A method for the synthesis of 3-oxa[3.1.1]propellane

Abstract

This invention discloses a method for synthesizing 3-oxa[3.1.1]spiropropane, belonging to the fields of organic synthetic chemistry and medicinal chemistry. This method is the first to introduce oxygen atoms into the high-strength skeleton of [3.1.1]spiropropane, successfully synthesizing the 3-oxa[3.1.1]spiropropane molecule. The specific synthetic route is as follows: starting with 3,3-bis(bromomethyl)oxacyclobutane, the 3-oxabicyclo[3.1.1]heptane diol skeleton is constructed sequentially via nucleophilic substitution with diethyl malonate, reduction, and intramolecular cyclization. Then, oxidation and Barton decarboxylation iodination are performed to obtain the key intermediate 1,3-diiodo-3-oxabicyclo[3.1.1]heptane, which is finally reacted with an organolithium reagent to obtain the target product. This invention fills a technological gap in the synthesis of heteroatom-substituted spiroalkyl, providing a key precursor for the subsequent development of its free radical bifunctionalization reaction and the construction of structurally diverse 3-oxabicyclic [3.1.1]heptane dominant skeletons. It has important application prospects in drug design, especially as a bio-electroisoster of meta-substituted aromatics.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthetic chemistry and medicinal chemistry, and specifically relates to a method for synthesizing 3-oxa[3.1.1]spiropropane, a tricyclic hydrocarbon molecule with high ring strain. Background Technology

[0002] Aromatic compounds are widely present in active molecules due to their planar two-dimensional structure, but excessive aromatic ring structures often have an adverse effect on the drug-like properties of compounds. In order to "escape the plane" and improve the physicochemical properties of drug molecules (such as solubility and metabolic stability), medicinal chemists have been committed to replacing aromatic rings with non-classical bioisosteres. Among them, the bicyclic [3.1.1]heptane (BCHep) skeleton is a bioisostere of meta-substituted aromatic hydrocarbons. Introducing oxygen atoms into BCHep can further optimize its properties; therefore, developing synthetic methods for oxaBCHep skeletons is of great value.

[0003] Currently, the mainstream method for constructing oxa BCHep is based on the (3+3) cycloaddition reaction of bicyclic [1.1.0]butane (BCB) with a triatomic dipole. However, this method has significant limitations: (1) the BCB substrate usually needs to be connected to aryl and electron-withdrawing groups at both ends, which restricts the substituents at the bridgehead of the product and makes subsequent derivatization difficult; (2) the reaction introduces substituents that are difficult to convert onto the three-carbon ring of the BCHep skeleton, which limits its application as a meta-substituted aromatic bioisostere; (3) there is a lack of efficient and universal methods for synthesizing 1,3-disubstituted oxa BCHep.

[0004] [3.1.1]Propellane is a class of highly strained tricyclic hydrocarbons, and the high reactivity of its bridgehead C-C bond makes it an ideal precursor for constructing BCHep via ring-opening reactions. Functionalization strategies based on [3.1.1]propellane can precisely introduce the desired functional group at the bridgehead, avoiding the problem of introducing redundant substituents on the carbon ring, making it more suitable for drug design. Although this compound has been theoretically predicted to have potential applications as a highly strained heterocyclic skeleton, to date, no efficient synthetic method for directly introducing oxygen atoms into the [3.1.1]propellane skeleton has been reported in the prior art, which seriously hinders the in-depth application of this advantageous skeleton in drug development. Summary of the Invention

[0005] The purpose of this invention is to fill the gap in the prior art and provide a feasible method for synthesizing 3-oxa[3.1.1]spiropropane. Starting with readily available raw materials, this method achieves, for the first time, a complete synthetic pathway for this target molecule through a rationally designed multi-step reaction sequence. This provides a crucial intermediate basis for the subsequent development of its radical bifunctionalization reaction and the construction of structurally diverse 3-oxabicyclic[3.1.1]heptane drug skeletons.

[0006] The method for synthesizing 3-oxa[3.1.1]spiropropane provided by the present invention is characterized by comprising the following steps:

[0007] Step 1: Constructing 2-oxaspiro[3.3]heptane

[0008] Starting with 3,3-bis(bromomethyl)oxetane, a nucleophilic substitution reaction was carried out with diethyl malonate in the presence of a base to obtain diethyl 2-oxaspiro[3.3]heptane-6,6-dicarboxylic acid (compound 1).

[0009]

[0010] Step 2: Reduce diester to diol

[0011] The compound 1 obtained in step 1 was subjected to a reduction reaction to reduce its two ester groups to hydroxyl groups, yielding 2-oxaspiro[3.3]heptane-6,6-diethanol (compound 2).

[0012]

[0013] Step 3: Intramolecular cyclization to construct 3-oxabicyclo[3.1.1]heptane

[0014] Under Lewis acid catalysis, compound 2 undergoes an intramolecular nucleophilic substitution cyclization reaction to construct a bicyclic [3.1.1]heptane skeleton, yielding 3-oxabicyclo[3.1.1]heptane-1,3-diethanol (compound 3).

[0015]

[0016] Step 4: Oxidize the diol to a diacid

[0017] The dihydroxyl group of compound 3 was oxidized to a carboxyl group to obtain 3-oxabicyclo[3.1.1]heptane-1,3-dicarboxylic acid (compound 4).

[0018]

[0019] Step 5: Decarboxylation and iodination reaction

[0020] Compound 4 was decarboxylated with an iodine reagent under light to give 1,3-diiodo-3-oxabicyclo[3.1.1]heptane (compound 5, I2-BCHep).

[0021]

[0022] Step 6: Construction of propeller alkyl

[0023] Compound 5 was reacted with an organolithium reagent in an anhydrous ether solvent at low temperature to give an ether solution of 3-oxa[3.1.1]spiropropane (compound 6).

[0024]

[0025] In step 1 above, under argon protection, 3,3-bis(bromomethyl)oxetane, a base, and diethyl malonate are added to solvent A and reacted at 80–120 °C for 12–24 hours. After the reaction is complete, the mixture is separated and purified to obtain a colorless liquid compound 1. The base is any one of sodium methoxide, sodium ethoxide, sodium hydride, potassium carbonate, potassium phosphate, or sodium hydroxide. Solvent A is any one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), or tetrahydrofuran (THF). The molar ratio of 3,3-bis(bromomethyl)oxetane, the base, and diethyl malonate is 1:2.0–3.0:2.0–3.0.

[0026] In step 2 above, under argon protection, compound 1 and lithium aluminum hydride are stirred in solvent B at room temperature for 2–5 hours. After the reaction is complete, the reaction is quenched, filtered, and the filter residue is washed with ethyl acetate. The filtrates are combined and concentrated under reduced pressure to obtain compound 2. The molar ratio of compound 1 to lithium aluminum hydride is 1:2.0–3.0; solvent B is any one of THF, 1,4-dioxane, or diethyl ether.

[0027] In step 3 above, compound 2 and a Lewis acid are reacted in solvent C at room temperature for 6–8 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to obtain compound 3. The Lewis acid is any one of boron trifluoride diethyl ether, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc., and its amount is 10%–50% of the molar amount of compound 2. Solvent C is any one of tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, etc.

[0028] In step 4 above, N-methylmorpholine oxide and tetra-n-propylperruthenium(VII)ate ammonium are used as oxidants. Compound 3 and the oxidants are reacted in acetonitrile at room temperature for 6-8 hours to obtain compound 4. The molar ratio of compound 3 to N-methylmorpholine oxide and tetra-n-propylperruthenium(VII)ate ammonium is 1:8.0-10.0:0.01-0.05.

[0029] In step 5 above, compound 4 and the iodinated reagent are added to solvent D, and the mixture is irradiated with 50–200 W white light until it refluxes for 6–10 hours. After the reaction is complete, the mixture is separated and purified to obtain compound 5. The iodinated reagent is any one of N-iodosuccinimide, elemental iodine, or 1,3-diiodo-5,5-dimethylhydantoin, and the molar ratio of compound 4 to the iodinated reagent is 1:1.0–3.0. Solvent D is any one of carbon tetrachloride, dichloromethane, or chloroform.

[0030] In step 6 above, under argon protection and at -78 to -40 degrees Celsius... o At temperature C, compound 5 and an organolithium reagent were reacted in an anhydrous ether solvent with stirring for 1–3 hours. The organolithium reagent was selected from any one of methyllithium, phenyllithium, n-butyllithium, etc., and the molar ratio of compound 5 to the organolithium reagent was 1:1.0–2.0. The anhydrous ether solvent was any one of diethyl ether, dibutyl ether, etc. After the reaction was complete, sodium bicarbonate was added, and the mixture was stirred and filtered. The filtrate was kept at -10 to -40°C. o Store at C to directly obtain an ether solution of 3-oxa[3.1.1]spiropane. For pure product, store at -10 to -30 °C. o C. Remove the solvent by distillation under reduced pressure, but note that the compound is sensitive to heat and concentration processes, and is usually more stable to store and use in solution form (such as dissolved in the ether solvent used in the reaction).

[0031] The beneficial effects of this invention are as follows:

[0032] 1. This invention discloses for the first time a practical synthetic method for 3-oxa[3.1.1]spiropropane. Through reasonable route design, the target molecule was successfully constructed efficiently from readily available raw materials in six steps, filling the technical gap in its synthetic methodology.

[0033] 2. This invention utilizes a functionalization strategy for propeller alkyl intermediates to precisely introduce substituents at the 1,3-position of the bridgehead, avoiding the introduction of additional substituents that are difficult to remove onto the carbon ring. Each step of the reaction involves a mature organic transformation, is simple to operate, highly reproducible, and has the potential for large-scale preparation. The synthesized 1,3-diiodo-3-oxabicyclo[3.1.1]heptane (compound 5) can be used as a universal precursor to efficiently construct diverse 1,3-disubstituted 3-oxabicyclo[3.1.1]heptane derivatives through radical or nucleophilic substitution reactions.

[0034] 3. The 3-oxa[3.1.1]spirolide and its derivatives provided by this invention can be used as bioisosteres of meta-substituted aromatic hydrocarbons in drug molecule design. Compared with traditional aromatic ring structures, such bridged ring skeletons can significantly improve the solubility, metabolic stability and conformational diversity of drug molecules, overcoming the adverse effects of traditional aromatic hydrocarbon structures on drugability.

[0035] 4. The synthetic route of this invention has a wide range of raw material sources, controllable costs, mild reaction conditions, and simple post-processing. None of the intermediates require harsh purification conditions or special equipment, which lays a solid foundation for subsequent industrial scale-up and derivatization research. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0037] Example 1

[0038] The synthetic route and method for 3-oxa[3.1.1]spiroane in this embodiment are as follows:

[0039]

[0040] Step 1: Constructing 2-oxaspiro[3.3]heptane

[0041] Under argon protection, 14.88 g (0.372 mol) of NaH and 270 mL of DMF were added to a dry reaction flask. While cooling in an ice bath, 62.5 g (0.391 mol) of diethyl malonate was slowly added. After stirring for 1 hour, 45 g (0.186 mol) of 3,3-bis(bromomethyl)oxetane was slowly added dropwise. After the addition was complete, the ice bath was removed, and the temperature was raised to 120°C. o The reaction was carried out at C for 16 hours. After the reaction was complete, the mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using a mixture of petroleum ether / ethyl acetate at a volume ratio of 50:1 to 5:1 as the eluent) to give a colorless liquid compound 1 in 87% yield.

[0042] The structural characterization data of compound 1 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (s,4H), 6.78 (q, J = 7.1 Hz, 4H), 5.33 (s, 4H), 3.84 (t, J = 7.1 Hz, 6H); 13 C NMR(101 MHz, Chloroform-d) δ 171.4, 83.2, 61.6, 47.9, 38.9, 38.2, 14.0; HRMS(APCI-TOF) m / z: C 12 H 19 O5 [M + H] + Theoretical value: 243.1227; Measured value: 243.1220.

[0043] Step 2: Reduce diester to diol

[0044] Under argon protection at -78 °C, 15 g (61.8 mmol) of compound 1 and 375 mL of anhydrous THF were added to a dry reaction flask. 60 mL of anhydrous THF solution of 2.5 mol / L lithium aluminum hydride was slowly added dropwise. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was complete, 15.6 mL of 15% NaOH aqueous solution and 15.6 mL of water were added dropwise to quench the reaction. The mixture was filtered, and the residue was washed with ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain crude compound 2 (7.81 g, 49.4 mmol, yield 80%), which could be used directly in the next step without further purification.

[0045] Step 3: Intramolecular cyclization to construct 3-oxabicyclo[3.1.1]heptane

[0046] 7.81 g (49.4 mmol) of compound 2 was dissolved in 350 mL of anhydrous dichloromethane. Under ice bath cooling, 1.5 mL (11.9 mmol) of boron trifluoride diethyl ether was slowly added. After stirring for 30 minutes, the ice bath was removed, and the reaction was continued at room temperature for 6 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 3 (6.01 g, 38.5 mmol, yield 78%), which could be used directly for the next step without further purification.

[0047] Step 4: Oxidize the diol to a diacid

[0048] 6.01 g (38.5 mmol) of compound 3 was dissolved in 200 mL of acetonitrile. Under ice bath cooling, 40.0 g (341 mmol) of N-methylmorpholine oxide and 300 mg (0.85 mmol) of tetra-n-propylruthenium(VII) peracetic acid were slowly added dropwise, and the reaction was stirred at room temperature for 6 hours. After the reaction was complete, 80 mL of isopropanol was added to quench the reaction. Most of the acetonitrile and isopropanol were removed by evaporation under reduced pressure. The remaining solution was added to dilute hydrochloric acid and extracted multiple times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid compound 4 (2.65 g, 14.2 mmol, yield 37%), which could be used directly for the next step without further purification.

[0049] Step 5: Decarboxylation and iodination reaction

[0050] 1.12 g (6 mmol) of compound 4 and 3.42 g (9 mmol) of 1,3-diiodo-5,5-dimethylhydantoin were added to 60 mL of carbon tetrachloride and refluxed under 100 W white light for 10 hours. After the reaction was complete, the mixture was washed with 10% sodium thiosulfate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (using a 5:1 mixture of petroleum ether and dichloroethylene as eluent) to give compound 5 (0.67 g, 1.9 mmol, yield 32%).

[0051] The structural characterization data of compound 5 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 4.05 (s,4H), 3.21-3.08 (m, 2H), 3.02-2.88 (m, 2H); 13 C NMR (101 MHz, Chloroform-d) δ76.5, 55.6, 24.6. HRMS (APCI-TOF) m / z: C6H9I2O[M + H] + Theoretical value: 350.8737; Measured value: 350.8736.

[0052] Step 6: Construction of propeller alkyl

[0053] Under argon protection and at -78 °C, 3.5 g (10.0 mmol) of compound 5 was added to a dry reaction flask, followed by the slow addition of 7.4 mL of a 1.9 mol / L dibutyl ether solution of phenyllithium. After the addition was complete, the mixture was stirred at -78 °C for 2 hours. After the reaction was complete, 1.17 g (14.0 mmol) of sodium bicarbonate was added, and the mixture was stirred and filtered. The filtrate was stored at -20 °C to directly yield a dibutyl ether solution of 3-oxa[3.1.1]spiropropane (11.4 mL, 0.75 mol / L, 8.55 mmol, yield 85%).

[0054] The structural characterization data of compound 6 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.82 (s,4H), 2.64 (t, J = 1.6 Hz, 2H), 1.79 (t, J = 1.6 Hz, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 74.1, 54.0, 28.3.

[0055] The 3-oxa[3.1.1]spiropropane synthesized in this invention can be used as a key molecular building block to synthesize anticancer active molecule 10 (Angew. Chem. Int. Ed. 2025, 64, e202505519). The specific synthesis steps are as follows:

[0056]

[0057] Step 1: Add 72 mg of Ir(ppy)3 photosensitizer to a 100 mL reaction tube, purge with nitrogen three times, and then add 45 mL of trimethylacetonitrile, 1.09 g (4.5 mmol) of methyl iodide pentovalinate, and 9 mL of a 0.75 mol / L solution of 3-oxa[3.1.1]spiropropane in diethyl ether under a nitrogen atmosphere. The reaction mixture is then irradiated with 456 nm blue light at room temperature for 12 hours. After the reaction is complete, the reaction solution is evaporated to dryness and purified by silica gel column chromatography (using a mixture of PE:DCM = 3:1 → PE:EtOAc = 20:1 as the eluent) to obtain 912 mg of colorless oily compound 7, with a yield of 60%.

[0058] The structural characterization data of compound 7 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 4.15 (s, 2H), 3.91 (s, 2H), 3.80 (s, 2H), 2.62-2.53 (m, 2H), 2.46-2.34 (m, 2H), 1.20 (s, 9H); 13 C NMR (101 MHz, Chloroform-d) δ 178.2, 78.2, 70.4, 66.0, 47.0,46.2, 39.1, 27.4, 27.3; HRMS(I)m / z C 14 H 12 F3O4 [M + Na] + Theoretical value: 361.0271, measured value: 361.0277.

[0059] Step 2: Add 405.6 mg (1.2 mmol) of compound 7 to a 10 mL reaction tube, followed by 84 mg (0.24 mmol) of iron triacetylacetone. The nitrogen atmosphere was purged three times. Under a nitrogen atmosphere, 1.6 mL of tetrahydrofuran and 72 µL (0.48 mmol) of N,N,N',N'-tetramethylethylenediamine (TMEDA) were added sequentially. The reaction was allowed to proceed for 5 minutes. Then, 3.84 mL of a 0.5 mol / L solution of 4-(trifluoromethoxy)phenyl magnesium bromide in tetrahydrofuran was added dropwise over 1 hour. The reaction was continued at room temperature for another hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with diethyl ether, dried over anhydrous sodium sulfate, and the concentrated product was purified by column chromatography (using a mixture of PE:DCM = 3:1 → PE:EtOAc = 20:1 as the eluent) to obtain 228 mg of a colorless oily compound 8, with a yield of 51%.

[0060] The structural characterization data of compound 8 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.19-7.13(m, 2H), 7.13-7.08 (m, 2H), 3.96 (s, 2H), 3.89 (s, 2H), 3.84 (s, 2H), 2.18-2.08 (m, 2H), 2.07-2.00 (m, 2H), 1.20 (s, 9H); 13 C NMR (101 MHz, Chloroform- d )δ 178.4, 148.0 (d, J = 2.0 Hz), 143.4, 127.0, 121.2, 120.6 (d, J = 256.9 Hz),76.3, 71.8, 67.0, 43.8, 39.4, 39.1, 37.5, 27.4; 19 F NMR (376 MHz, Chloroform- d ) δ -57.91; HRMS(APCI)m / z C 19 H 24 F3O4[M + H] + Theoretical value: 373.1621, measured value: 373.1619.

[0061] Step 3: In a 25 mL reaction flask, 186 mg (0.5 mmol) of compound 8, 6.0 mL of methanol, and 0.70 mL of 1 mol / L sodium hydroxide aqueous solution were added sequentially, and the reaction was carried out at 50 °C for 20 hours. After the reaction was complete, the methanol was removed by vacuum concentration. The crude product was then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 141.1 mg of a white solid compound, with a yield of 98%. This compound was directly added to the next step without further purification.

[0062] Step 4: Add 141.1 mg of the solid compound obtained in Step 3, 0.6 mL of acetonitrile, 0.6 mL of dichloromethane, and 1.0 mL of water to a 10 mL reaction flask. Then add 423.4 mg (1.96 mmol) of sodium periodate and 6 mg (0.024 mmol) of ruthenium trichloride hydrate. React at room temperature for 7 hours. After the reaction is complete, filter and concentrate under vacuum. Adjust the pH of the crude product to approximately 12 with 1 mol / L sodium hydroxide aqueous solution, extract with diethyl ether, adjust the pH of the aqueous phase to approximately 2 with 1 mol / L hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain 81.5 mg of white solid compound 9, with a yield of 55%. This compound can be directly added to the next step without purification.

[0063] Step 5: 26.8 mg (88.7 µmol) of compound 9, 18.4 mg (88.7 µmol) of 6-((2S,6R)-2,6-dimethylmorpholino)pyridine-3-amine and 40.5 mg (0.106 mmol) of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) were dissolved in 0.5 mL of DMF. 49.4 µL (0.355 mmol) of triethylamine was added, and the mixture was stirred at 50 °C for 8 hours. 2 mL of water and 2 mL of ethyl acetate were added, and the mixture was extracted and separated. The organic phase was washed with water, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (using a mixture of hexane and THF at a volume ratio of 2:1 as the eluent) to give compound 10 as a yellow solid, with a yield of 70%.

[0064] The structural characterization data of compound 10 are as follows: 1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J= 2.8 Hz, 1H), 7.86 (dd, J = 9.1, 2.8 Hz, 1H), 7.23-7.08 (m, 4H), 6.61 (d, J= 9.1 Hz, 1H), 4.16 (s, 2H), 3.97 (dd, J = 12.7, 1.8 Hz, 1H), 3.88 (s, 2H), 3.71 (dqd, J = 10.5, 6.2, 2.5 Hz, 2H), 2.55-2.40 (m, 6H), 1.26 (s, 3H), 1.25(s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 171.1, 156.7, 148.2, 142.4, 140.0,131.8, 127.0, 125.1, 121.3, 120.6 (q, J = 258.5 Hz), 107.1, 75.6, 71.7, 71.3,51.3, 45.1, 42.4, 38.5, 19.1; 19 F NMR (376 MHz, Chloroform-d) δ -57.9; HRMS(ESI) m / z C 25 H 28 F3N3O4Na [M+Na] + Theoretical value: 514.1924, measured value: 514.1932.

Claims

1. A method for synthesizing 3-oxa[3.1.1]spiropropane, characterized in that, Includes the following steps: Step 1: Constructing 2-oxaspiro[3.3]heptane Starting with 3,3-bis(bromomethyl)oxetane, a nucleophilic substitution reaction was carried out with diethyl malonate in the presence of a base to give compound 1; Step 2: Reduce diester to diol The compound 1 obtained in step 1 was subjected to a reduction reaction to reduce its two ester groups to hydroxyl groups, resulting in compound 2. Step 3: Intramolecular cyclization to construct 3-oxabicyclo[3.1.1]heptane Under Lewis acid catalysis, compound 2 underwent an intramolecular nucleophilic substitution cyclization reaction to construct a bicyclic [3.1.1]heptane skeleton, yielding compound 3; Step 4: Oxidize the diol to a diacid The dihydroxyl group of compound 3 was oxidized to a carboxyl group to obtain compound 4; Step 5: Decarboxylation and iodination reaction Compound 4 was decarboxylated with an iodine reagent under light irradiation to obtain compound 5; Step 6: Construction of propeller alkyl Compound 5 was reacted with an organolithium reagent at temperatures ranging from -78°C to -40°C. o The reaction was carried out in anhydrous ether solvent under C. After the reaction was completed, sodium bicarbonate was added, and the mixture was stirred and filtered to obtain an ether solution of compound 6, namely an ether solution of 3-oxa[3.1.1]spiropropane. 。 2. The method for synthesizing 3-oxa[3.1.1]spiropropane according to claim 1, characterized in that, In step 1, the molar ratio of 3,3-bis(bromomethyl)oxetane, the base, and diethyl malonate is 1:2.0–3.0:2.0–3.0, and the base is any one of sodium methoxide, sodium ethoxide, sodium hydride, potassium carbonate, potassium phosphate, and sodium hydroxide; the temperature of the nucleophilic substitution reaction is 80–150 °C. o C. The solvent used in the reaction is any one of N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran.

3. The method for synthesizing 3-oxa[3.1.1]spiropropane according to claim 1, characterized in that, In step 2, the reducing agent for the reduction reaction is lithium aluminum hydride, and the molar ratio of compound 1 to lithium aluminum hydride is 1:2.0 to 3.

0. The reduction reaction is carried out at room temperature, and the solvent used is any one of tetrahydrofuran, 1,4-dioxane, or diethyl ether.

4. The method for synthesizing 3-oxa[3.1.1]spiropropane according to claim 1, characterized in that, In step 3, the Lewis acid is any one of boron trifluoride ether, p-toluenesulfonic acid, hydrochloric acid, and sulfuric acid, and its amount is 10% to 50% of 2 moles of the compound; the cyclization reaction is carried out at room temperature, and the solvent used is any one of tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, and ethyl acetate.

5. The method for synthesizing 3-oxa[3.1.1]spiropropane according to claim 1, characterized in that, In step 4, N-methylmorpholine oxide and tetra-n-propyl perruthenate ammonium are used as oxidants, and the oxidation reaction is carried out at room temperature. The molar ratio of compound 3 to N-methylmorpholine oxide and tetra-n-propyl perruthenate ammonium is 1:8.0~10.0:0.01~0.

05.

6. The method for synthesizing 3-oxa[3.1.1]spiropropane according to claim 1, characterized in that, In step 5, the iodination reagent is any one of N-iodosuccinimide, elemental iodine, or 1,3-diiodo-5,5-dimethylhydantoin, and the molar ratio of compound 4 to the iodination reagent is 1:1.0 to 3.0; the reaction is carried out under reflux irradiation with 50 to 200 W white light, and the solvent used in the reaction is any one of carbon tetrachloride, dichloromethane, or chloroform.

7. The 3-oxa[…] according to claim 1 3.1.1] A method for synthesizing propellerane, characterized in that, In step 6, the organolithium reagent is selected from any one of methyllithium, phenyllithium, and n-butyllithium, and the molar ratio of compound 5 to the organolithium reagent is 1:1.0 to 2.0; the anhydrous ether solvent is any one of diethyl ether and dibutyl ether.

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