Kinetic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid

A technology of aryl allyl tertiary alcohol and aryl allyl tertiary alcohol, which is applied in the field of dynamic resolution of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid, can solve the problem of catalytic asymmetric synthesis, which is less reported, Loss of stereochemical integrity, difficulty in splitting reactions, etc., achieve good industrial application prospects, avoid the use of transition metals, and have a wide range of applications

Active Publication Date: 2022-01-28
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0008] Based on the above literature research, it is found that the construction of chiral tertiary alcohols is still dominated by the asymmetric addition reaction of organoboron to aldehydes and ketones catalyzed by transition metals. However, the intervention of transition metals greatly limits the scope of application of the reaction. Currently, there are great difficulties and challenges in obtaining chiral tertiary alcohols through kinetic resolution catalyzed by small organic molecules: (1) Most studies focus on For secondary alcohols, and for tertiary alcohols, chiral kinetic resolution reactions are difficult to occur due to the three relatively hindered groups
(2) Nucleophilic substitution reactions of tertiary alcohols usually proceed as unimolecular nucleophilic substitution reactions, and highly substituted carbon centers tend to form more stable carbocations or ion-pair intermediates, resulting in partial or complete loss of stereochemical integrity
Moreover, the construction of chiral dihydroisobenzofuran skeletons is still dominated by chiral resolution, and there are few reports on its catalytic asymmetric synthesis.

Method used

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  • Kinetic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid
  • Kinetic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid
  • Kinetic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: the synthesis of product III-1 and IV-1

[0062]

[0063] Experimental procedure: in N 2 Under protection, the reaction system was sealed for anhydrous and oxygen-free treatment, and the temperature was adjusted to 0°C. In a 10mL reaction flask, I-1 (0.1mmol, 1.0equiv) and chiral binaphthol catalyst (R)- L1 (0.015mmol, 0.15equiv), additives Molecular sieves (160 mg) and a solvent of chloroform (0.5 mL) were used for the reaction. The reaction was monitored by HPLC analysis until the reaction was completed, the reaction system was filtered through diatomaceous earth and concentrated, and the concentrated crude product was separated and purified by column chromatography, and the eluent was petroleum / ethyl acetate=5 / 1 (v / v) , the target compound III-1 was obtained as a white foamy solid with a yield of 47% and an ee value of 92%. [α] D 20 =–17.28 (c 1.0, CHCl 3 ) 1 H NMR (600MHz, DMSO-d 6 )δ7.56(d, J=7.6Hz, 1H), 7.45(dd, J=7.8, 1.8Hz, 3H), 7.35–7....

Embodiment 2

[0073] Embodiment 2: the synthesis of product III-2 and IV-2

[0074] The compound shown in Formula I-1 in Example 1 is replaced by the compound shown in Formula I-2 in equivalent molar amounts, and all the other operating steps are the same as in Example 1 to finally obtain the corresponding compounds III-2 and IV-2 .

[0075]

[0076] The product III-2 was obtained as a white foamy solid with a yield of 42% and an ee value of 93%. [α] D 20 =–5.29 (c1.0, CHCl 3 ). 1 H NMR (400MHz, DMSO-d 6 )δ7.55(d, J=7.0Hz, 1H), 7.42(dd, J=12.4, 4.4Hz, 3H), 7.36–7.27(m, 3H), 7.27–7.15(m, 4H), 6.91(d ,J=16.0Hz,1H),6.87(d,J=8.8Hz,2H),6.39(d,J=16.0Hz,1H),6.20(s,1H),5.05(t,J=5.4Hz,1H ),4.46(dd,J=14.4,5.4Hz,1H),4.16(dd,J=14.4,5.2Hz,1H),3.73(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ157.8, 143.6, 141.1, 138.3, 137.2, 136.7, 128.6, 128.0, 127.4, 127.4, 127.2, 127.1, 126.6, 126.4, 125.9, 113.2, 79.2, 78.4, 61.0, 55.0, 39.3, 3.95, 39.9 ,39.1,38.9.HRMS(ESI)m / z calcd.for C 23 h 22 NaO 3 [M+Na...

Embodiment 3

[0078] Embodiment 3: the synthesis of product III-3 and IV-3

[0079] The compound shown in Formula I-1 in Example 1 is replaced by the compound shown in Formula I-3 in equivalent molar amounts, and all the other operating steps are the same as in Example 1 to finally obtain the corresponding compounds III-3 and IV-3 .

[0080]

[0081] The product III-3 was obtained as a white foamy solid with a yield of 30% and an ee value of 70%. [α] D 20 =–7.19 (c1.0, CHCl 3 ). 1 H NMR (400MHz, DMSO-d 6 )δ7.55(d, J=7.4Hz, 1H), 7.44(dd, J=7.6, 1.2Hz, 1H), 7.39–7.28(m, 7H), 7.29–7.18(m, 2H), 7.13(d ,J=8.0Hz,2H),6.86(d,J=16.0Hz,1H),6.38(d,J=16.0Hz,1H),6.28(s,1H),5.06(t,J=5.4Hz,1H ),4.46(dd,J=14.4,5.4Hz,1H),4.11(dd,J=14.4,5.2Hz,1H),2.28(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ146.5,143.6,141.1,136.7,136.0,133.8,129.2,128.0,127.8,127.3,127.2,126.7,126.5,126.4,126.2,125.9,78.7,60.9,20.8.HRMS(ESI)m / z C calcd 23 h 22 NaO 2 [M+Na] + :353.1620; found 353.1512.

[0082] The product IV-3 ...

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Abstract

The invention discloses a kinetic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid. In the presence of a solvent and an additive, an allyl tertiary alcohol compound as shown in a formula I is catalyzed by a chiral phosphoric acid catalyst as shown in a formula II, an aryl allyl tertiary alcohol compound, shown as a formula III, and a dihydroisobenzofuran compound, shown as a formula IV, with chiral centers respectively are generated bykinetic resolution, and the reaction equation is also shown. According to the invention,chiral phosphoric acid is used as the catalyst, an aryl allyl tertiary alcohol compound with high functional group compatibility and stable property is used as a catalytic substrate, and under the action of an additive, various chiral aryl allyl tertiary alcohol and dihydroisobenzofuran compounds are prepared. The preparation method disclosed by the invention is high in enantioselectivity and wide in substrate application range, and the obtained chiral aryl allyl tertiary alcohol with high optical activity and the dihydroisobenzofuran containing the tetra-substituted carbon chiral center have extremely high scientific research value and wide application prospect.

Description

technical field [0001] The invention relates to a chiral phosphoric acid-catalyzed kinetic resolution method for aryl allyl tertiary alcohols. Background technique [0002] Currently, the acquisition of chiral diaryl tertiary alcohol structures largely relies on transition metal-catalyzed asymmetric addition reactions [Collados J.F.; Solà R., Harutyunyan S.R.; Maciá B.ACS Catal.2016,6(3 ):1952–1970.]. Asymmetric dihydroxylation of alkenes [Heravi M.M.; Zadsirjan V.; Esfandyari M.; Lashaki T.B. Tetrahedron Asymmetry 2017, 28(8):987–1043.], Oxidation of chiral boronic esters [Scott H.K.; Aggarwal V.K. Chem Eur J 2011:9–15.], and ring opening of epoxides [Jacobsen E.N.; Kakiuchi F.; Konsler R.G.; Larrow J.F.; Tokunaga M. Tetrahedron Lett.1997,38(5):773–776 .], and the method of constructing chiral tertiary alcohol structure through transition metal-catalyzed asymmetric addition reaction of organoboron to carbonyl compounds has the characteristics of simple and efficient, conv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/87C07D409/04C07D409/06C07C33/30C07C33/28C07C33/48C07C29/74B01J31/02C07B57/00
CPCC07D307/87C07D409/04C07D409/06C07C29/74B01J31/0258C07B57/00C07B2200/07C07C2603/24C07C2603/26C07C33/30C07C33/28C07C33/483
Inventor 毛斌杜志乾孟鑫高庆俞传明
Owner ZHEJIANG UNIV OF TECH
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