic and inorganic peroxide species defining the possible equilibria are given in Scheme 11. The computational results reveal large differences between the protonated ozonides and bis-peroxides. Gratifyingly, protonation shifts the equilibrium even further toward the bicyclic ozonides, which are favored in the protonated state by ∼10 kcal/mol. Interestingly, the most stable protomers in both

a (A) Conformational profile of the parent anomeric system. (B) Attenuation of anomeric interactions imposed by molecular geometry: * interactions chair and boat bis-peroxides have all four nO → σC−O activated (in other words, the p-type lone of each of the four oxygen atoms has a suitable oriented C−O bond), whereas twisted-boat bisperoxides have only two strong interactions. The 2nd order perturbation energies are in kcal/mol at the B2PLYP-D2/6-311+ +G(d,p) level of theory. (C) NBO plots for four representative nO → * interactions illustrate the effect of bicyclic structure on the orbital σC−O overlap.

cases have the peroxide bridge opened via scission of one of the C−O bonds. These structures correspond to a monocyclic oxacarbenium ion, and their formation is assisted by an entropy increase associated with the ring opening. Despite a seeming similarity, the stabilization of the cationic center differs dramatically for the opened protomers of ozonides and bisperoxides. As shown recently, the stabilization of a cationic center by an ether oxygen is more efficient than stabilization by the two oxygens of a peroxide moiety. This difference in the donor ability of the two oxygen functionalities (“the inverse αeffect”)54b accounts for the nature of the observed products. The presence of an ester group has a modest effect on the prototropic equilibrium (Scheme 12) as the two ester oxygen atoms can serve as the additional protonation sites. A relatively stable ozonide protomer was found to form upon protonation at the ester carbonyl. This cation benefits from intramolecular H-bonding of the OH group with the ether bridge oxygen. The analogous bis-peroxide protomer is ∼7 kcal/mol less stable. However, at least at the calculated free energy surface, the most stable protomers for the ozonide and bis-peroxide still 4413


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Scheme 11. Relative Thermodynamic Stability of Protomers of a Representative Ozonide and Bis-peroxidea

Figure 3. Anomeric effects in the 6,7,8-trioxabicyclo[3.2.1]octane moiety are directly dependent on its dihedrals.

Scheme 9. Bridge Size Effect on the Sum of Anomeric Interactions in Ozonides and Bis-peroxidesa

a

Energies in kcal/mol.

■

CONCLUSION A general approach to the preparation of bicyclic ozonides is developed via the reaction of 1,5-diketones with H2O2, promoted by acids such as BF3·Et2O, H2SO4, p-TsOH, and HBF4. This process leads to the stereoisomeric bridged ozonides and provides a rare example of selective synthesis of ozonides without the use of ozone. The ozonide products are stable and can be isolated by column chromatography and fully characterized by NMR spectroscopy, mass-spectrometry, X-ray, and elemental analysis. The commonly expected bis-peroxide products, originating from the reaction of a bis-ketone with two molecules of H2O2, were not detected. Computational analysis suggests that acyclic bis-hydroperoxides should be dominant in the precyclization equilibrium of monocarbonyl compounds. The cyclization selectivity depends on the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in the [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the three-carbon bridge. Protonation further stabilizes ozonides in comparison to tetraoxanes and may also contribute to the high yields and selectivity for formation of the [3.2.1] bicyclic products. The synthesis provides practical access to gram quantities of the target ozonides including ozonides with pendant alkene and alkyne substituents that are not compatible with the classic peroxide routes. The ozone-free approach to ozonides reported in this work makes this field of peroxide chemistry readily available for further exploration.

a Only the interactions of the p-type oxygen lone pairs with the vicinal σ*C−O orbitals are considered.

Scheme 10. Relative Thermodynamic Stability of Diastereomeric Ozonides and Bis-peroxides Derived from the Substituted 1,5-Diketonesa

a

Energies in kcal/mol, at the (SMD = MeCN)/M06-2X/6-311+ +G(d,p) level of theory.

correspond to the open structures. Note that the attack of water at the cationic center of the open bis-peroxide followed by intramolecular displacement of the OOH moiety can transform this species to the isolated ozonide product. 4414


Article


ratio was from m/z 50 to 3000 Da, and external/internal calibration was done with an electrospray calibrant solution. A syringe injection was used for solutions in MeCN (flow rate 3 μL/min). Nitrogen was applied as a dry gas; the interface temperature was set at 180 °C. The TLC analysis was carried out on silica gel chromatography plates: Macherey-Nagel Alugram UV254; sorbent silica 60, specific surface (BET) ∼ 500 m2/g, mean pore size 60 Å, specific pore volume 0.75 mL/g, particle size 5−17 μm; binder highly polymeric product, which is stable in almost all organic solvents and resistant toward aggressive visualization reagents. The melting points were determined on a Kofler hot-stage apparatus. Chromatography of 1,5-diketones was performed on silica gel (0.060−0.200 mm, 60 Å, CAS 7631-86-9). Chromatography of ozonides was performed on silica gel (0.040−0.060 mm, 60 Å, CAS 7631-86-9). Dichloromethane, acetonitrile, petroleum ether (PE) (40:70), ethyl acetate (EA), ethyl acetoacetate, tert-butyl acetoacetate, methyl vinyl ketone, benzyl and alkyl halides, 98% H2SO4, p-TsOH·H2O, HBF4 (50% aqueous solution), BF3·Et2O, H2O2 (35% aqueous solution), MgSO4, NaHCO3, NaI, CeCl3·7H2O, and Na2S2O3 were purchased from Acros. A solution of H2O2 in Et2O (3.7 M) was prepared by the extraction with Et2O (5 × 100 mL) from a 35% aqueous solution (100 mL) followed by drying over MgSO4. For the synthesis of ozonides, acetonitrile was distilled over P2O5. Synthesis of 1,5-Diketones 1a−v. 1,5-Diketones 1a−r,22,23 1s,24 and 1t,u25 and 1,5-diketoaldehyde 1v22,26 were synthesized according to known procedures. 1,5-Diketones 1f,k,n,q are previously undescribed compounds. Other 1,5-diketones and 1,5-diketoaldehyde 1v are known compounds. General Procedure for Preparation of 1,5-Diketones 1f,k,n,q. Methyl vinyl ketone (1.2 mol/1.0 mol of β-keto ester), cerium(III) chloride (0.2 mol/1.0 mol of β-keto ester), and sodium iodide (0.1 mol/1.0 mol of β-keto ester) were successively added with stirring to the corresponding β-keto ester (1.5 g. 4.06−5.85 mmol) at 20−25 °C. Solid β-keto esters were dissolved in 5 mL of CH3CN prior to the reaction, whereas liquid β-keto esters can be used neat. The reaction mixture was stirred at room temperature for 24 h. Then EtOAc (30 mL) was added, and the reaction mixture was stirred another 30 min. After that, the mixture was transferred into a separating funnel, and H2O (10 mL) and two drops of 36% aq HCl were added. The aqueous phase was separated; the organic phase was washed by a saturated aq solution of Na2S2O3 and then with water (2 × 10 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. 1,5-Diketones were isolated by chromatography on SiO2 using the PE/EA mixture as the eluent with a gradient of EA from 10 to 90 vol % Ethyl 2-Acetyl-5-oxohexanoate (1a): colorless oil; yield 67%, 1.55g, 7.72 mmol; Rf = 0.52 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.99− 2.18 (m, 2H), 2.11 (s, 3H), 2.22 (s, 3H), 2.48 (t, J = 7.1 Hz, 2H), 3.47 (t, J = 7.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.58 Ethyl 5-Methyl-3-oxo-2-(3-oxobutyl)hexanoate (1b): light yellow oil; yield 87%, 1,83 g, 7.57 mmol; Rf = 0.43 (TLC, PE/ EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 0.88 (d, J = 2.3 Hz, 3H), 0.90 (d, J = 2.3 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.95−2.25 (m, 3H), 2.10 (s, 3H), 2.34−2.43 (m, 2H), 2.46 (t, J = 7.1 Hz, 2H), 3.46 (t, J = 7.1 Hz, 1H), 4.15 (q, J = 7.1 Hz,

Scheme 12. Relative Thermodynamic Stability of Protomers of a Representative Ozonide (Top) and Bis-peroxide (Bottom) Substituted with an Ester groupa

a

Energies in kcal/mol.

■

EXPERIMENTAL SECTION Caution! Although we have encountered no difficulties in working with the peroxides described below, the proper precautions, such as the use of shields and fume hoods and the avoidance of transition metal salts, heating, and shaking, should be taken whenever possible. General Information. NMR spectra were recorded on a commercial instrument (300.13 MHz for 1H, 75.48 MHz for 13 C) in CDCl3. High resolution mass spectra (HRMS) were measured using electrospray ionization (ESI); the mass analyzer type is TOF.57 The measurements were done in a positive ion mode (interface capillary voltage 4500 V); the mass 4415


Article

The Journal of Organic Chemistry 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 21.8, 22.5, 22.6, 24.3, 30.0, 40.7, 51.0, 57.9, 61.5, 169.6, 204.6, 207.5. Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C, 64.67; H, 9.28. tert-Butyl 2-Acetyl-5-oxohexanoate (1c): yellow oil; yield 62%, 1.34 g, 5.88 mmol; Rf = 0.28 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.37 (s, 9H), 1.89−2.00 (m, 2H), 2.04 (s, 3H), 2.13 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 3.30 (t, J = 7.2 Hz, 1H). The physical and spectral data were consistent with those previously reported.23a Ethyl 2-Acetyl-2-methyl-5-oxohexanoate (1d): colorless oil; yield 92%, 2.05 g, 9.57 mmol; Rf = 0.36 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H), 1.29 (s, 3H), 1.92−2.16 (m, 2H), 2.09 (s, 3H), 2.11 (s, 3H), 2.26−2.46 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.58 Ethyl 2-Acetyl-2-ethyl-5-oxohexanoate (1e): slightly yellow oil; yield 67%, 1.45 g, 6.35 mmol; Rf = 0.29 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 0.72 (t, J = 7.6 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.73−1.92 (m, 2H), 1.93−2.35 (m, 10H), 4.13 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.59 Ethyl 2-Acetyl-2-butyl-5-oxohexanoate (1f): slightly yellow oil; yield 79%, 1.63 g, 6.36 mmol; Rf = 0.38 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 0.80 (t, J = 7.3 Hz, 3H), 0.90−1.09 (m, 2H), 1.12−1.30 (m, 5H), 1.63−1.84 (m, 2H), 1.90−2.13 (m, 8H), 2.16−2.34 (m, 2H), 4.05−4.18 (m, 2H); 13C NMR (75.48 MHz, CDCl3) δ 13.8, 14.0, 23.0, 25.1, 26.0, 26.7, 29.9, 31.9, 38.3, 61.3, 62.5,172.2, 205.2, 207.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C14H24NaO4]+ 279.1567, found 279.1571. Anal. Calcd for C14H24O4: C, 65.60; H, 9.44. Found: C, 65.62; H, 9.53. Ethyl 2-Acetyl-2-(3-oxobutyl)octanoate (1g): slightly yellow oil; yield 71%, 1.41 g, 4.97 mmol; Rf = 0.33 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 0.85 (t, J = 6.6 Hz, 3H), 0.97−1.17 (m, 2H), 1.19−1.34 (m, 9H), 1.69−1.91 (m, 2H), 1.98−2.22 (m, 8H), 2.23−2.41 (m, 2H), 4.12−4.24 (m, 2H). The physical and spectral data were consistent with those previously reported.22 Ethyl 2-Acetyl-2-allyl-5-oxohexanoate (1h): colorless oil; yield 80%, 1.69 g, 7.05 mmol; Rf = 0.45 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 2.00− 2.19 (m, 8H), 2.21−2.43 (m, 2H), 2.48−2.64 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 5.01−5.13 (m, 2H), 5.47−5.65 (m, 1H). The physical and spectral data were consistent with those previously reported.60 Ethyl 2-Acetyl-5-oxo-2-(prop-2-yn-1-yl)hexanoate (1i): colorless oil; yield 69%, 1.47 g, 6.17 mmol; Rf = 0.31 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 1.99 (t, J = 2.6 Hz, 1H), 2.07−2.45 (m, 4H), 2.11 (s, 3H), 2.16 (s, 3H), 2.62−2.79 (m, 2H), 4.12−4.27 (m, 2H). The physical and spectral data were consistent with those previously reported.22 Diethyl 2-Acetyl-2-(3-oxobutyl)succinate (1j): slightly yellow oil; yield 76%, 1.51 g, 5.27 mmol; Rf = 0.23 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 2.10 (s, 3H), 2.15−2.40 (m, 4H), 2.23 (s, 3H), 2.77−2.92 (m, 2H), 4.07 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.60 Diethyl 2-Acetyl-2-(3-oxobutyl)pentanedioate (1k): slightly yellow oil; yield 82%, 1.60 g, 5.34 mmol; Rf = 0.41 (TLC, PE/

EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.14−1.34 (m, 6H), 1.97−2.25 (m, 12H), 2.26−2.46 (m, 2H), 4.01−4.26 (m, 4H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 14.3, 25.3, 26.9, 27.0, 29.2, 30.1, 38.1, 60.8, 61.7, 61.8, 171.8, 172.7, 204.7, 207.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C15H24NaO6]+ 323.1465, found 323.1461. Anal. Calcd for C15H24O6: C, 59.98; H, 8.05. Found: C, 60.10; H, 8.15. Ethyl 2-Acetyl-2-(2-cyanoethyl)-5-oxohexanoate (1l): slightly yellow crystals; yield 64%, 1.33 g, 5.24 mmol; mp = 52−54 °C (lit.1 mp = 52−54 °C); Rf = 0.26 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.93−2.50 (m, 8H), 2.12 (s, 3H), 2.15 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.22 Ethyl 2-Acetyl-2-benzyl-5-oxohexanoate (1m): white crystals; yield 73%, 1.44 g, 4.97 mmol; mp = 48−49 °C; Rf = 0.56 (TLC, PE/EA, 2:1). 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 2.00−2.23 (m, 2H), 2.15 (s, 3H), 2.16 (s, 3H), 2.28−2.57 (m, 2H), 3.08−3.31(m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H), 7.21−7.33 (m, 3H). The physical and spectral data were consistent with those previously reported.61 Ethyl 2-Acetyl-2-(4-bromobenzyl)-5-oxohexanoate (1n): white crystals; yield 85%, 1.57 g, 4.26 mmol; mp = 74−76 °C; Rf = 0.53 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 1.96−2.18 (m, 2H), 2.11 (s, 3H), 2.12 (s, 3H), 2.24−2.50 (m, 2H), 3.04 (d, J = 14.1 Hz, 1H), 3.17 (d, J = 14.1 Hz, 1H), 4.06−4.24 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 25.7, 27.7, 30.1, 37.9, 38.3, 61.7, 63.9, 121.3, 131.65, 131.7, 135.1, 171.6, 205.0, 206.8; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C17H21BrNaO4]+ 391.0515, found 391.0511. Anal. Calcd for C17H21BrO4: C, 55.30; H, 5.73; Br, 21.64. Found: C, 55.30; H, 5.78; Br, 21.72. tert-Butyl 2-Acetyl-2-(4-bromobenzyl)-5-oxohexanoate (1o): colorless oil; yield 85%, 1.55 g, 3.90 mmol; Rf = 0.37 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.42 (s, 9H), 1.96−2.47 (m, 4H), 2.11 (s, 3H), 2.12 (s, 3H), 3.01 (d, J = 14.1 Hz, 1H), 3.12 (d, J = 14.1 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H). The physical and spectral data were consistent with those previously reported.22 Ethyl 2-Acetyl-2-(4-nitrobenzyl)-5-oxohexanoate (1p): white crystals; yield 85%, 1.61 g, 4.81 mmol; mp = 84−86 °C (lit.1 mp = 84−86 °C); Rf = 0.36 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 2.01− 2.22 (m, 2H), 2.13 (s, 3H), 2.14 (s, 3H), 2.26−2.52 (m, 2H), 3.13 (d, J = 13.9 Hz, 1H), 3.32 (d, J = 13.9 Hz, 1H), 4.05−4.24 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.6 Hz, 2H). The physical and spectral data were consistent with those previously reported.22 Ethyl 2-Acetyl-2-(4-methylbenzyl)-5-oxohexanoate (1q): white crystals; yield 79%, 1.54 g, 5.06 mmol; mp = 62−64 °C; Rf = 0.67 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.94−2.19 (m, 2H), 2.11 (s, 3H), 2.13 (s, 3H), 2.23−2.53 (m, 2H), 2.28 (s, 3H), 2.99−3.25 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 21.1, 25.5, 27.7, 30.1, 38.0, 38.4, 61.6, 64.0, 129.2, 129.8, 132.7, 136.8, 171.9, 205.4, 207.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C18H24NaO4]+ 327.1567, found 327.1562. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.01; H, 7.96. 4416


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at 20−25 °C for 1 h. The followings steps of the procedure were the same as in runs 1−4. Procedure for Peroxidation of 1p with the Use of a 35% Aqueous Solution of H2O2 and H2SO4 (Table 1, Runs 12−19). A 35% aqueous solution of H2O2 (0.152 g, 1.56 mmol, 1.5 mol H2O2/1.0 mol 1p; in the case of run 14: 0.304 g, 3.12 mmol, 3.0 mol H2O2/1.0 mol 1p) and 98% H2SO4 (0.104−1.144 g, 1.04−11.44 mmol, 1.0−11.0 mol H2SO4/1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h or 5 h. The followings steps of the procedure were the same as in runs 1−4. Procedure for Peroxidation of 1p with the Use of a 35% Aqueous Solution of H2O2 and p-TsOH·H2O (Table 1, Runs 20 and 21). A 35% aqueous solution of H2O2 (0.152 g, 1.56 mmol, 1.5 mol H2O2/1.0 mol 1p) and p-TsOH·H2O (1.582−1.978g, 8.32−10.4 mmol, 8.0−10.0 mol p-TsOH·H2O/ 1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. The followings steps of the procedure were the same as in runs 1−4. Procedure for Peroxidation of 1p with the Use of a 35% Aqueous Solution of H2O2 and 50% Aqueous HBF4 (Table 1, Runs 22 and 23). A 35% aqueous solution of H2O2 (0.152 g, 1.56 mmol, 1.5 mol H2O2/1.0 mol 1p) and 50% aqueous solution of HBF4 (1.46−2.16 g, 8.32−12.48 mmol, 8.0−12.0 mol HBF4/1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h or 5 h. The followings steps of the procedure were the same as in runs 1−4. Experimental Procedures for Tables 2−5. General Procedure for the Synthesis of Ozonides from Diketones 1a−u and Ketoaldehyde 1v. A 3.7 M ethereal solution of H2O2 (0.36−0.84 mL, 1.32−3.09 mmol, 1.5 mol H2O2/1.0 mol 1a−v) and BF3·Et2O (0.062−0.146 g, 0.44−1.03 mmol, 0.5 mol BF3·Et2O/1.0 mol 1a−v) were successively added with stirring to a solution of 1,5-dicarbonyl compound 1a−v (0.350 g, 0.88−2.06 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. After that, a mixture of CH2Cl2/PE = 1:1 (10 mL) and water (0.5 mL) were added. Then NaHCO3 was added with stirring until the pH reached 7.0. The precipitate was filtered off, and the filtrate was dried over MgSO4. The precipitate was filtered off, and the solvent was removed in the vacuum of a water jet pump. Ozonides 2a−q, 2t−v, and 3a−q in individual form were isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 1 to 5 vol %. Mixtures of ozonides 2a−s and 3a−s were isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 5 to 20 vol %. Mixtures: 2a and 3a 257.0 mg, 1.19 mmol, yield 68%; 2b and 3b 85.8 mg, 0.33 mmol, yield 23%; 2c and 3c 228.5 mg, 0.94 mmol, yield 61%; 2d and 3d 267.1 mg, 1.16 mmol, yield 71%; 2e and 3e 247.2 mg, 1.01 mmol, yield 66%; 2f and 3f 323.5 mg, 1.19 mmol, yield 87%; 2g and 3g 310.5 mg, 1.03 mmol, yield 84%; 2h and 3h 309.8 mg, 1.21 mmol, yield 83%; 2i and 3i 183.0 mg, 0.72 mmol, yield 49%; 2j and 3j 240.2 mg, 0.79 mmol, yield 65%; 2k and 3k 280.2 mg, 0.89 mmol, yield 76%; 2l and 3l 316.3 mg, 1.17 mmol, yield 85%; 2m and 3m 306.5 mg, 1.00 mmol, yield 83%; 2n and 3n 328.6 mg, 0.85 mmol,

Ethyl 2-Oxo-1-(3-oxobutyl)cyclohexanecarboxylate (1r): slightly yellow oil; yield 87%, 1.84 g, 7.66 mmol; Rf = 0.35 (TLC, PE/EA, 5:1); 1H HMR (300.13 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H), 1.33−2.10 (m, 7H), 2.07 (s, 3H), 2.22−2.59 (m, 5H), 4.15 (q, J = 7.1 Hz, 2H). The physical and spectral data were consistent with those previously reported.58 2,2′-Methylenedicyclohexanone (1s): white crystals with a colorless oil; yield 45%, 2.50 g, 12.0 mmol; 1H NMR (300.13 MHz, CDCl3) δ 0.77−2.55 (m, 20H); 13C NMR (75.48 MHz, CDCl3) δ 25.0, 25.3, 28.2, 28.4, 29.8, 30.7, 34.5, 35.5, 42.1, 42.5, 47.9, 49.1, 213.4, 214.0. The physical and spectral data were consistent with those previously reported.24 4-Phenylheptane-2,6-dione (1t): colorless oil; yield 75%, 0.81 g, 3.98 mmol; 1H NMR (300.13 MHz, CDCl3) δ 2.06 (s, 6H, CH3), 2.70−2.87 (m, 4H, CH2), 3.65−3.78 (m, 1H, CH), 7.17−7.34 (m, 5H, CH); 13C NMR (75.48 MHz, CDCl3) δ 30.5, 36.6, 49.8, 126.9, 127.4, 128.8, 143.6, 207.3. The physical and spectral data were consistent with those previously reported.25 4-Isopropylheptane-2,6-dione (1u): colorless oil; yield 70%, 0.77 g, 4.53 mmol; 1H NMR (300.13 MHz, CDCl3) δ 0.84 (d, J = 6.8 Hz, 6H), 1.61−1.74 (m, 1H), 2.13 (s, 6H), 2.19−2.50 (m, 5H). The physical and spectral data were consistent with those previously reported.25 5-Oxo-3-phenylhexanal (1v): colorless oil; yield 80%, 0.76 g, 4.0 mmol; 1H NMR (300.13 MHz, CDCl3) δ 2.04 (s, 3H), 2.64−2.86 (m, 4H), 3.65−3.84 (m, 1H), 7.11−7.37 (m, 5H). 9.63 (s, 1H). The physical and spectral data were consistent with those previously reported.22 Procedure for Peroxidation of 1p with the Use of a 35% Aqueous Solution of H2O2 and BF3·Et2O (Table 1, Runs 1−4). A 35% aqueous solution of H2O2 (0.152 g, 1.56 mmol, 1.5 mol H2O2/1.0 mol 1p) and BF3·Et2O (0.148−0.886 g, 1.04−6.24 mmol, 1.0−6.0 mol BF3·Et2O/1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. After that time, a mixture of CH2Cl2/PE = 1:1 (10 mL) and water (0.5 mL) was added. Then, NaHCO3 was added with stirring until the pH reached 7.0. The precipitate was filtered off. The filtrate was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. The yields of 2p and 3p were determined from the 1H NMR spectroscopic data. (The characteristic signal is a singlet of the CH3CCH2 group at 1.50 ppm for the ozonide 2p and 1.57 ppm for the ozonide 3p.) 1,4Dinitrobenzene was used as the internal standard. Procedure for Peroxidation of 1p with the Use of a 3.7 M Ethereal Solution of H2O2 and BF3·Et2O (Table 1, Runs 5−10). A 3.7 M ethereal solution of H2O2 (0.28−0.84 mL, 1.04−3.12 mmol, 1.0−3.0 mol H2O2/1.0 mol 1p) and BF3· Et2O (0.074−0.59 g, 0.52−4.16 mmol, 0.5−4.0 mol BF3·Et2O/ 1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. The followings steps of the procedure were the same as in runs 1−4. Procedure for Peroxidation of 1p with the Use of a Complex of H2O2 with Urea and BF3·Et2O (Table 1, Run 11). A complex of H2O2 with urea (0.146 g, 1.56 mmol; 1.5 mol H2O2/1.0 mol 1p) and BF3·Et2O (0.074 g, 0.52 mmol; 0.5 mol BF3·Et2O/1.0 mol 1p) were successively added with stirring to a solution of 1,5-diketone 1p (0.350 g, 1.04 mmol) in CH3CN (5 mL) at 20−25 °C. The reaction mixture was stirred 4417


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physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2S*,5S*)-1,2,5-Trimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2d): colorless oil; yield 37%, 139.2 mg, 0.60 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.20 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.65 (s, 3H), 1.71−1.80 (m, 1H), 1.97−2.15 (m, 3H), 4.17 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.6, 20.8, 21.9, 28.7, 33.1, 49.1, 61.0, 109.5, 110.9, 173.7. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2S*,5R*)-1,2,5-Trimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3d): colorless oil; yield 20%, 75.2 mg, 0.33 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.36 (s, 3H), 1.46−1.60 (m, 1H), 1.50 (s, 3H), 1.56 (s, 3H), 1.74−1.96 (m, 2H), 2.59−2.75 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.7, 19.5, 20.8, 28.0, 31.0, 48.9, 61.0, 108.7, 110.8, 174.1. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2S*,5S*)-2-Ethyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2e): colorless oil; yield 52%, 194.8 mg, 0.80 mmol; Rf = 0.42 (TLC, PE/EA, 20:1); 1H NMR (300.13 MHz, CDCl3) δ 0.79 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.37−1.54 (m, 1H), 1.47 (s, 3H), 1.67 (s, 3H), 1.74−1.99 (m, 3H), 2.04−2.32 (m, 2H), 4.19 (q, J = 7.2 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 8.2, 14.3, 18.7, 20.6, 25.2, 28.1, 33.0, 53.8, 61.0, 108.9, 111.4, 172.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C12H20NaO5]+ 267.1203, found 267.1203. Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 59.02; H, 8.30. Ethyl (1S*,2S*,5R*)-2-Ethyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3e): colorless oil; yield 9%, 33.7 mg, 0.14 mmol; Rf = 0.36 (TLC, PE/EA, 20:1); 1 H NMR (300.13 MHz, CDCl3) δ 0.84 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.58 (s, 3H), 1.62−2.01 (m, 5H), 2.59−2.73 (m, 1H), 4.16 (q, J = 7.4 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 9.3, 14.3, 18.9, 20.7, 21.7, 24.5, 31.1, 53.7, 60.9, 109.6, 111.3, 172.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C12H20NaO5]+ 267.1203, found 267.1207. Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 59.20; H, 8.32. Ethyl (1R*,2S*,5S*)-2-Butyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2f): slightly yellow oil; yield 40%, 148.7 mg, 0.55 mmol; Rf = 0.40 (TLC, PE/EA, 20:1); 1H NMR (300.13 MHz, CDCl3) δ 0.86 (t, J = 7.0 Hz, 3H, CH3CH2CH2), 0.80−1.06 (m, 1H, CCH2CH2CH2), 1.18− 1.34 (m, 3H, CCH2CH2CH2), 1.27 (t, J = 7.0 Hz, 3H, CH3CH2O), 1.35−1.53 (m, 1H, CCH2CH2CH2), 1.46 (s, 3H, CH3CCH2), 1.67 (s, 3H, CH3CC), 1.72−1.97 (m, 3H, CCH2CH2CH2, CH2CCH3, C(O)CCH2CH2), 2.05−2.19 (m, 2H, CH 2 CCH 3 , C(O)CCH 2 CH 2 ), 4.11−4.25 (m, 2H, OCH 2 CH 3 ); 13 C NMR (75.48 MHz, CDCl3 ) δ 14.0 (CH 3 CH 2 ), 14.3 (CH 3 CH 2 O), 18.7 (CH 3 CC), 20.6 (CH3CCH2), 23.1 (CCH2CH2CH2), 25.7 (C(O)CCH2CH2), 26.0 (CCH2CH2), 33.0 (CH3CCH2), 34.9 (CCH2CH2CH2), 53.3 (CH2CC), 60.9 (OCH2CH3), 109.6 (OCCH2), 111.3 (OCC), 173.0 (C(O)OEt); HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C14H24NaO5]+ 295.1516, found 295.1514. Anal. Calcd for C14H24O5 C, 61.74; H, 8.88. Found: C, 62.02; H, 8.73. Ethyl (1S*,2S*,5R*)-2-Butyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3f): colorless oil; yield 25%, 93.0 mg, 0.34 mmol; Rf = 0.33 (TLC, PE/EA, 20:1);

yield 90%; 2o and 3o 254.9 mg, 0.62 mmol, yield 70%; 2p and 3p 330.0 mg, 0.94 mmol, yield 90%; 2q and 3q 257.9 mg, 0.80 mmol, yield 70%. Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2a): colorless oil; yield 20%, 75.6 mg, 0.35 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.62 (s, 3H), 1.67−1.81 (m, 1H), 1.81−2.01 (m, 1H), 2.02−2.27 (m, 1H), 2.27−2.50 (m, 1H), 2.73 (d, J = 6.2 Hz, 1H), 4.04−4.29 (m, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 20.5, 21.0, 21.1, 31.1, 46.8, 60.9, 108.1, 110.0, 171.3. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2S*,5R*)-1,5-Dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3a): white crystals; yield 48%, 181.4 mg, 0.84 mmol; mp = 50−51 °C (lit.22 mp = 49−50 °C); 1 H NMR (300.13 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.70−1.98 (m, 3H), 2.37−2.57 (m, 1H), 2.77 (dd, J = 12.3, 4.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H); 13 C NMR (75.48 MHz, CDCl3) δ 14.3, 20.4, 21.0, 21.3, 33.4, 49.4, 60.9, 107.7, 108.7, 171.6. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*, 2S* ,5S* )- 1-Isobutyl- 5-methyl-6 ,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2b): colorless oil; yield 5%, 18.7 mg, 0.07 mmol; Rf = 0.53 (TLC, PE/EA, 10:1); 1 H NMR (300.13 MHz, CDCl3) δ 0.93 (d, J = 2.3 Hz, 3H), 0.95 (d, J = 2.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.67−2.07 (m, 5H, CH2), 2.09−2.24 (m, 1H), 2.29−2.46 (m, 1H), 2.76 (d, J = 6.1 Hz, 1H), 4.06−4.27 (m, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 20.6, 21.0, 23.3, 24.2, 31.3, 42.6, 45.7, 60.8, 109.2, 109.7, 171.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H22NaO5]+ 281.1359, found 281.1369. Anal. Calcd for C13H22O5: C, 60.45; H, 8.58. Found: C, 60.60; H, 8.72. Ethyl (1S*, 2S* ,5R* )- 1-Isobutyl- 5-methyl-6 ,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3b): colorless oil; yield 15%, 56.0 mg, 0.22 mmol; Rf = 0.45 (TLC, PE/EA, 10:1); 1 H NMR (300.13 MHz, CDCl3) δ 0.93 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.49 (s, 3H), 1.45−1.65 (m, 1H), 1.67−2.07 (m, 5H, CH2), 2.36−2.54 (m, 1H), 2.76 (dd, J = 12.2, 4.8 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H); 13 C NMR (75.48 MHz, CDCl3) δ 14.3, 20.9, 21.6, 23.2, 23.5, 24.3, 33.4, 41.1, 48.8, 60.8, 108.5, 109.2, 171.9; HRMS (ESITOF) m/z [M + Na]+ calcd for [C13H22NaO5]+ 281.1359, found 281.1369. Anal. Calcd for C13H22O5: C, 60.45; H, 8.58. Found: C, 60.62; H, 8.70. tert-Butyl (1R*,2S*,5S*)-1,5-Dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2c): white crystals; yield 24%, 90.0 mg, 0.37 mmol; mp = 38−39 °C (lit.22 mp = 38−39 °C); 1 H NMR (300.13 MHz, CDCl3) δ 1.46 (s, 9H), 1.50 (s, 3H), 1.61 (s, 3H), 1.71 (dd, J = 13.4, 5.8 Hz, 1H), 1.85 (dd, J = 13.4, 5.8, Hz, 1H), 2.12 (td, J = 13.4, 5.8 Hz, 1H), 2.24−2.41 (m, 1H), 2.63 (d, J = 6.3 Hz, 1H); 13C NMR (75.48 MHz, CDCl3) δ 20.5, 21.0, 21.2, 28.2, 31.0, 47.6, 81.3, 108.3, 109.9, 170.6. The physical and spectral data were consistent with those previously reported.22 tert-Butyl (1S*,2S*,5R*)-1,5-Dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3c): white crystals; yield 34%, 127.3 mg, 0.52 mmol; mp = 34−35 °C (lit.22 mp = 34−35 °C); 1 H NMR (300.13 MHz, CDCl3) δ 1.44 (s, 9H), 1.49 (s, 3H), 1.57 (s, 3H), 1.68−1.96 (m, 3H), 2.32−2.51 (m, 1H), 2.66 (dd, J = 12.3, 4.8 Hz, 1H); 13C NMR (75.48 MHz, CDCl3) δ 20.4, 21.0, 21.3, 28.1, 33.5, 50.1, 81.3, 107.9, 108.6, 170.9. The 4418


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The Journal of Organic Chemistry H NMR (300.13 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H, CH3CH2CH2), 1.00−1.14 (m, 1H, CCH2CH2CH2), 1.18−1.37 (m, 3H, CCH2CH2CH2), 1.25 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.48 (s, 3H, CH3CCH2), 1.57 (s, 3H, CH3CC), 1.61−1.90 (m, 5H, CCH2CH2CH2, CH2CCH3, C(O)CCH2CH2), 2.59−2.74 (m, 1H, C(O)CCH2CH2), 4.15 (q, J = 7.1 Hz, 2H, OCH 2 CH 3 ); 13 C NMR (75.48 MHz, CDCl 3 ) δ 14.0 (CH 3 CH 2 ), 14.2 (CH 3 CH 2 O), 18.9 (CH 3 CC), 20.7 (CH3CCH2), 22.3 (C(O)CCH2CH2), 23.3 (CCH2CH2CH2), 27.2 (CCH2CH2), 31.2 (CH3CCH2), 31.4 (CCH2CH2CH2), 53.4 (CH2CC), 61.0 (OCH2CH3), 108.9 (OCCH2), 111.4 (OCC), 173.0 (C(O)OEt); HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C14H24NaO5]+ 295.1516, found 295.1510. Anal. Calcd for C14H24O5: C, 61.74; H, 8.88. Found: C, 62.00; H, 8.63. Ethyl (1R*,2S*,5S*)-2-Hexyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2g): slightly yellow oil; yield 65%, 240.3 mg, 0.80 mmol; 1H NMR (300.13 MHz, CDCl3) δ 0.86 (t, J = 6.7 Hz, 3H), 0.91−1.08 (m, 1H), 1.18− 1.34 (m, 10H), 1.36−1.50 (m, 1H), 1.47 (s, 3H), 1.68 (s, 3H), 1.73−1.97 (m, 3H), 2.06−2.19 (m, 2H), 4.14−4.23 (m, 2H); 13 C NMR (75.48 MHz, CDCl3) δ 14.1, 14.3, 18.8, 20.7, 22.7, 23.8, 25.7, 29.7, 31.7, 33.0, 35.2, 53.4, 60.9, 109.6, 111.3, 173.0. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2S*,5R*)-2-Hexyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3g): colorless oil; yield 9%, 33.3 mg, 0.11 mmol; 1H NMR (300.13 MHz, CDCl3) δ 0.79−0.94 (m, 3H), 0.97−1.36 (m, 11H), 1.49 (s, 3H), 1.58 (s, 3H), 1.62−1.90 (m, 5H), 2.58−2.77 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 14.3, 18.9, 20.7, 22.4, 22.7, 25.0, 29.9, 31.2, 31.75, 31.78, 53.4, 61.0, 108.9, 111.4, 173.0. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-2- Allyl-1,5-dimethyl-6,7,8 trioxabicyclo[3.2.1]octane-2-carboxylate (2h): slightly yellow oil; yield 40%, 149.3 mg, 0.58 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 1.68 (s, 3H), 1.73−2.23 (m, 5H), 2.63 (dd, J = 13.2, 6.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.99−5.14 (m, 2H), 5.50−5.70 (m, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 18.7, 20.7, 26.0, 32.9, 39.8, 53.1, 61.1, 109.8, 110.9, 118.9, 132.4, 172.4. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2R*,5R*)-2- Allyl-1,5-dimethyl-6,7,8 trioxabicyclo[3.2.1]octane-2-carboxylate (3h): slightly yellow oil; yield 23%, 85.9 mg, 0.33 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.50 (s, 3H), 1.57 (s, 3H), 1.60−1.83 (m, 3H), 2.47 (dd, J = 13.9, 8.7 Hz, 1H), 2.56−2.77 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 5.03−5.14 (m, 2H), 5.54− 5.72 (m, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 18.8, 20.8, 22.7, 30.8, 36.4, 52.8, 61.2, 109.0, 110.9, 118.8, 133.7, 172.6. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-1,5-Dimethyl-2-(prop-2-yn-1-yl)-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2i): slightly yellow oil; yield 31%, 115.8 mg, 0.46 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.45 (s, 3H), 1.58 (s, 3H), 1.74−1.84 (m, 1H), 1.88−2.08 (m, 2H), 2.10−2.36 (m, 3H), 2.75 (dd, J = 16.2, 2.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 18.3, 20.5, 25.6, 26.2, 32.9, 52.3, 61.3, 71.1, 79.1, 109.7, 110.0, 171.4. The physical and spectral data were consistent with those previously reported.22 1

Ethyl (1S*,2R*,5R*)-1,5-Dimethyl-2-(prop-2-yn-1-yl)-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3i): white crystals; yield 14%, 52.3 mg, 0.21 mmol; mp = 62−64 °C (lit.22 mp = 62−64 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.52 (s, 3H), 1.75−1.88 (m, 2H), 1.94− 2.07 (m, 2H), 2.64 (dd, J = 16.7, 2.7 Hz, 1H), 2.69−2.90 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.6, 20.7, 22.6, 23.5, 30.8, 52.7, 61.5, 71.2, 80.2, 109.3, 110.0, 171.6. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-2-(2-Ethoxy-2-oxoethyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2j): colorless oil; yield 28%, 103.5 mg, 0.34 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.49 (s, 3H), 1.60 (s, 3H), 1.73−1.83(m, 1H), 1.93−2.03 (m, 1H), 2.23−2.37 (m, 2H), 2.45 (d, J = 15.6 Hz, 1H), 2.99 (d, J = 15.6 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 14.3, 18.5, 20.7, 25.8, 32.7, 40.5, 50.8, 60.8, 61.4, 110.0, 110.2, 170.4, 171.9. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2R*,5R*)-2-(2-Ethoxy-2-oxoethyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3j): colorless oil; yield 18%, 66.5 mg, 0.22 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.53 (s, 3H), 1.79−1.89 (m, 2H), 1.90−2.00 (m, 1H), 2.77 (d, J = 16.6 Hz, 1H), 2.83−2.97 (m, 1H), 3.01 (d, J = 16.6 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 14.3, 18.8, 20.6, 23.6, 31.1, 36.9, 51.1, 60.8, 61.5, 109.1, 110.2, 171.0, 172.0. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-2-(3-Ethoxy-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2k): colorless oil; yield 53%, 195.4 mg, 0.62 mmol; Rf = 0.45 (TLC, PE/ EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 1.68 (s, 3H), 1.72− 2.36 (m, 8H), 4.10 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 14.3, 18.7, 20.6, 25.4, 29.1, 30.1, 32.8, 52.5, 60.7, 61.3, 109.6, 110.0, 172.3, 172.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C15H24NaO7]+ 339.1414, found 339.1412. Anal. Calcd for C15H24O7: C, 56.95; H, 7.65. Found: C, 57.05; H, 7.70. Ethyl (1S*,2R*,5R*)-2-(3-Ethoxy-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3k): colorless oil, yield 19%, 70.0 mg, 0.22 mmol; Rf = 0.33 (TLC, PE/ EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.18−1.30 (m, 6H), 1.48 (s, 3H), 1.56 (s, 3H), 1.52−1.63 (m, 1H), 1.72−1.86 (m, 2H), 2.05−2.29 (m, 4H), 2.62−2.77 (m, 1H), 4.05−4.22 (m, 4H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 14.3, 18.8, 20.6, 22.4, 26.4, 30.2, 30.9, 52.7, 60.7, 61.3, 108.9, 110.9, 172.4, 173.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C15H24NaO7]+ 339.1414, found 339.1407. Anal. Calcd for C15H24O7: C, 56.95; H, 7.65. Found: C, 57.10; H, 7.76. Ethyl (1R*,2S*,5S*)-2-(2-Cyanoethyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2l): white crystals, yield 46, 171.2 mg, 0.64 mmol; mp = 83−84 °C (lit. 1 mp = 83−84 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 1.50 (s, 3H), 1.66 (s, 3H), 1.80−1.89 (m, 2H), 1.90− 2.12 (m, 2H), 2.13−2.41 (m, 4H), 4.25 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 12.4, 14.2, 18.5, 20.6, 25.1, 30.8, 32.6, 52.2, 61.8, 109.7, 110.4, 118.9, 171.5. The physical and spectral data were consistent with those previously reported.22 4419


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The Journal of Organic Chemistry Ethyl (1S*,2S*,5R*)-2-(2-Cyanoethyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3l): colorless oil; yield 14%, 52.1 mg, 0.19 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H), 1.52 (s, 3H), 1.53 (s, 3H), 1.61−1.72 (m, 1H), 1.79−1.93 (m, 2H), 2.15−2.45 (m, 4H), 2.75−2.89 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 13.4, 14.2, 18.6, 20.6, 22.1, 27.1, 30.9, 52.7, 61.8, 109.0, 110.3, 119.4, 171.8. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-2-Benzyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2m): white crystals; yield 43%, 158.8 mg, 0.52 mmol; mp = 59−60 °C; Rf = 0.67 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.30 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.52 (s, 3H, CH3CCH2), 1.59− 1.88 (m, 2H, CCH2CH2C), 1.86 (s, 3H, CH3CC), 1.97−2.16 (m, 2H, CCH2CH2C), 2.67 (d, J = 12.9 Hz, 1H, CCH2C), 3.39 (d, J = 12.9 Hz, 1H, CCH2C), 4.23 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.06−7.17 (m, 2H, CH), 7.20−7.33 (m, 3H, CH); 13 C NMR (75.48 MHz, CDCl3) δ 14.2 (CH3CH2O), 18.8 (CH3CC), 20.6 (CH3CCH2), 25.8 (C(O)CCH2CH2), 32.9 (CH 3 CCH 2 ), 41.0 (CCH 2 C), 54.3 (CC(O)), 61.1 (OCH2CH3), 109.9 (OCCH2), 111.2 (OCC), 126.9 (CH), 128.3 (CH), 130.0 (CH), 136.1 (CCH2), 172.5 (C(O)OEt); HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C17H22NaO5]+ 329.1359, found 329.1360. Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C, 66.79; H, 7.41. Ethyl (1S*,2R*,5R*)-2-Benzyl-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3m): white crystals; yield 26%, 96.0 mg, 0.31 mmol; mp = 42−43 °C; Rf = 0.63 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H, CH3CH2O), 1.49−1.63 (m, 1H, C(O)CCH2CH2), 1.59 (s, 3H, CH3CCH2), 1.72 (s, 3H, CH3CC), 1.78−2.04 (m, 2H, CH2CCH3), 2.62 (td, J = 13.5, 6.3 Hz, 1H, C(O)CCH2CH2), 3.07 (d, J = 13.6 Hz, 1H, CCH2C), 3.39 (d, J = 13.6 Hz, 1H, CCH2C), 4.17 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.09−7.17 (m, 2H, CH), 7.20−7.34 (m, 3H, CH); 13C NMR (75.48 MHz, CDCl3) δ 14.1 (CH3CH2O), 19.1 (CH3CC), 20.9 (CH3CCH2), 21.8 (C(O)CCH2CH2), 31.2 (CH3CCH2), 37.7 (CCH2C), 54.4 (CC(O)), 61.2 (OCH2CH3), 109.2 (OCCH2), 111.5 (OCC), 126.9 (CH), 128.4 (CH), 130.0 (CH), 137.3 (CCH2), 172.6 (C(O)OEt); HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C17H22NaO5]+ 329.1359, found 329.1356. Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C, 66.55; H, 7.59. Ethyl (1R*,2R*,5S*)-2-(4-Bromobenzyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2n): white crystals; yield 55%, 200.8 mg, 0.52 mmol; mp = 108−109 °C; Rf = 0.63 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.54−1.83 (m, 2H), 1.79 (s, 3H), 1.89−2.13 (m, 2H), 2.58 (d, J = 12.9 Hz, 1H), 3.29 (d, J = 12.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 6.95 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.7, 20.6, 25.7, 32.9, 40.4, 54.1, 61.3, 109.9, 111.0, 121.0, 131.5, 131.7, 135.2, 172.3; HRMS (ESITOF) m/z [M + Na]+ calcd for [C17H21BrNaO5]+ 407.0465, found 407.0462. Anal. Calcd for C17H21BrO5: C, 53.00; H, 5.49; Br, 20.74. Found: C, 53.12; H, 5.53; Br, 20.32. Ethyl (1S*,2R*,5R*)-2-(4-Bromobenzyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3n): white crystals; yield 25%, 91.3 mg, 0.24 mmol; mp = 104−105 °C; Rf = 0.59 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H), 1.47 (ddd, J = 14.4, 5.3, 2.3 Hz, 1H), 1.55 (s, 3H), 1.66 (s, 3H), 1.73−1.96 (m, 2H), 2.61

(td, J = 13.2, 6.6 Hz, 1H), 2.99 (d, J = 13.6 Hz, 1H), 3.31 (d, J = 13.6 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 19.1, 20.8, 21.8, 31.2, 37.1, 54.3, 61.4, 109.2, 111.3, 121.0, 131.6, 131.8, 136.3, 172.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C17H21BrNaO5]+ 407.0465, found 407.0461. Anal. Calcd for C17H21BrO5: C, 53.00; H, 5.49; Br, 20.74. Found: C, 53.03; H, 5.40; Br, 20.76. tert-Butyl (1R*,2R*,5S*)-2-(4-Bromobenzyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2o): white crystals; yield 30%, 109.2 mg, 0.26 mmol; mp = 94−96 °C. (lit.22 mp = 94−96 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.46 (s, 9H), 1.48 (s, 3H), 1.37−1.60 (m, 1H), 1.76 (s, 3H), 1.66−1.82 (m, 1H), 1.84−2.13 (m, 2H), 2.53 (d, J = 12.9 Hz, 1H), 3.28 (d, J = 12.9 Hz, 1H), 7.01 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 19.1, 20.8, 22.0, 28.1, 31.3, 36.9, 54.7, 82.1, 109.1, 111.4, 120.8, 131.4, 131.9, 136.6, 171.5. The physical and spectral data were consistent with those previously reported.22 tert-Butyl (1S*,2R*,5R*)-2-(4-Bromobenzyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3o): white crystals; yield 17%, 61.9 mg, 0.15 mmol; mp = 102−104 °C (lit.22 mp = 102−104 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.35−1.47 (m, 1H), 1.43 (s, 9H), 1.54 (s, 3H), 1.63 (s, 3H), 1.74−1.93 (m, 2H), 2.49−2.65 (m, 1H), 2.95 (d, J = 13.7 Hz, 1H), 3.30 (d, J = 13.7 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 18.6, 20.7, 25.8, 28.1, 32.9, 40.3, 54.3, 81.9, 109.7, 111.2, 120.8, 131.3, 131.9, 135.4, 171.4. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-2-(4-nitrobenzyl)-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (2p): white crystals; yield 54%, 198.0 mg, 0.56 mmol; mp = 97−98 °C (lit.22 mp = 97−98 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.51−1.65 (m, 1H), 1.68−1.83 (m, 1H), 1.79 (s, 3H), 1.94−2.13 (m, 2H), 2.74 (d, J = 12.7 Hz, 1H), 3.44 (d, J = 12.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 19.0, 20.8, 21.9, 31.1, 37.4, 54.4, 61.7, 109.2, 111.0, 123.6, 131.0, 144.2, 147.2, 172.2. The physical and spectral data were consistent with those previously reported.22 Ethyl (1S*,2R*,5R*)-1,5-Dimethyl-2-(4-nitrobenzyl)-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (3p): white crystals; yield 30%, 110.0 mg, 0.31 mmol; mp = 143−144 °C (lit.22 mp = 143−144 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.35−1.46 (m, 1H), 1.56 (s, 3H), 1.66 (s, 3H), 1.78−1.98 (m, 2H), 2.59−2.75 (m, 1H), 3.16 (d, J = 13.5 Hz, 1H), 3.46 (d, J = 13.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 8.75 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 19.0, 20.8, 21.9, 31.1, 37.4, 54.4, 61.7, 109.2, 111.0, 123.6, 131.0, 145.2, 147.2, 172.2. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-1,5-Dimethyl-2-(4-methylbenzyl)6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2q): white crystals; yield 24%, 88.4 mg, 0.28 mmol; mp = 62−64 °C; Rf = 0.51 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.54−1.78 (m, 2H), 1.81 (s, 3H), 1.91−2.12 (m, 2H), 2.30 (s, 3H), 2.59 (d, J = 12.9 Hz, 1H), 3.30 (d, J = 12.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.8, 20.6, 21.2, 25.8, 32.9, 40.6, 54.3, 61.1, 109.9, 111.2, 129.0, 129.8, 132.9, 136.4, 172.6; HRMS (ESI-TOF) m/z [M + Na] + calcd for [C 18 H 24 NaO 5 ] + 4420


Article


1.61 (s, 3H), 1.87−2.04 (m, 2H), 2.06−2.21 (m, 2H), 3.59− 3.76 (m, 1H), 5.92 (s, 1H), 7.17−7.41 (m, 5H); 13C NMR (75.48 MHz, CDCl3) δ 21.0, 34.4, 36.9, 41.8, 102.8, 108.0, 126.9, 127.1, 128.9, 143.3. The physical and spectral data were consistent with those previously reported.22 Peroxidation of 1,5-Diketones 1a,d,g,j,p in the Gram Scale. A 3.7 M ethereal solution of H2O2 (1.22−2.03 mL, 4.50−7.50 mmol for 1a,d,j,p or 4.28 mL, 15.83 mmol for 1g, 1.5 mol H2O2/1.0 mol 1,5-diketone 1) and BF3·Et2O (0.330 g, 2.33 mmol for 1d, 0.748 g, 5.28 mmol for 1g, 0.5 mol BF3· Et2O/1.0 mol 1d or 1g; 0.851−1.419 g, 6.00−10.00 mmol, 2.0 mol BF3·Et2O/1.0 mol 1a, 1j, 1p) were successively added with stirring to a solution of 1,5-diketones 1a,d,j, or p (1.00 g, 3.00− 5.00 mmol) or 1g (3.00 g, 10.55 mmol) in CH3CN (10 or 30 mL for 1g) at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 1 h. After that, a mixture of CH2Cl2/PE = 1:1 (20 mL) and water (0.5 mL) were added. Then NaHCO3 was added with stirring until the pH reached 7.0. The precipitate was filtered off, and the filtrate was dried over MgSO4. The precipitate was filtered off, and the solvent was removed in the vacuum of a water jet pump. The mixtures 2a and 3a, 2d and 3d, 2g and 3g, 2j and 3j, as well as 2p and 3p were isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 5 to 20 vol %. Mixtures: 2a and 3a 0.626 g, 2.90 mmol, yield 58%; 2d and 3d 0.795 g, 3.45 mmol, yield 74%; 2g and 3g 2.10 g, 7.00 mmol, yield 66%; 2j and 3j 0.813 g, 2.69 mmol, yield 77%; 2p and 3p 0.953 g, 2.71 mmol, yield 91%. Reactions of Ozonides 2j and 3j with Saving of Ozonide Cycle. Synthesis of 2-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (5) from Ethyl (1R*,2R*,5S*)-2-(2-Ethoxy-2oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]ctane-2-carboxylate (2j) and 2-((1S*,2R*,5R*)-2-(Ethoxycarbonyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (4) from Ethyl (1S*,2R*,5R*)-2-(2-Ethoxy-2-oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3j). An aqueous solution of KOH (0.111 g, 1.98 mmol KOH in 2 mL of water) was added to solution of ozonide 2j or 3j (0.300 g, 0.99 mmol) in EtOH (5 mL) with stirring at 20−25 °C. The reaction mixture was stirred at 20−25 °C for 24 h. Then H2SO4 was added with stirring under cooling until the pH reached 4.0. After that, CH2Cl2 (20 mL) and H2O (10 mL) were added. The organic layer was separated, and acid 4 or 5 was extracted with CH2Cl2 (3 × 15 mL) from the aqueous layer. The combined organic layers were washed with water (5 mL), dried over MgSO4, and filtered. The solvent was removed in the vacuum of a water jet pump. Crude product 4 or 5 was washed with petroleum ether (4 × 5 mL) to obtain pure ozonide 4 or 5. 2-((1S*,2R*,5R*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (4): white crystals, yield 74%, 0.200 g, 0.73 mmol; mp = 106−108 °C; 1H NMR (300.13 MHz, CDCl 3 ) δ 1.25 (t, J = 7.1 Hz, 3H, CH3CH2OC(O)C), 1.50 (s, 3H, CH3CCH2), 1.51 (s, 3H, CH3CC), 1.73−2.03 (m, 3H, CH2CCH3, C(O)CCH2CH2), 2.77−3.11 (m, 3H, C(O)CCH2CH2, CCH2C(O)), 4.19 (q, J = 7.1 Hz, 2H, CC(O)OCH2CH3), 8.81 (br s, 1H, OH); 13C NMR (75.48 MHz, CDCl3) δ 14.1 (CH3CH2OC(O)C), 18.6 (CH3CC), 20.5 (CH3CCH2), 23.4 (C(O)CCH2CH2), 31.0 (CH 3 CCH 2 ), 36.4 (CCH 2 C(O)), 51.0 (CC(O)), 61.7 (OCH2CH3), 109.1 (OCCH2), 109.9 (OCC), 171.9 (C(O)OEt), 176.9 (CH2C(O)OH); HRMS (ESI-TOF) m/z [M +

343.1529, found 343.1526. Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.55; H, 7.58. Ethyl (1S*,2R*,5R*)-1,5-Dimethyl-2-(4-methylbenzyl)6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (3q): white crystals; yield 25%, 92.1 mg, 0.29 mmol; mp = 48−50 °C; Rf = 0.47 (TLC, PE/EA, 10:1); 1H NMR (300.13 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.56 (s, 3H), 1.47−1.62 (m, 1H), 1.68 (s, 3H), 1.74−2.03 (m, 2H), 2.30 (s, 3H), 2.58 (td, J = 13.2, 6.5 Hz, 1H), 3.00 (d, J = 13.6 Hz, 1H), 3.32 (d, J = 13.6 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 19.1, 20.9, 21.1, 21.8, 31.2, 37.3, 54.5, 61.2, 109.2, 111.5, 129.1, 129.9, 134.1, 136.5, 172.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C18H24NaO5]+ 343.1518, found 343.1518. Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.52; H, 7.65. Ethyl-3-methylhexahydro-3,9a-epoxybenzo[c][1,2]dioxepine-5a(3H)-carboxylate (2r and 3r): slightly yellow oil; yield 62%, 231.4 mg, 0.90 mmol; Rf = 0.70 (TLC, PE/EA, 7:1); 2r/3r = 2:1; 1H NMR (300.13 MHz, CDCl3), for 2r, δ 1.18− 1.41 (m, 5H, CH3CH2O, CH24CH25), 1.47 (s, 3H, CH3A), 1.42−2.01 (m, 7H, CH23, CH24, CH25, CH26, CH2C), 2.03− 2.14 (m, 2H, CH2D), 2.50−2.66 (m, 1H, CH26), 4.09−4.27 (m, 2H, CH2O); H NMR (300.13 MHz, CDCl3), for 3r, δ 1.18− 1.41 (m, 4H, CH3CH2O, CH24), 1.49 (s, 3H, CH3A), 1.42− 2.01 (m, 9H, CH23, CH24, CH25, CH26, CH2C, CH2D), 2.23− 2.45 (m, 2H, CH26, CH2D), 4.09−4.27 (m, 2H, CH3CH2O); 13 C NMR (75.48 MHz, CDCl3), for 2r, δ 14.3 (CH3CH2O), 20.8 (CAH3), 21.6 (C4H2), 23.4 (C5H2), 29.0 (CDH2), 30.4 (C 6 H 2 ), 33.0 (C C H 2 ), 34.9 (C 3 H 2 ), 50.1 (C 2 ), 60.8 (CH3CH2O), 109.0 (CB), 109.3 (C1), 173.1 (C(O)OEt); 13C NMR (75.48 MHz, CDCl3), for 3r, δ 14.3 (CH3CH2O), 21.4 (CAH3), 22.3 (C4H2), 24.0 (C5H2), 27.5 (CDH2), 30.0 (C6H2), 31.2 (CCH2), 32.2 (C3H2), 49.6 (C2), 60.6 (CH3CH2O), 107.6 (CB), 109.8 (C1), 174.0 (C(O)OEt); HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H20NaO5]+ 279.1203, found 279.1193. Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 61.03; H, 7.98. Decahydro-2H-4a,6a-epoxydibenzo[c,f ][1,2]dioxepine (2s and 3s): white crystals, yield 85%, 320.4 mg, 1.43 mmol; mp = 85−86 °C (lit.22 mp = 85−86 °C); 2s/3s = 2:1; 1H NMR (300.13 MHz, CDCl3) δ 0.90−2.00 (m, 20H); 13C NMR (75.48 MHz, CDCl3) δ 23.72, 23.74, 24.2, 24.87, 24.93, 25.2, 30.16, 30.23, 30.5, 30.6, 31.37, 31.47, 32.3, 32.6, 37.0, 40.6, 41.0, 108.2, 109.1, 109.3. The physical and spectral data were consistent with those previously reported.22 1,5-Dimethyl-3-phenyl-6,7,8-trioxabicyclo[3.2.1]octane (2t): white crystals; yield 83%, 313.3 mg, 1.42 mmol; mp = 68− 70 °C (lit.22 mp = 68−70 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.60 (s, 6H), 1.86−2.00 (m, 2H), 2.14 (dd, J = 14.0, 5.6 Hz, 2H), 3.60−3.77 (m, 1H), 7.21−7.40 (m, 5H); 13C NMR (75.48 MHz, CDCl3) δ 21.4, 35.4, 41.1, 109.0, 126.8, 127.1, 128.8, 143.5. The physical and spectral data were consistent with those previously reported.22 3-Isopropyl-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane (2u): light yellow oil; yield 71%, 271.9 mg, 1.46 mmol; 1H NMR (300.13 MHz, CDCl3) δ 0.87 (d, J = 6.7 Hz, 6H), 1.31− 1.44 (m, 3H), 1.50 (s, 6H), 1.85−1.96 (m, 2H), 1.98−2.16 (m, 1H); 13C NMR (75.48 MHz, CDCl3) δ 19.8, 21.6, 32.6, 35.3, 37.9, 108.9. The physical and spectral data were consistent with those previously reported.22 1-Methyl-3-phenyl-6,7,8-trioxabicyclo[3.2.1]octane (2v): white crystals; yield 70%, 265.6 mg, 1.29 mmol; mp = 82−84 °C (lit.22 mp = 82−84 °C); 1H NMR (300.13 MHz, CDCl3) δ 4421


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product 7 or 9 was washed with petroleum ether (4 × 5 mL) to obtain pure product 7 or 9. Product 8 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 20 to 40 vol %. Ethyl (1R*,2R*,5S*)-1,5-Dimethyl-2-(2-morpholino-2-oxoethyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (7): white crystals; yield 75%, 0.185 g, 0.54 mmol; mp = 108− 110 °C (lit.22 mp = 108−110 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.21 (t, J = 7.1 Hz, 3H), 1.41 (s, 3H), 1.53 (s, 3H), 1.62−1.79 (m, 2H), 2.17−2.36 (m, 1H), 2.37−2.51 (m, 1H), 2.45 (d, J = 15.8 Hz, 1H), 2.85 (d, J = 15.8 Hz, 1H), 3.31−3.65 (m, 8H), 4.08−4.22 (m, 2H); 13C NMR (75.48 MHz, CDCl3) δ 13.9, 18.4, 20.6, 25.9, 32.4, 38.7, 41.8, 45.9, 50.7, 61.0, 66.4, 66.7, 110.0, 110.4, 167.9, 172.3. The physical and spectral data were consistent with those previously reported.22 Ethyl (1R*,2R*,5S*)-2-(2-((4-Fluorophenyl)amino)-2-oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (8): white crystals; yield 67%, 0.180 g, 0.49 mmol; mp = 148−150 °C; 1H NMR (300.13 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.62 (s, 3H), 1.70−2.07 (m, 2H), 2.24−2.45 (m, 3H), 3.15 (d, J = 14.3 Hz, 1H), 4.21−4.33 (m, 2H), 6.96 (dd, J = 9.7, 8.5 Hz, 2H), 7.37−7.47 (m, 2H), 7.62 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 18.5, 20.7, 25.5, 32.6, 42.9, 51.1, 61.6, 110.2, 110.4, 115.7 (d, JC−F = 22.5 Hz), 121.9 (d, JC−F = 7.8 Hz), 133.7 (d, JC−F = 2.6 Hz), 159.5 (d, JC−F = 243.8 Hz), 167.8, 172.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C18H22FNNaO6]+ 390.1323, found 393.1306. Anal. Calcd for C18H22FNO6: C, 58.85; H, 6.04; F, 5.17; N, 3.81. Found: C, 58.80; H, 6.05; F, 5.01; N, 3.81. Ethyl (1R*,2R*,5S*)-2-(2-(((3S*,5S*,7S*)-Adamantan-1yl)amino)-2-oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (9): white crystals; yield 44%, 0.130 g, 0.32 mmol; mp = 208−210 °C; 1H NMR (300.13 MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H), 1.46 (s, 3H), 1.56 (s, 3H), 1.38−2.15 (m, 18H), 2.17−2.36 (m. 2H), 2.87 (d, J = 13.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 5.25 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.5, 20.7, 25.2, 29.4, 32.6, 36.4, 41.6, 43.0, 51.1, 52.2, 61.3, 110.0, 110.5, 168.1, 172.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C22H34NO6]+ 408.2381, found 408.2390. Anal. Calcd for C22H33NO6: C, 64.84; H, 8.16; N, 3.44. Found: C, 64.87; H, 8.30; N, 3.48. Synthesis of Ethyl (1R*,2S*,5S*)-2-(3-Hydroxypropyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (11) from Ethyl (1R*,2R*,5S*)-2-(3-Ethoxy-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2k). LiAlH4 (0.053 g, 1.26 mmol) was added to solution of ozonide 2k (0.200 g, 0.632 mmol) in (dry) Et2O (10 mL) with stirring at −78 °C. The reaction mixture was stirred at −78 °C for 1 h. After that, an aqueous solution of NaOH (5M, 5 mL) and H2O (15 mL) were added with stirring to the reaction mixture at −78 °C. Then the reaction mixture was warmed to room temperature, and Et2O (30 mL) was added. The organic layer was separated, and alcohol 11 was extracted with Et2O (3 × 15 mL) from the aqueous layer. The combined organic layers were washed with water (5 mL), dried over MgSO4, and filtered. The solvent was removed in the vacuum of a water jet pump, and pure product 11 was obtained. Ethyl (1R*,2S*,5S*)-2-(3-Hydroxypropyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (11): yellow oil; yield 98%, 0.169 g, 0.619 mmol; Rf = 0.70 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 1.67 (s, 3H), 1.41−2.21 (m, 8H), 3.58 (t, J = 6.2 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 5.29 (s, 1H); 13C NMR

H]+ calcd for [C12H19O7]+ 275.1125, found 275.1122. Anal. Calcd for C12H18O7: C, 52.55; H, 6.62. Found: C, 52.48; H, 6.73. 2-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (5): white crystals; yield 80%, 0.217 g, 0.79 mmol, mp = 104−106 °C (lit.22 mp = 104−106 °C); 1H NMR (300.13 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.50 (s, 3H), 1.59 (s, 3H), 1.72−1.85 (m, 1H), 1.88−2.04 (m, 1H), 2.24−2.41 (m, 2H), 2.50 (d, J = 16.3 Hz, 1H), 3.07 (d, J = 16.3 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 9.32 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.1, 18.4, 20.7, 25.8, 32.5, 40.2, 50.5, 61.5, 109.9, 110.1, 171.8, 176.8. The physical and spectral data were consistent with those previously reported.22 Synthesis of Ethyl (1S*,2R*,5R*)-1,5-Dimethyl-2-(2-morpholino-2-oxoethyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (6) from 2-((1S*,2R*,5R*)-2-(Ethoxycarbonyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (4). Ethyl chloroformate (0.079 g, 0.73 mmol) and triethylamine (0.074g, 0.73 mmol) were added with stirring to a solution of 4 (0.100 g, 0.36 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at 0−5 °C for 1 h. Then morpholine (0.095g, 1.09 mmol) was added. The mixture was stirred at 0−5 °C for 1 h. Then CH2Cl2 (10 mL) was added, and the mixture was washed with water (1 × 5 mL), a 5% aqueous H2SO4 solution (2 × 5 mL), a 5% aqueous NaHCO3 solution (2 × 5 mL), and again water (1 × 5 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. Crude product 6 was washed with petroleum ether (4 × 5 mL) to obtain pure product 6. Ethyl (1S*,2R*,5R*)-1,5-Dimethyl-2-(2-morpholino-2-oxoethyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (6): white crystals; yield 53%, 0.066 g, 0.19 mmol; mp = 118− 120 °C; 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.0 Hz, 3H), 1.49 (s, 3H), 1.52 (s, 3H), 1.64−1.91 (m, 2H), 1.99−2.15 (m, 1H), 2.70 (d, J = 16.5 Hz, 1H), 2.86−3.03 (m, 1H), 2.96 (d, J = 16.5 Hz, 1H), 3.41−3.79 (m, 8H), 4.08−4.27 (m, 2H); 13 C NMR (75.48 MHz, CDCl3) δ 14.2, 18.9, 20.6, 23.1, 31.3, 35.1, 42.1, 46.0, 51.2, 61.3, 66.8, 109.0, 110.6, 168.6, 172.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C16H26NO7]+ 344.1704, found 344.1694. Anal. Calcd for C16H25NO7: C, 55.97; H, 7.34; N, 4.08. Found: C, 56.05; H, 7.42; N, 4.12. Synthesis of Ethyl (1R*,2R*,5S*)-1,5-Dimethyl-2-(2-morpholino-2-oxoethyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (7), Ethyl (1R*,2R*,5S*)-2-(2-((4-Fluorophenyl)amino)-2-oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (8), and Ethyl (1R*,2R*,5S*)-2-(2(((3S*,5S*,7S*)-Adamantan-1-yl)amino)-2-oxoethyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (9) from 2-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octan-2-yl)acetic Acid (5). Ethyl chloroformate (0.158 g, 1.46 mmol) and triethylamine (0.148 g, 1.46 mmol) were added with stirring to a solution of 5 (0.200 g, 0.73 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at 0−5 °C for 1 h. Then morpholine (0.191 g, 2.19 mmol), 4-fluoraniline (0.243 g, 2.19 mmol), or 1-adamantanamine hydrochloride (0.411 g, 2.19 mmol) was added. The mixture was stirred at 0−5 °C for 1 h. Then CH2Cl2 (20 mL) was added, and the mixture was washed with water (1 × 10 mL), a 5% aqueous H2SO4 solution (2 × 10 mL), a 5% aqueous NaHCO3 solution (2 × 10 mL), and again water (1 × 10 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. Crude 4422


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The Journal of Organic Chemistry (75.48 MHz, CDCl3) δ 14.2, 18.7, 20.6, 25.6, 27.1, 31.4, 32.9, 52.9, 61.2, 62.9, 109.6, 111.2, 172.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H22NaO6]+ 297.1309, found 297.1310. Anal. Calcd for C13H22O6: C, 56.92; H, 8.08. Found: C, 57.12; H, 8.25. Synthesis of Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-2-(3(tosyloxy)propyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (12) from Ethyl (1R*,2S*,5S*)-2-(3-Hydroxypropyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (11). 4-Methylbenzenesulfonyl chloride (0.277 g, 1.45 mmol), triethylamine (0.147 g, 1.45 mmol), and DMAP (0.009 g, 0.073 mmol) were added with stirring to a solution of 11 (0.200 g, 0.729 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. Then the reaction mixture was warmed to room temperature and stirred at 20−25 °C overnight. The solvent was removed in the vacuum of a water jet pump. Product 12 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 10 to 15 vol %. Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-2-(3-(tosyloxy)propyl)6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (12): white crystals; yield 74%, 0.231 g, 0.539 mmol; mp = 94−96 °C; Rf = 0.45 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.33−1.89 (m, 6H), 1.45 (s, 3H), 1.49 (s, 3H), 1.96−2.18 (m, 2H), 2.43 (s, 3H), 3.97 (t, J = 5.0 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.6, 20.6, 21.7, 23.7, 25.5, 31.1, 32.8, 52.6, 61.3, 70.4, 109.6, 110.8, 128.0, 130.0, 133.1, 145.0, 172.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C20H28NaO8S]+ 451.1397, found 451.1393. Anal. Calcd for C20H28O8S: C, 56.06; H, 6.59; S, 7.48. Found: C, 56.15; H, 6.72; S, 7.60. Synthesis of Ethyl (1R*,2S*,5S*)-2-(3-Azidopropyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (13) from Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-2-(3-(tosyloxy)propyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (12). Sodium azide (0.023 g, 0.35 mmol) was added with stirring to a solution of 12 (0.100 g, 0.233 mmol) in DMF (5 mL) at 20−25 °C. The mixture was stirred at 45 °C for 8 h. The solvent was removed in the vacuum of an oil pump. Product 13 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 10 to 15 vol %. Ethyl (1R*,2S*,5S*)-2-(3-Azidopropyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (13): yellow oil, yield 62%, 0.043 g, 0.144 mmol; Rf = 0.53 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 1.22−2.22 (m, 8H), 1.28 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 1.66 (s, 3H), 3.24 (t, J = 6.3 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.7, 20.6, 23.6, 25.7, 32.4, 32.9, 51.6, 52.9, 61.3, 109.6, 111.0, 172.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H21N3NaO5]+ 322.1373, found 322.1379. Anal. Calcd for C13H21N3O5: C, 52.16; H, 7.07; N, 14.04. Found: C, 52.25; H, 7.15; N, 14.20. Synthesis of Ethyl (1R*,2S*,5S*)-2-(3-(Benzylamino)propyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (14) from Ethyl (1R*,2S*,5S*)-1,5-Dimethyl-2-(3(tosyloxy)propyl)-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (12). Benzylamine (0.033 g, 0.315 mmol) was added with stirring to a solution of 12 (0.090 g, 0.21 mmol) in DMF (5 mL) at 20−25 °C. The mixture was stirred at 45 °C for 6 h. The solvent was removed in the vacuum of a water jet pump. Product 14 was isolated by chromatography on SiO2 using a

PE/EA mixture as the eluent with a gradient of EA from 50 to 100 vol %. Ethyl (1R*,2S*,5S*)-2-(3-(Benzylamino)propyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (14): yellow oil; yield 29%, 0.022 g, 0.061 mmol; Rf = 0.23 (TLC, EA); 1H NMR (300.13 MHz, CDCl3) δ 1.18−2.22 (m, 9H), 1.27 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.67 (s, 3H), 2.59 (t, J = 6.9 Hz, 2H), 3.77 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.56−2.63 (m, 5H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 18.7, 20.7, 24.3, 25.7, 32.92, 32.95, 49.4, 53.1, 53.8, 61.1, 109.6, 111.2, 127.2, 128.4, 128.6, 172.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C20H30NO5]+ 364.2118, found 364.2118. Anal. Calcd for C20H29NO5: C, 66.09; H, 8.04; N, 3.85. Found: C, 66.20; H, 8.24; N, 4.02. Synthesis of Ethyl (1R*,2S*,5S*)-2-(3-((3-(1,4-Dimethyl2,3,5,6-tetraoxabicyclo[2.2.1]heptan-7-yl)propanoyl)oxy)propyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (15) from Ethyl (1R*,2S*,5S*)-2-(3-Hydroxypropyl)1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (11). In an argon atmosphere, the ozonide 11 (0.100 g, 0.36 mmol) was added to a solution of tetraoxane acid (0.078 g, 0.38 mmol) and DMAP (0.026 g, 0.21 mmol) in CH2Cl2 (2 mL), with stirring at 0 °C. Then DCC (0.148g, 0.72 mmol) was added, and reaction mixture was then slowly warmed to room temperature and stirred for 4 h. After that, the precipitate was filtered off and the solvent was removed in the vacuum of a water jet pump. Product 15 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 10 to 100 vol %. Ethyl (1R*,2S*,5S*)-2-(3-((3-(1,4-Dimethyl-2,3,5,6tetraoxabicyclo[2.2.1]heptan-7-yl)propanoyl)oxy)propyl)1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (15): colorless oil; yield 60%, 0.100 g, 0.022 mmol; Rf = 0.64 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.20− 2.20 (m, 10H), 1.27 (t, J = 7.1 Hz, 3H), 1.47 (s, 3H), 1.56 (s, 6H), 1.65 (s, 3H), 2.49 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 6.0 Hz, 1H), 4.05 (t, J = 6.3 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H); 13C NMR (75.48 MHz, CDCl3) δ 9.9, 14.2, 18.6, 19.2, 20.6, 23.3, 25.5, 31.6, 31.7, 32.8, 52.8, 58.2, 61.2, 64.8, 109.6, 110.8, 111.0, 172.4, 172.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C21H32NaO11]+ 483.1837, found 483.1836. Anal. Calcd for C21H32O11: C, 54.78; H, 7.00. Found: C, 54.85; H, 7.20. Synthesis of 3-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octan-2-yl)propanoic Acid (16) from Ethyl (1R*,2R*,5S*)-2-(3-Ethoxy-3-oxopropyl)-1,5dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (2k). An aqueous solution of KOH (0.168 g, 3 mmol KOH in 5 mL of water) was added to a solution of ozonide 2k (0.476 g, 1.5 mmol) in EtOH (10 mL) with stirring at 20−25 °C. The reaction mixture was stirred at 40 °C for 2 h. Then H2SO4 was added with stirring under cooling until the pH reached 4.0. After that, CH2Cl2 (20 mL) and H2O (10 mL) were added. The organic layer was separated, and acid 15 was extracted with CH2Cl2 (3 × 15 mL) from the aqueous layer. The combined organic layers were washed with water (5 mL), dried over MgSO4, and filtered. The solvent was removed in the vacuum of a water jet pump. Crude product 16 was washed with petroleum ether (4 × 5 mL), and pure product 15 was obtained. 3-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octan-2-yl)propanoic Acid (16): white crystals, yield 82%, 0.355 g, 1.23 mmol; mp = 95−97 °C; Rf = 0.11 (TLC, PE/EA, 5:1); 1H NMR (300.13 MHz, CDCl3) δ 4423


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8.04 (d, J = 8.8 Hz, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.13, 14.16, 18.8, 20.55, 20.57, 25.3, 25.5, 28.9, 29.0, 30.4, 30.73, 30.77, 30.84, 32.8, 34.9, 44.9, 52.5, 52.6, 61.2, 62.9, 109.50, 109.53, 111.0, 117.0, 117.1, 119.8, 120.0, 121.54, 121.56, 124.41, 124.46, 125.1, 125.4, 126.3, 126.7, 127.2, 128.1, 128.3, 129.3, 129.4, 130.5, 131.2, 132.2, 133.5, 133.7, 144.1, 152.3, 155.41, 155.44, 171.8, 171.9, 172.3, 172.4; HRMS (ESITOF) m/z [M + Na]+ calcd for [C40H42N4NaO8]+ 729.2895, found 729.2890. Anal. Calcd for C40H42N4O8: C, 67.97; H, 5.99; N, 7.93. Found: C, 68.15; H, 6.10; N, 8.15. Reduction of Ozonides 2p and 3p with Triphenylphosphine in an NMR Tube. Triphenylphosphine (86.0 mg, 0.33 mmol) was added to a solution of ozonide 2p or 3p (40.0 mg, 0.11 mmol) in CDCl3 (0.7 mL). The course of the reaction was monitored in an NMR tube. Only signals of diketone 1p were observed 8 h after the mixing of the reagents. Reduction of Ozonide 5 with Triphenylphosphine. Triphenylphosphine (1.5 mol PPh3/1 mol of ozonide 5) was added to a solution of ozonide 5 (1.00 mmol) in CHCl3 (10.0 mL). The reaction mixture was stirred at 20−25 °C for 24 h. After that time, CH2Cl2 (10 mL) and a solution of NaHCO3 (10 mL, 1.20 mmol NaHCO3) were added. Then the mixture was transferred into a separating funnel. The organic phase was separated, and the aqueous phase was washed by CH2Cl2 (2 × 20 mL). After that, 36% aq HCl was added to the aqueous phase until the pH reached 2.0. Then product 10 was extracted from the aqueous phase by CH2Cl2 (2 × 20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. 3-Acetyl-3(ethoxycarbonyl)-6-oxoheptanoic acid 10 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 15 to 40 vol %. 3-Acetyl-3-(ethoxycarbonyl)-6-oxoheptanoic Acid (10): slightly yellow oil; yield 80%, 0.207 g, 0.80 mmol; 1H NMR (300.13 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 2.12 (s, 3H), 2.24 (s, 3H), 2.06−2.50 (m, 4H), 2.80−3.00 (m, 2H), 4.19 (q, J = 7.1 Hz), 9.41 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.0, 26.8, 27.1, 30.1, 37.1, 38.3, 60.3, 62.1, 171.0, 176.1, 204.3, 207.1. The physical and spectral data were consistent with those previously reported.22

1.29 (t, J = 7.1 Hz, 3H), 1.49 (s, 3H), 1.69 (s, 3H), 1.74−2.45 (m, 8H), 4.20 (q, J = 7.1 Hz, 2H), 8.86 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.2, 18.7, 20.6, 25.4, 28.8, 29.8, 32.8, 61.4, 109.7, 110.9, 172.6, 178.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H20NaO7]+ 311.1101, found 311.1103. Anal. Calcd for C13H20O7: C, 54.16; H, 6.99. Found: C, 54.28; H, 7.15. Synthesis of Ethyl (1R*,2R*,5S*)-2-(3-((3-Azidopropyl)amino)-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (17) from 3-((1R*,2R*,5S*)-2-(Ethoxycarbonyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octan-2yl)propanoic Acid (16). Ethyl chloroformate (0.149 g, 1.38 mmol) and triethylamine (0.139 g, 1.38 mmol) were added with stirring to a solution of 16 (0.200 g, 0.69 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at 0−5 °C for 1 h. Then 3-azidopropan-1-amine (0.191 g, 2.07 mmol) was added. The mixture was stirred at 0−5 °C for 1 h. Then CH2Cl2 (20 mL) was added, and the mixture was washed with water (1 × 10 mL), a 5% aqueous H2SO4 solution (2 × 10 mL), a 5% aqueous NaHCO3 solution (2 × 10 mL), and again water (1 × 10 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed in the vacuum of a water jet pump. Ozonide 17 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 20 to 40 vol %. Ethyl (1R*,2R*,5S*)-2-(3-((3-Azidopropyl)amino)-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (17): white crystals; yield 63%, 0.159 g, 0.43 mmol; mp = 54−56 °C; Rf = 0.16 (TLC, PE/EA, 2:1); 1H NMR (300.13 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H), 1.48 (s, 3H), 1.69 (s, 3H), 1.60−2.28 (m, 10H), 3.22−3.44 (m, 4H), 4.20 (q, J = 7.1 Hz, 2H), 5.66 (br s, 1H); 13C NMR (75.48 MHz, CDCl3) δ 14.3, 18.8, 20.6, 25.5, 28.9, 30.8, 31.2, 32.8, 37.5, 49.6, 52.7, 61.4, 109.62, 111.0, 172.1, 172.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C16H27N4O6]+ 371.1925, found 371.1923. Anal. Calcd for C16H26N4O6: C, 51.88; H, 7.08; N, 15.13. Found: C, 51.98; H, 7.28; N, 15.25. Synthesis of Ethyl (1R*,2R*,5S*)-2-(3-{[3-(4,19-Dihydro1H-dinaphtho[1′,2′:9,10;2″,1″:7,8][1,6]dioxecino[3,4-d][1,2,3]triazol-1-yl)propyl]amino}-3-oxopropyl)-1,5-dimethyl6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (18) from Ethyl (1R*,2R*,5S*)-2-(3-((3-Azidopropyl)amino)-3-oxopropyl)-1,5-dimethyl-6,7,8-trioxabicyclo[3.2.1]octane-2-carboxylate (16). Alkyne (13,14-didehydro-12,15-dihydrodinaphtho[1,2-d:2′,1′-b][1,6]dioxecine) (0.068 g, 0.202 mmol) was added with stirring to a solution of azide 17 (0.050 g, 0.135 mmol) in CH2Cl2 (5 mL) at 20−25 °C. The mixture was stirred at 20−25 °C for 72 h. The solvent was removed in the vacuum of a water jet pump. Product 18 was isolated by chromatography on SiO2 using a PE/EA mixture as the eluent with a gradient of EA from 50 to 100 vol %. Ethyl (1R*,2R*,5S*)-2-(3-{[3-(4,19-Dihydro-1H-dinaphtho[1′,2′:9,10;2″,1″:7,8][1,6]dioxecino[3,4-d][1,2,3]triazol-1-yl)propyl]amino}-3-oxopropyl)-1,5-dimethyl-6,7,8trioxabicyclo[3.2.1]octane-2-carboxylate (18): white crystals; yield 95%, 0.090 g, 0.128 mmol; mp = 144−146 °C; Rf = 0.54 (TLC, EA); 1H NMR (300.13 MHz, CDCl3) δ 1.18−1.33 (m, 3H), 1.48, 1.50 (s, 3H), 1.67, 1.68 (s, 3H), 1.43−2.15 (m, 11H), 2.67−2.82 (m, 1H), 4.03−4.43 (m, 4H), 5.01 (d, J = 13.0 Hz, 1H), 5.23 (d, J = 14.0 Hz, 1H), 5.33−5.43 (m, 1H), 5.33−5.50 (m, 1H), 5.76 (d, J = 14.0 Hz, 1H), 6.96−7.05 (m, 1H), 7.12−7.35 (m, 4H), 7.39−7.56 (m, 3H), 7.77 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H),

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00130. Crystal data for 2p (CIF) Crystal data for 2v (CIF) Crystal data for 3a (CIF) Crystal data for 3p (CIF) Crystal data for 4 (CIF) Crystal data for 5 (CIF) NMR and HRMS spectra for the synthesized compounds, X-ray data for 2p, 2v, 3a, 3p, 4, and 5, computational details, and calculated geometries (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Phone: +7 (499) 1356428. Fax: + 7 (499) 1355328. ORCID

Ivan A. Yaremenko: 0000-0003-1068-9051 4424


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Gabriel dos Passos Gomes: 0000-0002-8235-5969 Igor V. Alabugin: 0000-0001-9289-3819 Alexander O. Terent’ev: 0000-0001-8018-031X Author Contributions ○

I.A.Y. and G.D.P.G. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

This work was supported by the Russian Science Foundation to Y.I. (Grant no. 17-73-10364). The computational studies were supported by the National Science Foundation to A.I. (Grant no. CHE-1465142). G.G. is grateful to IBM for the 2016 IBM Ph.D. Scholarship.

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