一种由羟基脯氨酸及其衍生物制备吡咯里西啶骨架的方法与流程

本发明属于化学制药和精细化工制备技术领域，即一锅法制备吡咯里西啶生物碱，尤其是过程不涉及金属催化，最重要的是参与反应的氨基酸不需要预活化或者加入活化试剂，羧酸直接参与的clasien缩合反应，高效的生成一种多官能团取代的吡咯里西啶生物碱结构。本发明为高效制备官能化的吡咯里西啶生物碱衍生物提供了一条可行的技术路线和设计策略，在化工制药和精细化工领域有广阔的应用。

背景技术：

吡咯里西啶类生物碱（pyrrolizidinealkaloids，pas，1）是一类具有吡咯双烷结构的重要生物碱，存在于多种植物中，用于抵御昆虫、植物病菌等侵害,目前发现了近660多种pas，其中大部分对人和动物有毒性[smithl,culvenorc.plantsourcesofhepatotoxicpyrrolizidinealkaloids[j].j.nat.prod.,1981,44(2):129-152]，fda于2012年发布了pas的毒性警示（badbugbook，bbb）[http://www.fda.gov/food/foodborneillnesscontaminants/causesofillnessbadbugbook/ucm070710.htm]。另一方面，吡咯里西啶结构骨架也广泛存在于许多具有重要生理活性的天然产物中，例如吡咯里西啶糖苷化合物2，有研究表明其具有抑制bel-7402人肝癌细胞和hl-60人早幼粒白血病细胞增长的活性[liucm,wanghx,weisl,gaok.pyrrolizidinealkaloidsandbisabolanesesquiterpenesfromtherootsofligulariacymbulifera[j].helv.chim.acta.,2008,91(2):308-316]；化合物3和4具有抑制l1210细胞复制的活性^[4]；化合5是一种极具潜力的flt3-itd激酶抑制剂[lisowskiv,léonces,kraus-berthierl,sopková-deoliveirasantosj,pierréa,atassig,caignardd-h,renardp,raults.design,synthesis,andevaluationofnovelthienopyrrolizinonesasantitubulinagents[j].j.med.chem.,2004,47(6):1448-1464]等。

文献主要采用多步合成法，从吡咯环出发，经多次官能团引入和转化，得到最终化合物。例如化合物6的合成，从异香兰素出发，经过五步反应，完成对其的合成,收率65%[lisowskiv,léonces,kraus-berthierl,sopková-deoliveirasantosj,pierréa,atassig,caignardd-h,renardp,raults.design,synthesis,andevaluationofnovelthienopyrrolizinonesasantitubulinagents[j].j.med.chem.,2004,47(6):1448-1464]。

2008年batra课题组报道了三步合成吡咯里西啶衍生物的方法，丙烯酸甲酯7和吡咯通过baylis-hillman反应得到关键中间体8，然后碱解、多聚磷酸催化的分子内酰基化生成吡咯里西啶环，收率42%-74%[nags,madapas,batras.applicationofprimaryallylaminederivativesofbaylis-hillmanadductstoheterocyclicsynthesis:generationof5-benzyl-4(3h)-pyrimidinonesand2-benzylidene-2,3-dihydropyrrolizin-1-ones1[j].synthesis,2008,2008(1):101-109]。

2013年yang研究组报道了钯-铜催化β-羰基酰胺二烯化合物9的分子内c-h胺化串联c-c偶联反应，在甲苯和dmso混合溶剂中，80℃下反应高效合成多取代氢化吡咯里西啶化合物，收率76%[xingd,yangd.pd(ii)-catalyzedintramolecular1,2-aminoalkylationofconjugated1,3-dienesforthesynthesisofpyrrolizidines[j].org.lett.,2013,15(17):4370-4373]。

同年sansano等也报道了醋酸银催化脯氨酸酯、芳香醛和缺电子烯烃的三组分1,3-偶极环加成反应，合成了一系列多取代的吡咯里西啶衍生物，收率62%-83%[mancebo-aracilj,nájerac,sansanojm.multicomponentsynthesisofunnaturalpyrrolizidinesusing1,3-dipolarcycloadditionofprolineesters[j].chem.commun.,2013,49(95):11218-11220]。

综合相关文献可以看出，吡咯里西啶的合成方法研究十分有限，往往采用多步合成方法或者涉及昂贵的金属作为催化剂，适用范围也极其有限。因此亟需发展一种高效、原料易得、成本低廉、易于工业放大即经济可行的制备吡咯里西啶衍生物的合成方法。

技术实现要素：

本发明在现有技术科研成果的基础上，发现了一种采用成本低廉的4-羟基脯氨酸及其衍生物与酮直接clasien缩合芳构化，一锅法制备多取代多功能化的吡咯里西啶衍生物。该方法无需惰性气体保护和金属催化，重要的是参与反应的氨基酸不需要预活化或加入活化试剂，操作简便，原子利用率高，底物应用范围广阔，适宜工业放大，具有良好的工业化前景，克服现有技术的不足。

所述方法的主要步骤是：在酸催化剂存在条件下，由酮（其结构式如式ⅰ所示）与4-羟基脯氨酸或其衍生物（其结构式如式ⅱ所示）在反应介质中，于0℃~200℃（优选60℃~160℃）反应，制得目标物吡咯里西啶衍生物（其结构如式ⅲ所示）。

其中，式ⅰ的r¹,r²各自为c1~c6的烃基，c5~c10的芳香环或含有o、n、s的芳香杂环；r¹,r²也可以是由c2~c6碳链构成的环烃基。

式ⅱ的r³为h，c5~c10的芳基和含o、s、n的芳杂环，苄基，c1~c6的烃基，酯基，以及含有硝基，氰基，卤素，酯基，氨基，烷氧基取代的上述基团；r⁴为含c1~c6的酰基，c5~c11的芳（杂）酰基，c1~c6的烃基；r⁵为c1~c6的烷氧基，苄氧基或羟基；r⁶为h,叔丁氧羰基,苄基，烯丙基。

由于酮、羟基脯氨酸等原料和催化剂均为大宗商业产品，可以预见该方法能够有效控制成本，适宜工业生产。

具体实施方案

在本发明一个优选的技术方案中，式ⅰ所示化合物和式ⅱ所示化合物的摩尔比为1：0.8~10，更有选的技术方案是：式ⅰ所示化合物和式ⅱ所示化合物的摩尔比为1：1.0~6。

在本发明另一个优选技术方案中，所说的酸性催化剂为有机羧酸、有机磺酸或硫酸，所说的有机羧酸或有机硫酸如（但不限于）：甲酸、乙酸、丙酸、异丁酸、环己基甲酸、苯甲酸、苯乙酸、脯氨酸、4-羟基-l-脯氨酸、三氟乙酸、甲磺酸、苯磺酸或对甲苯磺酸等；

更优选的酸性催化剂是乙酸、丙酸、三氟乙酸或者脯氨酸。

在本发明又一个优选的技术方案中，所述的反应介质是有机溶剂或者离子液体，如（但不限于）：甲苯、二甲苯、乙酸、1，4-二氧六环、n,n-二甲基甲酰胺（dmf）、n,n-二甲基乙酰胺、二甲亚砜（dmso）、环丁砜、溴化1-丁基-3-甲基咪唑盐、1-丁基-3-甲基咪唑四氟硼酸盐或1-丁基-3-甲基咪唑六氟磷酸盐等；

本发明推荐使用的溶剂是：甲苯、n，n-二甲基甲酰胺（dmf）和二甲基亚砜（dmso）；

所述有机溶剂的建议用量为10ml~20ml/g酮，即每克酮（式ⅰ所示化合物）需用10ml~20ml所述的有机溶剂。

在本发明的优点：

1、该反应操作简便，只需一锅反应就可以高效的制备吡咯里西啶衍生物，易于放大工业生产。

2、该反应无需昂贵的金属催化，所用的脯氨酸无需预热或者添加其他活化试剂，一步合成吡咯里西啶，该反应的产品结构新颖。

3、该反应的产物某些表现出动物毒性和在天然产物中广泛存在，可为进一步研究其毒性和生物活性提供支持。

下面通过实施例对本发明作进一步说明，其目的仅在于更好的理解本发明的内容。因此，本发明的保护范围不受所举之例的限制。

实施例操作通法：

将酮ⅰa-r（0.5当量）和相应的氨基酸ⅱa-c（3.0当量）混合于甲苯（2ml）与丙酸（1ml）的混合溶剂中，140℃反应12小时。反应结束后冷却至室温，加入30ml的乙酸乙酯稀释，再用饱和碳酸氢钠中和，乙酸乙酯萃取三次，合并有机相，依次用水和饱和氯化钠各洗一次，无水硫酸钠干燥。抽滤，滤液浓缩后柱层析得相应的产物ⅲ（石油醚/乙酸乙酯洗脱体系）。

将1.5mmol的ⅱd-f溶解于2ml的二氯甲烷中，搅拌下加入2ml的三氟乙酸，tlc跟踪至ⅱ完全转化（约15分钟）。完全脱boc保护基后将溶剂减压除掉，加入相应的酮ⅰ以及甲苯和丙酸，于140℃反应12小时。反应结束后冷却至室温，加入30ml的乙酸乙酯稀释，再用饱和碳酸氢钠中和，乙酸乙酯萃取三次，合并有机相，依次用水和饱和氯化钠各洗一次，无水硫酸钠干燥。抽滤，滤液浓缩后柱层析得相应的产物ⅲ石油醚/乙酸乙酯洗脱体系）。

实例1：

cis-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲaa,ab,ac.

¹hnmr(400mhz,cdcl3)δ7.06–7.00(m,1h),6.70(d,j=3.9hz,1h),6.49(dd,j=3.9,2.3hz,1h),4.59(dd,j=12.8,7.0hz,1h),3.12(dd,j=11.9,6.9hz,1h),2.24–2.04(m,2h),1.86–1.73(m,1h),1.53(m,2h),1.48–1.31(m,3h).¹³cnmr(101mhz,cdcl3)δ191.9,131.8,121.7,116.1,107.5,54.1,50.2,30.1,22.5,20.8,19.5.hrms(esi)m/zcalcdforc11h13no(m+h⁺):175.0997,found:175.0995.lightyellowoil.

实例2：

cis-5,6,7,8,9,9a-hexahydrocyclohepta[b]pyrrolizin-10(4h)-one,ⅲba.

¹hnmr(400mhz,cdcl3)δ7.01(s,1h),6.71(d,j=3.9hz,1h),6.53(dd,j=3.6,2.4hz,1h),4.69(td,j=8.7,3.6hz,1h),3.34–3.19(m,1h),2.18(m,1h),2.13–1.82(m,3h),1.70(m,2h),1.46(d,j=9.8hz,4h).¹³cnmr(101mhz,cdcl3)δ192.05,132.63,121.24,116.78,107.11,59.42,55.76,32.93,30.80,27.77,27.63,24.89.hrms(esi)m/zcalcdforc12h15no(m+h⁺):190.1232,found:190.1228.lightyellowoil.

实例3：

cis-ethyl10-oxo-4a,5,6,7,8,9,9a,10-octahydrocyclohepta[b]pyrrolizine-7-carboxylate,ⅲca.

¹hnmr(400mhz,cdcl3)δ7.04(s,1h),6.72(d,j=3.8hz,1h),6.53(d,j=14.5hz,1h),4.71–4.61(m,1h),4.19–4.10(q,j=7.1hz,2h),3.31–3.20(m,1h),2.47–2.28(m,3h),2.25–2.15(m,1h),2.11–2.00(m,1h),1.81(m,2h),1.72–1.63(m,2h),1.27(t,j=7.0hz,3h).¹³cnmr(101mhz,cdcl3)δ191.05,175.14,132.08,121.40,117.07,107.56,60.55,59.34,55.81,46.90,30.78,30.60,27.69,25.49,14.22.hrms(esi)m/zcalcdforc15h19no3(m+h⁺):262.1443,found:262.1439.lightyellowsolid.

实例4：

cis-6,7,8,9,10,10a-hexahydro-4ah-cycloocta[b]pyrrolizin-11(5h)-one,ⅲda.

¹hnmr(400mhz,cdcl3)δ7.03(d,j=7.8hz,1h),6.69(d,j=3.6hz,1h),6.54–6.50(m,1h),4.38–4.28(m,1h),2.99–2.87(m,1h),2.49(m,1h),2.40–2.25(m,1h),1.92–1.82(m,3h),1.68(m,2h),1.61–1.39(m,5h).¹³cnmr(101mhz,cdcl3)δ191.7,131.8,120.9,116.6,107.3,60.7,56.5,35.7,30.0,27.2,26.8,23.6(2c).hrms(esi)m/zcalcdforc13h17no(m+h⁺):204.1388,found:204.1385.lightyellowoil.

实例5：

cis-7-methyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲea.

¹hnmr(400mhz,cdcl3)δ6.95(d,j=1.4hz,1h),6.58(d,j=3.9hz,1h),6.37(dd,j=3.8,2.3hz,1h),4.48(dd,j=15.2,6.8hz,1h),3.10(td,j=6.9,2.2hz,1h),2.27(dd,j=18.2,6.1hz,1h),2.23–2.10(m,1h),1.40(m,1h),1.33–1.07(m,3h),0.99–0.86(m,1h),0.84(d,j=6.3hz,3h).¹³cnmr(101mhz,cdcl3)δ192.9,131.9,121.1,116.0,108.2,53.3,50.6,33.0,28.6,27.95,26.5,22.34.hrms(esi)m/zcalcdforc12h15no(m+h⁺):190.1232,found:190.1225.colorlesssolid.

实例6：

cis-7-ethyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲfa.

¹hnmr(400mhz,cdcl3)δ7.03(d,j=1.3hz,1h),6.70(d,j=3.9hz,1h),6.48(dd,j=3.9,2.3hz,1h),4.59(dd,j=13.9,7.5hz,1h),3.21(td,j=7.0,2.6hz,1h),2.38(d,j=13.8hz,1h),2.25(m,1h),1.61–1.48(m,1h),1.40–1.15(m,5h),1.08–0.96(m,1h),0.88(t,j=7.2hz,3h).¹³cnmr(101mhz,cdcl3)δ191.6,131.6,121.9,116.0,107.4,54.4,50.5,34.0,31.3,29.6,28.5,26.5,11.3.hrms(ei)m/zcalcdforc13h17no(m⁺):203.1310,found:203.1311.colorlesssolid.

实例7：

cis-7-phenyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲga.

¹hnmr(400mhz,cdcl3)δ7.32–7.26(m,2h),7.23–7.16(m,3h),7.06(d,j=1.3hz,1h),6.74(d,j=3.7hz,1h),6.50(dd,j=3.8,2.3hz,1h),4.66(dd,j=15.3,6.9hz,1h),3.31(td,j=7.0,1.5hz,1h),2.66–2.59(m,1h),2.53–2.47(m,1h),2.45–2.38(m,1h),1.84–1.69(m,2h),1.64–1.54(m,1h),1.44–1.33(m,1h).¹³cnmr(101mhz,cdcl3)δ190.9,146.2,131.4,128.5(2c),126.8(2c),126.4,122.2,116.2,107.7,53.9,51.0,39.2,32.8,30.5,28.4.hrms(esi)m/zcalcdforc17h17no(m+h⁺):252.1388,found:252.1382.colorlesssolid.

实例8：

cis-ethyl9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indole-7-carboxylate,ⅲha.

¹hnmr(400mhz,cdcl3)δ7.07(d,j=1.2hz,1h),6.72–6.67(m,1h),6.50(dd,j=3.9,2.3hz,1h),4.68(dd,j=13.0,7.2hz,1h),4.12(q,j=7.1hz,2h),3.27(m,1h),2.52–2.44(m,1h),2.42–2.33(m,1h),2.32–2.23(m,1h),1.92(m,1h),1.64(dt,j=12.1,4.5hz,2h),1.53–1.42(m,1h),1.25(t,j=7.1hz,3h).¹³cnmr(101mhz,cdcl3)δ190.5,175.2,131.6,122.0,116.5,107.8,60.6,53.5,49.1,37.1,29.3,24.2,22.1,14.2.hrms(esi)m/zcalcdforc14h17no3(m+h⁺):248.1287,found:248.1284.

实例9：

cis-7-(trifluoromethyl)-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲia.

¹hnmr(400mhz,cdcl3)δ7.07(s,1h),6.74(d,j=3.9hz,1h),6.56–6.47(m,1h),4.73(dd,j=12.8,6.0hz,1h),3.37–3.25(m,1h),2.50(m,1h),2.31–2.11(m,2h),1.86–1.71(m,1h),1.63–1.43(m,3h).¹³cnmr(101mhz,cdcl3)δ189.8,131.7,127.7(q,j=278.6hz,cf3),122.2,117.0,108.0,53.3,48.3,35.7(q,j=27.1hz),28.5,20.3(d,j=2.9hz),18.0(d,j=2.5hz).hrms(esi)m/zcalcdforc12h12f3no(m+h⁺):244.0949,found:244.0943.lightyellowoil.

实例10:

cis-7-(4-hydroxyphenyl)-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲja.

¹hnmr(400mhz,dmso-d6)δ9.21(s,1h),7.40(s,1h),7.01(d,j=8.2hz,2h),6.69(d,j=8.2hz,2h),6.63(d,j=3.7hz,1h),6.49(d,j=1.3hz,1h),4.76(dd,j=15.0,7.1hz,1h),3.37(m,1h),2.42(m,1h),2.31–2.18(m,2h),1.74(m,1h),1.49(m,2h),1.20–1.12(m,1h).¹³cnmr(101mhz,dmso-d6)δ195.8,160.8,141.9,135.9,132.6(2c),128.5,120.8,120.3(2c),111.9,58.5,55.7,43.5,37.9,35.5,34.0.hrms(esi)m/zcalcdforc17h17no2(m+h⁺):268.1338,found:268.1334.off-whitesolid.

实例11：

2-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indol-7-yl)isoindoline-1,3-dione,ⅲka.

¹hnmr(400mhz,cdcl3)δ7.71(dt,j=7.0,3.5hz,2h),7.65–7.60(m,2h),7.00(d,j=1.2hz,1h),6.65(d,j=3.7hz,1h),6.44(dd,j=3.9,2.2hz,1h),4.71(dd,j=12.9,7.0hz,1h),4.20–4.07(m,1h),3.34(m,1h),2.59–2.42(m,2h),2.37–2.25(m,1h),2.03–1.90(m,1h),1.60–1.41(m,2h).¹³cnmr(101mhz,cdcl3)δ190.0,168.0(2c),134.0(2c),131.8(2c),131.6,123.2(2c),122.2,116.7,107.9,53.2,49.8,44.4,30.1,24.7,24.1.hrms(esi)m/zcalcdforc19h16n2o3(m+h⁺):321.1239,found:321.1237.lightyellowsolid.

实例12：

cis-9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indol-7-ylpropionate,ⅲla.

¹hnmr(400mhz,cdcl3)δ7.03(t,j=6.6hz,1h),6.74(dd,j=3.9,0.8hz,1h),6.52(dd,j=3.9,2.3hz,1h),4.92(m,1h),4.64(m,1h),3.30(q,j=6.9hz,1h),2.35–2.28(m,3h),2.27–2.22(m,1h),2.01(m,1h),1.90–1.77(m,1h),1.69–1.60(m,1h),1.51(m,1h),1.14(t,j=7.6hz,3h).¹³cnmr(101mhz,cdcl3)δ190.7,173.6,131.6,121.8,116.7,108.1,67.7,53.2,48.0,27.8,27.6,26.7,25.8,9.1.hrms(esi)m/zcalcdforc14h17no3(m+h⁺):248.1287,found:248.1287.lightyellowoil.

实例13：

n-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indol-7-yl)acetamide,ⅲma.

¹hnmr(400mhz,cd3od)δ7.21(s,1h),6.70(d,j=3.9hz,1h),6.58–6.48(m,1h),4.71(dd,j=13.7,7.0hz,1h),3.67(m,1h),3.36(m,1h),2.48–2.30(m,2h),1.94(s,3h),1.73(m,2h),1.47–1.34(m,2h).¹³cnmr(101mhz,cd3od)δ193.0,172.5,132.3,124.6,117.9,109.4,54.8,51.1,45.3,30.8,29.0,28.2,23.2.hrms(esi)m/zcalcdforc13h16n2o2(m+h⁺):233.1290,found:233.1285.lightyellowsolid.

实例14：

cis-2,3-dimethyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲna.

¹hnmr(400mhz,cdcl3)δ7.02(d,j=1.3hz,1h),6.71(d,j=3.9hz,1h),6.52(dd,j=3.9,2.3hz,1h),4.17–4.06(m,1h),2.69(qd,j=7.4,4.8hz,1h),1.62(d,j=6.5hz,3h),1.35(d,j=7.4hz,3h).¹³cnmr(101mhz,cdcl3)δ191.9,132.1,120.9,116.7,107.7,58.2,53.9,20.3,14.1.hrms(esi)m/zcalcdforc9h11no(m+h⁺):150.0919,found:150.0914.lightyellowoil.

实例15：

cis-2-isopropyl-3-methyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲoa¹.

¹hnmr(400mhz,cdcl3)δ7.02(d,j=1.3hz,1h),6.68(dd,j=4.0,0.9hz,1h),6.51(dd,j=3.9,2.3hz,1h),4.36(qd,j=6.5,3.8hz,1h),2.62(t,j=3.9hz,1h),2.48–2.37(m,1h),1.57(d,j=6.5hz,3h),1.08–1.06(m,3h),0.89(d,j=6.8hz,3h).¹³cnmr(101mhz,cdcl3)δ191.4,133.0,121.1,116.7,107.3,64.7,52.2,28.9,22.8,20.7,17.7.hrms(esi)m/zcalcdforc11h15no(m+h⁺):177.1154,found:177.1154.lightyellowoil.

实例16：

cis-2-methyl-3-propyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲpa¹.

¹hnmr(400mhz,cdcl3)δ7.02(d,j=1.4hz,1h),6.75–6.67(m,1h),6.54–6.49(m,1h),4.26–4.03(m,1h),2.82–2.66(m,1h),2.08–1.86(m,2h),1.83–1.71(m,1h),1.57–1.43(m,1h),1.37(d,j=7.4hz,3h),1.01(t,j=8.4,3h).¹³cnmr(101mhz,cdcl3)δ192.2,132.1,121.5,116.7,107.5,62.4,51.7,37.7,18.5,15.7,14.0.hrms(esi)m/zcalcdforc11h15no(m+h⁺):178.1232,found:178.1128.lightyellowoil.

实例17：

cis-3-methyl-2-propyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲqa.

¹hnmr(400mhz,cdcl3)δ6.94(d,j=1.2hz,1h),6.62(d,j=3.9hz,1h),6.44(dd,j=3.9,2.3hz,1h),4.17(m,1h),2.57(m,1h),1.85(m,1h),1.58–1.47(m,4h),1.44–1.33(m,2h),0.90(t,j=7.3hz,3h).¹³cnmr(101mhz,cdcl3)δ191.7,132.3,121.0,116.8,107.5,58.9,56.5,32.6,21.8,20.5,14.1.hrms(esi)m/zcalcdforc11h15no(m+h⁺):178.1232,found:178.1130.lightyellowoil.

实例18：

cis-2-butyl-3-methyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲra.

¹hnmr(400mhz,cdcl3)δ7.01(d,j=1.3hz,1h),6.69(dd,j=3.9,0.8hz,1h),6.51(m,1h),4.24(m,1h),2.67–2.60(m,1h),2.01–1.89(m,1h),1.67–1.55(m,4h),1.46–1.35(m,4h),0.95–0.89(m,3h).¹³cnmr(101mhz,cdcl3)δ191.6,132.3,121.0,116.7,107.5,59.0,56.4,30.1,29.4,22.74(s),21.8,13.9.hrms(esi)m/zcalcdforc12h17no(m+h⁺):192.1388,found:192.1383.lightyellowoil.

实例19：

cis-3-methyl-2-pentyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲsa.

¹hnmr(400mhz,cdcl3)δ7.01(t,j=3.0hz,1h),6.69(dd,j=4.0,0.9hz,1h),6.51(m,1h),4.24(m,1h),2.63(m,1h),2.00–1.88(m,1h),1.67–1.54(m,4h),1.43(m,2h),1.38–1.27(m,4h),0.94–0.84(m,3h).¹³cnmr(101mhz,cdcl3)δ191.6,132.3,121.0,116.7,107.5,59.1,56.4,31.8,30.4,26.9,22.4,21.8,14.0.hrms(esi)m/zcalcdforc13h19no(m+h⁺):206.1545,found:206.1540.lightyellowoil.

实例20：

cis-2-methyl-3-pentyl-2,3-dihydro-1h-pyrrolizin-1-one,ⅲta.

¹hnmr(400mhz,cdcl3)δ7.02(d,j=1.5hz,1h),6.70(dd,j=5.1,4.5hz,1h),6.52(dd,j=3.9,2.3hz,1h),4.08–4.02(m,1h),2.76(m,1h),2.08–1.96(m,1h),1.85–1.73(m,1h),1.54–1.30(m,9h),0.95–0.86(m,3h).¹³cnmr(101mhz,cdcl3)δ192.2,132.1,121.5,116.7,107.5,62.6,51.7,35.4,31.7,24.8,22.5,15.7,14.0.hrms(esi)m/zcalcdforc13h19no(m+h⁺):206.1545,found:206.1544.lightyellowoil.

实例21：

(±)-3-methyl-2-(propan-2-ylidene)-2,3-dihydro-1h-pyrrolizin-1-one,ⅲua.

¹hnmr(400mhz,cdcl3)δ6.95(s,1h),6.72(s,1h),6.47(s,1h),5.04(d,j=6.2hz,1h),2.40(s,3h),1.95(s,3h),1.56(d,j=6.3hz,3h).lightyellowoil.

实例22：

cis-2-methyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲad.

¹hnmr(400mhz,cdcl3)δ6.83(s,1h),6.52(s,1h),4.53(dd,j=12.8,6.8hz,1h),3.08(dd,j=12.0,6.7hz,1h),2.17(s,3h),2.15–2.03(m,2h),1.87–1.69(m,2h),1.59–1.48(m,2h),1.44–1.38(m,2h).¹³cnmr(101mhz,cdcl3)δ191.8,131.5,127.4,120.8,107.9,54.1,49.7,29.9,22.6,20.7,19.4,12.5.hrms(esi)m/zcalcdforc12h15no(m+h⁺):190.1232,found:190.1229.lightyellowoil.

实例23：

cis-2-benzyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲae.

¹hnmr(400mhz,cdcl3)δ7.27(m,2h),7.19(m,3h),6.78(s,1h),6.53(s,1h),4.48(dd,j=12.9,6.7hz,1h),3.86(s,2h),3.03(dd,j=12.1,6.6hz,1h),2.13–2.01(m,2h),1.82–1.69(m,1h),1.55–1.43(m,2h),1.41–1.30(m,3h).¹³cnmr(101mhz,cdcl3)δ191.9,141.1,131.6,131.5,128.6(2c),128.4(2c),126.0,120.6,107.3,54.1,49.7,33.8,29.9,22.5,20.7,19.4.hrms(esi)m/zcalcdforc18h19no(m+h⁺):266.1545.found:266.1542.lightyellowsolid.

实例24：

cis-2-phenyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲaf.

¹hnmr(400mhz,cdcl3)δ7.51(d,j=7.5hz,2h),7.35(t,j=7.6hz,2h),7.31(s,1h),7.23(dd,j=13.5,6.2hz,1h),6.97(s,1h),4.58(dd,j=13.0,6.7hz,1h),3.10(dd,j=12.0,6.6hz,1h),2.28–2.03(m,2h),1.87–1.70(m,1h),1.63–1.49(m,2h),1.47–1.31(m,3h).¹³cnmr(101mhz,cdcl3)δ192.2,134.7,132.5,132.4,128.9(2c),126.6,125.4(2c),118.8,104.3,54.5,49.9,30.1,22.6,20.8,19.6.hrms(esi)m/zcalcdforc17h17no(m+h⁺):252.1388,found:252.1385.lightyellowsolid.

实例25：

ethyl2-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indol-2-yl)acetate,ⅲag.

¹hnmr(400mhz,cdcl3)δ7.03(s,1h),6.63(s,1h),4.56(dd,j=12.9,6.9hz,1h),4.16(q,j=7.1hz,2h),3.54(s,2h),3.08(dd,j=12.0,6.8hz,1h),2.18-2.06(m,2h),1.82-1.76(m,1h),1.56-1.49(m,2h),1.45-1.33(m,3h),1.27(t,j=7.1hz,3h).¹³cnmr(101mhz,cdcl3)δ191.9,171.7,131.5,123.6,121.1,107.8,60.9,54.3,49.8,33.4,30.0,22.5,20.8,19.5,14.2.hrms(esi)m/zcalcdforc15h19no3(m+h⁺):262.1443,found:262.1440.lightyellowoil.

实例26：

ethyl2-(cis-9-oxo-7-phenyl-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indol-2-yl)acetate,ⅲgg.

¹hnmr(400mhz,cdcl3)δ7.31–7.27(m,2h),7.21–7.17(m,3h),7.08(s,1h),6.66(s,1h),4.65(dd,j=15.0,7.0hz,1h),4.17(q,j=7.1hz,2h),3.55(s,2h),3.31-3.27(m,1h),2.64–2.59(m,1h),2.56–2.39(m,2h),1.84-1.73(m,2h),1.64-1.55(m,1h),1.46-1.37(m,1h),1.27(t,j=7.1hz,3h).¹³cnmr(101mhz,cdcl3)δ190.7,171.6,146.1,131.0,128.5(2c),126.7(2c),126.3,123.7,121.5,107.9,60.9,54.0,50.5,39.1,33.4,32.6,30.4,28.2,14.2.hrms(esi)m/zcalcdforc21h23no3(m+h⁺):338.1756,found:338.1751.whitesolid.

实例27：

cis-ethyl2-methyl-9-oxo-5,6,7,8,8a,9-hexahydro-4ah-pyrrolo[1,2-a]indole-7-carboxylate,ⅲhd.

¹hnmr(400mhz,cdcl3)δ6.85(s,1h),6.53(s,1h),4.60(dd,j=12.9,6.8hz,1h),4.13(q,j=7.1hz,2h),3.23(m,1h),2.43(m,2h),2.23(m,1h),2.17(s,3h),1.91(m,1h),1.63(m,2h),1.54–1.43(m,1h),1.25(t,j=7.1hz,3h).¹³cnmr(101mhz,cdcl3)δ190.2,175.4,131.3,127.8,121.2,108.1,60.6,53.4,48.6,37.0,29.1,24.2,21.9,14.2,12.4.hrms(esi)m/zcalcdforc15h19no3(m+h⁺):262.1443,found:262.1439.whitesolid.

实例28：

cis-2,7-dimethyl-6,7,8,8a-tetrahydro-4ah-pyrrolo[1,2-a]indol-9(5h)-one,ⅲgd.

¹hnmr(400mhz,cdcl3)δ6.84(s,1h),6.50(s,1h),4.50(dd,j=14.5,7.0hz,1h),3.20–3.13(m,1h),2.35(d,j=13.5hz,1h),2.23(m,1h),2.16(s,3h),1.55–1.46(m,1h),1.45–1.36(m,1h),1.35–1.24(m,3h),0.93(d,j=6.3hz,3h).¹³cnmr(101mhz,cdcl3)δ191.2,131.1,127.2,121.1,107.8,54.0,50.2,31.7,30.8,29.2,27.6,22.3,12.4.hrms(esi)m/zcalcdforc13h17no(m+h⁺):204.1388,found:204.1383.whitesolid。