Enantioselective synthesis of condensed and transannular ring skeletons containing pyrrolidine moiety

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

Fanyang Mo ${}^{a}$ , Fei Li ${}^{a}$ , Di Qiu ${}^{a}$ , Jianbo Wang ${}^{a, b, * }$

莫凡洋${}^{a}$，李飞${}^{a}$，邱迪${}^{a}$，王剑波${}^{a, b, * }$

${}^{\mathrm{a}}$ 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

${}^{\mathrm{a}}$ 北京分子科学国家实验室(BNLMS)和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

${}^{\mathrm{b}}$ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

${}^{\mathrm{b}}$ 中国科学院有机金属化学国家重点实验室，上海 200032，中国

A R T I C L E I N F O

文章信息

Article history:

文章历史:

Received 4 October 2009

于2009年10月4日收到

Received in revised form 29 November 2009

于2009年11月29日收到修订稿

Accepted 4 December 2009

于2009年12月4日接受

Available online 26 December 2009

于2009年12月26日在线发表

Keywords:

关键词:

Enantioselective synthesis

对映选择性合成

Diazo compounds

重氮化合物

Nucleophilic addition

亲核加成

Pyrrolidine

吡咯烷

Ring-closing olefin metathesis

闭环烯烃复分解反应

A B S T R A C T

摘要

A new approach toward condensed and transannular ring structures containing pyrrolidine unit has been developed, based on diastereoselective nucleophilic addition of lithium enolate of $\alpha$ -diazoacetoacetate to chiral $N$ -sulfinyl imine and ring-closing metathesis.

基于 $\alpha$ -重氮乙酰乙酸锂烯醇盐与手性 $N$ -亚磺酰基亚胺的非对映选择性亲核加成反应以及关环复分解反应，开发了一种合成含吡咯烷单元的稠环和跨环结构的新方法。

1. Introduction

1. 引言

The enantioselective construction of pyrrolidine skeletons, a frequently observed structural unit in various alkaloid type natural products, pharmaceutical molecules, etc., is of current interest. ${}^{1,2}$ Among the various pyrrolidine-containing structures, condensed and transannluar ring skeletons are important structural subunits present in many alkaloids and are common scaffolds in biologically active and pharmaceutically significant compounds. ${}^{3}$ For example, (+)-harmicine was extracted from the Malaysian plant Kopsia griffithii by Kam and Sim and showed strong anti-Leishmania activity. ${}^{4}$ Polyhydroxylated pyrrolizidines and indolizidines (related to iminosugars) such as Swainsonine have increasingly gained attention because of their ability to inhibit glycosidases (Scheme 1). ${}^{5}$

对吡咯烷骨架进行对映选择性构建是当前研究的热点，吡咯烷骨架是各种生物碱类天然产物、药物分子等中常见的结构单元。${}^{1,2}$ 在各种含吡咯烷的结构中，稠合和跨环环骨架是许多生物碱中存在的重要结构亚基，并且是生物活性和药学上重要化合物中的常见支架。${}^{3}$ 例如，Kam和Sim从马来西亚植物Kopsia griffithii中提取了(+)-哈尔明碱，其显示出很强的抗利什曼原虫活性。${}^{4}$ 多羟基化的吡咯里西啶和吲哚里西啶(与亚氨基糖有关)，如苦马豆素，因其抑制糖苷酶的能力而越来越受到关注(方案1)。${}^{5}$

Besides the classical total synthesis approach to complex structures, particularly attractive is the development of synthetic methodologies that allow for the preparation of a large number of structurally similar analogs from limited few common intermediates. ${}^{6}$ As a part of our program for the development of novel synthetic methodology based on diazo compounds, we have recently developed a concise and efficient method to construct

除了用于构建复杂结构的经典全合成方法外，特别有吸引力的是开发能够从有限的几种常见中间体制备大量结构相似类似物的合成方法。${}^{6}$ 作为我们基于重氮化合物开发新型合成方法计划的一部分，我们最近开发了一种简洁有效的方法来构建

5-substituted 2-oxo and 3-oxo pyrrolidines with high enantiomeric purity. ${}^{7}$ Here we report the further application of this methodology to the enantioselective synthesis of condensed and transannular ring skeletons containing pyrrolidine units.

对映体纯度高的5-取代-2-氧代和3-氧代吡咯烷。${}^{7}$ 在此，我们报告了该方法在对映选择性合成含吡咯烷单元的稠合和跨环环骨架中的进一步应用。

This new approach to condensed and transannular ring skeletons is outlined in Scheme 2. With the reactions that have been reported previously, we can easily prepare 2-oxo-5-vinyl-pyrrolidine 1. Introducing the side chains that contain olefin moiety to either N or C3 position affords key intermediates 2 and 3, respectively. Ring-closing metathesis (RCM), ${}^{8}$ which has emerged as powerful tool to construct ring system through intramolecular $\mathrm{C} = \mathrm{C}$ bond formation, is applied to 2 and 3 to afford condensed and transannular ring systems4and ${\mathbf{5}}^{9}$

这种构建稠合和跨环环骨架的新方法在方案2中概述。利用先前报道的反应，我们可以轻松制备2-氧代-5-乙烯基-吡咯烷1。将含有烯烃部分的侧链引入N或C3位置分别得到关键中间体2和3。闭环复分解反应(RCM)，${}^{8}$ 它已成为通过分子内$\mathrm{C} = \mathrm{C}$ 键形成构建环系统的强大工具，应用于2和3以得到稠合和跨环环系统4和${\mathbf{5}}^{9}$

Corresponding author. Fax: +86 10 6275 1708.
通讯作者。传真:+86 10 6275 1708。

(J. Wang).

(J. Wang)。

Scheme 2.

方案2。

1.1. Results and discussions

1.1. 结果与讨论

The investigation began with the preparation of chiral pyrrolidine 10 (Scheme 3). First, diastereoselective addition of lithium enolate of $\alpha$ -diazoacetoacetate 7 to chiral $N$ -sulfinyl imine 6 afforded $\delta - N$ -sulfinylamino $\alpha$ -diazo $\beta$ -ketoester 8 in 70% yield. HPLC analysis showed compound 8 with 97% de. The absolute configuration of the newly generated chiral center in $\beta$ -ketoester 8 was established by X-ray analysis of its single crystal. ${}^{10}$ The absolute configuration is also confirmed by converting 8 into known compounds (vide infra). When the chiral center of sulfur has $S$ configuration, the newly formed chiral center has $R$ configuration. This stereochemical outcome is consistent with the previous reports of the addition of enolates derived from esters or ketones to chiral N-sulfinyl imines. ${}^{{11},{12}}$

研究始于手性吡咯烷10的制备(方案3)。首先，将$\alpha$ -重氮乙酰乙酸酯7的烯醇锂对映选择性加成到手性$N$ -亚磺酰亚胺6上，以70%的产率得到$\delta - N$ -亚磺酰氨基$\alpha$ -重氮$\beta$ -酮酯8。HPLC分析显示化合物8的非对映体过量为97%。通过对$\beta$ -酮酯8的单晶进行X射线分析，确定了新生成的手性中心的绝对构型。${}^{10}$ 通过将8转化为已知化合物(见下文)也证实了绝对构型。当硫的手性中心具有$S$ 构型时，新形成的手性中心具有$R$ 构型。这种立体化学结果与先前关于酯或酮衍生的烯醇盐对手性N-亚磺酰亚胺加成的报道一致。${}^{{11},{12}}$

Scheme 3.

方案3。

Our previous study has shown that $N$ -sulfinyl group is liable to decompose in the Wolff rearrangement reaction, which is under irradiation conditions. Thus, the N-sulfinyl group is replaced by $N$ -Boc group in two steps. First, $\beta$ -ketoester8was treated with 5 equiv of TFA in MeOH to remove the $N$ -sulfinyl auxiliary, giving the free amine as the trifluoroacetate salt. Being neutralized with 6 equiv of ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ , the amine was treated with ${\mathrm{{Boc}}}_{2}\mathrm{O}$ and catalytic amount of DMAP, affording N-Boc protected diazo compound9in 95% yield. Irradiation of diazo compound9with high-pressure $\mathrm{{Hg}}$ lamp $\left( {\lambda > {300}\mathrm{\;{nm}}}\right)$ in a Pyrex tube gave $\left( {5R}\right)$ -2-oxo-3-allyloxy-carbonyl-5-vinylpyrrolidine 10 in 60% isolated yield. ${}^{7,{13}}$

我们之前的研究表明，$N$ -亚磺酰基在光照条件下的沃尔夫重排反应中容易分解。因此，分两步将N-亚磺酰基替换为$N$ -Boc基团。首先，将$\beta$ -酮酯8在甲醇中用5当量的TFA处理以除去$N$ -亚磺酰基辅助基团，得到游离胺的三氟乙酸盐。用6当量的${\mathrm{{Et}}}_{3}\mathrm{\;N}$ 中和后，将胺用${\mathrm{{Boc}}}_{2}\mathrm{O}$ 和催化量的DMAP处理，以95%的产率得到N-Boc保护的重氮化合物9。在派热克斯管中用高压$\mathrm{{Hg}}$ 灯$\left( {\lambda > {300}\mathrm{\;{nm}}}\right)$ 照射重氮化合物9，以60%的分离产率得到$\left( {5R}\right)$ -2-氧代-3-烯丙氧基羰基-5-乙烯基吡咯烷10。${}^{7,{13}}$

With 10 in hand, we next proceeded to build the condensed rings based on the strategy summarized in Scheme 2. The condensed alkaloid structure can be built from 10 through N-alkylation and ring-closing metathesis. Thus, $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ -catalyzed deal-lyloxycarbonylation ${}^{14}$ in the presence of morpholine afforded (5R)- N-Boc-2-oxo-5-vinylpyrrolidine 11 in 88% yield. Removal of the nitrogen protecting group with 5 equiv of TFA in ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ gave $\left( R\right) - 2 -$ oxo-5-vinylpyrrolidine in nearly quantitative yield. $\left( R\right) - 2 -$ Oxo-5- vinylpyrrolidine was then reacted with allyl bromide, homoallyl bromide, and pent-4-enyl 4-methylbenzenesulfonate, respectively, in the presence of base to give the products 13, 14, and 15 as the precursors for the next RCM reaction. Finally, the pyrrolidines 13, 14, and 15 were subjected to the RCM reaction by using second generation Grubbs catalyst. The expected ring-closing products 16, 17, and 18 were obtained in nearly quantitative yields (Scheme 4). Products 16, 17, and 18 are potentially valuable chiral building blocks for enantioselective synthesis of polysubstituted pyrrolizi-dines and indolizidines. ${}^{15}$

得到10后，我们接下来按照方案2总结的策略构建稠环。稠合生物碱结构可以通过N-烷基化和闭环复分解从10构建。因此，在吗啉存在下，$\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ -催化的脱烯丙氧基羰基化${}^{14}$ 反应以得88%的产率得到(5R)-N-Boc-2-氧代-5-乙烯基吡咯烷11。在${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ 中用5当量的TFA除去氮保护基团，以几乎定量的产率得到$\left( R\right) - 2 -$ 氧代-5-乙烯基吡咯烷。然后，$\left( R\right) - 2 -$ 氧代-5-乙烯基吡咯烷分别在碱存在下与烯丙基溴、高烯丙基溴和4-戊烯基对甲苯磺酸酯反应，得到产物13、14和15，作为下一步RCM反应的前体。最后，使用第二代格拉布催化剂对吡咯烷13、14和15进行RCM反应。以几乎定量的产率得到预期的闭环产物16、17和18(方案4)。产物16、17和18是对映选择性合成多取代吡咯里西啶和吲哚里西啶潜在有价值的手性砌块。${}^{15}$

Next, we conceived the further application of pyrrolidine 10 in the construction of transannular ring structures. As shown in Scheme 2, by introducing an alkene moiety on C3 of pyrolidine ring, the transannular ring structures could be built by the same RCM strategy. First, the pyrrolidine 10 was subjected to Pd-catalyzed decarboxylative allylic alkylation, with the expectation that C3 allylation might occur simultaneously. However, the desired intramolecular allylic alkylation process did not occur when 10 was catalyzed by $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ using THF as solvent (Eq. 1). Changing solvent and Pd catalyst were attempted, but all efforts proved to be fruitless.

接下来，我们设想了吡咯烷10在构建跨环结构中的进一步应用。如图2所示，通过在吡咯烷环的C3上引入一个烯烃部分，可以通过相同的RCM策略构建跨环结构。首先，将吡咯烷10进行钯催化的脱羧烯丙基烷基化反应，期望C3烯丙基化可能同时发生。然而，当使用四氢呋喃作为溶剂，由$\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$催化10时，所需的分子内烯丙基烷基化过程并未发生(式1)。尝试了改变溶剂和钯催化剂，但所有努力都没有结果。

We then attempted a different approach, which was direct allylic alkylation of 10 followed by deallyloxycarbonylation. As outlined in Scheme 5, treatment of 10 in acetone with allyl bromide and ${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}$ at ${60}^{ \circ }\mathrm{C}$ for $3\mathrm{\;h}$ furnished a pair of diastereoisomers20in 87% yield, which was subjected to the Pd-catalyzed deal-lyloxycarbonylation to afford two products 19a and 19b in 1:1 ratio. Compounds 19a and 19b could be separated with chromatography column and their structure could be assigned by NOE experiments. The cis isomer 19a was then subjected to RCM reaction with Grubbs second catalyst, affording the ring-closing product (+)-23 in nearly quantitative yield.

然后我们尝试了一种不同的方法，即对10进行直接烯丙基烷基化，然后进行脱烯丙氧羰基化反应。如方案5所示，在丙酮中用烯丙基溴和${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}$在${60}^{ \circ }\mathrm{C}$下处理10 $3\mathrm{\;h}$，得到一对非对映异构体20，产率为87%，然后将其进行钯催化的脱烯丙氧羰基化反应，得到两种产物19a和19b，比例为1:1。化合物19a和19b可以通过色谱柱分离，其结构可以通过NOE实验确定。然后将顺式异构体19a与格拉布第二代催化剂进行RCM反应，以几乎定量的产率得到闭环产物(+)-23。

Scheme 5.

方案5。

Compound (-)-23 is a key intermediate in the total synthesis of an anti-influenza neuramidase inhibitor Oseltamivir (Tamiflu) reported by Corey and co-workers (Scheme 6). ${}^{16}$

化合物(-)-23是科里及其同事报道的抗流感神经氨酸酶抑制剂奥司他韦(达菲)全合成中的关键中间体(方案6)。${}^{16}$

Scheme 6.

方案6。

With the same approach, [4.2.1] bicyclic system (+)-24 could be synthesized by easily changing allyl bromide to homoallyl bromide in the alkylation of10and then following the same subsequent steps as for the synthesis of $\left( +\right) - \mathbf{{23}}$ .

采用相同的方法，通过在10的烷基化反应中轻松地将烯丙基溴改为高烯丙基溴，然后按照与合成$\left( +\right) - \mathbf{{23}}$相同的后续步骤，可以合成[4.2.1]双环体系(+)-24。

Finally, total synthesis of $\left( R\right)$ -Pyrrolam ${\mathrm{A}}^{17}$ has been achieved with this methodology (Scheme 7). RCM precursor (R)-25 was obtained from 12 via simple reduction and acylation with a yield of 60% and then (R)-25 was subjected to RCM reaction catalyzed by 10 mol % of Grubbs second catalyst to give (R)-Pyrolam A 26 in 68% isolated yield.

最后，用这种方法实现了$\left( R\right)$ -吡咯酰胺${\mathrm{A}}^{17}$的全合成(方案7)。RCM前体(R)-25通过简单的还原和酰化反应从12中获得，产率为60%，然后将(R)-25用10 mol%的格拉布第二代催化剂催化进行RCM反应，以68%的分离产率得到(R)-吡咯酰胺A 26。

Scheme 7.

方案7。

2. Conclusions

2. 结论

In summary, we have developed versatile routes to condensed and transannular ring structures containing pyrrolidine unit. These products may be potential scaffolds for the synthesis of alkaloids of biological and pharmaceutical interests. In addition, (R)-Pyrolam A was synthesized enantioselectively, further exhibiting application flexibility of this methodology. Efforts to apply this chemistry to the synthesis of alkaloids of more structural complexity are underway in our laboratory.

总之，我们已经开发出了合成含吡咯烷单元的稠环和跨环结构的通用方法。这些产物可能是用于合成具有生物学和药学意义的生物碱的潜在骨架。此外，还对(R)-Pyrolam A进行了对映选择性合成，进一步展示了该方法的应用灵活性。我们实验室正在努力将该化学方法应用于合成结构更复杂的生物碱。

3. Experimental section

3. 实验部分

3.1. General

3.1. 一般方法

Caution: diazo compounds are generally toxic and potentially explosive. They should be handled with care in a well-ventilated fume hood.

注意:重氮化合物通常有毒且有潜在爆炸风险。应在通风良好的通风橱中小心处理。

3.1.1. (R)-Allyl 2-diazo-5-((S)-4-methylphenylsulfinamido)-3-oxo-hept-6-enoate (8). To a solution of ${\mathbf{6}}^{18}\left( {{193}\mathrm{{mg}},1\mathrm{{mmol}}}\right)$ in ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2} \; \left( {{25}\mathrm{\;{mL}}}\right)$ was added LiHMDS $(2\mathrm{{mmol}},{1.0}\mathrm{M}$ in hexane) at $- {78}^{ \circ }\mathrm{C}$ and then 7 (252mg,1.5 mmol) in ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {5\mathrm{\;{mL}}}\right)$ was dropped in the solution in 5 min. After stirring for another ${10} - {15}\mathrm{\;{min}}$ , the reaction was quenched with saturated aqueous ${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$ at $- {78}^{ \circ }\mathrm{C}$ and then warmed quickly to room temperature. The organic layer was separated and the aqueous layer was extracted with ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {2 \times {15}\mathrm{\;{mL}}}\right)$ . The organic layers were combined and dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ . Then the solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate 3:1) to give the addition products $\mathbf{8}\left( {{252}\mathrm{{mg}},{70}\% \text{ yield }}\right)$ . IR (film) 3208, 2137, 1714, 1649, 1371, 1304, 1090, 1057, 1016, 923, 813, ${746}{\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}\mathrm{{NMR}}\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 7.57}\left( {\mathrm{\;d}, J = {7.8}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.28}(\mathrm{\;d}$ , $J = {7.8}\mathrm{\;{Hz}},2\mathrm{\;H}),{6.02} - {5.87}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{5.37} - {5.21}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.82}(\mathrm{\;d}, J = {7.2}\mathrm{\;{Hz}}$ , 1H), 4.70-4.67 (m, 2H), 4.31 (qd, J=6.1, 7.2 Hz, 1H), 3.19 (dd, J=4.5, ${16.5}\mathrm{\;{Hz}},1\mathrm{H}),{3.08}\left( {\mathrm{{dd}}, J = {7.1},{16.5}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.40}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) 6 190.1, 160.6, 141.7, 141.1, 138.1, 131.1, 129.3, 125.4, 119.2,116.6,65.8,53.1,45.6,21.2; EIMS $(m/z$ , relative intensity): 361 (4), 243 (3), 222 (25), 194 (9), 171 (7), 155 (7), 139 (100), 123 (17), 108 (16), 91 (58), 77 (13), 65 (23), 41 (100), 27 (16). HRMS (EI) calcd for ${\mathrm{C}}_{17}{\mathrm{H}}_{19}{\mathrm{\;N}}_{3}{\mathrm{O}}_{4}\mathrm{\;S}$ 361.1096, found ${361.1095}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {127.0}\left( {{c0.8},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.1. (R)-烯丙基 2-重氮-5-((S)-4-甲基苯亚磺酰胺基)-3-氧代-庚-6-烯酸酯(8)。在${\mathbf{6}}^{18}\left( {{193}\mathrm{{mg}},1\mathrm{{mmol}}}\right)$于${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2} \; \left( {{25}\mathrm{\;{mL}}}\right)$的溶液中，于$- {78}^{ \circ }\mathrm{C}$加入己烷中的 LiHMDS$(2\mathrm{{mmol}},{1.0}\mathrm{M}$，然后在 5 分钟内将${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {5\mathrm{\;{mL}}}\right)$中的 7(252mg，1.5 mmol)滴入该溶液。再搅拌${10} - {15}\mathrm{\;{min}}$后，于$- {78}^{ \circ }\mathrm{C}$用饱和水溶液${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$淬灭反应，然后迅速升温至室温。分离有机层，水层用${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {2 \times {15}\mathrm{\;{mL}}}\right)$萃取。合并有机层，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥。然后在减压下除去溶剂，所得粗产物通过柱色谱(石油醚/乙酸乙酯 3:1)纯化，得到加成产物$\mathbf{8}\left( {{252}\mathrm{{mg}},{70}\% \text{ yield }}\right)$。红外光谱(薄膜)3208、2137、1714、1649、1371、1304、1090、1057、1016、923、813、${746}{\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}\mathrm{{NMR}}\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 7.57}\left( {\mathrm{\;d}, J = {7.8}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{7.28}(\mathrm{\;d}$、$J = {7.8}\mathrm{\;{Hz}},2\mathrm{\;H}),{6.02} - {5.87}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{5.37} - {5.21}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.82}(\mathrm{\;d}, J = {7.2}\mathrm{\;{Hz}}$、1H)，4.70 - 4.67(m，2H)，4.31(qd，J = 6.1，7.2 Hz，1H)，3.19(dd，J = 4.5，${16.5}\mathrm{\;{Hz}},1\mathrm{H}),{3.08}\left( {\mathrm{{dd}}, J = {7.1},{16.5}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.40}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(75 MHz，CDCl3)δ 190.1、160.6、141.7、141.1、138.1、131.1、129.3、125.4、119.2、116.6、65.8、53.1、45.6、21.2；电子轰击质谱$(m/z$，相对强度):361(4)，243(3)，222(25)，194(9)，171(7)，155(7)，139(100)，123(17)，108(16)，91(58)，77(13)，65(23)，41(100)，27(16)。高分辨质谱(EI)计算值${\mathrm{C}}_{17}{\mathrm{H}}_{19}{\mathrm{\;N}}_{3}{\mathrm{O}}_{4}\mathrm{\;S}$为 361.1096，实测值${361.1095}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {127.0}\left( {{c0.8},{\mathrm{{CHCl}}}_{3}}\right)$。

3.1.2. (R)-Allyl 5-(tert-butoxycarbonylamino)-2-diazo-3-oxo-hept-6- enoate (9). The addition product $8\left( {{1.083}\mathrm{\;g},3\mathrm{{mmol}}}\right)$ was treated with TFA $({1.710}\mathrm{\;g},{15}\mathrm{{mmol}},{5.0}$ equiv) in $\mathrm{{MeOH}}\left( {{20}\mathrm{\;{mL}}}\right)$ at ${0}^{ \circ }\mathrm{C}$ . The reaction was monitored by TLC and the sulfinyl group in 8 was removed in about $2\mathrm{\;h}$ to give the corresponding trifluoroacetate salt. The solution was concentrated, and then was dissolved in THF $\left( {{20}\mathrm{\;{mL}}}\right)$ . The solution was treated with ${\mathrm{{Boc}}}_{2}\mathrm{O}({770}\mathrm{{mg}},{3.6}\mathrm{{mmol}}$ , 1.2 equiv), ${\mathrm{{Et}}}_{3}\mathrm{\;N}$ (1.818 g,18 mmol,6 equiv) and a catalytic amount of DMAP ( ${18}\mathrm{{mg}},{0.15}\mathrm{{mmol}},{0.05}$ equiv) at $0{}^{ \circ }\mathrm{C}$ . After stirred for about $2\mathrm{\;h}$ at this temperature, the solution was concentrated and purified by flash chromatography (petroleum ether/ethyl acetate 10:1) to give the $N$ -Boc protected diazo product $\mathbf{9}({920}\mathrm{{mg}}$ , yield 95%) as a yellow oil. IR (film) 3374, 2974, 2135, 1712, 1650, 1366, 1308,1169,922,743 ${\mathrm{{cm}}}^{-1}$ ; ${}^{1}\mathrm{H}$ NMR (300 MHz, CDCl ${}_{3}$ ) $\delta$ 6.01-5.81 $\left( {m,{2H}}\right) ,{5.39} - {5.29}\left( {m,{2H}}\right) ,{5.23} - {5.09}\left( {m,{3H}}\right) ,{4.73}(d,{2H}$ , $J = {5.7}\mathrm{\;{Hz}}),{4.60}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{3.21} - {3.14}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.43}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$ (75 MHz, CDCl3) δ 190.4, 160.8, 155.0, 137.6, 131.2, 119.2, 114.8, 79.3, 65.9,49.5, 44.3, 28.2; EIMS $\left( {m/z\text{ , relative intensity): 323 (1), 267 }}\right)$ (23), 250 (8), 154 (9), 136 (10), 100 (25), 57 (100), 41 (49), 29 (7). HRMS (EI) calcd for ${\mathrm{C}}_{15}{\mathrm{H}}_{21}{\mathrm{\;N}}_{3}{\mathrm{O}}_{5}{323.1481}$ , found ${323.1485}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} \; - {36.4}\left( {{c1.4},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.2. (R)-烯丙基5-(叔丁氧羰基氨基)-2-重氮-3-氧代-庚-6-烯酸酯(9)。将加成产物$8\left( {{1.083}\mathrm{\;g},3\mathrm{{mmol}}}\right)$用三氟乙酸($({1.710}\mathrm{\;g},{15}\mathrm{{mmol}},{5.0}$当量)在$\mathrm{{MeOH}}\left( {{20}\mathrm{\;{mL}}}\right)$中于${0}^{ \circ }\mathrm{C}$处理。通过薄层色谱法监测反应，8中的亚磺酰基在约$2\mathrm{\;h}$内被除去，得到相应的三氟乙酸盐。将溶液浓缩，然后溶解在四氢呋喃($\left( {{20}\mathrm{\;{mL}}}\right)$)中。将溶液用${\mathrm{{Boc}}}_{2}\mathrm{O}({770}\mathrm{{mg}},{3.6}\mathrm{{mmol}}$(1.2当量)、${\mathrm{{Et}}}_{3}\mathrm{\;N}$(1.818 g，18 mmol，6当量)和催化量的4-二甲氨基吡啶(${18}\mathrm{{mg}},{0.15}\mathrm{{mmol}},{0.05}$当量)在$0{}^{ \circ }\mathrm{C}$处理。在此温度下搅拌约$2\mathrm{\;h}$后，将溶液浓缩并通过快速柱色谱法(石油醚/乙酸乙酯10:1)纯化，得到$N$-Boc保护的重氮产物$\mathbf{9}({920}\mathrm{{mg}}$(产率95%)，为黄色油状物。红外光谱(薄膜)3374、2974、2135、1712、1650、1366、1308、1169、922、743${\mathrm{{cm}}}^{-1}$；${}^{1}\mathrm{H}$核磁共振谱(300 MHz，CDCl${}_{3}$)$\delta$6.01 - 5.81$\left( {m,{2H}}\right) ,{5.39} - {5.29}\left( {m,{2H}}\right) ,{5.23} - {5.09}\left( {m,{3H}}\right) ,{4.73}(d,{2H}$，$J = {5.7}\mathrm{\;{Hz}}),{4.60}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{3.21} - {3.14}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.43}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}$(75 MHz，CDCl3)δ190.4、160.8、155.0、137.6、131.2、119.2、114.8、79.3、65.9、49.5、44.3、28.2；电子轰击质谱$\left( {m/z\text{ , relative intensity): 323 (1), 267 }}\right)$(23)、250(8)、154(9)、136(10)、100(25)、57(100)、41(49)、29(7)。高分辨质谱(EI)计算值为${\mathrm{C}}_{15}{\mathrm{H}}_{21}{\mathrm{\;N}}_{3}{\mathrm{O}}_{5}{323.1481}$，实测值为${323.1485}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} \; - {36.4}\left( {{c1.4},{\mathrm{{CHCl}}}_{3}}\right)$。

3.1.3. (R)-3-Allyl 1-tert-butyl 2-oxo-5-vinylpyrrolidine-1,3-dicarboxylate (10). A solution of $\mathbf{9}\left( {{920}\mathrm{{mg}},{2.85}\mathrm{{mmol}}}\right)$ in benzene $\left( {{200}\mathrm{\;{mL}}}\right)$ in a Pyrex tube was irradiated with a 500 W high-pressure Hg lamp with a water-cooled tube inserted into the solvent. The reaction temperature was kept at about ${35}^{ \circ }\mathrm{C}$ . The reaction was complete in about $3\mathrm{\;h}$ (monitored by IR and TLC). The solution was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (petroleum ether/ethyl acetate 8:1) to give the diastereomeric mixture of the corresponding 3-allyl-oxycarbonyl-2-oxo pyrrolidines 10 (504 mg, yield 60%) as a yellowy oil. The diastereomeric mixture could not be separated by column chromatography. IR (film) 2977, 1786, 1731, 1368, 1298, 1251, 1150, 970,925 ${\mathrm{{cm}}}^{-1}$ ; ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ 6.00-5.79 (m,2H), 5.42-5.17 (m, 4H), 4.75-4.51 (m, 3H), 3.67-3.53 (m, 1H), 2.70-2.66 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.26} - {2.03}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ 168.5, 168.2, 149.2, 137.5, 136.0, 131.3, 131.2, 118.9, 118.8, 116.5, 115.8, 83.4, 66.4, 66.3, 59.0, 57.6, 49.0, 48.3, 28.2, 27.8; EIMS $(m/z$ , relative intensity): 295 (3), 280 (5), 239 (40), 195 (20), 154 (100), 136 (95), 110 (98), 67 (46), 57 (52), 41 (66). HRMS (EI) calcd for ${\mathrm{C}}_{15}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{5}$ 295.1420, found 295.1422.

3.1.3. (R)-3-烯丙基-1-叔丁基-2-氧代-5-乙烯基吡咯烷-1,3-二羧酸酯(10)。将$\mathbf{9}\left( {{920}\mathrm{{mg}},{2.85}\mathrm{{mmol}}}\right)$在苯$\left( {{200}\mathrm{\;{mL}}}\right)$中的溶液置于派热克斯玻璃管中，用插入溶剂中的水冷管的500W高压汞灯照射。反应温度保持在约${35}^{ \circ }\mathrm{C}$。反应在约$3\mathrm{\;h}$内完成(通过红外光谱和薄层色谱监测)。溶液在减压下浓缩得到粗产物，通过快速柱色谱法(石油醚/乙酸乙酯8:1)纯化，得到相应的3-烯丙基-氧羰基-2-氧代吡咯烷10的非对映体混合物(504mg，产率60%)，为淡黄色油状物。该非对映体混合物不能通过柱色谱法分离。红外光谱(薄膜)2977、1786、1731、1368、1298、1251、1150、970、925${\mathrm{{cm}}}^{-1}$；${}^{1}\mathrm{H}$核磁共振(300MHz，${\mathrm{{CDCl}}}_{3}$)$\delta$6.00 - 5.79(m，2H)，5.42 - 5.17(m，4H)，4.75 - 4.51(m，3H)，3.67 - 3.53(m，1H)，2.70 - 2.66$\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.26} - {2.03}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(75MHz，${\mathrm{{CDCl}}}_{3}$)$\delta$168.5、168.2、149.2、137.5、136.0、131.3、131.2、118.9、118.8、116.5、115.8、83.4、66.4、66.3、59.0、57.6、49.0、48.3、28.2、27.8；电子轰击质谱$(m/z$，相对强度):295(3)，280(5)，239(40)，195(2)，154(100)，136(95)，110(98)，67(46)，57(52)，41(66)。高分辨质谱(电子轰击)计算值为${\mathrm{C}}_{15}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{5}$295.1420，实测值为295.1422。

3.1.4. (R)-tert-Butyl 2-oxo-5-vinylpyrrolidine-1-carboxylate (11) Compound ${10}\left( {{183}\mathrm{{mg}},{0.62}\mathrm{{mmol}}}\right)$ was dissolved in THF ${\left( {10}\mathrm{{mL}}\right) }_{\Delta }$ , and then morpholine $({81}\mathrm{{mg}},{0.93}\mathrm{{mmol}},{1.5}$ equiv) and $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ (36 mg, 0.031 mmol, 5 mol%) were added in room temperature. When the reaction was complete as monitored by TLC, the solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether/ethyl acetate 5:1) to give the pyrrolidine derivative 11 (115 mg, yield 88%) as a yellow oil. IR (film) 2981,1782,1750,1717,1367,1305,1255,1153,1020,850 ${\mathrm{{cm}}}^{-1}$ ; ${}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.91} - {5.80}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.20} - {5.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.67} - \; {4.62}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.64} - {2.52}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.47} - {2.37}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.30} - {2.17}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${1.86} - {1.77}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 174.2},{149.5}$ , 136.4,115.0,82.6,59.4,30.8,27.7,24.0; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {27.7}\left( {{c0.95},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.4. (R)-2-氧代-5-乙烯基吡咯烷-1-羧酸叔丁酯(11)将化合物${10}\left( {{183}\mathrm{{mg}},{0.62}\mathrm{{mmol}}}\right)$溶于四氢呋喃${\left( {10}\mathrm{{mL}}\right) }_{\Delta }$，然后在室温下加入吗啉$({81}\mathrm{{mg}},{0.93}\mathrm{{mmol}},{1.5}$当量)和$\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$(36毫克，0.031毫摩尔，5摩尔%)。通过薄层层析监测反应完成后，将溶液减压浓缩，并通过快速柱色谱法(石油醚/乙酸乙酯5:1)纯化，得到黄色油状的吡咯烷衍生物11(115毫克，产率88%)。红外光谱(薄膜)2981、1782、1750、1717、1367、1305、1255、1153、1020、850${\mathrm{{cm}}}^{-1}$；${}^{1}\mathrm{H}$核磁共振$\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.91} - {5.80}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.20} - {5.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.67} - \; {4.62}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.64} - {2.52}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.47} - {2.37}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.30} - {2.17}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，${1.86} - {1.77}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 174.2},{149.5}$，136.4、115.0、82.6、59.4、30.8、27.7、24.0；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {27.7}\left( {{c0.95},{\mathrm{{CHCl}}}_{3}}\right)$。

3.1.5. (R)-2-Oxo-5-vinylpyrrolidine ${\left( {12}\right) }^{19}$ . TFA $\left( {{684}\mathrm{{mg}},6\mathrm{{mmol}}}\right)$ in 5 equiv) was added to a solution of ${11}\left( {{252}\mathrm{{mg}},{1.2}\mathrm{{mmol}}}\right)$ in ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{10}\mathrm{\;{mL}}}\right)$ at $0{}^{ \circ }\mathrm{C}$ and then the reaction was allowed to continue in room temperature overnight. When being completed as monitored by TLC, the reaction was neutralized by saturated ${\mathrm{{NaHCO}}}_{3}$ to $\mathrm{{pH}} \approx 7$ . The organic layer was separated and the aqueous layer was extracted with ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {2 \times {15}\mathrm{\;{mL}}}\right)$ . The organic layers were then combined and dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ . The solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether/ethyl acetate 1:1) to give the title compound ${12}\left( {{131}\mathrm{{mg}}}\right)$ in nearly quantitative yield as a yellow oil. ${}^{1}\mathrm{H}$ NMR (300 MHz, CDCl ${}_{3}$ ) $\delta$ 7.20 (s,1H),5.81 (ddd, $J = {6.7},{10.1},{16.9}\mathrm{\;{Hz}},1\mathrm{H}),{5.26} - {5.10}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.23} - {4.17}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.45} -$ 2.27 (m, 3H), 1.90-1.78 (m, 1H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) δ 178.8, 138.4,115.4,56.6,29.8,27.7; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {39.2}\left( {{c1},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.5. (R)-2-氧代-5-乙烯基吡咯烷${\left( {12}\right) }^{19}$。将三氟乙酸$\left( {{684}\mathrm{{mg}},6\mathrm{{mmol}}}\right)$(5当量)加入到${11}\left( {{252}\mathrm{{mg}},{1.2}\mathrm{{mmol}}}\right)$在${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{10}\mathrm{\;{mL}}}\right)$中的溶液中，于$0{}^{ \circ }\mathrm{C}$温度下，然后使反应在室温下继续过夜。通过薄层色谱监测反应完成后，用饱和${\mathrm{{NaHCO}}}_{3}$中和反应至$\mathrm{{pH}} \approx 7$。分离有机层，水层用${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {2 \times {15}\mathrm{\;{mL}}}\right)$萃取。然后合并有机层，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥。溶液在减压下浓缩，并通过快速柱色谱法(石油醚/乙酸乙酯1:1)纯化，以几乎定量的产率得到标题化合物${12}\left( {{131}\mathrm{{mg}}}\right)$，为黄色油状物。${}^{1}\mathrm{H}$核磁共振(300兆赫兹，CDCl${}_{3}$)$\delta$7.20(单峰，1H)，5.81(ddd，$J = {6.7},{10.1},{16.9}\mathrm{\;{Hz}},1\mathrm{H}),{5.26} - {5.10}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.23} - {4.17}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.45} -$2.27(多重峰，3H)，1.90 - 1.78(多重峰，1H)；${}^{13}\mathrm{C}$核磁共振(75兆赫兹，CDCl3)δ178.8，138.4，115.4，56.6，29.8，27.7；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {39.2}\left( {{c1},{\mathrm{{CHCl}}}_{3}}\right)$。

3.1.6. (R)-1-Substituted-5-vinylpyrrolidin-2-ones 13, 14, and 15. The title compounds were obtained from 12 according to literature procedure. ${}^{20}$

3.1.6. (R)-1-取代-5-乙烯基吡咯烷-2-酮13、14和15。根据文献方法从12得到标题化合物。${}^{20}$

3.1.7. (R)-1-Allyl-2-oxo-5-vinylpyrrolidine (13). IR (film) 2980, 1687, 1643,1406,1278,1253,1189,1128,992,923,844,726 ${\mathrm{{cm}}}^{-1};{}^{1}\mathrm{H}$ NMR (300 MHz, CDC1, $\delta$ 5.76-5.59 (m, 2H), 5.24-5.09 (m, 4H), 4.29 (ddt, $J = {15.3},{4.8},{1.5}\mathrm{\;{Hz}},1\mathrm{H}),{4.05}$ (dt, $J = {8.1},{5.4}\mathrm{\;{Hz}},1\mathrm{H}),{3.41}(\mathrm{{dq}}$ , $J = {7.5},{1.2}\mathrm{\;{Hz}},1\mathrm{\;H}),{2.52} - {2.32}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.30} - {2.18}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {1.72} \; \left( {\mathrm{m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 174.6},{137.4},{132.3},{117.9},{117.6}$ , 60.6, 42.8, 29.8, 25.2; EIMS $\left( {m/z\text{ , relative intensity): 151 (37), 136 }}\right) \; \left( {31}\right) ,{124}\left( {55}\right) ,{96}\left( {19}\right) ,{84}\left( {11}\right) ,{67}\left( {41}\right) ,{54}\left( {28}\right) ,{41}\left( {100}\right) ,{39}\left( {60}\right) ,{27}$ (35); HRMS (ESI) calcd for ${\mathrm{C}}_{9}{\mathrm{H}}_{13}\mathrm{{NONa}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {174.0889}$ , found 174.0887. ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {165.1}\left( {{c1.3},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.7. (R)-1-烯丙基-2-氧代-5-乙烯基吡咯烷(13)。红外光谱(薄膜)2980、1687、1643、1406、1278、1253、1189、1128、992、923、844、726 ${\mathrm{{cm}}}^{-1};{}^{1}\mathrm{H}$ 核磁共振(300兆赫，CDCl，$\delta$ 5.76 - 5.59(多重峰，2H)，5.24 - 5.09(多重峰，4H)，4.29(ddt，$J = {15.3},{4.8},{1.5}\mathrm{\;{Hz}},1\mathrm{H}),{4.05}$ (dt，$J = {8.1},{5.4}\mathrm{\;{Hz}},1\mathrm{H}),{3.41}(\mathrm{{dq}}$ ，$J = {7.5},{1.2}\mathrm{\;{Hz}},1\mathrm{\;H}),{2.52} - {2.32}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.30} - {2.18}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {1.72} \; \left( {\mathrm{m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 174.6},{137.4},{132.3},{117.9},{117.6}$ ，60.6，42.8，29.8，25.2；电子轰击质谱 $\left( {m/z\text{ , relative intensity): 151 (37), 136 }}\right) \; \left( {31}\right) ,{124}\left( {55}\right) ,{96}\left( {19}\right) ,{84}\left( {11}\right) ,{67}\left( {41}\right) ,{54}\left( {28}\right) ,{41}\left( {100}\right) ,{39}\left( {60}\right) ,{27}$ (35)；高分辨质谱(电喷雾电离)计算值为 ${\mathrm{C}}_{9}{\mathrm{H}}_{13}\mathrm{{NONa}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {174.0889}$ ，实测值为174.0887。${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {165.1}\left( {{c1.3},{\mathrm{{CHCl}}}_{3}}\right)$ 。

3.1.8. (R)-1-(But-3-enyl)-2-oxo-5-vinylpyrrolidine ${\left( \mathbf{{14}}\right) }^{21}$ . IR (film) 2974,1687,1415,1256,993,920 ${\mathrm{{cm}}}^{-1}$ ; ${}^{1}\mathrm{H}$ NMR (300 MHz, CDC ${\mathrm{l}}_{3}$ ) $\delta$ 5.82-5.61 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.30} - {5.01}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.09} - {4.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.71} -$ 3.41 (m, 1H), 2.99-2.90 (m, 1H), 2.47-2.33 (m, 2H), 2.30-2.15 (m, 3H), 1.88-1.56 (m, 1H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) $\delta$ 174.8, 137.7, 135.2, 117.7, 116.6, 61.2, 39.7, 31.7, 30.0, 25.4; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {58.2}(c$ 0.85, ${\mathrm{{CHCl}}}_{3}$ ).

3.1.8. (R)-1-(丁-3-烯基)-2-氧代-5-乙烯基吡咯烷 ${\left( \mathbf{{14}}\right) }^{21}$ 。红外光谱(薄膜)2974,1687,1415,1256,993,920 ${\mathrm{{cm}}}^{-1}$ ；${}^{1}\mathrm{H}$ 核磁共振氢谱(300兆赫，CDC ${\mathrm{l}}_{3}$ )$\delta$ 5.82 - 5.61 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.30} - {5.01}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.09} - {4.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.71} -$ 3.41(多重峰，1H)，2.99 - 2.90(多重峰，1H)，2.47 - 2.33(多重峰，2H)，2.30 - 2.15(多重峰，3H)，1.88 - 1.56(多重峰，1H)；${}^{13}\mathrm{C}$ 核磁共振碳谱(75兆赫，CDCl3)$\delta$ 174.8，137.7，135.2，117.7，116.6，61.2，39.7，31.7，30.0，25.4；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {58.2}(c$ 0.85，${\mathrm{{CHCl}}}_{3}$ )。

3.1.9. (R)-1-(Pent-4-enyl)-2-oxo-5-vinylpyrrolidine ${\left( \mathbf{{15}}\right) }^{21} \cdot {}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.86-5.74 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{5.72} - {5.60}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.27} - {5.19} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{5.05} - {4.94}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.08} - {4.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.59} - {3.49}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , 2.95-2.86 (m, 1H), 2.48-2.34 (m, 2H), 2.30-2.16 (m, 1H), 2.036 (q, $J = {7.5}\mathrm{\;{Hz}},2\mathrm{H}),{1.80} - {1.69}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.67} - {1.46}\left( {\mathrm{\;m},2\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) δ 174.8, 137.8, 137.6, 117.7, 114.8, 61.3, 40.1, 30.9, 30.0,26.3,25.4; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {62.6}\left( {{c0.95},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.1.9. (R)-1-(戊-4-烯基)-2-氧代-5-乙烯基吡咯烷 ${\left( \mathbf{{15}}\right) }^{21} \cdot {}^{1}\mathrm{H}$ 核磁共振 $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.86 - 5.74 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{5.72} - {5.60}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.27} - {5.19} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{5.05} - {4.94}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.08} - {4.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.59} - {3.49}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，2.95 - 2.86(多重峰，1H)，2.48 - 2.34(多重峰，2H)，2.30 - 2.16(多重峰，1H)，2.036(四重峰，$J = {7.5}\mathrm{\;{Hz}},2\mathrm{H}),{1.80} - {1.69}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.67} - {1.46}\left( {\mathrm{\;m},2\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ 核磁共振碳谱(75兆赫，CDCl3)δ 174.8，137.8，137.6，117.7，114.8，61.3，40.1，30.9，30.0，26.3，25.4；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {62.6}\left( {{c0.95},{\mathrm{{CHCl}}}_{3}}\right)$ 。

3.2. General procedure for the RCM reaction

3.2. 关环复分解反应的通用步骤

Compound 13,14 or 15 (0.08 mmol) was dissolved in dry ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$ (100 mL) under nitrogen atmosphere. Second generation Grubbs catalyst (24 mg, 10 mol%) was added. The resulting mixture was heated at reflux temperature (monitored by TLC). After completion of the reaction, the solvent was then evaporated, and the residual oil was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give the ring-closing product 16, 17 or 18 in nearly quantitative yields.

化合物13、14或15(0.08 mmol)在氮气气氛下溶于干燥的${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}$(100 mL)中。加入第二代格拉布催化剂(24 mg，10 mol%)。将所得混合物加热至回流温度(通过薄层色谱监测)。反应完成后，蒸发溶剂，残余油状物通过硅胶柱快速色谱法(石油醚/乙酸乙酯5:1)纯化，以几乎定量的产率得到关环产物16、17或18。

3.2.1. (R)-5,7a-Dihydro-1H-pyrrolizin-3(2H)-one (16) ${}^{{21},{22}}{.}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.92} - {5.86}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.71} - {4.63}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.43} - {4.36} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{3.71} - {3.64}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.79} - {2.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.46} - {2.30}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , ${1.89} - {1.75}\left( {\mathrm{\;m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 177.9},{130.5},{128.1}$ , 67.4, 49.6, 34.0, 29.5; IR (film) 3474, 2917, 1681, 1459, 1391, 1280, ${1190},{990},{769}{\mathrm{\;{cm}}}^{-1}$ ; EIMS ( $m/z$ , relative intensity): ${123}\left( {50}\right) ,{122}$ (17), 94 (6), 80 (8), 67 (100), 55 (52), 39 (52), 32 (13), 27 (32); HRMS (ESI) calcd for ${\mathrm{C}}_{7}{\mathrm{H}}_{9}\mathrm{{NONa}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {146.0576}$ , found ${146.0571}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} \; - {19.5}\left( {c\;{0.5},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.1. (R)-5,7a-二氢-1H-吡咯里嗪-3(2H)-酮(16)${}^{{21},{22}}{.}^{1}\mathrm{H}$核磁共振$\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.92} - {5.86}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.71} - {4.63}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.43} - {4.36} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{3.71} - {3.64}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.79} - {2.67}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.46} - {2.30}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，${1.89} - {1.75}\left( {\mathrm{\;m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 177.9},{130.5},{128.1}$，67.4，49.6，34.0，29.5；红外(薄膜)3474，2917，1681，1459，1391，1280,${1190},{990},{769}{\mathrm{\;{cm}}}^{-1}$；电子轰击质谱($m/z$，相对强度):${123}\left( {50}\right) ,{122}$(17)，94(6)，80(8)，67(100)，55(52)，39(52)，32(13)，27(32)；高分辨质谱(电喷雾电离)计算值为${\mathrm{C}}_{7}{\mathrm{H}}_{9}\mathrm{{NONa}}\left( {\mathrm{M} + \mathrm{{Na}}}\right) {146.0576}$，实测值为${146.0571}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} \; - {19.5}\left( {c\;{0.5},{\mathrm{{CHCl}}}_{3}}\right)$。

3.2.2. (R)-1,2,5,6-Tetrahydroindolizin-3(8aH)-one (17) ${}^{{21},{23}}$ . ${}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.28} - {5.67}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.24} - {4.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.90} - {2.81} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.55} - {2.39}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.30} - {2.20}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.11} - {2.02}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${1.67} - {1.53}\left( {\mathrm{\;m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 172.9},{128.1},{124.8}$ , 54.8, 36.1, 31.5, 26.2, 24.4; IR (film) 2919, 1685, 1437, 1421, 1363, 1306,1265,841 ${\mathrm{{cm}}}^{-1};{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {94.0}\left( {{c0.8},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.2. (R)-1,2,5,6-四氢吲哚里嗪-3(8aH)-酮(17)${}^{{21},{23}}$ 。${}^{1}\mathrm{H}$ 核磁共振 $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.28} - {5.67}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.24} - {4.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.90} - {2.81} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.55} - {2.39}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.30} - {2.20}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.11} - {2.02}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，${1.67} - {1.53}\left( {\mathrm{\;m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 172.9},{128.1},{124.8}$ ，54.8，36.1，31.5，26.2，24.4；红外光谱(薄膜)2919，1685，1437，1421，1363，1306，1265，841 ${\mathrm{{cm}}}^{-1};{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {94.0}\left( {{c0.8},{\mathrm{{CHCl}}}_{3}}\right)$ 。

3.2.3. (R)-5,6,7,9a-Tetrahydro-1H-pyrrolo[1,2-a]azepin-3(2H)-one ${\left( \mathbf{{18}}\right) }^{21} \cdot {}^{1}\mathrm{H}$ NMR (300 MHz, CDCl ${}_{3}$ ) $\delta$ 5.80-5.72 (m,1H),5.49 (ddd, J=1.8, 3.7, 11.4 Hz, 1H), 4.37-4.31 (m, 1H), 4.12-4.03 (m, 1H), 3.05- 2.97 (m, 1H), 2.50-1.74 (m, 8H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) Å 174.6, 131.8,131.4,58.3,42.6,29.9,27.5,26.7,26.2; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {7.9}$ (c 1.35, ${\mathrm{{CHCl}}}_{3}$ ).

3.2.3. (R)-5,6,7,9a-四氢-1H-吡咯并[1,2-a]氮杂环庚-3(2H)-酮${\left( \mathbf{{18}}\right) }^{21} \cdot {}^{1}\mathrm{H}$ 核磁共振(300兆赫，氘代氯仿${}_{3}$ )$\delta$ 5.80 - 5.72(多重峰，1H)，5.49(三重双合峰，J = 1.8，3.7，11.4赫兹，1H)，4.37 - 4.31(多重峰，1H)，4.12 - 4.03(多重峰，1H)，3.05 - 2.97(多重峰，1H)，2.50 - 1.74(多重峰，8H)；${}^{13}\mathrm{C}$ 核磁共振(75兆赫，氘代氯仿)Å 174.6，131.8，131.4，58.3，42.6，29.9，27.5，26.7，26.2；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {7.9}$ (c 1.35，${\mathrm{{CHCl}}}_{3}$ )。

3.2.4. (5R)-3-Allyl 1-tert-butyl 3-allyl-2-oxo-5-vinylpyrrolidine-1,3- dicarboxylate (20). To a solution of10(118 mg,0.4 mmol) in acetone $\left( {9\mathrm{\;{mL}}}\right)$ were successively added ${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}({66}\mathrm{{mg}},{0.48}\mathrm{{mmol}}$ , 1.2 equiv), ${\mathrm{{Bu}}}_{4}\mathrm{{NBr}}$ (26 mg,0.08 mmol,0.2 equiv), and allyl bromide (145 mg, 1.2 mmol, 3 equiv). The resulting mixture was heated at ${60}^{ \circ }\mathrm{C}$ for $3\mathrm{\;h}$ (monitored by TLC). After cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 7:1) to give the title compound as a yellow oil $\left( {{117}\mathrm{{mg}},{87}\% }\right) .{}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \; \delta$ 5.96-5.63 $\left( {\mathrm{m},3\mathrm{H}}\right) ,{5.38} - {5.31}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{4.66} - {4.61}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.56} - \; {4.49}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.88} - {2.51}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.39} - {2.25}\left( {\mathrm{\;m},{1.5}\mathrm{H}}\right) ,{1.80} - {1.70}$ (m, 0.5H), 1.50 (s, 9H); ${}^{13}$ C NMR (75 MHz, CDCl, 119.9, 118.9, 118.6, 169.7, 138.3, 137.2, 132.3, 131.9, 131.2, 120.1, 119.9, 118.9, 118.6, 116.3, 115.9, 115.7, 83.5, 83.3, 76.5, 66.3, 66.3, 58.0, 57.3, 56.4, 56.1, 39.4,38.3,33.2,32.6,27.8; EIMS ( $m/z$ , relative intensity): 335 (5), 279 (18), 235 (12), 194 (55), 176 (25), 150 (100), 136 (45), 108 (20), 79 (25), 57 (35), 41 (44); HRMS (EI) calcd for ${\mathrm{C}}_{18}{\mathrm{H}}_{25}{\mathrm{{NO}}}_{5}$ 335.1733, found 335.1735.

3.2.4. (5R)-3-烯丙基 1-叔丁基 3-烯丙基-2-氧代-5-乙烯基吡咯烷-1,3-二羧酸酯(20)。向10(118毫克，0.4毫摩尔)在丙酮$\left( {9\mathrm{\;{mL}}}\right)$中的溶液中依次加入${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}({66}\mathrm{{mg}},{0.48}\mathrm{{mmol}}$(1.2当量)、${\mathrm{{Bu}}}_{4}\mathrm{{NBr}}$(26毫克，0.08毫摩尔，0.2当量)和烯丙基溴(145毫克，1.2毫摩尔，3当量)。所得混合物在${60}^{ \circ }\mathrm{C}$加热$3\mathrm{\;h}$(通过薄层色谱法监测)。冷却至室温后，混合物在减压下浓缩。残余物通过快速柱色谱法(石油醚/乙酸乙酯 7:1)纯化，得到标题化合物，为黄色油状物$\left( {{117}\mathrm{{mg}},{87}\% }\right) .{}^{1}\mathrm{H}$核磁共振$\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \; \delta$5.96 - 5.63$\left( {\mathrm{m},3\mathrm{H}}\right) ,{5.38} - {5.31}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{4.66} - {4.61}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.56} - \; {4.49}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.88} - {2.51}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.39} - {2.25}\left( {\mathrm{\;m},{1.5}\mathrm{H}}\right) ,{1.80} - {1.70}$(m，0.5H)，1.50(s，9H)；${}^{13}$碳核磁共振(75兆赫，CDCl，119.9，118.9，118.6，169.7，138.3，137.2，132.3，131.9，131.2，120.1，119.9，118.9，118.6，116.3，115.9，115.7，83.5，83.3，76.5，66.3，66.३，58.0，57.3，56.4，56.1，39.4，38.3，33.2，32.6，27.8；电子轰击质谱($m/z$，相对强度):335(5)，279(18)，235(12)，194(55)，176(25)，150(100)，136(45)，108(20)，79(25)，57(35)，41(44)；高分辨质谱(电子轰击)计算值为${\mathrm{C}}_{18}{\mathrm{H}}_{25}{\mathrm{{NO}}}_{5}$335.1733，实测值为335.1735。

3.2.5. (5R)-tert-Butyl 3-allyl-2-oxo-5-vinylpyrrolidine-1-carboxyl-ates (19a and 19b). Compound 20 (117 mg, 0.35 mmol) was dissolved in THF (8 mL), and then morpholine (46 mg, 0.524 mmol, 1.5 equiv) and $\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$ (20 mg,0.0175 mmol,5 mol%) were added at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether/ethyl acetate 7:1) to give ${19}\mathrm{a}\left( {{42}\mathrm{{mg}}}\right)$ and ${19}\mathrm{b}\left( {{41}\mathrm{{mg}}}\right)$ , both as a yellow oil. Compound 19a: ${R}_{f} = {0.6}$ (petroleum ether/EtOAc 3:1). IR (film) 2954,2924, 2853,1783,1725,1458,1368,1299,1255,1154,916 ${\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.84-5.70 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.23} - {5.06}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.45}(\mathrm{{dd}}$ , $J = {9.0},{6.0}\mathrm{\;{Hz}},1\mathrm{H}),{2.69} - {2.53}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.39} - {2.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.24} - {2.14} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.57} - {1.52}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right)$ 6 175.6, 149.9, 138.9, 134.9, 117.2, 115.5, 82.9, 58.6, 42.2, 35.2, 30.2, 27.8; EIMS $(m/z$ , relative intensity): 251 (28),236 (4),195 (100),151 (92), 109 (95), 79 (83), 67 (92), 56 (85), 41 (84); HRMS (EI) calcd for ${\mathrm{C}}_{14}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{3}{251.1521}$ , found ${251.1523}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {17.1}\left( {{c0.96},{\mathrm{{CHCl}}}_{3}}\right)$ . Compound 19b: ${R}_{f} = {0.7}$ (petroleum ether/EtOAc 3:1). IR (film) 2954, 2924,2845,1783,1717,1461,1299,1255,1154,912 ${\mathrm{{cm}}}^{-1}$ ; ${}^{1}\mathrm{H}$ NMR $\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.91-5.69 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.19} - {5.05}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.62} - {4.57} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.72} - {2.60}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.23} - {2.12}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.01} - {1.86}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , 1.50 (s,9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 175.0,149.7,136.3,134.8, 117.2,115.1,82.7,57.3,40.7,34.2,30.4,27.8; EIMS $\left( {m/z}\right.$ , relative intensity): 251 (30), 236 (6), 195 (100), 151 (90), 109 (93), 79 (82), 67 (90), 56 (84), 41 (82); HRMS (EI) calcd for ${\mathrm{C}}_{14}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{3}{251.1521}$ , found 251.1523; ${\left\lbrack \alpha \right\rbrack }_{D}^{20} + {33.5}\left( {c\text{ 1.1, CHC }{\mathrm{l}}_{3}}\right)$ .

3.2.5. (5R)-叔丁基3-烯丙基-2-氧代-5-乙烯基吡咯烷-1-羧酸酯(19a和19b)。将化合物20(117毫克，0.35毫摩尔)溶于四氢呋喃(8毫升)，然后在室温下加入吗啉(46毫克，0.524毫摩尔，1.5当量)和$\mathrm{{Pd}}{\left( {\mathrm{{PPh}}}_{3}\right) }_{4}$(20毫克，0.0175毫摩尔，5摩尔%)。反应完成后，将溶液减压浓缩，并用快速柱色谱法(石油醚/乙酸乙酯7:1)纯化，得到${19}\mathrm{a}\left( {{42}\mathrm{{mg}}}\right)$和${19}\mathrm{b}\left( {{41}\mathrm{{mg}}}\right)$，均为黄色油状物。化合物19a:${R}_{f} = {0.6}$(石油醚/乙酸乙酯3:1)。红外光谱(薄膜)2954、2924、2853、1783、1725、1458、1368、1299、1255、1154、916 ${\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$核磁共振$\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.84 - 5.70 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.23} - {5.06}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.45}(\mathrm{{dd}}$，$J = {9.0},{6.0}\mathrm{\;{Hz}},1\mathrm{H}),{2.69} - {2.53}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.39} - {2.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.24} - {2.14} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.57} - {1.52}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.50}\left( {\mathrm{\;s},9\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right)$ 6 175.6、149.9、138.9、134.9、117.2、115.5、82.9、58.6、42.2、35.2、30.2、27.8；电子轰击质谱$(m/z$，相对强度):251(28)、236(4)、195(100)、151(92)、109(95)、79(83)、67(92)、56(85)、41(84)；高分辨质谱(电子轰击)计算值为${\mathrm{C}}_{14}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{3}{251.1521}$，实测值为${251.1523}.{\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {17.1}\left( {{c0.96},{\mathrm{{CHCl}}}_{3}}\right)$。化合物19b:${R}_{f} = {0.7}$(石油醚/乙酸乙酯3:1)。红外光谱(薄膜)2954、2924、2845、1783、1717、1461、1299、1255、1154、912 ${\mathrm{{cm}}}^{-1}$；${}^{1}\mathrm{H}$核磁共振$\left( {{300}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 5.91 - 5.69 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{5.19} - {5.05}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{4.62} - {4.57} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.72} - {2.60}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.23} - {2.12}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.01} - {1.86}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，1.50(单峰，9H)；${}^{13}\mathrm{C}$核磁共振(75兆赫，${\mathrm{{CDCl}}}_{3}$)δ 175.0、149.7、136.3、134.8、117.2、115.1、82.7、57.3、40.7、34.2、30.4、27.8；电子轰击质谱$\left( {m/z}\right.$，相对强度):251(30)、236(6)、195(100)、151(90)、109(93)、79(82)、67(90)、56(84)、41(82)；高分辨质谱(电子轰击)计算值为${\mathrm{C}}_{14}{\mathrm{H}}_{21}{\mathrm{{NO}}}_{3}{251.1521}$，实测值为251.1523；${\left\lbrack \alpha \right\rbrack }_{D}^{20} + {33.5}\left( {c\text{ 1.1, CHC }{\mathrm{l}}_{3}}\right)$。

3.2.6. (1R,5R)-tert-Butyl 7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate ${\left( \left( +\right) - {23}\right) }^{16}$ . Compound 19a (20 mg,0.08 mmol) was dissolved in dry ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{40}\mathrm{\;{mL}}}\right)$ under nitrogen atmosphere. Second generation Grubbs catalyst ( $1\mathrm{{mg}},1\mathrm{{mol}}\%$ ) was added. The resulting mixture was heated at reflux temperature for ${0.5}\mathrm{\;h}$ (monitored by TLC). The solvent was then evaporated, and the residual oil was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give the ring-closing product (+)-23 (18 mg, quant.) as a pale yellow oil. IR (film) 2978, 2929, 1782, 1751, 1707, 1345, 1309, 1252,1160,1138,911,784,676 ${\mathrm{{cm}}}^{-1};{}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta = {6.34} - {6.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.72} - {5.66}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.36} - {4.33}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.85} - {2.84} \; \left( {m,{1H}}\right) ,{2.52} - {2.36}\left( {m,{2H}}\right) ,{2.31} - {2.24}\left( {m,{1H}}\right) ,{2.00}({dd}, J = 9,{12Hz}$ , 1H,),1.52 (s,9H); ${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{75}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{176.3},{149.4},{130.7},{127.8}$ , 82.5,52.5,41.5,31.7,28.6,28.0; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} = {121.0}\left( {{c0.92},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.6. (1R，5R)-叔丁基7-氧代-6-氮杂双环[3.2.1]辛-3-烯-6-羧酸酯 ${\left( \left( +\right) - {23}\right) }^{16}$ 。化合物19a(20毫克，0.08毫摩尔)在氮气气氛下溶于干燥的 ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{40}\mathrm{\;{mL}}}\right)$ 中。加入第二代格拉布催化剂( $1\mathrm{{mg}},1\mathrm{{mol}}\%$ )。将所得混合物在回流温度下加热 ${0.5}\mathrm{\;h}$ (通过薄层层析监测)。然后蒸发溶剂，残余油状物通过硅胶柱快速层析(石油醚/乙酸乙酯5:1)纯化，得到闭环产物(+)-23(18毫克，定量)，为浅黄色油状物。红外光谱(薄膜)2978、2929、1782、1751、1707、1345、1309、1252、1160、1138、911、784、676 ${\mathrm{{cm}}}^{-1};{}^{1}\mathrm{H}$ 核磁共振谱(300兆赫， ${\mathrm{{CDCl}}}_{3}$ ) $\delta = {6.34} - {6.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{5.72} - {5.66}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.36} - {4.33}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.85} - {2.84} \; \left( {m,{1H}}\right) ,{2.52} - {2.36}\left( {m,{2H}}\right) ,{2.31} - {2.24}\left( {m,{1H}}\right) ,{2.00}({dd}, J = 9,{12Hz}$ ，1H，)，1.52(单峰，9H)； ${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{75}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{176.3},{149.4},{130.7},{127.8}$ ，82.5、52.5、41.5、31.7、28.6、28.0； ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} = {121.0}\left( {{c0.92},{\mathrm{{CHCl}}}_{3}}\right)$ 。

3.2.7. (R)-3-Allyl 1-tert-butyl 3-(but-3-enyl)-2-oxo-5-vinylpyrro-lidine-1,3-dicarboxylate (21). The title compound was obtained as a yellow oil (85%), following the method we employed for the preparation of 20. IR (film) 2982, 1785, 1728, 1303, 1199, 1153, ${918}{\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$ NMR (300 MHz, CDCl ${}_{3}$ ) $\delta$ 5.96-5.70 (m,3H),5.37-5.12 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{5.06} - {4.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.66} - {4.52}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.75}(\mathrm{\;{dd}}, J = {7.8}$ , 13.5 Hz, 0.4H), 2.47 (dd, J=2.7, 13.5 Hz, 0.6H), 2.32-1.96 (m, 3.5H), 1.92-1.78 (m, 1H), 1.72-1.65 (m, 0.5H), 1.50-1.49 (d, 9H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl3) δ 171.1, 171.0, 170.3, 169.8, 149.4, 138.3, 137.1, 137.0, 136.9, 131.2, 118.9, 118.6, 116.3, 115.8, 115.8, 115.3, 83.4, 83.2, 76.4, 66.2, 66.2, 58.0, 57.2, 57.1, 56.6, 56.0, 34.6, 34.2, 33.6, 33.5, 28.8, 28.5, 27.8; EIMS $(m/z$ , relative intensity): 293 (12),276 (4),249 (16),239 (46), 208 (8), 195 (57), 57 (86), 41 (100), 28 (21). Anal. Calcd for ${\mathrm{C}}_{19}{\mathrm{H}}_{27}{\mathrm{{NO}}}_{5}$ : C, 65.31; H, 7.79; N, 4.01. Found: C, 65.19; H, 7.81; N, 4.03.

3.2.7. (R)-3-烯丙基-1-叔丁基 3-(3-丁烯基)-2-氧代-5-乙烯基吡咯烷-1,3-二羧酸酯(21)。按照我们制备 20 的方法，得到标题化合物为黄色油状物(85%)。红外光谱(薄膜)2982、1785、1728、1303、1199、1153，${918}{\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$ 核磁共振(300 MHz，CDCl ${}_{3}$ ) $\delta$ 5.96 - 5.70(m，3H)，5.37 - 5.12 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{5.06} - {4.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{4.66} - {4.52}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.75}(\mathrm{\;{dd}}, J = {7.8}$ ，13.5 Hz，0.4H)，2.47(dd，J = 2.7，13.5 Hz，0.6H)，2.32 - 1.96(m，3.5H)，1.92 - 1.78(m, ； ${}^{13}\mathrm{C}$ 核磁共振(75 MHz，CDCl3)δ 171.1、171.0、170.3、169.8、149.4、138.3、137.1、137.0、136.9、131.2、118.9、118.6、116.3、115.8、115.8、115.3、83.4、83.2、76.4、66.2、66.2、58.0、57.2、57.1、56.6、56.0、34.6、34.2、33.6、33.5、28.8、28.5、27.8；电子轰击质谱 $(m/z$ ，相对强度):293(12)、276(4)、249(16)、239(46)、208(8)、195(57)、57(86)、4()Anal. Calcd for ${\mathrm{C}}_{19}{\mathrm{H}}_{27}{\mathrm{{NO}}}_{5}$ : C, 65.31; H, 7.79; N, 4.01. Found: C, 65.19; H, 7.81; N, 4.(此处原文似乎有部分缺失，翻译时尽量按原样呈现)

3.2.8. (5R)-tert-Butyl 3-(but-3-enyl)-2-oxo-5-vinylpyrrolidine-1- carboxylates (22a and 22b). Compound 21 (200 mg, 0.57 mmol) was dissolved in THF $\left( {8\mathrm{\;{mL}}}\right)$ , and then morpholine $({75}\mathrm{{mg}}$ , 0.86 mmol, 1.5 equiv), Pd(PPh3)4 (33 mg, 0.0286 mmol, 5 mol%) were added at room temperature. The resulting mixture was stirred for about $2\mathrm{\;h}$ (monitored by TLC). After the reaction was complete, the solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether/ethyl acetate 7:1) to give 22a (61mg) and 22b (63mg) both as a yellow oil. Compound 22a: ${R}_{f} = {0.6}$ (petroleum ether/EtOAc 3:1). ${}^{1}\mathrm{H}$ NMR (300 MHz, CDCl3) δ 5.85-5.72 (m, 2H), 5.31-5.13 (m, 3H), 5.07-4.98 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{4.43}\left( {\mathrm{q}, J = {7.3}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.54} - {2.33}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.24} - {1.97}\left( {\mathrm{\;m},3\mathrm{H}}\right)$ , 1.50 (s,9H),1.47-1.40 (m,1H); ${}^{13}\mathrm{C}$ NMR (75 MHz, CDCl ${}_{3}$ ) $\delta$ 176.2, 149.9, 138.9, 137.4, 115.5, 115.4, 82.9, 58.7, 41.9, 31.2, 30.3, 27.8; IR (film) 2980, 1782, 1746, 1721, 1367, 1299, 1256, 1152, 914 c ${\mathrm{m}}^{-1}$ ; EIMS $\left( {m/z\text{ , relative intensity }}\right) : {209}\left( {17}\right) ,{192}\left( 4\right) ,{165}\left( {10}\right) ,{155}\left( {56}\right) ,{111}$ (28), 84 (34), 67 (25), 57 (100), 49 (53), 41 (50), 29 (28). Anal. Calcd for ${\mathrm{C}}_{15}{\mathrm{H}}_{23}{\mathrm{{NO}}}_{3}$ : C, 67.90; H, 8.74; N, 5.28. Found: C, 67.81; H, 8.66; N, 5.06. ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {0.7}\left( {{c1.2},{\mathrm{{CHCl}}}_{3}}\right)$ . Compound 22b: ${R}_{f} = {0.7}$ (petroleum ether/EtOAc 3:1). ${}^{1}\mathrm{H}$ NMR (300 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 5.91-5.72 (m,2H), 5.19-5.13 (m, 2H), 5.07-4.97 (m, 2H), 4.62-4.57 (m, 1H), 2.62-2.51 $\left( {m,{1H}}\right) ,{2.21} - {1.99}\left( {m,{4H}}\right) ,{1.91} - {1.80}\left( {m,{1H}}\right) ,{1.50}\left( {d,{9H}}\right) ,{1.45} - {1.37} \; \left( {\mathrm{m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 175.7},{149.7},{137.5},{136.3},{115.3}$ , 115.1, 82.6, 57.3, 40.4, 31.1, 31.0, 29.2, 27.8; IR (film) 2980, 1782, 1748,1718,1306,1199,1152,913 ${\mathrm{\;{cm}}}^{-1}$ ; EIMS $(m/z$ , relative intensity): 209 (65), 192 (11), 165 (20), 155 (100), 137 (11), 121 (11), 111 (50), 94 (29), 67 (26), 57 (86), 41 (33), 29 (37); Anal. Calcd for ${\mathrm{C}}_{15}{\mathrm{H}}_{23}{\mathrm{{NO}}}_{3}$ : C, 67.90; H, 8.74; N, 5.28. Found: C, 67.83; H, 8.72; N, 5.38. ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {17.6}\left( {{c0.4},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.8. (5R)-叔丁基3-(3-丁烯基)-2-氧代-5-乙烯基吡咯烷-1-羧酸酯(22a和22b)。将化合物21(200毫克，0.57毫摩尔)溶于四氢呋喃$\left( {8\mathrm{\;{mL}}}\right)$，然后加入吗啉$({75}\mathrm{{mg}}$(0.86毫摩尔，1.5当量)、四(三苯基膦)钯(33毫克，0.0286毫摩尔，5摩尔%)，在室温下搅拌。所得混合物搅拌约$2\mathrm{\;h}$(通过薄层色谱法监测)。反应完成后，溶液在减压下浓缩，并用快速柱色谱法(石油醚/乙酸乙酯7:1)纯化，得到22a(61毫克)和22b(63毫克)，均为黄色油状物。化合物22a:${R}_{f} = {0.6}$(石油醚/乙酸乙酯3:1)。${}^{1}\mathrm{H}$核磁共振氢谱(300兆赫，氘代氯仿)δ5.85 - 5.72(多重峰，2H)，5.3l - 5.13(多重峰，3H)，5.07 - 4.98$\left( {\mathrm{m},2\mathrm{H}}\right) ,{4.43}\left( {\mathrm{q}, J = {7.3}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.54} - {2.33}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.24} - {1.97}\left( {\mathrm{\;m},3\mathrm{H}}\right)$，1.50(单峰，9H)，1.47 - 1.40(多重峰，1H)；${}^{13}\mathrm{C}$核磁共振碳谱(75兆赫，氘代氯仿${}_{3}$)$\delta$176.2，149.9，138.9，137.4，115.5，115.4，82.9，58.7，41.9，31.2，30.3，27.8；红外光谱(薄膜)2980，1782，1746，1721，1367，1299，1256，1152，914 c${\mathrm{m}}^{-1}$；电子轰击质谱$\left( {m/z\text{ , relative intensity }}\right) : {209}\left( {17}\right) ,{192}\left( 4\right) ,{165}\left( {10}\right) ,{155}\left( {56}\right) ,{111}$(28)，84(34)，67(25)，57(100)，49(53)，41(50)，29(28)。分析计算值${\mathrm{C}}_{15}{\mathrm{H}}_{23}{\mathrm{{NO}}}_{3}$:碳，67.90；氢，8.74；氮，5.28。实测值:碳，67.81；氢，8.66；氮，5.06。${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {0.7}\left( {{c1.2},{\mathrm{{CHCl}}}_{3}}\right)$。化合物22b:${R}_{f} = {0.7}$(石油醚/乙酸乙酯3:1)。${}^{1}\mathrm{H}$核磁共振氢谱(300兆赫，${\mathrm{{CDCl}}}_{3}$)δ5.91 - 5.72(多重峰，2H)，5.19 - 5.13(多重峰，2H)，5.07 - 4.97(多重峰，2H)，4.62 - 4.57(多重峰，1H)，2.62 - 2.51$\left( {m,{1H}}\right) ,{2.21} - {1.99}\left( {m,{4H}}\right) ,{1.91} - {1.80}\left( {m,{1H}}\right) ,{1.50}\left( {d,{9H}}\right) ,{1.45} - {1.37} \; \left( {\mathrm{m},1\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{75}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 175.7},{149.7},{137.5},{136.3},{115.3}$，115.1，82.6，57.3，40.4，31.1，31.0，29.2，27.8；红外光谱(薄膜)2980，1782，1748，1718，1306，1199，l152，913${\mathrm{\;{cm}}}^{-1}$；电子轰击质谱$(m/z$，相对强度):209(65)，192(11)，165(20)，155(100)，137(11)，121(11)，111(50)，94(29)，67(26)，57(86)，41(33)，29(37)；分析计算值${\mathrm{C}}_{15}{\mathrm{H}}_{23}{\mathrm{{NO}}}_{3}$:碳，67.90；氢，8.74；氮，5.28。实测值:碳，67.83；氢，8.72；氮，5.38。${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {17.6}\left( {{c0.4},{\mathrm{{CHCl}}}_{3}}\right)$。

3.2.9. (1R,6R)-tert-Butyl 8-oxo-7-azabicyclo[4.2.1]non-4-ene-7-carboxylate (24). The title compound was obtained as a pale yellow oil in nearly quantitative yield, following the method we employed for the preparation of (+)-23. Compound 24: IR (film) 2977, 2934, 1781, 1746,1713,1366,1304,1273,1255,1146,1011,840,781 ${\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$ NMR (400 MHz, CDCl, ${}_{3}$ ) 6 6.06 (ddd, J=3.0, 6.5, 11.0 Hz, 1H), 5.87 (ddd, $J = {3.2},{8.4},{11.3}\mathrm{\;{Hz}},1\mathrm{H}),{4.52}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.93} - {2.89}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.43} - \; {2.16}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.86} - {1.78}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.74}\left( {\mathrm{\;d}, J = {12.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{1.51}\left( {\mathrm{\;s},9\mathrm{H}}\right)$ ; ${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{100}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{177.2},{149.7},{133.2},{132.5},{82.6},{56.1},{44.2}$ , 33.2, 32.0, 28.0, 24.7; EIMS $(m/z$ , relative intensity): 237 (7), 181 (36), 164 (24), 137 (39), 121 (13), 109 (12), 93 (36), 79 (28), 57 (100), 41 (45), 29 (19), 27 (12). Anal. Calcd for ${\mathrm{C}}_{13}{\mathrm{H}}_{19}{\mathrm{{NO}}}_{3}$ : C, 65.80; H, 8.07; N, 5.90. Found: C, 65.83; H, 8.02; N, 5.78. [α] ${}_{\mathrm{D}}^{20} + {6.0}\left( {{c1.0},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.9. (1R，6R)-叔丁基8-氧代-7-氮杂双环[4.2.1]壬-4-烯-7-羧酸盐(24)。按照我们制备(+)-23所采用的方法，得到标题化合物为浅黄色油状物，产率接近定量。化合物24:红外光谱(薄膜)2977、2934、1781、1746、1713、1366、1304、1273、1255、1146、1011、840、781 ${\mathrm{\;{cm}}}^{-1};{}^{1}\mathrm{H}$ 核磁共振氢谱(400兆赫兹，CDCl，${}_{3}$ )δ 6.06(ddd，J = 3.0、6.5、11.0赫兹，1H)，5.87(ddd，$J = {3.2},{8.4},{11.3}\mathrm{\;{Hz}},1\mathrm{H}),{4.52}\left( {\mathrm{t}, J = {7.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{2.93} - {2.89}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.43} - \; {2.16}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.86} - {1.78}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.74}\left( {\mathrm{\;d}, J = {12.1}\mathrm{\;{Hz}},1\mathrm{H}}\right) ,{1.51}\left( {\mathrm{\;s},9\mathrm{H}}\right)$ ；${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{100}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{177.2},{149.7},{133.2},{132.5},{82.6},{56.1},{44.2}$ ，33.2、32.0、28.0、24.7；电子轰击质谱 $(m/z$ ，相对强度):237(7)，181(36)，164(24)，137(39)，121(13)，109(12)，93(36)，79(28)，57(100)，41(45)，29(19)，27(12)。分析。计算得到 ${\mathrm{C}}_{13}{\mathrm{H}}_{19}{\mathrm{{NO}}}_{3}$ 的值:C，65.80；H，8.07；N，5.90。实测值:C，65.83；H，8.02；N，5.78。[α] ${}_{\mathrm{D}}^{20} + {6.0}\left( {{c1.0},{\mathrm{{CHCl}}}_{3}}\right)$ 。

3.2.10. (R)-1-(2-Vinylpyrrolidin-1-yl)prop-2-en-1-one ((R)-25) ${}^{24} \; {\mathrm{{LiAlH}}}_{4}\left( {{40}\mathrm{{mg}},{1.05}\mathrm{{mmol}},{1.2}\text{ equiv) was added to a stirred solution }}\right)$ of ${12}\left( {{98}\mathrm{{mg}},{0.88}\mathrm{{mmol}}}\right)$ in THF $\left( {5\mathrm{\;{mL}}}\right)$ at $0{}^{ \circ }\mathrm{C}$ under a nitrogen atmosphere. After $5\mathrm{\;{min}}$ the reaction mixture was allowed to reflux for about $4\mathrm{\;h}$ (monitored by TLC). After cooling to room temperature, the reaction mixture was quenched with saturated aqueous potassium sodium tartrate tetrahydrate and stirred for another $2\mathrm{\;h}$ . Then the mixture was extracted with ethyl acetate $\left( {{10}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic layers were dried $\left( {{\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}}\right)$ and evaporated in vacuo. The resulting residue was used in next step without further purification. To this residue were added $2\mathrm{\;{mL}}$ EtOAc, $2\mathrm{\;{mL}}$ water, and ${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}$ (242 mg,1.76 mmol,2 equiv) and then cooled to $0{}^{ \circ }\mathrm{C}$ , and then acryloyl chloride (119mg, 1.32 mmol, 1.5 equiv) was added dropwise to this mixture. This acylation reaction proceeded very fast. After about $5\mathrm{\;{min}}$ the reaction mixture was extracted with ethyl acetate $\left( {5\mathrm{\;{mL}} \times 3}\right)$ and combined organic layers were dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ . Concentration in vacuo followed by flash chromatography on a column of silica gel (petroleum ether/EtOAc 2:1), afforded the desired product 25 (80 mg, 60% yield) as a yellow oil. ${}^{1}\mathrm{H}$ NMR (200 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta$ 6.57-6.26 (m, $2\mathrm{H}$ ),5.90-5.70 (m, 1H), 5.67-5.58 (m, 1H), 5.20-5.03 (m, 2H), 4.51-4.44 (m, 1H), 3.71- ${3.50}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.23} - {1.71}\left( {\mathrm{\;m},4\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{50}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 165.0}$ , 138.1, 136.9, 128.8, 128.6, 127.6, 127.1, 115.2, 114.1, 59.2, 58.5, 46.7, 46.1,32.3,30.2,23.5,21.4; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {23.2}\left( {{c1.13},{\mathrm{{CHCl}}}_{3}}\right)$ .

3.2.10. (R)-1-(2-乙烯基吡咯烷-1-基)丙-2-烯-1-酮((R)-25)${}^{24} \; {\mathrm{{LiAlH}}}_{4}\left( {{40}\mathrm{{mg}},{1.05}\mathrm{{mmol}},{1.2}\text{ equiv) was added to a stirred solution }}\right)$在氮气气氛下于四氢呋喃$\left( {5\mathrm{\;{mL}}}\right)$中在$0{}^{ \circ }\mathrm{C}$下的${12}\left( {{98}\mathrm{{mg}},{0.88}\mathrm{{mmol}}}\right)$。在$5\mathrm{\;{min}}$之后，使反应混合物回流约$4\mathrm{\;h}$(通过TLC监测)。冷却至室温后，用饱和酒石酸钾钠四水合物水溶液淬灭反应混合物，并再搅拌$2\mathrm{\;h}$。然后用乙酸乙酯$\left( {{10}\mathrm{\;{mL}} \times 3}\right)$萃取混合物。合并的有机层干燥$\left( {{\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}}\right)$并真空蒸发。所得残余物无需进一步纯化即可用于下一步。向该残余物中加入$2\mathrm{\;{mL}}$乙酸乙酯、$2\mathrm{\;{mL}}$水和${\mathrm{K}}_{2}{\mathrm{{CO}}}_{3}$(242mg，1.76mmol，2当量)，然后冷却至$0{}^{ \circ }\mathrm{C}$，然后向该混合物中滴加丙烯酰氯(119mg，1.32mmol，1.5当量)。该酰化反应进行得非常快。在约$5\mathrm{\;{min}}$之后，用乙酸乙酯$\left( {5\mathrm{\;{mL}} \times 3}\right)$萃取反应混合物，合并的有机层在${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$上干燥。真空浓缩，然后在硅胶柱(石油醚/乙酸乙酯2:1)上进行快速色谱分离，得到所需产物25(80mg，产率60%)，为黄色油状物。${}^{1}\mathrm{H}$核磁共振(200MHz，${\mathrm{{CDCl}}}_{3}$)$\delta$6.57 - 6.26(m，$2\mathrm{H}$)，5.90 - 5.70(m，1H)，5.67 - 5.58(m，1H)，5.20 - 5.03(m，2H)，4.51 - 4.44(m，1H)，3.71 - ${3.50}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.23} - {1.71}\left( {\mathrm{\;m},4\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{50}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 165.0}$，138.1，136.9，128.8，128.6，127.6，127.1，115.2，114.1，59.2，58.5，46.7，46.1，32.3，30.2，23.5，21.4；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} + {23.2}\left( {{c1.13},{\mathrm{{CHCl}}}_{3}}\right)$。

3.2.11. (R)-Pyrrolam $A{\left( \mathbf{{26}}\right) }^{17}$ . Second generation Grubbs catalyst $\left( {{24}\mathrm{{mg}},{10}\mathrm{{mol}}\% }\right)$ was added to a solution of $\mathbf{{25}}\left( {{42}\mathrm{{mg}},{0.28}\mathrm{{mmol}}}\right)$ in dry toluene ${100}\mathrm{\;{mL}}$ under nitrogen atmosphere. The resulting mixture was heated at ${80}^{ \circ }\mathrm{C}$ for ${12}\mathrm{\;h}$ (monitored by TLC). The solvent was then evaporated, and the residual oil was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give the ring-closing product 26 (23 mg, 68% yield) as a white solid. ${}^{1}\mathrm{H}$ NMR (200 MHz, CDCl ${}_{3}$ ) 7.20 (dd, $J = {1.7}$ ,5.8 Hz,1H),6.04 (dd, $J = {1.5},{5.7}\mathrm{\;{Hz}},1\mathrm{H}),{4.30} - {4.22}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.55} - {3.41}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.33} - {3.20} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.37} - {2.24}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.20} - {2.04}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.23} - {0.96}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ; ${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{50}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \;\delta \;$ 175.6,148.7,128.4,67.7,41.8,29.8,28.9; ${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {25.9}\left( c\right. {0.7}$ in $\left. {\mathrm{{CHCl}}}_{3}\right)$ .

3.2.11. (R)-吡咯胺$A{\left( \mathbf{{26}}\right) }^{17}$。在氮气氛围下，将第二代格拉布催化剂$\left( {{24}\mathrm{{mg}},{10}\mathrm{{mol}}\% }\right)$加入到$\mathbf{{25}}\left( {{42}\mathrm{{mg}},{0.28}\mathrm{{mmol}}}\right)$于无水甲苯${100}\mathrm{\;{mL}}$中的溶液中。所得混合物在${80}^{ \circ }\mathrm{C}$加热${12}\mathrm{\;h}$(通过薄层色谱监测)。然后蒸发溶剂，残余油状物通过硅胶柱快速色谱法(石油醚/乙酸乙酯1:1)纯化，得到闭环产物26(23毫克，产率68%)，为白色固体。${}^{1}\mathrm{H}$核磁共振(200兆赫，CDCl${}_{3}$)7.20(双重峰，$J = {1.7}$，5.8赫兹，1氢)，6.04(双重峰，$J = {1.5},{5.7}\mathrm{\;{Hz}},1\mathrm{H}),{4.30} - {4.22}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.55} - {3.41}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.33} - {3.20} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.37} - {2.24}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.20} - {2.04}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.23} - {0.96}\left( {\mathrm{\;m},1\mathrm{H}}\right)$；${}^{13}\mathrm{C}\;\mathrm{{NMR}}\left( {{50}\;\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \;\delta \;$175.6，148.7，128.4，67.7，41.8，29.8，28.9；${\left\lbrack \alpha \right\rbrack }_{\mathrm{D}}^{20} - {25.9}\left( c\right. {0.7}$在$\left. {\mathrm{{CHCl}}}_{3}\right)$中。

Acknowledgements

致谢

The project is generously supported by NSFC (Grant No. 20832002, 20772003, 20821062), the Ministry of Education of China, and National Basic Research Program of China (973 Program, No. 2009CB825300).

本项目得到了国家自然科学基金(项目批准号:20832002、20772003、20821062)、中国教育部以及国家重点基础研究发展计划(973计划，项目编号:2009CB825300)的慷慨资助。

Supplementary data

补充数据

Supplementary data associated with this article can be found in the online version, at doi:10.1016/j.tet.2009.12.013.

与本文相关的补充数据可在在线版本中获取，链接为:doi:10.1016/j.tet.2009.12.013。

References and notes

参考文献和注释

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CCDC-746178 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
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