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. 2025 Feb 26;27(9):2037–2041. doi: 10.1021/acs.orglett.4c04629

Triethylamine-Catalyzed Cyclization of Unsaturated Hydroperoxides in the Presence of Triethylammonium Hydrochloride: A Synthesis of 1,2-Dioxanes

John P Stasiak 1, K A Woerpel 1,*
PMCID: PMC11894669  PMID: 40009755

Abstract

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Unsaturated hydroperoxides were synthesized from dienes using a regioselective cobalt-catalyzed hydroperoxidation reaction. Subsequent intramolecular oxa-Michael reactions in the presence of triethylammonium hydrochloride (HNEt3Cl) and catalytic Et3N formed 1,2-dioxanes, in several cases with high diastereoselectivity. These 1,2-dioxanes could be transformed to their respective carboxylic acids, without affecting the integrity of the peroxide linkage, to form compounds with structures that resemble biologically active natural products.

The six-membered-ring cyclic peroxide (1,2-dioxane) motif is found in many natural products1 and small molecules with antimalarial,2,3 anticancer,4 and antifungal5 activity, as illustrated by peroxyplakoric acid A1 methyl ester (1),6 ethyl plakortide Z (2),5 stolonoxide E (3),7 and diacarnoxide B (4)8,9 (Figure 1). Because of the biological activity of these compounds, efforts have been made to develop methods for their synthesis.10−12

Figure 1.

Figure 1

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Natural and biologically active 1,2-dioxanes.

We envisioned that 1,2-dioxanes could be synthesized13,14 in two steps from readily available dienes 5 (Scheme 1). This route presented two challenges, however. The regioselective peroxidation of a compound containing two different C=C linkages was not assured,15 and cyclizations of intermediate peroxyl radicals would form undesired products.16 Even if this reaction could be made regioselective and chemoselective, the base-mediated cyclization of an OOH group onto a tethered enoate6,10,11 is not typically high-yielding because the enolate intermediate that would be formed17 can attack the peroxide group to form an epoxide.18

Scheme 1. Synthetic Pathway for Synthesis of 1,2-Dioxanes.

Scheme 1

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In this Letter, we report a synthesis of 1,2-dioxanes by a regioselective peroxidation of a compound containing two alkene moieties followed by an intramolecular oxa-Michael addition reaction. Hydroperoxidation with oxygen and HMe2Si–O–SiMe2H (TMDSO) catalyzed by cobalt(II) picolinate (Co(pic)2) occurred regioselectively. Cyclization reactions under buffered acidic conditions limited the amount of side-products, forming the desired 1,2-dioxanes with high diastereoselectivity in several cases. Subsequent derivatization of these 1,2-dioxanes furnished carboxylic acids whose structures mimic natural products (Figure 1).

Initial efforts began with the optimization of the regioselective peroxidation using diene 8, which was used as a mixture of regioisomers and diastereomers. Peroxidation using catalysts 10–13 (Scheme 2) under standard conditions gave complex mixtures of peroxide products (Table 1, entries 1–4). No resonances were detected by NMR spectroscopy that could be attributed to alkenes or to monoperoxides 9a or 9aa. By contrast, subjecting dienes 8aa, 8ab, and 8ac to standard hydroperoxidation conditions using cobalt(II) 5,10,15,20-tetraphenylporphine (CoII(tpp))19 (14) and Co(pic)220 (15) formed hydroperoxide 9a (Table 1, entries 5–7), although small amounts (15%) of products were also formed where peroxidation had occurred at both C=C double bonds. The reaction with Co(pic)2 (15) was optimal because cobalt-containing materials could be removed from the unpurified reaction mixture by filtration through a small pad of silica gel (eq 1).

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Scheme 2. Catalysts Employed.

Scheme 2

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Table 1. Optimization of Peroxidation.

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entry catalyst silane solvent conv (%) product
1 10 SiEt3H ClCH2CH2Cl 100 –
2 11 SiEt3H ClCH2CH2Cl 100 –
3 12 SiEt3H ClCH2CH2Cl 50 –
4 13 SiEt3H ClCH2CH2Cl 100 –
5a 14b SiEt3H i-PrOH:CH2Cl2 30 9a
6 14 SiEt3H i-PrOH:CH2Cl2 100 9a
7 15c TMDSO i-PrOH 100 9a
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a

1.1 equiv of silane was used.

b

0.0010 mol % of catalyst was used.

c

5.0 mol % of catalyst was used.

With conditions that provided unsaturated hydroperoxide 9a, it was then necessary to establish conditions for the cyclization step. The use of basic conditions that had been reported previously (Table 2)10,11,17 did result in formation of product 16a, but the epoxide 17,17 which was presumably formed from the β-peroxy enolate 18 (eq 2), was also formed. The use of n-Bu4NF, which had been successful in reactions in the case of unsaturated lactones,21 was also ineffective (Table 2, entry 4). The yield of the desired product could not be optimized beyond 59% under these conditions.

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Table 2. Cyclization of Unsaturated Hydroperoxide 9a Using Known Conditions.

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entry base (equiv) solvent NMR yield (%)a time (h)
1 Et2NH (0.06) CF3CH2OH 26 16
2 Et2NH (0.07) CF3CH2OH:CH2Cl2 59 16
3 CsOH (6) (F3C)2CHOH:MeOH 29 72
4 n-Bu4NF (2.4) CF3CH2OH 0 24
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a

Mesitylene was used as an internal standard.

b

Calculated from one-pulse 1H NMR spectra.

To avoid the formation of epoxide 17, the β-peroxy enolate 18 would need to be trapped before it could break the O–O bond. At first, LiCl was added in attempts to trap the enolate (Table 3, entry 1). Instead of using basic conditions, use of a Lewis acidic metal salt and mildly acidic conditions, HNEt3Cl buffered with Et3N,22 gave better yields (Table 3, entries 2–3). The use of the polar protic solvent11,23,24 trifluoroethanol gave the highest yields (Table 3, entries 3–4), likely because the conditions solvated the anion, preventing formation of the epoxide.25−27 Under these conditions, the presence of lithium chloride was not required (Table 3, entry 4). Adjusting the amount of NEt3 and HNEt3Cl led to optimal yields. Excess HNEt3Cl was necessary to obtain higher isolated yields of 16a, suggesting that this ammonium salt protonates the enolate intermediate11 to minimize the formation of epoxide 17 (as illustrated in Table 3, entries 4–5). Using stoichiometric and catalytic amounts of Et3N gave comparable yields, highlighting the more important role played by HNEt3Cl than Et3N. The optimized conditions are shown in eq 3.

graphic file with name ol4c04629_0003.jpg 3

Table 3. Optimization of Cyclization Conditions using 9a.

entry additive solvent NMR yield (%)a drb
1 LiCl CH2Cl2 51 65:35
2 LiCl (CF3)2HCOH 51 61:39
3 LiCl CF3CH2OH 69 57:43
4 _ CF3CH2OH 80 53:47
5c _ CF3CH2OH 17 52:48
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a

Mesitylene was used as an internal standard.

b

Calculated from one-pulse 1H NMR spectra.

c

0.3 equiv of HNEt3Cl was used.

The optimized hydroperoxidation and cyclization reactions were general for the synthesis of 1,2-dioxanes (Scheme 3). Substitution on the terminal double bond in diene substrates did not affect regioselectivity, as seen by comparing reactions to form unsaturated hydroperoxides 9d and trans-9g. This result showcases the high regioselectivity of hydrometalation of alkenes by Co(pic)2-derived metal hydrides28 compared to hydrides derived from cobalt(II) porphyrin complexes, which reacted with electron-deficient conjugated dienes more efficiently.15,19,20 The relative configuration of the enoate did not affect the regioselectivity of hydroperoxidation. Lower yields for the hydroperoxidation reactions to form hydroperoxides 9e and 9i reflect the sensitivity of the reaction to steric effects. In these cases, higher quantities (50%) of bis(hydroperoxides) were formed.

Scheme 3. Synthesis of Unsaturated Hydroperoxides.

Scheme 3

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The cyclization of the hydroperoxides formed in Scheme 3 occurred in 30–78% yield under the optimized conditions (Scheme 4). 1,2-Dioxanes 16a–c and 16e were formed as a mixture of diastereomers, possibly due to the similar sizes of the groups at the geminally substituted carbon atom.29 When the groups near the OOH group were sterically different in size, however, as illustrated by formation of 1,2-dioxane 16f, the product was formed as a single diastereomer, whose stereochemistry was determined by X-ray crystallographic analysis. Similar high stereoselectivity was observed for the formation of 1,2-dioxanes 16g, 16h, and 16i. Formation of 1,2-dioxane 16h required longer reaction times, possibly due to the decrease in the electrophilicity of an enamide when compared to an enoate.28 The observed 1,2-trans and 1,4-trans stereoselectivity of these reactions is likely due to the preference for substituents at C-2 or C-4 to be equatorial in the transition state leading to the product (Figure 2).30 An analogous argument would explain the 1,3-cis stereoselectivity seen in dioxane 16j with the same preference for the substituent to be equatorial in the transition state. The 1,2-trans stereochemical relationship is the same as found in ethyl plakortide Z (2, Figure 1).31

Scheme 4. Substrate Scope of 1,2-Dioxane Synthesis.

Scheme 4

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Figure 2.

Figure 2

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Origin of 1,4-diastereoselectivity.

Because many 1,2-dioxane natural products contain a free CO2H group in one of the substituents,1,32 it was important to optimize conditions to reveal this group in the presence of the endoperoxide group. Subjecting 1,2-dioxane 16a to base-mediated hydrolysis conditions with lithium hydroxide33 led to epoxide products. This result is consistent with the optimization studies, which indicate that basic conditions can form an enolate intermediate,11 leading to epoxide formation. To circumvent this decomposition pathway, methyl ester 16a was instead reduced to an aldehyde intermediate using diisobutylaluminum hydride, which did not reduce the peroxide moiety.34,35 The aldehyde intermediate was then oxidized36 to form carboxylic acid 20a (Scheme 5). These conditions formed a number of 1,2-dioxanes that resemble natural products such as 3.

Scheme 5. Synthesis of Carboxylic Acid Derivatives of 1,2-Dioxanes.

Scheme 5

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In conclusion, nonconjugated dienes containing various functional groups can be transformed to unsaturated hydroperoxides regioselectively using Co(pic)2 as the catalyst. These unsaturated hydroperoxides underwent acid-catalyzed cyclization using triethylammonium hydrochloride and catalytic triethylamine in 2,2,2-trifluoroethanol to afford 1,2-dioxanes in good yield and diastereoselectively in cases where substituents were sterically differentiated.

Acknowledgments

Research reported in this publication was supported by the National Institute of General Medical Sciences of the United States National Institutes of Health under award number 1R35GM148203. The authors acknowledge NYU’s Shared Instrumentation Facility and the support provided by NSF award CHE-01162222 and NIH award S10-OD016343. The authors thank Dr. Chin Lin (NYU) and Joel Tang (NYU) for their assistance with NMR spectroscopy and mass spectrometry. The authors also thank Alexander Shtukenberg (NYU) for his assistance with X-ray crystallography.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c04629.

  • Detailed experimental procedures, X-ray data, stereochemical proofs, and NMR spectra of all compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol4c04629_si_001.pdf (6.3MB, pdf)

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Associated Data

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Supplementary Materials

ol4c04629_si_001.pdf (6.3MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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