Method for directly constructing tetra-substituted allenic acid compound with high optical activity

An optically active, allenoic acid technology, applied in the preparation of organic compounds, organic chemistry methods, chemical instruments and methods, etc., can solve the problems of narrow substrate range, poor atomic economics, and low reaction yields

Active Publication Date: 2020-06-19
FUDAN UNIV
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  • Application Information

AI Technical Summary

Problems solved by technology

Usually, these methods have major limitations, such as low reaction yield, narrow substrate range, poor functional group tolerance, poor atom economics, etc.

Method used

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  • Method for directly constructing tetra-substituted allenic acid compound with high optical activity
  • Method for directly constructing tetra-substituted allenic acid compound with high optical activity
  • Method for directly constructing tetra-substituted allenic acid compound with high optical activity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] Wherein, mol means mole, toluene means toluene, COballoon means carbon monoxide balloon, ee means enantiomeric excess percentage.

[0049] Add PdCl sequentially to a dry Schlenk reaction tube 2 (0.0036g, 0.02mmol), chiral bisphosphine ligand (R)-L4c (0.057g, 0.048mmol), monophosphine ligand PPh 3 (0.0527g, 0.2mmol), and (PhO) 2 PO 2H (0.0501 g, 0.2 mmol). After the reaction tube was plugged with a rubber stopper, the vacuum pump was connected, and the argon gas was replaced three times under an argon atmosphere. ), water (360 μL, d=1.0 g / mL, 0.36 g, 20 mmol), toluene (2 mL). After turning off the argon gas, place the reaction tube in a liquid nitrogen bath to freeze for 3 minutes, insert a carbon monoxide balloon (about 1 liter), and replace the carbon monoxide three times in a carbon monoxide atmosphere, then remove the liquid nitrogen bath, and wait for the reaction system to return to room temperature and melt into a liquid , place the reaction tube ...

Embodiment 2

[0051]

[0052] Operation is with embodiment 1. PdCl 2 (0.0036g, 0.02mmol), (R)-L4c (0.0564g, 0.048mmol), PPh 3 (0.0523g, 0.2mmol), (PhO) 2 PO 2 H (0.05g, 0.2mmol), (±)-1b (0.2157g, 1mmol), water (360μL, d=1.0g / mL, 0.36g, 20mmol), toluene (5mL), at 0°C, reaction 18 Hour. Flash column chromatography (eluent: petroleum ether (60-90°C) / diethyl ether / dichloromethane=30 / 1 / 1, petroleum ether (60-90°C) / ethyl acetate=8 / 1) obtained chiral Allenoic acid product (S)-2b (0.1029g, 42%): oil; 96%ee (HPLC conditions: AS-H column, hexane / i-PrOH=98 / 2, 1.0mL / min, λ=214nm ,t R (major)=6.5min,t R (minor)=9.3min); [α] D 26 =+106.7 (c=1.50, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ):δ=7.29-7.22(m,1H,Ar-H),7.22-7.12(m,3H,Ar-H),2.40(s,3H,CH 3 ),2.35-2.05(m,5H,CH 2 and CH 3 ),1.55-1.40(m,2H,CH 2 ),1.40-1.27(m,2H,CH 2 ),0.90(t,J=7.2Hz,3H,CH 3 ); 13 C NMR (100MHz, CDCl 3 ):δ=210.2,173.8,136.2,136.0,130.6,127.9,127.6,125.9,104.5,98.9,30.1,28.1,22.2,20.4,19.9,13.8; IR(neat):v=3200-2410(br)...

Embodiment 3

[0054]

[0055] Operation is with embodiment 1. PdCl 2 (0.0036g, 0.02mmol), (R)-L4c (0.0571g, 0.048mmol), PPh 3 (0.0526g, 0.2mmol), (PhO) 2 PO 2 H (0.0499g, 0.2mmol), (±)-1c (0.2165g, 1mmol), water (360μL, d=1.0g / mL, 0.36g, 20mmol), toluene (5mL), at -5 ℃, the reaction 18 hours. Flash column chromatography (eluent: petroleum ether (60-90°C) / diethyl ether / dichloromethane=30 / 1 / 1, petroleum ether (60-90°C) / ethyl acetate=8 / 1) obtained chiral Allenoic acid product (S)-2c (0.0687g, 28%): solid; 94%ee (HPLC conditions: AS-H column, hexane / i-PrOH=98 / 2, 1.0mL / min, λ=214nm, t R (major)=6.5min,t R (minor)=7.8min); [α] D 26 =+16.5 (c=1.00, CHCl 3 ). Melting point: 96.8-98.5°C (measured directly after the solvent evaporates to dryness). 1 H NMR (400MHz, CDCl 3 ):δ=7.27-7.20(m,1H,Ar-H),7.20-7.15(m,2H,Ar-H),7.07(d,J=7.2Hz,1H,Ar-H),2.40-2.28( m,5H,CH 2 and CH 3 ),2.18(s,3H,CH 3 ),1.51-1.41(m,2H,CH 2 ),1.41-1.28(m,2H,CH 2 ), 0.88(t, J=7.4Hz, 3H, CH 3 ); 13 C NMR (100MHz...

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Abstract

The invention discloses a method for directly constructing a tetra-substituted allenic acid compound with high optical activity, wherein tertiary propargyl alcohol, carbon monoxide and water react inan organic solvent under the actions of a palladium catalyst, a chiral diphosphine ligand, a monophosphine ligand and organic phosphoric acid to directly construct an axially chiral allenic acid compound with high optical activity in one step. The method has characteristics of simple operation, easily available raw materials and reagents, mild reaction conditions, wide substrate universality, goodfunctional group compatibility and high reaction enantioselectivity (90%-99% ee). According to the invention, the allenic acid compound with high optical activity can be used as an important intermediate for constructing compounds such as gamma-butyrolactone compounds containing tetra-substituted chiral quaternary carbon centers, tetra-substituted allenol and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for directly constructing highly optically active four-substituted allenoic acid compounds. [0002] technical background [0003] Allene compounds with axial chirality widely exist in natural products and drug molecules, and are a very important class of compounds (Ref: (a) Hoffmann- A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51, 2818 .). How to construct a four-substituted chiral quaternary carbon center has been widely studied in the past ten years and has achieved fruitful results. However, compared with the construction of compounds containing a four-substituted chiral quaternary carbon center, the four-substituted There are still great challenges in the synthesis of permanent allene compounds, and the reported methods are still very limited. The main reason is tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/14C07C57/42C07C57/60C07C253/30C07C255/41C07D333/24C07D307/58
CPCC07C51/14C07C253/30C07D333/24C07D307/58C07B2200/07C07C2602/10C07C57/42C07C57/60C07C255/41C07C255/36C07B53/00C07C51/12
Inventor 麻生明郑伟锋钱辉
Owner FUDAN UNIV
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