Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalytic Cascade Reactions under Curtin–Hammett Conditions

Observations of nonlinear
effects of catalyst enantiopurity on
product enantiomeric excess in asymmetric catalysis are often used
to infer that more than one catalyst species is involved in one or
more reaction steps. We demonstrate here, however, that in the case
of asymmetric catalytic cascade reactions, a nonlinear effect may
be observed in the absence of any higher order catalyst species or
any reaction step involving two catalyst species. We illustrate this
concept with an example from a recent report of an organocatalytic
enantioselective [10 + 2] stepwise cyclization reaction. The disruption
of pre-equilibria (Curtin–Hammett equilibrium) in reversible
steps occurring prior to the final irreversible product formation
step can result in an alteration of the final product ee from what would be expected based on a linear relationship with
the enantiopure catalyst. The treatment accounts for either positive
or negative nonlinear effects in systems over a wide range of conditions
including “major-minor” kinetics or the more conventional
“lock-and-key” kinetics. The mechanistic scenario proposed
here may apply generally to other cascade reaction systems exhibiting
similar kinetic features and should be considered as a viable alternative
model whenever a nonlinear effect is observed in a cascade sequence
of reactions.

在不对称催化（asymmetric catalysis）领域，研究者常借助对催化剂对映体纯度（catalyst enantiopurity）与产物对映体过量值（enantiomeric excess, ee）之间非线性效应的观测结果，推断单步或多步反应过程中存在多种催化剂活性物种。然而本文证实，在不对称催化级联反应（asymmetric catalytic cascade reactions）体系中，即便不存在高阶催化剂物种或涉及双催化剂物种的反应步骤，同样可观测到非线性效应。我们以近期发表的一项有机催化（organocatalytic）对映选择性[10+2]分步环化反应的研究报道为例，阐释了这一概念。在最终不可逆产物生成步骤之前的可逆步骤中，若预平衡（pre-equilibria，即寇顿-哈米特平衡（Curtin–Hammett equilibrium））被打破，最终产物的ee值将偏离基于纯对映催化剂的线性关系预期。该理论可解释涵盖"major-minor"动力学与更常规"lock-and-key"动力学在内的多种体系中的正、负非线性效应。本文提出的机理模型可普遍适用于其他具备相似动力学特征的级联反应体系，且在反应级联序列中观测到非线性效应时，应将其作为一种可行的替代机理模型加以考量。