Steering together all four Ugi pieces The nearly 60-year-old Ugi reaction is a remarkably efficient means of linking together four molecular building blocks: an aldehyde, an amine, a carboxylic acid, and an isocyanide. Because each component is independently tunable, the reaction is especially well suited to the assembly of diverse compound libraries. However, stereoselectivity has been a challenge. Zhang et al. now show that chiral phosphoric acids can catalyze the four-component coupling with high enantioselectivity (see the Perspective by Riva). Theory suggests that a hydrogen-bonded complex involving the phosphoric acid and carboxylic acid sets the stereochemistry for isocyanide attack on an imine intermediate. Science, this issue p. eaas8707; see also p. 1072 A chiral phosphoric acid derivative enantioselectively links together an aldehyde, a carboxylic acid, an amine, and an isocyanide. INTRODUCTION The four-component Ugi reaction (Ugi-4CR) assembles peptide-like α-acylaminoamides through one-pot reaction of a carbonyl compound, an amine, an acid, and an isocyanide. Ugi-4CR is well suited for diversity-oriented synthesis applicable in drug discovery, as it facilitates rapid access to diverse libraries of biologically important molecules. The high step economy and atom efficiency of the reaction, as well as its convergent nature, foster its wide use in the synthesis of heterocyclic scaffolds, natural products, macrocycles, polymers, and other target molecules. Despite these practical advantages, the long-standing stereochemical challenges of the Ugi reaction have yet to be fully addressed. Consequently, access to chiral Ugi products for drug candidate exploration is hindered. RATIONALE The chiral phosphoric acid (CPA) framework was targeted as a catalyst for asymmetric Ugi-4CR. The heightened acidity of CPAs over carboxylic acids is perceived to accelerate the kinetics of the enantioselective Ugi reaction so as to outcompete the background reaction. Also, self-assembled heterodimerization between the CPA and carboxylic acid brings about a dual effect: enhanced acidity of the catalyst and nucleophilicity of the carboxylic acid. Both of these favor the catalytic enantioselective Ugi-4CR. A myriad of well-established or custom CPAs with well-defined chiral pockets could be readily applied, potentially leading to complete stereocontrol. A CPA that could suppress the Passerini and other side reactions would enable rapid imine formation and its preferential activation over the carbonyl group. RESULTS A catalytic asymmetric Ugi-4CR was accomplished with 1,1′-spirobiindane-7,7′-diol (SPINOL)–derived CPA4 and CPA6 as organocatalysts. The reaction exhibited broad substrate compatibility and good to excellent enantioselectivity [up to 99% enantiomeric excess (ee)]. Activation of the imine might be accomplished by CPA–carboxylic acid heterodimer catalysis via a bifunctional activation mode, which was supported by experiments (carboxylic acids with varying pKa values and steric properties yielded products with a range of ee values) and density functional theory (DFT) calculations (lowest energy among all the considered activation modes). The calculated free energy profile for the catalytic Ugi reaction gave three CPA-combined key transition states, which highlighted the bifunctional property of the CPA. In the favored enantio-determining transition states, the aryl groups fit into the pocket formed by the two substituents (cyclohexyl rings) of the catalyst, revealing the importance of noncovalent interactions in controlling the stereochemical outcome of this reaction. CONCLUSION This operationally simple one-pot enantioselective Ugi-4CR harnesses inherent benefits of multicomponent reaction and organocatalysis to access up to 86 enantioenriched α-acylaminoamides, which are otherwise challenging to obtain via conventional methods, from four achiral building blocks in excellent yields and enantioselectivities. DFT calculations gave a detailed catalytic mechanism, especially with respect to activation modes and enantio-determining transition states. Because amide functionality constitutes the defining primary linkage in proteins, we foresee multiple uses of this asymmetric four-component Ugi protocol for the synthesis of chiral peptides and components of natural products. We also anticipate that this work will initiate the further development of asymmetric multicomponent chemistry. Design and exploration of catalytic asymmetric Ugi-4CR. The Ugi reaction constructs α-acylaminoamide compounds by combining an aldehyde or ketone, an amine, a carboxylic acid, and an isocyanide in a single flask. Its appealing features include inherent atom and step economy together with the potential to generate products of broad structural diversity. However, control of the stereochemistry in this reaction has proven to be a formidable challenge. We describe an efficient enantioselective four-component Ugi reaction catalyzed by a chiral phosphoric acid derivative that delivers more than 80 α-acylaminoamides in good to excellent enantiomeric excess. Experimental and computational studies establish the reaction mechanism and origins of stereoselectivity.

中文翻译：

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不对称磷酸催化的四组分 Ugi 反应

将所有四个 Ugi 部分结合在一起 将近 60 年历史的 Ugi 反应是将四个分子结构单元连接在一起的非常有效的方法：醛、胺、羧酸和异氰化物。由于每个组件都是独立可调的，因此该反应特别适合组装不同的化合物库。然而，立体选择性一直是一个挑战。张等人。现在表明手性磷酸可以以高对映选择性催化四组分偶联（参见 Riva 的观点）。理论表明，涉及磷酸和羧酸的氢键配合物设定了异氰化物攻击亚胺中间体的立体化学。科学，这个问题 p。eaas8707; 另见第。1072 手性磷酸衍生物对映选择性地将醛连接在一起，羧酸、胺和异氰化物。引言 四组分 Ugi 反应 (Ugi-4CR) 通过羰基化合物、胺、酸和异氰化物的一锅反应组装肽样 α-酰基氨基酰胺。Ugi-4CR 非常适合适用于药物发现的面向多样性的合成，因为它有助于快速访问不同的生物重要分子库。该反应的高步骤经济性和原子效率，以及其收敛性，促进了其在杂环支架、天然产物、大环、聚合物和其他目标分子的合成中的广泛应用。尽管有这些实际优势，但 Ugi 反应长期存在的立体化学挑战尚未得到充分解决。因此，阻碍了获得用于候选药物探索的手性 Ugi 产品。基本原理 手性磷酸 (CPA) 框架被用作不对称 Ugi-4CR 的催化剂。CPA 比羧酸更高的酸度被认为会加速对映选择性 Ugi 反应的动力学，从而胜过背景反应。此外，CPA 和羧酸之间的自组装异二聚化带来了双重效果：提高了催化剂的酸度和羧酸的亲核性。这两者都有利于催化对映选择性 Ugi-4CR。可以很容易地应用无数成熟或定制的具有明确手性口袋的 CPA，从而可能导致完全立体控制。可以抑制 Passerini 和其他副反应的 CPA 将能够快速形成亚胺并优先激活羰基。结果 用 1,1'-spirobiindane-7,7'-diol (SPINOL) 衍生的 CPA4 和 CPA6 作为有机催化剂完成了催化不对称 Ugi-4CR。该反应表现出广泛的底物相容性和良好的对映选择性[高达 99% 的对映体过量 (ee)]。亚胺的活化可以通过 CPA-羧酸异二聚体催化通过双功能激活模式来完成，这得到了实验（具有不同 pKa 值和空间性质的羧酸产生具有一系列 ee 值的产物）和密度泛函理论（DFT）的支持) 计算（所有考虑的激活模式中最低的能量）。催化 Ugi 反应的计算自由能曲线给出了三个 CPA 组合的关键过渡态，这突出了 CPA 的双功能特性。在有利的对映体决定过渡态中，芳基适合由催化剂的两个取代基（环己基环）形成的口袋，揭示了非共价相互作用在控制该反应的立体化学结果中的重要性。结论 这种操作简单的一锅对映选择性 Ugi-4CR 利用多组分反应和有机催化的固有优势，以优异的产率和对映选择性从四个非手性构件中获得多达 86 种富含对映体的 α-酰基氨基酰胺，否则通过常规方法难以获得。DFT 计算给出了详细的催化机制，特别是在激活模式和对映确定过渡态方面。因为酰胺功能构成了蛋白质中的主要连接，我们预见到这种不对称四组分 Ugi 方案可用于合成手性肽和天然产物组分的多种用途。我们还预计这项工作将启动不对称多组分化学的进一步发展。催化不对称 Ugi-4CR 的设计与探索。Ugi 反应通过在单个烧瓶中结合醛或酮、胺、羧酸和异氰化物来构建 α-酰基氨基酰胺化合物。其吸引人的特点包括固有的原子和阶梯经济以及产生广泛结构多样性产品的潜力。然而，在该反应中控制立体化学已被证明是一项艰巨的挑战。我们描述了一种由手性磷酸衍生物催化的高效对映选择性四组分 Ugi 反应，该反应可提供超过 80 种 α-酰基氨基酰胺，且对映体过量。实验和计算研究确定了立体选择性的反应机制和起源。