β-取代色氨酸合成方法及其在Maremycins和TMC-95A的合成应用研究

β-Substituted tryptophans are important building blocks in the assembly of bioactive natural products. For example, β-methyl tryptophan is biosynthetic precursor of maremycin A and B, and TMC-95A-D contain the β-hydroxyl tryptophan moiety. Stereospecific synthesis of these structures is a huge synthetic challenge which has attracted considerable interests. We proposed herein to develop a Palladium-catalyzed alkylation of C(sp3)-H bonds using secondary alkyl bromides or iodides as the alkylation reagents. The synthesis of β-methyl tryptophans and β-hydroxyl tryptophans via sequential C(sp3)-H bonds activation will be carried out by using this alkylation reaction as key method. We will also apply this sequential C(sp3)-H bonds activation strategy to the total synthesis of maremycin A/B and the formal synthesis of TMC-95A. This represents an atom- and step-economical route compared to other strategies.

β-取代色氨酸广泛存在于具有生物活性的天然产物中，例如生物碱maremycin A和B含有β-甲基色氨酸，蛋白酶体抑制剂TMC-95A-D中含有β-羟基色氨酸片段，此类分子的合成极具挑战性。我们拟发展钯催化的以仲烷基溴代物或碘代物为烷基化试剂的sp3碳氢键活化反应，并以此为关键反应，采用串联sp3碳氢键活化的策略，构建β-甲基色氨酸和β-羟基色氨酸。最终，我们将该串联碳氢键活化反应用于maremycin A和B的全合成以及TMC-95A的形式合成。与已有策略相比，该合成路线具有原子经济性和步骤经济性的优点。

通过该项目的实施，针对以碳氢键活化为关键反应合成β-取代色氨酸的研究开展工作，并最终以串联sp3碳氢键芳基化/甲基化为关键反应，线性14步，总产率9.3%完成了maremycin A和B的发散全合成。在项目资助下，发表标注基金号论文3篇，撰写英文专著章节2章。在此工作启发下，我们也以sp3碳氢键芳基化和吲哚2位碳氢键异戊烯基化位关键反应，完成了吲哚类生物碱tryprostatin A的全合成。