近年来，基于自由基的偶联反应获得了快速的发展，相对于传统的过渡金属催化的偶联反应，它具有独特的化学反应特性。例如，基于自由基的两亲电试剂之间的交叉还原偶联反应，两亲核试剂之间的氧化偶联反应等。随着自由基参与的偶联反应的深入研究，自由基化学在有机合成中的应用也越来越多。但应用在复杂天然产物的全合成研究中则具有很大的挑战性，主要的原因是：（1）许多产生自由基的方法不适用于复杂底物；（2）自由基的反应活性高，在复杂底物上其反应的可预测性差，难以控制。本论文以天然产物全合成为导向，发展了两个基于自由基化学的合成方法学：（1）以简单易制备的酰基咪唑类化合物为底物，在镍的催化作用下与芳基/烷基溴代物发生还原偶联形成酮类化合物，并成功的应用于药物分子托卡硼和一个呋喃二萜的合成；（2）发现TEMPO能调控自由基[3+2]环化反应的进程，并成功地构建出对映-贝壳杉烷型和贝叶烷类二萜分子骨架中[3.2.1]桥环结构。利用此策略合成了11个具有不同氧化态的含[3.2.1]桥环结构的四环二萜天然产物。本论文基于此，分为两部分进行探究。

第一部分探究镍催化的酰基咪唑与烷基/芳基溴代物还原偶联形成酮的研究：我们发现一级、二级和三级酰基咪唑，在以NiI₂为催化剂、二联吡啶为配体、Zn为还原剂、ZnBr₂为添加剂、DMF为溶剂的条件下，60 ℃反应20小时，能广泛地与各种芳基溴代物、烷基溴代物以及杂芳环溴代物偶联，以中等到良好的收率形成酮类化合物。详细的机理研究发现位阻较小的一级、二级酰基咪唑通过自由基的方式切断酰胺C-N键，而位阻较大的三级酰胺通过氧化加成的方式切断酰胺C-N键。

第二部分探究TEMPO调控的自由基[3+2]环化反应构建对映-贝壳杉烷型和贝叶烷类二萜分子骨架中[3.2.1]桥环结构的研究。[3.2.1]桥环上有多个手性中心，空间结构拥挤，是合成这类二萜天然产物的难点。我们发现以高烯丙基三级醇草酸甲酯为原料，Zn为还原剂，PBI为配体，DMA作为溶剂，在TEMPO和路易斯酸MgCl₂和TMSCl的作用下，与丙烯酸苄酯在40 ℃反应16小时以中等收率得到[3.2.1]桥环结构。详细的机理研究表明TEMPO在调控该自由基串联环化反应中起到关键作用。在该反应体系下，TEMPO很快被还原成Zn(TEMPO)₂，接着选择性地与反应过程中位阻较小的自由基中间体发生S_H2反应形成烷基锌试剂，然后从配体PBI或者后处理的过程中获得一个氢原子生成目标产物。运用该策略，我们成功地合成了10个具有不同氧化态的对映-贝壳杉烷型二萜类天然产物和1个贝叶烷类天然产物。

In recent years, radical-based coupling reactions have gained rapid development with unique chemical reactivity relative to traditional transition metal-catalyzed coupling reactions. For example, the free radical-based cross-reductive coupling reaction between two electrophiles, and oxidative cross coupling between two nucleophiles. With the in-depth study of coupling reactions involving free radicals, the application of free radical chemistry in organic synthesis is also increasing. However, the application in the total synthesis of complex natural products is very challenging. The main reasons are: (1) Many methods for generating free radicals are not suitable for complex substrates; (2) The predictability of radical reactions on complex substrates is poor and difficult to control due to the high reactivity of free radicals. In this thesis, oriented to the total synthesis of natural products, two radical-based synthesis methodologies were developed: (1) Nickel catalyzed reductive cross-coupling of easily-prepared acyl-imidazolides with aryl/alkyl bromides to form ketones via amide C-N bond activation, and successfully applied this method to the synthesis of a furan diterpene and the precursor of drug Tolcapone; (2) It was found that TEMPO can regulate the process of free radical [3+2] cyclization reaction, and successfully constructed the [3.2.1] bridged ring structure in the molecular skeleton of ent-kaurane and beyerane diterpenoids. Using this strategy, 11 different oxidation states tetracyclic diterpene natural products with [3.2.1] bridged ring structures were synthesized. Based on this, this thesis is divided into two parts.

The first part introduces the nickel-catalyzed reductive cross-coupling reaction of acyl imidazolides with alkyl/aryl bromides: We found that primary, secondary and tertiary alkyl acyl imidazolides can be coupled with various aryl bromides, alkyl bromides as well as heteroaromatic bromides to form ketones in moderate to good yields under the reaction conditions of NiI₂ as catalyst, bipyridine as ligand, Zn as reducing agent, ZnBr₂ as additive, DMF as solvent, and reacted at 60 °C for 20 hours. The detailed mechanism study found that the sterically less-hindered acyl imidazolides undergo C–N bond cleavage by single-electron transfer, whereas sterically encumbered acyl imidazoles go through C–N bond cleavage via oxidative addition (two-electron process).

The second part introduces the TEMPO-mediated free radical [3+2] cyclization reaction to construct the [3.2.1] bridged ring structure in the ent-kaurane and beyerane diterpenoids molecular frameworks. There are multiple chiral centers on the [3.2.1] bridge ring, and the spatial structure is crowded, which is the difficulty in synthesizing these diterpene natural products. We found that using homoallyl tertiary alcohol methyl oxalate as raw material, Zn as reductant, PBI as ligand, DMA as solvent, under the action of TEMPO, Lewis acid MgCl₂ and TMSCl, reacted with benzyl acrylate at 40 °C for 16 hours gave the bicyclo[3.2.1]octane motif in moderate yield. Detailed mechanistic studies revealed that TEMPO plays a key role in regulating the radical [3+2] cyclization reaction. Under this reaction system, TEMPO was quickly reduced to Zn(TEMPO)₂, and then selectively reacted with less steric hindrance free radical intermediates to obtain the target product via SH2 pathway. Using this strategy, we successfully synthesized 10 ent-kaurane and one beyerane diterpenoids.