Complex Induced Proximity Effect (CIPE)

• Overview: Predicts the stereochemistry of nucleophilic addition reactions involving carbonyl groups adjacent to chelating groups (e.g., hydroxyl, methoxy).
• Key Idea: Chelation by a metal ion restricts conformational freedom, leading to predictable stereochemical outcomes.
• Example: Chelation-controlled aldol reactions.

Complex‐Induced Proximity Effect (CIPE) is a phenomenon that enhances deprotonation in organic reactions. CIPE involves the transient formation of complexes that bring reactive sites into proximity, facilitating selective and efficient transformations. The concept has roots in organolithium chemistry and builds on the pioneering work on directed ortho metalation (DoM). Mechanistic studies highlight CIPE's role in regioselective and stereoselective reactions by analyzing experimental data, including isotope labeling and kinetic measurements. This understanding enables advancements in synthesizing complex organic molecules, such as natural products and functional materials.

• CIPE enhances deprotonation by forming transient complexes between organolithium bases and substrates.
• Mechanistic studies validate CIPE as a two-step process, involving complexation followed by proton transfer.
• CIPE directs regioselectivity in lithiation reactions, enabling synthetic control over complex organic transformations.
• Case studies, including natural product syntheses, highlight CIPE’s practical applications.
• Computational and structural analyses provide a deeper understanding of CIPE’s mechanistic nuances.

In General

The genral CIPE proceeds as follows.  The association of 1 with an organolithium reagent forms the complex 2. Directed lithiation of 2 via intermediate 3 leads to the formation of 4, which can then react with an electrophile to yield 5 (Scheme 1). Examples of CIPE include not only deprotonative mono- and dilithiations but also heteroatom–lithium exchanges, innovative displacements, and additions.

Examples

ortho-metalation

Treatment of 7a with LDA results in the formation of 6 through a directed lithiation followed by an anionic ortho-Fries rearrangement. In contrast, for 7b or 7c, the typical metalation site is inaccessible. As a result, deprotonation occurs on the remote ring, driven by the thermodynamic preference arising from the initial complexation between the directing group and the organolithium reagent.

Asymmetric Alkylations

A CIPE can be operative in both the formation and the reaction of an organolithium intermediate.  A CIPE can influence both the formation and the subsequent reactions of an organolithium intermediate. For example, dilithiation of compound 13 proceeds through intermediate 14 to yield 15. In contrast, lithiation of ethylbenzene, which serves as a model for benzylic lithiation in the absence of a complexing group, predominantly results in metalation of the aromatic ring. The reaction of 15 with methyl iodide produces compound 16 with high diastereoselectivity (91:9).

The diastereoselectivity arises not during the initial dilithiation but instead during the methylation step, which represents an asymmetric substitution involving the remote stereogenic center of the carbanion and the stereogenic center adjacent to the nitrogen atom. Complexation between the centers and the lithium atom brings them into close proximity, creating a stereochemical influence. This influence leads to an energy difference between competing transition states, resulting in enrichment of the diastereomer.