Catalytic Asymmetric Diastereodivergent Deracemization
Catalytic Asymmetric Diastereodivergent Deracemization
复制标题
DOI：
10.1002/anie.201106321
复制
发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
Maulide, Nuno
中科院分区：
文献类型：
--
作者：
Luparia, Marco;Oliveira, Maria Teresa;Maulide, Nuno
尽管不对称催化在过去几十年中蓬勃发展，[1]大多数对映体纯化合物的大规模制备仍然依赖于外消旋体的拆分技术，其中一半的起始材料被浪费。相反，外消旋体的催化“去外消旋化”，导致理论上100%产率的对映体纯产物，是一种有吸引力的替代策略。[2]在催化去外消旋化方法中，对映会聚过程、动态动力学拆分（DKR）和动态动力学不对称转化（DYKAT）是最常用的方法（方案1）。值得注意的是，所有这些现有技术允许获得最多两种不同的产物（产物P的两种对映异构体）。钯催化的烯丙基烷基化反应（也称为Tsuji-Trost反应）是一种用于形成C13 C键的强大而通用的合成工具，在过去几年中已被详尽地研究。[3，4]其教科书机制通常涉及两个不同的立体定向步骤（方案2a）：1）通过钯催化剂电离烯丙基亲电体，其进行转化，随后2）亲核攻击，其是亲核依赖性的：“不稳定”亲核试剂（通俗地称为“硬”）倾向于攻击金属中心，通过还原消除导致保留，而“稳定的”碳亲核试剂（通常称为“软”）导致具有反转配置的外层攻击。[5]由于所谓的“软”亲核试剂是迄今为止最常用的，这导致了钯催化烯丙基烷基化的著名的“双反转=保留”教科书规则。[3，6-11]我们在此报道了通过钯催化的烯丙基烷基化的前所未有的非对映异构体配体控制的去外消旋化概念，其提供了通过偏离“双反转”规则形成的产物的每一种可能的立体异构体的潜在途径。我们建议将该过程命名为“非对映异构体去外消旋化”（方案2 B）。我们已经报道了顺式取代的环丁烯2的外消旋立体选择性合成，其中应变外消旋内酯1（易于从2-吡喃酮以定量产率制备）[12]作为关键底物（方案3）。[13]鉴于观察到的高非对映选择性时，三苯基膦（PPh 3）作为配体，我们研究了可能性的deracemization 1的对映体纯的手性配体的作用。[4]在我们的配体筛选开始时，我们惊讶地获得了可变量的顺式和反式二取代的环丁烯产物，这取决于所采用的配体（参见支持信息）。值得注意的是，
Despite the blossoming of asymmetric catalysis over the last few decades,[1] the majority of large-scale preparations of enantiopure compounds still rely on resolution techniques of racemates, wherein half of the starting material is wasted. In contrast, the catalytic “deracemization” of a racemate, leading to a theoretical 100% yield of enantiomerically pure product, is an attractive alternative strategy.[2] Enantioconvergent processes, dynamic kinetic resolution (DKR) and dynamic kinetic asymmetric transformation (DYKAT) are the most popular among catalytic deracemization methods (Scheme1). Notably, all these state-of-the-art techniques allow a maximum of two different products to be obtained (the two enantiomers of the product P). The palladium-catalyzed allylic alkylation (also known as the Tsuji–Trost reaction) is a powerful and versatile synthetic tool for CÀC bond formation that has been exhaustively studied over the past years.[3, 4] Its textbook mechanism typically involves two distinct, stereospecific steps (Scheme 2a): 1) the ionization of the allylic electrophile by the palladium catalyst, which proceeds with inversion, followed by 2) nucleophilic attack, which is nucleophile-dependent:“non-stabilized” nucleophiles (colloquially referred to as “hard”) tend to attack the metal center, leading to retention through reductive elimination whereas “stabilized” carbon nucleophiles (typically referred to as “soft”) lead to outersphere attack with inversion of configuration.[5] Since socalled “soft” nucleophiles are by far the most often employed, this led to the celebrated “double inversion= retention” textbook rule for palladium-catalyzed allylic alkylation.[3, 6–11] We report herein on an unprecedented diastereodivergent ligand-controlled deracemization concept through palladiumcatalyzed allylic alkylation, that offers potential access to each one of the possible stereoisomers of the product formed by deviating from the “double-inversion” rule. We propose the name “diastereodivergent deracemization” for this process (Scheme 2 b).We have already reported a racemic stereoselective synthesis of cis-substituted cyclobutenes 2, in which the strained racemic lactone 1 (readily prepared from 2-pyrone in quantitative yield)[12] featured as the pivotal substrate (Scheme 3).[13] Given the high diastereoselectivities observed when triphenylphosphine (PPh3) was employed as a ligand, we investigated the possibility of deracemization of 1 by the action of an enantiopure chiral ligand.[4] At the onset of our ligand screening, we were surprised at obtaining both cis-and trans-disubstituted cyclobutene products in variable amounts, depending on the ligand employed (see Supporting Information). Notably, phosphoramidites