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Studies toward the Synthesis of (R)-(+)-Harmicine

英文原文与中文译文逐段对照 · English original with Chinese translation

Mo, Fanyang(莫凡洋) Li, Fei(李飞) Qiu, Di(邱頔) Zhang, Yan*(张艳) Wang, Jianbo*(王剑波)

莫凡洋 李飞 邱頔 张艳* 王剑波*

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China

北京分子科学国家实验室(BNLMS)及教育部生物有机化学与分子工程重点实验室，北京大学化学与分子工程学院，北京 100871，中国

The study toward the total synthesis of $\left( R\right) - \left( +\right)$ -harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of $\left( R\right) - \left( +\right)$ -harmicine, has been completed by the methodology based on photo-induced Wolff rearrangement of $\alpha$ -diazo- $\beta$ -carbonyl compounds.

本文报道了关于$\left( R\right) - \left( +\right)$ -哈尔明碱全合成的研究。通过基于$\alpha$ -重氮-$\beta$ -羰基化合物光诱导Wolff重排的方法，完成了$\left( R\right) - \left( +\right)$ -哈尔明碱主要骨架吡咯烷酮的对映选择性合成。

Keywords diastereoselective synthesis, (R)-( + )-harmicine, diazo compounds, Wolff rearrangement, photo-induced reaction

关键词 非对映选择性合成，(R)-( + )-哈尔明碱，重氮化合物，Wolff重排，光诱导反应

Introduction

引言

(R)-(+)-Harmicine (1), a tetracyclic $\beta$ -carboline alkaloid, was first isolated from the leaves of Kopsia grif-fithii by Sim et al. ${}^{\left\lbrack 1\right\rbrack }$ in 1998. This natural product contains a tetrahydro- $\beta$ -carboline unit and a pyrrolidine unit. It exhibits strong anti-leishmania activity. The synthesis of $\left( R\right)$ -(+)-harmicine has attracted great interest because of its unique structure and potential biological activities. A variety of investigations on the synthesis of harmicine have been reported, either in the form of racemic mixture or in the form of optically pure isomers. Knölker and Agarwal reported the first synthesis of racemic harmcine, starting from 4,9-dihydro-3H-pyrido- $\left\lbrack {3,4 - b}\right\rbrack$ indole. ${}^{\left\lbrack 2\mathrm{a}\right\rbrack }$ Three years later, another three-step approach of the synthesis of racemic harmcine was completed from the readily available 4,4-diethoxybutan- 1-amine. ${}^{\left\lbrack 2b\right\rbrack }$ Subsequently, Czarnocki and coworkers achieved the enantioselective synthesis of optically pure $\left( R\right)$ -(+)-harmicine via the asymmetric transfer hydrogenation (ATH) reaction in 2007. ${}^{\left\lbrack 3\mathrm{a}\right\rbrack }$ In the same year, Allin and coworkers completed a facile asymmetric synthesis of $\left( R\right)$ -(+)-harmicine via a step of highly di-atereoselective $N$ -acyliminium cyclzation methodology developed by the same group. ${}^{\left\lbrack 3b\right\rbrack }$ On the other hand, Jacobsen and coworkers completed the synthesis of $\left( R\right)$ -(+)-harmicine starting from tryptamine. The key step in Jacobsen’s synthesis is the enantioselective Pictet-Spengler-type cyclization of hydroxylactam by chiral thiourea catalysis. ${}^{\left\lbrack 4\mathrm{a}\right\rbrack }$ More recently, a cascade one pot condensation including intramolecauler cyclization and Pictet-Spengler reaction for the synthesis of racemic harmicine was completed by Jana and coworker. ${}^{\left\lbrack 4\mathrm{\;b}\right\rbrack }$ In 2009, Ojima and coworkers reported the efficient preparation of racemic harmicine, employing their newly developed Rh-catalyzed cyclohydrocarbon-ylation-bicyclization of $N$ -allylic amides of arylacetic acids. ${}^{\left\lbrack 5\right\rbrack }$ Previous literatures have showed that most of the syntheses of harmicine starts from tryptamine, and the chiral centers are established through asymmetric catalytic reactions. In general, chiral ligands with complicated structure are needed to achieve the high enanti-oselectivity.

(R)-(+)-哈尔米辛(1)是一种四环$\beta$-咔啉生物碱，于1998年由西姆等人${}^{\left\lbrack 1\right\rbrack }$首次从印度萝芙木的叶子中分离出来。这种天然产物含有一个四氢$\beta$-咔啉单元和一个吡咯烷单元。它具有很强的抗利什曼原虫活性。由于其独特的结构和潜在的生物活性，$\left( R\right)$-(+)-哈尔米辛的合成引起了极大的兴趣。关于哈尔米辛合成的各种研究已经报道，既有外消旋混合物形式的，也有光学纯异构体形式的。克诺尔克和阿加瓦尔报道了从4,9-二氢-3H-吡啶$\left\lbrack {3,4 - b}\right\rbrack$吲哚开始的外消旋哈尔米辛的首次合成。${}^{\left\lbrack 2\mathrm{a}\right\rbrack }$三年后，另一种从易得的4,4-二乙氧基丁-1-胺完成外消旋哈尔米辛合成的三步方法也完成了。${}^{\left\lbrack 2b\right\rbrack }$随后，查诺茨基及其同事在2007年通过不对称转移氢化(ATH)反应实现了光学纯$\left( R\right)$-(+)-哈尔米辛的对映选择性合成。${}^{\left\lbrack 3\mathrm{a}\right\rbrack }$同年，阿林及其同事通过同一小组开发的一步高非对映选择性$N$-酰基亚胺离子环化方法完成了$\left( R\right)$-(+)-哈尔米辛的简便不对称合成。${}^{\left\lbrack 3b\right\rbrack }$另一方面，雅各布森及其同事从色胺开始完成了$\left( R\right)$-(+)-哈尔米辛的合成。雅各布森合成的关键步骤是通过手性硫脲催化的羟基内酰胺的对映选择性Pictet-Spengler型环化反应。${}^{\left\lbrack 4\mathrm{a}\right\rbrack }$最近，贾纳及其同事完成了一种包括分子内环化和Pictet-Spengler反应的级联一锅缩合反应，用于合成外消旋哈尔米辛。${}^{\left\lbrack 4\mathrm{\;b}\right\rbrack }$2009年，大岛及其同事报道了使用他们新开发的铑催化的芳基乙酸$N$-烯丙基酰胺的环氢化-双环化反应高效制备外消旋哈尔米辛。${}^{\left\lbrack 5\right\rbrack }$以前的文献表明，大多数哈尔米辛的合成都是从色胺开始的，并且手性中心是通过不对称催化反应建立的。一般来说，需要结构复杂的手性配体才能实现高对映选择性。

Recently, we have developed a new approach toward the enantioselective construction of pyrrolidine ring, based on diastereoselective nucleophilic addition of lithium enolate of $\alpha$ -diazoacetate to chiral $N$ -sulfinyl imine and Wolff rearrangement. ${}^{\left\lbrack 6 - 8\right\rbrack }$ Herein, we report the application of this methodology in the synthesis of (R)-(+)-harmicine (1) (Figure 1).

最近，我们基于$\alpha$-重氮乙酸酯的烯醇锂对手性$N$-亚磺酰亚胺的非对映选择性亲核加成和Wolff重排，开发了一种对映选择性构建吡咯烷环的新方法。${}^{\left\lbrack 6 - 8\right\rbrack }$在此，我们报道该方法在合成(R)-(+)-哈尔米辛(1)(图1)中的应用。

Experimental

实验

All reactions with air- and moisture-sensitive components were performed under a nitrogen atmosphere. Anhydrous ethyl ether, toluene, benzene and tetrahydrofuran were freshly distilled from Na before use. Dichloromethane was distilled from calcium hydride. The boiling point of petroleum ether is between 60 and 90 °C. 200—300 mesh silica gel for the chromatography was employed. ${}^{1}\mathrm{H}$ NMR (300 MHz) and ${}^{13}\mathrm{C}$ NMR (70 MHz) spectra were measured on a Bruker-400 ARX spectrometer. Chemical shifts are reported relative to tetramethylsilane (TMS) as the internal standard. Mass spectra were determined on a VG ZAB-HS mass spectrometer. IR was recorded with a Nicolet Avatar 330 FT-IR infrared spectrometer.

所有涉及对空气和湿气敏感组分的反应均在氮气气氛下进行。无水乙醚、甲苯、苯和四氢呋喃在使用前均用金属钠新鲜蒸馏。二氯甲烷用氢化钙蒸馏。石油醚的沸点在60至90 °C之间。使用200 - 300目的硅胶进行柱色谱。${}^{1}\mathrm{H}$ NMR (300 MHz) 和 ${}^{13}\mathrm{C}$ NMR (70 MHz) 谱在Bruker - 400 ARX光谱仪上测定。化学位移以四甲基硅烷 (TMS) 为内标进行报告。质谱在VG ZAB - HS质谱仪上测定。红外光谱用Nicolet Avatar 330傅里叶变换红外光谱仪记录。

Received July 3, 2012; accepted August 29, 2012.

2012年7月3日收到；2012年8月29日接受。

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200672 or from the author.

本文的支持信息可从以下网址获取:http://dx.doi.org/10.1002/cjoc.201200672 或向作者索取。

1_152_216_627_597_0.jpg

Figure 1 Synthetic plan for $\left( R\right) - \left( +\right)$ -harmicine (1).

图1 $\left( R\right) - \left( +\right)$ -哈尔米辛 (1) 的合成路线

Ethyl 1H-indole-2-carboxylate (3) ${}^{\left\lbrack 9\right\rbrack }$

1H-吲哚-2-羧酸乙酯(3) ${}^{\left\lbrack 9\right\rbrack }$

1H-Indole-2-carboxylic acid (2) (2.0 g, 12.4 mmol) was dissolved in absolute ethanol $\left( {{12}\mathrm{\;{mL}}}\right)$ and cooled to 0 °C by ice-water bath. Sulfuryl dichloride (1.6 mL, 22.4 mmol, 2 equiv.) was added to the solution dropwise and the mixture was then refluxed for another $2\mathrm{\;h}$ while monitored by TLC. Ethanol and excessive sulfuryl dichloride were evaporated under vacuum upon completion of the reaction. Dichoromethane (20 mL) was added to dissolve the crude product. The solution was washed by saturated aqueous sodium carbonate (25 $\mathrm{{mL}} \times 2$ ), and the combined organic layer was dried over anhydrous sodium sulfate. Crude product 3 was obtained as yellow oil after removing the solvent under vacuum. ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {9.22}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ , 7.70—7.67 (m, 1H), 7.44—7.41 (m, 1H), 7.34—7.29 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{7.24} - {7.23}\left( {\mathrm{m},1\mathrm{H}}\right) ,{7.17} - {7.12}\left( {\mathrm{m},1\mathrm{H}}\right) ,{4.42} \; \left( {\mathrm{q}, J = {7.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{1.42}\left( {\mathrm{t}, J = {7.2}\mathrm{\;{Hz}},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$ (75 MHz, CDCl3) 6: 162.1, 136.8, 127.4, 125.2, 122.5, 120.7, 111.8, 108.6, 61.0, 14.3.

1H-吲哚-2-羧酸(2)(2.0 g, 12.4 mmol)溶于无水乙醇$\left( {{12}\mathrm{\;{mL}}}\right)$，用冰水浴冷却至0°C。向溶液中滴加二氯亚砜(1.6 mL, 22.4 mmol, 2当量)，然后将混合物回流另外$2\mathrm{\;h}$，同时用TLC监测。反应完成后，在真空下蒸发乙醇和过量的二氯亚砜。加入二氯甲烷(20 mL)溶解粗产物。溶液用饱和碳酸钠水溶液(25 $\mathrm{{mL}} \times 2$)洗涤，合并的有机层用无水硫酸钠干燥。在真空下除去溶剂后，得到黄色油状的粗产物3。${}^{1}\mathrm{H}$核磁共振(300 MHz, ${\mathrm{{CDCl}}}_{3}$) $\delta : {9.22}\left( {\mathrm{\;s},1\mathrm{H}}\right)$, 7.70 - 7.67(m, 1H), 7.44 - 7.41(m, 1H), 7.34 - 7.29 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{7.24} - {7.23}\left( {\mathrm{m},1\mathrm{H}}\right) ,{7.17} - {7.12}\left( {\mathrm{m},1\mathrm{H}}\right) ,{4.42} \; \left( {\mathrm{q}, J = {7.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{1.42}\left( {\mathrm{t}, J = {7.2}\mathrm{\;{Hz}},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$(75 MHz, CDCl3) 6: 162.1, 136.8, 127.4, 125.2, 122.5, 120.7, 111.8, 108.6, 61.0, 14.3。

Ethyl 1-benzyl-1H-indole-2-carboxylate ${\left( 4\right) }^{\left\lbrack 9\right\rbrack }$

1-苄基-1H-吲哚-2-羧酸乙酯 ${\left( 4\right) }^{\left\lbrack 9\right\rbrack }$

Well powdered potassium hydroxide (1.9 g, 34 mmol) was dissolved in anhydrous DMSO (20 mL) under stirring in a ${100}\mathrm{{mL}}$ round-bottomed flask. Carboxylate (3) (1.6 g, 8.5 mmol) was added to the solution and the mixture was stirred for ${30}\mathrm{\;{min}}$ to give yellow solution. Then benzyl bromide (2 mL, 17 mmol) was added and the solution was stirred for $1\mathrm{\;h}$ while monitored by TLC. The mixture was cooled to $0{}^{ \circ }\mathrm{C}$ and the excessive potassium hydroxide was neutralized by saturated aqueous ammonium chloride solution. Ethyl ether $\left( {{30}\mathrm{\;{mL}} \times 2}\right)$ was added to extract the product and organic layers were combined and washed by deionized water $\left( {{20}\mathrm{\;{mL}}}\right)$ . The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporator under vacuum. The residue was purified by flash column chromatography (petroleum : ethyl acetate $= {30}\text{ : }1, V\text{ : }V)$ on silica gel to give carboxylate (4) in 97% yield (2.3 g). White solid; ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {7.70} - {7.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.43} - {7.36}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , 7.34-7.28 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{7.24} - {7.10}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{7.04} - {7.01} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{5.82}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{4.30}\left( {\mathrm{q}, J = {7.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{1.32}(\mathrm{t}$ , $J = {7.2}\mathrm{\;{Hz}},3\mathrm{H});{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta : {161.8}$ , 139.4, 138.2, 128.4, 127.6, 127.0, 126.1, 126.0, 125.1, 122.5, 120.7, 110.9, 110.7, 60.5, 47.7, 14.2.

将充分研细的氢氧化钾(1.9 g，34 mmol)在一个${100}\mathrm{{mL}}$圆底烧瓶中于搅拌下溶解于无水二甲基亚砜(20 mL)中。向该溶液中加入羧酸酯(3)(1.6 g，8.5 mmol)，并将混合物搅拌${30}\mathrm{\;{min}}$以得到黄色溶液。然后加入苄基溴(2 mL，17 mmol)，并将溶液搅拌$1\mathrm{\;h}$，同时通过薄层色谱法进行监测。将混合物冷却至$0{}^{ \circ }\mathrm{C}$，并用饱和氯化铵水溶液中和过量的氢氧化钾。加入乙醚$\left( {{30}\mathrm{\;{mL}} \times 2}\right)$以萃取产物，合并有机层并用去离子水$\left( {{20}\mathrm{\;{mL}}}\right)$洗涤。有机层用无水硫酸钠干燥，然后通过蒸发器在真空下去除溶剂。残余物通过快速柱色谱法(硅胶上的石油醚:乙酸乙酯$= {30}\text{ : }1, V\text{ : }V)$)纯化，以97%的产率得到羧酸酯(4)(2.3 g)。白色固体；${}^{1}\mathrm{H}$核磁共振(300 MHz，${\mathrm{{CDCl}}}_{3}$)$\delta : {7.70} - {7.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.43} - {7.36}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，7.34 - 7.28$\left( {\mathrm{m},2\mathrm{H}}\right) ,{7.24} - {7.10}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{7.04} - {7.01} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{5.82}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{4.30}\left( {\mathrm{q}, J = {7.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{1.32}(\mathrm{t}$，$J = {7.2}\mathrm{\;{Hz}},3\mathrm{H});{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta : {161.8}$，139.4，138.2，128.4，127.6，127.0，126.1，126.0，125.1，122.5，120.7，110.9，110.7，60.5，47.7，14.2。

(1-Benzyl-1H-indol-2-yl)methanol (5) and 1-benzyl- 1H-indole-2-carbaldehyde (6)

(1-苄基-1H-吲哚-2-基)甲醇(5)和1-苄基-1H-吲哚-2-甲醛(6)

Carboxylate (4) (4.853 g, 17.4 mmol) was added to a 500 mL round bottom flask and dissolved in THF (100 mL). The solution was cooled to $0{}^{ \circ }\mathrm{C}$ and lithium aluminium hydride (660 mg, 17.4 mmol) was added slowly. The system was stirred for ${30}\mathrm{\;{min}}$ at $0{}^{ \circ }\mathrm{C}$ until the starting material was completely consumed. Aqueous sodium hydroxide (15%, 20 mL) and deionized water $\left( {{40}\mathrm{\;{mL}}}\right)$ was added gradually to quench the reaction and the precipitate was filtered and washed by ethyl acetate. Organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum and the crude alcohol (5) was then dissolved with dichloromethane (25 mL). Manganese dioxide $\left( {{7.57}\mathrm{\;g},{87}\mathrm{{mmol}}}\right)$ was added to the solution and the mixture was stirred for another ${32}\mathrm{\;h}$ while monitored by TLC. Excessive manganese dioxide was filtered and washed by ethyl acetate. The filtration was evaporated under vacuum to remove the solvent. The residue was purified by flash column chromatography (petroleum : ethyl acetate $= {50}\text{ : }1, V\text{ : }V)$ on silica gel to yield carbaldehyde (6) (2.954 g). Compound (5): ${}^{1}\mathrm{H}$ NMR (300 MHz, CDCl3) δ: 7.61-7.58 (m, 1H), 7.24-7.06 (m, 6H), 6.95-6.92 (m, 2H), 6.46 (s, 1H), ${5.36}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{4.61}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.87}\left( {\mathrm{\;s},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, CDC1, 3 ) & 138.6, 137.9, 137.8, 128.7, 127.3, 127.2, 125.9, 122.2, 120.8, 119.8, 109.7, 102.1, 57.4, 46.7. Compound (6): white solid; 72% yield by two steps; ${}^{1}\mathrm{H}$ NMR (300 Hz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {9.89}$ (s, $1\mathrm{H}$ ), 7.76-7.73 (m, 1H), 7.37-7.31 (m, 3H), 7.27-7.14 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{7.09} - {7.07}\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.82}\left( {\mathrm{\;s},2\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$ (75 Hz, CDCl3) δ: 182.5, 142.3, 140.5, 137.6, 135.3, 128.5, 127.2, 127.1, 126.5, 123.4, 121.1, 118.2, 110.9, 47.8.

将羧酸盐(4)(4.853 g，17.4 mmol)加入到500 mL圆底烧瓶中，溶于四氢呋喃(100 mL)。溶液冷却至$0{}^{ \circ }\mathrm{C}$，缓慢加入氢化铝锂(660 mg，17.4 mmol)。体系在$0{}^{ \circ }\mathrm{C}$搅拌${30}\mathrm{\;{min}}$，直至原料完全消耗。逐渐加入15%的氢氧化钠水溶液(20 mL)和去离子水$\left( {{40}\mathrm{\;{mL}}}\right)$淬灭反应，过滤沉淀并用乙酸乙酯洗涤。分离有机层，用无水硫酸钠干燥。在真空下蒸发除去溶剂，粗醇(5)随后溶于二氯甲烷(25 mL)。向溶液中加入二氧化锰$\left( {{7.57}\mathrm{\;g},{87}\mathrm{{mmol}}}\right)$，混合物再搅拌${32}\mathrm{\;h}$，同时用薄层色谱监测。过滤除去过量的二氧化锰，并用乙酸乙酯洗涤。滤液在真空下蒸发以除去溶剂。残余物通过硅胶柱快速柱色谱法(石油醚:乙酸乙酯$= {50}\text{ : }1, V\text{ : }V)$)纯化，得到醛(6)(2.954 g)。化合物(5):${}^{1}\mathrm{H}$核磁共振(300 MHz，CDCl3)δ:7.61 - 7.58(m，1H)，7.24 - 7.06(m，6H)，6.95 - 6.92(m，2H)，6.46(s，1H)，${5.36}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{4.61}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{1.87}\left( {\mathrm{\;s},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(75 MHz，CDC1,3)& 138.6，137.9，137.8，128.7，127.3，127.2，125.9，122.2，120.8，119.8，109.7，102.1，57.4，46.7。化合物(6):白色固体；两步产率72%；${}^{1}\mathrm{H}$核磁共振(300 Hz，${\mathrm{{CDCl}}}_{3}$)$\delta : {9.89}$(s，$1\mathrm{H}$)，7.76 - 7.73(m，1H)，7.37 - 7.31(m，3H)，7.27 - 7.14 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{7.09} - {7.07}\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.82}\left( {\mathrm{\;s},2\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$(75 Hz，CDCl3)δ:182.5，142.3，140.5，137.6，135.3，128.5，127.2，127.1，126.5，123.4，121.1，118.2，110.9，47.8。

(1H-Indol-2-yl) methanol (13) ${}^{\left\lbrack {11}\right\rbrack }$

(1H-吲哚-2-基)甲醇(13) ${}^{\left\lbrack {11}\right\rbrack }$

Lithium aluminum hydride (1.5 equiv.) was added by portion to the solution of crude product (3) (1 mmol) in THF (100 mL) under vigorous stirring. Several drops of aqueous sodium hydroxide (15%) and deionized water $\left( {{50}\mathrm{\;{mL}}}\right)$ were gradually added to the reaction system. The white precipitation was filtered and washed with ethyl acetate. The organic layer of filtration was separated and the water layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was removed by evaporator under vacuum. The crude residue was purified by flash column chromatography (petroleum : ethyl acetate $= {30} : 1, V : V$ ) on silica gel to yield a pale solid compound (13) (>99%). ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {8.34}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.57} - {7.48}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.24} - {7.02} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{6.33}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{4.65}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{2.45}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ .

在剧烈搅拌下，将氢化铝锂(1.5当量)分批加入到粗产物(3)(1毫摩尔)在四氢呋喃(100毫升)中的溶液中。向反应体系中逐渐加入几滴氢氧化钠水溶液(15%)和去离子水$\left( {{50}\mathrm{\;{mL}}}\right)$。过滤白色沉淀并用乙酸乙酯洗涤。分离过滤的有机层，水层用乙酸乙酯萃取。合并有机层，用无水硫酸钠干燥，并用蒸发器在真空下去除溶剂。粗残余物通过在硅胶上的快速柱色谱法(石油醚:乙酸乙酯$= {30} : 1, V : V$)纯化，得到浅色固体化合物(13)(>99%)。${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta : {8.34}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.57} - {7.48}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.24} - {7.02} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{6.33}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{4.65}\left( {\mathrm{\;s},2\mathrm{H}}\right) ,{2.45}\left( {\mathrm{\;s},1\mathrm{H}}\right)$。

tert-Butyl 2-formyl-1H-indole-1-carboxylate (15) ${}^{\left\lbrack {11},{12}\right\rbrack }$

2-甲酰基-1H-吲哚-1-羧酸叔丁酯(15) ${}^{\left\lbrack {11},{12}\right\rbrack }$

Alcohol (13) (4.551 g, 31 mmol) was dissolved to dichloromethane (100 mL) in a ${500}\mathrm{\;{mL}}$ round-bottomed flask under stirring. Manganese dioxide (13.5 g, 155 mmol, 5 equiv.) was then added to the solution and the mixture was stirred for another ${40}\mathrm{\;h}$ while monitored by TLC. The excessive manganese dioxide was filtered and washed by ethyl acetate. The filtration was evaporated under vacuum to afford the crude aldehyde (14). The crude product was dissolved in THF and cooled to $0{}^{ \circ }\mathrm{C}$ by ice-water bath. Then triethyl amine $({3.7}\mathrm{\;g},{1.2}$ equiv.), di-tert-butyl dicarbonate $\left( {{\mathrm{{Boc}}}_{2}\mathrm{O},{7.9}\mathrm{\;g},{1.2}}\right.$ equiv.) and ${N}^{\prime },{N}^{\prime }$ -dimethylaminopyridine (DMAP,380 mg, 10 mol%) were added to the solution. The ice-water bath was removed and the mixture was stirred for another $2\mathrm{\;h}$ at room temperature. The solvent was evaporated under vacuum and the residue was purified by flash column chromatography (petroleum : ethyl acetate $= {40}\text{ : }1, V\text{ : }V)$ on silica gel to yield aldehyde (15) (87% yield for two steps). Aldehyde (14), white solid; ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {9.86}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{9.72}(\mathrm{\;s}$ , 1H), ${7.83} - {7.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.58} - {7.48}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , 7.42-7.38 (m, 1H), 7.29-7.25 (m, 1H), 7.20-7.11 (m, 1H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) δ: 182.3, 138.2, 135.8, 127.1, 123.3, 121.3, 121.0, 115.0, 112.6. Aldehyde (15): ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ : 10.43 (s, 1H), ${8.18} - {8.15}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.68} - {7.65}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , 7.51-7.43 (m, 1H), 7.32-7.26 (m, 1H), 1.72 (s, 9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ : 184.0,149.7,137.7, 128.1, 127.3, 123.7, 123.0, 116.3, 116.2, 115.9, 85.5, 28.0.

将醇(13)(4.551 g, 31 mmol)溶解于置于${500}\mathrm{\;{mL}}$圆底烧瓶中的二氯甲烷(100 mL)中，搅拌。然后向溶液中加入二氧化锰(13.5 g, 155 mmol, 5当量)，混合物再搅拌${40}\mathrm{\;h}$，同时用薄层色谱法监测。过滤除去过量的二氧化锰，并用乙酸乙酯洗涤。滤液在真空下蒸发，得到粗醛(14)。将粗产物溶于四氢呋喃，用冰水浴冷却至$0{}^{ \circ }\mathrm{C}$。然后向溶液中加入三乙胺$({3.7}\mathrm{\;g},{1.2}$当量)、二叔丁基二碳酸酯$\left( {{\mathrm{{Boc}}}_{2}\mathrm{O},{7.9}\mathrm{\;g},{1.2}}\right.$当量)和${N}^{\prime },{N}^{\prime }$-二甲基氨基吡啶(DMAP, 380 mg, 10摩尔%)。移去冰水浴，混合物在室温下再搅拌$2\mathrm{\;h}$。在真空下蒸发溶剂，残余物通过快速柱色谱法(硅胶上的石油醚:乙酸乙酯$= {40}\text{ : }1, V\text{ : }V)$)纯化，得到醛(15)(两步产率87%)。醛(14)，白色固体；${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta : {9.86}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{9.72}(\mathrm{\;s}$，1H)，${7.83} - {7.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.58} - {7.48}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，7.42 - 7.38(多重峰，1H)，7.29 - 7.25(多重峰，1H)，7.20 - 7.11(多重峰，1H)；${}^{13}\mathrm{C}$核磁共振(75兆赫，氯仿-d) δ: 182.3, 138.2, 135.8, 127.1, 123.3, 121.3, 121.0, 115.0, 112.6。醛(15): ${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta$: 10.43(单峰，1H)，${8.18} - {8.15}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.68} - {7.65}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，7.51 - 7.43(多重峰，1H)，7.32 - 7.26(多重峰，1H)，1.72(单峰，9H)；${}^{13}\mathrm{C}$核磁共振(75兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta$: 184.0,149.7,137.7, 128.1, 127.3, 123.7, 123.0, 116.3, 116.2, 115.9, 85.5, 28.0。

General procedures for the preparation of sulfinim- ide (8) and (16)

制备亚磺酰亚胺(8)和(16)的一般步骤

Carbaldehyde (6) or (15) (13.7 mmol) was added to a ${500}\mathrm{\;{mL}}$ round-bottomed flask and dissolved in dichloromethane (100 mL). Chiral sulfinamide (7) (2.3 g, 15 mmol) and $\mathrm{{Ti}}{\left( {\mathrm{O}}^{i}\mathrm{{Pr}}\right) }_{4}$ (12.3 mL,41 mmol) were added to the solution and the mixture was refluxed for 5 h to complete the reaction. The system was cooled to 0 °C and was then quenched by saturated aqueous sodium dicarbonate. The yellow precipitation was filtered and washed with dichloromethane. Organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum and the crude residue was purified by flash column chromatography (petroleum : ethyl acetate $= {15}\text{ : }1, V\text{ : }V)$ on silica gel to yield the sulfinimide (8) or (16).

将醛(6)或(15)(13.7 mmol)加入到一个${500}\mathrm{\;{mL}}$圆底烧瓶中，并溶于二氯甲烷(100 mL)。将手性亚磺酰胺(7)(2.3 g, 15 mmol)和$\mathrm{{Ti}}{\left( {\mathrm{O}}^{i}\mathrm{{Pr}}\right) }_{4}$(12.3 mL, 41 mmol)加入到该溶液中，混合物回流5小时以完成反应。将体系冷却至0°C，然后用饱和碳酸氢钠水溶液淬灭。过滤黄色沉淀并用二氯甲烷洗涤。分离有机层并用无水硫酸钠干燥。通过真空蒸发除去溶剂，粗残余物通过在硅胶上用石油醚:乙酸乙酯$= {15}\text{ : }1, V\text{ : }V)$进行快速柱色谱纯化，得到亚磺酰亚胺(8)或(16)。

$\left( {S, Z}\right) - N$ -((1-Benzyl-1H-indol-2-yl)methylene)-4-mthyl benzenesulfinimide (8)

$\left( {S, Z}\right) - N$ -((1-苄基-1H-吲哚-2-基)亚甲基)-4-甲基苯亚磺酰亚胺(8)

Pale yellow oil,85% yield, ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {116.9}({c1.5}$ in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 $\mathrm{{Hz}},{\mathrm{{CDCl}}}_{3}$ ) $\delta$ : ${8.77}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ , 7.70—7.67 (m, 1H), 7.41—7.38 (m, 2H), 7.29—7.27 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{7.17} - {7.10}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{6.92} - {6.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{5.92} \; \left( {\mathrm{d}, J = {6.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.75}\left( {\mathrm{\;d}, J = {6.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.35}(\mathrm{\;s}$ , 3H); ${}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {151.5},{142.0},{141.3}$ , 140.6, 137.7, 133.0, 129.6, 128.3, 126.9, 126.1, 125.9, 124.5, 122.5, 120.8, 115.1, 110.4, 48.0, 21.3; IR (film) v: 3054, 3031, 2922, 1586, 1451, 1352, 1094, 1070, 807, 749,736,725,694,684 ${\mathrm{{cm}}}^{-1}$ ; EI-MS $(m/z$ , relative intensity): 278 (14), 232 (69), 139 (53), 123 (24), 91 (100), 65 (30). HRMS (ESI) calcd for ${\mathrm{C}}_{23}{\mathrm{H}}_{21}{\mathrm{\;N}}_{2}\mathrm{{OS}}\left( {\mathrm{M} + \mathrm{H}}\right)$ 373.1369; found 373.1368.

浅黄色油状物，产率85%，${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {116.9}({c1.5}$于${\mathrm{{CHCl}}}_{3}$中); ${}^{1}\mathrm{H}$核磁共振(300 $\mathrm{{Hz}},{\mathrm{{CDCl}}}_{3}$ ) $\delta$ : ${8.77}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ ，7.70—7.67(多重峰，1H)，7.41—7.38(多重峰，2H)，7.29—7.27 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{7.17} - {7.10}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{6.92} - {6.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{5.92} \; \left( {\mathrm{d}, J = {6.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.75}\left( {\mathrm{\;d}, J = {6.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.35}(\mathrm{\;s}$ ，3H); ${}^{13}\mathrm{C}$核磁共振(75兆赫，${\mathrm{{CDCl}}}_{3}$ ) $\delta : {151.5},{142.0},{141.3}$ ，140.6，137.7，133.0，129.6，128.3，126.9，126.1，125.9，124.5，122.5，120.8，115.1，110.4，48.0，21.3;红外光谱(薄膜)v: 3054，3031，2922，1586，1451，1352，1094，1070，807，749，736，725，694，684 ${\mathrm{{cm}}}^{-1}$ ;电子轰击质谱$(m/z$ ，相对强度):278(14)，232(69)，139(53)，123(24)，91(100)，65(30)。高分辨质谱(电喷雾电离)计算值为${\mathrm{C}}_{23}{\mathrm{H}}_{21}{\mathrm{\;N}}_{2}\mathrm{{OS}}\left( {\mathrm{M} + \mathrm{H}}\right)$ 373.1369;实测值为373.1368。

(S, Z)-tert-Butyl 2-((p-tolylsulfinylimino)methyl)-1H- indole-1-carboxylate (16)

(S, Z)-2-((对甲苯基亚磺酰亚氨基)甲基)-1H-吲哚-1-羧酸叔丁酯(16)

Yellow solid, 90% yield, ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {44.5}({c1.0}$ in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {9.35}$ (s, $1\mathrm{H}$ ), ${8.28} - {8.12}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.72} - {7.57}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{7.44} - {7.23} \; \left( {\mathrm{m},5\mathrm{H}}\right) ,{2.40}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{1.72}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ :154.0,149.7,141.7,141.6,137.9,134.9, 129.8, 128.1, 126.9, 124.7, 123.5, 122.0, 115.9, 114.0, 85.5, 28.2, 21.4; IR (film) v: 2974, 1736, 1570, 1534, 1441, 1382, 1327, 1219, 1159, 1120, 1098, 747, 675 ${\mathrm{{cm}}}^{-1}$ ; EI-MS (m/z, relative intensity): 242 (5),169 (10), 142 (100), 91 (32), 57 (81), 41 (39). Anal. calcd for ${\mathrm{C}}_{21}{\mathrm{H}}_{22}{\mathrm{\;N}}_{2}{\mathrm{O}}_{3}\mathrm{\;S} : \mathrm{C}{65.95},\mathrm{H}{5.80},\mathrm{\;N}{7.32}$ ; found $\mathrm{C}{65.95}$ , H 5.85, N 7.31.

黄色固体，产率90%，${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {44.5}({c1.0}$于${\mathrm{{CHCl}}}_{3}$中); ${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta : {9.35}$(单峰，$1\mathrm{H}$)，${8.28} - {8.12}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.72} - {7.57}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{7.44} - {7.23} \; \left( {\mathrm{m},5\mathrm{H}}\right) ,{2.40}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{1.72}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(75兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta$:154.0,149.7,141.7,141.6,137.9,134.9, 129.8, 128.1, 126.9, 124.7, 123.5, 122.0, 115.9, 114.0, 85.5, 28.2, 21.4;红外(薄膜)v: 2974, 1736, 1570, 1534, 1441, 1382, 1327, 1219, 1159, 1120, 1098, 747, 675 ${\mathrm{{cm}}}^{-1}$;电子轰击质谱(质荷比，相对强度): 242(5),169(10), 142(100), 91(32), 57(81), 41(39)。分析计算值为${\mathrm{C}}_{21}{\mathrm{H}}_{22}{\mathrm{\;N}}_{2}{\mathrm{O}}_{3}\mathrm{\;S} : \mathrm{C}{65.95},\mathrm{H}{5.80},\mathrm{\;N}{7.32}$;实测值$\mathrm{C}{65.95}$，氢5.85，氮7.31。

General procedure for preparation of sulfinimide (10) and (17)

制备亚磺酰亚胺 (10) 和 (17) 的通用方法

LiHMDS (2 mL, 2 equiv., 1.0 mol/L solution in cyclohexane) was added to chilly solution of chiral sulfinimide (8) in dichloromethane (10 mL) at -78 °C. Then the solution of diazoester (9) (1.5 equiv.) in dichloromethane was added dropwise to the mixture in 5 min. The system was stirred for another 15 min until no sulfinimide could be monitored by TLC. Saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction and the solid was melted by warm blowing. Deionized water $\left( {{10}\mathrm{\;{mL}}}\right)$ was added to the system and dicholoromethane was used to extract the product $\left( {{20}\mathrm{\;{mL}} \times 2}\right)$ . Organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum and the crude residue was purified by flash column chromatography (petroleum : ethyl acetate $= 3 : 1, V : V$ ) on silica gel to afford the corresponding diazoester.

将LiHMDS(2 mL，2当量，1.0 mol/L环己烷溶液)加入到-78℃下二氯甲烷(10 mL)中的手性亚磺酰亚胺 (8) 的冰冷溶液中。然后在5分钟内将重氮酯 (9)(1.5当量)的二氯甲烷溶液滴加到混合物中。将体系再搅拌15分钟，直到TLC监测不到亚磺酰亚胺。加入饱和氯化铵水溶液(10 mL)淬灭反应，通过温热吹气使固体熔化。向体系中加入去离子水$\left( {{10}\mathrm{\;{mL}}}\right)$，并用二氯甲烷萃取产物$\left( {{20}\mathrm{\;{mL}} \times 2}\right)$。合并有机层，用无水硫酸钠干燥。通过在硅胶上进行快速柱色谱(石油醚:乙酸乙酯$= 3 : 1, V : V$)蒸发除去溶剂，得到相应的重氮酯。

(R)-Allyl 5-(1-benzyl-1H-indol-2-yl)-2-diazo-5-((S)-4- methylphenylsulfinamido)-3-oxo-pentanoate (10)

(R)-5-(1-苄基-1H-吲哚-2-基)-2-重氮基-5-((S)-4-甲基苯亚磺酰胺基)-3-氧代戊酸烯丙酯(10)

Yellow oil, yield ${77}\% ,{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {26.4}({c0.86}$ in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {7.63} - {7.57}(\mathrm{\;m}$ , 1H), 7.34-7.20 (m, 6H), 7.16-7.01 (m, 6H), 6.55 (s, 1H), 5.98-5.85 (m, 1H), 5.58 (dd, J=23.4, 6.3 Hz, 2H), 5.37-5.22 (m, 3H), 4.69 (d, J=5.7 Hz, 2H), 4.61 (d, $J = {8.4}\mathrm{\;{Hz}},1\mathrm{H}),{3.74}$ (dd, $J = {17.4},{10.2}\mathrm{\;{Hz}},1\mathrm{H}$ ), ${3.51}\left( {\mathrm{{dd}}, J = {17.4},{11.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.34}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$ (75 MHz, CDC1, 5) & 189.4, 160.6, 141.8, 141.3, 138.9, 137.5, 137.4, 131.2, 129.3, 128.6, 127.2, 127.2, 126.1, 125.1, 122.2, 120.7, 119.9, 119.2, 109.9, 100.9, 65.8, 48.1, 46.7, 45.9, 21.2; IR (film) v: 3031, 2137, 1715, 1649, 1462, 1452, 1371, 1302, 1086, 1065, 1017, 831, ${730}{\mathrm{\;{cm}}}^{-1}$ ; EI-MS $\left( {m/z\text{ , relative intensity }}\right) : {390}\left( {13}\right) ,{374} \; \left( 4\right) ,{333}\left( 5\right) ,{299}\left( 5\right) ,{218}\left( 7\right) ,{124}\left( 7\right) ,{91}\left( {100}\right) ,{65}\left( {11}\right) ,$ 28 (71); HRMS (ESI) calcd for ${\mathrm{C}}_{30}{\mathrm{H}}_{29}{\mathrm{\;N}}_{4}{\mathrm{O}}_{4}\mathrm{\;S}\left( {\mathrm{M} + \mathrm{H}}\right)$ 541.19040, found 541.1909.

黄色油状物，在${77}\% ,{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {26.4}({c0.86}$中的产率为${\mathrm{{CHCl}}}_{3}$；${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$) $\delta : {7.63} - {7.57}(\mathrm{\;m}$，1H)，7.34 - 7.20(多重峰，6H)，7.16 - 7.01(多重峰，6H)，6.55(单峰，1H)，5.98 - 5.85(多重峰，1H)，5.58(双重双重峰，J = 23.4，6.3赫兹，2H)，5.37 - 5.22(多重峰，3H)，4.69(双重峰，J = 5.7赫兹，2H)，4.61(双重峰，$J = {8.4}\mathrm{\;{Hz}},1\mathrm{H}),{3.74}$(双重双重峰，$J = {17.4},{10.2}\mathrm{\;{Hz}},1\mathrm{H}$)，${3.51}\left( {\mathrm{{dd}}, J = {17.4},{11.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.34}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$(75兆赫，CDC1，5)和189.4，160.6，141.8，141.3，138.9，137.5，137.4，131.2，129.3，128.6，127.2，127.2，126.1，125.1，122.2，120.7，119.9，119.2，109.9，100.9，65.8，48.1，46.7，45.9，21.2；红外光谱(薄膜)ν: 3031，2137，1715，1649，1462，1452，1371，1302，1086，1065，1017，831，${730}{\mathrm{\;{cm}}}^{-1}$；电子轰击质谱$\left( {m/z\text{ , relative intensity }}\right) : {390}\left( {13}\right) ,{374} \; \left( 4\right) ,{333}\left( 5\right) ,{299}\left( 5\right) ,{218}\left( 7\right) ,{124}\left( 7\right) ,{91}\left( {100}\right) ,{65}\left( {11}\right) ,$ 28(71)；高分辨质谱(电喷雾电离)计算得到${\mathrm{C}}_{30}{\mathrm{H}}_{29}{\mathrm{\;N}}_{4}{\mathrm{O}}_{4}\mathrm{\;S}\left( {\mathrm{M} + \mathrm{H}}\right)$ 541.19040，实测值541.1909。

tert-Butyl 2-((R)-5-(allyloxy)-4-diazo-1-((S)-4-methyl phenylsulfinamido)-3,5-dioxopentyl)-1H-indole-1- carboxylate (17)

2-((R)-5-(烯丙氧基)-4-重氮基-1-((S)-4-甲基苯亚磺酰胺基)-3,5-二氧代戊基)-1H-吲哚-1-羧酸叔丁酯(17)

Dark red solid, ${73}\%$ yield, ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {92.4}\left( {c.{1.0}}\right.$ in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ : 8.04-8.01 (m, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.50-7.47 (m, 1H), 7.28-7.25 (m, 3H), 7.22-7.16 (m, 1H), 6.68 (s, 1H), 5.96-5.83 (m, 1H), 5.70-5.54 (m, 2H), 5.35-5.25 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{4.66}\left( {\mathrm{{dt}}, J = {5.7},{1.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{3.78} - {3.71}(\mathrm{\;m}$ , 1H), 3.51 (dd, J=16.8, 5.7 Hz, 1H), 2.39 (s, 3H), 1.69 (s, 9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) δ: 189.8, 160.6, 150.5, 142.2, 141.1, 140.8, 136.7, 131.3, 129.3, 128.5, 125.6, 124.3, 122.8, 120.7, 119.2, 115.7, 109.4, 84.8, 65.8, 50.2, 45.2, 28.1, 21.3; IR (film) v: 2977, 2926, 2139, 1719, 1650, 1453, 1370, 1326, 1304, 1213, 1156, 1117,1090,1065,910,810,768,734 ${\mathrm{{cm}}}^{-1}$ ; EI-MS $(m/z$ , relative intensity): ${300}\left( {17}\right) ,{284}\left( {15}\right) ,{267}\left( {10}\right) ,{246}$ (38), 209 (23), 170 (23), 144 (24), 124 (65), 91 (100), 77 (24), 44 (73), 39 (47); HRMS (ESI) calcd for ${\mathrm{C}}_{28}{\mathrm{H}}_{31}{\mathrm{\;N}}_{4}{\mathrm{O}}_{6}\mathrm{\;S}\left( {\mathrm{M} + \mathrm{H}}\right) {551.1959}$ , found 551.1965.

暗红色固体，${73}\%$收率，${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {92.4}\left( {c.{1.0}}\right.$于${\mathrm{{CHCl}}}_{3}$中); ${}^{1}\mathrm{H}$核磁共振氢谱(300兆赫兹，${\mathrm{{CDCl}}}_{3}$) $\delta$: 8.04 - 8.01(多重峰，1H)，7.31(双峰，J = 8.4赫兹，2H)，7.50 - 7.47(多重峰，1H)，7.28 - 7.25(多重峰，3H)，7.22 - 7.16(多重峰，1H)，6.68(单峰，1H)，5.96 - 5.83(多重峰，1H)，5.70 - 5.54(多重峰，2H)，5.35 - 5.25 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{4.66}\left( {\mathrm{{dt}}, J = {5.7},{1.2}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{3.78} - {3.71}(\mathrm{\;m}$，1H)，3.51(双二重峰，J = 16.8, 5.7赫兹，1H)，2.39(单峰，3H)，1.69(单峰，9H); ${}^{13}\mathrm{C}$核磁共振碳谱(75兆赫兹，CDCl₃) δ: 189.8, 160.6, 150.5, 142.2, 141.1, 140.8, 136.7, 131.3, 129.3, 128.5, 125.6, 124.3, 122.8, 120.7, 119.2, 115.7, 109.4, 84.8, 65.8, 50.2, 45.2, 28.1, 21.3; 红外光谱(薄膜) ν: 297,7, 2926, 2139, 1719, 1650, 1453, 1370, 1326, 1304, 1213, 1156, 1117,1090,1065,910,810,768,734 ${\mathrm{{cm}}}^{-1}$; 电子轰击质谱$(m/z$,(相对强度): ${300}\left( {17}\right) ,{284}\left( {15}\right) ,{267}\left( {10}\right) ,{246}$(38)，209(23)，170(23)，144(24)，124(65)，91(100)，77(24)，44(7)，39(47); 高分辨质谱(电喷雾电离)计算值为${\mathrm{C}}_{28}{\mathrm{H}}_{31}{\mathrm{\;N}}_{4}{\mathrm{O}}_{6}\mathrm{\;S}\left( {\mathrm{M} + \mathrm{H}}\right) {551.1959}$，实测值为551.1965。

General procedures for preparation of diazoesters 11 and 18

制备重氮酯11和18的通用方法

The addition product (10) or (17) was dissolved in methanol and cooled to 0 °C. Trifluoroacetic acid (TFA, 5.0 equiv.) was added to the solution and the ice-water bath was removed. The system was warmed to room temperature gradually and was stirred for another $2\mathrm{\;h}$ . The solvent was removed by evaporating under vacuum and the crude residue was dissolved in THF and cooled to 0 °C. Triethyl amine (6 equiv.), Boc2O (1.2 equiv.) and ${N}^{\prime },{N}^{\prime }$ -dimethylaminopyridine (5 mol%) were added to the solution. Then ice-water bath was taken away and the mixture was stirred for another $2\mathrm{\;h}$ at room temperature. Solvent was removed by evaporation under vacuum and the residue was purified by flash column chromatography (petroleum: ethyl acetate $= {10}\text{ : }1$ , $V:V$ ) on silica gel to yield $N$ -Boc protected diazoester 11 or 18.

加成产物(10)或(17)溶于甲醇并冷却至0°C。向溶液中加入三氟乙酸(TFA，5.0当量)，并移除冰水浴。体系逐渐升温至室温并再搅拌$2\mathrm{\;h}$。通过真空蒸发除去溶剂，粗残余物溶于THF并冷却至0°C。向溶液中加入三乙胺(6当量)、二碳酸二叔丁酯(Boc2O，1.2当量)和${N}^{\prime },{N}^{\prime }$-二甲基氨基吡啶(5 mol%)。然后移走冰水浴，混合物在室温下再搅拌$2\mathrm{\;h}$。通过真空蒸发除去溶剂，残余物通过硅胶柱快速色谱法(石油醚:乙酸乙酯$= {10}\text{ : }1$，$V:V$)纯化，得到$N$-Boc保护的重氮酯11或18。

(R)-Allyl 5-(1-benzyl-1/4-indol-2-yl)-5-(tert-butoxy- carbonylamino)-2-diazo-3-oxopentanoate (11)

(R)-5-(1-苄基-1H-吲哚-2-基)-5-(叔丁氧羰基氨基)-2-重氮-3-氧代戊酸烯丙酯(11)

Yellow solid, ${95}\%$ yield, ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {80.5}({c1.0}$ in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {7.58} - {7.56}(\mathrm{\;m}$ , 1H), 7.25-7.10 (m, 5H), 7.09-7.00 (m, 3H), 6.46 (s, 1H), 5.99-5.86 (m, 1H), 5.51-5.43 (m, 3H), 5.37-5.28 (m, 2H), 4.88 (d, J=8.1 Hz, 1H), 4.70 (d, $J = {5.4}\mathrm{\;{Hz}},2\mathrm{H}),{3.67}\left( {\mathrm{\;{dd}}, J = {15.9},{9.3}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{3.38}$ (dd, $J = {15.9},{9.3}\mathrm{\;{Hz}},1\mathrm{H}),{1.29}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) 6: 189.3, 160.9, 154.3, 139.6, 137.6, 137.3, 131.2, 128.5, 127.2, 127.0, 126.0, 122.0, 120.5, 119.7, 119.1, 109.9, 99.6, 79.6, 65.8, 46.6, 44.7, 43.7, 28.0; IR (film) v: 3346, 2141, 1718, 1678, 1517, 1464, 1356, 1313, 1285, 1246, 1167, 1014, 730 cm ${}^{-1}$ ; EI-MS (m/z, relative intensity): 474 (3), 374 (8), 283 (7), 218 (9), 91 (100), 57 (21), 41 (44). HRMS (ESI) calcd for ${\mathrm{C}}_{28}{\mathrm{H}}_{30}{\mathrm{\;N}}_{4}{\mathrm{O}}_{5}\mathrm{\;{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {525.2108}$ , found 525.2130.

黄色固体，${95}\%$收率，${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {80.5}({c1.0}$于${\mathrm{{CHCl}}}_{3}$中)；${}^{1}\mathrm{H}$核磁共振氢谱(300兆赫兹，${\mathrm{{CDCl}}}_{3}$) $\delta : {7.58} - {7.56}(\mathrm{\;m}$，1H)，7.25 - 7.10(多重峰，5H)，7.09 - 7.00(多重峰，3H)，6.46(单峰，1H)，5.99 - 5.86(多重峰，1H)，5.51 - 5.43(多重峰，3H)，5.37 - 5.28(多重峰，2H)，4.88(双峰，J = 8.1赫兹，1H)，4.70(双峰，$J = {5.4}\mathrm{\;{Hz}},2\mathrm{H}),{3.67}\left( {\mathrm{\;{dd}}, J = {15.9},{9.3}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{3.38}$(双重峰，$J = {15.9},{9.3}\mathrm{\;{Hz}},1\mathrm{H}),{1.29}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振碳谱(75兆赫兹，CDCl3)δ:189.3，160.9，154.3，139.6，137.6，137.3，131.2，128.5，127.2，127.0，126.0，122.0，120.5，119.7，119.1，109.9，99.6，79.6，65.8，46.6，44.7，43.7，28.0；红外光谱(薄膜)ν:3346，2141，1718，1678，1517，1464，1356，1313，1285，1246，1167，1014，730厘米${}^{-1}$；电子轰击质谱(m/z，相对强度):474(3)，374(8)，283(7)，218(9)，91(100)，57(21)，41(44)。高分辨质谱(电喷雾电离)计算值为${\mathrm{C}}_{28}{\mathrm{H}}_{30}{\mathrm{\;N}}_{4}{\mathrm{O}}_{5}\mathrm{\;{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {525.2108}$，实测值为525.2130。

(R)-tert-Butyl 2-(5-(allyloxy)-1-(tert-butoxycarbon- ylamino)-4-diazo-3,5-dioxopent-yl)-1H-indole-1-car- boxylate (18)

(R)-2-叔丁基 2-(5-(烯丙氧基)-1-(叔丁氧羰基氨基)-4-重氮-3,5-二氧代戊基)-1H-吲哚-1-羧酸酯(18)

Yellow solid,94% yield, ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {45.0}(c$ 1.45 in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {8.04}(\mathrm{\;d}, J = {8.4} \; \mathrm{{Hz}},1\mathrm{H}),{7.47}\left( {\mathrm{\;d}, J = {7.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{7.27} - {7.16}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , ${6.61}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{6.05}\left( {\mathrm{\;d}, J = {9.0}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.93} - {5.80}(\mathrm{\;m}$ , 2H), 5.32-5.24 (m, 2H), 4.65 (d, J=5.7 Hz, 2H), 3.73 (dd, $J = {16.2},{6.0}\mathrm{\;{Hz}},1\mathrm{H}),{3.34}$ (dd, $J = {15.9},{5.1}\mathrm{\;{Hz}}$ , 1H), 1.72 (s, 9H), 1.43 (s, 9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3})\delta$ :190.3,160.6,154.8,150.3,140.4,136.7, 131.2, 128.5, 124.0, 122.7, 120.5, 119.1, 115.6, 108.7, 84.6, 79.4, 65.8, 46.6, 43.7, 28.3, 28.1; IR (film) v: 2977, 2926, 2136, 1718, 1652, 1488, 1453, 1368, 1327, 1158, 1116, 1085, 1054, 911, 769, 735 cm ${}^{-1}$ ; EI-MS (m/z, relative intensity): 384 (5), 328 (15), 284 (16), 270 (15), 226 (10), 145 (20), 57 (100), 41 (71). HRMS (ESI) calcd for ${\mathrm{C}}_{26}{\mathrm{H}}_{32}{\mathrm{\;N}}_{4}{\mathrm{O}}_{7}\mathrm{{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right)$ 535.2163, found 535.2160.

黄色固体，产率94%，${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {45.0}(c$ 1.45于${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$核磁共振(300兆赫，${\mathrm{{CDCl}}}_{3}$ ) $\delta : {8.04}(\mathrm{\;d}, J = {8.4} \; \mathrm{{Hz}},1\mathrm{H}),{7.47}\left( {\mathrm{\;d}, J = {7.2}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{7.27} - {7.16}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ ，${6.61}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{6.05}\left( {\mathrm{\;d}, J = {9.0}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.93} - {5.80}(\mathrm{\;m}$ ，2H)，5.32 - 5.24(多重峰，2H)，4.65(双峰，J = 5.7赫兹，2H)，3.73(双二重峰，$J = {16.2},{6.0}\mathrm{\;{Hz}},1\mathrm{H}),{3.34}$ (双二重峰，$J = {15.9},{5.1}\mathrm{\;{Hz}}$ ，1H)，1.72(单峰，9H)，1.43(单峰，9H); ${}^{13}\mathrm{C}$核磁共振(75兆赫，${\mathrm{{CDCl}}}_{3})\delta$ :190.3,160.6,154.8,150.3,140.4,136.7,131.2,128.5,124.0,122.7,120.5,119.1,115.6,108.7,84.6,79.4,65.8,46.6,4,3.7,28.3,28.1;红外(薄膜)v: 2977,2926,2136,1718,1652,1488,1453,1368,1327,1158,1116,1085,1054,911,769,735厘米${}^{-1}$ ;电子轰击质谱(质荷比，相对强度):384(5)，328(15)，284(16)，270(15)，226(10)，145(20)，57(100)，4(71)。高分辨质谱(电喷雾电离)计算值为${\mathrm{C}}_{26}{\mathrm{H}}_{32}{\mathrm{\;N}}_{4}{\mathrm{O}}_{7}\mathrm{{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right)$ 535.2163，实测值为535.2160。

(5R)-3-Allyl N-tert-butyl 5-(1-(tert-butoxycarbonyl)- 1H-indol-2-yl)-2-oxopyrrolidine-1,3-dicarboxylate (19)

(5R)-3-烯丙基 N-叔丁基 5-(1-(叔丁氧羰基)-1H-吲哚-2-基)-2-氧代吡咯烷-1,3-二羧酸酯(19)

$N$ -Boc protected diazoester (18) was dissolved in benzene and subjected to irradiation $({500}\mathrm{\;W},\mathrm{{Hg}}$ lamp, Pyrex tube) under stirring. The system was kept at room temperature by cooling water condenser and the irradiation was kepted for $4\mathrm{\;h}$ until no IR signal of diazo moiety in around ${2100}{\mathrm{\;{cm}}}^{-1}$ could be observed. The mixture was then transferred to round-bottomed flask. Solvent was removed by evaporation under vacuum and the residue was purified by flash column chromatography (petroleum : ethyl acetate $= {10} : 1, V : V$ ) on silica gel to afford 2-oxopyrrolidine (19). Yield 64%, colorless oil; ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta : {8.09} - {8.01}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${7.49} - {7.42}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.32} - {7.18}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{6.42}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ , ${6.04}\left( {\mathrm{\;d}, J = {8.7}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.98} - {5.85}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${5.40} - {5.06}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.75} - {4.42}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.71}(\mathrm{\;{dd}}, J =$ 12.3,8.4 Hz,1 H), 2.96-2.85 (m,1 H), 2.54-2.30 (m, 1H), 1.71 (s, 9H), 1.44 (s, 9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ :168.8,168.1,149.9,149.2,139.9,136.6, 131.3, 131.2, 128.2, 124.3, 123.1, 120.4, 118.7, 115.6, 115.6, 105.7, 105.6, 84.8, 83.6, 66.2, 54.8, 54.7, 47.9, 47.9, 29.5, 28.1, 27.7, 27.6; IR (film) v: 2932, 1790, 1730, 1454, 1369, 1328, 1290, 1250, 1148, 1117, 1084, 913,848,769,739 ${\mathrm{{cm}}}^{-1}$ ; EI-MS $\left( {m/z\text{ , relative intensity }}\right)$ : 484 (6), 384 (10), 328 (7), 284 (68), 226 (39), 199 (21), 171 (14), 51 (100), 41 (68). HRMS (ESI) calcd for ${\mathrm{C}}_{26}{\mathrm{H}}_{32}{\mathrm{\;N}}_{2}{\mathrm{O}}_{7}\mathrm{\;{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right)$ 507.2102, found 507.2101.

$N$ -Boc 保护的重氮酯(18)溶解于苯中，在搅拌下用$({500}\mathrm{\;W},\mathrm{{Hg}}$灯(派热克斯玻璃管)进行照射。通过冷却冷凝器将体系保持在室温，照射持续$4\mathrm{\;h}$，直到在约${2100}{\mathrm{\;{cm}}}^{-1}$处未观察到重氮部分的红外信号。然后将混合物转移至圆底烧瓶。在真空下通过蒸发除去溶剂，残余物通过硅胶柱快速柱色谱法(石油醚:乙酸乙酯$= {10} : 1, V : V$ )纯化，得到 2-氧代吡咯烷(19)。产率 64%，无色油状物；${}^{1}\mathrm{H}$ NMR(300 MHz,${\mathrm{{CDCl}}}_{3}$ ) $\delta : {8.09} - {8.01}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，${7.49} - {7.42}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.32} - {7.18}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{6.42}\left( {\mathrm{\;s},1\mathrm{H}}\right)$ ，${6.04}\left( {\mathrm{\;d}, J = {8.7}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{5.98} - {5.85}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，${5.40} - {5.06}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.75} - {4.42}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.71}(\mathrm{\;{dd}}, J =$ 12.(此处原文可能有误，推测应为 12.3),8.4 Hz,1 H), 2.96 - 2.85 (m,1 H), 2.54 - 2.30 (m, 1H), 1.71 (s, 9H), 1.44 (s, 9H); ${}^{13}\mathrm{C}$ NMR(75 MHz,${\mathrm{{CDCl}}}_{3}$ ) $\delta$ :168.8,168.1,149.9,149.2,139.9,136.6, 131.3, 131.2, 128.2, 124.3, 123.1, 120.4, 118.7, 115.6, 115.6, 105.7, 105.6, 84.8, 83.6, 66.2, 54.8, 54.7, 47.9, 47.9, 29.5, 28.1, 27.7, 27.6; IR(膜) v: 2932, 1790, 1730, 1454, 1369, 1328, 1290, 1250, 1148, 1117, 1084, 913,848,769,739 ${\mathrm{{cm}}}^{-1}$ ; EI-MS $\left( {m/z\text{ , relative intensity }}\right)$ : 484 (6), 384 (10), 328 (7), 284 (68), 226 (39), 199 (21), 171 (14), 51 (100), 41 (68). HRMS(ESI)计算值为${\mathrm{C}}_{26}{\mathrm{H}}_{32}{\mathrm{\;N}}_{2}{\mathrm{O}}_{7}\mathrm{\;{Na}}\left( {\mathrm{M} + \mathrm{{Na}}}\right)$ 507.2102，实测值为 507.2101。

(R)-tert-Butyl 2-(1-(tert-butoxycarbonyl)-5-oxo- pyrrolidin-2-yl)-1H-indole-1-carboxylate (20)

(R)-2-叔丁基 2-(1-(叔丁氧羰基)-5-氧代吡咯烷-2-基)-1H-吲哚-1-甲酸酯 (20)

Wolff rearrangement product (19) (454 mg, 0.94 mmol) was dissolved in ${20}\mathrm{\;{mL}}$ THF at room temperature in a ${100}\mathrm{\;{mL}}$ round-bottomed flask. Morpholine (261 mg,3 equiv.) and $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}\left( {{55}\mathrm{{mg}},5\mathrm{{mol}}\% }\right)$ were added to the solution and the mixture was stirred for $6\mathrm{\;h}$ . Solvent was removed by evaporating under vacuum and the residue was purified by flash column chromatography (petroleum: ethyl acetate $= 5 : 1$ , $V:V)$ on silica gel to produce oxopyrrolidine (20) (0.268 g). White solid, yield ${71}\% ,{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {139.2}(c$ 0.5 in ${\mathrm{{CHCl}}}_{3}$ ); ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ : ${8.09} - {8.06}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.49} - {7.46}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.32} - {7.20} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{6.44}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{6.00}\left( {\mathrm{\;d}, J = {6.9}\mathrm{\;{Hz}},1\mathrm{H}}\right)$ , 3.77-3.73 (m, 1H), 2.71-2.60 (m, 1H), 2.56-2.41 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{2.07} - {2.01}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.92} - {1.83}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.71} \; \left( {\mathrm{s},9\mathrm{H}}\right) ,{1.40}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ : 174.4, 150.1, 149.6, 140.9, 136.6, 128.5, 124.1, 123.0, 120.4, 115.6, 105.6, 84.6, 83.0, 56.6, 30.5, 28.1, 27.7, 25.4; IR (film) v: 2926, 1785, 1731, 1369, 1328, 1305, 1282,1252,1152,1116,1084,744 ${\mathrm{{cm}}}^{-1}$ ; EI-MS (m/z, relative intensity): 400 (5), 300 (6), 200 (100), 183 (11), 171 (17), 156 (19), 117 (10), 89 (11), 57 (90), 41 (63), 29 (22). HRMS (ESI) calcd for ${\mathrm{C}}_{22}{\mathrm{H}}_{28}{\mathrm{\;N}}_{2}{\mathrm{O}}_{5}\mathrm{{Na}}$ [(M + Na) ${}^{ + }$ ] 423.1890, found 423.1887.

室温下，将 Wolff 重排产物 (19)(454 毫克，0.94 毫摩尔)溶解在 ${20}\mathrm{\;{mL}}$ 四氢呋喃中，置于 ${100}\mathrm{\;{mL}}$ 圆底烧瓶中。向溶液中加入吗啉(261 毫克，3 当量)和 $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}\left( {{55}\mathrm{{mg}},5\mathrm{{mol}}\% }\right)$，混合物搅拌 $6\mathrm{\;h}$ 。减压蒸发除去溶剂，残余物通过快速柱色谱法(石油醚:乙酸乙酯 $= 5 : 1$ ，硅胶 $V:V)$ )纯化，得到氧代吡咯烷 (20)(0.268 克)。白色固体，产率 ${71}\% ,{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {139.2}(c$ 0.5 在 ${\mathrm{{CHCl}}}_{3}$ 中；${}^{1}\mathrm{H}$ 核磁共振谱(300 兆赫兹，${\mathrm{{CDCl}}}_{3}$ )$\delta$ :${8.09} - {8.06}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.49} - {7.46}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{7.32} - {7.20} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{6.44}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{6.00}\left( {\mathrm{\;d}, J = {6.9}\mathrm{\;{Hz}},1\mathrm{H}}\right)$ ，3.77 - 3.73(m，1H)，2.71 - 2.60(m，1H)，2.56 - 2.41 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{2.07} - {2.01}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.92} - {1.83}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.71} \; \left( {\mathrm{s},9\mathrm{H}}\right) ,{1.40}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ :174.4，150.1，149.6，140.9，136.6，128.5，124.1，123.0，120.4，115.6，105.6，84.6，83.0，56.6，30.5，28.1，27.7，25.4；红外光谱(薄膜)v:2926，1785，1731，1369，1328，1305，1282，1252，1152，1116，1084，744 ${\mathrm{{cm}}}^{-1}$ ；电子轰击质谱(m/z，相对强度):400(5)，300(6)，200(100)，183(11)，171(17)，156(19)，117(10)，89(11)，57(90)，41(63)，29(22)。高分辨质谱(电喷雾电离)计算值为 ${\mathrm{C}}_{22}{\mathrm{H}}_{28}{\mathrm{\;N}}_{2}{\mathrm{O}}_{5}\mathrm{{Na}}$ [(M + Na) ${}^{ + }$ ] 423.1890，实测值 423.1887。

Results and Discussion

结果与讨论

As shown in Scheme 1, starting from commercially available 1H-indole-2-carboxylic acid (2), crude ethyl-1H-indole-2-carboxylate (3) was prepared in quantitative yield by chlorination and subsequent esterification. Then, the nitrogen of the indole ring was protected by benzyl group in 97% yield. ${}^{\left\lbrack 9\right\rbrack }N$ -Protected carboxylate (4) was subsequently reduced to alcohol (5), which was then oxidized to aldehyde (6). $\mathrm{{Ti}}{\left( \mathrm{O}i - \mathrm{{Pr}}\right) }_{4}$ - promoted condensation of aldehyde (6) with chiral sulfinamide (7) led to the formation of sulfinimide (8) in 85% yield. ${}^{\left\lbrack 7,8\right\rbrack }$

如图式1所示，从市售的1H-吲哚-2-羧酸(2)开始，通过氯化和随后的酯化反应，以定量产率制备了粗品1H-吲哚-2-羧酸乙酯(3)。然后，吲哚环的氮以97%的产率被苄基保护。${}^{\left\lbrack 9\right\rbrack }N$ -保护的羧酸盐(4)随后被还原为醇(5)，然后醇(5)被氧化为醛(6)。$\mathrm{{Ti}}{\left( \mathrm{O}i - \mathrm{{Pr}}\right) }_{4}$ -促进的醛(6)与手性亚磺酰胺(7)的缩合反应以85%的产率得到亚磺酰亚胺(8)。${}^{\left\lbrack 7,8\right\rbrack }$

With sulfinimide (8) in hand, diastereoselective addition of $\alpha$ -diazo- $\beta$ -oxoester ${\left( \mathbf{9}\right) }^{\left\lbrack {10}\right\rbrack }$ to8in the presence of LiHMDS was carried out (Scheme 2). The addition reaction proceeded with high diastereoselectivty and 10 were obtained as essentially single stereoisomer. Since our previous study has indicated that the $N$ -sulfinyl group was not compatible with the subsequent photochemical conditions, ${}^{\left\lbrack 6\mathrm{\;b}\right\rbrack }$ so the $N$ -sulfinyl group was replaced by tert-butyloxycarbonyl (Boc), and the $N$ -Boc diazo compound (11) was subjected to the photolysis. However, the subsequent irradiation of 11 with Hg lamp (500 W) failed to afford the expected cyclization product. The irradiation of diazo compound (12), in which the Boc protecting group was removed, also failed to afford the expected cyclization product.

得到亚磺酰亚胺(8)后，在LiHMDS存在下，将$\alpha$ -重氮- $\beta$ -氧代酯${\left( \mathbf{9}\right) }^{\left\lbrack {10}\right\rbrack }$ 非对映选择性地加成到8上(图式2)。加成反应以高非对映选择性进行，得到的10基本上是单一立体异构体。由于我们之前的研究表明$N$ -亚磺酰基与随后的光化学条件不兼容，${}^{\left\lbrack 6\mathrm{\;b}\right\rbrack }$ 所以将$N$ -亚磺酰基替换为叔丁氧羰基(Boc)，并且对$N$ -Boc重氮化合物(11)进行光解。然而，随后用汞灯(500 W)照射11未能得到预期的环化产物。去除Boc保护基的重氮化合物(12)的照射也未能得到预期的环化产物。

It is conceivable that the electronic properties of the $N$ -protecting group on indole ring may affect the stability of the starting material as well as the products. An electron-rich indole ring may not be compatible under the irradiation condition. We then considered preparing diazo compound (18), in which the $N$ -protecting group is more electron-withdrawing Boc, as the precursor for photoinduced Wolff rearrangement. Therefore, we designed to synthesize aldehyde (15), which bears electron-withdrawing Boc protecting group (Scheme 3). Starting from carboxylate (3), aldehyde (15) could be synthesized in three steps with good yield. ${}^{\left\lbrack {11} - {13}\right\rbrack }$ Sulfinimide (16) was then prepared through the condensation of 15 with chiral sulfinamide (7). Again, highly diastereoselective addition of $\alpha$ -diazo- $\beta$ -oxoester (9) to 16 took place in the presence of LiHMDS and led to the formation of optically pure diazoester (17) in 73% yield. Then the similar steps as for the preparation of 11 were followed to synthesize $N$ -Boc protected compound 18 in 95% yield. To our delight, irradiation of 18 led to the expected Wolff rearrangement and subsequent cyclization afforded 19 in 64% yield. This result testified our original conjecture that the Wolff rearrangement was affected by the electronic properties of the $N$ -protecting group on indole ring. Finally, the Pd-catalyzed removal of allyl oxycarbonyl group on 3-position of the newly formed pyrrolidinone ring was conducted with decarboxylation in the presence of 3 equiv. alents of morpholine. ${}^{\left\lbrack {14}\right\rbrack }$ It was noted that slightly higher yield of pyrrolidinone (20) could be obtained when $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ was added by portion.

可以想象，吲哚环上$N$ -保护基的电子性质可能会影响起始原料以及产物的稳定性。富电子的吲哚环在照射条件下可能不兼容。然后我们考虑制备重氮化合物(18)，其中$N$ -保护基是吸电子性更强的Boc，作为光诱导Wolff重排的前体。因此，我们设计合成带有吸电子Boc保护基的醛(15)(图式3)。从羧酸盐(3)开始，可以通过三步以良好的产率合成醛(15)。${}^{\left\lbrack {11} - {13}\right\rbrack }$ 然后通过15与手性亚磺酰胺(7)的缩合反应制备亚磺酰亚胺(16)。同样，在LiHMDS存在下，$\alpha$ -重氮- $\beta$ -氧代酯(9)与16发生高度非对映选择性加成反应，以73%的产率得到光学纯的重氮酯(17)。然后按照制备11的类似步骤，以95%的产率合成$N$ -Boc保护的化合物18。令我们高兴的是，照射18导致预期的Wolff重排，随后环化以64%的产率得到19。该结果证实了我们最初的推测，即Wolff重排受吲哚环上$N$ -保护基的电子性质影响。最后，在3当量吗啉存在下，通过脱羧反应进行钯催化的新形成的吡咯烷酮环3-位烯丙氧羰基的去除。${}^{\left\lbrack {14}\right\rbrack }$ 注意到当$\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ 分批加入时，可以得到略高收率的吡咯烷酮(20)。

Scheme 1 Preparation of chiral sulfinimide (8)

图式1 手性亚磺酰亚胺(8)的制备

4_903_260_578_461_0.jpg

Reagents and conditions: (a) ${\mathrm{{SOCl}}}_{2}$ (2 equiv.), $\mathrm{{EtOH}},{0}^{ \circ }\mathrm{C}$ , then, reflux, 2 h, quant.; (b) BnBr (2 equiv.), KOH (4 equiv.), DMSO, r.t., 1 h, 97%; (c) LiAlH4 (1 equiv.), THF, r.t., 0.5 h, >99%; (d) MnO ${}_{2}$ (5 equiv.), CH ${}_{2}{\mathrm{{Cl}}}_{2}$ , r.t., 32 h, 72%; (e) 7 (1.1 equiv.), Ti(Oi-Pr)4 (3 equiv.), CH ${\mathrm{{Cl}}}_{2}{\mathrm{{Cl}}}_{2}$ , reflux, 5 h, 85%.

试剂及条件:(a) ${\mathrm{{SOCl}}}_{2}$(2当量)，$\mathrm{{EtOH}},{0}^{ \circ }\mathrm{C}$，然后回流，2小时，产率定量；(b) 苄基溴(2当量)，氢氧化钾(4当量)，二甲基亚砜，室温，1小时，产率97%；(c) 氢化铝锂(1当量)，四氢呋喃，室温，0.5小时，产率>99%；(d) 二氧化锰${}_{2}$(5当量)，氯甲烷${}_{2}{\mathrm{{Cl}}}_{2}$，室温，32小时，产率72%；(e) 7(1.1当量)，四异丙氧基钛(3当量)，氯甲烷${\mathrm{{Cl}}}_{2}{\mathrm{{Cl}}}_{2}$，回流，5小时，产率85%。

Scheme 2 Attempted photoinduced Wolff rearrangement/ cyclization

方案2 尝试的光诱导沃尔夫重排/环化反应

4_868_1010_637_612_0.jpg

Reagents and conditions: (a) LiHMDS (2 equiv.), 8, ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}, - {78}^{ \circ }\mathrm{C}$ , 77%; (b) TFA (5 equiv.), MeOH, 0 ${}^{ \circ }\mathrm{C}$ to r.t.; (c) Boc2O (1.1 equiv.), ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ (6 equiv.) 5 mol% DMAP, THF, $0{}^{ \circ }\mathrm{C}$ to r.t.,95%, two steps; (d) ${hv}$ , Hg lamp (500 W), benzene,4 h; (e) 1) TFA (5 equiv.), MeOH, ${0}^{ \circ }\mathrm{C},{\mathrm{{Cy}}}_{2}\mathrm{{NMe}}$

试剂及条件:(a) 双(三甲基硅基)氨基锂(2当量)，8，${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}, - {78}^{ \circ }\mathrm{C}$，产率77%；(b) 三氟乙酸(5当量)，甲醇，0${}^{ \circ }\mathrm{C}$至室温；(c) 二碳酸二叔丁酯(1.1当量)，${\mathrm{{Et}}}_{3}\mathrm{\;N}$(6当量)，5摩尔%4-二甲氨基吡啶，四氢呋喃，$0{}^{ \circ }\mathrm{C}$至室温，产率95%，两步反应；(d) ${hv}$，汞灯(500瓦)，苯，4小时；(e) 1) 三氟乙酸(5当量)，甲醇，${0}^{ \circ }\mathrm{C},{\mathrm{{Cy}}}_{2}\mathrm{{NMe}}$

Scheme 3 Enantioselective synthesis of indole (20)

方案3 吲哚(20)的对映选择性合成

5_163_257_610_950_0.jpg

Reagents and conditions: (a) LiAlH ${}_{4}$ (1.5 equiv.), THF, r.t.,1 h, quant.; (b) ${\mathrm{{MnO}}}_{2}$ (5 equiv.), ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ , r.t.,40 h; (c) ${\mathrm{{Boc}}}_{2}\mathrm{O}$ (1.2 equiv.), Et ${}_{3}\mathrm{\;N}$ (1.2 equiv.), 10 mol% DMAP, THF, 0 ${}^{ \circ }\mathrm{C}$ to r.t., 2 h, 87%, two steps; (d) 7 (1.1 equiv.), Ti(Oi-Pr)4 (3 equiv.), ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ , reflux, 5 h, 90%; (e) LiHMDS (2 equiv.), 9 (1.5 equiv.), ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ , -78 ${}^{ \circ }\mathrm{C},{73}\%$ ; (f) TFA (5 equiv.), MeOH, ${0}^{ \circ }\mathrm{C}$ to r.t.; (g) ${\mathrm{{Boc}}}_{2}\mathrm{O}$ (1.2 equiv.), ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ (6 equiv.) 5 mol% DMAP, THF, $0{}^{ \circ }\mathrm{C}$ to r.t. 94%, two steps; (h) ${hv}$ 500 W Hg lamp, benzene,4 h,64%; (i) Pd(PP ${\mathrm{h}}_{3}{)}_{4}\left( {5\mathrm{\;{mol}}\% }\right)$ , morpholine (3 equiv.), THF, r.t., $6\mathrm{\;h},{71}\%$ .

试剂及条件:(a) 氢化铝锂${}_{4}$(1.5当量)，四氢呋喃，室温，1小时，产率定量；(b) ${\mathrm{{MnO}}}_{2}$(5当量)，${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$，室温，40小时；(c) ${\mathrm{{Boc}}}_{2}\mathrm{O}$(1.2当量)，二乙胺${}_{3}\mathrm{\;N}$(1.2当量)，10摩尔%4-二甲氨基吡啶，四氢呋喃，0${}^{ \circ }\mathrm{C}$至室温，2小时，产率87%，两步反应；(d) 7(1.1当量)，四异丙氧基钛(3当量)，${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$，回流，5小时，产率90%；(e) 双(三甲基硅基)氨基锂(2当量)，9(1.5当量)，${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$，-78${}^{ \circ }\mathrm{C},{73}\%$；(f) 三氟乙酸(5当量)，甲醇，${0}^{ \circ }\mathrm{C}$至室温；(g) ${\mathrm{{Boc}}}_{2}\mathrm{O}$(1.2当量)，${\mathrm{{Et}}}_{3}\mathrm{\;N}$(6当量)，5摩尔%4-二甲氨基吡啶，四氢呋喃，$0{}^{ \circ }\mathrm{C}$至室温，产率94%，两步反应；(h) ${hv}$，500瓦汞灯，苯，4小时，产率64%；(i) 钯(PP${\mathrm{h}}_{3}{)}_{4}\left( {5\mathrm{\;{mol}}\% }\right)$，吗啉(3当量)，四氢呋喃，室温，$6\mathrm{\;h},{71}\%$。

Conclusions

结论

We have successfully employed the diastereoselec-tive nucleophilic addition of lithium enolate of $\alpha$ -diazoacetate to chiral $N$ -sulfinyl imine and subsequent photoinduced Wolff rearrangement/cyclization in the synthesis of an intermediate which contains the required chiral center and three rings for the synthesis of $\left( R\right)$ -(+)-harmicine. Further study is undergoing and the results will be reported in due course.

我们已成功地将$\alpha$ -重氮乙酸酯的烯醇锂盐非对映选择性亲核加成到手性$N$ -亚磺酰亚胺上，随后进行光诱导的沃尔夫重排/环化反应，以合成一种中间体，该中间体含有合成$\left( R\right)$ -(+)-哈尔米辛所需的手性中心和三个环。进一步的研究正在进行中，结果将适时报道。

Acknowledgement

致谢

The project is supported by the National Natural Science Foundation of China (No. 21072009, 21172005), National Basic Research Program of China (973 Program, No. 2009CB825300) and the Research Fund for the Doctoral Program of Higher Education (No. 20090001120014).

本项目受中国国家自然科学基金(项目编号:21072009，21172005)、中国国家基础研究计划(973计划，项目编号:2009CB825300)以及高等学校博士学科点专项科研基金(项目编号:20090001120014)资助。

References

参考文献

[1] Kam, T. S.; Sim, K. M. Phytochemistry 1998, 47, 145.

[2] (a) Knölker, H.-J.; Agarwal, S. Synlett 2004, 10, 1767; (b) King, F. D. J. Heterocyclic Chem. 2007, 44, 1459.

[3] (a) Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406; (b) Allin, S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P. Tetrahedron Lett. 2007, 48, 5669.

[4] (a) Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404; (b) Sanaboina, C.; Jana, S.; Chidara, S.; Patro, B.; Raolji, G. B.; Eppakayala, L. Tetrahedron Lett. 2012, 53, 5027.

[5] Chiou, W. -H.; Lin, G. -H.; Hsu, C. -C.; Chaterpaul, S. J.; Ojima, I. Org. Lett. 2009, 11, 2659.

[6] (a) Mo, F.; Li, F.; Qiu, D.; Wang, J. Tetrahedron 2010, 66, 1274; (b) Dong, C.; Mo, F.; Wang, J. J. Org. Chem. 2008, 73, 1971; (c) Dong, C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560.

[7] Zhao, Y.; Ma, Z.; Zhang, X.; Zou, Y.; Jin, X.; Wang, J. Angew. Chem., Int. Ed. 2004, 43, 5977.

[8] (a) Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. I 1998, 1919; (b) Wang, J.; Hou, Y.; Wu, P.; Qu, Z. Chan, A. S. C. Tetrahedron: Asymmetry 1999, 10, 4553; (c) Lee, D. J.; Kim, K.; Park, Y. J. Org. Lett. 2002, 4, 873.

[9] Sechi, M.; Neamati, N.; Derudas, M. J. Med. Chem. 2004, 47, 5298.

[10] Mueller, P.; Allenbach, Y. F.; Grass, S. Tetrahedron: Asymmetry 2005, 16, 2007.

[11] Kumamoto, T.; Nagayama, S.; Hayashi, Y.; Kojima, H.; David, L.; Nakanishi, W.; Ishikawa, T. Heterocycles 2008, 76, 1155.

[12] Van der Jeught, S.; De Vos, N.; Masschelein, K.; Ghiviriga, I.; Stevens, C. V. Eur. J. Org. Chem. 2010, 28, 5444.

[13] Vilsmeier, A.; Haack, A. Ber. 1937, 60, 119.

[14] (a) Contrell Jr., W. R.; Lovett, D.; Engles, T.; Anderson, B.; Bauta, W. E.; Wolstenholm-Hogg, P. C. Nucleosides, Nucleotides Nucleic Acids 2008, 27, 901; (b) Shibata, N.; Baldwin, J. E.; Jacobs, A.; Wood, M. E. Tetrahedron 1996, 52, 12839.