Rhodium-catalyzed desymmetrizing hydroformylation to build polychiral carbon ring nucleosides

Abstract

The application discloses a rhodium-catalyzed desymmetrization hydroformylation method for constructing polychiral center carbon ring nucleosides. The method for constructing polychiral center carbon ring nucleosides comprises the following steps: under the condition of an inert atmosphere, an acetylacetone dicarbonyl rhodium metal precursor and a chiral ligand are added into an organic solvent to prepare a catalyst solution, the catalyst solution is mixed with a substrate, and a reaction is carried out under the condition of a hydrogen atmosphere and a carbon monoxide atmosphere; after the reaction is completed, filtration and purification are carried out, and polychiral center cycloalkyl aldehyde is obtained; and the aldehyde group is converted to obtain the polychiral center carbon ring nucleosides. The method for constructing polychiral center carbon ring nucleosides has the advantages of high selectivity, wide substrate compatibility, high reaction efficiency, easy conversion of products, and the like. The whole reaction process can obtain polychiral center cycloalkyl aldehyde in one step with extremely high enantioselectivity and diastereoselectivity, the aldehyde group is converted, polychiral center carbon rings can be obtained with high yield, high dr value and high ee value, and the method is simple and easy to operate.

Description

Technical Field

[0001] This application relates to the field of multichiral central carbocyclic nucleoside synthesis technology, and in particular to a method for constructing multichiral central carbocyclic nucleosides. Background Technology

[0002] Nucleoside analogues play a crucial role in organic synthetic chemistry. The structural unit of a nucleoside consists of a glycosyl group and a base. Carbocyclic nucleosides are nucleoside derivatives in which the oxygen atom in the glycosyl group is replaced with a methylene group, while the base structure remains unchanged. The all-carbon ring structure increases the stability of the CN bond between the glycosyl group and the base, and also possesses unique biological activities. Many carbocyclic nucleosides have been reported, but only a few have been developed into drugs usable by humans, such as Neplanocine A, abacavir, carbadox, and D-form. Current reports on carbocyclic nucleosides mainly focus on five-membered carbocyclic nucleosides, with only a few reports on six-membered carbocyclic nucleosides, and only one reported case of a seven-membered carbocyclic nucleoside. The specific structural features of the glycosyl group and the derivatization of the base in carbocyclic nucleosides may make them a chemically diverse molecular library. Therefore, it is necessary to synthesize more diverse carbocyclic nucleoside structures and develop more efficient synthetic methods. The key structural segment of carbocyclic nucleosides is the all-carbon-cyclic glycosyl group, and the structural basis of the glycosyl group is a multi-chiral carbon ring. Existing construction strategies include olefin metathesis reactions, Aldol reactions, radical cyclization reactions, transition metal-catalyzed cyclization reactions, transition metal-involved cyclization reactions (as reactants), and cycloaddition reactions of intracyclic alkenes. However, these methods require long synthetic steps or necessary isomer resolution, resulting in low synthetic efficiency. Summary of the Invention

[0003] The purpose of this application is to provide a novel method for constructing multichiral central carbocyclic nucleosides.

[0004] To achieve the above objectives, this application adopts the following technical solution:

[0005] One aspect of this application discloses a method for constructing a multichiral central carbocyclic nucleoside, comprising: adding an acetylacetone dicarbonyl rhodium metal precursor and a chiral ligand to an organic solvent under an inert atmosphere to prepare a catalyst solution; mixing the catalyst solution with a substrate and reacting under a hydrogen and carbon monoxide atmosphere; after the reaction, filtering and purification to obtain a multichiral central cycloalkyl aldehyde; and converting the aldehyde group to obtain the multichiral central carbocyclic nucleoside of this application. The aldehyde group exhibits high reactivity, and the conversion of the aldehyde group is described in reference to existing technologies and will not be elaborated here.

[0006] It should be noted that this application creatively utilizes rhodium-catalyzed desymmetric hydroformylation to construct multichiral central carbocyclic nucleosides, exhibiting broad substrate compatibility. In one implementation of this application, corresponding multichiral central carbocyclic nucleosides can be constructed using five-membered, six-membered, seven-membered, and heterocyclic substrates. This greatly increases the synthetic diversity of carbocyclic nucleoside compounds, providing more possibilities for the development of carbocyclic nucleoside drugs. Furthermore, the multichiral central carbocyclic nucleoside construction method of this application yields multichiral central cycloalkyl aldehydes in one step with extremely high enantiomeric and diastereoselectivity. Utilizing the high reactivity of the aldehyde group for corresponding transformations, the efficient synthesis of chiral carbocyclic rings can be achieved. The construction method of this application can obtain multichiral carbocyclic rings with high yield, high dr value, and high ee value, and is simple and easy to operate.

[0007] In one implementation of this application, the substrate is the structure shown in equation (1) or equation (2).

[0008] Equation (1) ,

[0009] Equation (2) ,

[0010] In formula (1), n ​​= 1, 2 or 3; in formula (1) and formula (2), R1 is selected from at least one of OTBS, OTMS, OTES, OTIPS, OTBDPS, OSiPhMe2, OAc, OTr, COOMe, and R2 is selected from at least one of H, Me, Et, nBu, and cyclopentyl; in formula (2), R3 is selected from at least one of phenyl, benzyl, naphthyl ring, benzocyclopentyl, and other benzene rings with substituents.

[0011] In one implementation of this application, the chiral ligand is at least one of the following:

[0012] , , , , , , , , .

[0013] In one implementation of this application, the acetylacetone dicarbonyl rhodium metal precursor is Rh(C5H7O2)(CO)2.

[0014] In one implementation of this application, the organic solvent is at least one selected from toluene, dioxane, THF, CH3CN, hexane, cyclohexane, heptane, benzene, DCM, and DCE.

[0015] In one implementation of this application, the reaction conditions are a stirred reaction at 50~150 °C for at least 12 h.

[0016] In one implementation of this application, the molar ratio of acetylacetone dicarbonyl rhodium metal precursor to chiral ligand in the catalyst solution is 1:1 to 1:4; and the molar ratio of catalyst to substrate in the reaction is 1:20 to 1:100000.

[0017] In one implementation of this application, the filtration includes silica gel column filtration.

[0018] In one implementation of this application, purification includes column chromatography purification or recrystallization purification.

[0019] Another aspect of this application discloses a multichiral central carbocyclic nucleoside, which is prepared by the method of this application.

[0020] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:

[0021] The method for constructing multi-chiral central carbocyclic nucleosides presented in this application has the advantages of high selectivity, broad substrate compatibility, high reaction efficiency, and easy product conversion. The entire reaction process yields multi-chiral central cycloalkyl aldehydes in one step with extremely high enantiomeric and diastereoselectivity. The conversion of the aldehyde group can obtain multi-chiral carbon rings with high yield, high dr value, and high ee value. The method is simple and easy to operate. Attached Figure Description

[0022] Figure 1 This is a simulated structural diagram of CCDC 2471076 in the embodiments of this application. Detailed Implementation

[0023] Asymmetric hydroformylation is a promising method for desymmetrization. For symmetrical intracyclic alkenes, asymmetric hydroformylation can construct chiral cycloalkyl aldehydes in one step. Utilizing the high reactivity of the aldehyde group for corresponding transformations, efficient synthesis of chiral carbocyclic rings can be achieved.

[0024] This work focuses primarily on cyclopentene derivatives as substrates. Identical substituents are introduced on both sides of the cyclopentene, maintaining a uniform orientation of the substituents to obtain symmetrical intracyclic alkenes. After desymmetry and hydroformylation, cycloalkylaldehydes with trichiral centers are obtained, followed by transformation to yield a trichiral carbocyclic ring. Building upon this foundation, the scope of applicable olefin substrates is further expanded to include trichiral and tetrachiral substrates.

[0025] Based on the above research and understanding, this application creatively provides a method for constructing a multi-chiral central carbocyclic nucleoside, comprising adding an acetylacetone dicarbonyl rhodium metal precursor and a chiral ligand to an organic solvent under an inert atmosphere to prepare a catalyst solution, mixing the catalyst solution with the substrate, and reacting under an atmosphere of hydrogen and carbon monoxide; after the reaction is completed, filtering and purifying to obtain a multi-chiral central cycloalkyl aldehyde, and converting the aldehyde group to obtain the multi-chiral central carbocyclic nucleoside of this application.

[0026] The method described in this application yields a multichiral central cycloalkyl aldehyde in one step with extremely high enantiomeric and diastereoselectivity. Transformation of the aldehyde group can produce multichiral carbocyclic rings with high yields, high dr values, and high ee values. In one implementation of this application, the reaction TON was tested, showing that the TON of this reaction can reach 86,000. The method described in this application exhibits extremely high stereoselectivity, broad substrate compatibility, extremely high reaction efficiency, and easy conversion of the product.

[0027] The present application will be further described in detail below through specific embodiments. These embodiments are merely illustrative and should not be construed as limiting the present application. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other devices, materials, or methods. In some cases, certain operations related to the present application are not shown or described in the specification to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; a complete understanding of the related operations can be obtained from the description in the specification and general technical knowledge in the art.

[0028] Unless otherwise specified, all reagents used in the following examples are commercial products manufactured by brands such as Anengji, Bieder Pharmaceuticals, Bailingwei, Leyan, Sigma-Aldrich, and Xins. All solvents used are ultra-dry solvents containing molecular sieves, manufactured by companies such as Anengji and Bailingwei. The silica gel used in the column chromatography was 200-300 mesh, manufactured by Qingdao Haiyang Chemical Co., Ltd. The TLC silica gel plates were Sanpont brand products. A domestically produced 50 mL reaction vessel was used for the hydroformylation reaction. All NMR data in this article were measured using a Bruker AVANCE NEO 400 MHz or Bruker AVANCE NEO 600 MHz NMR spectrometer. An Agilent brand high-performance liquid chromatograph was used. A Rudolf brand polarimeter was used.

[0029] Example

[0030] I. Substrate Synthesis and Characterization

[0031] Substrate 1b is a commercially available compound. The synthesis method for substrate 1h follows existing techniques. The general procedure (step 1) is as follows:

[0032]

[0033] General Step 1: Under argon atmosphere, cis-4-cyclopenten-1,3-diol (500 mg, 5 mmol) and imidazole (1.8 g, 26.5 mmol) were dissolved in 15 mL of dry DMF solvent and stirred for 30 minutes. Tert-butyldimethylchlorosilane (2 g, 13.5 mmol) was dissolved in 15 mL of dry DMF, and this solution was added dropwise to the above solution at room temperature. The reaction was allowed to proceed for 12 hours at room temperature. After the reaction was complete, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed ten times with 50 mL of water, and once with 50 mL of saturated brine. After drying with anhydrous sodium sulfate, the mixture was purified by column chromatography (PE / EA = 50:1) to obtain a colorless oily liquid, 1.6 g, 97%. Using this step, replacing tert-butyldimethylchlorosilane with different chlorosilanes can synthesize substrates 1a, 1c, 1d, 1e, 1g, and 1i, all with yields exceeding 70%. Additionally, the synthesis of cyclopentenyl glycol used in some substrate synthesis methods follows existing techniques. Using cyclopentenyl glycol in the general step 1 can synthesize substrates 1j, 1l, 1m, 1n, 1o, 1s, and 1t, all of which are colorless oily liquids.

[0034] The general technical approach for step 2 is as follows:

[0035]

[0036] General Step 2: Under argon atmosphere, cis-4-cyclopenten-1,3-diol (100 mg, 1 mmol), triphenylchloromethane (732 mg, 3 mmol), and DMAP (18.3 mg, 0.15 mmol) were dissolved in 20 mL of dry dichloromethane. Triethylamine (212 mg, 2.1 mmol) was then slowly added dropwise. The reaction was carried out at room temperature for 12 hours. After the reaction was complete, the solvent was removed, and the mixture was quenched with 20 mL of water. The mixture was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 10:1) to obtain a white solid, 300 mg, 51%. This step can be used to synthesize substrate 1f.

[0037] The general technical approach for step 3 is as follows:

[0038]

[0039] General Step 3: Synthesis of cyclopentenyl diol. Acetophenone (467 mg, 3.89 mmol) and bis(trimethylsiloxy)cyclobutene (1.50 mL, 5.84 mmol) were dissolved in 7 mL of dry dichloromethane under argon atmosphere. Boron trifluoride diethyl ether solution (0.72 mL, 5.84 mmol) was added dropwise under an ice-water bath. The mixture was stirred at room temperature for 12 hours, then quenched with 50 mL of water. The mixture was extracted three times with 50 mL of dichloromethane, washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 10:1) to obtain a yellow oil. Under argon atmosphere, the cyclopentanedione (2.8 g, 15 mmol) obtained in the previous step was dissolved in 100 mL of dry methanol solvent, and copper bromide (7.37 g, 33.0 mmol) was added. The mixture was refluxed for two hours, cooled, and then 25 mL of water and 50 mL of hydrochloric acid solution (1M) were added to remove methanol. The mixture was extracted three times with 75 mL of ethyl acetate, washed once with 50 mL of saturated saline, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 10:1) to obtain a bright yellow oily substance. The cyclopentenedione (5.00 mmol, 930 mg) obtained in the previous step was dissolved in methanol, and CeCl3·7H2O (4.66 g, 12.50 mmol) was added. The mixture was stirred for half an hour, and sodium borohydride solid (416 mg, 11 mmol) was slowly added under an ice-water bath. The mixture was stirred for two hours, and then 5 mL of water and 10 mL of hydrochloric acid solution (1M) were slowly added to remove methanol under reduced pressure. The mixture was extracted three times with 75 mL of ethyl acetate, washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 5:1) to obtain an amorphous solid. Then, the general step 1 above was repeated to obtain substrates 1k, 1p, 1q, 1r, 1u, 1v, 1w, 1x, 1y, 1z, 1aa, 1ab, 1ac, 1ad, 1ae, 1af, and 1ag, all of which were colorless oils.

[0040] The NMR data for all substrates are as follows:

[0041] (3R, 5S)-3, 5-bis((tert-butyldimethylsilyl)oxy)cyclopent-1-ene (1a). Colorless oil, 328 mg, 99% yield (PE : EA = 20:1). 1H NMR (600 MHz, CDCl3) δ 5.79 (s, 2H), 4.67 – 4.56 (m, 2H), 2.66 (dt, J =12.7, 6.5 Hz, 1H), 1.52 (dt, J = 12.7, 6.5 Hz, 1H), 0.89 (s, 18H), 0.08 (s,6H), 0.07 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ 135.9, 75.0, 45.2, 25.9, 18.2, -4.5, -4.6. HRMS (ESI) m / z calcd for C 17 H 36 O2Si2Na [M+Na] + : 351.2146, found:351.2144

[0042] (3R,5S)-3,5-bis((trimethylsilyl)oxy)cyclopent-1-ene (1b). Colorless oil, 378 mg, 70% yield (PE : EA = 20:1). 1 HNMR (400 MHz, CDCl3) δ 5.69 (s, 2H), 4.63 – 4.38 (m, 2H), 2.57 – 2.50 (m,1H), 1.44 – 1.38 (m, 1H), 0.00 (s, 18H). 13 C NMR (101 MHz, CDCl3) δ 135.7,74.4, 44.7, 0.0. HRMS (ESI) m / z calcd for C 11 H 24 O2Si2Na [M+Na] + :267.1207,found: 267.1208

[0043] (3R,5S)-3,5-bis((triethylsilyl)oxy)cyclopent-1-ene (1c). Colorless oil, 290 mg, 75% yield (PE : EA = 20:1). 1H NMR (400MHz, CDCl3) δ 5.74 (s, 2H), 4.56 – 4.53 (m, 2H), 2.63 – 2.57 (m, 1H), 1.51 –1.45 (m, 1H), 0.89 (t, J = 8.0 Hz, 18H), 0.54 (q, J = 7.8 Hz, 12H). 13 C NMR(151 MHz, CDCl3) δ 136.0, 74.6, 45.2, 6.8, 4.8. HRMS (ESI) m / z calcd forC 17 H 36 O2Si2Na [M+Na] + :351.2146, found: 351.2149

[0044] (3R,5S)-3,5-bis((triisopropylsilyl)oxy)cyclopent-1-ene (1d). Colorless oil, 150 mg, 90% yield (PE : EA = 20:1). 1 HNMR (600 MHz, CDCl3) δ 5.85 (s, 2H), 4.71 (t, J = 6.5 Hz, 2H), 2.78 – 2.72(m, 1H), 1.65 – 1.61 (m, 1H), 1.12 – 1.05 (m, 42H). 13 C NMR (151 MHz, CDCl3) δ136.0, 74.9, 45.8, 18.0, 18.0, 12.2. HRMS (ESI) m / z calcd for C 23 H 48 O2Si2Na [M+Na] + :435.3085, found: 435.3088

[0045] (3R, 5S)-3, 5-bis((tert-butyldiphenylsilyl)oxy)cyclopent-1-ene (1e). Colorless oil, 576 mg, 99% yield(PE : EA = 20:1). 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.55 (m, 8H), 7.36 – 7.30(m, 4H), 7.29 – 7.25(m, 8H), 5.61 (s, 2H), 4.44 – 4.36 (m, 2H), 2.29 – 2.22(m, 1H), 1.74 – 1.68 (m, 1H), 0.98 (s, 18H). 13 C NMR (101 MHz, CDCl3) δ 135.9,135.9, 134.4, 134.3, 129.7, 127.7, 75.8, 44.9, 27.0, 19.2. HRMS (ESI) m / zcalcd for C 37 H 44 O2Si2Na [M+Na] + :599.2772, found: 599.2770

[0046] (3R,5S)-3,5-bis((dimethyl(phenyl)silyl)oxy)cyclopent-1-ene (1f). Colorless oil, 264 mg, 90% yield (PE : EA =20:1). 1 H NMR (600 MHz, CDCl3) δ 7.59 – 7.57 (m, 4H), 7.40 – 7.35 (m, 6H), 5.76(s, 2H), 4.55 (t, J = 6.5 Hz, 2H), 2.55 – 2.50 (m, 1H), 1.73 – 1.60 (m, 1H),0.38 (s, 12H). 13 C NMR (151 MHz, CDCl3) δ 138.1, 135.8, 133.5, 129.5, 127.8,74.9, 44.7, -1.1, -1.1. HRMS (ESI) m / z calcd for C 21 H 28 O2Si2Na [M+Na] + :391.1520, found: 391.1523

[0047] (3R,5S)-3,5-bis(trityloxy)cyclopent-1-ene (1h).White solid, 300 mg, 51% yield (PE : EA = 10:1), mp 131.0-133.8 °C. 1 H NMR(400 MHz, CDCl3) δ 7.49 – 7.45 (m, 12H), 7.29 – 7.25 (m, 12H), 7.24 – 7.20(m, 6H), 4.81 (s, 2H), 4.20 (t, J = 6.6 Hz, 2H), 1.86 – 1.62 (m, 2H). 13 C NMR(101 MHz, CDCl3) δ 145.0, 134.8, 128.8, 127.7, 126.9, 87.1, 76.3, 41.6. HRMS(ESI) m / z calcd for C 43 H 36 O2Na [M+Na] + :607.2607, found: 607.2615

[0048] (((1R, 3S)-2, 2-dimethylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1j). Colorless oil, 145 mg, 99%yield (PE : EA = 20:1). 1 H NMR (600 MHz, CDCl3) δ 5.65 (s, 2H), 4.17 (s, 2H),1.07 (s, 3H), 0.90 (s, 18H), 0.78 (s, 3H), 0.06 (s, 12H). 13 C NMR (151 MHz,CDCl3) δ 134.2, 82.4, 50.4, 25.9, 25.3, 18.2, 16.3, -4.5, -4.8. HRMS (ESI) m / z calcd for C 19 H 40 O2Si2Na [M+Na]+ :379.2459, found: 379.2458

[0049] (1R, 4S)-1, 4-bis((tert-butyldimethylsilyl)oxy)spiro[4.4]non-2-ene (1k). Colorless oil, 305 mg, 33% yield for 4 steps (PE :EA = 20:1). 1 H NMR (400 MHz, CHCl3) δ 5.73 (s, 2H), 4.25 (s, 2H), 1.79 – 1.75(m, 2H), 1.57 – 1.56 (m, 6H), 0.89 (s, 18H), 0.06 – 0.05 (m, 12H). 13 C NMR(101 MHz, CHCl3) δ 135.4, 81.9, 61.3, 37.5, 25.8, 25.4, 25.2, 18.1, -4.2, -4.8. HRMS (ESI) m / z calcd for C 21 H 42 O2Si2Na [M+Na] + :405.1615, found: 405.2616

[0050] (3R, 6S)-3, 6-bis((tert-butyldimethylsilyl)oxy)cyclohex-1-ene (1l). Colorless oil, 567 mg, 99% yield (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 5.66 (d, J = 1.3 Hz, 2H), 4.10 (t, J = 4.7 Hz, 2H),1.81 – 1.72 (m, 2H), 1.70 – 1.57 (m, 2H), 0.89 (s, 18H), 0.06 (s, 12H). 13 CNMR (101 MHz, CDCl3) δ 132.2, 66.2, 28.8, 26.1, 18.4, -4.4, -4.4. HRMS (ESI)m / z calcd for C 18 H 38 O2Si2Na [M+Na] + :365.2302, found: 365.2302

[0051] (3R, 7S)-3, 7-bis((tert-butyldimethylsilyl)oxy)cyclohept-1-ene (1m). Colorless oil, 350 mg, 99% yield (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 5.60 (s, 2H), 4.23 – 4.20 (m, 2H), 1.92 – 1.88 (m,1H), 1.73 – 1.68 (m, 2H), 1.62 – 1.58 (m, 1H), 1.54 – 1.45 (m, 2H), 0.89 (s,18H), 0.06 (s, 6H), 0.05 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 136.5, 73.1,36.7, 26.0, 24.7, 18.4, -4.5, -4.6. HRMS (ESI) m / z calcd for C 19 H 40 O2Si2Na [M+Na] + :379.2459, found: 379.2459

[0052] (3R, 6S)-3, 6-bis((tert-butyldimethylsilyl)oxy)-2, 3, 6, 7-tetrahydrooxepine (1n). Colorless oil, 400 mg, 99% yield (PE: EA = 20:1). 1 H NMR (600 MHz, CDCl3) δ 5.58 (s, 2H), 4.36 – 4.34 (m, 2H),3.74 – 3.71 (m, 2H), 3.19 (t, J = 10.6 Hz, 2H), 0.82 (s, 18H), 0.07 (s, 6H),0.06 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ 135.4, 76.3, 71.8, 25.9, 18.3, -4.6,-4.8. HRMS (ESI) m / z calcd for C 18 H 38O3Si2Na [M+Na] + :381.2251, found: 381.2250

[0053] tert-butyl (3R, 6S)-3, 6-bis((tert-butyldimethylsilyl)oxy)-2, 3, 6, 7-tetrahydro-1H-azepine-1-carboxylate (1o).Colorless oil, 421 mg, 99% yield (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ5.58 (d, J = 8.2 Hz, 2H), 4.29 – 4.22 (m, 2H), 4.09 – 4.05 (m, 1H), 3.93 –3.89 (m, 1H), 2.81 – 2.75 (m, 1H), 2.69 – 2.63 (m, 1H), 1.48 (s, 9H), 0.89(s, 18H), 0.12 – 0.11 (m, 6H), 0.10 – 0.08 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ154.8, 135.2 (d, J = 57.9 Hz), 80.1, 70.5 (d, J = 59.9 Hz), 54.3 (d, J = 57.3Hz), 28.7, 25.9, 18.2, -4.5. HRMS (ESI) m / z calcd for C 23 H 47 NO4Si2Na [M+Na] + :480.2936, found: 480.2935

[0054] (((1R, 2S, 3S)-2-methyl-2-phenylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1aa). Colorless oil, 120 mg,17% yield for 4 steps (PE : EA = 20:1). 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J= 8.4, 1.4 Hz, 2H), 7.15 (t, J = 7.5 Hz, 2H), 7.10 (d, J = 7.3 Hz, 1H), 5.89(s, 2H), 4.36 (s, 2H), 1.52 (s, 3H), 0.66 (s, 18H), -0.12 (s, 6H), -0.26 (s,6H). 13 C NMR (101 MHz, CDCl3) δ 139.7, 135.3, 130.8, 125.9, 125.4, 84.6, 55.8,25.8, 18.1, 1.2, -4.8, -4.9. HRMS (ESI) m / z calcd for C 24 H 42 O2Si2Na [M+Na] + :441.2615, found: 441.2616

[0055] (((1R, 2S, 3S)-2-ethyl-2-phenylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ab). Colorless oil, 367mg, 15% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.50 –7.40 (m, 2H), 7.35 – 7.25 (m, 2H), 7.21 – 7.16 (m, 1H), 5.81 (s, 2H), 4.89(s, 2H), 0.95 (s, 18H), 0.90 – 0.84 (m, 5H), 0.10 (s, 6H), 0.09 (s, 6H). 13 CNMR (101 MHz, CDCl3) δ 148.9, 133.9, 127.9, 126.9, 125.6, 81.7, 61.4, 26.4,25.8, 18.0, 12.7, -3.9, -4.9. HRMS (ESI) m / z calcd for C 25 H 44 O2Si2Na [M+Na]+ :455.2772, found: 455.2768

[0056] (((1R, 2S, 3S)-2-butyl-2-phenylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ac). Colorless oil, 401mg, 14 % yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.51 –7.46 (m, 2H), 7.35 – 7.25 (m, 2H), 7.22 – 7.17 (m, 1H), 5.81 (s, 2H), 4.90(s, 2H), 1.36 – 1.16 (m, 6H), 0.96 (s, 18H), 0.96 – 0.84 (m, 3H), 0.12 (s,6H), 0.11 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 149.3, 133.9, 127.9, 126.8,125.6, 81.7, 61.4, 34.4, 30.3, 25.8, 24.2, 18.0, 14.2, -3.8, -4.9. HRMS (ESI)m / z calcd for C 27 H 48 O2Si2Na [M+Na] + :483.3085, found: 483.3081

[0057] (((1R, 2S, 3S)-2-benzyl-2-methylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ad). Colorless oil, 200 mg,98% yield (PE : EA = 20:1). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m, 2H),7.25 – 7.19 (m, 2H), 7.18 – 7.11 (m, 1H), 5.86 (d, J = 1.1 Hz, 2H), 4.13 (d,J = 1.1 Hz, 2H), 2.89 (s, 2H), 0.94 (s, 18H), 0.77 (s, 3H), 0.13 (s, 6H),0.10 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 141.3, 135.6, 131.3, 127.6, 125.3,82.7, 51.7, 36.7, 26.1, 24.4, 18.4, -3.5, -4.3. HRMS (ESI) m / z calcd forC 25 H 44 O2Si2Na [M+Na] + : 455.2772, found: 455.2772

[0058] (1S, 2R, 5S)-2, 5-bis((tert-butyldimethylsilyl)oxy)-2', 3'-dihydrospiro[cyclopentane-1, 1'-inden]-3-ene (1ae). Colorlessoil, 132 mg, 98% yield (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J= 7.1 Hz, 1H), 7.13 – 7.08 (m, 2H), 7.04 – 6.99 (m, 1H), 5.95 (s, 2H), 4.44(s, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.07 (t, J = 7.3 Hz, 2H), 0.69 (s, 18H), -0.13 (s, 6H), -0.21 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 142.6, 135.7, 130.1,126.1, 124.3, 123.1, 82.7, 65.0, 38.6, 31.0, 25.7, 18.0, -4.8, -5.1. HRMS(ESI) m / z calcd for C 25 H 42 O2Si2Na [M+Na] + :453.2615, found: 453.2614

[0059] (((1R, 2S, 3S)-2-methyl-2-(naphthalen-2-yl)cyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1af).Colorless oil, 300 mg, 21% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400MHz, CDCl3) δ 7.79 – 7.74 (m, 2H), 7.72 (s, 1H), 7.62 – 7.50 (m, 2H), 7.41 –7.35 (m, 2H), 5.96 (s, 2H), 4.46 (s, 2H), 1.66 (s, 3H), 0.61 (s, 18H), -0.12(s, 6H), -0.31 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 138.4, 135.4, 132.9, 132.1,131.5, 128.1, 127.6, 127.2, 124.8, 124.6, 124.1, 84.8, 56.0, 26.2, 25.7,18.1, -4.7, -4.8. HRMS (ESI) m / z calcd for C 28 H 44 O2Si2Na [M+Na] + : 491.2772,found: 491.2772

[0060] (((1R, 2S, 3S)-2-methyl-2-(p-tolyl)cyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ag). Colorless oil, 194mg, 13 % yield for 4 steps (PE : EA = 20:1). 1 H NMR (600 MHz, CDCl3) δ 7.43 –7.40 (m, 2H), 7.22 – 7.19 (m, 2H), 6.12 (d, J = 3.2 Hz, 2H), 4.58 (d, J = 3.3Hz, 2H), 2.51 (s, 3H), 1.73 (s, 3H), 0.93 (s, 18H), 0.12 (s, 6H), 0.00 (s,6H). 13 C NMR (151 MHz, CDCl3) δ 136.4, 135.1, 134.4, 130.6, 126.5, 84.4, 55.5,25.7, 20.9, 18.1, -2.9, -4.9, -5.0. HRMS (ESI) m / z calcd for C 25 H 44 O2Si2Na [M+Na] + :455.2772, found: 455.2769

[0061] (((1R,2s,3S)-2-(4-ethylphenyl)-2-methylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ah). Colorless oil, 150mg, 21% yield for 4 steps (PE : EA = 20:1). 1H NMR (400 MHz, CDCl3) δ 7.19(d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 5.88 (s, 2H), 4.33 (s, 2H),2.59 – 2.53 (m, 2H), 1.50 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H), 0.67 (s, 18H), -0.13 (s, 6H), -0.26 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 141.1, 136.6, 135.1,130.7, 125.3, 84.5, 55.3, 28.6, 25.9, 25.7, 18.0, 16.2, -4.9, -5.0. HRMS(ESI) m / z calcd for C 26 H 46 O2Si2Na [M+Na] + :469.2928, found: 469.2937

[0062] (((1R,2s,3S)-2-(4-isopropylphenyl)-2-methylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ai). Colorless oil,184 mg, 7% yield for 4 steps (PE : EA = 20:1). 1 H NMR (600 MHz, CDCl3) δ 7.18(d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 5.88 (s, 2H), 4.32 (s, 2H),2.85 – 2.78 (m, 1H), 1.51 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H), 0.64 (s, 18H), -0.13 (s, 6H), -0.28 (s, 6H). 13C NMR (151 MHz, CDCl3) δ 145.7, 136.7, 135.2,130.5, 123.7, 84.6, 55.2, 33.8, 25.9, 25.6, 24.2, 18.0, -4.9, -5.1. HRMS(ESI) m / z calcd for C 27 H 48 O2Si2Na [M+Na] + :483.3085, found: 483.3090

[0063] (((1R, 2S, 3S)-2-(4-(tert-butyl)phenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1aj).Colorless oil, 308 mg, 19 % yield for 4 steps (PE : EA = 20:1). 1 H NMR (600MHz, CDCl3) δ 7.21 – 7.18 (m, 2H), 7.17 – 7.15 (m, 2H), 5.89 (s, 2H), 4.33(s, 2H), 1.52 (s, 3H), 1.27 (s, 9H), 0.64 (s, 18H), -0.12 (s, 6H), -0.28 (s,6H). 13 C NMR (151 MHz, CDCl3) δ 147.8, 136.3, 135.2, 130.2, 122.5, 84.6, 55.0,34.1, 31.4, 25.6, 18.0, -2.9, -4.9, -5.1. HRMS (ESI) m / z calcd forC 28 H 50 O2Si2Na [M+Na] + :497.3241, found: 497.3239

[0064] (((1R, 2S, 3S)-2-methyl-2-(m-tolyl)cyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ak). Colorless oil, 79 mg, 7%yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.11 – 7.03 (m,3H), 6.93 – 6.90 (m, 1H), 5.90 (d, J = 0.7 Hz, 2H), 4.33 (d, J = 0.7 Hz, 2H),2.28 (s, 3H), 1.48 (s, 3H), 0.68 (s, 18H), -0.14 (s, 6H), -0.25 (s, 6H). 13 CNMR (101 MHz, CDCl3) δ 139.4, 135.1, 134.4, 132.9, 126.8, 126.0, 125.7, 84.5,55.3, 26.2, 25.7, 21.6, 18.0, -4.9, -5.0. HRMS (ESI) m / z calcd forC 25 H 44 O2Si2Na [M+Na] + :455.2772, found: 455.2766

[0065] (((1R,2s,3S)-2-(3,5-dimethylphenyl)-2-methylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1al).Colorless oil, 114 mg, 13% yield for 4 steps (PE : EA = 20:1). 1H NMR (600MHz, CDCl3) δ 6.92 (s, 2H), 6.74 (s, 1H), 5.90 (d, J = 0.7 Hz, 2H), 4.33 (d,J = 0.7 Hz, 2H), 2.25 (d, J = 0.8 Hz, 6H), 1.44 (s, 3H), 0.71 (s, 18H), -0.13(s, 6H), -0.22 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ 139.3, 135.1, 134.4, 128.9,126.7, 84.3, 55.3, 26.6, 25.7, 21.5, 18.1, -4.8, -5.0. HRMS (ESI) m / z calcdfor C 26 H 46 O2Si2Na [M+Na] + :469.2928, found: 469.2933

[0066] (((1R, 2S, 3S)-2-(4-fluorophenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1am). Colorless oil,68 mg, 9% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.27 –7.23 (m, 2H), 6.89 – 6.82 (m, 2H), 5.87 (s, 2H), 4.33 (s, 2H), 1.51 (s, 3H),0.67 (s, 18H), -0.11 (s, 6H), -0.25 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 161.4(d, J = 242.6 Hz), 135.5 (d, J = 3.3 Hz), 135.3, 132.2 (d, J = 7.6 Hz), 112.5(d, J = 20.6 Hz), 84.5, 55.4, 26.0, 25.8, 18.1, -4.7, -4.9. 19F NMR (377 MHz,CDCl3) δ -119.4. HRMS (ESI) m / z calcd for C 24 H 41 FO2Si2Na [M+Na] + :459.2521,found: 459.2519

[0067] (((1R, 2S, 3S)-2-(4-chlorophenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1an). Colorless oil,70 mg, 9% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.26 –7.20 (m, 2H), 7.17 – 7.10 (m, 2H), 5.87 (s, 2H), 4.37 – 4.34 (m, 2H), 1.51(s, 3H), 0.67 (s, 18H), -0.09 (s, 6H), -0.23 (s, 6H). 13 C NMR (101 MHz, CDCl3)δ 138.5, 135.2, 132.2, 131.3, 125.9, 84.5, 55.7, 25.7, 18.1, -2.8, -4.7, -4.8. HRMS (ESI) m / z calcd for C 24 H 41 ClO2Si2Na [M+Na] + : 475.2226, found:475.2226

[0068] (((1R, 2S, 3S)-2-(4-bromophenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ao). Colorless oil,94 mg, 10 % yield for 4 steps (PE : EA = 20:1). 1H NMR (400 MHz, CDCl3) δ 7.24– 7.23 (m, 2H), 7.17 – 7.10 (m, 2H), 5.83 (s, 2H), 4.31 (s, 2H), 1.47 (s,3H), 0.64 (s, 18H), -0.14 (s, 6H), -0.27 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ138.9, 135.1, 132.5, 128.7, 119.4, 84.3, 55.7, 25.6, 25.5, 17.9, -4.8, -5.0.HRMS (ESI) m / z calcd for C 24 H 41 BrO2Si2Na [M+Na] + :519.1720, found: 519.1720

[0069] (((1R,2s,3S)-2-(4-methoxyphenyl)-2-methylcyclopent-4-ene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ap). Colorless oil,97 mg, 11% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.24– 7.19 (m, 2H), 6.75 – 6.70 (m, 2H), 5.88 (s, 2H), 4.31 (s, 2H), 3.77 (s,3H), 1.48 (s, 3H), 0.69 (s, 18H), -0.13 (s, 6H), -0.25 (s, 6H). 13 C NMR (101MHz, CDCl3) δ 157.5, 135.1, 132.0, 131.8, 111.3, 84.4, 55.3, 54.9, 26.0,25.7, 18.1, -4.9. HRMS (ESI) m / z calcd for C 25 H 44 O3Si2Na [M+Na] + :459.2721,found: 471.2721

[0070] (((1R, 2S, 3S)-2-(3-bromophenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1aq). Colorless oil,105 mg, 14% yield for 4 steps (PE : EA = 20:1). 1 H NMR (400 MHz, CDCl3) δ 7.38(t, J = 1.9 Hz, 1H), 7.20 – 7.15 (m, 2H), 6.97 (t, J = 7.9 Hz, 1H), 5.81 (s,2H), 4.28 (s, 2H), 1.43 (s, 3H), 0.61 (s, 18H), -0.17 (s, 6H), -0.28 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 142.4, 135.2, 134.7, 128.6, 128.5, 127.5, 120.3,84.4, 55.7, 25.8, 18.1, 1.2, -4.7, -4.9. HRMS (ESI) m / z calcd forC 24 H 41 BrO2Si2Na [M+Na] + :519.1720, found: 519.1719

[0071] (((1R, 2S, 3S)-2-(3-fluorophenyl)-2-methylcyclopent-4-ene-1, 3-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1ar). Colorless oil,50 mg, 3% yield for 4 steps (PE : EA = 20:1). 1 H NMR (600 MHz, CDCl3) δ 7.1 –7.0 (m, 3H), 6.8 – 6.8 (m, 1H), 5.9 (s, 2H), 4.4 (s, 2H), 1.5 (s, 3H), 0.7(s, 18H), -0.1 (s, 6H), -0.2 (s, 6H).13 C NMR (151 MHz, CDCl3) δ 161.5 (d, J =239.8 Hz), 142.5 (d, J = 7.9 Hz), 135.1, 126.8 (d, J = 8.1 Hz), 125.6 (d, J =2.4 Hz), 118.3 (d, J = 22.2 Hz), 112.0 (d, J = 20.8 Hz), 84.3, 55.8, 25.6,25.6, 17.9, -4.9, -5.0. 19 F NMR (377 MHz, CDCl3) δ -117.5. HRMS (ESI) m / zcalcd for C 24 H 41 FO2Si2Na [M+Na] + :459.2521, found: 459.2518

[0072] II. General Methods for Asymmetric Hydroformylation

[0073] In an argon-atmosphere glove box, 0.002 mmol of acetylacetone dicarbonyl rhodium metal precursor and 0.006 mmol of chiral ligand were added to a 3 mL hydride vial, followed by 0.1 mL of toluene. The mixture was stirred for five minutes. Then, 0.1 mmol of substrate and the prepared catalyst solution were added to another vial. This vial was placed in a reaction vessel, removed from the glove box, and purged three times with hydrogen to replace the argon gas in the reaction vessel. Hydrogen (2.5 atm) and carbon monoxide (2.5 atm) were then introduced sequentially, and the reaction vessel was stirred at 60 °C for 24 h. After the reaction was complete, the pressure was released, and the product was filtered through a short silica gel column. After NMR confirmation of the dr value, column chromatography was used for purification. After NMR confirmation, the yield was calculated, optical rotation was measured, and high-resolution mass spectrometry (HPLC) was performed. The aldehyde product was then converted, and the ee value was determined by HPLC or gas chromatography. The reagents used in the conversion are noted after the product data.

[0074] III. Results and Discussion

[0075] 1. Filtering by criteria

[0076] In this work, compound 1a was used as a template substrate for ligand screening and reaction condition screening. The technical route is as follows:

[0077]

[0078] First, ligand screening was conducted using common hydroformylation conditions: 2 mol% Rh(acac)(CO)2, 6 mol% L, 60 °C, CO / H2 = 5 / 5 bar, and toluene as solvent for 24 h. The selected ligands were primarily commercially available ligands and previously reported dominant ligands for asymmetric hydroformylation.

[0079] , , , , , , , , .

[0080] The ligand screening is shown in Table 1. Using (S,R)-YanPhos ligands, the target product was obtained with high activity and selectivity (entry 1). Using (S,S)-YanPhos still showed high activity, but the dr value was low and the ee value was poor (entry 2). Using XuPhos resulted in high activity and dr value, but the ee value was not ideal (entry 3 and entry 10). Therefore, the XuPhos series of ligands are not suitable for this reaction. When using (S... C ,R PWhen using (R,R)-DuanPhos and (S,S)-QuinoxP*, the conversion rate was less than 60%, and the dr value was poor, but the ee value reached 90% (entry 4 and entry 5). Using the four ligands (R,R)-Ph-BPE, (S,S)-Me-DuPhos, (S,S)-Benzp*, and (S)-C3-TunePhos*, the activity did not exceed 30% (entry 6~9), proving that these ligand skeletons are unsuitable for this type of substrate. The YanPhos and XuPhos series ligands showed good activity, with (S,R)-YanPhos exhibiting the best performance and the highest ee value. Therefore, this work determined (S,R)-YanPhos as the optimal ligand. Next, the reaction temperature and gas partial pressure were screened. Reactions were attempted at 50 °C, 80 °C, and 100 °C for 24 h. When the temperature was decreased to 50 °C (entry 11), the conversion rate slightly decreased; when the temperature was increased to 80 °C (entry 12), the reaction effect remained unchanged; and when the temperature was increased to 100 °C (entry 13), the reaction ee value slightly decreased. Lowering the gas partial pressure to CO / H2 = 2.5 / 2.5 bar (entry 14) did not change the reaction effect, and the substrate was completely converted. Therefore, the optimal reaction conditions were determined to be 2 mol% Rh(acac)CO2, 6 mol% (S,R)-YanPhos, 60 °C, CO / H2 = 2.5 / 2.5 bar, with toluene as the solvent, for 24 h.

[0081] Table 1. Screening results of chiral ligands and reaction conditions for substrate 1a [a]

[0082] entry <![CDATA[L * ]]> <![CDATA[Conv. [b] ]]> <![CDATA[dr [b] ]]> <![CDATA[ee of 2a [c] ]]> 1 (S,R)-YanPhos 99% >20:1 99% 2 (S,S)-YanPhos 99% 8.3:1 55% 3 Cl-XuPhos-2 99% >20:1 11% 4 <![CDATA[(S C ,R P )-DuanPhos]]> 52% 2.7:1 -92% 5 (S,S)-QuinoxP* 57% 3.6:1 -89% 6 (R,R)-Ph-BPE 25% >20:1 -89% 7 (S,S)-Me-DuPhos 12% 4.8:1 -79% 8 (S,S)-Benzp* 22% 4.6:1 -82% 9 <![CDATA[(S)-C3-TunePhos*]]> 7% - - 10 Cl-XuPhos-1 92% >20:1 62% <![CDATA[11 [d] ]]> (S,R)-YanPhos 89% >20:1 99% <![CDATA[12 [e] ]]> (S,R)-YanPhos 99% >20:1 99% <![CDATA[13 [f] ]]> (S,R)-YanPhos 99% >20:1 95% <![CDATA[14 [g] ]]> (S,R)-YanPhos 99% >20:1 99%

[0083] In Table 1, [a] all reactions were carried out at a scale of 0.1 mmol, using 1 mL toluene as solvent, containing 2 mol% Rh(acac)(CO)2 and 6 mol% ligand, at a pressure of 5 / 5 bar (CO / H2) and at 60 °C for 24 h. [b] Determined by 1H NMR analysis of the crude reaction mixture. dr = 2a / 3a. [c] The enantiomeric transcendence (ee) of 2a was determined by HPLC analysis using a chiral stationary phase after the reaction mixture underwent a Wittig reaction with methyl (triphenylphosphine) acetate. [d] Carried out at 50 °C. [e] Carried out at 80 °C. [f] Carried out at 100 °C. [g] Carried out at a CO / H2 = 2.5 / 2.5 bar.

[0084] 2. Scope of application for olefin substrates

[0085] After determining the optimal conditions through condition screening, this work began to explore substrate expansion: using various protected cyclopentenols as representative substrates, the reaction stably constructed three stereocenters and exhibited excellent compatibility with silicon-based protecting groups, including TBS, TMS, TES, TIPS, TBDPS, and PhMe2Si, all of which could be successfully converted to obtain products 2a–2f, demonstrating high enantioselectivity (97–99% ee) and high diastereoselectivity (dr > 20:1). Substrates containing acetyl, triphenylmethyl, or ester groups also reacted effectively, yielding products 2g–2i while maintaining high stereoselectivity. For highly substituted cyclopentene substrates, by appropriately increasing the catalyst dosage and reaction temperature, high yields and excellent stereoselectivity could still be obtained, with the diastereoselectivity of representative products 2j and 2k both greater than 20:1, and the enantioselectivity reaching 99% ee. The method of this invention is also applicable to larger ring systems. Six-membered and seven-membered carbon ring substrates yielded products 2l and 2m, respectively, both exhibiting excellent stereochemical control. Seven-membered heterocyclic substrates can also be effectively converted to obtain products 2n and 2o, demonstrating good adaptability to conformationally flexible substrates. The absolute configuration of diol compound 4 derived from product 2a was determined by single-crystal X-ray diffraction analysis (CCDC 2471076), and the stereochemical configurations of the remaining products were inferred by analogy.

[0086] Building upon this foundation, the present invention further enables the construction of four continuous three-dimensional centers in a one-step reaction.

[0087]

[0088] The simulated structure diagram of CCDC 2471076 is as follows: Figure 1 As shown.

[0089] Reaction conditions: substrate (0.1 mmol), Rh(CO)₂(acac) (3 mol %), ligand (6 mol %), CO / H₂ (2.5 / 2.5 bar), toluene (0.2 mL), 80 °C, 36 hours. Enantiomer ee was analyzed by gas chromatography (GC) or high-performance liquid chromatography (HPLC) using a chiral stationary phase. Optical rotation (dr) was determined by 1H NMR. Separation yield.

[0090] The model substrate 1aa can be efficiently converted to product 2aa (>20:1 dr, 95% ee), with substituents varying widely, including alkyl, benzyl, and sterically hindered aryl groups (2ab–2af), without significantly affecting the stereoselectivity of the reaction. Aromatic substrates containing 4-alkyl, 3- or 3,5-substituted aryl groups, and substituents with different electronic properties (2ag–2ap) also exhibit good reaction consistency, with the resulting products generally showing enantioselectivity of 91–98% ee and excellent diastereoselectivity; 3-halogenated aryl substrates 2aq and 2ar also react smoothly. Furthermore, for sterically hindered bridged bicyclic ortho-dicarboxylic acid ester substrates, the method of this invention can still efficiently achieve desymmetric transformation to obtain products 2as–2au, constructing up to five stereocenters in a single molecule. Regardless of whether the substrate is exo or endo configuration, the reactivity and stereoselectivity remain stable, demonstrating the method's good tolerance to complex skeletons and configurational differences.

[0091] The NMR data for all products are as follows:

[0092] (1S,2S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)cyclopentane-1-carbaldehyde (2a). Colorless oil, 35 mg, 97% yield, 99% ee;[α] 25 D = +43.5 (c= 0.1, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 9.71 (d, J = 2.0Hz, 1H), 4.27 (q, J = 7.2 Hz, 1H), 4.14 – 4.05 (m, 1H), 3.05 – 2.95 (m, 1H), 2.20 (dt, J = 13.3, 6.7 Hz, 1H), 1.98 – 1.88 (m, 1H), 1.85 – 1.75 (m, 1H), 1.67 – 1.57 (m, 1H), 0.86 – 0.81 (m, 18H), 0.01 – 0.00 (m, 12H). 13C NMR (101MHz, CDCl3) δ 202.9, 72.1, 70.5, 59.1, 45.4, 34.2, 25.8, 25.7, 18.0, 17.9, -4.6, -4.8, -4.9. HRMS (ESI) m / z calcd for C 18 H 38 O3Si2H[M+H] + :359.2432, found:359.2428. UPLC: Chiralpak OD-3 column, hexane / isopropanol = 100 / 0; flow rate= 0.4 mL / min; UV detection at 210 nm; t1 = 3.4 min (minor), t2 = 4.3 min(major). NOTE: The enantiomeric excess was determined by UPLC after reactionwith methyl (triphenylPhosphoranylidene) acetate.

[0093] (1S,2S,4S)-2,4-bis((trimethylsilyl)oxy)cyclopentane-1-carbaldehyde (2b). Colorless oil, 25 mg, 91% yield, 99% ee;[α] 25 D = +27.6 ( c = 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.73 (d, J = 1.6Hz, 1H), 4.28 (q, J = 7.4 Hz, 1H), 4.10 – 4.06 (m, 1H), 3.05 – 2.99 (m, 1H),2.27 (dt, J = 13.1, 6.7 Hz, 1H), 2.01 (dt, J = 14.1, 7.3 Hz, 1H), 1.87 – 1.81(m, 1H), 1.68 – 1.64 (m, 1H), 0.10 (s, 9H), 0.10 (s, 9H). 13C NMR (151 MHz,CDCl3) δ 201.6, 70.4, 68.9, 57.4, 44.1, 32.8, -1.0, -1.0. HRMS (ESI) m / zcalcd for C 12 H 26 O3Si2Na[M+Na] + :297.1312, found: 297.1316. HPLC: Chiralpak OD-Hcolumn, hexane / isopropanol = 99 / 1; flow rate = 1.0 mL / min; UV detection at254 nm; t1 = 14.5 min (major). t2 = 15.5 min (minor). NOTE: The enantiomericexcess was determined by HPLC after condensation with 1-Methyl-1-phenylhydrazine

[0094] (1S,2S,4S)-2,4-bis((triethylsilyl)oxy)cyclopentane-1-carbaldehyde (2c). Colorless oil, 35 mg, 98% yield, 98% ee;[α] 25 D = +16.2 ( c= 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.75 (d, J = 1.9 Hz,1H), 4.31 (q, J = 7.3 Hz, 1H), 4.13 – 4.07 (m, 1H), 3.06 – 3.01 (m, 1H), 2.27(dt, J = 13.2, 6.7 Hz, 1H), 2.03 – 1.96 (m, 1H), 1.88 – 1.81 (m, 1H), 1.71 –1.65 (m, 1H), 0.96 – 0.92 (m, 18H), 0.60 – 0.55 (m, 12H). 13C NMR (151 MHz,CDCl3) δ 202.8, 71.7, 70.1, 58.8, 45.5, 34.1, 6.7, 6.7, 4.7, 4.7. HRMS (ESI)m / z calcd for C 18 H 38 O3Si2Na[M+Na] + :381.2251, found: 381.2256. HPLC: ChiralpakOD-3 column, hexane / isopropanol = 99 / 1; flow rate = 1.0 mL / min; UV detectionat 254 nm; t1 = 6.9 min (minor), t2 = 8.1 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with methyl(triphenylPhosphoranylidene) acetate

[0095] (1S,2S,4S)-2,4-bis((triisopropylsilyl)oxy)cyclopentane-1-carbaldehyde (2d). Colorless oil, 41 mg, 93% yield, 99% ee;[α] 25 D = +25.7 (c= 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 9.79 (d, J = 2.0 Hz,1H), 4.49 (q, J = 6.6 Hz, 1H), 4.24 (p, J = 5.7 Hz, 1H), 3.15 – 3.05 (m, 1H),2.31 (dt, J = 13.4, 6.7 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.96 – 1.87 (m, 1H),1.80 – 1.72 (m, 1H), 1.06 – 1.04 (m, 42H). 13C NMR (101 MHz, CDCl3) δ 203.0,72.4, 71.0, 59.8, 46.1, 34.8, 18.0, 18.0, 12.1, 12.1. HRMS (ESI) m / z calcdfor C 24 H 50 O3Si2Na[M+Na] + : 465.3190, found: 465.3199. HPLC: Chiralpak OD-3column, hexane / isopropanol = 99 / 1; flow rate = 1.0 mL / min; UV detection at254 nm; t1 = 5.2 min (minor), t2 = 7.8 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with methyl(triphenylPhosphoranylidene) acetate

[0096] (1S,2S,4S)-2,4-bis((tert-butyldiphenylsilyl)oxy)cyclopentane-1-carbaldehyde (2e). Colorless oil, 57.5mg, 95% yield, 97% ee; [α] 25 D = +17.9 (c = 1.0, CHCl3). 1 H NMR (600 MHz,CDCl3) δ 9.24 (s, 1H), 7.68 – 7.63 (m, 8H), 7.43 (q, J = 6.7 Hz, 4H), 7.38(m, 8H), 4.30 (q, J = 6.7 Hz, 1H), 4.10 (q, J = 5.8 Hz, 1H), 3.20 (q, J = 8.2Hz, 1H), 1.92 (t, J = 11.3 Hz, 1H), 1.88 (t, J = 5.6 Hz, 2H), 1.75 (dt, J =14.1, 7.3 Hz, 1H), 1.10 (s, 18H). 13C NMR (151 MHz, CDCl3) δ 202.6, 136.0,136.0, 135.8, 135.8, 134.2, 134.1, 133.8, 133.5, 130.0, 129.9, 129.8, 129.7,127.9, 127.8, 127.8, 127.7, 73.4, 72.3, 59.7, 45.0, 34.6, 27.1, 19.2. HRMS(ESI) m / z calcd for C 38 H 46 O3Si2Na[M+Na] + :629.2878, found: 629.2878. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 254 nm; t1 = 8.1 min (minor), t2 = 8.9 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0097] (1S,2S,4S)-2,4-bis((dimethyl(phenyl)silyl)oxy)cyclopentane-1-carbaldehyde (2f). Colorless oil, 36 mg, 91% yield,98% ee; [α] 25 D = +26.0 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J =1.9 Hz, 1H), 7.56 – 7.52 (m, 4H), 7.40 – 7.34 (m, 6H), 4.23 (q, J = 7.2 Hz,1H), 4.07 – 4.01 (m, 1H), 3.09 – 3.01 (m, 1H), 2.13 – 2.07 (m, 1H), 1.90 –1.84 (m, 2H), 1.74 – 1.67 (m, 1H), 0.36 (s, 6H), 0.34 (s, 6H). 13 C NMR (101MHz, CDCl3) δ 203.7, 139.2, 138.7, 134.8, 134.7, 131.1, 130.9, 129.2, 129.1,73.1, 71.8, 59.8, 46.1, 35.1, -0.1, -0.2. HRMS (ESI) m / z calcd forC 22 H 30 O3Si2Na[M+Na] + :421.1625, found: 421.1630. HPLC (Chiralpak OD-H column,hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 210 nm; t1= 4.5 min (minor), t2 = 4.8 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0098] (1S,3S,4S)-4-formylcyclopentane-1,3-diyl diacetate(2g). Colorless oil, 18 mg, 84% yield, 93% ee; [α] 25 D = -4.8 ( c= 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.90 (dd, J = 15.6, 7.8 Hz, 1H), 5.86 – 5.80 (m,1H), 5.24 – 5.18 (m, 1H), 3.73 (s, 3H), 2.95 – 2.80 (m, 1H), 2.18 – 2.10 (m,1H), 2.06 – 1.87 (m, 7H), 1.76 – 1.64 (m, 2H), 1.50 – 1.39 (m, 1H). 13 C NMR(151 MHz, CDCl3) δ 170.7, 167.1, 151.8, 119.9, 76.2, 51.5, 40.6, 39.0, 32.2,30.3, 21.3. HRMS (ESI) m / z calcd for C 13 H 18 O6Na[M+Na] + : 293.0996, found:293.0993. GC: Chiralpak Supelco’s Beta Dex 120 column, temperature program:80 °C, stay 5 mins,3 °C / min to 210 °C, stay 5 mins, Flow rate = 1.0 mL / min;t1 = 38.5 min (minor), t2 = 39.1 min (major). NOTE: The yield, [α] 25 D , NMR,HRMS were determined after reaction with methyl (triphenylPhosphoranylidene)acetate.

[0099] methyl (E)-3-((1R,2S,4S)-2,4-bis(trityloxy)cyclopentyl)acrylate (2h). Colorless oil, 57.5 mg, 95% yield, 96% ee; [α] 25 D = +36.3 ( c = 1.0, CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.47 – 7.39 (m, 12H),7.26 – 7.21 (m, 18H), 6.37 (dd, J = 15.6, 8.5 Hz, 1H), 5.53 – 5.50 (m, 1H),3.82 – 3.78 (m, 1H), 3.68 (s, 3H), 3.61 – 3.58 (m, 1H), 2.64 – 2.58 (m, 1H),1.52 – 1.49 (m, 1H), 1.31 – 1.27 (m, 1H), 1.16 – 1.11 (m, 1H), 1.01 – 0.96(m, 1H). 13 C NMR (151 MHz, CDCl3) δ 166.9, 150.6, 145.0, 144.8, 129.0, 128.8,127.9, 127.9, 127.8, 127.3, 127.0, 126.9, 120.4, 87.1, 87.0, 78.0, 73.0,51.4, 48.0, 41.1, 36.8. HRMS (ESI) m / z calcd for C 47 H 42 O4Na[M+Na] + :693.2975,found: 693.2976. UPLC: Chiralpak IB-U column, hexane / isopropanol = 99 / 1; flowrate = 0.1 mL / min; UV detection at 230 nm; t1 = 11.6 min (minor), t2 = 13.8min (major). NOTE: The yield, [α] 25 D , NMR, HRMS were determined aftercondensation with methyl (triphenylPhosphoranylidene) acetate. Theenantiomeric excess was determined by UPLC after reaction with methyl(triphenylPhosphoranylidene) acetate.

[0100] dimethyl (1S,3S,4S)-4-formylcyclopentane-1,3-dicarboxylate (2i). Colorless oil, 18 mg, 83% yield, 91% ee; [α] 25 D = +4.4 (c= 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.74 – 9.71 (m, 1H), 3.72 (s, 3H),3.69 (s, 3H), 3.39 – 3.33 (m, 1H), 3.27 – 3.21 (m, 1H), 2.82 – 2.74 (m, 1H),2.34 (dt, J = 13.3, 8.0 Hz, 1H), 2.24 – 2.20 (m, 2H), 2.19 – 2.15 (m, 1H). 13 CNMR (151 MHz, CDCl3) δ 200.6, 174.5, 174.0, 53.6, 52.3, 52.0, 43.2, 42.8,33.1, 29.4. HRMS (ESI) m / z calcd for C 10 H 14 O5Na[M+Na] + :237.0733, found:237.0735. HPLC (Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate =1.0 mL / min; UV detection at 210 nm; t1 = 16.9 min (major), t2 = 19.0 min(minor). NOTE: The enantiomeric excess was determined by HPLC after reactionwith methyl (triphenylPhosphoranylidene) acetate

[0101] (1S,2R,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3,3-dimethylcyclopentane-1-carbaldehyde (2j). Colorless oil, 35 mg, 92%yield, 99% ee; [α] 25 D = +24.5 ( c = 0.1, CHCl3). 1 H NMR (600 MHz, CDCl3) δ9.75 (d, J = 2.3 Hz, 1H), 3.80 (d, J = 7.9 Hz, 1H), 3.56 (t, J = 8.4 Hz, 1H),2.88 – 2.83 (m, 1H), 2.06 – 2.00 (m, 1H), 1.78 – 1.71 (m, 1H), 0.94 (s, 3H),0.89 (s, 9H), 0.89 (s, 9H), 0.81 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02(s, 3H), 0.00 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 203.1, 78.1, 76.7, 56.2,46.4, 30.5, 25.9, 25.9, 24.9, 18.2, 18.1, 14.3, -4.3, -4.3, -4.3, -4.8. HRMS(ESI) m / z calcd for C 20 H 42 O3Si2Na[M+Na] + :409.2564, found: 409.2569. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 230 nm; t1 = 5.0 min (minor), t2 = 5.7 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0102] (1R,2S,4S)-1,4-bis((tert-butyldimethylsilyl)oxy)spiro[4.4]nonane-2-carbaldehyde (2k). Colorless oil, 35 mg, 73% yield, 99%ee; [α] 25 D = +17.0 (c = 0.1, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.74 (d, J =2.5 Hz, 1H), 3.99 (d, J = 7.3 Hz, 1H), 3.74 (t, J = 7.6 Hz, 1H), 2.84 – 2.79(m, 1H), 1.98 – 1.93 (m, 1H), 1.74 – 1.68 (m, 3H), 1.60 – 1.56 (m, 2H), 1.55– 1.49 (m, 4H), 0.88 (d, J = 1.2 Hz, 18H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02(s, 3H), -0.00 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 202.9, 57.8, 57.2, 35.3,31.6, 27.0, 26.4, 25.8, 25.8, 24.9, 18.0, 17.9, -4.3, -4.3, -4.4, -5.0. HRMS(ESI) m / z calcd for C 22 H 44 O3Si2Na[M+Na] + : 435.2721, found: 435.2717. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 230 nm; t1 = 6.0 min (minor), t2 = 7.1 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0103] (1S,2S,5R)-2,5-bis((tert-butyldimethylsilyl)oxy)cyclohexane-1-carbaldehyde (2l). Colorless oil, 35.0 mg, 94% yield, 99%ee; [α] 25 D = +20.5 (c = 2.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.83 (d, J =2.1 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.81 (td, J = 9.7, 4.1 Hz, 1H), 2.81 – 2.76(m, 1H), 1.87 – 1.74 (m, 2H), 1.73 – 1.67 (m, 1H), 1.67 – 1.62 (m, 1H), 1.53– 1.45 (m, 1H), 1.45 – 1.37 (m, 1H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s,3H), 0.04 (s, 3H), 0.04 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 205.8, 71.0, 65.2,52.8, 32.2, 31.5, 29.7, 26.0, 25.9, 18.2, 18.1, -3.8, -4.7, -4.7, -4.8. HRMS(ESI) m / z calcd for C 19 H 40 O3Si2Na[M+Na] + :395.2408, found: 395.2403. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 254 nm; t1 = 5.4 min (minor), t2 = 5.8 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0104] (1S,2S,6R)-2,6-bis((tert-butyldimethylsilyl)oxy)cycloheptane-1-carbaldehyde (2m). Colorless oil, 33.2 mg, 86% yield, 99% ee;[α] 25 D = +14.0 (c = 0.1, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 1.4Hz, 1H), 4.15 – 4.08 (m, 1H), 4.06 – 4.00 (m, 1H), 3.04 – 2.99 (m, 1H), 1.97– 1.86 (m, 1H), 1.85 – 1.75 (m, 2H), 1.68 – 1.44 (m, 4H), 1.32 – 1.24 (m,1H), 0.88 (s, 9H), 0.86 (s, 9H), 0.06 (s, 3H), 0.03 (s, 6H), 0.03 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 204.6, 71.5, 68.2, 52.9, 38.4, 37.3, 31.2, 25.8, 25.8,18.1, 17.9, 17.4, -4.1, -4.8, -4.8, -4.8. HRMS (ESI) m / z calcd forC 20 H 42 O3Si2Na[M+Na] + :409.2564, found: 409.2569. HPLC (Chiralpak OD-H column,hexane / isopropanol = 97 / 3; flow rate = 1.0 mL / min; UV detection at 230 nm; t1= 6.7 min (major), t2 = 11.2 min (minor). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0105] (E)-2-(((3R,4R,6S)-3,6-bis((tert-butyldimethylsilyl)oxy)oxepan-4-yl)methylene)-1-methyl-1-phenylhydrazine(2n). Colorless oil, 45.2 mg, 93% yield, 95% ee; [α] 25 D = +50.0 ( c = 0.01,CHCl3). 1 H NMR (600 MHz, CDCl3) δ 7.19 – 7.14 (m, 4H), 6.89 (d, J = 5.0 Hz,1H), 6.77 – 6.75 (m, 1H), 4.08 – 4.03 (m, 1H), 3.79 – 3.71 (m, 3H), 3.53 –3.49 (m, 1H), 3.49 – 3.45 (m, 1H), 3.13 (s, 3H), 2.98 – 2.93 (m, 1H), 2.13 –2.08 (m, 1H), 1.82 – 1.76 (m, 1H), 0.81 (s, 9H), 0.78 (s, 9H), -0.03 (s, 3H),-0.04 (s, 3H), -0.05 (s, 3H), -0.09 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 148.3,137.5, 128.9, 119.6, 114.6, 77.1, 75.7, 75.4, 69.9, 42.6, 33.1, 32.6, 25.9,25.8, 18.1, 18.0, -4.2, -4.5, -4.6, -4.7. HRMS (ESI) m / z calcd forC 26 H 48 N2O3Si2H[M+H] + : 493.3276, found: 493.3282. HPLC (Chiralpak OD-H column,hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 254 nm; t1= 5.1 min (minor), t2 = 6.3 min (major). NOTE: The Yield, [α]25 D , NMR, HRMSwere determined after reaction with 1-Methyl-1-phenylhydrazine. Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0106] tert-butyl (3R,4R,6S)-3,6-bis((tert-butyldimethylsilyl)oxy)-4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)azepane-1-carboxylate (2o). Colorless oil, 50 mg, 93% yield, 93% ee; [α] 25 D = +13.9 (c= 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 7.23 – 7.15 (m, 4H), 6.87 (dd, J =26.9, 4.9 Hz, 1H), 6.79 (t, J = 6.9 Hz, 1H), 4.31 – 4.16 (m, 1H), 4.13 – 4.06(m, 1H), 3.95 – 3.82 (m, 1H), 3.82 – 3.62 (m, 1H), 3.16 – 3.13 (m, 3H), 2.91– 2.62 (m, 3H), 2.18 – 2.09 (m, 1H), 1.72 – 1.54 (m, 1H), 1.43 – 1.36 (m,9H), 0.85 – 0.80 (m, 18H), 0.09 – -0.06 (m, 12H). 13C NMR (151 MHz, CDCl3) δ155.2, 154.9, 148.3, 137.5, 137.0, 128.9, 119.6, 114.6, 114.5, 79.9, 79.5,74.0, 73.2, 67.8, 67.6, 54.5, 54.1, 54.0, 53.8, 42.9, 42.8, 34.2, 33.8, 32.6,32.6, 28.6, 28.5, 25.9, 25.8, 25.8, 18.1, 18.1, 18.0, -4.0, -4.2, -4.6, -4.7,-4.7, -4.7. HRMS (ESI) m / z calcd for C 31 H 57 N3O4Si2Na[M+Na] + :614.3780, found:614.3786. HPLC iralpak OD-H column, hexane / isopropanol = 99 / 1; flow rate =1.0 mL / min; UV detection at 254 nm; t1 = 12.3 min (minor), t2 = 15.4 min(major). NOTE: The Yield, [α] 25 D , NMR (conformational isomerism), HRMS weredetermined after reaction with 1-Methyl-1-phenylhydrazine. The enantiomericexcess was determined by HPLC after reaction with 1-Methyl-1-phenylhydrazine.

[0107] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methyl-3-phenylcyclopentane-1-carbaldehyde (2aa). Colorless oil, 43mg, 96% yield, 95% ee; [α] 25 D = +52.0 ( c = 0.1, CHCl3).1 H NMR (600 MHz,CDCl3) δ 9.80 (d, J = 2.2 Hz, 1H), 7.59 – 7.56 (m, 2H), 7.25 – 7.21 (m, 2H),7.19 – 7.16 (m, 1H), 4.16 (d, J = 8.4 Hz, 1H), 3.83 – 3.78 (m, 1H), 3.13 –3.07 (m, 1H), 2.08 – 2.03 (m, 1H), 1.83 – 1.76 (m, 1H), 1.43 (s, 3H), 0.83(s, 9H), 0.80 (s, 9H), 0.01 (s, 6H), 0.00 (s, 3H), -0.01 (s, 3H). 13 C NMR (151MHz, CDCl3) δ 202.7, 139.3, 130.4, 126.5, 125.7, 79.2, 77.6, 56.5, 52.8,31.3, 26.2, 25.7, 25.7, 17.9, 17.9, -4.4, -4.5, -4.6, -5.0. HRMS (ESI) m / zcalcd for C 25 H 44 O3Si2H[M+H] + :449.2902, found: 449.2898. HPLC (Chiralpak OD-Hcolumn, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at254 nm; t1 = 5.1 min (minor), t2 = 6.3 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0108] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-ethyl-3-phenylcyclopentane-1-carbaldehyde (2ab). Colorless oil, 46 mg,99% yield, 98% ee; [α] 25 D = +26.4 (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ9.68 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H),7.21 – 7.16 (m, 1H), 4.68 (d, J = 6.0 Hz, 1H), 4.35 (t, J = 6.4 Hz, 1H), 3.14– 3.02 (m, 1H), 2.08 (dd, J = 14.8, 7.6 Hz, 1H), 2.02 (dd, J = 9.0, 6.4 Hz,2H), 1.95 – 1.85 (m, 1H), 0.89 (s, 18H), 0.76 (t, J = 7.4 Hz, 3H), 0.02 (s,6H), -0.04 (s, 3H), -0.06 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.5, 143.8,128.0, 127.3, 126.1, 78.2, 76.8, 58.1, 57.4, 32.0, 25.9, 25.8, 22.5, 18.1,18.0, 10.2, -4.2, -4.3, -4.8, -5.1. HRMS (ESI) m / z calcd for C 26 H 46 O3Si2Na[M+Na] +:485.2878, found: 485.2875. HPLC (Chiralpak OD-H column, hexane / isopropanol = 96 / 4; flow rate = 1.0 mL / min; UV detection at 230 nm; t1 = 6.7min (minor), t2 = 7.5 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0109] (1S,2R,3S,4S)-3-butyl-2,4-bis((tert-butyldimethylsilyl)oxy)-3-phenylcyclopentane-1-carbaldehyde (2ac). Colorlessoil, 49 mg, 99% yield, 97% ee; [α] 25 D = +30.3 (c = 1.0, CHCl3). 1 H NMR (400MHz, CDCl3) δ 9.66 (d, J = 2.2 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.29 (dd, J =8.6, 6.9 Hz, 2H), 7.21 – 7.15 (m, 1H), 4.66 (d, J = 6.1 Hz, 1H), 4.35 (t, J =6.4 Hz, 1H), 3.11 – 3.03 (m, 1H), 2.05 – 1.95 (m, 3H), 1.85 – 1.75 (m, 1H),1.28 – 1.10 (m, 4H), 0.89 (d, J = 1.4 Hz, 18H), 0.81 (t, J = 7.1 Hz, 3H),0.02 (s, 6H), -0.05 (s, 3H), -0.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 202.4,144.3, 128.0, 127.1, 126.0, 78.4, 76.8, 58.0, 57.1, 32.0, 30.1, 27.6, 25.8,25.8, 24.1, 18.1, 18.0, 14.0, -4.2, -4.3, -4.7, -5.1. HRMS (ESI) m / z calcdfor C 28 H 50 O3Si2Na[M+Na] + :513.3191, found: 513.3188. HPLC (Chiralpak OD-Hcolumn, hexane / isopropanol = 96 / 4; flow rate = 1.0 mL / min; UV detection at230 nm; t1 = 6.7 min (minor), t2 = 8.0 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0110] (1S,2R,3S,4S)-3-benzyl-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methylcyclopentane-1-carbaldehyde (2ad). Colorlessoil, 42 mg, 90% yield, 98% ee; [α] 25 D = +63.0 ( c = 0.1, CHCl3). 1H NMR (400MHz, CDCl3) δ 9.68 (d, J = 2.1 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.17 – 7.13 (m,2H), 7.12 – 7.06 (m, 1H), 3.91 (d, J = 7.6 Hz, 1H), 3.67 (t, J = 7.9 Hz, 1H),2.90 – 2.76 (m, 2H), 2.68 (d, J = 13.5 Hz, 1H), 1.95 – 1.85 (m, 1H), 1.73 –1.63 (m, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.83 (s, 3H), 0.03 – 0.00 (m, 12H). 13 C NMR (101 MHz, CDCl3) δ 202.8, 140.3, 131.7, 127.3, 125.5, 79.0, 77.9,56.6, 50.4, 35.2, 31.0, 26.0, 25.9, 24.2, 18.2, 18.1, -4.2, -4.3, -4.5, -4.8.HRMS (ESI) m / z calcd for C 26 H 46 O3Si2Na[M+Na] + :485.2878, found: 485.2876. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 254 nm; t1 = 4.8 min (minor), t2 = 5.2 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0111] (1S,2R,3S,5S)-2,5-bis((tert-butyldimethylsilyl)oxy)-2',3'-dihydrospiro[cyclopentane-1,1'-indene]-3-carbaldehyde (2ae).Colorless oil, 44 mg, 96% yield, 99% ee; [α] 25 D = +31.4 (c = 1.0, CHCl3). 1 HNMR (400 MHz, CDCl3) δ 9.90 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H),7.15 – 7.12 (m, 2H), 7.11 – 7.06 (m, 1H), 4.23 (d, J = 5.7 Hz, 1H), 3.98 (t,J = 4.1 Hz, 1H), 3.40 – 3.30 (m, 1H), 2.87 – 2.83 (m, 2H), 2.05 – 1.98 (m,2H), 1.87 (t, J = 7.2 Hz, 2H), 0.80 (s, 9H), 0.72 (s, 9H), -0.11 (s, 3H), -0.14 (s, 3H), -0.21 (s, 3H), -0.43 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.9,144.8, 142.0, 130.4, 126.6, 124.9, 123.4, 79.5, 78.7, 63.9, 60.1, 37.8, 33.4,30.6, 25.8, 25.7, 17.9, 17.8, -5.0, -5.0, -5.1, -5.1. HRMS (ESI) m / z calcdfor C 26 H 44 O3Si2H[M+H] +:461.2902, found: 461.2895. HPLC (Chiralpak OD-H column,hexane / isopropanol = 96 / 4; flow rate = 1.0 mL / min; UV detection at 230 nm; t1= 9.9 min (minor), t2 = 13.2 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0112] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methyl-3-(naphthalen-2-yl)cyclopentane-1-carbaldehyde (2af). Colorlessoil, 42 mg, 84% yield, 98% ee; [α] 25 D = +39.1 ( c = 0.1, CHCl3). 1 H NMR (600MHz, CDCl3) δ 9.83 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 7.81 – 7.70(m, 4H), 7.43 (d, J = 9.4 Hz, 2H), 4.25 (d, J = 8.5 Hz, 1H), 3.90 – 3.88 (m,1H), 3.23 – 3.17 (m, 1H), 2.11 – 2.06 (m, 1H), 1.87 – 1.80 (m, 1H), 1.53 (s,3H), 0.86 (s, 9H), 0.83 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H),0.02 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 202.7, 137.3, 132.7, 131.9, 129.5,128.9, 128.2, 127.2, 125.5, 125.3, 125.2, 79.3, 77.7, 56.3, 52.8, 31.3, 26.2,25.8, 25.7, 18.0, -4.3, -4.5, -4.6, -4.9. HRMS (ESI) m / z calcd for C 29 H 46 O3Si2H[M+H] + :521.2878, found: 521.2874. HPLC (Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 230 nm; t1 = 5.6min (minor), t2 = 8.8 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0113] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methyl-3-(p-tolyl)cyclopentane-1-carbaldehyde (2ag). Colorless oil, 43 mg,93% yield, 98% ee; [α] 25 D = +122.0 ( c = 0.1, CHCl3). 1H NMR (600 MHz, CDCl3)δ 9.79 (d, J = 2.2 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.07 – 7.03 (m, 2H), 4.12(d, J = 8.6 Hz, 1H), 3.80 – 3.77 (m, 1H), 3.09 – 3.04 (m, 1H), 2.31 (s, 3H),2.06 – 2.01 (m, 1H), 1.80 – 1.74 (m, 1H), 1.40 (s, 3H), 0.85 (s, 9H), 0.82(s, 9H), 0.04 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H), 0.00 (s, 3H). 13 C NMR (151MHz, CDCl3) δ 202.9, 136.3, 135.0, 130.2, 127.3, 79.1, 77.5, 56.2, 52.3,31.1, 26.3, 25.8, 25.7, 20.9, 18.0, 17.9, -4.3, -4.5, -4.6, -4.9. HRMS (ESI)m / z calcd for C 26 H 46 O3Si2H[M+H] + :463.3058, found:463.3053. HPLC (Chiralpak OD-H column, hexane / isopropanol = 96 / 4; flow rate = 1.0 mL / min; UV detection at230 nm; t1 = 4.7 min (minor), t2 = 6.0 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0114] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(4-ethylphenyl)-3-methylcyclopentane-1-carbaldehyde (2ah). Colorless oil,46 mg, 97% yield, 97% ee; [α] 25 D = +24.6 (c = 1.0, CHCl3). 1 H NMR (400 MHz,CDCl3) δ 9.78 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.4Hz, 2H), 4.11 (d, J = 8.6 Hz, 1H), 3.80 – 3.76 (m, 1H), 3.10 – 3.02 (m, 1H),2.61 (q, J = 7.6 Hz, 2H), 2.07 – 1.99 (m, 1H), 1.83 – 1.73 (m, 1H), 1.39 (s,3H), 1.22 (t, J = 7.6 Hz, 3H), 0.83 (s, 9H), 0.80 (s, 9H), 0.01 (s, 3H), 0.00(s, 3H), -0.00 (s, 3H), -0.02 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.9,141.4, 136.5, 130.3, 126.0, 79.3, 77.7, 56.4, 52.4, 31.2, 28.3, 26.3, 25.8,25.7, 18.0, 18.0, 15.4, -4.3, -4.5, -4.6, -4.9. HRMS (ESI) m / z calcd forC 27 H 48 O3Si2Na[M+Na] +: 499.3034, found: 499.3042. HPLC (Chiralpak OD-H column,hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 230 nm; t1= 6.3 min (minor), t2 = 8.8 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0115] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(4-isopropylphenyl)-3-methylcyclopentane-1-carbaldehyde (2ai). Colorlessoil, 41 mg, 84% yield, 97% ee; [α] 25 D = +24.3 (c = 1.0, CHCl3). 1 H NMR (400MHz, CDCl3) δ 9.81 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.10 (d, J= 8.4 Hz, 2H), 4.14 (d, J = 8.5 Hz, 1H), 3.85 – 3.78 (m, 1H), 3.15 – 3.06 (m,1H), 2.92 – 2.83 (m, 1H), 2.11 – 2.03 (m, 1H), 1.87 – 1.77 (m, 1H), 1.42 (s,3H), 1.26 (s, 3H), 1.25 (s, 3H), 0.85 (s, 9H), 0.82 (s, 9H), 0.02 (s, 3H),0.01 (s, 3H), 0.00 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 203.0, 146.0, 136.6,130.2, 124.5, 79.5, 77.9, 56.7, 52.5, 33.5, 31.3, 26.3, 25.8, 25.7, 24.0,24.0, 18.0, 17.9, -4.3, -4.5, -4.6, -4.9. HRMS (ESI) m / z calcd forC 28 H 50 O3Si2Na[M+Na] + : 513.3190, found: 513.3198. HPLC (Chiralpak OD-H column,hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 254 nm; t1= 4.4 min (minor), t2 = 5.4 min (major). NOTE: The enantiomeric excess wasdetermined by HPLC after reaction with 2,4- dinitrophenylhydrazine.

[0116] (1S,2R,3S,4S)-3-(4-(tert-butyl)phenyl)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methylcyclopentane-1-carbaldehyde (2aj). Colorlessoil, 47 mg, 93% yield, 98% ee; [α] 25 D = +92.0 (c = 0.1, CHCl3). 1H NMR (600MHz, CDCl3) δ 9.79 (d, J = 2.3 Hz, 1H), 7.50 – 7.48 (m, 2H), 7.24 – 7.21 (m,2H), 4.11 (d, J = 8.5 Hz, 1H), 3.80 (t, J = 7.9 Hz, 1H), 3.12 – 3.06 (m, 1H),2.08 – 2.02 (m, 1H), 1.85 – 1.78 (m, 1H), 1.41 (s, 3H), 1.30 (s, 9H), 0.83(s, 9H), 0.80 (s, 9H), -0.00 (s, 3H), -0.01 (s, 3H), -0.02 (s, 3H), -0.03 (s,3H). 13 C NMR (151 MHz, CDCl3) δ 202.0, 147.2, 135.1, 128.9, 122.3, 78.5, 76.0,55.8, 51.4, 33.2, 30.4, 30.3, 25.2, 24.8, 24.7, 17.0, 16.9, -5.4, -5.6, -5.6,-6.0. HRMS (ESI) m / z calcd for C 29 H 52 O3Si2H[M+H] + : 505.3528, found: 505.3522.HPLC (Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 254 nm; t1 = 6.1 min (minor), t2 = 7.8 min (major). NOTE:The enantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0117] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methyl-3-(m-tolyl)cyclopentane-1-carbaldehyde (2ak). Colorless oil, 35 mg,76% yield, 98% ee; [α] 25 D = +15.8 (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ9.80 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 6.8 Hz, 2H), 7.13 (t, J = 8.0 Hz, 1H),7.00 (d, J = 7.4 Hz, 1H), 4.14 (d, J = 8.5 Hz, 1H), 3.82 – 3.78 (m, 1H), 3.15– 3.05 (m, 1H), 2.32 (s, 3H), 2.09 – 2.00 (m, 1H), 1.84 – 1.74 (m, 1H), 1.41(s, 3H), 0.85 (s, 9H), 0.82 (s, 9H), 0.04 (s, 3H), 0.02 (s, 6H), 0.00 (s,3H). 13 C NMR (101 MHz, CDCl3) δ 202.9, 139.3, 135.6, 131.5, 127.2, 126.5,79.2, 77.6, 56.4, 52.7, 31.3, 26.4, 25.8, 25.7, 21.7, 18.0, 17.9, -4.3, -4.5,-4.6, -4.9. HRMS (ESI) m / z calcd for C 26 H 46 O3Si2H[M+H] +: 463.3058, found:463.3054. HPLC (Chiralpak OD-H column, hexane / isopropanol = 96 / 4; flow rate =1.0 mL / min; UV detection at 230 nm; t1 = 7.2 min (minor), t2 = 12.0 min(major). NOTE: The enantiomeric excess was determined by HPLC after reactionwith 2,4- dinitrophenylhydrazine.

[0118] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(3,5-dimethylphenyl)-3-methylcyclopentane-1-carbaldehyde (2al).Colorless oil, 47 mg, 99% yield, 98% ee; [α] 25 D = +17.2 (c = 1.0, CHCl3). 1 HNMR (400 MHz, CDCl3) δ 9.79 (d, J = 2.3 Hz, 1H), 7.28 (s, 2H), 6.83 (s, 1H),4.13 (d, J = 8.5 Hz, 1H), 3.80 (dd, J = 9.3, 7.6 Hz, 1H), 3.13 – 3.05 (m,1H), 2.28 (s, 6H), 2.08 – 1.99 (m, 1H), 1.83 – 1.75 (m, 1H), 1.39 (s, 3H),0.87 (s, 9H), 0.84 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02(s, 3H). 13C NMR (101 MHz, CDCl3) δ 203.0, 139.4, 135.5, 128.3, 127.3, 79.1,77.5, 56.2, 52.5, 31.2, 26.5, 25.8, 25.7, 21.6, 18.0, -4.3, -4.4, -4.6, -4.9.HRMS (ESI) m / z calcd for C 27 H 48 O3Si2Na[M+Na] + : 499.3034, found: 499.3042. HPLC(Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 230 nm; t1 = 6.0 min (minor), t2 = 8.8 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0119] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(4-fluorophenyl)-3-methylcyclopentane-1-carbaldehyde (2am). Colorless oil,38 mg, 83% yield, 97% ee; [α] 25 D = +26.5 (c = 0.1, CHCl3). 1H NMR (600 MHz,CDCl3) δ 9.80 – 9.78 (m, 1H), 7.54 (dd, J = 8.6, 5.6 Hz, 2H), 6.93 (t, J =8.7 Hz, 2H), 4.15 (d, J = 8.3 Hz, 1H), 3.78 (t, J = 8.2 Hz, 1H), 3.10 – 3.03(m, 1H), 2.08 – 2.02 (m, 1H), 1.79 – 1.70 (m, 1H), 1.41 (s, 3H), 0.83 (s,9H), 0.80 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H), -0.02 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 202.5, 161.3 (d, J = 244.1 Hz), 135.0 (d, J = 3.4Hz), 131.9 (d, J = 7.5 Hz), 113.2 (d, J = 20.2 Hz), 79.1, 77.5, 56.6, 52.5,31.3, 26.3, 25.7, 25.7, 17.9, 17.9, -4.4, -4.5, -4.6, -5.0. 19 F NMR (377 MHz,CDCl3) δ -118.0. HRMS (ESI) m / z calcd for C 25 H 43 FO3Si2H[M+H] + : 467.2808, found:467.2807. HPLC (Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate =1.0 mL / min; UV detection at 230 nm; t1 = 8.0 min (minor), t2 = 14.7 min(major). NOTE: The enantiomeric excess was determined by HPLC after reactionwith 2,4- dinitrophenylhydrazine.

[0120] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(4-chlorophenyl)-3-methylcyclopentane-1-carbaldehyde (2an). Colorless oil,43 mg, 89% yield, 91% ee; [α] 25 D = +73.4 ( c = 0.1, CHCl3). 1 H NMR (400 MHz,CDCl3) δ 9.79 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8Hz, 2H), 4.16 (d, J = 8.4 Hz, 1H), 3.78 (dd, J = 9.1, 7.4 Hz, 1H), 3.06 (dd,J = 7.0, 4.8 Hz, 1H), 2.08 – 2.00 (m, 1H), 1.79 – 1.68 (m, 1H), 1.40 (s,3H), 0.83 (s, 9H), 0.80 (s, 9H), 0.01 (s, 6H), 0.01 (s, 3H), -0.01 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.4, 137.9, 131.8, 131.7, 126.7, 79.0, 77.4,56.4, 52.6, 31.3, 26.1, 25.7, 25.7, 17.9, 17.9, -4.4, -4.5, -4.6, -4.9. HRMS(ESI) m / z calcd for C 25 H 43 ClO3Si2Na[M+Na] +:505.2331, found: 505.2329. HPLC(Chiralpak OD-3 column, hexane / isopropanol = 90 / 10; flow rate = 1.0 mL / min;UV detection at 230 nm; t1 = 4.7 min (minor), t2 = 6.9 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0121] (1S,2R,3S,4S)-3-(4-bromophenyl)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methylcyclopentane-1-carbaldehyde (2ao). Colorlessoil, 50 mg, 95% yield, 97% ee; [α] 25 D = +11.1 ( c = 0.05, CHCl3). 1 H NMR (600MHz, CDCl3) δ 9.79 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.36 (d, J= 8.7 Hz, 2H), 4.16 (d, J = 8.4 Hz, 1H), 3.77 (dd, J = 9.2, 7.5 Hz, 1H), 3.08– 3.02 (m, 1H), 2.07 – 2.01 (m, 1H), 1.77 – 1.69 (m, 1H), 1.39 (s, 3H), 0.83(s, 9H), 0.81 (s, 9H), 0.01 (d, J = 1.2 Hz, 6H), 0.01 (s, 3H), -0.01 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 202.4, 138.5, 132.3, 129.6, 120.1, 78.9, 77.3,77.0, 56.3, 52.6, 31.3, 26.0, 25.7, 25.7, 17.9, 17.9, -4.4, -4.5, -4.6, -4.9.HRMS (ESI) m / z calcd for C 25 H 43 BrO3Si2H[M+H] + :527.2007, found: 527.2002. HPLC(Chiralpak OD-3 column, hexane / isopropanol = 90 / 10; flow rate = 1.0 mL / min;UV detection at 230 nm; t1 = 4.7 min (minor), t2 = 7.3 min (major). NOTE: Theenantiomeric excess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0122] (1S,2R,3S,4S)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-(4-methoxyphenyl)-3-methylcyclopentane-1-carbaldehyde (2ap). Colorless oil,47 mg, 98% yield, 97% ee; [α] 25 D = +47.0 (c = 1.0, CHCl3). 1H NMR (400 MHz,CDCl3) δ 9.53 (d, J = 2.2 Hz, 1H), 7.29 – 7.25 (m, 2H), 6.56 – 6.50 (m, 2H),3.86 (d, J = 8.5 Hz, 1H), 3.54 (s, 3H), 3.52 – 3.48 (m, 1H), 2.84 – 2.76 (m,1H), 1.83 – 1.73 (m, 1H), 1.56 – 1.44 (m, 1H), 1.14 (s, 3H), 0.59 (s, 9H),0.57 (s, 9H), -0.23 (s, 3H), -0.24 (s, 6H), -0.26 (s, 3H). 13 C NMR (101 MHz,CDCl3) δ 202.8, 157.5, 131.5, 131.4, 111.9, 79.2, 77.6, 56.4, 55.1, 52.1,31.2, 26.3, 25.8, 25.7, 18.0, 18.0, -4.3, -4.5, -4.6, -4.9. HRMS (ESI) m / zcalcd for C 26 H 46 O4Si2H[M+H] + :501.2827, found: 501.2833. HPLC (Chiralpak OD-Hcolumn, hexane / isopropanol = 97 / 3; flow rate = 1.0 mL / min; UV detection at230 nm; t1 = 5.8 min (minor), t2 = 8.0 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with 2,4-dinitrophenylhydrazine.

[0123] (1S,2R,3S,4S)-3-(3-bromophenyl)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methylcyclopentane-1-carbaldehyde (2aq). Colorlessoil, 45 mg, 86% yield, 98% ee; [α] 25 D = +55.3 (c = 0.1, CHCl3). 1 H NMR (600MHz, CDCl3) δ 9.80 (d, J = 2.0 Hz, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.54 – 7.52(m, 1H), 7.34 – 7.30 (m, 1H), 7.11 (t, J = 7.9 Hz, 1H), 4.17 (d, J = 8.3 Hz,1H), 3.79 (t, J = 8.1 Hz, 1H), 3.12 – 3.07 (m, 1H), 2.0 – 2.02 (m, 1H), 1.80– 1.73 (m, 1H), 1.40 (s, 3H), 0.84 (s, 9H), 0.81 (s, 9H), 0.02 - 0.01 (m,9H), 0.01 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 202.4, 142.0, 133.8, 128.9,128.8, 128.1, 121.0, 79.0, 77.5, 56.5, 53.0, 31.4, 26.1, 25.7, 25.7, 17.9,17.9, -4.4, -4.5, -4.6, -4.9. HRMS (ESI) m / z calcd for C 25 H 43 BrO3Si2H[M+H] + :527.2007, found: 527.2004. HPLC (Chiralpak OD-H column, hexane / isopropanol =95 / 5; flow rate = 1.0 mL / min; UV detection at 230 nm; t1 = 9.3 min (minor), t2= 16.2 min (major).

[0124] (1S,2R,3S,4S)-3-(3-bromophenyl)-2,4-bis((tert-butyldimethylsilyl)oxy)-3-methylcyclopentane-1-carbaldehyde (2ar). Colorlessoil, 25 mg, 89% yield, 95% ee; [α] 25 D = +14.2 (c = 0.05, CHCl3). 1 H NMR (600MHz, CDCl3) δ 9.80 (d, J = 2.1 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.21 – 7.17 (m,1H), 6.91 – 6.86 (m, 1H), 4.17 (d, J = 8.3 Hz, 1H), 3.79 (dd, J = 9.0, 7.4Hz, 1H), 3.13 – 3.07 (m, 1H), 2.09 – 2.03 (m, 1H), 1.82 – 1.74 (m, 1H), 1.41(s, 3H), 0.83 (s, 9H), 0.80 (s, 9H), 0.02 – 0.00 (m, 9H), -0.01 (s, 3H). 13 CNMR (151 MHz, CDCl3) δ 202.4, 161.8 (d, J = 241.4 Hz), 142.1 (d, J = 7.2 Hz),127.6 (d, J = 8.2 Hz), 125.9 (d, J = 2.7 Hz), 117.7 (d, J = 22.4 Hz), 112.6(d, J = 20.8 Hz), 79.0, 77.5, 56.5, 52.9, 31.3, 26.1, 25.7, 25.7, 17.9, 17.9,-4.4, -4.5, -4.6, -5.0. 19 F NMR (565 MHz, CDCl3) δ -115.5 (dt, J = 14.1, 7.2Hz). HRMS (ESI) m / z calcd for C 25 H 43 FO3Si2H[M+H] +:467.2810, found: 467.2807.HPLC (Chiralpak OD-H column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 230 nm; t1 = 9.1 min (minor), t2 = 16.6 min (major).

[0125] Dimethyl (1S,2S,3R,4R,5S)-5-formylbicyclo[2.2.1]heptane-2,3-dicarboxylate (2as). Colorless oil, 23 mg, 95% yield, 93% ee; [α] 25 D = +25.6 (c = 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.65 (s, 1H), 3.63 (s,3H), 3.63 (s, 3H), 2.95 (s, 1H), 2.84 – 2.79 (m, 2H), 2.64 (d, J = 4.5 Hz,1H), 2.37 (dd, J = 9.2, 5.3 Hz, 1H), 2.05 – 2.00 (m, 2H), 1.43 – 1.37 (m,1H), 1.18 (dd, J = 10.8, 2.5 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 201.3, 173.1,172.7, 53.4, 51.9, 51.8, 50.6, 50.3, 40.9, 39.8, 33.9, 29.4. HRMS (ESI) m / zcalcd for C 12 H 16 O5Na[M+Na] +:263.0890, found: 263.0891. HPLC (Chiralpak OD-Hcolumn, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at210 nm; t1 = 25.3 min (minor), t2 = 42.1 min (major). NOTE: The enantiomericexcess was determined by HPLC after reaction with methyl(triphenylPhosphoranylidene) acetate

[0126] Dimethyl (1R,2S,3R,4S,5S)-5-formylbicyclo[2.2.1]heptane-2,3-dicarboxylate (2at). Colorless oil, 23 mg, 95% yield, 96% ee; [α] 25 D = +9.4 (c = 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.72 (s, 1H), 3.67 (s,3H), 3.66 (s, 3H), 3.26 (dd, J = 9.2, 5.9 Hz, 1H), 3.15 – 3.12 (m, 1H), 3.00– 2.98 (m, 1H), 2.90 – 2.87 (m, 1H), 2.67 (t, J = 4.6 Hz, 1H), 1.89 – 1.84(m, 1H), 1.76 – 1.72 (m, 1H), 1.37 – 1.30 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ202.5, 172.6, 172.4, 51.7, 51.6, 48.3, 46.4, 46.3, 40.7, 40.4, 37.5, 25.2.HRMS (ESI) m / z calcd for C 12 H 16 O5Na[M+Na] +:263.0890, found: 263.0890. HPLC(Chiralpak IA column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UVdetection at 210 nm; t1 = 18.7 min (minor), t2 = 28.0 min (major).

[0127] Dimethyl (1S,2S,3R,4R,5S)-5-formylbicyclo[2.2.2]octane-2,3-dicarboxylate (2au). Colorless oil, 21 mg, 83% yield, 92% ee; [α] 25 D = +26.0 (c = 1.0, CHCl3). 1 H NMR (600 MHz, CDCl3) δ 9.72 (s, 1H), 3.67(s, 3H), 3.66 (s, 3H), 3.14 – 3.10 (m, 2H), 2.86 (d, J = 11.0 Hz, 1H), 2.59(s, 1H), 2.13 (s, 1H), 1.92 – 1.86 (m, 1H), 1.67 – 1.64 (m, 1H), 1.63 – 1.59(m, 2H), 1.52 – 1.49 (m, 1H), 1.46 – 1.43 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ203.9, 173.8, 173.3, 51.8, 51.6, 45.1, 45.0, 43.3, 28.0, 26.2, 25.1, 21.6,20.8. HRMS (ESI) m / z calcd for C 13 H 18 O5Na[M+Na] +:277.1046, found: 277.1049.HPLC (Chiralpak IA column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 210 nm; t1 = 20.7 min (minor), t2 = 40.4 min (major).

[0128] 3. High TON experiments and derivatization experiments

[0129] Because CO gas is involved in the hydroformylation reaction, and CO can adsorb onto the d-orbital electrons of transition metals, causing CO to coordinate at the metal center and thus poisoning the metal, the TON (total energy) of asymmetric hydroformylation remains largely unexplored compared to other asymmetric catalysis fields. Currently, the highest reported TON for asymmetric hydroformylation has not exceeded 10,000. This is a major reason why, despite numerous reported catalysts, including many with high activity and selectivity, asymmetric hydroformylation has not yet been industrialized. In this work, we first attempted a reaction condition of TON = 2000, obtaining results identical to the standard conditions. Subsequently, we tried a TON = 20000, Rh(acac)(CO)2 / (S,R)-YanPhos = 1 / 4, 80 ℃, 48 h, with satisfactory results (Conv. > 99%, dr > 20:1.99% ee). This work further explored an S / C ratio of 50000 and increased the temperature to 90 °C, while keeping other conditions constant, achieving a conversion rate of 75% and an ee of 95%. This work hypothesizes that in the later stages of the reaction, due to the decreased substrate concentration, the catalyst becomes less effective at interacting with the substrate, leading to a slower reaction rate. Therefore, this work extended the reaction time to 96 h, experimenting with an S / C ratio of 100000 and reacting at 90 °C for 96 h, ultimately achieving a conversion rate of 86%, i.e., 86000 TON, dr > 20:1, and 93.3% ee. This result is exciting, representing the highest TON ever achieved in asymmetric hydroformylation, while maintaining high enantiomeric selectivity, greatly increasing the industrialization potential of asymmetric hydroformylation. Finally, this work was derivatized and synthesized. After obtaining product 2a under standard conditions, it was transformed by: 1. reducing the aldehyde group with sodium borohydride; 2. protecting the reduced hydroxyl group with triphenylmethyl; 3. removing the silicon protecting group with TBAF; thus, the five-membered chiral carbon ring 5 was obtained. This chiral carbon ring was first reported in 1994 and can be used to synthesize a series of carbocyclic nucleosides.

[0130] The technical routes for high-TON experiments and derivatization experiments are as follows:

[0131]

[0132] 4. Summary

[0133] This work successfully achieved the desymmetric hydroformylation of cyclopentene, cyclohexene, and cycloheptene derivatives using an Rh / YanPhos catalytic system, yielding multi-chiral cycloalkyl aldehydes in one step with extremely high enantiomeric and diastereoselectivity. Transformation of the aldehyde group yielded multi-chiral carbocyclic rings in high yields, with high dr values ​​and high ee values. The TON of the reaction was measured, showing a TON of up to 86,000. This work exhibits extremely high stereoselectivity, broad substrate compatibility, extremely high reaction efficiency, and readily convertible products.

[0134] This work reports on symmetrical 1,2-disubstituted intracyclic alkenes as substrates. The introduction of the silicon protecting group increases the electron cloud density of the carbon-carbon double bond, making it easier for the carbon-carbon double bond to coordinate with the metal, thus increasing the reactivity of the substrate to some extent. Based on this idea, for some less reactive substrates, such as trisubstituted and tetrasubstituted alkenes, the reactivity of the substrate can also be increased by introducing electron-donating groups.

[0135] In the field of carbocyclic nucleoside synthesis chemistry, the efficient stereoselective construction of chiral carbocyclic rings has been a subject of continuous exploration. Using asymmetric hydroformylation as a desymmetry strategy for cyclopentene derivatives offers a balance between high stereoselectivity and high atom economy, making it an ideal method for constructing chiral carbocyclic rings. In this work, 33 substrates were used to yield multi-chiral central cycloalkyl aldehydes with excellent selectivity and good yields. Through aldehyde group conversion, chiral carbocyclic intermediates for carbocyclic nucleoside synthesis could be directly obtained.

[0136] In the field of hydroformylation, linear hydroformylation has achieved large-scale industrial applications, while asymmetric hydroformylation has not yet been industrialized due to issues such as catalyst toxicity and reaction efficiency. The desymmetric hydroformylation reaction reported in this paper exhibits extremely high TON and maintains excellent selectivity, which is undoubtedly a significant breakthrough in the industrialization of asymmetric hydroformylation.

[0137] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. A method for constructing multichiral central carbocyclic nucleotides, characterized in that: The process includes adding an acetylacetone dicarbonyl rhodium metal precursor and a chiral ligand to an organic solvent under an inert atmosphere to prepare a catalyst solution, mixing the catalyst solution with the substrate, and reacting under an atmosphere of hydrogen and carbon monoxide. After the reaction is completed, the mixture is filtered and purified to obtain a multi-chiral central cycloalkyl aldehyde, and the aldehyde group is converted to obtain the multi-chiral central carbocyclic nucleoside.

2. The method according to claim 1, characterized in that: The substrate is the structure shown in formula (1) or formula (2). Equation (1) , Equation (2) , In formula (1), n ​​= 1, 2 or 3; in formula (1) and formula (2), R1 is selected from at least one of OTBS, OTMS, OTES, OTIPS, OTBDPS, OSiPhMe2, OAc, OTr, COOMe, and R2 is selected from at least one of H, Me, Et, nBu, and cyclopentyl; in formula (2), R3 is selected from at least one of phenyl, benzyl, naphthyl ring, benzocyclopentyl, and other benzene rings with substituents.

3. The method according to claim 1, characterized in that: The chiral ligand is at least one of the following: 、 、 、 、 、 、 、 、 。 4. The method according to claim 1, characterized in that: The acetylacetone dicarbonyl rhodium metal precursor is Rh(C5H7O2)(CO)2.

5. The method according to any one of claims 1-4, characterized in that: The organic solvent is at least one of toluene, dioxane, THF, CH3CN, hexane, cyclohexane, heptane, benzene, DCM, and DCE.

6. The method according to any one of claims 1-4, characterized in that: The reaction conditions are: stirring at 50-150 °C for at least 12 h.

7. The method according to any one of claims 1-4, characterized in that: In the catalyst solution, the molar ratio of acetylacetone dicarbonyl rhodium metal precursor to chiral ligand is 1:1 to 1:4; in the reaction, the molar ratio of catalyst to substrate is 1:20 to 1:100000.

8. The method according to any one of claims 1-4, characterized in that: The filtration includes silica gel column filtration.

9. The method according to any one of claims 1-4, characterized in that: The purification includes column chromatography purification or recrystallization purification.

10. A multichiral central carbocyclic nucleotide, characterized in that: Prepared by the method described in any one of claims 1-9.

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