School of Chemistry, University of Bristol , Cantock's Close, BS8 1TS, United Kingdom.
J Am Chem Soc. 2017 Aug 30;139(34):11877-11886. doi: 10.1021/jacs.7b05457. Epub 2017 Aug 16.
The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.
硼酸酯的立体选择性试剂控制同系化反应是少数可重复的合成转化之一，如果实现自动化，就可以成为真正的分子制造机器的基础。最近，α-锡基三异丙基苯甲酸酯和α-亚磺酰基氯化物已成为硼酸酯迭代同系化的有用构建块。然而，α-锡基苯甲酸酯需要使用大量难以获得且昂贵的手性二胺 sparteine 的（+）或（-）对映异构体来制备；此外，这些构建块以及同系化过程中生成的副产物被认为具有毒性。另一方面，α-亚磺酰基氯化物难以制备高对映体纯度，并且在同系化反应条件下容易发生有害的酸碱副反应，导致立体选择性低。在这里，我们表明，使用这两种构建块的混合物，即α-亚磺酰基三异丙基苯甲酸酯，在很大程度上克服了上述缺点。通过用 Andersen 容易获得的薄荷衍生的亚磺酸盐的 α-镁化苯甲酸酯与任一对映体进行磺酰化反应，或者用对映纯的 S-手性 α-亚磺酰基苯甲酸酯进行α-烷基化反应，我们已经制备了一系列高对映体纯的单取代和二取代的α-亚磺酰基苯甲酸酯，其中一些带有敏感的官能团。开发了 Barbier 型反应条件，允许这些构建块在硼酸酯的存在下转化为锂（t-BuLi）和镁（i-PrMgCl·LiCl）卡宾，从而实现高效和高立体特异性的同系化反应。使用镁卡宾可以在引入敏感官能团（如烷基/芳基卤化物、叠氮化物和酯）的情况下增长碳链。使用对空间位阻不太敏感的锂卡宾可以形成空间位阻较大的碳-碳键。我们还表明，这些构建块可以在三到四步迭代同系化过程中连续使用，无需进行柱层析分离，即可获得具有非常高的对映选择性和非对映选择性的连续取代的碳链。
