Enantioselective Catalysis with<scp>s‐Block</scp>Organometallics

Stegner, Philipp; Harder, Sjoerd

doi:10.1002/9783527818020.ch10

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…24 Throughout the evolution of these lithiation-substitution sequences, the generality and applicability of this approach has been well demonstrated for substrates that incorporate Lewis basic (directing) or anion stabilizing subunits. 25 For example, ortho-lithiations in aromatic systems not only emerged as the go to method for substitution reactions but also played a major role in the advancement of NMR techniques for organometallic structure determinations. 26 In addition, enantioselective α-lithiations of saturated nitrogen heterocycles later evolved as a critical strategy in the synthesis of building blocks for drug discovery in the early 1980s.…”

Section: Direct Lithiation (Path A) Vs Complex-induced Proximity Lith...mentioning

confidence: 99%

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

Crockett

Piña

Nguyen

et al. 2022

Preprint

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The selective functionalization of saturated oxygen heterocycles at positions remote to the embedded heteroatoms remains an outstanding challenge in organic synthesis. Although many methods exist for the undirected replacement of C–H bonds with heteroatomic subunits the number of site selective C–H functionalization reactions for the introduction of carbon-carbon bonds pales in comparison. This paper describes the initial stages of a long-term program aimed at elucidating how organolithium reagents can be re-engineered to selectively deprotonate and functionalize saturated heterocycles at new locations. Through rigorous NMR spectroscopic investigations, it was determined for the first time that the addition of Lewis basic phosphoramides can shift the equilibrium of strong organolithium bases, such as t-BuLi, to include the triple ion pair (t-Bu–Li–t-Bu) / L4Li which serves as a reservoir for the highly reactive separated ion pair t-Bu / L4Li . Because the Li-atom’s valences are saturated the Lewis acidity is significantly decreased and the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp3-CH bonds to be deprotonated. In certain cases, this enabled the removal of stronger C–H bonds in the presence of weaker C–H bonds. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol (lithium nucleophilic coupling – “LiNC”) of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.

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Section: Direct Lithiation (Path A) Vs Complex-induced Proximity Lith...mentioning

confidence: 99%

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

Crockett

Piña

Nguyen

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The widespread application of organolithium reagents can be ascribed to their innate ability to predictably transform organic substrates into organolithium compounds, priming them to be further functionalized. , Throughout the evolution of these lithiation-substitution sequences, the generality of this approach has been well demonstrated for substrates that incorporate Lewis basic (directing) or anion stabilizing subunits . For example, directed α-lithiations of heterocycles emerged as a critical strategy for the synthesis of building blocks in drug discovery (Figure A) .…”

Section: Introductionmentioning

confidence: 99%

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

et al. 2023

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The effects of Lewis basic phosphoramides on the aggregate structure of t-BuLi have been investigated in detail by NMR and DFT methods. It was determined that hexamethylphosphoramide (HMPA) can shift the equilibrium of t-BuLi to include the triple ion pair (t-Bu–Li–t-Bu)−/HMPA4Li+ which serves as a reservoir for the highly reactive separated ion pair t-Bu–/HMPA4Li+. Because the Li-atom’s valences are saturated in this ion pair, the Lewis acidity is significantly decreased; in turn, the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp3 C–H bonds to be deprotonated. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.

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Enantioselective Catalysis withs‐BlockOrganometallics

Cited by 2 publications

References 42 publications

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

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