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Chiral phosphoric acid catalyzed allyl tertiary alcohol kinetic resolution method

An allyl tertiary alcohol, kinetic resolution technology, applied in organic chemistry methods, chemical instruments and methods, organic chemistry and other directions, can solve the synthesis strategy difficult to promote tertiary alcohols, enantiomeric surface differentiation reduced, kinetics There are few problems such as splitting research, to achieve the effect of wide substrate application, high enantioselectivity and conversion rate, good application prospect and social value

Active Publication Date: 2021-04-23
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0004] In the past few decades, the synthesis methods of chiral tertiary alcohols, especially chiral allyl tertiary alcohols, are still very limited, and the strategy of obtaining chiral allyl tertiary alcohols through kinetic resolution is challenging. : (1) Compared with racemic secondary alcohols, chiral secondary alcohols are obtained by kinetic resolution. Since there are three different substituent groups on the carbon of tertiary alcohols, the steric hindrance is larger and the reactivity is lower. The corresponding dynamic There are still few studies on chemical resolution, and only a few cases of chiral phosphoric acid and metal combined catalysis have been reported, and there are no reported cases of chiral phosphoric acid catalysis alone; The method of tertiary alcohol is mainly based on metal catalysis or combined catalysis of metal and chiral ligand, the reaction conditions are relatively harsh, the substrate applicability is narrow, and it is also contrary to green chemistry; The reduced enantiomeric surface differentiation due to the smaller steric and electronic differences of the central non-hydrogen substituents, as well as the unfavorable steric hindrance and strong propensity for carbocation intermediates, are themselves easily mediated by acid-catalyzed or base-catalyzed racemization
Therefore, the synthesis strategy applicable to optically active secondary alcohols is not easy to be extended to tertiary alcohols. It is the present invention to develop a kind of green, simple reaction conditions and a wide range of substrates suitable for catalytic systems. High enantioselective synthesis of chiral tertiary alcohols Focus on solving technical problems

Method used

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  • Chiral phosphoric acid catalyzed allyl tertiary alcohol kinetic resolution method
  • Chiral phosphoric acid catalyzed allyl tertiary alcohol kinetic resolution method
  • Chiral phosphoric acid catalyzed allyl tertiary alcohol kinetic resolution method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of product III-1 and IV-1

[0029]

[0030] Experimental procedure: in N 2 Under protection, the reaction system was sealed for anhydrous and oxygen-free treatment, and the temperature was adjusted to 5°C. In a 25mL reaction flask, compound I-1 (0.05mmol, 1.0equiv) and chiral binaphthol catalyst (R) were sequentially added -L2 (0.0075mmol, 0.15equiv), additive (additive is: Molecular sieves (75mg)), and the solvent was 1,2-dichloroethane (5.0mL), and the reaction was carried out. The reaction was monitored by HPLC analysis until the reaction was completed, the reaction system was filtered through diatomaceous earth and concentrated, and the obtained concentrate was separated and purified to obtain target compound III-1 and target compound IV-1 respectively.

[0031] The resulting concentrated crude product was separated and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (v / v)) to obtain the target compou...

Embodiment 2

[0033] Embodiment 2: the synthesis of product III-2 and IV-2

[0034] The experimental method of embodiment 2 repeats embodiment 1, and difference is only " the compound shown in formula I-1 in embodiment 1 is replaced with the compound shown in formula I-2 of equivalent molar amount ", all the other operations The steps are the same as in Example 1 to finally obtain the corresponding compounds III-2 and IV-2.

[0035]

[0036] The product III-2 was obtained as a white solid with a yield of 42% and an ee value of 96%. [α] D 20 =–5.0 (c 1.0, CHCl 3 ). 1 H NMR (400MHz, DMSO–d 6 )δ7.53–7.47(m,2H),7.45–7.39(m,2H),7.38–7.27(m,4H),7.24–7.16(m,2H),6.63(d,J=16.0Hz,1H) ,6.58(d,J=16.1Hz,1H),5.32(s,1H),4.38(t,J=5.2Hz,1H),3.36–3.20(m,2H),1.98–1.77(m,2H), 1.98–1.80(m,1H),1.34–1.20(m,1H). 13 CNMR (100MHz, DMSO–d 6 )δ161.7(d, J=243.6Hz), 147.2, 137.5, 133.5(d, J=3.0Hz), 128.1(d, J=7.9Hz), 127.8, 126.1, 125.4, 124.7, 115.4(d, J =21.5Hz), 75.4, 61.2, 27.2. 19 F NMR (376MHz, DMSO–...

Embodiment 3

[0038] Embodiment 3: the synthesis of product III-3 and IV-3

[0039] The experimental method of embodiment 3 repeats embodiment 1, and difference is only " the compound shown in formula I-1 in embodiment 1 is replaced with the compound shown in formula I-3 of equivalent molar amount ", all the other operations The steps are the same as in Example 1 to finally obtain the corresponding compounds III-3 and IV-3.

[0040]

[0041] The product III-3 was obtained as a white solid with a yield of 42% and an ee value of 93%. [α] D 20 =–7.0 (c 1.0, CHCl 3 ). 1 H NMR (400MHz, Benzene-d 6 )δ7.56(dd,J=8.4,1.3Hz,2H),7.32–7.18(m,4H),7.16–7.00(m,1H),6.84–6.67(m,3H),6.37(d,J= 16.0Hz,1H),3.42–3.32(m,3H),3.28(s,3H),2.10–1.90(m,3H),1.65–1.32(m,2H),1.04–0.82(m,1H). 13 C NMR (100MHz, C 6 D. 6 )δ159.7,147.1,134.8,130.3,128.5,128.3,127.9,126.8,126.1,114.4,76.6,63.0,54.8,40.1,27.2.HRMS(ESI)m / z calcd.for C 19 h 22 NaO 3 [M+Na] + :321.1461; found 321.1460.

[0042] The product IV-3 wa...

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Abstract

The invention discloses a chiral phosphoric acid catalyzed allyl tertiary alcohol kinetic resolution method.In the presence of an organic solvent and an additive, an (E)-alkenyl substituted diol compound shown in a formula I is subjected to a kinetic resolution reaction under the catalysis of a chiral phosphoric acid catalyst shown in a formula II to obtain achiral allyl tertiary alcohol (E)-alkenyl substituted diol derivative as shown in a formula III and an (E)-2-alkenyl substituted tetrahydrofuran compound as shown in a formula IV, and the reaction formula is shown as the specification. The method utilizes the chiral phosphoric acid as the catalyst, the (E)-alkenyl substituted diol compound with good functional group compatibility and stable properties is used as a substrate, and various chiral allyl tertiary alcohol (E)-alkenyl substituted diol derivatives and (E)-2-alkenyl substituted tetrahydrofuran compounds are efficiently prepared under the action of a single additive. According to the preparation method, the substrate application range is wide, the reaction conditions are simple, the obtained two products with high optical activity can be further converted into multiple natural products and important intermediates of medicine, and high application value is achieved.

Description

technical field [0001] The invention relates to a chiral phosphoric acid catalyzed kinetic resolution method for allyl tertiary alcohol. Background technique [0002] Chiral tertiary alcohols contain three different substituent groups and one hydroxyl group on the carbon chiral center. They are important structural units and widely exist in biologically active natural compounds, non-natural compounds and medicines. Natural products and important intermediates of chiral drugs, such as genaconazole, levconazole, posaconazole, etc., which are widely used in clinical antifungal drugs, all contain structural units of chiral tertiary alcohols [Acetti, D.; Brenna, E.; Fuganti, C.; Gatti, F.G.; Serra, S. Tetrahedron: Asymmetry 2009, 20, 2413–2420.]. Especially the asymmetric synthesis of chiral allyl tertiary alcohols is still a very challenging research field. The kinetic resolution of racemic allyl tertiary alcohols is one of the most effective and reliable methods for the synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B57/00C07C29/88C07C33/30C07C41/44C07C43/23C07D307/06C07D307/10C07D307/12C07D309/06C07D333/16C07D409/04C07D409/06B01J31/02
CPCC07B57/00C07C29/88C07D307/12C07D307/10C07D307/06C07D333/16C07D409/06C07D409/04C07C41/44C07D309/06B01J31/0258C07B2200/07C07C33/30C07C43/23
Inventor 毛斌高庆张朝焕孟鑫王建飞李蒙俞传明
Owner ZHEJIANG UNIV OF TECH
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