Cholate-Based Synthesis of Size-Tunable Cage Compounds

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

Qinghai Zhang

张清海

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Cholate-based synthesis of size-tunable cage compounds

基于胆酸盐的尺寸可调笼状化合物的合成

Cholate-based Synthesis of Size-tunable Cage Compounds

基于胆酸盐的尺寸可调笼状化合物的合成

Lingling Peng, Fanyang Mo and Qinghai Zhang*

彭玲玲、莫凡洋和张青海*

Department of Integrative Structural and Computational Biology, The Scripps Research

美国加利福尼亚州拉霍亚市斯克里普斯研究所综合结构与计算生物学系

Institute, La Jolla, California 92037, United States

邮编92037

Table of Contents

目录

Abstract: We describe cholate-based cage amphiphiles with a unique architecture that combines elements of structural rigidity and flexibility. The cage compounds are built by extending and bridging three polar chains underneath the concave steroid rings of cholate, and capping with another rigid, symmetrically trifunctionalized cyanuric acid moiety. The connecting chains are varied to include, for instance, oligo(ethylene glycol) or chains containing 1,2,3-triazole units, to present flexibility in the chemical and structural space and potentially deliver functional molecules for molecular recognition applications. Cholic acid is a principal component of bile acids found in the bile of mammals and other vertebrates that emulsify dietary fats to promote their digestion and absorption. A representative of facial amphiphiles, cholate features three small $\alpha$ -hydroxy groups positioned on one side of the rigid, slightly concave steroid surface. Natural bile acids and their analog molecules have long been used pharmacologically for the dissolution of gallstones, ${}^{1,2}$ and in membrane biochemistry for their capacity to partition into cellular membranes and to solubilize lipids and membrane proteins. ${}^{3,4}$ Additionally, considerable interest has focused on the design of bile acid-templated “smart materials”, in forms such as tandem oligomers or dendrimers, for the purpose of delivering biologics, drugs, and other guest molecules in solution or across cell membranes. ${}^{5 - {17}}$ Of these designs, macrocyclic architectures of cholic/deoxycholic acid have been created via connections through the terminal 24-carboxylate and the hydroxyl groups (or modifier groups). There is a case report in which small cage compounds are built through cyclodimerization of chenodeoxycholic acid. ${}^{18}$

摘要:我们描述了具有独特结构的基于胆酸盐的笼状两亲物，其结合了结构刚性和灵活性的元素。笼状化合物是通过在胆酸盐的凹面类固醇环下方延伸和桥接三条极性链，并与另一个刚性、对称三官能化的氰尿酸部分封端而构建的。连接链可以变化，例如包括聚乙二醇或含有1,2,3 - 三唑单元的链，以在化学和结构空间中提供灵活性，并有可能为分子识别应用输送功能分子。胆酸是哺乳动物和其他脊椎动物胆汁中发现的胆汁酸的主要成分，它乳化膳食脂肪以促进其消化和吸收。作为面两亲物的代表，胆酸盐在刚性、略凹的类固醇表面的一侧具有三个小的$\alpha$ - 羟基。天然胆汁酸及其类似分子长期以来在药理学上用于溶解胆结石，${}^{1,2}$ 并且在膜生物化学中因其能够分配到细胞膜中并溶解脂质和膜蛋白而被使用。${}^{3,4}$ 此外，人们对设计胆汁酸模板化的“智能材料”(如串联低聚物或树枝状聚合物形式)给予了相当大的关注，目的是在溶液中或跨细胞膜输送生物制品、药物和其他客体分子。${}^{5 - {17}}$ 在这些设计中，通过末端24 - 羧酸盐和羟基(或修饰基团)的连接创建了胆酸/脱氧胆酸的大环结构。有一个案例报告是通过鹅去氧胆酸的环二聚化构建小的笼状化合物。${}^{18}$

While many molecular designs based on bile acids take advantage of their unique facial amphiphilicity and assembly properties, novel compounds can also be conceived by appending additional polar groups beneath the steroid scaffold to increase facial amphiphilicity and introduce additional functions. ${}^{{19} - {22}}$ We report here the synthesis of size-tunable cage compounds starting from a single cholate molecule and bridging three polar chains that extend from the ${3\alpha },{7\alpha },{12\alpha }$ -OH groups (Figure 1). Our exploration of such a molecular design originated with our study of facial amphiphiles for membrane protein structural biology applications. Our group has recently developed new steroid-and peptide-based facial amphiphiles to sequester the hydrophobic surfaces of integral membrane proteins. ${}^{{23} - {25}}$ Variation of polar segments of the cholate-based amphiphiles significantly impacts membrane protein crystal growth, potentially by mediating surface contacts of protein-detergent complexes (PDCs). To diversify the polar functionalities of facial amphiphiles and in an attempt to restrict the flexibility of these polar segments which may favor ordered PDC assembly during crystal growth, we set out to investigate the possibility of bridging all three flexible polar chains of cholate-derived amphiphiles in cage-like macrocycles. To our knowledge this type of structure has not been explored in the literature.

虽然许多基于胆汁酸的分子设计利用了它们独特的面两亲性和组装特性，但也可以通过在类固醇支架下方附加额外的极性基团来构思新的化合物，以增加面两亲性并引入额外的功能。${}^{{19} - {22}}$ 我们在此报告从单个胆酸盐分子开始合成尺寸可调的笼状化合物，并桥接从${3\alpha },{7\alpha },{12\alpha }$ - OH基团延伸的三条极性链(图1)。我们对这种分子设计的探索源于我们对面两亲物在膜蛋白结构生物学应用中的研究。我们小组最近开发了新的基于类固醇和肽的面两亲物，以隔离整合膜蛋白的疏水表面。${}^{{23} - {25}}$ 基于胆酸盐的两亲物的极性片段的变化显著影响膜蛋白晶体生长，可能是通过介导蛋白质 - 去污剂复合物(PDC)的表面接触。为了使面两亲物的极性功能多样化，并试图限制这些极性片段的灵活性，这可能有利于晶体生长过程中有序的PDC组装，我们着手研究在笼状大环中桥接胆酸盐衍生的两亲物的所有三条柔性极性链的可能性。据我们所知，这种类型的结构在文献中尚未被探索。

Figure 1. Drawings of (a) cholic acid structure, (b) cholic acid-derived facial amphiphiles, with three introduced polar side chains, and (c) a new cage compound design in which the flexible side chains underneath the steroid ring of cholate are bridged.

图1. (a)胆酸结构、(b)具有三条引入的极性侧链的胆酸衍生的面两亲物以及(c)一种新的笼状化合物设计的示意图，其中胆酸盐类固醇环下方的柔性侧链被桥接。

To cyclize the polar residues attached to -OH positions of cholate, we attempted a strategy of joining the chains in one step using a trifunctionalized moiety, such as cyanuric acid (Figure 2a). Initial success was achieved by treatment of the bromide substituent of cholane precursor 1, which we used in previous amphiphile synthesis, ${}^{24}$ with 4 equiv of DBU and 15 equiv of cyanuric acid. The desired cage molecule 2 was isolated in 23% yield, along with 18% of a di-cyanuric substituted byproduct 3 in which two chains were joined with one cyanuric unit (judged by mass and NMR spectroscopic analyses). The exact structure of this byproduct was not assigned, being inessential to the present report. We did not detect tri-cyanuric acid-substituted product in this reaction by mass spectroscopic analysis of the crude products, suggesting that intramolecular ${\mathrm{S}}_{\mathrm{N}}2$ attack of bromo-chain by the firstly attached cyanuric acid moiety can effectively compete with intermolecular reactions. Decreasing the stoichiometry of cyanuric acid to 1.5 equiv suppressed the formation of 3, and slightly increased the yield of 2 (26%). The identity of 2 was confirmed by molecular mass, NMR spectroscopic analyses, and its X-ray crystal structure (Figure 2a), which shows extreme rigidity due to the constraint of the short linkers between the top steroid and bottom cyanuric ring structures. Layered scaffold interactions in the crystal packing of 2 were observed, with one layer contributed by head-to-tail hydrophobic interaction between steroid moieties, and the other layer from stacking of apposing cyanuric moieties (Figure 2b).

为了使连接在胆酸盐 -OH 位置上的极性残基环化，我们尝试了一种策略，即使用三官能化部分(如氰尿酸)一步连接这些链(图 2a)。通过用 4 当量的 DBU 和 15 当量的氰尿酸处理我们在之前两亲物合成中使用的胆烷前体 1 的溴取代基 ${}^{24}$，取得了初步成功。所需的笼状分子 2 以 23% 的产率分离出来，同时还有 18% 的二氰尿酸取代副产物 3，其中两条链与一个氰尿酸单元相连(通过质谱和 NMR 光谱分析判断)。该副产物的确切结构未确定，对本报告来说并非关键内容。通过对粗产物的质谱分析，我们在该反应中未检测到三氰尿酸取代产物，这表明首先连接的氰尿酸部分对溴链的分子内 ${\mathrm{S}}_{\mathrm{N}}2$ 攻击可以有效地与分子间反应竞争。将氰尿酸的化学计量比降至 1.5 当量可抑制 3 的形成，并略微提高了分子 2 的产率(26%)。通过分子量、NMR 光谱分析及其 X 射线晶体结构(图 2a)确认了分子 2 的身份，该结构由于顶部甾体和底部氰尿酸环结构之间短连接体的限制而显示出极高的刚性。在分子 2 的晶体堆积中观察到分层支架相互作用，一层由甾体部分之间的头对尾疏水相互作用形成，另一层由相对的氰尿酸部分的堆积形成(图 2b)。

Figure 2. (a) Synthesis of cage compound 2 by bridging the three flexible side chains on the steroid rings of cholate with cyanuric acid in one step. Ball-and-stick drawing of the X-ray crystal structure of 2 is shown with $\mathrm{C}$ atoms in grey, $\mathrm{O}$ atoms in red, and $\mathrm{N}$ atoms in blue. (b) Crystal packing of 2 viewed along the a-axis of the unit cells (black box), displaying hydrophobic steroid-steroid interactions as well as interactions between cyanuric acid moieties.

图 2. (a) 通过用氰尿酸一步桥接胆酸盐甾体环上的三个柔性侧链合成笼状化合物 2。2 的 X 射线晶体结构的球棍图显示，$\mathrm{C}$ 原子为灰色，$\mathrm{O}$ 原子为红色，$\mathrm{N}$ 原子为蓝色。(b) 沿晶胞的 a 轴观察到的 2 的晶体堆积(黑色框)，显示了疏水的甾体 - 甾体相互作用以及氰尿酸部分之间的相互作用。

Although typically difficult to synthesize, covalent cage compounds are fascinating molecules with many unique applications such as in molecular recognition, controlled substrate binding/release, and use as nano reaction vessels. ${}^{{26} - {37}}$ Given the extreme structural rigidity of compound 2 and its very small cage cavity, it is an intriguing idea that larger cage compounds might be readily built from cholate for adaptable cage size. Here we extended the synthesis of cholate-templated cages by attaching oligo(ethylene glycol) (PEG) chains to make molecules analogous to 2 and to cryptands ${}^{{38},{39}}$ (Scheme 1). We started the synthesis from the ${3\alpha },{7\alpha },{12\alpha }$ -tri(2-hydroxyethoxy)cholane 4, which was conveniently prepared from cholic acid in three steps. ${}^{24}$ Universal tosylation of the OH groups gave 5. The reaction of 5 with NaH-deprotonated ethylene glycol, diethylene glycol or triethylene glycol elongated the PEG chains in specific manner. After conversion of triols 6 to tribromides 7, treatment with cyanuric acid in the presence of DBU was successful in giving the cyclized cage products 8 in 25-64% yield. We note that the cyclization yield was highest for linkers containing two ethylene glycol units (compound 8a), possibly due to relieved strain for cage formation compared to cyclization of 2, and the more favorable proximity of the three chains compared to cyclization of larger cage compounds (8b and 8c). This series of cage compounds showed a range of internal cavity volumes, thus conferring suitability for potential encapsulation of guest molecules of different sizes (Figure 3).

尽管共价笼状化合物通常难以合成，但它们是具有许多独特应用的迷人分子，例如在分子识别、可控底物结合/释放以及用作纳米反应容器方面。${}^{{26} - {37}}$ 鉴于化合物 2 的极端结构刚性及其非常小的笼腔，一个有趣的想法是，可以很容易地从胆酸盐构建更大的笼状化合物以实现可适应的笼尺寸。在这里，我们通过连接聚乙二醇(PEG)链扩展了胆酸盐模板笼的合成，以制备类似于 2 和穴状配体 ${}^{{38},{39}}$ 的分子(方案 1)。我们从 ${3\alpha },{7\alpha },{12\alpha }$ - 三(2 - 羟基乙氧基)胆烷 4 开始合成，它可以通过三步从胆酸方便地制备得到。${}^{24}$ OH 基团的通用甲苯磺酰化得到 5。5 与用 NaH 去质子化的乙二醇、二甘醇或三甘醇反应以特定方式延长了 PEG 链。将三醇 6 转化为三溴化物 7 后，在 DBU 存在下用氰尿酸处理成功得到了环化笼状产物 8，产率为 25 - 64%。我们注意到，对于含有两个乙二醇单元的连接体(化合物 8a)，环化产率最高，这可能是因为与分子 2 的环化相比，笼形成时的应变得到缓解，并且与更大笼状化合物(8b 和 8c)的环化相比，三条链的接近度更有利。这一系列笼状化合物显示出一系列内部腔体积，因此适合潜在地封装不同大小的客体分子(图 3)。

Scheme 1. Synthesis of PEG-linked cage compounds.

方案 1. PEG 连接的笼状化合物的合成。

Figure 3. Computational space-filled structures of 2, 8a-c (from left to right), showing increasing volume of the cage cavity along with decreased structural rigidity.

图 3. 2、8a - c 的计算空间填充结构(从左到右)，显示笼腔体积增加以及结构刚性降低。

The above cage compounds were barely soluble in water, although they could be effectively solubilized in mixed detergent solutions for potential studies in aqueous solutions. Removal of the 24-caboxylate group in these molecules, following our previous design of facial amphiphiles, obviously contributed to their water insolubility. We envision that it may be desirable to retain the terminal carboxylic acid to alleviate solubility concerns, and to serve as an additional functionalization site. For these reasons, we synthesized compound 17 as well (Scheme 2). Briefly, allylation of the three hydroxyl groups of cholic acid and the subsequent reduction of carboxylic acid to hydroxyl were carried out in one pot to give 9 in 95% yield. After benzyl protection of the 24-OH group (10), ozonolysis of the alkenes and ${\mathrm{{NaBH}}}_{4}$ reduction of the resulting aldehydes were performed to give 11 in a combined yield of 93%. Subsequent transformations from 11 to 15 were similar to the route described in Scheme 1. Finally, benzyl deprotection (16) by hydrogenation and oxidation of the resulting OH group to restore the carboxylic acid (17) using Jones reagent were conducted. Like cholate, the salt form of compound 17 exhibited the expected solubility in ${\mathrm{H}}_{2}\mathrm{O}$ (up to 5% w/v) and formed micelles. Its critical micelle concentration (CMC) was determined as ${0.52}\mathrm{{mM}}\left( {{0.054}\% \mathrm{w}/\mathrm{v}}\right)$ using a hydrophobic dye (orange OT) solubilization assay. ${}^{40}$

上述笼状化合物几乎不溶于水，尽管它们可以在混合洗涤剂溶液中有效溶解，以便在水溶液中进行潜在研究。按照我们之前对面型两亲分子的设计，去除这些分子中的24-羧酸盐基团显然导致了它们的水不溶性。我们设想，保留末端羧酸可能有助于缓解溶解性问题，并作为一个额外的功能化位点。出于这些原因，我们还合成了化合物17(方案2)。简要地说，胆酸的三个羟基进行烯丙基化，随后将羧酸还原为羟基，一锅法得到产率为95%的9。在对24-OH基团进行苄基保护(10)后，对烯烃进行臭氧分解，并对所得醛进行${\mathrm{{NaBH}}}_{4}$还原，得到产率为93%的11。随后从11到15的转化与方案1中描述的路线相似。最后，通过氢化进行苄基脱保护(16)，并使用琼斯试剂将所得OH基团氧化以恢复羧酸(17)。与胆酸盐一样，化合物17的盐形式在${\mathrm{H}}_{2}\mathrm{O}$中表现出预期的溶解度(高达5% w/v)并形成胶束。使用疏水染料(橙黄OT)增溶测定法测定其临界胶束浓度(CMC)为${0.52}\mathrm{{mM}}\left( {{0.054}\% \mathrm{w}/\mathrm{v}}\right)$。${}^{40}$

Scheme 2. Synthesis of cage 17 bearing the terminal carboxylic acid group.

方案2. 带有末端羧酸基团的笼状化合物17的合成。

To further illustrate the versatility of cholate-templated cage synthesis and possibly deliver different functional molecules, we also used the popular Cu(I)-catalyzed azide-alkyne Huisgen cycloaddition, the so-called click chemistry, ${}^{41}$ for efficient linker conjugation. The corresponding 1,2,3-triazole units have been documented to function as H-bond donors and acceptors, ${}^{42}$ bind halide anions, ${}^{{43},{44}}$ and act as metal-binding ligands. ${}^{45}$ From the previous trimesylate intermediate 18 described in scheme 1, we conveniently made the tri-azide fragments19by reaction with ${\mathrm{{NaN}}}_{3}$ . These azides $\mathbf{{19a}}$ -c, respectively containing one, two and three ethylene glycol units, were coupled with tri-propargyl-substituted cyanuric acid 20 in the presence of ${\mathrm{{CuSO}}}_{4}$ and the Cu(II)-reducing sodium ascorbate. As a result, all click reactions led to the corresponding cage products 21 in good yields (66-74%).

为了进一步说明胆酸盐模板笼状化合物合成的多功能性，并可能递送不同的功能分子，我们还使用了流行的铜(I)催化的叠氮化物-炔烃惠斯根环加成反应，即所谓的点击化学，${}^{41}$用于有效的连接子共轭。相应的1,2,3-三唑单元已被证明可作为氢键供体和受体，${}^{42}$结合卤化物阴离子，${}^{{43},{44}}$并作为金属结合配体。${}^{45}$从方案1中描述的先前的三甲磺酸酯中间体18，我们通过与${\mathrm{{NaN}}}_{3}$反应方便地制备了三叠氮片段19。这些叠氮化物$\mathbf{{19a}}$ -c分别含有一个、两个和三个乙二醇单元，在${\mathrm{{CuSO}}}_{4}$和还原铜(II)的抗坏血酸钠存在下与三炔丙基取代的三聚氰酸20偶联。结果，所有点击反应都以良好的产率(66-74%)得到了相应的笼状产物21。

Scheme 3. Synthesis of triazole-linked cage compounds by click chemistry.

方案3. 通过点击化学合成三唑连接的笼状化合物。

Finally, we show that these cage compounds, depending on the functional groups in the linker region, can bind different substrates. For example, addition of ${\mathrm{{KPF}}}_{6}$ to a solution of $\mathbf{{8a}}$ or $\mathbf{{8b}}$ in ${d}_{6}$ -acetone led to ${}^{1}\mathrm{H}$ NMR chemical shifts in a region ( $\sim 3 - 4\mathrm{{ppm}}$ ) inclusive of proton signals for the PEG linkers (Figure 4a and 4b). In contrast, titration of ${\mathrm{{KPF}}}_{6}$ to the smallest cage 2 solution had no effect on its NMR spectrum. These results support the binding of ${\mathrm{K}}^{ + }$ in the medium sized cage cavity in 8a or 8b, but not in 2. Similarly, we observed apparent chemical shifts on the ${}^{1}\mathrm{H}$ NMR spectra of the triazole-containing cage 21a upon addition of fluoride, chloride, bromide or iodide anions in the forms of tetrabutylammonium salt in ${d}_{6}$ -acetone. We showed in Figure 4c the singlet proton peaks on each triazole ring of ${21}\mathbf{a}$ , which are well separated from all other upfield peaks (<5 ppm). The degree of chemical shift changes also varied in each case, roughly following an order of ${\mathrm{{Cl}}}^{ - } > {\mathrm{{Br}}}^{ - } > {\mathrm{F}}^{ - }/{\mathrm{I}}^{ - }$ , likely indicative of a level of selectivity. Future investigations of the selectivity and binding modes and affinities of this class of compounds for different substrates are warranted.

最后，我们表明，这些笼状化合物根据连接区中的官能团不同，能够结合不同的底物。例如，向$\mathbf{{8a}}$或$\mathbf{{8b}}$在${d}_{6}$ -丙酮中的溶液中加入${\mathrm{{KPF}}}_{6}$，会导致${}^{1}\mathrm{H}$ NMR化学位移出现在一个区域($\sim 3 - 4\mathrm{{ppm}}$)，该区域包括PEG连接基的质子信号(图4a和4b)。相比之下，将${\mathrm{{KPF}}}_{6}$滴定到最小的笼状化合物2的溶液中，对其NMR谱没有影响。这些结果支持${\mathrm{K}}^{ + }$在8a或8b的中等大小笼腔中发生结合，但在2中不发生结合。同样，我们观察到，在${d}_{6}$ -丙酮中加入四丁基铵盐形式的氟离子、氯离子、溴离子或碘离子后，含三唑的笼状化合物21a的${}^{1}\mathrm{H}$ NMR谱出现了明显的化学位移。我们在图4c中展示了${21}\mathbf{a}$每个三唑环上的单质子峰，它们与所有其他高场峰(<5 ppm)分得很开。每种情况下化学位移变化的程度也有所不同，大致遵循${\mathrm{{Cl}}}^{ - } > {\mathrm{{Br}}}^{ - } > {\mathrm{F}}^{ - }/{\mathrm{I}}^{ - }$的顺序，这可能表明存在一定程度的选择性。有必要对这类化合物对不同底物的选择性、结合模式和亲和力进行进一步研究。

Figure 4. ${}^{1}\mathrm{H}$ NMR spectra in ${d}_{6}$ -acetone showing that cage compounds (a) 8a,(b) 8b and (c) 21a bind potassium $\left( {{\mathrm{{KPF}}}_{6},{10}}\right.$ equiv in a and b) and halide $\left( {{\mathrm{{Bu}}}_{4}\mathrm{{NX}}}\right.$ salt,5 equiv in c) ions, respectively.

图4. 在${d}_{6}$ -丙酮中的${}^{1}\mathrm{H}$ NMR谱表明，笼状化合物(a)8a、(b)8b和(c)21a分别结合了$\left( {{\mathrm{{KPF}}}_{6},{10}}\right.$当量的钾离子(a和b)和卤化物$\left( {{\mathrm{{Bu}}}_{4}\mathrm{{NX}}}\right.$盐(c中为5当量)离子。

In summary, we synthesized a series of novel cage molecules based on the facial amphiphilic cholate template. Structural diversity was achieved by selecting linkers with different functional groups and at various lengths. These cage compounds could be made soluble in aqueous solution to enhance their functional utility. Preliminary studies have demonstrated that these cage molecules could bind metal or halide ions. We envision that novel cage compounds can also be prepared with other linkers and/or different cap molecules other than the cyanuric acid unit employed herein. Thus, the cholic acid platform provides a versatile and easily accessible platform for generating a new class of covalent cage amphiphiles to potentially recognize a variety of substrates, beyond the scope of ionic compounds studied herein.

总之，我们基于面两亲性胆酸盐模板合成了一系列新型笼状分子。通过选择具有不同官能团和不同长度的连接基实现了结构多样性。这些笼状化合物可以制成可溶于水溶液的形式，以增强其功能实用性。初步研究表明，这些笼状分子可以结合金属离子或卤离子。我们设想，除了本文使用的氰尿酸单元外，还可以用其他连接基和/或不同的封端分子制备新型笼状化合物。因此，胆酸平台为生成一类新型共价笼状两亲物提供了一个通用且易于获得的平台，有可能识别本文研究的离子化合物范围之外的各种底物。

Experimental Section

实验部分

Synthesis of 3a,7a,12a-Tri-(2-bromoethoxy)-cholane (1). To a solution of 3α,7α,12α-Tri-(2-hydroxyethoxy)-cholane ${}^{24}$ (4,2.0 g,3.91 mmol) in dry THF (20 mL) was added triethylamine (3.95 mL, 27.37 mmol) with stirring. Methanesulfonyl chloride (1.81 mL,23.46 mmol) was then added to the mixture dropwise at $0{}^{ \circ }\mathrm{C}$ . The reaction was continued with stirring at rt, and completed in $4\mathrm{\;h}$ as judged by TLC analysis. Water was added to quench the reaction and the solution was extracted with EtOAc $\left( {{50}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic phases were washed with brine, dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and then concentrated in vacuo. The residue, without purification, was dissolved in acetone (20 mL). LiBr (3.4 g, 39.1 mmol) was then added at rt and the suspension was heated at 50 ${}^{ \circ }\mathrm{C}$ overnight. After simple workup, the mixture was purified by silica gel chromatography (eluent: hexanes/EtOAc = 20:1 to 10:1) to give 1 as a pale yellowish solid (1.64 g, 60% over two steps). ${}^{1}\mathrm{H}$ NMR (600 MHz, CDCl3) δ 3.86-3.82 (m, 2H), ${3.78} - {3.76}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , ${3.57} - {3.55}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.50} - {3.43}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{3.34} - {3.32}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.17} - {3.13} \; \left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.24} - {2.18}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.11} - {2.08}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.99} - {1.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.85} - {1.79}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , 1.73-1.65 (m, 5H), 1.57-1.53 (m, 1H), 1.49-1.45 (m, 1H), 1.39-1.14 (m, 8H), 1.06-0.84 $\left( {\mathrm{m},{12}\mathrm{H}}\right) ,{0.65}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR $\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{81.5},{80.3},{76.6},{69.1},{68.7},{68.2}$ , 46.38, 46.36, 42.4, 41.9, 39.7, 38.4, 35.8, 35.3, 35.2, 35.0, 31.3, 31.2, 31.0, 29.4, 28.0, 27.8, 27.6, 23.5, 23.4, 23.0, 19.4, 18.1, 14.7, 12.6; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{30}{\mathrm{H}}_{51}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{3}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{719.1280}$ , found 719.1281.

3a,7a,12a-三-(2-溴乙氧基)-胆甾烷(1)的合成。向3α,7α,12α-三-(2-羟乙氧基)-胆甾烷${}^{24}$(4,2.0 g,3.91 mmol)的干燥四氢呋喃(20 mL)溶液中，搅拌下加入三乙胺(3.95 mL, 27.37 mmol)。然后在$0{}^{ \circ }\mathrm{C}$将甲磺酰氯(1.81 mL,23.46 mmol)逐滴加入混合物中。反应在室温下继续搅拌，并在$4\mathrm{\;h}$通过TLC分析判断反应完成。加入水淬灭反应，溶液用乙酸乙酯$\left( {{50}\mathrm{\;{mL}} \times 3}\right)$萃取。合并的有机相用盐水洗涤，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，然后真空浓缩。残余物未经纯化，溶于丙酮(20 mL)。然后在室温下加入溴化锂(3.4 g, 39.1 mmol)，悬浮液在50${}^{ \circ }\mathrm{C}$加热过夜。经过简单的后处理，混合物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯 = 20:1至10:1)纯化，得到1，为淡黄色固体(1.64 g，两步产率60%)。${}^{1}\mathrm{H}$核磁共振(600 MHz, CDCl3) δ 3.86 - 3.82 (m, 2H)，${3.78} - {3.76}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，${3.57} - {3.55}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.50} - {3.43}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{3.34} - {3.32}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.17} - {3.13} \; \left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.24} - {2.18}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.11} - {2.08}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.99} - {1.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.85} - {1.79}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，1.73 - 1.65 (m, 5H)，1.57 - 1.53 (m, 1H)，1.49 - 1.45 (m, 1H)，1.39 - 1.14 (m, 8H)，1.06 - 0.84$\left( {\mathrm{m},{12}\mathrm{H}}\right) ,{0.65}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振$\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta \;{81.5},{80.3},{76.6},{69.1},{68.7},{68.2}$，46.38, 46.36, 42.4, 41.9, 39.7, 38.4, 35.8, 35.3, 35.2, 35.0, 31.3, 31.2, 31.0, 29.4, 28.0, 27.8, 27.6, 23.5, 23.4, 23.0, 19.4, 18.1, 14.7, 12.6; 高分辨质谱(电喷雾飞行时间)计算值为${\mathrm{C}}_{30}{\mathrm{H}}_{51}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{3}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{719.1280}$，实测值为719.1281。

General Procedure for the Preparation of Cage Compounds 2 and 8a-c. To a solution of 1 (200 mg, 0.29 mmol) and cyanuric acid (56 mg, 0.43 mmol) in dry DMF was added DBU (132mg,0.87 mmol) at rt. The reaction was heated at ${75}^{ \circ }\mathrm{C}$ with stirring for 1 day. The mixture was concentrated to dryness directly in vacuo. The residue was purified by silica gel column chromatography (eluent: hexanes/EtOAc = 4:1 to 2:1) to give 2 as a white solid $\left( {{43.0}\mathrm{{mg}},{26}\% }\right)$ . Crystals of 2 for crystallography were grown in about a week in DMSO solution open to air, allowing water absorption. ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ ${4.56} - {4.50}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.44} - {4.40}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.31} - {4.26}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.05} - {3.92}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.73} - {3.67} \; \left( {\mathrm{m},4\mathrm{H}}\right) ,{3.48} - {3.43}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.41} - {3.39}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.37} - {3.35}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.21} - {3.18}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${2.41} - {2.35}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.02} - {1.78}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.65} - {1.62}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.54} - {1.03}\left( {\mathrm{\;m},{14}\mathrm{H}}\right) ,{0.96} - {0.83} \; \left( {\mathrm{m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 150.0},{149.3},{149.2},{77.8},{75.8}$ , 74.2,64.2,61.6,60.1,46.7,45.8,43.9,43.7,41.8,40.1,39.7,39.3,38.4,35.4,34.9,34.8, 34.7, 29.8, 29.0, 28.3, 27.8, 23.8, 21.7, 20.4, 19.6, 18.4, 14.7, 12.0; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{33}{\mathrm{H}}_{51}{\mathrm{\;N}}_{3}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{586.3850}$ , found 586.3850.

制备笼状化合物2和8a - c的通用步骤。将1(200毫克，0.29毫摩尔)和氰尿酸(56毫克，0.43毫摩尔)在干燥的N, N - 二甲基甲酰胺中的溶液在室温下加入1,8 - 二氮杂双环[5.4.0]十一碳 - 7 - 烯(132毫克，0.87毫摩尔)。反应在${75}^{ \circ }\mathrm{C}$下加热搅拌1天。混合物直接在真空中浓缩至干。残余物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯 = 4:1至2:1)纯化，得到白色固体形式的2$\left( {{43.0}\mathrm{{mg}},{26}\% }\right)$ 。用于晶体学的2的晶体在大约一周内在暴露于空气中的二甲基亚砜溶液中生长，允许吸水。${}^{1}\mathrm{H}$核磁共振(500兆赫，氘代氯仿${}_{3}$ )δ${4.56} - {4.50}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.44} - {4.40}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.31} - {4.26}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.05} - {3.92}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.73} - {3.67} \; \left( {\mathrm{m},4\mathrm{H}}\right) ,{3.48} - {3.43}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.41} - {3.39}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.37} - {3.35}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.21} - {3.18}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，${2.41} - {2.35}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.02} - {1.78}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.65} - {1.62}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{1.54} - {1.03}\left( {\mathrm{\;m},{14}\mathrm{H}}\right) ,{0.96} - {0.83} \; \left( {\mathrm{m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 150.0},{149.3},{149.2},{77.8},{75.8}$ ，74.2，64.2，61.6，60.1，46.7，45.8，43.9，43.7，41.8，40.1，39.7，39.3，38.4，35.4，34.9，34.8，34.7，29.8，29.0，28.3，27.8，23.8，21.7，20.4，19.6，18.4，14.7，12.0；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{33}{\mathrm{H}}_{51}{\mathrm{\;N}}_{3}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{586.3850}$ ，实测值为586.3850。

8a: white solid; ${}^{1}\mathrm{H}$ NMR (500 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 4.25-4.21 (m,1H),4.16-4.07 (m,4H), ${3.95} - {3.86}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.79} - {3.36}\left( {\mathrm{\;m},{15}\mathrm{H}}\right) ,{3.18} - {3.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.99} - {2.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.14} - {1.82} \; \left( {\mathrm{m},5\mathrm{H}}\right) ,{1.74} - {1.11}\left( {\mathrm{\;m},{16}\mathrm{H}}\right) ,{1.03} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.86} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.61}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 149.17, 149.15, 149.08, 81.8, 80.3, 76.5, 71.4, 71.12, 71.06, 70.6, 70.0, 68.8, 68.7, 67.7, 67.2, 46.7, 46.4, 42.8, 42.6, 42.0, 41.7, 39.5, 38.3, 35.6, 35.3, 35.2, 34.9, 28.9, 28.4, 27.7, 27.2, 23.8, 23.4, 23.0, 19.4, 18.3, 14.6, 12.7; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{39}{\mathrm{H}}_{63}{\mathrm{\;N}}_{3}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{718.4637}$ , found 718.4638.

8a:白色固体；${}^{1}\mathrm{H}$核磁共振(500兆赫，${\mathrm{{CDCl}}}_{3}$)δ 4.25 - 4.21(多重峰，1个氢原子)，4.16 - 4.07(多重峰，4个氢原子)，${3.95} - {3.86}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.79} - {3.36}\left( {\mathrm{\;m},{15}\mathrm{H}}\right) ,{3.18} - {3.15}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.99} - {2.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.14} - {1.82} \; \left( {\mathrm{m},5\mathrm{H}}\right) ,{1.74} - {1.11}\left( {\mathrm{\;m},{16}\mathrm{H}}\right) ,{1.03} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.86} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.61}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(125兆赫，氘代氯仿)δ 149.17，149.15，149.08，81.8，80.3，76.5，71.4，71.12，71.06，70.6，70.0，68.8，68.7，67.7，67.2，46.7，46.4，42.8，42.6，42.0，41.7，39.5，38.3，35.6，35.3，35.2，34.9，28.9，28.4，27.7，27.2，23.8，23.4，23.0，19.4，18.3，14.6, 12.7；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{39}{\mathrm{H}}_{63}{\mathrm{\;N}}_{3}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{718.4637}$，实测值为718.4638。

8b: white solid; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 4.23-4.14 (m,3H),4.09-4.01 (m,3H), ${3.85} - {3.51}\left( {\mathrm{\;m},{28}\mathrm{H}}\right) ,{3.45} - {3.43}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.27} - {3.17}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.07} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.16} - {2.02} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{1.92} - {1.68}\left( {\mathrm{m},1\mathrm{H}}\right) ,{1.81} - {1.12}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.04} - {0.90}\left( {\mathrm{m},2\mathrm{H}}\right) ,{0.86} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$ , ${0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR $\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 149.24},{149.19},{80.8},{79.2},{76.3},{71.38}$ , 71.35,71.1,71.0,70.73,70.67,70.6,70.3,68.5,68.2,67.8,67.6,67.5,67.3,46.8,46.1, 42.5, 42.2, 42.11, 42.07, 41.8, 39.7, 38.4, 35.4, 35.3, 35.0, 34.9, 28.8, 27.9, 27.6, 27.3, 23.2,22.8,22.7,19.3,18.0,14.7,12.4; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{45}{\mathrm{H}}_{75}{\mathrm{\;N}}_{3}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 850.5423, found 850.5421.

8b:白色固体；${}^{1}\mathrm{H}$核磁共振(500兆赫，氘代氯仿${}_{3}$)δ 4.23 - 4.14(多重峰，3H)，4.09 - 4.01(多重峰，3H)，${3.85} - {3.51}\left( {\mathrm{\;m},{28}\mathrm{H}}\right) ,{3.45} - {3.43}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.27} - {3.17}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.07} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.16} - {2.02} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{1.92} - {1.68}\left( {\mathrm{m},1\mathrm{H}}\right) ,{1.81} - {1.12}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.04} - {0.90}\left( {\mathrm{m},2\mathrm{H}}\right) ,{0.86} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$，${0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振$\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 149.24},{149.19},{80.8},{79.2},{76.3},{71.38}$，71.35，71.1，71.0，70.73，70.67，70.6，70.3，68.5，68.2，67.8，67.6，67.5，67.3，46.8，46.1，42.5，42.2，42.11，42.07，41.8，39.7，38.4，35.4，35.3，35.0，34.9，28.8，27.9，27.6，27.3，23.2，22.8,22.7,19.3,18.0,14.7,12.4；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{45}{\mathrm{H}}_{75}{\mathrm{\;N}}_{3}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 850.5423，实测值为850.5421。

8c: colorless oil; ${}^{1}\mathrm{H}$ NMR (600 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 4.18-4.06 (m,7H),3.78-3.56 (m,39H), ${3.46} - {3.44}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.31} - {3.30}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.24} - {3.21}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.07} - {3.04}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.16} - {2.06} \; \left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.93} - {1.88}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.79} - {1.60}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{1.52} - {1.15}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{1.01} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , ${0.92} - {0.84}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 149.21},{149.19},{81.2}$ , 80.0,76.4,71.2,71.0,70.9,70.84,70.79,70.78,70.69,70.67,70.6,70.44,70.39,70.37, 68.7,68.5,67.6,67.4,46.8,46.2,42.7,42.04,41.98,41.95,39.7,38.4,35.6,35.4,35.2, 35.0, 29.0, 28.0, 27.7, 27.4, 23.3, 23.00, 22.95, 19.4, 18.0, 14.7, 12.5; HRMS (ESI-TOF) calcd. for ${\mathrm{C}}_{51}{\mathrm{H}}_{87}{\mathrm{\;N}}_{3}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{982.6210}$ , found982.6200.

8c:无色油状物；${}^{1}\mathrm{H}$核磁共振(600兆赫，${\mathrm{{CDCl}}}_{3}$)δ 4.18 - 4.06(多重峰，7H)，3.78 - 3.56(多重峰，39H)，${3.46} - {3.44}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.31} - {3.30}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.24} - {3.21}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.07} - {3.04}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.16} - {2.06} \; \left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.93} - {1.88}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.79} - {1.60}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{1.52} - {1.15}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{1.01} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，${0.92} - {0.84}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 149.21},{149.19},{81.2}$，80.0，76.4，71.2，71.0，70.9，70.84，70.79，70.78，70.69，70.67，70.6，70.44，70.39，70.37，68.7，68.5，67.6，67.4，46.8，46.2，42.7，42.04，41.98，41.95，39.7，38.4，35.6，35.4，35.2，35.0，29.0，28.0，27.7，27.4，23.3，23.00，22.95，19.4，18.0，14.7，12.5；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{51}{\mathrm{H}}_{87}{\mathrm{\;N}}_{3}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{982.6210}$，实测值982.6200。

Synthesis of ${3\alpha },{7\alpha },{12\alpha }$ -Tri-(2-tosylateethoxy)-cholane (5). To a solution of $4({1.0}\mathrm{\;g},{1.96}$ mmol) in dry ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{60}\mathrm{\;{mL}}}\right)$ were added triethylamine $\left( {{2.72}\mathrm{\;{mL}},{19.6}\mathrm{{mmol}}}\right)$ and 4-dimethylaminopyridine $\left( {{50}\mathrm{{mg}},{0.4}\mathrm{{mmol}}}\right)$ at ${0}^{ \circ }\mathrm{C}$ . 4-Toluenesulfonyl chloride $({1.87}\mathrm{\;g}$ , 9.8 mmol) was then added in portions. The reaction temperature was allowed to increase overnight to rt. The reaction was quenched with saturated ${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$ solution, and extracted with ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{30}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic phases were washed with brine, dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: hexanes/EtOAc = 5:1 to 3:1) to give 5 as an orange-colored solid $\left( {{1.28}\mathrm{\;g},{67}\% }\right)$ . ${}^{1}\mathrm{H}$ NMR $\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 7.78-7.74 $\left( {\mathrm{m},6\mathrm{H}}\right) ,{7.34} - {7.29}\left( {\mathrm{\;m},6\mathrm{H}}\right)$ , 4.18-4.00 (m, 6H), 3.73-3.60 (m, 4H), 3.49-3.47 (m, 1H), 3.40-3.32 (m, 2H), 3.28-3.27 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{3.06} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.42} - {2.41}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{2.06} - {1.90}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.81} - {1.09}\left( {\mathrm{\;m},{18}\mathrm{H}}\right)$ , 0.99-0.81 (m, 12H), 0.61 (s, 3H); ${}^{13}\mathrm{C}$ NMR (125 MHz, CDCl ${}_{3}$ ) δ 144.9, 144.82, 144.81, 133.2, 133.1, 133.0, 130.01, 129.93, 129.90, 128.1, 128.01, 127.98, 81.7, 80.1, 76.7, 70.0, 69.6, 69.4, 66.4, 66.2, 65.4, 46.5, 46.3, 42.5, 41.7, 39.5, 38.3, 35.6, 35.1, 34.9, 34.6, 28.9, 28.0, 27.7, 27.4, 23.14, 23.09, 22.9, 21.7, 19.4, 17.8, 14.7, 12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{51}{\mathrm{H}}_{72}{\mathrm{O}}_{12}{\mathrm{\;S}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 973.4264, found 973.4259.

${3\alpha },{7\alpha },{12\alpha }$-三-(2-对甲苯磺酸乙酯基)胆甾烷(5)的合成。向$4({1.0}\mathrm{\;g},{1.96}$毫摩尔的溶液中，在干燥的${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{60}\mathrm{\;{mL}}}\right)$中于${0}^{ \circ }\mathrm{C}$加入三乙胺$\left( {{2.72}\mathrm{\;{mL}},{19.6}\mathrm{{mmol}}}\right)$和4-二甲氨基吡啶$\left( {{50}\mathrm{{mg}},{0.4}\mathrm{{mmol}}}\right)$。然后分批加入4-甲苯磺酰氯$({1.87}\mathrm{\;g}$(9.8毫摩尔)。反应温度过夜升至室温。用饱和${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$溶液淬灭反应，并用${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{30}\mathrm{\;{mL}} \times 3}\right)$萃取。合并的有机相用盐水洗涤，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，并在真空中浓缩。残余物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯=5:1至3:1)纯化，得到橙色固体5$\left( {{1.28}\mathrm{\;g},{67}\% }\right)$。${}^{1}\mathrm{H}$核磁共振$\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$7.78 - 7.74$\left( {\mathrm{m},6\mathrm{H}}\right) ,{7.34} - {7.29}\left( {\mathrm{\;m},6\mathrm{H}}\right)$，4.18 - 4.00(多重峰，6H)，3.73 - 3.60(多重峰，4H)，3.49 - 3.47(多重峰，1H)，3.40 - 3.32(多重峰，2H)，3.28 - 3.27$\left( {\mathrm{m},1\mathrm{H}}\right) ,{3.06} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.42} - {2.41}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{2.06} - {1.90}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.81} - {1.09}\left( {\mathrm{\;m},{18}\mathrm{H}}\right)$，0.99 - 0.81(多重峰，12H)，0.61(单峰，3H)；${}^{13}\mathrm{C}$核磁共振(125兆赫兹，CDCl${}_{3}$)δ144.9，144.82，144.81，133.2，133.1，133.0，130.01，129.93，129.90，128.1, , , 128. .01, 127.98, 81.7, 80.1, 76.7, 70.0, 69.6, 69.4, 66.4, 66.2, 65.4, 46.5, 46.3, 42.5, 41.7, 39.5, 38.3, 35.6, 35.1, 34.9, 34.6, 28.9, 28.0, 27.7, 27.4, 23.14, 23. .09, 22.9, 21.7, 19.4, 17.8, 14.7, 12.5；高分辨质谱(电喷雾飞行时间)计算值为${\mathrm{C}}_{51}{\mathrm{H}}_{72}{\mathrm{O}}_{12}{\mathrm{\;S}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$973.4264，实测值为973.4259。

Synthesis of 6a-c. To a solution of ethylene glycol (0.86 ml, 15.5 mmol) in dry THF (5 mL) was slowly added NaH (60% in mineral oil, 124 mg, 3.1 mmol) at rt. The suspension was heated at ${70}^{ \circ }\mathrm{C}$ for ${0.5}\mathrm{\;h}$ before being cooled to rt. 5 (300 mg,0.31 mmol) was added, and then the reaction was continued with stirring at ${70}^{ \circ }\mathrm{C}$ for 1 day. The reaction was then quenched with saturated ${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$ solution, and extracted with EtOAc $\left( {{20}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic phases were washed with brine, dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {20} : 1$ to 10:1) to give 6a as a yellow oil $\left( {{118}\mathrm{{mg}},{60}\% }\right)$ . ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 3.78-3.54 (m, 25H), 3.47-3.45 (m, 1H), 3.29-3.21 (m, 3H), 3.12-3.08 (m, 1H), 2.30-2.22 (m, 1H), 2.13-2.04 (m, 2H), 1.91-1.59 (m, 8H), 1.48-1.09 (m, 10H), 1.01-0.81 (m, 12H), 0.62 (s, 3H); ${}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 81.0, 80.7, 76.4, 73.0, 72.8, 70.8, 70.7, 70.5, 68.4, 68.3, 67.6, 61.7, 61.63, 61.56, 46.8, 46.1, 42.4, 42.0, 39.5, 38.3, 35.4, 35.3, 35.2, 34.9, 28.8, 27.9, 27.6, 26.8, 23.3, 22.8, 19.3, 18.1, 14.6, 12.5; MS (ESI) calcd for ${\mathrm{C}}_{36}{\mathrm{H}}_{66}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{665.5}$ , found 665.5.

6a - c的合成。在室温下，将乙二醇(0.86 ml，15.5 mmol)溶于干燥的四氢呋喃(5 mL)中，缓慢加入氢化钠(60%的矿物油溶液，124 mg，3.1 mmol)。将悬浮液在${70}^{ \circ }\mathrm{C}$加热${0.5}\mathrm{\;h}$，然后冷却至室温。加入5(300 mg，0.31 mmol)，然后在${70}^{ \circ }\mathrm{C}$搅拌反应1天。然后用饱和${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$溶液淬灭反应，并用乙酸乙酯$\left( {{20}\mathrm{\;{mL}} \times 3}\right)$萃取。合并的有机相用盐水洗涤，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，并在真空中浓缩。残余物通过硅胶柱色谱法(洗脱剂:${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {20} : 1$至10:1)纯化，得到黄色油状的6a$\left( {{118}\mathrm{{mg}},{60}\% }\right)$。${}^{1}\mathrm{H}$核磁共振(500 MHz，CDCl${}_{3}$)δ 3.78 - 3.54(m，25H)，3.47 - 3.45(m，1H)，3.29 - 3.21(m，3H)，3.12 - 3.08(m，1H)，2.30 - 2.22(m，1H)，2.13 - 2.04(m，2H)，1.91 - 1.59(m，8H)，1.48 - 1.09(m，10H)，1.01 - 0.81(m，12H)，0.62(s，3H)；${}^{13}\mathrm{C}$核磁共振(125 MHz，CDCl3)δ 81.0，80.7，76.4，73.0，72.8，70.8，70.7，70.5，68.4，68.3，67.6，61.7，61.63，61.56，46.8，46.1，42.4，42.0，39.5，38.3，35.4，35.3，35.2，34.9，28.8，27.9，27.6，26.8，23.3，22.8，19.3，18.1，14.6，12.5；质谱(电喷雾电离)计算值为${\mathrm{C}}_{36}{\mathrm{H}}_{66}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{665.5}$，实测值为665.5。

6b: yellow oil; ${}^{1}\mathrm{H}$ NMR (600 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 3.77-3.55 (m,37H),3.49-3.47 (m,1H), 3.34-3.31 (m, 1H), 3.28-3.25 (m, 2H), 3.11-3.07 (m, 1H), 2.20-2.13 (m, 1H), 2.08-2.03 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.92} - {1.87}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.82} - {1.60}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{1.55} - {1.12}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{1.02} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , 0.93-0.84 (m, 10H), 0.63 (s, 3H); ${}^{13}\mathrm{C}$ NMR (150 MHz, CDCl ${}_{3}$ ) δ 81.4, 80.3, 76.4, 72.72, 72.71, 72.66, 71.0, 70.92, 70.91, 70.8, 70.73, 70.71, 70.63, 70.62, 70.4, 68.2, 68.1, 67.2, 61.83, 61.78, 46.8, 46.2, 42.7, 42.0, 39.7, 38.4, 35.6, 35.4, 35.1, 35.0, 29.0, 28.0, 27.7, 27.4,23.3,23.0,19.4,18.0,14.7,12.6; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{42}{\mathrm{H}}_{78}{\mathrm{O}}_{12}{\left\lbrack {\mathrm{M}}^{ + }\mathrm{H}\right\rbrack }^{ + }$ 775.5572, found 775.5566.

6b:黄色油状物；${}^{1}\mathrm{H}$核磁共振谱(600 MHz，${\mathrm{{CDCl}}}_{3}$ )δ 3.77 - 3.55(m，37H)，3.49 - 3.47(m，1H)，3.34 - 3.31(m，1H)，3.28 - 3.25(m，2H)，3.11 - 3.07(m，1H)，2.20 - 2.13(m，1H)，2.08 - 2.03 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.92} - {1.87}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.82} - {1.60}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{1.55} - {1.12}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{1.02} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ ，0.93 - 0.84(m，10H)，0.63(s，3H)；${}^{13}\mathrm{C}$核磁共振谱(150 MHz，CDCl ${}_{3}$ )δ 81.4、80.3、76.4、72.72、72.71、72.66、71.0、70.92、70.91、70.8、70.73、70.71、70.63、70.62、70.4、68.2、68.1、67.2、61.83、61.78、46.8、46.2、42.7、42.0、39.7、38.4、35.6、35.4、35.1、35.0、29.0、28.0、27.7、27.4、23.3、23.0、19.4、18.0、14.7、12.6；高分辨率质谱(ESI - TOF)计算值${\mathrm{C}}_{42}{\mathrm{H}}_{78}{\mathrm{O}}_{12}{\left\lbrack {\mathrm{M}}^{ + }\mathrm{H}\right\rbrack }^{ + }$ 775.5572，实测值775.5566。

6c: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 3.69-3.55 (m,47H),3.45-3.43 (m,1H), ${3.31} - {3.21}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.09} - {3.03}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.14} - {2.07}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.03} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.89} - {1.83} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.78} - {1.08}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{0.99} - {0.93}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.90} - {0.80}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (125 MHz, CDC1, 3) & 81.3, 80.1, 76.2, 72.7, 72.6, 70.9, 70.8, 70.72, 70.70, 70.66, 70.62, 70.60, 70.55, 70.5, 70.39, 70.37, 70.3, 68.01, 67.95, 67.1, 61.7, 46.6, 46.2, 42.6, 41.9, 39.6, 38.4, 35.5, 35.3, 35.0, 34.9, 28.9, 28.0, 27.7, 27.4, 23.2, 23.0, 22.9, 19.3, 17.8, 14.6,12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{48}{\mathrm{H}}_{90}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 907.6358, found 907.6352.

6c:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，CDCl${}_{3}$)δ 3.69 - 3.55(多重峰，47H)，3.45 - 3.43(多重峰，1H)，${3.31} - {3.21}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.09} - {3.03}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.14} - {2.07}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.03} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.89} - {1.83} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.78} - {1.08}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{0.99} - {0.93}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.90} - {0.80}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(125兆赫兹，CDC1, 3)& 81.3, 80.1, 76.2, 72.7, 72.6, 70.9, 70.8, 70.72, 70.70, 70.66, 70.62, 70.60, 70.55, 70.5, 70.39, 70.37, 70.3, 68.01, 67.95, 67.1, 61.7, 46.6, 46.2, 42.6, 41.9, 39.6, 38.4, 35.5, 35.3, 35.0, 34.9, 28.9, 28.0, 27.7, 27.4, 23.2, 23.0, 22.9, 19.3, 17.8, 14.6,12.5；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{48}{\mathrm{H}}_{90}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 907.6358，实测值为907.6352。

Compounds 7a-c were prepared using a procedure similar to the synthesis of 1. 7a: colorless oil; ${}^{1}\mathrm{H}$ NMR (600 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 3.94-3.90 (m,1H),3.84-3.80 (m,5H), ${3.73} - {3.57}\left( {m,{10H}}\right) ,{3.54} - {3.44}\left( {m,{7H}}\right) ,{3.34} - {3.24}\left( {m,{3H}}\right) ,{3.12} - {3.09}\left( {m,{1H}}\right) ,{2.19} - {2.13} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.08} - {2.03}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.94} - {1.81}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.84} - {1.13}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.04} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , 0.93-0.84 (m, 10H), 0.64 (s, 3H); ${}^{13}\mathrm{C}$ NMR (150 MHz, CDCl3) δ 81.2, 80.2, 76.4, 71.6, 71.4, 71.3, 71.0, 70.9, 70.7, 68.20, 68.18, 67.3, 46.8, 46.2, 42.6, 42.0, 39.7, 38.4, 35.6, 35.4, 35.1, 35.0, 31.1, 30.8, 30.6, 28.9, 28.0, 27.8, 27.3, 23.3, 23.0, 22.9, 19.4, 18.0, 14.7,

化合物7a - c的制备采用了与化合物1合成类似的方法。7a:无色油状物；${}^{1}\mathrm{H}$核磁共振(600兆赫兹，${\mathrm{{CDCl}}}_{3}$)δ 3.94 - 3.90(多重峰，1H)，3.84 - 3.80(多重峰，5H)，${3.73} - {3.57}\left( {m,{10H}}\right) ,{3.54} - {3.44}\left( {m,{7H}}\right) ,{3.34} - {3.24}\left( {m,{3H}}\right) ,{3.12} - {3.09}\left( {m,{1H}}\right) ,{2.19} - {2.13} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.08} - {2.03}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.94} - {1.81}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.84} - {1.13}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.04} - {0.97}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，0.93 - 0.84(多重峰，10H)，0.64(单峰，3H)；${}^{13}\mathrm{C}$核磁共振(150兆赫兹，氯仿-d)δ 81.2，80.2，76.4，71.6，71.4，71.3，71.0，70.9, 70.7，68.20，68.18，67.3，46.8，46.2，42.6，42.0，39.7，38.4，35.6，35.4，35.1，35.0，31.1，30.8，30.6，28.9，28.0，27.8，27.3，23.3，23.0，22.9，19.4，18.0，14.7

12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{36}{\mathrm{H}}_{63}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{851.2067}$ , found851.2067. 7b: yellow oil; ${}^{1}\mathrm{H}$ NMR $\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 3.80} - {3.77}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{3.72} - {3.53}\left( {\mathrm{\;m},{22}\mathrm{H}}\right)$ , 3.47-3.43 (m, 7H), 3.34-3.29 (m, 1H), 3.28-3.23 (m, 2H), 3.09-3.05 (m, 1H), 2.17-2.09 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.05} - {1.97}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.91} - {1.85}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.11}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.01} - {0.82}\left( {\mathrm{\;m},{12}\mathrm{H}}\right)$ , ${0.61}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR $\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 81.4,80.2,76.2,71.3,71.2,71.1,70.9,70.8, 70.74,70.71,70.69,70.65,70.59,68.0,67.9,67.2,46.6,46.2,42.6,42.0,39.6,38.4,35.6, 35.4, 35.04, 34.96, 30.5, 30.4, 28.9, 28.0, 27.7, 27.5, 23.2, 23.00, 22.97, 19.4, 17.8, 14.7, 12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{42}{\mathrm{H}}_{75}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{961.3034}$ , found961.3036.

12.5；高分辨质谱(ESI - TOF)计算值 ${\mathrm{C}}_{36}{\mathrm{H}}_{63}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{851.2067}$ ，实测值 851.2067。7b:黄色油状物；${}^{1}\mathrm{H}$ 核磁共振 $\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 3.80} - {3.77}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{3.72} - {3.53}\left( {\mathrm{\;m},{22}\mathrm{H}}\right)$ ，3.47 - 3.43(多重峰，7H)，3.34 - 3.29(多重峰，1H)，3.28 - 3.23(多重峰，2H)，3.09 - 3.05(多重峰，1H)，2.17 - 2.09 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.05} - {1.97}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.91} - {1.85}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.11}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.01} - {0.82}\left( {\mathrm{\;m},{12}\mathrm{H}}\right)$ ；${0.61}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ 核磁共振 $\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 81.4、80.2、76.2、71.3、71.2、71.1、70.9、70.8、70.74、70.71、70.69、70.65、70.59、68.0、67.9、67.2、46.6、46.2、42.6、42.0、39.6、38.4、35.6、35.4、35.04、34.96、30.5、30.4、28.9、28.0、27.7、27.5、23.2、23.00、22.97、19.4、17.8、14.7、12.5；高分辨质谱(ESI - TOF)计算值 ${\mathrm{C}}_{42}{\mathrm{H}}_{75}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{961.3034}$ ，实测值 961.3036。

7c: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 3.80-3.77 (m,6H),3.68-3.54 (m,35H), 3.47-3.44 (m, 6H), 3.33-3.24 (m, 3H), 3.10-3.05 (m, 1H), 2.17-2.10 (m, 1H), 2.05-1.97 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.91} - {1.85}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.79} - {1.13}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.01} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.92} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$ , ${0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 81.4,80.3,76.3,71.3,71.0,70.9,70.79, 70.75,70.74,70.68,70.6,67.9,67.8,67.3,46.6,46.2,42.7,42.0,39.7,38.4,35.6,35.4 35.04, 35.01, 30.4, 29.0, 28.0, 27.8, 27.5, 23.2, 23.1, 23.0, 19.4, 17.8, 14.7, 12.6; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{48}{\mathrm{H}}_{87}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1093.3820, found 1093.3824.

7c:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，CDCl${}_{3}$)δ 3.80 - 3.77(多重峰，6H)，3.68 - 3.54(多重峰，35H)，3.47 - 3.44(多重峰，6H)，3.33 - 3.24(多重峰，3H)，3.10 - 3.05(多重峰，1H)，2.17 - 2.10(多重峰，1H)，2.05 - 1.97$\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.91} - {1.85}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.79} - {1.13}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.01} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.92} - {0.83}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$，${0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 81.4,80.3,76.3,71.3,71.0,70.9,70.79, 70.75,70.74,70.68,70.6,67.9,67.8,67.3,46.6,46.2,42.7,42.0,39.7,38.4,35.6,35.4 35.04, 35.01, 30.4, 29.0, 28.0, 27.8, 27.5, 23.2, 23.1, 23.0, 19.4, 17.8, 14.7, 12.6；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{48}{\mathrm{H}}_{87}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1093.3820，实测值为1093.3824。

Synthesis of compound ${\mathbf{9}}^{46}$ . To a solution of cholic acid (10 g,24.5 mmol) in dry THF $\left( {{150}\mathrm{\;{mL}}}\right)$ was slowly added $\mathrm{{NaH}}\left( {{60}\% \text{ in mineral oil,14.7 g,37.5 mol) at }0{}^{ \circ }\mathrm{C}\text{ . The }}\right)$ reaction was stirred at rt for ${0.5}\mathrm{\;h}$ before allyl iodide ( ${22.4}\mathrm{\;{mL}},{245}\mathrm{{mmol}}$ ) was added. The reaction was continued at rt for $4\mathrm{\;h}$ , then again cooled to ${0}^{ \circ }\mathrm{C}$ , and an additional 50 mL of dry THF was added. To this solution was slowly added LiAl ${\mathrm{H}}_{4}\left( {{2.8}\mathrm{\;g},{73.5}\mathrm{{mmol}}}\right)$ in portions. The reaction temperature was allowed to increase to rt and stirred overnight. The reaction was carefully quenched by the addition of $3\mathrm{\;{mL}}{\mathrm{H}}_{2}\mathrm{O}$ at ${0}^{ \circ }\mathrm{C}$ , followed by the addition of $6\mathrm{\;{mL}}{10}\% \mathrm{{NaOH}}$ and $9\mathrm{\;{mL}}{\mathrm{H}}_{2}\mathrm{O}$ . The solid precipitate was filtered and washed with EtOAc. The organic solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (eluent: hexanes/EtOAc = 5:1 to 2.5:1) to give9as a white solid $\left( {{11.8}\mathrm{\;g},{94}\% }\right)$ . ${}^{1}\mathrm{H}$ NMR $\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.96} - {5.84}\left( {\mathrm{\;m},3\mathrm{H}}\right)$ ,5.29-5.17 $\left( {\mathrm{m},3\mathrm{H}}\right) ,{5.12} - {5.04}\left( {\mathrm{m},3\mathrm{H}}\right) ,{4.07} - {4.03}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.98} - {3.97}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.77} - {3.73}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${3.70} - {3.66}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.61} - {3.54}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.53} - {3.51}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.30} - {3.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.15} - {3.09} \; \left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.28} - {2.21}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.19} - {2.11}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.02} - {1.96}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {0.94}\left( {\mathrm{\;m},{19}\mathrm{H}}\right)$ , ${0.91} - {0.90}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.87}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 136.1, 35.7, 35.4, 35.0, 31.8, 29.5, 28.9, 28.1, 27.7, 27.5, 23.3, 23.0, 17.8, 12.6; MS (ESI) calcd 35.7, 35.4, 35.0, 31.8, 29.5, 28.9, 28.1, 27.7, 27.5, 23.3, 23.0, 17.8, 12.6; MS (ESI) calcd for ${\mathrm{C}}_{33}{\mathrm{H}}_{54}{\mathrm{O}}_{4}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{537.4}$ , found 537.4.

化合物${\mathbf{9}}^{46}$的合成。在干燥四氢呋喃中的胆酸(10 g，24.5 mmol)溶液中，缓慢加入$\mathrm{{NaH}}\left( {{60}\% \text{ in mineral oil,14.7 g,37.5 mol) at }0{}^{ \circ }\mathrm{C}\text{ . The }}\right)$，反应在室温下搅拌${0.5}\mathrm{\;h}$，然后加入烯丙基碘(${22.4}\mathrm{\;{mL}},{245}\mathrm{{mmol}}$)。反应在室温下继续进行$4\mathrm{\;h}$，然后再次冷却至${0}^{ \circ }\mathrm{C}$，并加入另外50 mL干燥四氢呋喃。向该溶液中分批缓慢加入LiAl${\mathrm{H}}_{4}\left( {{2.8}\mathrm{\;g},{73.5}\mathrm{{mmol}}}\right)$。反应温度升至室温并搅拌过夜。在${0}^{ \circ }\mathrm{C}$小心加入$3\mathrm{\;{mL}}{\mathrm{H}}_{2}\mathrm{O}$淬灭反应，接着加入$6\mathrm{\;{mL}}{10}\% \mathrm{{NaOH}}$和$9\mathrm{\;{mL}}{\mathrm{H}}_{2}\mathrm{O}$。过滤固体沉淀并用乙酸乙酯洗涤。有机溶液在真空下浓缩，残余物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯 = 5:1至2.5:1)纯化，得到白色固体9$\left( {{11.8}\mathrm{\;g},{94}\% }\right)$。${}^{1}\mathrm{H}$核磁共振$\left( {{500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 5.96} - {5.84}\left( {\mathrm{\;m},3\mathrm{H}}\right)$，5.29 - 5.17$\left( {\mathrm{m},3\mathrm{H}}\right) ,{5.12} - {5.04}\left( {\mathrm{m},3\mathrm{H}}\right) ,{4.07} - {4.03}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.98} - {3.97}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.77} - {3.73}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，${3.70} - {3.66}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.61} - {3.54}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.53} - {3.51}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.30} - {3.29}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.15} - {3.09} \; \left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.28} - {2.21}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.19} - {2.11}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.02} - {1.96}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {0.94}\left( {\mathrm{\;m},{19}\mathrm{H}}\right)$，${0.91} - {0.90}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.87}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$136.1，35.7，35.4，35.0，31.8，29.5，28.9，28.1，27.7，27.5，23.3，23.0，17.8，12.6；质谱(电喷雾电离)计算值35.7，35.4，35.0，31.8，29.5，28.9，28.1，27.7，27.5，23.3，23.0，17.8，12.6；质谱(电喷雾电离)计算值为${\mathrm{C}}_{33}{\mathrm{H}}_{54}{\mathrm{O}}_{4}{\left\lbrack \mathrm{M} + \mathrm{{Na}}\right\rbrack }^{ + }{537.4}$，实测值537.4。

Synthesis of compound 10. To a solution of $\mathbf{9}\left( {3\mathrm{\;g},{5.82}\mathrm{{mmol}}}\right)$ in dry DMF ( ${15}\mathrm{\;{mL}}$ ) was added NaH (60% in mineral oil,702mg,17.46 mmol) at $0{}^{ \circ }\mathrm{C}$ . The mixture was stirred at rt for ${0.5}\mathrm{\;h}$ . Then benzyl bromide $\left( {{1.08}\mathrm{\;{mL}},{8.76}\mathrm{{mmol}}}\right)$ was added to the solution at $0{}^{ \circ }\mathrm{C}$ . The reaction was heated at ${60}^{ \circ }\mathrm{C}$ with stirring for $3\mathrm{\;h}$ . The reaction was quenched with saturated ${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$ after being cooled to ${0}^{ \circ }\mathrm{C}$ . The solution was extracted with EtOAc (60 $\mathrm{{mL}} \times 3)$ . The combined organic phases were washed with brine, dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: hexanes/EtOAc = 5: 1 to 1:4) to give 10 as a yellow oil (3.9 g, 95%). ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 7.32-7.31 (m,4H),7.26-7.23 (m,1H),5.96-5.85 (m, 3H), 5.30-5.18 (m, 3H), 5.13-5.04 (m, 3H), 4.48 (s, 2H), 4.08-4.03 (m, 2H), 3.99-3.97 (m, 2H), 3.78-3.74 (m, 1H), 3.71-3.67 (m, 1H), 3.53-3.51 (m, 1H), 3.42 (t, J = 5.0 Hz, 2H), 3.31-3.30 (m, 1H), 3.15-3.09 (m, 1H), 2.29-2.13 (m, 3H), 2.03-1.97 (m, 1H), 1.84-0.94 $\left( {\mathrm{m},{19}\mathrm{H}}\right) ,{0.91} - {0.90}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.87}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) : \delta \; = {138.8},{136.04},{136.03},{135.9},{128.4},{127.6},{127.4},{116.2},{115.5},{80.8},{79.2},{74.9},{72.8}$ , 71.2,69.4,69.3,68.7,46.5,46.4,42.6,42.0,39.8,35.6,35.4,35.1,35.0,32.3,28.9,28.0, 27.7,27.5,26.5,23.3,23.0,17.8,12.6; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{40}{\mathrm{H}}_{60}{\mathrm{O}}_{4}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 605.4570, found 605.4564.

化合物10的合成。在干燥的N, N - 二甲基甲酰胺(${15}\mathrm{\;{mL}}$)中加入$\mathbf{9}\left( {3\mathrm{\;g},{5.82}\mathrm{{mmol}}}\right)$的溶液，于$0{}^{ \circ }\mathrm{C}$加入氢化钠(60%的矿物油悬浮液，702毫克，17.46毫摩尔)。混合物在室温下搅拌${0.5}\mathrm{\;h}$。然后在$0{}^{ \circ }\mathrm{C}$向溶液中加入苄基溴$\left( {{1.08}\mathrm{\;{mL}},{8.76}\mathrm{{mmol}}}\right)$。反应在${60}^{ \circ }\mathrm{C}$加热搅拌$3\mathrm{\;h}$。冷却至${0}^{ \circ }\mathrm{C}$后，用饱和${\mathrm{{NH}}}_{4}\mathrm{{Cl}}$淬灭反应。溶液用乙酸乙酯(60 $\mathrm{{mL}} \times 3)$)萃取。合并的有机相用盐水洗涤，经${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，并在真空下浓缩。残余物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯 = 5:1至1:4)纯化，得到黄色油状的10(3.9克，产率95%)。${}^{1}\mathrm{H}$核磁共振(500兆赫，氘代氯仿${}_{3}$)δ 7.32 - 7.31(多重峰，4H)，7.26 - 7.23(多重峰，1H)，5.96 - 5.85(多重峰，3H)，5.30 - 5.18(多重峰，3H)，5.13 - 5.04(多重峰，3H)，4.48(单峰，2H)，4.08 - 4.03(多重峰，2H)，3.99 - 3.97(多重峰，2H)，3.78 - 3.74(多重峰，1H)，3.71 - 3.67(多重峰，1H)，3.53 - 3.51(多重峰，1H)，3.42(三重峰，J = 5.0赫兹，2H)，3.31 - 3.30(多重峰，1H)，3.15 - 3.09(多重峰，1H)，2.29 - 2.13(多重峰，3H)，2.03 - 1.97(多重峰，1H)，1.84 - 0.94 $\left( {\mathrm{m},{19}\mathrm{H}}\right) ,{0.91} - {0.90}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.87}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) : \delta \; = {138.8},{136.04},{136.03},{135.9},{128.4},{127.6},{127.4},{116.2},{115.5},{80.8},{79.2},{74.9},{72.8}$，71.2，69.4，69.3，68.7，46.5，46.4，42.6，42.0，39.8，35.6，35.4，35.1，35.0，32.3，28.9，28.0，27.7，27.5，26.5，23.3，23.0，17.8，12.6；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{40}{\mathrm{H}}_{60}{\mathrm{O}}_{4}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 605.4570，实测值为605.4564。

Synthesis of compound 11. Ozone was bubbled into a solution of 10 (3.9 g, 6.45 mmol) in ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{50}\mathrm{\;{mL}}}\right)$ and $\mathrm{{MeOH}}\left( {{25}\mathrm{\;{mL}}}\right)$ at $- {78}^{ \circ }\mathrm{C}$ until blue color persisted. Excess ozone was removed with oxygen flow till the blue color disappeared. ${\mathrm{{Me}}}_{2}\mathrm{\;S}({2.4}\mathrm{\;{mL}},{32.25}$ mmol) was then added. The solution was stirred for another ${10}\mathrm{\;{min}}$ before the addition of ${\mathrm{{NaBH}}}_{4}\left( {{1.47}\mathrm{\;g},{38.7}\mathrm{{mmol}}}\right)$ in ${10}\mathrm{\;{mL}}$ of ${10}\% \mathrm{{NaOH}}$ solution. The reaction was allowed to slowly increase to rt. Upon completion, the reaction was carefully quenched with 10% $\mathrm{{HCl}}$ solution (to $\mathrm{{pH}}5 - 6$ ) at ${0}^{ \circ }\mathrm{C}$ to eliminate excess ${\mathrm{{NaBH}}}_{4}$ . The mixture was extracted with ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{100}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic phases were dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {25} : 1$ to ${12} : 1$ ) to give 11 as a colorless oil $\left( {{3.7}\mathrm{\;g},{93}\% }\right)$ . ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 7.30-7.29 (m, 4H), 7.24-7.22 (m, 1H), 4.46 (s, 2H), 3.74-3.51 (m, 14H), ${3.40}\left( {\mathrm{t}, J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{3.30} - {3.28}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.18} - {3.09}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.22} - {2.14}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , ${2.12} - {2.05}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.94} - {1.88}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.85} - {1.60}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.54} - {1.16}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{1.09} - {0.97} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{0.93} - {0.89}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.86}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 138.7, 128.2, 127.5, 127.4, 80.9, 79.6, 76.3, 72.8, 70.9, 70.2, 69.6, 69.1, 62.0, 61.9, 61.8, 46.6, 46.2, 42.5, 41.7, 39.5, 35.4, 35.1, 34.9, 34.7, 32.2, 28.8, 27.8, 27.5, 27.0, 26.3, 23.2, 22.9,22.7,18.0,12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{37}{\mathrm{H}}_{60}{\mathrm{O}}_{7}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 617.4412, found 617.4414.

化合物11的合成。将臭氧鼓泡通入10(3.9 g，6.45 mmol)在${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{50}\mathrm{\;{mL}}}\right)$和$\mathrm{{MeOH}}\left( {{25}\mathrm{\;{mL}}}\right)$中的溶液中，于$- {78}^{ \circ }\mathrm{C}$下进行，直至蓝色持续存在。用氧气流除去过量的臭氧，直至蓝色消失。然后加入${\mathrm{{Me}}}_{2}\mathrm{\;S}({2.4}\mathrm{\;{mL}},{32.25}$ mmol。在加入${\mathrm{{NaBH}}}_{4}\left( {{1.47}\mathrm{\;g},{38.7}\mathrm{{mmol}}}\right)$于${10}\mathrm{\;{mL}}$的${10}\% \mathrm{{NaOH}}$溶液之前，将溶液再搅拌${10}\mathrm{\;{min}}$。使反应缓慢升温至室温。反应完成后，在${0}^{ \circ }\mathrm{C}$用10%的$\mathrm{{HCl}}$溶液小心淬灭(至$\mathrm{{pH}}5 - 6$)，以除去过量的${\mathrm{{NaBH}}}_{4}$。混合物用${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{100}\mathrm{\;{mL}} \times 3}\right)$萃取。合并的有机相用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤并真空浓缩。残余物通过硅胶柱色谱法(洗脱剂:${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {25} : 1$至${12} : 1$)纯化，得到无色油状的11 $\left( {{3.7}\mathrm{\;g},{93}\% }\right)$。${}^{1}\mathrm{H}$核磁共振(500 MHz，CDCl ${}_{3}$)δ 7.30 - 7.29(m，4H)，{7.24 - 7.22(m，1H)，4.46(s，2H)，3.74 - 3.51(m，14H)，${3.40}\left( {\mathrm{t}, J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}}\right) ,{3.30} - {3.28}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.18} - {3.09}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{2.22} - {2.14}\left( {\mathrm{\;m},1\mathrm{H}}\right)$，${2.12} - {2.05}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.94} - {1.88}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.85} - {1.60}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.54} - {1.16}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{1.09} - {0.97} \; \left( {\mathrm{m},2\mathrm{H}}\right) ,{0.93} - {0.89}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.86}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 138.7，128.2，127.5，127.4，80.9，79.6，76.3，72.8，70.9，70.2，69.6，69.1，62.0，61.9，61.8，46.6，46.2，42.5，41.7，39.5，35.4，35.1，34.9，34.7，3I.2，28.8，27.8，27.5，27.0，26.3，23.2，22.9，22.7，18.0，12.5；高分辨质谱(电喷雾飞行时间)计算值为${\mathrm{C}}_{37}{\mathrm{H}}_{60}{\mathrm{O}}_{7}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 617.4412，实测值为617.4414。

Compound 12 was prepared from 11 similarly to the synthesis of 5. 12: white solid; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl3) δ 7.77-7.73 (m, 6H), 7.33-7.23 (m, 11H), 4.50 (s, 2H), ${4.14} - {4.00}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{3.70} - {3.61}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.50} - {3.48}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.44}\left( {\mathrm{t}, J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}}\right)$ , ${3.39} - {3.33}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.29} - {3.27}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.06} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.40} - {2.37}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{2.07} - {1.92} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{1.85} - {1.13}\left( {\mathrm{\;m},{18}\mathrm{H}}\right) ,{1.06} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.93} - {0.85}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 144.7, 144.65, 144.63, 138.6, 132.9, 132.8, 132.7, 129.82, 129.76, 129.7, 128.2, 127.82, 127.75, 127.7, 127.5, 127.3, 81.4, 79.8, 76.5, 72.6, 70.9, 69.8, 69.4, 69.3, 66.2, 66.0, 65.1, 46.2, 46.1, 42.4, 41.4, 39.3, 35.4, 34.9, 34.6, 34.4, 32.0, 28.6, 27.8, 27.4, 27.2, 26.2, 22.9, 22.7, 21.5, 21.4, 17.6, 12.3; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{58}{\mathrm{H}}_{78}{\mathrm{O}}_{13}{\mathrm{\;S}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1079.4683, found 1079.4678.

化合物12由11制备，其合成方法与5类似。12:白色固体；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，氘代氯仿)δ 7.77 - 7.73(多重峰，6H)，7.33 - 7.23(多重峰，11H)，4.50(单峰，2H)，${4.14} - {4.00}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{3.70} - {3.61}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.50} - {3.48}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.44}\left( {\mathrm{t}, J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}}\right)$ ，${3.39} - {3.33}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.29} - {3.27}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.06} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.40} - {2.37}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{2.07} - {1.92} \; \left( {\mathrm{m},3\mathrm{H}}\right) ,{1.85} - {1.13}\left( {\mathrm{\;m},{18}\mathrm{H}}\right) ,{1.06} - {0.95}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.93} - {0.85}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(125兆赫兹，氘代氯仿)δ 144.7，144.65，144.63，138.6，132.9，132.8，132.7，129.82，129.76，129.7，128.2，127.82，127.75，127.7，127.5，127.3，81.4，79.8，76.5，72.6，70.9，69.8，69.4，69.3，66.2，66.0, 65.1, 46.2, 46.1, 42.4, 41.4, 39.3, 35.4, 34.9, 34.6, 34.4, 32.0, 28.6, 27.8, 27.4, 27.2, 26.2, 22.9, 22.7, 21.5, 21.4, 17.6, 12.3；高分辨质谱(电喷雾电离飞行时间)计算值${\mathrm{C}}_{58}{\mathrm{H}}_{78}{\mathrm{O}}_{13}{\mathrm{\;S}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$为1079.4683，实测值为1079.4678。

Compound 13 was prepared from 12 similarly to the synthesis of 6a-c. 13: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ): $\delta = {7.28} - {7.26}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{7.24} - {7.19}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.44}\left( {\mathrm{\;s},2\mathrm{H}}\right)$ , ${3.66} - {3.52}\left( {\mathrm{\;m},{45}\mathrm{H}}\right) ,{3.44} - {3.42}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.40} - {3.37}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.31} - {3.20}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.13} - {3.02} \; \left( {\mathrm{m},4\mathrm{H}}\right) ,{2.14} - {2.06}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.02} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.90} - {1.84}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.78} - {0.91}\left( {\mathrm{\;m},{19}\mathrm{H}}\right)$ , 0.90-0.86 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{0.82}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.58}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) : \delta = {138.7}$ , 128.3, 127.6, 127.4, 81.2, 80.0, 76.1, 72.8, 72.58, 72.55, 71.0, 70.9, 70.7, 70.64, 70.62, 70.59,70.54,70.52,70.48,70.47,70.31,70.30,70.26,67.9,67.8,67.0,61.6,46.5,46.1, 42.5, 41.8, 39.5, 35.4, 35.2, 34.9, 34.8, 32.2, 28.8, 27.9, 27.6, 27.3, 26.4, 23.0, 22.90, 22.86,17.7,12.4; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{55}{\mathrm{H}}_{96}{\mathrm{O}}_{16}{\left\lbrack {\mathrm{M}}^{ + }\mathrm{H}\right\rbrack }^{ + }$ 1013.6771, found 1013.6775.

化合物13由12制备，其合成方法与6a - c类似。13:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，CDCl ${}_{3}$ ):$\delta = {7.28} - {7.26}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{7.24} - {7.19}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{4.44}\left( {\mathrm{\;s},2\mathrm{H}}\right)$ ，${3.66} - {3.52}\left( {\mathrm{\;m},{45}\mathrm{H}}\right) ,{3.44} - {3.42}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.40} - {3.37}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.31} - {3.20}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{3.13} - {3.02} \; \left( {\mathrm{m},4\mathrm{H}}\right) ,{2.14} - {2.06}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.02} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.90} - {1.84}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.78} - {0.91}\left( {\mathrm{\;m},{19}\mathrm{H}}\right)$ ，0.90 - 0.86 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{0.82}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.58}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) : \delta = {138.7}$ ，128.3，127.6，127.4，81.2，80.0，76.1，72.8，72.58，72.55，71.0，70.9，70.7，70.64，70.62，70.59，70.54，70.52，70.48，70.47，70.31，70.30，70.26，67.9，67.8，67.0，61.6，46.5，46.1，42.5，41.8，39.5，35.4，35.2，34.9，34.8，32.2，28.8，27.9，27.6，27.3，26.4，23.0，22.90，22.86，17.7，12.4；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{55}{\mathrm{H}}_{96}{\mathrm{O}}_{16}{\left\lbrack {\mathrm{M}}^{ + }\mathrm{H}\right\rbrack }^{ + }$ 1013.6771，实测值为1013.6775。

Compound 14 was prepared from 13 similarly to the synthesis of 7a-c. 14: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl3) δ 7.34-7.31 (m, 4H), 7.28-7.23 (m, 1H), 4.48 (s, 2H), 3.80-3.77 $\left( {\mathrm{m},6\mathrm{H}}\right) ,{3.66} - {3.56}\left( {\mathrm{m},{34}\mathrm{H}}\right) ,{3.47} - {3.41}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.34} - {3.25}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.11} - {3.05}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ , 2.18-2.10 (m, 1H), 2.06-1.98 (m, 2H), 1.94-1.88 (m, 1H), 1.82-0.94 (m, 19H), 0.91-0.90 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{0.86}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{N}\mathrm{M}\mathrm{R}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 138.8,128.4,127.6, 127.5, 81.4, 80.2, 76.2, 72.9, 71.3, 71.2, 71.0, 70.83, 70.77, 70.73, 70.66, 70.6, 67.85, 67.80, 67.2, 46.6, 46.2, 42.6, 42.0, 39.7, 35.6, 35.4, 35.03, 34.98, 32.3, 30.42, 30.40, 29.0, 28.0, 27.7, 27.5, 26.5, 23.2, 23.1, 23.0, 17.8, 12.6; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{55}{\mathrm{H}}_{93}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{13}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1199.4245, found 1199.4241.

化合物 14 由 13 制备，方法与 7a - c 的合成类似。14:黄色油状物；${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl3) δ 7.34 - 7.31 (m, 4H)，7.28 - 7.23 (m, 1H)，4.48 (s, 2H)，3.80 - 3.77 $\left( {\mathrm{m},6\mathrm{H}}\right) ,{3.66} - {3.56}\left( {\mathrm{m},{34}\mathrm{H}}\right) ,{3.47} - {3.41}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.34} - {3.25}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.11} - {3.05}\left( {\mathrm{\;m},1\mathrm{H}}\right)$ ，2.18 - 2.10 (m, 1H)，2.06 - 1.98 (m, 2H)，1.94 - 1.88 (m, 1H)，1.82 - 0.94 (m, 19H)，0.91 - 0.90 $\left( {\mathrm{m},4\mathrm{H}}\right) ,{0.86}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{N}\mathrm{M}\mathrm{R}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 138.8、128.4、127.6、127.5、81.4、80.2、76.2、72.9、71.3、71.2、71.0、70.83、70.77、70.73、70.66、70.6、67.85、67.80、67.2、46.6、46.2、42.6、42.0、39.7、35.6、35.4、35.03、34.98、32.3、30.42、30.40、29.0、28.0、27.7、27.5、26.5、23.2、23.1、23.0、17.8、12.6；HRMS (ESI - TOF) 计算值 ${\mathrm{C}}_{55}{\mathrm{H}}_{93}{\mathrm{{Br}}}_{3}{\mathrm{O}}_{13}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 为 1199.4245，实测值为 1199.4241。

Compound 15 was prepared from the reaction of cyanuric acid and 14 similarly to the synthesis of 2 and 8a-c. 15: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 7.32-7.28 (m,4H), 7.26-7.21 (m, 1H), 4.46 (s, 2H), 4.14-4.01 (m, 5H), 3.75-3.52 (m, 41H), 3.41-3.39 (m, 3H), 3.31-3.17 (m, 3H), 3.04-2.99 (m, 1H), 2.15-2.00 (m, 3H), 1.92-1.86 (m, 1H), 1.78-0.92 (m, 19H), 0.89-0.86 (m, 4H), 0.83 (s, 3H), 0.60 (s, 3H); ${}^{13}\mathrm{C}$ NMR (125 MHz, ${\mathrm{{CDCl}}}_{3})\delta$ 149.08,149.06,138.7,128.3,127.6,127.4,81.0,79.8,76.3,72.8,71.1,71.0, 70.9,70.8,70.7,70.64,70.62,70.53,70.50,70.3,70.25,70.22,68.5,68.4,67.5,67.2, 46.6, 46.0, 42.5, 41.9, 41.83, 41.81, 39.5, 35.4, 35.3, 35.1, 34.8, 32.2, 28.9, 27.9, 27.6, 27.3, 26.4, 23.1, 22.9, 22.8, 17.9, 12.4; MS (ESI) calcd for ${\mathrm{C}}_{58}{\mathrm{H}}_{93}{\mathrm{\;N}}_{3}{\mathrm{O}}_{16}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1088.7, found 1088.7.

化合物15由氰尿酸和14反应制备，其合成方法与2和8a - c的合成类似。15:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫，${\mathrm{{CDCl}}}_{3}$)δ 7.32 - 7.28(m，4H)，7.26 - 7.21(m，1H)，4.46(s，2H)，4.14 - 4.01(m，5H)，3.75 - 3.52(m，41H)，3.41 - 3.39(m，3H)，3.31 - 3.17(m，3H)，3.04 - 2.99(m，1H)，2.15 - 2.00(m，3H)，1.92 - 1.86(m，1H)，1.78 - 0.92(m，19H), 0.89 - 0.86(m，4H)，0.83(s，3H)，0.60(s，3H)；${}^{13}\mathrm{C}$核磁共振(125兆赫，${\mathrm{{CDCl}}}_{3})\delta$ 149.08,149.06,138.7,128.3,127.6,127.4,81.0,79.8,76.3,72.8,71.1,71.0, 70.9,70.8,70.7,70.64,70.62,70.53,70.50,70.3,70.25,70.22,68.5,68.4,67.5,67.2, 46.6, 46.0, 42.5, 41.9, 41.83, 41.81, 39.5, 35.4, 35.3, 35.1, 34.8, 32.2, 28.9, 27.9, 27.6, 27.3, 26.4, 23.1, 22.9, 22.8, 17.9, 12.4；质谱(电喷雾电离)计算值为${\mathrm{C}}_{58}{\mathrm{H}}_{93}{\mathrm{\;N}}_{3}{\mathrm{O}}_{16}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1088.7，实测值为1088.7。

Synthesis of 16. Hydrogenation of $\mathbf{{15}}\left( {{240}\mathrm{{mg}},{0.22}\mathrm{{mmol}}}\right)$ in the presence of ${10}\% \mathrm{{Pd}}/\mathrm{C}$ catalyst was conducted in MeOH ( $5\mathrm{\;{mL}}$ ), giving 16 as a white solid ( ${219}\mathrm{{mg}},{99}\%$ ). ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl3) δ 4.05-4.01 (m, 6H), 3.65-3.49 (m, 42H), 3.39-3.37 (m, 1H), ${3.23} - {3.17}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.00} - {2.96}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.08} - {1.98}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.90} - {1.84}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.71} - {0.91} \; \left( {\mathrm{m},{19}\mathrm{H}}\right) ,{0.83} - {0.82}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.79}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.56}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 149.01,148.97,80.9,79.6,76.0,70.9,70.7,70.6,70.54,70.50,70.44,70.41,70.36,70.21, 70.19,70.1,68.4,68.1,67.44,67.38,67.0,63.3,46.2,46.0,42.5,41.79,41.75,41.7,39.4, 35.2, 35.1, 34.9, 34.7, 31.7, 29.1, 28.7, 27.8, 27.5, 27.2, 23.0, 22.8, 22.7, 17.8, 12.3; MS (ESI) calcd for ${\mathrm{C}}_{51}{\mathrm{H}}_{87}{\mathrm{\;N}}_{3}{\mathrm{O}}_{16}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{998.6}$ , found 998.6.

16的合成。在${10}\% \mathrm{{Pd}}/\mathrm{C}$催化剂存在下，于甲醇($5\mathrm{\;{mL}}$)中对$\mathbf{{15}}\left( {{240}\mathrm{{mg}},{0.22}\mathrm{{mmol}}}\right)$进行氢化反应，得到白色固体16(${219}\mathrm{{mg}},{99}\%$)。${}^{1}\mathrm{H}$核磁共振(500兆赫兹，氘代氯仿)δ 4.05 - 4.01(多重峰，6H)，3.65 - 3.49(多重峰，42H)，3.39 - 3.37(多重峰，1H)，${3.23} - {3.17}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.00} - {2.96}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.08} - {1.98}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.90} - {1.84}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.71} - {0.91} \; \left( {\mathrm{m},{19}\mathrm{H}}\right) ,{0.83} - {0.82}\left( {\mathrm{\;m},4\mathrm{H}}\right) ,{0.79}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.56}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \delta$ 149.01,148.97,80.9,79.6,76.0,70.9,70.7,70.6,70.54,70.50,70.44,70.41,70.36,70.21, 70.19,70.1,68.4,68.1,67.44,67.38,67.0,63.3,46.2,46.0,42.5,41.79,41.75,41.7,39.4, 35.2, 35.1, 34.9, 34.7, 31.7, 29.1, 28.7, 27.8, 27.5, 27.2, 23.0, 22.8, 22.7, 17.8, 12.3；质谱(电喷雾电离)计算值为${\mathrm{C}}_{51}{\mathrm{H}}_{87}{\mathrm{\;N}}_{3}{\mathrm{O}}_{16}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{998.6}$，实测值为998.6。

Synthesis of 17. To a solution of ${16}\left( {{200}\mathrm{{mg}},{0.2}\mathrm{{mmol}}}\right)$ in acetone $\left( {5\mathrm{\;{mL}}}\right)$ was added Jones reagent $\left( {{2.7}\mathrm{M},{0.22}\mathrm{{mL}},{0.6}\mathrm{{mmol}}}\right)$ . The reaction was stirred at ${0}^{ \circ }\mathrm{C}$ for ${0.5}\mathrm{\;h}$ before quenching with isopropanol. The solution was filtered through celite, washed with acetone, and then concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {20} : 1$ to 10:1) to give 17 as a white solid (170 mg, 84%). 1H NMR (600 MHz, CDCl3) 5 4.11-4.05 (m, 6H), 3.75-3.55 (m, 40H), 3.44-3.42 (m, 1H), 3.28-3.20 (m, 3H), 3.06-3.02 (m, 1H), 2.39-2.36 (m, 1H), 2.25-2.21 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.14} - {2.02}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.95} - {1.90}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.81} - {1.17}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.00} - {0.89}\left( {\mathrm{\;m},4\mathrm{H}}\right)$ , ${0.85}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 179.2},{149.18},{149.15},{81.0}$ , 79.9,76.2,71.1,70.9,70.79,70.75,70.72,70.69,70.64,70.63,70.58,70.34,70.32,68.5, 68.4,67.58,67.57,67.3,46.2,46.1,42.6,42.0,41.94,41.91,41.87,39.6,35.3,35.1,34.9, 30.8, 28.9, 28.0, 27.5, 27.4, 23.2, 23.0, 22.9, 17.6, 12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{51}{\mathrm{H}}_{85}{\mathrm{\;N}}_{3}{\mathrm{O}}_{17}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{1012.5951}$ , found 1012.5959.

17的合成。向丙酮$\left( {5\mathrm{\;{mL}}}\right)$中${16}\left( {{200}\mathrm{{mg}},{0.2}\mathrm{{mmol}}}\right)$的溶液中加入琼斯试剂$\left( {{2.7}\mathrm{M},{0.22}\mathrm{{mL}},{0.6}\mathrm{{mmol}}}\right)$。反应在${0}^{ \circ }\mathrm{C}$下搅拌${0.5}\mathrm{\;h}$，然后用异丙醇淬灭。溶液通过硅藻土过滤，用丙酮洗涤，然后真空浓缩。残余物通过硅胶柱色谱法(洗脱剂:${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}} = {20} : 1$至10:1)纯化，得到白色固体17(170mg，84%)。1H NMR(600MHz，CDCl3)δ4.11 - 4.05(m，6H)，3.75 - 3.55(m，40H)，3.44 - 3.42(m，1H)，3.28 - 3.20(m，3H)，3.06 - 3.02(m，1H)，2.39 - 2.36(m，1H)，2.25 - 2.21$\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.14} - {2.02}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.95} - {1.90}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.81} - {1.17}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.00} - {0.89}\left( {\mathrm{\;m},4\mathrm{H}}\right)$，${0.85}\left( {\mathrm{\;s},3\mathrm{H}}\right) ,{0.62}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{150}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) {\delta 179.2},{149.18},{149.15},{81.0}$，79.9,76.2,71.1,70.9,70.79,70.75,70.72,70.69,70.64,70.63,70.58,70.34,70.32,68.5, 68.4,67.58,67.57,67.3,46.2,46.1,42.6,42.0,41.94,41.91,41.87,39.6,35.3,35.1,34.9, 30.8, 28.9, 28.0, 27.5, 27.4, 23.2, 23.0, 22.9, 17.6, 12.5；高分辨质谱(电喷雾飞行时间)计算值为${\mathrm{C}}_{51}{\mathrm{H}}_{85}{\mathrm{\;N}}_{3}{\mathrm{O}}_{17}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{1012.5951}$，实测值为1012.5959。

Synthesis of triazide compounds 19a-c. To a solution of $\mathbf{{18a}}\left( {{4.6}\mathrm{\;g},{6.17}\mathrm{{mmol}}}\right)$ in DMSO $\left( {{20}\mathrm{\;{mL}}}\right)$ was added ${\mathrm{{NaN}}}_{3}\left( {{2.4}\mathrm{\;g},{37.02}\mathrm{{mmol}}}\right)$ . The reaction was heated at ${80}^{ \circ }\mathrm{C}$ overnight with stirring. After cooling, water was added and the solution was extracted with ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{100}\mathrm{\;{mL}} \times 3}\right)$ . The combined organic phases were washed with brine, dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: hexanes/EtOAc = 20:1 to 6:1) to give 19a as a colorless oil (2.3 g, 64%). ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl ${}_{3}$ ) δ 3.75-3.71 (m, 1H), 3.66-3.60 (m, 3H), 3.53-3.51 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{3.38} - {3.11}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{2.27} - {2.12}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.01} - {1.95}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.87} - {1.62}\left( {\mathrm{\;m},7\mathrm{H}}\right)$ , 1.55-1.45 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.39} - {1.11}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.05} - {0.88}\left( {\mathrm{m},9\mathrm{H}}\right) ,{0.84} - {0.81}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right)$ ; ${}^{13}\mathrm{C}$ NMR (125 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 91.1,90.0,87.5,87.2,87.0,86.6,61.5,61.3,61.1,56.5, 56.1, 52.1, 51.8, 49.6, 48.3, 45.6, 45.3, 44.9, 44.7, 38.9, 37.8, 37.7, 37.3, 33.4, 32.88, 32.86,29.3,27.9,24.7,22.4; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{30}{\mathrm{H}}_{51}{\mathrm{\;N}}_{9}{\mathrm{O}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{586.4187}$ , found 586.4176.

三叠氮化合物19a - c的合成。向二甲基亚砜$\left( {{20}\mathrm{\;{mL}}}\right)$中$\mathbf{{18a}}\left( {{4.6}\mathrm{\;g},{6.17}\mathrm{{mmol}}}\right)$的溶液中加入${\mathrm{{NaN}}}_{3}\left( {{2.4}\mathrm{\;g},{37.02}\mathrm{{mmol}}}\right)$。反应在${80}^{ \circ }\mathrm{C}$下搅拌加热过夜。冷却后，加入水，并用${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}\left( {{100}\mathrm{\;{mL}} \times 3}\right)$萃取溶液。合并的有机相用盐水洗涤，用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，并在真空中浓缩。残余物通过硅胶柱色谱法(洗脱剂:己烷/乙酸乙酯 = 20:1至6:1)纯化，得到无色油状的19a(2.3 g，64%)。${}^{1}\mathrm{H}$核磁共振(500兆赫兹，CDCl${}_{3}$)δ 3.75 - 3.71(多重峰，1H)，3.66 - 3.60(多重峰，3H)，3.53 - 3.51$\left( {\mathrm{m},1\mathrm{H}}\right) ,{3.38} - {3.11}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{2.27} - {2.12}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{2.01} - {1.95}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.87} - {1.62}\left( {\mathrm{\;m},7\mathrm{H}}\right)$，1.55 - 1.45$\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.39} - {1.11}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.05} - {0.88}\left( {\mathrm{m},9\mathrm{H}}\right) ,{0.84} - {0.81}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{0.64}\left( {\mathrm{\;s},3\mathrm{H}}\right)$；${}^{13}\mathrm{C}$核磁共振(125兆赫兹，${\mathrm{{CDCl}}}_{3}$)δ 91.1,90.0,87.5,87.2,87.0,86.6,61.5,61.3,61.1,56.5, 56.1, 52.1, 51.8, 49.6, 48.3, 45.6, 45.3, 44.9, 44.7, 38.9, 37.8, 37.7, 37.3, 33.4, 32.88, 32.86,29.3,27.9,24.7,22.4；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{30}{\mathrm{H}}_{51}{\mathrm{\;N}}_{9}{\mathrm{O}}_{3}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{586.4187}$，实测值为586.4176。

19b: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 3.77-3.73 (m,1H), 3.71-3.55 (m,15 H), 3.50-3.48 (m, 1H), 3.45-3.25 (m, 9H), 3.13-3.07 (m, 1H), 2.20-2.12 (m, 1H), 2.09-2.01 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.93} - {1.87}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {1.11}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.03} - {0.94}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.91} - {0.84}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$ , ${0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (125 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 81.3,80.3,76.4,71.2,71.0,70.8,70.2,70.1, 70.0,68.10,68.07,67.4,51.0,50.9,50.8,46.7,46.2,42.6,42.0,39.7,38.4,35.6,35.4 35.1, 35.0, 28.9, 28.0, 27.7, 27.4, 23.2, 22.9, 19.4, 17.9, 14.7, 12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{36}{\mathrm{H}}_{63}{\mathrm{\;N}}_{9}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{718.4974}$ , found 718.4973.

19b:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，${\mathrm{{CDCl}}}_{3}$)δ 3.77 - 3.73(多重峰，1H)，3.71 - 3.55(多重峰，15H)，3.50 - 3.48(多重峰，1H)，3.45 - 3.25(多重峰，9H)，3.13 - 3.07(多重峰，1H)，2.20 - 2.12(多重峰，1H)，第2.09 - 2.01 $\left( {\mathrm{m},2\mathrm{H}}\right) ,{1.93} - {1.87}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.83} - {1.11}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{1.03} - {0.94}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.91} - {0.84}\left( {\mathrm{\;m},{10}\mathrm{H}}\right)$，${0.63}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(125兆赫兹，${\mathrm{{CDCl}}}_{3}$)δ 81.3、80.3、76.4、71.2、71.0、70.8、70.2、70.1、70.0、68.10、68.07、67.4、51.0、50.9、50.8、46.7、46.2、42.6、42.0、39.7、38.4、35.6、35.4、35.1、35.0、28.9、28.0、27.7、27.4、23.2、22.9、19.4、17.9、14.7、12.5；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{36}{\mathrm{H}}_{63}{\mathrm{\;N}}_{9}{\mathrm{O}}_{6}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{718.4974}$，实测值为718.4973。

19c: yellow oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, ${\mathrm{{CDCl}}}_{3}$ ) δ 3.68-3.51 (m, ${28}\mathrm{H}$ ), 3.45-3.43 (m,1H), ${3.36} - {3.21}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.08} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.15} - {2.07}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.03} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.89} - {1.83} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.76} - {1.09}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{0.99} - {0.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.86} - {0.80}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 81.3, 80.1, 76.2, 71.0, 70.81, 70.75, 70.73, 70.69, 70.65, 70.63, 70.59, 69.98, 69.96, 67.9, 67.8, 67.1, 50.65, 50.63, 46.5, 46.1, 42.6, 41.9, 39.6, 38.3, 35.5, 35.3, 34.94, 34.87, 28.8, 27.9, 27.6, 27.4, 23.1, 22.92, 22.87, 19.2, 17.7, 14.6, 12.4; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{42}{\mathrm{H}}_{75}{\mathrm{\;N}}_{9}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + } : {850.5760}$ , found 850.5757.

19c:黄色油状物；${}^{1}\mathrm{H}$核磁共振(500兆赫兹，${\mathrm{{CDCl}}}_{3}$)δ 3.68 - 3.51(多重峰，${28}\mathrm{H}$)，3.45 - 3.43(多重峰，1个氢)，${3.36} - {3.21}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.08} - {3.02}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.15} - {2.07}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.03} - {1.96}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.89} - {1.83} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{1.76} - {1.09}\left( {\mathrm{\;m},{17}\mathrm{H}}\right) ,{0.99} - {0.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{0.86} - {0.80}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.59}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}$核磁共振(125兆赫兹，氯仿-d)δ 81.3、80.1、76.2、71.0、70.81、70.75、70.73、70.69、70.65、70.63、70.59、69.98、69.96、67.9、67.8、67.1、50.65、50.63、46.5、46.1、42.6、41.9、39.6、38.3、35.5、35.3、34.94、34.87、28.8、27.9、27.6、27.4、23.1、22.92、22.87、19.2、17.7、14.6、12.4；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{42}{\mathrm{H}}_{75}{\mathrm{\;N}}_{9}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + } : {850.5760}$，实测值为850.5757。

Typical Procedure for the Preparation of Cage Compounds 21a-c. Azide 19a (100 mg, 0.17 mmol) and alkyne ${20}^{47}\left( {{77}\mathrm{{mg}},{0.20}\mathrm{{mmol}}}\right)$ were mixed in $4\mathrm{\;{mL}}t - \mathrm{{BuOH}}$ and $2\mathrm{\;{mL}} \; {\mathrm{H}}_{2}\mathrm{O}$ . To the mixture was added ${\mathrm{{CuSO}}}_{4}\left( {{17}\mathrm{{mg}},{0.10}\mathrm{{mmol}}}\right)$ and sodium ascorbate (51.0 mg, 0.26 mmol). The reaction was stirred overnight at rt. After concentration in vacuo to remove most $t$ -BuOH, water was added and the solution was extracted using EtOAc (20 $\mathrm{{mL}} \times 3)$ . The combined organic phases were dried over ${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: ${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}}$ = 20:1 to 10:1) to give 21a as a colorless oil (108 mg, 66%). ${}^{1}\mathrm{H}$ NMR (500 MHz, ${\mathrm{{CDCl}}}_{3}$ ) $\delta \sim {7.89}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.78}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.73}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{4.62} - {4.35}\left( {\mathrm{\;m},{12}\mathrm{H}}\right) ,{4.22} - {4.16}\left( {\mathrm{\;m},6\mathrm{H}}\right)$ , ${3.96} - {3.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.82} - {3.68}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.57} - {3.48}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{3.42} - {3.38}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.16} - {3.14} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.85} - {2.81}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.70}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.60} - {1.10}\left( {\mathrm{\;m},{15}\mathrm{H}}\right) ,{1.06} - {0.96}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , ${0.84} - {0.74}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.58}\left( {\mathrm{\;d}, J = {10.0}\mathrm{\;{Hz}},3\mathrm{H}}\right) ,{0.49}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \; \delta = {158.3},{158.2},{142.3},{142.1},{142.0},{124.3},{124.2},{123.8},{81.0},{80.2},{76.6},{67.1},{66.7},{66.4},$ 62.0,61.9,50.71,50.66,50.5,46.8,45.9,44.4,44.3,44.2,42.5,41.4,39.41,39.37,39.2, 38.0, 35.1, 34.8, 34.7, 34.6, 28.6, 27.8, 27.4, 27.1, 22.8, 22.7, 19.3, 17.6, 14.3, 12.2; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{48}{\mathrm{H}}_{72}{\mathrm{\;N}}_{12}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{961.5618}$ , found 961.5612.

制备笼状化合物21a - c的典型步骤。将叠氮化物19a(100毫克，0.17毫摩尔)和炔烃${20}^{47}\left( {{77}\mathrm{{mg}},{0.20}\mathrm{{mmol}}}\right)$在$4\mathrm{\;{mL}}t - \mathrm{{BuOH}}$和$2\mathrm{\;{mL}} \; {\mathrm{H}}_{2}\mathrm{O}$中混合。向混合物中加入${\mathrm{{CuSO}}}_{4}\left( {{17}\mathrm{{mg}},{0.10}\mathrm{{mmol}}}\right)$和抗坏血酸钠(51.0毫克，0.26毫摩尔)。反应在室温下搅拌过夜。在真空中浓缩以除去大部分$t$ - 丁醇，加入水，并用乙酸乙酯(20 $\mathrm{{mL}} \times 3)$ )萃取溶液。合并的有机相用${\mathrm{{Na}}}_{2}{\mathrm{{SO}}}_{4}$干燥，过滤，并在真空中浓缩。残余物通过硅胶柱色谱法(洗脱剂:${\mathrm{{CH}}}_{2}{\mathrm{{Cl}}}_{2}/\mathrm{{MeOH}}$ = 20:1至10:1)纯化，得到无色油状的21a(108毫克，66%)。${}^{1}\mathrm{H}$核磁共振(500兆赫兹，${\mathrm{{CDCl}}}_{3}$ )$\delta \sim {7.89}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.78}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{7.73}\left( {\mathrm{\;s},1\mathrm{H}}\right) ,{4.62} - {4.35}\left( {\mathrm{\;m},{12}\mathrm{H}}\right) ,{4.22} - {4.16}\left( {\mathrm{\;m},6\mathrm{H}}\right)$ ，${3.96} - {3.94}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.82} - {3.68}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.57} - {3.48}\left( {\mathrm{\;m},7\mathrm{H}}\right) ,{3.42} - {3.38}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.16} - {3.14} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.85} - {2.81}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.80} - {1.70}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{1.60} - {1.10}\left( {\mathrm{\;m},{15}\mathrm{H}}\right) ,{1.06} - {0.96}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ ，${0.84} - {0.74}\left( {\mathrm{\;m},{10}\mathrm{H}}\right) ,{0.58}\left( {\mathrm{\;d}, J = {10.0}\mathrm{\;{Hz}},3\mathrm{H}}\right) ,{0.49}\left( {\mathrm{\;s},3\mathrm{H}}\right) ;{}^{13}\mathrm{C}\mathrm{{NMR}}\left( {{125}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}}\right) \; \delta = {158.3},{158.2},{142.3},{142.1},{142.0},{124.3},{124.2},{123.8},{81.0},{80.2},{76.6},{67.1},{66.7},{66.4},$ 62.0,61.9,50.71,50.66,50.5,46.8,45.9,44.4,44.3,44.2,42.5,41.4,3,39.41,39.37,39.2, 38.0, 35.1, 34.8, 34.7, 34.6, 28.6, 27.8, 27.4, 27.1, 22.8, 22.7, 19.3, 17.6, 14.3, 12.2；高分辨质谱(电喷雾飞行时间)计算值为${\mathrm{C}}_{48}{\mathrm{H}}_{72}{\mathrm{\;N}}_{12}{\mathrm{O}}_{9}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{961.5618}$ ，实测值为961.5612。

21b: colorless oil; ${}^{1}\mathrm{H}$ NMR ( ${500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}$ ) δ 7.75 (s,2H),7.71 (s,1H),4.52-4.40 (m, ${12}\mathrm{H}),{4.27} - {4.24}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{4.01} - {3.97}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.87} - {3.77}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.73}$ (t, $J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}$ ), ${3.64} - {3.59}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.55} - {3.44}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{3.30} - {3.26}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.23} - {3.19}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.09} - {3.05} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.16} - {2.09}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.05} - {1.98}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.87} - {1.60}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.48} - {1.44}\left( {\mathrm{\;m},2\mathrm{H}}\right)$ , 1.35-1.09 (m, 8H), 1.00-0.91 (m, 2H), 0.86-0.80 (m, 10H), 0.62 (s, 3H); ${}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 158.4, 142.5, 123.9, 123.8, 81.1, 80.1, 76.4, 70.9, 70.8, 70.7, 69.7, 69.3, 69.2, 68.1, 67.7, 67.1, 62.11, 62.09, 50.6, 50.4, 50.2, 46.9, 46.1, 44.7, 44.64, 44.61, 42.6, 41.7, 39.5, 39.4, 38.4, 35.4, 35.25, 35.17, 34.9, 28.8, 28.0, 27.6, 27.3, 23.2, 22.79, 22.75, 19.3,18.0,14.6,12.5; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{54}{\mathrm{H}}_{84}{\mathrm{\;N}}_{12}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1093.6404, found 1093.6408.

21b:无色油状物；${}^{1}\mathrm{H}$核磁共振(${500}\mathrm{{MHz}},{\mathrm{{CDCl}}}_{3}$)δ 7.75(单峰，2H)，7.71(单峰，1H)，4.52 - 4.40(多重峰，${12}\mathrm{H}),{4.27} - {4.24}\left( {\mathrm{\;m},6\mathrm{H}}\right) ,{4.01} - {3.97}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.87} - {3.77}\left( {\mathrm{\;m},3\mathrm{H}}\right) ,{3.73}$(三重峰，$J = {5.0}\mathrm{\;{Hz}},2\mathrm{H}$)，${3.64} - {3.59}\left( {\mathrm{\;m},9\mathrm{H}}\right) ,{3.55} - {3.44}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{3.30} - {3.26}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{3.23} - {3.19}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{3.09} - {3.05} \; \left( {\mathrm{m},1\mathrm{H}}\right) ,{2.16} - {2.09}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{2.05} - {1.98}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.87} - {1.60}\left( {\mathrm{\;m},8\mathrm{H}}\right) ,{1.48} - {1.44}\left( {\mathrm{\;m},2\mathrm{H}}\right)$，1.35 - 1.09(多重峰，8H)，1.00 - 0.91(多重峰，2H)，0.86 - 0.80(多重峰，10H)，0.62(单峰，3H)；${}^{13}\mathrm{C}$核磁共振(125兆赫兹，氯仿-d)δ 158.4，142.5，123.9，123.8，81.1，80.1，76.4，70.9，70.8，70.7，69.7，69.3，69.2，68.1，67.7，67.1，62.11，62.09，50.6，50.4，50.2，46.9，46.1，44.7，44.64，44.61，42.6，41.7，39.5，39.4，38.4，35.4，35.25，35.17，34.9，28.8，28.0，27.6，27.3，23.2，22.79，22.75，19.3，18.0，14.6，12.5；高分辨质谱(电喷雾电离飞行时间)计算值为${\mathrm{C}}_{54}{\mathrm{H}}_{84}{\mathrm{\;N}}_{12}{\mathrm{O}}_{12}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }$ 1093.6404，实测值为1093.6408。

21c: colorless oil; ${}^{1}\mathrm{H}$ NMR (500 MHz, CDCl3) δ 7.74 (s,3H),4.47-4.43 (m,12H), 4.23-4.20 (m, 6H), 3.80-3.77 (m, 6H), 3.58-3.48 (m, 29H), 3.26-3.17 (m, 3H), 3.03-2.99 $\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.08} - {2.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.97} - {1.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.81} - {1.76}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.72} - {1.35}\left( {\mathrm{\;m},9\mathrm{H}}\right)$ , 1.28-1.03 (m, 8H), 0.95-0.86 (m, 2H), 0.84-0.74 (m, 10H), 0.55 (s, 3H); ${}^{13}\mathrm{C}$ NMR (125 MHz, CDCl3) δ 158.30, 158.28, 142.4, 123.8, 81.2, 80.0, 76.0, 70.8, 70.6, 70.5, 70.44, 70.41,70.35,70.3,70.2,69.1,67.8,67.6,67.0,62.0,50.2,46.5,46.0,44.4,42.6,41.7, 39.4, 39.24, 39.22, 38.2, 35.3, 35.1, 34.9, 34.8, 28.7, 27.9, 27.5, 27.3, 22.9, 22.85, 22.78, 19.1,17.7,14.4,12.4; HRMS (ESI-TOF) calcd for ${\mathrm{C}}_{60}{\mathrm{H}}_{96}{\mathrm{\;N}}_{12}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{1225.7191}$ , found 1225.7192.

21c:无色油状物；${}^{1}\mathrm{H}$核磁共振氢谱(500兆赫兹，氘代氯仿)δ 7.74(单峰，3H)，4.47 - 4.43(多重峰，12H)，4.23 - 4.20(多重峰，6H)，3.80 - 3.77(多重峰，6H)，3.58 - 3.48(多重峰，29H)，3.26 - 3.17(多重峰，3H)，3.03 - 2.99$\left( {\mathrm{m},1\mathrm{H}}\right) ,{2.08} - {2.00}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.97} - {1.89}\left( {\mathrm{\;m},2\mathrm{H}}\right) ,{1.81} - {1.76}\left( {\mathrm{\;m},1\mathrm{H}}\right) ,{1.72} - {1.35}\left( {\mathrm{\;m},9\mathrm{H}}\right)$，1.28 - 1.03(多重峰，8H)，0.95 - 0.86(多重峰，2H)，0.84 - 0.74(多重峰，10H)，0.55(单峰，3H)；${}^{13}\mathrm{C}$核磁共振碳谱(125兆赫兹，氘代氯仿)δ 158.30，158.28，142.4，123.8，81.2，80.0，76.0，70.8，70.6，70.5，70.44，70.41，70.35，70.3，70.2，69.1，67.8，67.6，67.0，62.0，50.2，46.5，46.0，44.4，42.6，41.7，39.4，39.24，39.22，38.2，35.3，35.1，34.9，34.8，28.7，27.9，27.5，27.3，22.9，22.85，22.78，19.1，17.7，14.4，12.4；高分辨质谱(电喷雾电离飞行时间质谱)计算值为${\mathrm{C}}_{60}{\mathrm{H}}_{96}{\mathrm{\;N}}_{12}{\mathrm{O}}_{15}{\left\lbrack \mathrm{M} + \mathrm{H}\right\rbrack }^{ + }{1225.7191}$，实测值为1225.7192。

Supporting Information

支持信息

${}^{1}\mathrm{H}$ and ${}^{13}\mathrm{C}$ NMR spectra, and crystallographic information file (CIF) of compound 2. This material is available free of charge via the Internet at http://pubs.acs.org.

${}^{1}\mathrm{H}$ 和 ${}^{13}\mathrm{C}$ 化合物2的核磁共振谱以及晶体学信息文件 (CIF)。此材料可通过互联网免费获取，网址为http://pubs.acs.org。

Notes

注释

The authors declare no competing financial interests.

作者声明不存在相互竞争的财务利益。

Acknowledgments

致谢

We thank Drs. J. Rebek and D. Ajami for helpful discussions, and Dr. C. Moore at the UCSD X-ray crystallography facility for collecting crystal diffraction data. The work is supported by National Institutes of Health grant R01 GM098538.

我们感谢J. Rebek博士和D. Ajami博士的有益讨论，以及加州大学圣地亚哥分校X射线晶体学设施的C. Moore博士收集晶体衍射数据。这项工作得到了美国国立卫生研究院R01 GM098538基金的支持。

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