Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Department of Chemistry, Dnipropetrovsk National University, Dnipropetrovsk 49010, Ukraine.
Nat Chem. 2014 Feb;7(2):171-7. doi: 10.1038/nchem.2150. Epub 2015 Jan 12.
5-Endo-trig cyclizations are generally considered to be kinetically unfavourable, as described by Baldwin's rules. Consequently, observation of this mode of reaction under kinetic control is rare. This is usually ascribed to challenges in achieving appropriate approach trajectories for orbital overlap in the transition state. Here, we describe a highly enantio- and diastereoselective route to complex indanes bearing all-carbon quaternary stereogenic centres via a 5-endo-trig cyclization catalysed by a chiral ammonium salt. Through computation, the preference for the formally disfavoured 5-endo-trig Michael reaction over the formally favoured 5-exo-trig Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group, which outweigh the importance of the approach trajectory as embodied by Baldwin's rules. Our experimental and theoretical findings demonstrate that geometric and stereoelectronic constraints may not be decisive in the observed outcome of irreversible ring-closing reactions.
5-endo-trig 环化反应通常被认为是动力学不利的，这符合鲍德温规则的描述。因此，在动力学控制下观察到这种反应模式是很少见的。这通常归因于在过渡态中实现轨道重叠的适当接近轨迹的挑战。在这里，我们描述了一种通过手性季铵盐催化的高度对映选择性和非对映选择性的途径，来合成具有全碳季碳立体中心的复杂茚满，通过计算表明，对于形式上不利的 5-endo-trig Michael 反应相对于形式上有利的 5-exo-trig Dieckmann 反应的偏好，是由于亲核基团的固有选择性的热力学贡献所致，这超过了鲍德温规则所体现的接近轨迹的重要性。我们的实验和理论发现表明，几何和立体电子约束在不可逆的闭环反应的观察结果中可能不是决定性的。
