CN105037366A - Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition - Google Patents

Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition Download PDF

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CN105037366A
CN105037366A CN201510458726.4A CN201510458726A CN105037366A CN 105037366 A CN105037366 A CN 105037366A CN 201510458726 A CN201510458726 A CN 201510458726A CN 105037366 A CN105037366 A CN 105037366A
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chiral
asymmetric
ligand
carbocyclic nucleoside
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郭海明
韩瑞杰
王东超
谢明盛
王海霞
张倩
渠桂荣
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Henan Normal University
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Abstract

The invention discloses a method for synthesizing a chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition. The reaction equation is as shown in the specification. According to the method for synthesizing a chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition, provided by the invention, a specific chiral catalyst is used, so that the chiral product can be obtained at a high yield and a high enantiomer excess value; besides, the reaction has the advantages that the operation is simple, the reaction condition is mild and the catalyst is inexpensive and easily obtainable, and a simple and practical synthetic method is provided for synthesis of chiral pentabasic carbocyclic nucleoside analogues.

Description

The method of a kind of asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues
Technical field
The invention belongs to chemistry and medical art, obtained the method for chirality five-membered Carbocyclic nucleoside analogues in particular to one by asymmetric [3+2] cycloaddition reaction.
Background technology
Nucleoside medicine has very important status in antiviral and antineoplastic chemotherapy medicine, and the drug development speed of this respect is very fast especially in recent ten years.To the structure of modification of natural nucleus glycoside be find new, the important means of antiviral more effectively, going on the market and be in the antiviral of clinical experimental stage at present, the overwhelming majority is nucleoside derivates, and therefore chirality five-membered carbocyclic nucleoside derivatives also becomes the compound of the antiviral potential of most.The problems such as but this type of medicine or ubiquity, and untoward reaction is many, bioavailability is low, easily produce resistance, metabolism is fast.Therefore modification is carried out to each position of nucleoside analog significant with the biological activity optimizing nucleoside medicine.
The base that the synthetic method of five yuan of traditional at present carbocyclic nucleosides mainly concentrates on purine or pyrimidine introduces five yuan of carbocyclic rings of a chirality.But chirality five-membered carbocyclic ring synthesis difficulty, synthesis step is many, causes product total recovery lower.Along with the fast development of studying and producing ucleosides new drug in the world, increasing to the demand of the chirality five-membered carbocyclic nucleoside with potential antiviral activity, therefore how efficiently the research of synthesis of chiral five yuan of carbocyclic nucleosides is extremely urgent, very urgent.
Summary of the invention
In order to solve the deficiencies in the prior art, seek easy, green, the efficient Asymmetrical annular-addition method of one and carry out synthesis of chiral five yuan of carbocyclic ring shape nucleoside analogs, expensive based on this type of compou nd synthesis process Raw of solution, the problem of process complexity, reference value is provided, for the research of novel antiviral and antitumor drug provides raw material to the synthesis of nucleoside medicine and application.
In order to realize object of the present invention, adopt following technical scheme: the method for a kind of asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues, reaction equation is as follows:
wherein: R 1be selected from the one in following groups: Cl, H, methoxyl group, oxyethyl group, piperidines, benzyloxy, dimethylin, phenyl; R 2be selected from the one in following groups: H, NH 2, Cl; R 3be selected from the one in following groups: methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl; R 4be selected from the one in following groups: methyl, ethyl, sec.-propyl, the tertiary butyl; The key that in formula, dotted line represents is singly-bound or double bond, and the ring at dotted line place is aromatic ring.Two X can be identical, also can be different.
Described method concrete steps are: with CH 2cl 2make solvent, to add Pd under nitrogen protection 2(dba) 3and ligand L, stirred at ambient temperature 20-30min, then adds two kinds of reactants successively, less than 25 degrees Celsius reactions;
Wherein: the structural formula of ligand L is:
Described method concrete steps are: under nitrogen protection with CH 2cl 2make solvent, by the Pd of 5mol% 2(dba) 3(0.0025mmol) and the ligand L (0.005mmol) of 10mol%, stirred at ambient temperature 20-30min, then acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol of α-base replacement is added successively, 1.5eq), 25 degrees Celsius of reactions; Wherein: the structural formula of ligand L is:
Described chirality five-membered Carbocyclic nucleoside analogues is selected from following 47 particular compound:
The step of the raw material for the synthesis of chirality five-membered carbocyclic nucleoside and analogue thereof of the present invention is as follows:
Wherein: R 1be selected from the one in following groups: Cl, H, methoxyl group, oxyethyl group, piperidines, benzyloxy, dimethylin, phenyl; R 2be selected from the one in following groups: H, NH 2, Cl; R 3be selected from the one in following groups: methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl.Two X can be identical, also can be different.
In a preferred embodiment of the present invention, the chirality five-membered carbocyclic nucleoside described in synthesis and the raw material of analogue thereof are selected from one in following 21 particular compound, are specially
In a preferred embodiment of the present invention, the concrete reaction conditions of the described feed process for the synthesis of chirality five-membered Carbocyclic nucleoside analogues is:
Under room temperature condition, by purine (10.0mmol), PPh 3(1mmol), sodium acetate (5mmol) joins in the toluene of 60mL, is then slowly added by acetic acid (5mmol) ethyl propiolate (10mmol), the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reacting completely.
The present invention, by using specific chiral catalyst and reaction conditions, can obtain chiral product with high yield and high enantiomeric excess.This reaction has several advantages such as simple to operate, reaction conditions is gentle, catalyzer is cheaply easy to get, for synthesis of chiral five yuan of Carbocyclic nucleoside analogues provide the synthetic method of a brief and practical.
Embodiment
Below in conjunction with embodiment, the present invention is elaborated.
Embodiment 1
Asymmetrical annular-addition reaction formula provided by the invention is as follows:
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%, ee1=91%, ee2=90% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.68(s,1H),8.34(s,1H),5.63-5.57(m,1H),5.02(d,J＝17.2Hz,1H),4.93(d,J＝10.4Hz,1H),4.23-4.16(m,2H),3.86(q,J＝7.6Hz,1H),3.80(s,3H),3.72(s,3H),3.60(d,J＝14.8Hz,1H),3.40(d,J＝15.2Hz,1H),2.98(q,J＝7.2Hz,1H),2.46(q,J＝5.6Hz,1H),1.13(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.4,171.2,169.2,152.1,151.5,151.2,144.1,133.4,131.4,119.2,62.9,57.2,53.5,49.7,42.2,37.1,13.8.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255. 1HNMR(400MHz,CDCl 3):δ8.69(s,1H),8.36(s,1H),5.82-5.73(m,1H),5.46(d,J＝17.2Hz,1H),5.37(d,J＝10.4Hz,1H),4.12(q,J＝7.2Hz,2H),4.01(d,J＝14.8Hz,1H),3.83(s,3H),3.81-3.76(m,1H),3.69(s,3H),2.91(d,J＝15.2Hz,1H),2.77(t,J＝13.2Hz,1H),2.56(q,J＝6.8Hz,1H),1.08(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.5,170.7,169.0,152.3,151.7,151.2,142.5,133.2,131.6,120.6,71.7,62.7,57.5,53.5,53.2,50.6,44.1,38.1,13.9.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255.
Embodiment 2
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 80%, ee1=81.4%, ee2=72.5% through column chromatography.
1HNMR(400MHz,CDCl 3):δ7.87(s,1H),5.61-5.52(m,1H),5.17(s,2H),5.05(d,J＝17.2Hz,1H),4.97(d,J＝10.4Hz,1H),4.23-4.15(m,2H),3.77(s,3H),3.72(s,3H),3.52(d,J＝15.2Hz,1H),3.31(d,J＝14.8Hz,1H),2.85(q,J＝7.2Hz,1H),2.57-2.51(m,2H),1.16(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.5,171.5,169.6,158.5,154.0,141.2,133.6,118.9,71.9,62.6,57.4,53.4,53.3,49.3,41.8,37.2,13.8.HRMS:exactmasscalcdforC 19H 22ClN 5O 6Na(M+Na) +requiresm/z474.1151,foundm/z474.1149. 1HNMR(400MHz,CDCl 3):δ8.01(s,1H),5.80-5.71(m,1H),5.42(d,J＝16.8Hz,1H),5.33(d,J＝10.0Hz,1H),5.08(s,2H),4.16-4.07(m,2H),3.95(d,J＝15.2Hz,1H),3.83(s,3H),3.71(s,3H),2.79(d,J＝15.2Hz,1H),2.67(t,J＝13.0Hz,1H),2.59-2.54(m,2H),1.09(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.6,171.0,169.5,158.6,154.2,139.4,133.4,128.5,125.2,120.2,71.2,62.4,57.6,52.5,50.4,44.0,38.0,35.1,14.0.HRMS:exactmasscalcdforC 19H 22ClN 5O 6Na(M+Na) +requiresm/z474.1151,foundm/z474.1150.
Embodiment 3
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 93%, ee1=90.5%, ee2=79.5% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.95(s,1H),8.77(d,J＝7.6Hz,2H),8.35(s,1H),7.58-7.52(m,3H),5.71-5.63(m,1H),5.05(d,J＝17.2Hz,1H),4.95(d,J＝10.4Hz,1H),4.26-4.16(m,2H),3.91-3.86(m,1H),3.80(s,3H),3.70(s,3H),3.65(d,J＝15.2Hz,1H),3.43(d,J＝15.2Hz,1H),2.98(q,J＝6.8Hz,1H),2.54(q,J＝5.2Hz,1H),1.13(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.5,171.4,169.7,154.8,152.0,143.1,133.8,131.0,129.7,128.6,118.8,71.9,70.0,62.7,57.3,53.4,53.4,49.7,42.3,37.2,13.9.HRMS:exactmasscalcdforC 25H 26N 4O 6Na(M+Na) +requiresm/z501.1745,foundm/z501.1745. 1HNMR(400MHz,CDCl 3):δ8.97(s,1H),8.78(d,J＝7.6Hz,2H),8.41(s,1H),7.59-7.53(m,3H),5.86-5.77(m,1H),5.48(d,J＝17.2Hz,1H),5.37(d,J＝10.4Hz,1H),4.16-4.08(m,3H),3.88-3.81(m,4H),3.69(s,3H),2.96(d,J＝15.2Hz,1H),2.82-2.76(m,1H),2.61-2.56(m,1H),1.08(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.7,170.9,169.5,154.9,153.0,152.2,141.5,135.6,133.6,131.0,129.7,128.7,120.3,71.3,62.5,57.6,53.4,53.1,50.6,44.2,38.2,13.9.HRMS:exactmasscalcdforC 25H 27N 4O 6(M+H) +requiresm/z479.1925,foundm/z479.1925.
Embodiment 4
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%, ee1=67.6%, ee2=77% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.47(s,1H),8.10(s,1H),5.63-5.55(m,1H),5.01(d,J＝17.2Hz,1H),4.91(d,J＝10.8Hz,1H),4.23-4.11(m,5H),3.88-3.82(m,1H),3.79(s,3H),3.72(s,3H),3.57(d,J＝14.8Hz,1H),3.37(d,J＝14.8Hz,1H),2.97-2.92(m,1H),2.50(q,J＝5.2Hz,1H),1.11(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.5,171.4,169.8,161.1,152.4,140.9,133.7,121.3,118.7,71.9,62.6,57.3,54.2,53.4,49.5,42.2,37.2,13.8.HRMS:exactmasscalcdforC 20H 24N 4O 7Na(M+Na) +requiresm/z455.1537,foundm/z455.1528.
1HNMR(400MHz,CDCl 3):δ8.48(s,1H),8.16(s,1H),5.82-5.75(m,1H),5.43(d,J＝17.2Hz,1H),5.34(d,J＝10.0Hz,1H),4.17(s,3H),4.13-4.07(m,2H),4.00(d,J＝15.2Hz,1H),3.82(s,3H),3.80-3.75(m,1H),3.67(s,3H),2.89(d,J＝15.2Hz,1H),2.75(t,J＝13.0Hz,1H),2.55(q,J＝6.8Hz,1H),1.06(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.6,170.9,169.5,161.0,152.5,151.8,139.3,133.4,121.5,120.1,71.3,62.3,57.5,54.2,53.3,53.1,50.3,44.2,38.1,13.9.HRMS:exactmasscalcdforC 20H 24N 4O 7Na(M+Na) +requiresm/z455.1537,foundm/z455.1530.
Embodiment 5
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 77%, ee1=71.2%, ee2=52.8% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.44(s,1H),8.08(s,1H),5.62-5.53(m,1H),5.01(d,J＝17.6Hz,1H),4.90(d,J＝10.8Hz,1H),4.64(q,J＝7.2Hz,2H),4.23-4.13(m,2H),3.88-3.79(m,1H),3.79(s,3H),3.72(s,3H),3.57(d,J＝14.8Hz,1H),3.38(d,J＝15.2Hz,1H),2.94(q,J＝6.8Hz,1H),2.51(q,J＝5.6Hz,1H),1.51(t,J＝7.2Hz,3H),1.12(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.5,171.5,169.8,160.8,151.7,140.7,133.7,121.3,118.7,95.3,71.8,63.1,62.6,57.3,53.4,49.4,42.1,37.2,14.5,13.8.HRMS:exactmasscalcdforC 21H 26N 4O 7Na(M+Na) +requiresm/z469.1694,foundm/z469.1695. 1HNMR(400MHz,CDCl 3):δ8.48(s,1H),8.16(s,1H),5.87-5.78(m,1H),5.45(d,J＝17.2Hz,1H),5.36(d,J＝10.4Hz,1H),4.67(q,J＝7.2Hz,2H),4.13(q,J＝7.2Hz,2H),4.03(d,J＝15.2Hz,1H),3.85(s,3H),3.83-3.78(m,1H),3.70(s,3H),2.91(d,J＝15.2Hz,1H),2.77(t,J＝13.0Hz,1H),2.58(q,J＝6.8Hz,1H),1.53(t,J＝7.2Hz,1H),1.09(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.6,170.9,169.5,160.8,152.6,151.9,139.2,133.5,121.6,120.1,71.4,63.1,62.3,57.6,53.3,53.1,50.3,44.2,38.1,14.5,13.9.HRMS:exactmasscalcdforC 21H 27N 4O 7(M+H) +requiresm/z469.1694,foundm/z469.1693.
Embodiment 6
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 70%, ee1=76.1%, ee2=68.0% through column chromatography.
1HNMR(400MHz,CDCl 3):δ7.65(s,1H),7.50(d,J＝7.6Hz,2H),7.37-7.28(m,1H),5.59-5.50(m,3H),5.06(d,J＝17.6Hz,1H),4.95(d,J＝10.4Hz,1H),4.79(s,2H),4.23-4.16(m,2H),3.78-3.73(m,7H),3.55(d,J＝14.8Hz,1H),2.81(q,J＝6.8Hz,1H),2.61(q,J＝4.8Hz,1H),1.17(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.8,171.6,170.1,161.0,158.6,154.4,138.3,136.4,134.0,128.3,128.3,127.9,118.5,115.4,71.6,68.0,62.4,57.6,53.3,53.2,49.3,41.9,37.4,13.9.HRMS:exactmasscalcdforC 26H 30N 5O 7(M+H) +requiresm/z524.2140,foundm/z524.2147. 1HNMR(400MHz,CDCl 3):δ7.84(s,1H),7.50(d,J＝7.6Hz,1H),7.37-7.30(m,1H),5.83-5.74(m,1H),5.55(s,2H),5.39(d,J＝17.2Hz,1H),5.30(d,J＝10.4Hz,1H),4.79(s,2H),4.14-4.06(m,2H),3.97(d,J＝15.2Hz,1H),3.83(s,3H),3.78-3.72(m,1H),3.68(s,3H),2.76(d,J＝15.2Hz,1H),2.66(t,J＝13.0Hz,1H),2.58-2.53(m,1H),1.08(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.7,171.1,170.0,161.0,158.8,154.7,136.4,133.7,128.4,128.2,127.9,119.7,100.0,70.9,68.0,62.1,57.6,53.3,53.1,50.2,44.2,37.9,14.0.HRMS:exactmasscalcdforC 26H 30N 5O 7(M+H) +requiresm/z524.2140,foundm/z524.2146.
Embodiment 7
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%, ee1=77.1%, ee2=55.9% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.23(s,1H),7.92(s,1H),5.67-5.58(m,1H),5.04(d,J＝17.2Hz,1H),4.93(d,J＝10.4Hz,1H),4.20-4.10(m,6H),3.83-3.79(m,1H),3.77(s,3H),3.69(s,3H),3.50(d,J＝15.2Hz,1H),3.13(d,J＝14.8Hz,1H),2.92(q,J＝6.8Hz,1H),2.51(q,J＝5.6Hz,1H),1.70(s,6H),1.12(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.5,170.1,153.8,152.0,151.2,136.5,134.0,119.5,118.2,71.3,62.4,57.2,53.3,53.3,49.3,42.3,37.2,26.0,24.8,13.8.HRMS:exactmasscalcdforC 24H 32N 5O 6(M+H) +requiresm/z486.2347,foundm/z486.2352. 1HNMR(400MHz,CDCl 3):δ8.26(s,1H),7.99(s,1H),5.83-5.74(m,1H),5.40(d,J＝17.2Hz,1H),5.30(d,J＝10.4Hz,1H),4.22-4.08(m,6H),4.00(d,J＝15.2Hz,1H),3.82(s,3H),3.78-3.71(m,1H),3.68(s,3H),2.83(d,J＝15.2Hz,1H),2.73(t,J＝13.0Hz,1H),2.51(q,J＝7.2Hz,1H),1.71-1.69(m,6H),1.08(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.8,171.1,169.8,153.8,152.2,151.4,135.0,133.8,119.7,70.8,62.2,57.5,53.3,53.1,50.1,44.2,38.0,26.1,24.8,14.0.HRMS:exactmasscalcdforC 24H 32N 5O 6(M+H) +requiresm/z486.2347,foundm/z486.2354.
Embodiment 8
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 94%, ee1=68.5%, ee2=68.4% through column chromatography.
1HNMR(400MHz,CDCl 3):δ7.91-7.86(m,4H 5aa+2H 5aa'),7.65-7.61(m,2H 5aa+1H 5aa'),7.50-7.44(m,4H 5aa+2H 5aa+2H 5aa'),7.36(s,1H 5aa'),5.74-5.63(m,2H 5aa+1H 5aa'),5.41-5.33(m,4H 5aa),5.15-5.07(m,2H 5aa'),4.19-4.07(m,4H 5aa+2H 5aa'),3.81-3.74(m,12H 5aa+6H 5aa'+2H 5aa+1H 5aa'),3.47-3.41(m,2H 5aa),3.18-3.08(m,2H 5aa),3.00(d,J＝14.0Hz,1H 5aa'),2.69-2.59(m,2H 5aa+1H 5aa'+1H 5aa'),2.41-2.35(m,2H 5aa+1H 5aa'),1.99-1.97(m,6H 5aa+3H 5aa'),1.23-1.17(m,6H 5aa+3H 5aa'). 13CNMR(100MHz,CDCl 3):δ173.2,172.2,170.9,170.8,170.0,169.3,168.4,162.4,150.5,149.8,137.0,135.9,135.0,134.9,133.4,131.4,130.5,129.1,128.9,120.0,118.4,109.8,73.6,73.1,62.5,62.4,56.7,56.4,53.6,53.4,53.3,52.9,48.3,48.2,44.3,40.8,37.9,37.8,14.0,13.9,12.9,12.8.HRMS:exactmasscalcdforC 26H 28N 2O 9Na(M+Na) +requiresm/z535.1687,foundm/z535.1687.
Embodiment 9
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 96.5%, ee1=76.0%, ee2=85.9% through column chromatography.
1HNMR(400MHz,CDCl 3):δ7.92-7.87(m,3H 5ba+2H 5ba'),7.66-7.61(m,3H 5ba+1H 5ba'),7.54(d,J＝8.4Hz,1H 5ba'),7.50-7.44(m,3H 5ba+2H 5ba'),5.82-5.77(m,1.5H 5ba+1H 5ba'),5.75-5.59(m,1.5H 5ba+1H 5ba'),5.39-5.32(m,3H 5ba),5.18-5.08(m,2H 5ba'),4.20-4.07(m,3H 5ba+2H 5ba'),3.78-3.74(m,9H 5ba+6H 5ba'+1.5H 5ba+1H 5ba'),3.45-3.38(m,1.5H 5ba),3.18-3.08(m,2H 5ba'),2.99(d,J＝14.0Hz,1H 5ba'),2.69-2.61(m,3H 5ba),2.41-2.36(m,1.5H 5ba+1H 5ba'),1.24-1.17(m,4.5H 5ba+3H 5ba'). 13CNMR(100MHz,CDCl 3):δ173.0,172.0,170.9,170.7,169.7,169.1,168.1,168.0,161.7,161.6,150.5,149.8,141.1,140.0,135.1,134.6,133.0,131.2,130.5,130.4,129.1,129.0,120.2,118.7,101.4,101.3,73.8,73.3,62.5,62.5,56.7,56.4,53.6,53.4,53.3,52.9,48.3,48.2,44.2,40.8,37.8,13.9,13.8.HRMS:exactmasscalcdforC 25H 26N 2O 9Na(M+Na) +requiresm/z521.1531,foundm/z521.1535.
Embodiment 10
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add ethyl propenoate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 89%, ee1=89.5%, ee2=88.5% through column chromatography.
1HNMR(400MHz,CDCl3):δ8.69(s,1H),8.39(s,1H),5.68-5.59(m,1H),5.02(d,J＝17.6Hz,1H),4.93(d,J＝10.8Hz,1H),4.29-4.09(m,6H),3.85(q,J＝8.0Hz,1H),3.57(d,J＝15.2Hz,1H),3.37(d,J＝14.8Hz,1H),2.96(q,J＝7.2Hz,1H),2.45(q,J＝5.2Hz,1H),1.28(t,J＝7.2Hz,3H),1.20(t,J＝7.2Hz,3H),1.13(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl3):δ172.1,170.2,169.0,152.3,151.7,151.2,142.6,133.4,120.4,71.9,62.6,62.3,62.0,57.8,50.7,43.9,38.1,14.1,13.9,13.9.HRMS:exactmasscalcdforC21H25ClN4O6Na(M+Na)+requiresm/z487.1355,foundm/z487.1362. 1HNMR(400MHz,CDCl3):δ8.70(s,1H),8.37(s,1H),5.83-5.75(m,1H),5.46(d,J＝17.2Hz,1H),5.37(d,J＝10.0Hz,1H),4.36-4.23(m,2H),4.15-4.10(m,4H),3.96(d,J＝15.2Hz,1H),3.83-3.76(m,1H),2.95(d,J＝14.8Hz,1H),2.79-2.73(m,H),2.55(q,J＝6.8Hz,1H),1.31(t,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H),1.09(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl3):δ171.0,170.8,169.2,152.2,151.5,144.1,133.5,131.4,119.0,62.8,62.4,62.4,57.3,49.7,42.3,36.9,36.9,14.0,13.9,13.8.HRMS:exactmasscalcdforC21H25ClN4O6Na(M+Na)+requiresm/z487.1355,foundm/z487.1359.
Embodiment 11
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add ethyl propenoate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 89%, ee1=91.4%, ee2=74% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.68(s,1H),8.39(s,1H),5.70-5.61(m,1H),5.11-4.93(m,4H),4.23-4.15(m,2H),3.83(q,J＝8.0Hz,1H),3.55(d,J＝15.2Hz,1H),3.32(d,J＝15.2Hz,1H),2.93(q,J＝7.2Hz,1H),2.42(q,J＝5.2Hz,1H),1.27-1.11(m,15H). 13CNMR(100MHz,CDCl 3):δ170.5,170.3,169.2,156.2,151.5,144.1,133.5,131.4,118.9,83.7,72.4,70.1,70.0,62.8,57.4,49.7,42.4,36.8,29.7,21.5,21.5,21.4,21.3,13.8.HRMS:exactmasscalcdforC 23H 30ClN 4O 6(M+H) +re quiresm/z493.1848,foundm/z493.1857. 1HNMR(400MHz,CDCl 3):δ8.70(s,1H),8.36(s,1H),5.84-5.75(m,1H),5.44(d,J＝16.8Hz,1H),5.35(d,J＝10.4Hz,1H),5.16-5.10(m,1H),4.96-4.90(m,1H),4.12(q,J＝6.8Hz,2H),3.88(d,J＝15.2Hz,1H),3.82-3.75(m,1H),2.96(d,J＝15.2Hz,1H),2.72(t,J＝12.8Hz,1H),2.53(q,J＝6.8Hz,1H),1.31-1.27(m,6H),1.19(d,J＝6.4Hz,3H),1.11-1.07(m,6H). 13CNMR(100MHz,CDCl 3):δ171.6,169.6,169.0,151.7,151.2,142.7,133.5,131.7,120.3,72.1,70.0,69.5,62.6,57.9,50.7,43.7,38.1,21.6,21.5,21.4,21.3,13.9.HRMS:exactmasscalcdforC 23H 30ClN 4O 6(M+H) +requiresm/z493.1848,foundm/ z493.1855.
Embodiment 12
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add ethyl propenoate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 98%, ee1=89.8%, ee2=44.6% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.68(s,1H),8.40(s,1H),5.71-5.63(m,1H),5.01(d,J＝17.2Hz,1H),4.92(d,J＝10.8Hz,1H),4.24-4.15(m,2H),3.83-3.78(m,1H),3.46(d,J＝15.2Hz,1H),3.23(d,J＝15.2Hz,1H),2.84(q,J＝7.2Hz,1H),2.37(q,J＝4.4Hz,1H),1.47(s,9H),1.37(s,9H),1.12( q,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ170.1,169.9,169.2,151.4,144.1,133.7,131.4,118.7,82.6,82.4,72.4,62.7,58.4,49.6,42.5,36.5,27.8,27.6,13.8.HRMS:exactmasscalcdforC 25H 33ClN 4O 6Na(M+Na) +re quiresm/z543.1981,foundm/z543.1979. 1HNMR(400MHz,CDCl3):δ8.70(s,1H),8.35(s,1H),5.85-5.76(m,1H),5.42(d,J＝17.2Hz,1H),5.33(d,J＝10.4Hz,1H),4.12(q,J＝6.8Hz,2H),3.81-3.71(m,2H),2.95(d,J＝15.2Hz,1H),2.66(t,J＝12.6Hz,1H),2.49( q,J＝7.2Hz,1H),1.51(s,9H),1.34(s,9H),1.10(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl3):δ171.3,169.2,169.1,152.3,151.7,151.1,142.7,133.7,120.1,82.5,81.8,72.2,62.5,59.1,50.6,43.5,38.0,27.9,27.6,14.0.HRMS:exactmasscalcdforC 25H 33ClN 4O 6Na(M+Na) +requiresm/z543.1981,foundm/z543.1987.
Embodiment 13
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add ethyl propenoate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%, ee1=87.5%, ee2=76.6% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.68(s,1H),8.35(s,1H),5.64-5.55(m,1H),5.01(d,J＝17.2Hz,1H),4.92(d,J＝10.4Hz,1H),3.87(q,J＝7.6Hz,1H),3.80(s,3H),3.72(d,J＝6.4Hz,6H),3.57(d,J＝15.2Hz,1H),3.40(d,J＝14.8Hz,1H),2.98(q,J＝7.2Hz,1H),2.46(dd,J＝14.4Hz,8.4Hz,1H). 13CNMR(100MHz,CDCl 3):δ172.5,169.7,152.2,151.8,151.3,142.4,133.1,120.6,71.8,57.6,53.5,53.2,53.2,50.7,44.1,38.1.HRMS:exactmasscalcdforC 18H 19ClN 4O 6Na(M+Na) +requiresm/z445.0885,foundm/z445.0876. 1HNMR(400MHz,CDCl 3):δ8.70(s,1H),8.38(s,1H),5.80-5.71(m,1H),5.47(d,J＝17.2Hz,1H),5.38(d,J＝10.4Hz,1H),4.00(d,J＝15.2Hz,1H),3.84(s,3H),3.81-3.76(m,1H),3.69(s,3H),3.62(s,3H),2.93(d,J＝15.2Hz,1H),2.77(t,J＝13.2Hz,1H),2.57(q,J＝7.2Hz,1H). 13CNMR(100MHz,CDCl 3):δ172.5,170.7,169.7,152.2,151.8,151.3,142.4,133.1,131.7,120.7,71.8,57.6,53.5,53.2,53.2,50.7,44.1,38.1.HRMS:exactmasscalcdforC 18H 19ClN 4O 6Na(M+Na) +requiresm/z445.0885,foundm/z445.0881.
Embodiment 14
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%, ee1=71.3%, ee2=69.1% through column chromatography.
1HNMR(400MHz,CDCl 3):δ8.32(s,1H),5.68-5.59(m,1H),5.04(d,J＝17.6Hz,1H),4.98(d,J＝10.8Hz,1H),4.28-4.16(m,2H),3.85-3.81(m,1H),3.79(s,3H),3.72(s,3H),3.58(d,J＝15.6Hz,1H),3.36(d,J＝15.6Hz,1H),2.97(q,J＝6.8Hz,1H),2.42(q,J＝5.2Hz,1H),1.18(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.2,171.1,168.8,153.4,152.4,151.9,144.8,133.2,130.5,119.3,72.7,63.1,57.2,53.5,53.5,49.8,42.2,37.0,13.8.HRMS:exactmasscalcdforC 19H 20Cl 2N 4O 6Na(M+Na) +requiresm/z493.0652,foundm/z493.0647. 1HNMR(400MHz,CDCl 3):δ8.36(s,1H),5.80-5.71(m,1H),5.47(d,J＝17.2Hz,1H),5.39(d,J＝10.4Hz,1H),4.21-4.11(m,2H),3.95(d,J＝15.2Hz,1H),3.85(s,1H),3.79-3.74(m,1H),3.71(s,3H),2.93(d,J＝15.2Hz,1H),2.81-2.74(m,1H),2.56(t,J＝6.8Hz,1H),1.13(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.5,170.6,168.7,153.6,152.8,152.0,143.2,133.1,130.8,120.8,72.0,62.9,57.7,53.5,53.2,50.9,43.9,38.3,29.7,14.0.HRMS:exactmasscalcdforC 19H 20Cl 2N 4O 6Na(M+Na) +requiresm/z493.0652,foundm/z493.0649.
The synthesis of raw material:
Under room temperature condition, by purine (10.0mmol, 1.54g), PPh 3(1mmol, 26mg), sodium acetate (5mmol, 16mg) join in the toluene of 60mL, then by acetic acid (5mmol, 300uL) ethyl propiolate (10mmol, 1.2mL) slowly add, the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reaction, after 6-chloropurine transforms completely, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extraction, then organic phase is with distilled water wash (3 × 30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, column chromatography for separation obtains product 1a6-chloro-9-ethyl propenoate purine 2.1g, productive rate 82%. 1HNMR(400MHz,CDCl 3):δ8.77(s,1H),8.37(s,1H),6.78(s,1H),6.45(s,1H),4.36(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ161.6,152.5,151.9,151.5,145.0,131.4,130.8,124.8,62.8,14.1.
Under room temperature condition, by 2-Cl-benzoglyoxaline (10.0mmol, 1.52g), PPh 3(1mmol, 26mg), sodium acetate (5mmol, 16mg) join in the toluene of 60mL, then by acetic acid (5mmol, 300uL) ethyl propiolate (10mmol, 1.2mL) slowly add, the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reaction, after 6-chloropurine transforms completely, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extraction, then organic phase is with distilled water wash (3 × 30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, column chromatography for separation obtains product 1.5g, productive rate 60%. 1HNMR(400MHz,CDCl 3):δ7.71-7.68(m,1H),7.31-7.26(m,2H),7.18-7.15(m,1H),6.89(s,1H),6.11(s,1H),4.26(q,J＝6.8Hz,2H),1.25(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ161.7,141.5,140.2,135.8,132.5,128.9,123.8,123.2,119.4,109.7,62.3,13.9.
Get dry 100ml round-bottomed flask one, weigh isatin (10.0mmol, 1.47g), PPh 3(1mmol, 26mg), sodium acetate (5mmol, 16mg) join in the toluene of 60mL, then by acetic acid (5mmol, 300uL) ethyl propiolate (10mmol, 1.2mL) slowly add, the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reaction, after 6-chloropurine transforms completely, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extraction, then organic phase is with distilled water wash (3 × 30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, column chromatography for separation obtains product 2.2g, productive rate 88%. 1HNMR(400MHz,CDCl 3):δ7.67(d,J＝7.2Hz,1H),7.595-7.554(m,1H),7.12(t,J＝7.4Hz,1H),6.77(t,J＝7.2Hz,2H),6.09(s,1H),4.28(q,J＝7.2Hz,2H),1.28(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ162.3,140.9,136.4,130.6,116.7,106.9,62.0,14.1.
Get dry 100ml round-bottomed flask one, weigh phthalic imidine (10.0mmol, 1.47g), PPh 3(1mmol, 26mg), sodium acetate (5mmol, 16mg) join in the toluene of 60mL, then by acetic acid (5mmol, 300uL) ethyl propiolate (10mmol, 1.2mL) slowly add, the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reaction, after 6-chloropurine transforms completely, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extraction, then organic phase is with distilled water wash (3 × 30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, column chromatography for separation obtains product 1.8g, productive rate 73%. 1HNMR(400MHz,CDCl 3):δ7.92(t,J＝2Hz,2H),7.79(t,J＝1.4Hz,2H),6.68(s,1H),5.99(s,1H),4.28(q,J＝6.8Hz,2H),1.30(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ166.4,162.2,134.5,131.8,129.4,127.7,123.9,62.0,14.1.
Get dry 100ml round-bottomed flask one, weigh 4,5-diphenyl-imidazole (10.0mmol, 2.2g), PPh 3(1mmol, 26mg), sodium acetate (5mmol, 16mg) join in the toluene of 60mL, then by acetic acid (5mmol, 300uL) ethyl propiolate (10mmol, 1.2mL) slowly add, the lower 105 degrees Celsius of backflows of condition of nitrogen gas.Thin-layer chromatography detects to reaction, after 6-chloropurine transforms completely, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extraction, then organic phase is with distilled water wash (3 × 30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, column chromatography for separation obtains product 1.94g, productive rate 61%. 1HNMR(400MHz,CDCl 3):δ7.65(d,J＝4.8Hz,2H),7.53(q,J＝1.2Hz,2H),7.35(d,J＝1.6Hz,3H),7.28-7.18(m,5H),6.39(d,J＝4.8Hz,1H),5.86(d,J＝4.8Hz,1H),3.99(q,J＝1.6Hz,2H),1.07(t,J＝6.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ137.5,134.9,134.1,130.3,128.7,128.4,128.1,127.1,126.7,124.4,62.0,13.8.
The preparation of vinylcyclopropane substrate:
Get the dry 100mL flask that magneton is housed, add 50mLTHF, in cryopump, be cooled to subzero 10 degrees Celsius, add NaH (2.2eq, 1.056g) gradually, then dimethyl malonate (10mmol is dripped, 1.143mL), stir 45min, then add 1,4-dibromo dibutene (10mmol, 2.12g) then stirring at room temperature 18h.Go out with shrend, water and ethyl acetate is added in reaction system, separatory, aqueous phase ethyl acetate (3 × 60mL) extracts, then organic phase is with distilled water wash (3 × 30mL), and anhydrous sodium sulfate drying, removes solvent under reduced pressure, column chromatography for separation obtains product 1.2g, productive rate 63%.
The synthesis of product:
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product 3aa is obtained, yield 66%, Dr=2:1, ee through column chromatography 1=91%.
1HNMR(400MHz,CDCl 3):δ8.68(s,1H),8.34(s,1H),5.63-5.57(m,1H),5.02(d,J＝17.2Hz,1H),4.93(d,J＝10.4Hz,1H),4.23-4.16(m,2H),3.86(q,J＝7.6Hz,1H),3.80(s,3H),3.72(s,3H),3.60(d,J＝14.8Hz,1H),3.40(d,J＝15.2Hz,1H),2.98(q,J＝7.2Hz,1H),2.46(q,J＝5.6Hz,1H),1.13(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ171.4,171.2,169.2,152.1,151.5,151.2,144.1,133.4,131.4,119.2,62.9,57.2,53.5,49.7,42.2,37.1,13.8.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255.
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane of α-base replacement successively
(0.075mmol, 1.5eq), 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product 3aa' is obtained, yield 33%, Dr=2:1, ee through column chromatography 1=90%.
1HNMR(400MHz,CDCl 3):δ8.69(s,1H),8.36(s,1H),5.82-5.73(m,1H),5.46(d,J＝17.2Hz,1H),5.37(d,J＝10.4Hz,1H),4.12(q,J＝7.2Hz,2H),4.01(d,J＝14.8Hz,1H),3.83(s,3H),3.81-3.76(m,1H),3.69(s,3H),2.91(d,J＝15.2Hz,1H),2.77(t,J＝13.2Hz,1H),2.56(q,J＝6.8Hz,1H),1.08(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ172.5,170.7,169.0,152.3,151.7,151.2,142.5,133.2,131.6,120.6,71.7,62.7,57.5,53.5,53.2,50.6,44.1,38.1,13.9.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255.
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product 3na is obtained, yield 50%, Dr=2:1, ee through column chromatography 1=92.2%
1HNMR(400MHz,CDCl 3):δ8.26(s,1H),7.92(s,1H),5.67-5.59(m,1H),5.03(d,J＝17.2Hz,1H),4.92(d,J＝10.8Hz,1H),4.22-4.12(m,2H),3.84-3.81(m,1H),3.78(s,3H),3.70(s,3H),3.53-3.50(m,6H),3.32(d,J＝14.8Hz,2H),2.94(q,J＝6.8Hz,1H),2.52(q,J＝5.6Hz,1H),1.11(t,J＝7.0Hz,3H). 13CNMR(100MHz,CDCl 3):δ182.1,171.9,171.8,170.8,158.6,151.6,137.8,134.9,125.3,123.9,118.6,117.9,113.0,73.0,62.6,57.3,53.3,49.0,40.2,37.8,30.9,13.8.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255.
Get a Xiu Langke pipe, with the Pd of 5mol% under nitrogen protection 2(dba) 3with the ligand L of 10mol%, with the CH newly steamed 2cl 2make solvent, stirred at ambient temperature 20min, then add acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol, 1.5eq) of α-base replacement successively, 25 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product 3na is obtained, yield 25%, Dr=2:1, ee through column chromatography 1=71%
1HNMR(400MHz,CDCl 3):δ7.68-7.65(m,1H),7.55-7.51(m,1H),7.15(t,J＝7.6Hz,1H),6.70(d,J＝8.0Hz,1H),6.05-5.96(m,1H),5.21-5.13(m,2H),4.80-4.74(m,1H),4.08(q,J＝7.2Hz,2H),3.79(s,3H),3.68(s,3H),3.45(d,J＝14.8Hz,1H),2.89(d,J＝14.4Hz,1H),2.61(d,J＝8.8Hz,1H),1.09(t,J＝7.2Hz,3H). 13CNMR(100MHz,CDCl 3):δ182.4,171.9,171.1,169.9,157.2,151.7,137.8,135.1,125.4,123.9,117.9,117.3,112.6,73.7,62.3,57.8,53.3,53.1,45.9,42.0,36.3,14.0.HRMS:exactmasscalcdforC 21H 22ClN 5O 4Na(M+Na) +requiresm/z466.1253,foundm/z466.1255.
According to the inventive method, synthesize 47 compounds altogether, specific as follows:
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims (4)

1. a method for asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues, it is characterized in that, reaction equation is as follows:
Wherein: R 1be selected from the one in following base: Cl, H, methoxyl group, oxyethyl group, piperidines, benzyloxy, dimethylin, phenyl; R 2be selected from the one in following groups: H, NH 2, Cl; R 3be selected from the one in following groups: methyl, ethyl, sec.-propyl, the tertiary butyl, benzyl; R 4be selected from the one in following groups: methyl, ethyl, sec.-propyl, the tertiary butyl; The key that in formula, dotted line represents is singly-bound or double bond, and the ring at dotted line place is aromatic ring.
2. the method for one according to claim 1 asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues, is characterized in that, described method tool step is: with CH 2cl 2make solvent, to add Pd under nitrogen protection 2(dba) 3and ligand L, stirred at ambient temperature 20-30min, then adds two kinds of reactants successively, less than 25 degrees Celsius reactions;
Wherein: the structural formula of ligand L is:
3. the method for one according to claim 1 asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues, it is characterized in that, described method concrete steps are: under nitrogen protection with CH 2cl 2make solvent, by the Pd of 5mol% 2(dba) 3(0.0025mmol) and the ligand L (0.005mmol) of 10mol%, stirred at ambient temperature 20-30min, then acrylate (0.05mmol) and the allyl group cyclopropane (0.075mmol of α-base replacement is added successively, 1.5eq), 25 degrees Celsius of reactions; Wherein: the structural formula of ligand L is:
4. the method for one according to claim 1 asymmetric [3+2] cycloaddition synthesis of chiral five yuan of Carbocyclic nucleoside analogues, is characterized in that, described chirality five-membered Carbocyclic nucleoside analogues is selected from following 47 particular compound:
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CN107698590A (en) * 2017-09-29 2018-02-16 河南师范大学 A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral
CN108558882A (en) * 2018-04-12 2018-09-21 河南师范大学 A method of five yuan of carbocyclic purine nucleosides of [3+2] cycloaddition synthesis of chiral based on connection olefin(e) acid ester
CN109485661A (en) * 2018-11-23 2019-03-19 河南师范大学 The method [3+2] cycloaddition synthesis benzothiazole and dislike azole compounds
CN110642843A (en) * 2019-10-18 2020-01-03 河南师范大学 Method for synthesizing chiral heteronucleoside analogue through asymmetric [3+2] cyclization reaction
CN111704571A (en) * 2020-07-20 2020-09-25 南宁师范大学 Preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde

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CN107698590A (en) * 2017-09-29 2018-02-16 河南师范大学 A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral
CN107698590B (en) * 2017-09-29 2020-02-18 河南师范大学 Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction
CN108558882A (en) * 2018-04-12 2018-09-21 河南师范大学 A method of five yuan of carbocyclic purine nucleosides of [3+2] cycloaddition synthesis of chiral based on connection olefin(e) acid ester
CN108558882B (en) * 2018-04-12 2020-08-04 河南师范大学 Method for synthesizing chiral five-membered carbocyclic purine nucleoside through [3+2] cycloaddition based on allenoic acid ester
CN109485661A (en) * 2018-11-23 2019-03-19 河南师范大学 The method [3+2] cycloaddition synthesis benzothiazole and dislike azole compounds
CN110642843A (en) * 2019-10-18 2020-01-03 河南师范大学 Method for synthesizing chiral heteronucleoside analogue through asymmetric [3+2] cyclization reaction
CN111704571A (en) * 2020-07-20 2020-09-25 南宁师范大学 Preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde

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