CN109627231B - Preparation method and application of chiral 1, 3-dioxane compound - Google Patents

Preparation method and application of chiral 1, 3-dioxane compound Download PDF

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CN109627231B
CN109627231B CN201811514946.4A CN201811514946A CN109627231B CN 109627231 B CN109627231 B CN 109627231B CN 201811514946 A CN201811514946 A CN 201811514946A CN 109627231 B CN109627231 B CN 109627231B
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CN109627231A (en
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张勇健
徐航
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Shanghai Jiaotong University
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/03—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by addition of hydroxy groups to unsaturated carbon-to-carbon bonds, e.g. with the aid of H2O2
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Abstract

The invention discloses a preparation method and application of chiral 1, 3-dioxane compounds, wherein racemic 2-substituted-2-vinyl oxetane compounds are used as raw materials, and the raw materials are reacted with formaldehyde under the catalysis of a chiral palladium complex generated by coordination of a palladium source and a chiral ligand as a catalyst to prepare the chiral 1, 3-dioxane compounds. The chiral compound provided by the invention is a precursor of a functionalized chiral 1, 3-diol compound, can be flexibly and conveniently subjected to functional transformation, and is an important chiral molecular building block for preparing chiral drugs and intermediates. The preparation method provided by the invention is an asymmetric cycloaddition reaction catalyzed by palladium, and has the advantages of high catalytic activity, high regioselectivity and enantioselectivity, mild reaction conditions and convenient and easily obtained reaction raw materials.

Description

Preparation method and application of chiral 1, 3-dioxane compound
Technical Field
The invention relates to a preparation method of a compound in the technical field of chemical industry, in particular to a preparation method and application of a chiral 1, 3-dioxane compound.
Background
Vinyl oxiranes are a widely used class of substrates in allylic substitution reactions. Under the catalysis of metal complexes such as Pd and Ir, a vinyl oxirane compound can be subjected to ring opening to form a zwitterionic intermediate and can be subjected to substitution reaction or cycloaddition reaction with a series of nucleophilic reagents or unsaturated electrophilic reagents, so that a plurality of complex molecules (He, J.; Ling, J.; Chiu, P.chem.Rev.2014,114,8037) with application values can be prepared. For allyl substitution reactions involving such compounds, great development has been achieved both in the deep excavation of nucleophiles or unsaturated electrophiles and in the induction of chirality. In contrast, 2-vinyloxetane compounds, which are homologs of vinyl oxiranes, are rarely reported to participate in allylic substitution reactions and only 1 of them is an asymmetric reaction (Wang, y.; Yang, l.; Rong, z.; Liu, t.; Liu, r.; Zhao, y.angelw.chem.int.ed.2018, 57, 1). Therefore, the method has very important significance for the intensive research on the allyl substitution reaction participated by the compounds and how to expand the allyl substitution reaction of the vinyl oxirane compounds into the compounds.
Chiral 1, 3-diols are important building blocks for a variety of drugs and natural products with physiological activity. Asymmetric synthesis of chiral 1, 3-diols relies primarily on aldol condensation-carbonyl reduction, conjugate addition-carbonyl reduction, or hydration of allyl alcohol (Chen, k.; Richter, j.m.; Baran, p.s.j.am. chem.soc.2008,130, 7247). However, these methods typically produce chiral 1, 3-diols having only primary or secondary alcohol structures, and for the construction of chiral 1, 3-diols having tertiary alcohol structures, these methods are often inefficient or impractical.
Disclosure of Invention
The invention aims to provide a preparation method and application of chiral 1, 3-dioxane compounds aiming at the defects in the prior art, the chiral 1, 3-dioxane compounds are prepared by reacting racemic 2-substituted-2-vinyl oxetane compounds with a formaldehyde aqueous solution, and the chiral 1, 3-dioxane compounds are palladium-catalyzed asymmetric cycloaddition reactions.
The purpose of the invention is realized by the following technical scheme:
in the method, in an organic solvent, a chiral palladium complex generated by coordination of a palladium source and a chiral ligand is used as a catalyst, and a racemic 2-substituted-2-vinyl oxetane compound II reacts with formaldehyde to prepare the chiral 1, 3-dioxane compound I;
the structural formulas of the compounds I, II and III are shown as follows:
Figure BDA0001901713180000021
wherein: r is C6-C12Aryl of (2), C whose substituent contains N, O or halogen6-C8Substituted aryl of (2), C8An arylalkyl group of (a).
Preferably, the formaldehyde is an aqueous formaldehyde solution.
Preferably, the organic solvent is tetrahydrofuran, dioxane, dichloromethane, toluene, diethyl ether, methylcyclopentyl ether, acetonitrile or cyclohexane.
Preferably, the palladium source is Pd2(dba)3、Pd2(dba)3CHCl3、Pd(dba)2、[Pd(allyl)Cl]2、Pd(OAc)2、Pd(CF3COO)2、Pd(CH3CN)2Cl2Or Pd (PhCN)2Cl2。
Preferably, the chiral ligand is one of chiral phosphine ligands having the following structure:
Figure BDA0001901713180000022
wherein X is C1-C10Alkyl of (C)6-C16Aryl or C of6-C16Substituted aryl of, OR1Or NR2R3Wherein R is1Is C1-C10Alkyl of (C)6-C16Aryl or C of6-C16Substituted aryl of, R2、R3Are respectively hydrogen and C1-C20Alkyl of (C)6-C20Aryl or C of6-C20Substituted aryl of (1).
Preferably, the mole ratio of the racemic 2-substituted-2-vinyl oxetane compound II, formaldehyde, palladium source and chiral ligand is 1 (1-20): 0.0001-0.05): 0.0001-0.20): 0.0001-0.40.
In a second aspect, the invention provides an application of the chiral 1, 3-dioxane compound I, which specifically comprises: the chiral 1, 3-dioxane compound Ia is used for preparing the chiral triol compound III. The method comprises the following specific steps:
1) the compound Ia firstly reacts with ruthenium trichloride and sodium periodate in an acetonitrile/water (1:1) mixed solvent at room temperature, and then reacts with lithium aluminum hydride in an ether solution to obtain a compound IV;
2) reacting the compound IV with trifluoroacetic anhydride and acetic acid at room temperature, and treating with potassium carbonate and methanol to obtain a chiral triol compound III; the structural formulas of the compounds Ia, III and IV are shown as follows:
Figure BDA0001901713180000031
preferably, the acetonitrile/water mixed solvent has a volume ratio of acetonitrile/water of 1: 1.
Preferably, the reaction is carried out with lithium aluminum hydride in an ether solution, wherein the reaction temperature is 0 ℃.
Compared with the prior art, the embodiment of the invention has at least one of the following beneficial effects:
1. the preparation method of the chiral 1, 3-dioxane compound provided by the invention comprises the steps of taking a racemic compound which is easy to prepare as a raw material, and preparing the racemic compound and a formaldehyde aqueous solution which is wide, stable and high in activity by a metal palladium asymmetric catalysis technology, so that the preparation method is efficient and convenient. The preparation method has good catalytic activity, high regioselectivity and stereoselectivity of reaction, mild reaction conditions, convenient and easily obtained reaction raw materials and important application prospect.
2. The chiral 1, 3-dioxane compounds provided by the invention are precursors of chiral 1, 3-diol, and are functionalized chiral quaternary carbon compounds, the compounds contain a quaternary carbon chiral center, and the quaternary carbon chiral center contains a vinyl group, so that the functional conversion can be flexibly and conveniently carried out respectively, and the chiral 1, 3-dioxane compounds are important chiral molecular building blocks applied to synthesis of various chiral compounds, such as preparation of chiral drugs and intermediates thereof.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
This example provides the preparation of chiral 1, 3-dioxanes Ia, using different ligands and reaction temperatures.
Pd is added into the reaction tube in sequence2(dba)3CHCl3(0.025mmol), chiral ligand (0.1mmol), Compound IIa (1.0mmol), aqueous Formaldehyde (10mmol), and tetrahydrofuranPyran (5.0mL) was reacted at 40 ℃ for 17 hours. And (3) evaporating the solvent under reduced pressure, and carrying out column chromatography on the residue to obtain the corresponding chiral 1, 3-dioxane compound Ia.
The reaction scheme of this example and the results of using different ligands and reaction temperatures to prepare chiral 1, 3-dioxanes Ia are shown below:
Figure BDA0001901713180000041
Figure BDA0001901713180000042
example 2
This example provides the preparation of chiral 1, 3-dioxanes Ia, with the results of the preparation using different solvents.
Pd is added into the reaction tube in sequence2(dba)3CHCl3(0.025mmol), chiral ligand 1b (0.1mmol), compound IIa (1.0mmol), aqueous formaldehyde (10mmol) and solvent (5.0mL) were reacted at 40 ℃ for 17 hours. And (3) evaporating the solvent under reduced pressure, and carrying out column chromatography on the residue to obtain the corresponding chiral 1, 3-dioxane compound Ia.
The reaction scheme of this example and the results of using different solvents to prepare chiral 1, 3-dioxanes Ia are shown below:
Figure BDA0001901713180000051
Figure BDA0001901713180000052
example 3 preparation of chiral 1, 3-dioxanes I
Pd is added into the reaction tube in sequence2(dba)3CHCl3(0.025mmol), chiral ligand 1b (0.1mmol), Compound II (1.0mmol), aqueous formaldehyde (10mmol) and diethyl ether (5.0mL) were reacted at 40 ℃ for 17 hours. Residue after evaporation of solvent under reduced pressureAnd performing chromatography on the residual column to obtain the corresponding 1, 3-dioxane compound I.
The following are chiral 1, 3-dioxane compounds I corresponding to different choices of R1H NMR、13C NMR spectrum data, all compounds were prepared by any of the methods of examples 1-2, with some differences in the corresponding yields and enantioselectivities.
Ia R ═ phenyl
1H NMR(400MHz,CDCl3)7.50–7.33(m,4H),7.30–7.21(m,1H),5.91(dd,J＝17.6,10.9Hz,1H),5.29(d,J＝10.9Hz,1H),5.17(d,J＝17.6Hz,1H),5.04(d,J＝6.4Hz,1H),4.92(d,J＝6.5Hz,1H),3.98(ddd,J＝11.4,7.5,3.8Hz,1H),3.86(ddd,J＝11.1,6.5,4.0Hz,1H),2.30(ddd,J＝14.0,7.5,4.0Hz,1H),2.23(ddd,J＝14.0,6.5,3.8Hz,1H)；13C NMR(101MHz,CDCl3)142.13,128.53,127.22,125.83,115.50,89.25,78.07,63.64,33.97；HRMS(ESI-MS):Calcd.for C12H14O2(M+Na):213.0891,Found:213.0890；HPLC conditions:Chiralcel OJ-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tminor＝15.83min,tmajor＝18.59min；92％ee.
Ib R is 4-phenyl
1H NMR(500MHz,CDCl3)7.67–7.56(m,4H),7.54–7.40(m,4H),7.39–7.29(m,1H),5.94(dd,J＝17.6,10.9Hz,1H),5.32(dd,J＝10.9,0.9Hz,1H),5.22(dd,J＝17.7,0.9Hz,1H),5.06(d,J＝6.4Hz,1H),4.95(d,J＝6.4Hz,1H),4.00(ddd,J＝11.4,7.7,3.7Hz,1H),3.89(ddd,J＝11.0,6.5,3.9Hz,1H),2.33(ddd,J＝14.0,7.7,3.9Hz,1H),2.26(ddd,J＝14.0,6.5,3.7Hz,1H)；13C NMR(126MHz,CDCl3)142.27,142.03,128.77,128.74,127.30,127.24,127.06,126.26,115.56,89.27,77.95,63.63,33.97；HRMS(ESI-MS):Calcd.forC18H18O2(M):266.1307,Found:266.1299；HPLC conditions:Chiralcel OD-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/99,tmajor＝12.48min,tminor＝13.93min；80％ee.
Ic: R ═ 4-methylphenyl
1H NMR(400MHz,CDCl3)7.29(d,J＝8.2Hz,2H),7.18(d,J＝7.9Hz,2H),5.90(dd,J＝17.6,10.9Hz,1H),5.25(d,J＝10.9Hz,1H),5.14(d,J＝17.6Hz,1H),5.02(d,J＝6.5Hz,1H),4.90(d,J＝6.5Hz,1H),3.97(ddd,J＝11.2,7.2,3.9Hz,1H),3.85(ddd,J＝11.1,6.8,3.9Hz,1H),2.34(s,3H),2.28(ddd,J＝14.0,7.2,3.9Hz,1H),2.21(ddd,J＝14.0,6.8,3.9Hz,1H)；13C NMR(101MHz,CDCl3)142.40,140.04,136.85,129.20,125.80,115.07,89.18,77.95,63.61,33.87,20.99；HRMS(ESI-MS):Calcd.for C13H16O2(M+Na):227.1048,Found:227.1059；HPLC conditions:Chiralcel AS-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/99,tmajor＝5.73min,tminor＝8.75min；94％ee.
Id, R ═ 4-methoxyphenyl
1H NMR(400MHz,CDCl3)7.50–7.32(m,4H),7.32–7.21(m,1H),5.91(dd,J＝17.6,10.9Hz,1H),5.29(dd,J＝10.9,0.9Hz,1H),5.17(dd,J＝17.6,0.9Hz,1H),5.04(d,J＝6.4Hz,1H),4.92(d,J＝6.5Hz,1H),3.98(ddd,J＝11.4,7.5,3.8Hz,1H),3.86(ddd,J＝11.1,6.5,4.0Hz,1H),2.30(ddd,J＝14.0,7.5,4.0Hz,1H),2.23(ddd,J＝14.0,6.5,3.8Hz,1H)；13C NMR(101MHz,CDCl3)158.63,142.42,135.00,127.14,115.05,113.79,89.11,77.78,63.58,55.20,33.88；HRMS(ESI-MS):Calcd.for C13H16O2(M+Na):243.0997,Found:243.1011；HPLC conditions:Chiralcel OJ-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/49,tminor＝13.91min,tmajor＝15.06min；81％ee.
Ie R is 3-methoxyphenyl
1H NMR(400MHz,CDCl3)7.28(t,J＝8.0Hz,1H),7.02–6.93(m,2H),6.81(ddd,J＝8.2,2.6,0.9Hz,1H),5.90(dd,J＝17.6,10.9Hz,1H),5.28(dd,J＝10.9,0.9Hz,1H),5.18(dd,J＝17.6,0.9Hz,1H),5.03(d,J＝6.4Hz,1H),4.92(d,J＝6.4Hz,1H),3.97(ddd,J＝11.3,7.4,3.8Hz,1H),3.86(ddd,J＝11.1,6.5,4.0Hz,1H),3.81(s,3H),2.28(ddd,J＝14.1,7.4,4.0Hz,1H),2.21(ddd,J＝14.0,6.5,3.9Hz,1H)；13C NMR(101MHz,CDCl3)159.79,144.90,141.92,129.48,118.09,115.47,112.36,111.75,89.23,77.96,63.61,55.21,33.93；HRMS(ESI-MS):Calcd.for C13H16O2(M+Na):243.0997,Found:243.1003；HPLCconditions:Lux 5u Cellulose-2,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/99,tmajor＝11.55min,tminor＝13.03min；86％ee.
If R is 2-methoxyphenyl
1H NMR(400MHz,CDCl3)7.63(dd,J＝7.8,1.8Hz,1H),7.24(ddd,J＝8.2,7.3,1.8Hz,1H),6.99(td,J＝7.6,1.2Hz,1H),6.87(dd,J＝8.2,1.2Hz,1H),6.09(dd,J＝17.6,10.9Hz,1H),5.25(dd,J＝10.9,1.3Hz,1H),5.22(dd,J＝17.6,1.3Hz,1H),5.14(d,J＝6.3Hz,1H),5.01(d,J＝6.3Hz,1H),3.94(ddd,J＝11.4,9.9,3.1Hz,1H),3.89–3.80(m,1H),2.54(ddd,J＝13.9,4.5,3.1Hz,1H),2.34(ddd,J＝14.2,10.0,4.5Hz,1H)；13C NMR(101MHz,CDCl3)155.98,139.90,132.74,128.22,126.14,120.76,115.69,111.52,88.84,63.70,55.18,33.75；HRMS(ESI-MS):Calcd.for C13H16O2(M+Na):243.0997,Found:243.1001；HPLCconditions:Chiralcel AD-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/98,tmajor＝6.40min,tminor＝7.06min；96％ee.
R is 2, 5-dimethoxyphenyl
1H NMR(400MHz,CDCl3)7.25(d,J＝3.0Hz,1H),6.84–6.72(m,2H),6.08(dd,J＝17.5,10.9Hz,1H),5.26(dd,J＝10.9,1.3Hz,1H),5.23(dd,J＝17.6,1.3Hz,1H),5.14(d,J＝6.4Hz,1H),5.01(d,J＝6.3Hz,1H),3.93(ddd,J＝11.4,10.1,3.0Hz,1H),3.85(dt,J＝11.4,4.4Hz,2H),3.79(s,3H),3.73(s,3H),2.52(ddd,J＝13.9,4.5,2.8Hz,1H),2.31(ddd,J＝14.3,10.1,4.6Hz,1H)；13C NMR(101MHz,CDCl3)153.77,150.14,139.71,134.23,115.91,112.86,112.71,112.13,88.83,63.68,55.89,55.70,33.71；HRMS(ESI-MS):Calcd.for C14H18O4(M+Na):273.1103,Found:273.1113；HPLC conditions:Lux 5uCellulose-2,220nm,flow rate:0.5mL/min,i-PrOH/hexanes＝1/99,tmajor＝13.13min,tminor＝14.31min；96％ee.
Ih R ═ 4-fluorophenyl
1H NMR(400MHz,CDCl3)7.44–7.32(m,2H),7.12–6.95(m,2H),5.88(dd,J＝17.7,10.9Hz,1H),5.32(dd,J＝10.9,0.9Hz,1H),5.17(dd,J＝17.7,0.9Hz,1H),5.03(d,J＝6.5Hz,1H),4.90(d,J＝6.5Hz,1H),3.97(ddd,J＝11.6,7.7,4.1Hz,1H),3.86(ddd,J＝11.4,5.8,4.2Hz,1H),2.29–2.16(m,2H)；13C NMR(101MHz,CDCl3)163.09,160.65,141.70,139.24,139.21,127.54,127.46,115.94,115.34,115.13,89.17,77.67,63.54,34.09；HRMS(ESI-MS):Calcd.for C12H13FO2(M+H):209.0978,Found:209.0980；HPLC conditions:Chiralcel AS-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tmajor＝6.88min,tminor＝12.38min；85％ee.
R ═ 4-chlorophenyl group
1H NMR(400MHz,CDCl3)7.39–7.28(m,4H),5.87(dd,J＝17.6,10.9Hz,1H),5.33(dd,J＝10.9,0.8Hz,1H),5.18(dd,J＝17.6,0.8Hz,1H),5.03(d,J＝6.5Hz,1H),4.90(d,J＝6.5Hz,1H),3.97(ddd,J＝11.6,7.5,4.3Hz,1H),3.85(ddd,J＝11.5,5.8,4.5Hz,1H),2.30–2.11(m,2H)；13C NMR(101MHz,CDCl3)142.10,141.46,133.04,128.60,127.21,116.16,89.20,77.66,63.52,33.98；HRMS(ESI-MS):Calcd.for C12H13ClO2(M+H):225.0682,Found:225.0674；HPLC conditions:Chiralcel AS-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tmajor＝4.95min,tminor＝6.68min；84％ee.
Ij R ═ 4-bromophenyl
1H NMR(400MHz,CDCl3)7.48(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),5.86(dd,J＝17.7,10.9Hz,1H),5.33(d,J＝10.8Hz,1H),5.18(d,J＝17.8Hz,1H),5.03(d,J＝6.5Hz,1H),4.90(d,J＝6.4Hz,1H),3.96(ddd,J＝11.7,7.5,4.3Hz,1H),3.85(dt,J＝11.1,4.9Hz,1H),2.27–2.15(m,2H)；13C NMR(101MHz,CDCl3)142.65,141.36,131.55,127.55,121.19,116.19,89.18,77.68,63.50,33.92；HRMS(ESI-MS):Calcd.for C12H13BrO2(M+H):269.0177,Found:269.0171；HPLC conditions:Chiralcel AS-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tmajor＝4.97min,tminor＝6.53min；80％ee.
Ik, R is 3, 4-dichlorophenyl
1H NMR(400MHz,CDCl3)7.51(d,J＝2.2Hz,1H),7.42(d,J＝8.4Hz,1H),7.23(dd,J＝8.4,2.2Hz,1H),5.84(dd,J＝17.7,10.9Hz,1H),5.39(dd,J＝10.9,0.7Hz,1H),5.23(dd,J＝17.6,0.7Hz,1H),5.03(d,J＝6.5Hz,1H),4.91(d,J＝6.5Hz,1H),3.96(ddd,J＝12.0,7.4,4.7Hz,1H),3.87(dt,J＝11.5,4.8Hz,1H),2.29–2.10(m,2H)；13C NMR(101MHz,CDCl3)144.29,140.64,132.60,131.20,130.39,127.82,125.06,116.95,89.21,77.27,63.44,33.98；HRMS(ESI-MS):Calcd.for C12H12Cl2O2(M+H):259.0293,Found:259.0286；HPLCconditions:Chiralcel AS-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tmajor＝4.65min,tminor＝6.15min；88％ee.
R ═ 3-nitrophenyl
1H NMR(500MHz,CDCl3)8.29(t,J＝2.1Hz,1H),8.14(ddd,J＝8.2,2.4,1.1Hz,1H),7.78(dt,J＝7.8,1.4Hz,1H),7.54(t,J＝8.0Hz,1H),5.89(dd,J＝17.7,10.9Hz,1H),5.46(d,J＝11.0Hz,1H),5.31(d,J＝17.7Hz,1H),5.09(d,J＝6.5Hz,1H),4.96(d,J＝6.5Hz,1H),4.00(ddd,J＝11.6,7.0,5.7Hz,1H),3.91(dt,J＝11.5,4.5Hz,1H),2.31–2.20(m,1H)；13C NMR(126MHz,CDCl3)148.43,146.63,140.23,131.67,129.43,122.25,120.71,117.66,89.24,77.42,63.43,34.13；HRMS(ESI-MS):Calcd.for C12H13NO4(M+Na):258.0742,Found:258.0748；HPLC conditions:Chiralcel AD-H column,220nm,flow rate:0.5mL/min,i-PrOH/hexanes＝1/99,tminor＝32.49min,tmajor＝34.40min；93％ee.
Im R1-naphthyl
1H NMR(500MHz,CDCl3)8.62(d,J＝7.8Hz,1H),7.95–7.77(m,2H),7.57–7.41(m,4H),6.26(dd,J＝17.6,10.9Hz,1H),5.21(d,J＝10.8Hz,1H),5.10(d,J＝17.5Hz,1H),4.96(d,J＝6.5Hz,1H),4.68(d,J＝6.6Hz,1H),4.16–4.00(m,2H),2.68–2.52(m,1H),2.39(dddd,J＝14.3,9.2,4.8,1.8Hz,1H)；13C NMR(126MHz,CDCl3)143.00,136.52,135.07,131.36,129.26,128.78,127.78,126.22,125.47,125.34,124.47,115.13,89.11,80.13,63.58,34.97；HRMS(ESI-MS):Calcd.for C16H16O2(M+Na):263.1048,Found:263.1054；HPLCconditions:Chiralcel OD-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/99,tminor＝14.50min,tmajor＝20.69min；99.5％ee.
In R2-naphthyl
1H NMR(500MHz,CDCl3)7.91–7.75(m,4H),7.58–7.38(m,3H),5.97(dd,J＝17.6,10.9Hz,1H),5.31(d,J＝10.9Hz,1H),5.21(d,J＝17.6Hz,1H),5.08(d,J＝6.5Hz,1H),4.95(d,J＝6.5Hz,1H),4.01(ddd,J＝11.3,7.5,3.7Hz,1H),3.90(ddd,J＝11.1,6.8,3.9Hz,1H),2.39(ddd,J＝14.0,7.5,3.9Hz,1H),2.30(ddd,J＝14.0,6.8,3.7Hz,1H)；13C NMR(126MHz,CDCl3)141.99,140.44,133.18,132.52,128.32,128.11,127.50,126.11,126.02,124.62,124.08,115.66,89.29,78.15,63.60,33.88；HRMS(ESI-MS):Calcd.forC16H16O2(M+Na):263.1048,Found:263.1049；HPLC conditions:Chiralcel OJ-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/9,tmajor＝20.29min,tminor＝22.42min；52％ee.
Io R2-phenylethyl
1H NMR(400MHz,CDCl3)7.33–7.23(m,2H),7.23–7.10(m,3H),5.79(dd,J＝17.9,11.1Hz,1H),5.43(dd,J＝11.1,1.0Hz,1H),5.23(dd,J＝17.9,1.0Hz,1H),4.95(d,J＝6.4Hz,1H),4.88(d,J＝6.4Hz,1H),3.92(dddd,J＝11.4,4.9,3.0,0.9Hz,1H),3.82(td,J＝11.3,2.8Hz,1H),2.74–2.53(m,2H),2.07–1.88(m,2H),1.87–1.72(m,2H)；13C NMR(101MHz,CDCl3)142.21,140.18,128.34,128.31,125.73,117.16,89.00,76.23,63.37,43.68,33.56,28.92；HRMS(ESI-MS):Calcd.for C14H18O2(M+Na):241.1204,Found:241.1208；HPLCconditions:Chiralcel AD-H column,220nm,flow rate:1.0mL/min,i-PrOH/hexanes＝1/19,tmajor＝5.19min,tminor＝5.49min；64％ee.
Example 4 preparation of Compound IV
Chiral 1, 3-dioxane compound Ia (107.4mg,0.56mmol), sodium periodate (362.3mg,1.69mmol) and ruthenium trichloride (3.5mg,0.017mmol) were dissolved in 10mL of a mixed solvent of acetonitrile/water (1:1) at room temperature and reacted for 20 hours. The reaction mixture was extracted with ethyl acetate, dried and concentrated to give the crude product. This was dissolved in 5mL of diethyl ether and cooled to 0 deg.C, lithium aluminum hydride (21.3mg,0.56mmol) was added and reacted at 0 deg.C for 12 hours. Filtration, removal of the solvent using a rotary evaporator and column chromatography purification gave compound IV (65.6mg, 60%).
1H NMR(500MHz,CDCl3)7.51-7.28(m,5H),4.91(d,J＝6.4Hz,1H),4.75(d,J＝6.6Hz,1H),3.98(dd,J＝11.6,4.8Hz,1H),3.63(t,J＝11.9Hz,1H),3.56(d,J＝11.6Hz,1H),3.38(dd,J＝12.1,6.1Hz,1H),2.74(s,1H),2.61(td,J＝13.4,5.0Hz,1H),2.11(d,J＝14.1Hz,1H)；13C NMR(125MHz,CDCl3)139.06,128.67,127.58,126.78,88.95,78.89,71.20,63.12,28.15；HRMS(ESI-MS):Calcd.for C11H14O3(M+Na):217.0841,Found:217.0846.
Example 5 preparation of Compound III
Acetic acid (18. mu.L, 0.3mmol) was added to a mixture of Compound IV (19.4mg,0.1mmol) and trifluoroacetic anhydride (42. mu.L, 0.3mmol) at room temperature for 3 hours. Then, 1mL of methanol and potassium carbonate (138.2mg,1.0mmol) were added thereto, and the reaction was carried out for 2 hours. Filtering, drying and evaporating the solvent. Purification by column chromatography gave compound III (15.7mg, 86%).
1H NMR(400MHz,CDCl3)7.68-7.01(m,5H),4.41(s,1H),3.87-3.43(m,4H),3.14(s,2H),2.29(ddd,J＝14.4,10.1,4.1Hz,1H),1.91(ddd,J＝14.8,4.6,2.9Hz,1H).；13C NMR(100MHz,CDCl3)143.37,128.40,127.12,125.26,78.02,70.45,59.38,38.91；HRMS(ESI-MS):Calcd.for C10H14O3(M+Na):205.0841,Found:205.0855.
The chiral compound of the above embodiment of the present invention is a precursor of a functionalized chiral 1, 3-diol compound, can be flexibly and conveniently subjected to functional transformation, and will be an important chiral molecular building block for preparing chiral drugs and intermediates. The preparation method provided by the invention is palladium-catalyzed asymmetric cycloaddition reaction, the preparation method has high catalytic activity, high regioselectivity and enantioselectivity and mild reaction conditions, and the bulk chemical formaldehyde and the easily prepared 2-substituted-2-vinyloxetane compound are used, so that the reaction raw materials are convenient and easy to obtain, and the preparation method has an important industrial application prospect.
Some embodiments of the present invention have been described above. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (8)

1. A preparation method of chiral 1, 3-dioxane compounds I is characterized in that in an organic solvent, a chiral palladium complex generated by coordination of a palladium source and a chiral ligand is used as a catalyst, and a racemic 2-substituted-2-vinyl oxetane compound II reacts with formaldehyde to prepare the chiral 1, 3-dioxane compounds I;
the structural formulas of the compounds I and II are shown as follows:
Figure DEST_PATH_IMAGE001
wherein: r is C6-C12Aryl of (2), C with the substituent being halogen6-C8Substituted aryl of (2), C8Arylalkyl of (a);
the chiral ligand is a chiral phosphine ligand with the following structure:
Figure 62435DEST_PATH_IMAGE002
。
2. the method for preparing chiral 1, 3-dioxane compound I according to claim 1, wherein the organic solvent is one of tetrahydrofuran, dioxane, dichloromethane, toluene, diethyl ether, methyl cyclopentyl ether, acetonitrile or cyclohexane.
3. The method of claim 1, wherein the palladium source is Pd for the preparation of chiral 1, 3-dioxane compound I2(dba)3、Pd2(dba)3CHCl3、[Pd(allyl)Cl]2、Pd(OAc)2、Pd(CF3COO)2、Pd(CH3CN)2Cl2Or Pd (PhCN)2Cl2One of them.
4. The process for preparing chiral 1, 3-dioxanes as claimed in claim 1 to 3, wherein the racemic 2-substituted-2-vinyloxetanes II and the aqueous formaldehyde solution are mixed in the range of 20 to 60oAnd C, carrying out a reaction.
5. The process for preparing chiral 1, 3-dioxanes according to claim 1 to 3, wherein the formaldehyde is an aqueous formaldehyde solution.
6. A method for preparing a chiral triol compound III, which is characterized by comprising the following steps:
chiral 1, 3-dioxanes Ia obtained by the process according to any one of claims 1 to 5;
the chiral 1, 3-dioxane compound Ia is adopted to prepare a chiral triol compound III, which comprises the following specific steps:
1) the compound Ia firstly reacts with ruthenium trichloride and sodium periodate in an acetonitrile/water mixed solvent at room temperature, and then reacts with lithium aluminum hydride in an ether solution to obtain a compound IV;
2) reacting the compound IV with trifluoroacetic anhydride and acetic acid at room temperature, and treating with potassium carbonate and methanol to obtain a chiral triol compound III; the structural formulas of the compounds Ia, III and IV are shown as follows:
Figure DEST_PATH_IMAGE003
。
7. the method of claim 6, wherein the volume ratio of acetonitrile/water in the acetonitrile/water mixed solvent is 1: 1.
8. The method of claim 7, wherein the chiral triol compound III is further reacted with lithium aluminum hydride in an ether solution at a reaction temperature of 0 ℃.
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