Stereoselective synthesis of α,α-chlorofluoro carbonyl compounds leading to the construction of fluorinated chiral quaternary carbon centers
Stereoselective synthesis of α,α-chlorofluoro carbonyl compounds leading to the construction of fluorinated chiral quaternary carbon centers
复制标题
DOI：
10.1002/anie.200801682
复制
发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Yamamoto, Hisashi
中科院分区：
文献类型：
--
作者：
Shibatomi, Kazutaka;Yamamoto, Hisashi
含氟有机分子的制备在医药和农业化学领域引起了相当大的关注。[1]用于获得这些分子的最具挑战性的合成操作之一是氟化手性碳中心的立体选择性构建。[2]为此目的开发了各种立体选择性亲电氟化试剂。[3]继Hintermann和Togni的研究之后，[4a]报道了高效的β-酮酯的催化不对称氟化反应。[4B，e]有机催化不对称氟化反应也已成功地实现了醛的不对称α-氟化反应。[5]尽管不对称α-氟化反应领域正在稳步发展，仍然需要一条灵活的路线来构建含氟季碳中心的立体选择性结构。我们建议合成具有光学活性的α，α-氯氟羰基化合物，这些化合物可以通过亲核取代反应立体选择性地转化为含氟季碳的各种手性分子(方案1)。令人惊讶的是，关于光学活性α，α-氯氟羰基化合物的合成[6]或它们的选择性转化的研究还很少。[7]在这里，我们首次从简单的醛或酮中合成了α，α-氯氟羰基化合物，并随后将其转化为各种光学活性分子，其中氟化的季碳中心与羰基相邻。我们的初步研究集中在有机催化不对称合成α，α-氯氟醛。根据我们的合成计划(方案1)，简单的α氟化或羰基化合物的氯化之后是不对称α卤化反应，这将引入另一个卤素取代基(Cl或F)，并将生成光学活性的α，α-氯氟羰基化合物。我们选择α-氯醛作为前驱体，因为它们可以很容易地从简单的醛合成。[8]如表1所示，以外消旋α，α-氯醛(RAC-1)和N-氟丁二酰亚胺(NFSI)为原料，以高的对映选择性(Er值从91：9到99：1)成功地合成了各种α-氯氟醛3。
The preparation of fluorine-containing organic molecules has attracted considerable attention in the field of pharmaceutical and agricultural chemistry.[1] One of the most challenging synthetic operations used to access these molecules is the stereoselective construction of a fluorinated chiral carbon center.[2] Various stereoselective electrophilic fluorination reagents have been developed for this purpose.[3] Following a study by Hintermann and Togni,[4a] efficient catalytic asymmetric fluorination reactions of β-ketoesters have been reported.[4b, e] Organocatalytic enantioselective α-fluorination reactions of aldehydes have also been successfully realized.[5] Although the field of asymmetric α-fluorination is progressing steadily, a flexible route for the stereoselective construction of fluorinated quaternary carbon centers is still required. We propose the synthesis of optically active α, α-chlorofluoro carbonyl compounds, which can be stereoselectively converted into various chiral molecules with a fluorinated quaternary carbon by nucleophilic substitution (Scheme 1). Surprisingly little attention has been given to the synthesis of optically active α, α-chlorofluoro carbonyl compounds [6] or their selective transformation.[7] Herein, we disclose the first enantioselective synthesis of α, α-chlorofluoro carbonyl compounds from simple aldehydes or ketones, and their subsequent transformation into a variety of optically active molecules in which the fluorinated quaternary carbon center is adjacent to the carbonyl group.Our initial studies focused on the organocatalytic asymmetric synthesis of α, α-chlorofluoro aldehydes. According to our synthetic plan (Scheme 1), simple α fluorination or chlorination of carbonyl compounds would be followed by asymmetric α halogenation, which introduces another halogen substituent (Cl or F), and would provide optically active α, α-chlorofluoro carbonyl compounds. We chose α-chloroaldehydes 1 as precursors because they can be easily synthesized from simple aldehydes.[8] As summarized in Table 1, various α, α-chlorofluoro aldehydes 3 were successfully synthesized with high enantioselectivity (er values ranging from 91: 9 to> 99: 1) from racemic α-chloroaldehydes (rac-1) and N-fluorosuccinimide (NFSI)