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1、摘 要Monomorine I天然生物碱是1973年Ritter实验室从Monomorium L.蚂蚁中分离出来的一种踪迹信息素，其中含有3，5-二取代吲哚里骨架。1985年Husson, H. P.实验室最早手性合成了Monomorine I并且确定了它的绝对构型。1993年研究者从中南美和马达加斯加岛上生活的箭蛙皮肤提取物中也发现了Monomorine I 和它的三个异构体的存在。这一发现有力地证明了箭蛙以Monomorium L.蚂蚁等作为食物储积Monomorine I的食物假说（dietary hypothesis）理论。由于这类生物碱从天然中提取出来的量特别少不足以对它们进行详细的
2、讨论和研究，为了进行进一步的药理研究，通过有机合成方法合成出Monomorine I很有必要。目前有很多化学研究者对Monomorine I进行了手性合成，其中Blechert 报告提出了最有效的7步对映选择性合成，但是实验产物不单一。通过有机逆合成分析，采用内酰胺作为原料，这里报告提出了一种产物单一，步骤简短的新的Monomorine I 全合成方法。 关键词：生物碱； Monomorine I； 内酰胺Abstract Monomorine I which is a kind of natural biological alkaloids,a trail pheromone of the
3、widespread pharaoh，s ant Monomorium pharaonis L, possessing a 3,5-disubstituted indolizidine skeleton，was separated in1973 of Ritter,F.J. The Husson, HP Labs first chiral synthesis of the Monomorine I and established its absolute configuration in 1985 . Researchers found Monomorine I and its three i
4、somers from frog skin extracts on Central and South America and the island of Madagascar in 1993. This finding proved the hypothesis (dietary hypothesis) theory which was the Monomorium L. ants as food of arrow frogs to storage Monomorine I .Because this kind of alkaloids extracted from natural is t
5、oo less to research their particular detail effection ,and in order to further the pharmacological research, through the organic synthesis synthesize Monomorine I is very necessary. There are a lot of chemistry researchers Monomorine I was chiral synthesis There are many international researches for
6、 the chiral synthesis of Monomorine I.Blechert have reported the most effective seven steps stereo-selectivity organic synthesis, but product diversification.The experiment is based on the inverse synthetic analysis, using beta-lactamase-producing as raw materials. Here report a new total synthesis
7、of Monomorine I with single product, short step .Key words: alkaloid； Monomorine I； lactam目 录文中简约用语一览表1前 言21. 结果与讨论41.1 实验一41.1.1 （-）-Monomorine I（-）-1的合成41.1.2 反应条件和试剂41.2 实验二51.2.1 （+）-1的合成51.2.2 反应条件和试剂62.实验部分62.1 （3）的合成62.2 （4）的合成72.3 （5）的合成92.4 （6）的合成102.5 (-)-Monomorine I的合成112.6 （8）的合成122.7（
8、9）的合成132.8 （10）的合成152.9 （11）的合成162.10 (+)-Monomorine I的合成17结 论19致 谢20参 考 文 献21文中简约用语一览表Ac acetyl(乙酰基)atm atmosphere（气氛；气压）Bn benzyl(苯甲基) Bu butyl(丁基)Cbz benzyloxycarbonyl(苄氧羰基)DMF N,N-dimethylformamide(二甲基甲酰胺)Et ethyl(乙烷基)IR infrared spectroscopy(红外光谱法)Me methyl(甲基)HMDS hexamethyldisilazide(六甲基二硅氮烷)
9、HRMS high resolution mass spectrometry(质谱分析法)mp melting point(熔点)MS mass spectrometry(质谱分析法)NMR Nuclear Magnetic Resonance(核磁共振)Pr propyl(丙基)rt room temperature(室温)THF tetrahydrofuran(四氢呋喃)TMEDA N,N,N,N-tetramethylethylenediamine (四甲基乙二胺)TMS trimethylsilyl(三甲基硅烷基)前 言1973年Ritter，F.J.和其他研究人员在实验室中从广泛法老
10、蚁Monomorium pharaonis L中提取出天然生物碱（+）-Monomorine I（1）1，由于蚂蚁种类众多难以分类且体积较小，Monomorium pharaonis L难以收集，（+）-Monomorine I的提取量较少。1993年在箭蛙皮肤提取物Melanophryniscus stelzneri中发现和（+）-Monomorine I生物碱相似含有3，5-二取代吲哚里骨架的生物碱和另外三个非对应异构体，并同时被命名为非对应异构体195B2。据食物假说，（+）-Monomorine I可能是由Monomorium pharaonis L作为青蛙等两栖类的食物而得以在青蛙皮
11、肤中聚集起来。有研究发现这些生物碱对中枢神经系统中的尼古丁受体具有一定的生物活性，特别的，7和4、2尼古丁受体在哺乳动物大脑是最丰富的亚型，7尼古丁受体对内皮细胞、血管平滑肌细胞、肺上皮细胞、皮肤角质细胞等非神经元细胞有影响,并参与细胞有丝分裂、分化、细胞骨架形成、细胞间联接、运动和迁移等细胞机制调节。但是这类生物碱从天然中提取出来的量特别少不足以对它们进行详细的讨论和研究，所以有机合成这些生物碱已经成为当今世界热点研究课题。从青蛙皮肤中提取出的195BS绝对构型未知，这个有趣的天然产物的绝对立体化学被Husson的第一个非对称合成确定，并被确认为测试实验1合成设想的可能性测试目标。迄今为止有
12、许多关于1的天然（+）-3和非天然（-）-enantionmers4 的对映选择性合成的研究报告。其中Blechert 5报告提出了（+）-1的最有效7步对映选择性合成，总收率达到35%；然而在这个合成中最终也是最重要的一步产出比例为5：1的（+）-1和3-差位异构体,产物不单一。这里本文提出用商用内酰胺26作为原料合成（-）-1的一个短的（5步）方案。Scheme 1 Scheme 21. 结果与讨论1.1 实验一 内酰胺2反应生成相应的苄氧羰基酰亚胺3，3经过Martin反应7过程生成无环酮4.由4派生出2，5-顺式-二取代吡咯烷5和triphenylsilant，5通过亚胺盐的阻碍较小的
13、-面减少立体选择性阻碍。5和甲基乙烯酮的交叉复分解反应在Grubbs的第二代催化剂8下生成不饱和酮6.6在催化氢化的条件下经过了最后的一个吲哚里西定环封闭合成（-）-Monomorine I（-）-1。在我们合成的（-）-1谱数据（1H和13C NMR）中显示5号位没有非对映左旋体的存在，这一结论被一致的报道过。3，41.1.1 （-）-Monomorine I（-）-1的合成 1.1.2 反应条件和试剂(a) LiHMDS,CbzCl,THF,-78到0(93%); (b) n-BuMgBr,TMEDA,THF, -78(73%);(c) Ph3SiH, BF3Et2OCH2Cl2, -78
14、到室温（96%）；（d）甲基乙烯基酮，Grubbs第二代催化剂（10 mol %）,CH2Cl2,回流（95%）；（e）20% Pd(OH)2,H2,1atm,EtOH(88%).1.2 实验二这种方法可以应用到方案二中所展示的一种叉开对映的过程中。因此，已知的内酰胺79通过反应转化生成相应的苄氧羰基酰亚胺8，8反应生成酮9.通过一亚胺离子中间体的环化生成吡咯烷10，10经过Wacker氧化成甲基酮11。在和方案一（-）-1的合成中从6以后相同的反应条件下， 11转化成（+）-1. （+）-1的合成和（-）-1在所有方面都相同除光学旋转的标志外。一个简洁的5步的立体选择性全合成（-）-Mono
15、morine I由商用内酰胺2合成，总受率54%。在合成（+）-Monomorine I中一个enantiodivergent 进程同时被报道。1.2.1 （+）-1的合成1.2.2 反应条件和试剂 (a) 10% Pd/C, H2, EtOAc, 1 atm; (b) LiHMDS, CbzCl, THF, -78 到 0 (在两步合成中96% ); (c) 5-pentenylMgBr, TMEDA, THF,-78 (57%); (d) Ph3SiH, BF3 Et2OCH2Cl2, -78 到室温 (90%); (e) PdCl2, CuCl, O2,H2O-DMF, 室温(86%);
16、 (f) 20% Pd(OH)2,H2, 1 atm, EtOH (84%).2.实验部分2.1 （3）的合成(2S)-()-2-Allyl-5-oxopyrrolidine-1-carboxylic Acid Benzyl Ester（3）量取THF（10ml）放入锥形瓶中，加入HMDS（0.59ml，2.83mmol）和n -Buli（1.6M 在正己烷中，1.77ml，2.83 mmol）在0 C下反应30min，生成LiHMDS备用。为了解决2（322mg，2.58mmol）在THF（10ml）的搅拌溶解，加入制备好的LiHMDS，反应温度为-78 ，然后反应混合物在同一温度下搅拌30
17、min。在-78 下取CbzCl（0.44ml，3.10mmol）加入反应混合物搅拌0.5h后加温到0C，时间在1h以上.该反应用饱和NaHCO3淬火，加水混合后用CH2Cl2（20ml）分四次提取。把提取的有机物集中在一起，用MgSO4干燥，过滤，蒸发到残渣，残渣用硅胶层析法（25g，正己烷/丙酮25:1-10:1）得到无色油3（621mg，93）。IR (neat) 3060, 1791, 1749, 1716, 1293 cm1; 1H NMR (500 MHz, CDCl3) 1.86 (1H, m), 2.10 (1H, m), 2.34 (1H, m), 2.47 (1H, m),
18、 2.50 (1H, m), 2.60 (1H, m), 4.27 (1H, m), 5.10 (2H, m), 5.28 (2H, ABq, J = 12.4 Hz), 5.73 (1H, m), 7.327.38 (3H, m), 7.407.44 (2H, m); 13C NMR (75 MHz, CDCl3) 21.5 (t), 30.8 (t), 37.4 (t), 56.7 (d), 67.3 (t), 118.3 (t), 127.4 (d), 127.7 (d), 127.9 (d), 132.2 (d), 134.7 (s), 150.6 (s), 173.3 (s); MS
19、 259 (M+), 91 (100); HRMS calcd for C15H17O3N 259.1207, found 259.1234; D 26 76.15 (c 1.00, CHCl3).To a stirring solution of 2 (322 mg, 2.58 mmol) in THF (10 mL) was added a solution of LiHMDS, prepared from HMDS (0.59 mL, 2.83 mmol) and n-BuLi (1.6 M in hexane, 1.77 mL, 2.83 mmol) in THF (10 mL) at
20、 0 C for 30 min, at 78 C, and then the resulting mixture was stirred at the same temperature for 30 min. To the reaction mixture was added CbzCl (0.44 mL, 3.10 mmol) at 78 C, and the reaction mixture was stirred at 78 C for 0.5 h and allowed to warm to 0 C over 1 h. The reaction was quenched with sa
21、turated NaHCO3, and the aqueous mixture was extracted with CH2Cl2 (20 mL 4). The organic extracts were combined, dried over MgSO4, filtered, and evaporated to give a residue, which was chromatographed on silica gel (25 g, hexane/acetone 25:110:1) to give 3 (621 mg, 93%) as a colorless oil.IR (neat)
22、3060, 1791, 1749, 1716, 1293 cm1; 1H NMR (500 MHz, CDCl3) 1.86 (1H, m), 2.10 (1H, m), 2.34 (1H, m), 2.47 (1H, m), 2.50 (1H, m), 2.60 (1H, m), 4.27 (1H, m), 5.10 (2H, m), 5.28 (2H, ABq, J = 12.4 Hz), 5.73 (1H, m), 7.327.38 (3H, m), 7.407.44 (2H, m); 13C NMR (75 MHz, CDCl3) 21.5 (t), 30.8 (t), 37.4 (t
23、), 56.7 (d), 67.3 (t), 118.3 (t), 127.4 (d), 127.7 (d), 127.9 (d), 132.2 (d), 134.7 (s), 150.6 (s), 173.3 (s); MS 259 (M+), 91 (100); HRMS calcd for C15H17O3N 259.1207, found 259.1234; D 26 76.15 (c 1.00, CHCl3).2.2 （4）的合成(1S)-()-1-(3-Oxo-n-heptyl)but-3-enylcarbamic Acid Benzyl Ester (4)取THF(10ml)，加
24、入n-BuBr(0.32ml,3.00mmol)和Mg(72mg,3.00mmol)回流制取n-BuMgBr备用，为了解决3在THF(5ml)中的搅拌溶解问题，加入制备好的n-BuMgBr，在 78 C下向 THF中加入TMEDA (0.48 mL, 3.00 mmol) ，反应混合物在同样温度下搅拌1.5h.该反应用i-PrOH (1 mL)淬火, 用 Et2O稀释.悬浮层用 10% HCl 水溶液冲洗, 用 MgSO4干燥, 过滤, 蒸发至残渣，残渣用硅胶层析凝胶(20 g, 正己烷/丙酮20:110:1)得到无色固体(mp 9092 C)4 (231 mg, 73%) 。IR (KBr)
25、 3306, 1704, 1686, 1546, 1262 cm1; 1H NMR (500 MHz, CDCl3) 0.89 (3H, t, J = 7.2 Hz), 1.28 (2H, sext, J = 7.2 Hz), 1.52 (2H, quint, J = 7.2 Hz), 1.63 (1H, m), 1.81 (1H, m), 2.22 (2H, m), 2.36 (2H, t-like, J = 6.4 Hz), 2.47 (2H, m), 3.68 (1H, br m), 4.60 (1H, br d, J = 8.5 Hz), 5.08 (4H, m), 5.75 (1H,
26、 m), 7.307.37 (5H, m); 13C NMR (75 MHz, CDCl3) 13.8 (q), 22.2 (t), 25.8 (t), 28.2 (t), 39.2 (t), 39.9 (t), 42.5 (t), 50.5 (d), 66.3 (t), 117.7 (t), 127.7 (d), 127.7 (d), 128.2 (d), 133.7 (d), 136.3 (s), 155.8 (s), 210.5 (s); MS 317 (M+), 276 (100); HRMS calcd for C19H27O3N 317.1989, found 317.1982;
27、D 26 16.86 (c 0.57, CHCl3). To a stirring solution of 3(259 mg, 1.00 mmol) in THF (5 ml) was added a solution of n-BuMgBr, prepared from n-BuBr (0.32 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF (10 ml) at reflux, and TMEDA (0.48 mL, 3.00 mmol) in THF at 78 C, and the reaction mixture was stirred
28、 at the same temperature for 1.5 h. The reaction was quenched with i-PrOH (1 ml), and diluted with Et2O. The ethereal layer was washed with 10% HCl aqueous solution, dried over MgSO4, filtered, and evaporated to give a residue, which was chromatographed on silica gel (20 g, hexane/acetone 20:110:1)
29、to give 4(231 mg, 73%) as a colorless solid (mp 9092 C).IR (KBr) 3306, 1704, 1686, 1546, 1262 cm1; 1H NMR (500 MHz, CDCl3) 0.89 (3H, t, J = 7.2 Hz), 1.28 (2H, sext, J = 7.2 Hz), 1.52 (2H, quint, J = 7.2 Hz), 1.63 (1H, m), 1.81 (1H, m), 2.22 (2H, m), 2.36 (2H, t-like, J = 6.4 Hz), 2.47 (2H, m), 3.68
30、(1H, br m), 4.60 (1H, br d, J = 8.5 Hz), 5.08 (4H, m), 5.75 (1H, m), 7.307.37 (5H, m); 13C NMR (75 MHz, CDCl3) 13.8 (q), 22.2 (t), 25.8 (t), 28.2 (t), 39.2 (t), 39.9 (t), 42.5 (t), 50.5 (d), 66.3 (t), 117.7 (t), 127.7 (d), 127.7 (d), 128.2 (d), 133.7 (d), 136.3 (s), 155.8 (s), 210.5 (s); MS 317 (M+)
31、, 276 (100); HRMS calcd for C19H27O3N 317.1989, found 317.1982; D 26 16.86 (c 0.57, CHCl3).2.3 （5）的合成(2S,5S)-()-2-Allyl-5-n-butylpyrrolidine-1-carboxylic Acid Benzyl Ester (5)取CH2Cl2 (5 mL)，加入BF3Et2O (0.27 mL, 2.16 mmol) 和Ph3SiH (280 mg, 1.08 mmol)备用，为了使4在78 C下在CH2Cl2 (5 mL)中搅拌溶解，加入备用溶液。混合物在相同温度下搅拌0
32、.5 h，然后在室温下反应2h.该反应在0 C下用饱和NaHCO3淬火，混合物用Et2O稀释。有机层被分离，水溶液层用Et2O (10 mL )分三次提取。把提取的有机物集合在一起，用MgSO4干燥，过滤，蒸发至残渣，所得残渣在硅胶层析凝胶(20 g, hexane/acetone 100:160:1)上，得到无色油状物5(156 mg, 96%)。IR (neat) 3079, 3029, 1698, 1405 cm1; 1H NMR (300 MHz, CDCl3) 0.88 (3H, br), 1.27 (5H, br), 1.381.80 (3H, m), 1.811.99 (2H,
33、m), 2.16 (1H, m), 2.59 (1H, br), 3.87 (2H, br), 4.995.09 (4H, m), 5.74 (1H, br), 7.247.40 (5H, m); 13C NMR (75 MHz, CDCl3) 14.1 (q), 22.6 (t), 28.5 (t), 29.2 (t), 35.1 (t), 39.4 (t), 40.0 (t), 57.7 and 58.1 (each d), 59.0 (d), 66.4 (t), 116.8 (t), 127.5 (d), 127.5 (d), 128.1 (d), 134.8 (d), 136.8 (s
34、), 155.0 (s); MS 301 (M+), 216 (100); HRMS calcd for C19H27O2N 301.2040, found 301.2027; D 26 7.83 (c 0.64, CHCl3).To a stirring solution of 4(171 mg, 0.54 mmol) in CH2Cl2 (5 mL) was added a solution of BF3Et2O (0.27 mL, 2.16 mmol) and Ph3SiH (280 mg, 1.08 mmol) in CH2Cl2 (5 mL) at 78 C, and the res
35、ulting mixture was stirred at the same temperature for 0.5 h, and then at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 aqueous solution at 0 C, and the mixture was diluted with Et2O. The organic layer was separated, and the aqueous layer was extracted with Et2O (10 mL 3)
36、. The organic extracts were combined, dried over MgSO4, filtered, and evaporated to give a residue, which was chromatographed on silica gel (20 g, hexane/acetone 100:160:1) to give 5 (156 mg, 96%) as a colorless oil. IR (neat) 3079, 3029, 1698, 1405 cm1; 1H NMR (300 MHz, CDCl3) 0.88 (3H, br), 1.27 (
37、5H, br), 1.381.80 (3H, m), 1.811.99 (2H, m), 2.16 (1H, m), 2.59 (1H, br), 3.87 (2H, br), 4.995.09 (4H, m), 5.74 (1H, br), 7.247.40 (5H, m); 13C NMR (75 MHz, CDCl3) 14.1 (q), 22.6 (t), 28.5 (t), 29.2 (t), 35.1 (t), 39.4 (t), 40.0 (t), 57.7 and 58.1 (each d), 59.0 (d), 66.4 (t), 116.8 (t), 127.5 (d),
38、127.5 (d), 128.1 (d), 134.8 (d), 136.8 (s), 155.0 (s); MS 301 (M+), 216 (100); HRMS calcd for C19H27O2N 301.2040, found 301.2027; D 26 7.83 (c 0.64, CHCl3).2.4 （6）的合成 (2S,5S)-()-2-n-Butyl-5-(4-oxopent-2E-enyl)pyrrolidine-1-carboxylic Acid Benzyl Ester (6)取CH2Cl2 (5 mL)，加入5 (47 mg, 0.16 mmol)，为了使5能搅拌
39、溶解，向反应器中加入甲基乙烯基酮(0.07 mL, 0.78 mmol)和Grubbs第二代催化剂(14 mg, 0.016 mmol)，由此产生的混合物加热回流6 h然后冷却。蒸发溶剂，残留物用层析硅胶凝胶(20 g, hexane/acetone 80:115:1)得到无色油状物6.IR (neat) 3048, 1697, 1405 cm1; 1H NMR (500 MHz, CDCl3) 0.86 (3H, br), 1.26 (5H, br), 1.66 (3H, br), 1.95 (2H, br), 2.16 and 2.21 (3H, br), 2.40 (1H, br), 2
40、.59 and 2.72 (1H, br), 3.85 (1H, br), 4.02 (1H, br), 5.12 (2H, ABq, J = 11.5 Hz), 6.05 (1H, br), 6.75 (1H, br), 7.297.37 (5H, m); 13C NMR (75 MHz, CDCl3) 14.1 (q), 22.6 (t), 26.7 (q), 28.5 (t), 29.3 (t), 29.5 (t), 35.5 (t), 38.2 (t), 57.6 (d), 58.6 and 59.2 (each d), 66.7 (t), 127.6 and 127.8 (each
41、d), 128.3 (d), 133.0 (d), 136.6 (s), 144.2 (d), 144.4 (d), 155.1 (s), 198.1 (s); MS 343 (M+), 216 (100); HRMS calcd for C21H29O3N 343.2148, found 343.2113; D 26 34.99 (c 0.90, CHCl3). To a stirring solution of 5 (47 mg, 0.16 mmol) in CH2Cl2 (5 mL) were added methyl vinyl ketone (0.07 mL, 0.78 mmol)
42、and Grubbs second catalyst (14 mg, 0.016 mmol), and the resulting mixture was refluxed for 6 h. After cooling, the solvent was evaporated, and the residue was chromatographed on silica gel (20 g, hexane/acetone 80:115:1) to give 6 (51 mg, 95%) as a colorless oil.IR (neat) 3048, 1697, 1405 cm1; 1H NM
43、R (500 MHz, CDCl3) 0.86 (3H, br), 1.26 (5H, br), 1.66 (3H, br), 1.95 (2H, br), 2.16 and 2.21 (3H, br), 2.40 (1H, br), 2.59 and 2.72 (1H, br), 3.85 (1H, br), 4.02 (1H, br), 5.12 (2H, ABq, J = 11.5 Hz), 6.05 (1H, br), 6.75 (1H, br), 7.297.37 (5H, m); 13C NMR (75 MHz, CDCl3) 14.1 (q), 22.6 (t), 26.7 (q
44、), 28.5 (t), 29.3 (t), 29.5 (t), 35.5 (t), 38.2 (t), 57.6 (d), 58.6 and 59.2 (each d), 66.7 (t), 127.6 and 127.8 (each d), 128.3 (d), 133.0 (d), 136.6 (s), 144.2 (d), 144.4 (d), 155.1 (s), 198.1 (s); MS 343 (M+), 216 (100); HRMS calcd for C21H29O3N 343.2148, found 343.2113; D 26 34.99 (c 0.90, CHCl3
45、).2.5 (-)-Monomorine I的合成(3S,5R,9R)-()-3-n-Butyl-5-methyloctahydroindolizine取EtOH (10 mL)，加入6(125 mg, 0.36 mmol)，为了使6能搅拌溶解，向此混合物中加入20% Pd(OH)2 (50 mg)，反应所得的悬浮层在1 atm下氢化48 h。反应加入的催化剂用过滤的方法去除，滤液蒸发得到淡粉红色的油状物质()-Monomorine I (62.2 mg, 88%)。IR (neat) 2956, 2929, 2859, 1456, 1378, 1319, 1206, 1130 cm1; 1H
46、 NMR (300 MHz, CDCl3) 0.86 (3H, t, J = 7.1 Hz), 1.12 (3H, d, J = 6.3 Hz), 1.181.38 (6H, m), 1.401.85 (6H, br m), 2.07 (1H, br), 2.22 (1H, m), 2.47 (1H, br t-like, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3) 14.2 (q), 22.7 (q), 22.9 (t), 24.9 (t), 29.5 (t), 29.7 (t), 30.2 (t), 30.7 (t), 35.6 (t), 39.4 (t),
47、60.4 (d), 63.1 (d), 67.3 (d); MS 195 (M+), 138 (100); 26D 33.14 (c 0.87, n-hexane), lit. D 26 35.6 (c 0.5, n-hexane).To a stirring solution of 6 (125 mg, 0.36 mmol) in EtOH (10 mL) was added 20% Pd(OH)2 (50 mg), and the resulting suspension was hydrogenated at 1 atm for 48 h. The catalyst was removed by filtration, and the filtrate was evaporated to give ()-Monomorine I (62.2 mg, 88%) as a pa
