Mechanism of Lithium Diisopropylamide-Mediated Ester Deprotonation:  The Role of Disolvated Monomers

Sun, Xiufeng; Kenkre, Sarita L.; Remenar, Julius F.; Gilchrist, James H.; Collum, David B.

doi:10.1021/ja970406k

Cited by 49 publications

(28 citation statements)

References 12 publications

(13 reference statements)

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“…There is strong evidence for precomplexation between lithium amide bases and carbonyl compounds prior to the proton transfer event in enolization reactions. 43–46 …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Pinnatoxins A and G and Revision of the Mode of Action of Pinnatoxin A

Aráoz¹,

Servent

Molgó³

et al. 2011

J. Am. Chem. Soc.

123

141

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Pinnatoxins belong to an emerging class of potent marine toxins of the cyclic imine group. Detailed studies of their biological effects have been impeded by unavailability of the complex natural product from natural sources. This work describes the development of a robust, scalable synthetic sequence relying on a convergent strategy that delivered a sufficient amount of the toxin for detailed biological studies and its commercialization for use by other research groups and regulatory agencies. A central transformation in the synthesis is the highly diastereoselective Ireland–Claisen rearrangement of a complex α,α-disubstituted allylic ester based on a unique mode for stereoselective enolization through a chirality match between the substrate and the lithium amide base. With synthetic pinnatoxin A, a detailed study has been performed that provides conclusive evidence for its mode of action as a potent inhibitor of nicotinic acetylcholine receptors selective for the human neuronal α7 subtype. The comprehensive electrophysiological, biochemical, and computational studies support the view that the spiroimine subunit of pinnatoxins is critical for blocking nicotinic acetylcholine receptor subtypes, as evidenced by analyzing the effect of a synthetic analogue of pinnatoxin A containing an open form of the imine ring. Our studies have paved the way for the production of certified standards to be used for mass-spectrometric determination of these toxins in marine matrices and for the development of tests to detect these toxins in contaminated shellfish.

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“…There is strong evidence for precomplexation between lithium amide bases and carbonyl compounds prior to the proton transfer event in enolization reactions. 43–46 …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Pinnatoxins A and G and Revision of the Mode of Action of Pinnatoxin A

Aráoz¹,

Servent

Molgó³

et al. 2011

J. Am. Chem. Soc.

123

141

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“…In the absence of any specific kinetic evidence indicating deprotonation via an open-dimer mechanism, I chose to computationally investigate the reaction of cyclopropylnitrile 5b and monomeric LiNH 2 . It is worth noting that although LDA in solution exists primarily as dimers and higher oligomers, Collum and co-workers [19][20][21] have kinetically established the intermediacy of mono-and disolvated LDA monomers in ester deprotonation and dehydrohalogenation reactions. Finally, although solvation is well known to have an important influence on organolithium structure, energy, and reactivity, [22][23][24][25][26][27][28][29] in this initial study solvent-free structures were examined.…”

Section: Resultsmentioning

confidence: 99%

Configurational stability of chiral lithiated cyclopropylnitriles: A density functional study

Carlier

2003

Chirality

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Chiral, configurationally stable lithiated nitriles would be valuable intermediates for asymmetric carbon-carbon bond-forming reactions. To gain insight into the design of such species, Walborsky's attempted enantioselective deprotonation/trapping reactions of a chiral cyclopropylnitrile were studied computationally up to the MP2(fc)/6-31+G* and B3LYP/6-31+G* levels. Investigation of cyclopropylnitrile/LiNH(2) deprotonation transition structures demonstrated a significant (20-23 kcal/mol) kinetic preference for N-lithiation, and a facile (4-6 kcal/mol barrier) "conducted tour" racemization pathway for the N-lithiated nitrile product. Addition of a model directing group (formyl) to the beta-carbon of the cyclopropyl ring is predicted to significantly favor C-lithiation over N-lithiation, both kinetically and thermodynamically. Thus, chiral beta-Lewis base substituted cyclopropylnitriles may serve as precursors to chiral, configurationally stable organolithium reagents.

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“…In the former case, Hayes and coworkers performed mechanistic studies using HF and MP2 calculations to distinguish between deprotonation reaction paths involving monomers and those involving dimers. It was concluded that a route containing solvated monomers was preferred over the route involving dimers [106], in accordance with kinetic data [107,108]. In the late 1990s and the early years of this millennium, the group of Ahlberg and coworkers studied the reaction mechanism of the epoxide deprotonation using a combination of kinetic experiments, natural abundance deuterium NMR, and computational techniques.…”

Section: Lithium Alkoxides and Lithium Amidesmentioning

confidence: 71%

Computational Perspectives on Organolithiums

Lill

Sten²

2014

Lithium Compounds in Organic Synthesis

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Mechanism of Lithium Diisopropylamide-Mediated Ester Deprotonation: The Role of Disolvated Monomers

Cited by 49 publications

References 12 publications

Total Synthesis of Pinnatoxins A and G and Revision of the Mode of Action of Pinnatoxin A

Total Synthesis of Pinnatoxins A and G and Revision of the Mode of Action of Pinnatoxin A

Configurational stability of chiral lithiated cyclopropylnitriles: A density functional study

Computational Perspectives on Organolithiums

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