The barrier to enantiomerization and dynamic resolution of N-Boc-2-lithiopiperidine and the effect of TMEDA

Coldham, Iain; Leonori, Daniele; Beng, Timothy K.; Gawley, Robert E.

doi:10.1039/b911024k

Cited by 26 publications

(43 citation statements)

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“…16 The stoichiometric DTR of rac - 7 by 8 in the presence of 2 equivalents of TMEDA has a large negative entropy of activation and a small enthalpy of activation (ΔH ‡ = 4.3±0.5 kcal/mol; ΔS ‡ = −55.9±1.8 cal/mol·K). The enantiomerization of 7 in the presence of 1 equivalent of TMEDA has ΔH ‡ = 18.1±0.7 kcal/mol and ΔS ‡ = 5.0±3.2 cal/mol·K.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously determined that enantioenriched 7 is configurationally stable at −80 °C. 16 Four spectra were obtained, and are shown in Figure 6 (~1 h accumulation time in each case). Most noticeably, the 1:1:1 triplet indicating a contact ion pair comprising one carbon and one lithium atom is evident in all four spectra.…”

Section: Resultsmentioning

confidence: 99%

“…We therefore sought another system for investigation, and chose 2-lithio- N -Boc-piperidine, 7 , shown to undergo stoichiometric resolution by the Coldham group in the presence of TMEDA (Scheme 4), 5f and whose inversion dynamics were investigated jointly by our two groups. 16 …”

Section: Introductionmentioning

confidence: 99%

“…Also, several other diamine ligands were tested, but failed to fill this catalytic role in the resolution – even TEEDA (tetraethyl ethylenediamine)! 16 …”

Section: Introductionmentioning

confidence: 99%

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Dynamics of Catalytic Resolution of 2-Lithio-N-Boc-piperidine by Ligand Exchange

et al. 2012

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The dynamics of the racemization, catalytic and stoichiometric dynamic resolution of 2-lithio-N-Boc-piperidine, 7, have been investigated. The kinetic order in TMEDA, for both racemization and resolution of the title compound, and the kinetic order in resolving ligands, have been determined. The catalytic dynamic resolution is 0.5-order in chiral ligand 8, 0.265 order in chiral ligand 10, and second order in TMEDA. The X-ray crystal structure of ligand 10 shows it to be an octamer. Dynamic NMR studies of the resolution process were obtained. Some of the requirements for a successful catalytic dynamic resolution by ligand exchange have been identified.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Also, several other diamine ligands were tested, but failed to fill this catalytic role in the resolution – even TEEDA (tetraethyl ethylenediamine)! 16 …”

Section: Introductionmentioning

confidence: 99%

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Dynamics of Catalytic Resolution of 2-Lithio-N-Boc-piperidine by Ligand Exchange

et al. 2012

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“…In contrast, treatment of the less hindered trimethyltin derivative 2ah with n-BuLi/ TMEDAw as much more successful and yielded [D]-1a in excellent yield and with complete stereoselectivity and retention of configuration (entries 3a nd 4), indicating that 2ah could indeed serve as au seful precursor to the corresponding organolithium species. [8] An understanding of the configurational stability of chiral organolithium species is crucial for exploiting their use in synthesis. [3,9] Interestingly,t he tertiary a-O-substituted organolithium species Li-1 were found to be chemically and configurationally stable below À40 8 8Cb ut at higher temperatures,d ecomposition rather than racemization occurred.…”

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Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary α‐Oxy‐ and α‐Thio‐Substituted Organolithium Species

et al. 2017

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Nonstabilized a-O-substituted tertiary organolithium species are difficult to generate,and the a-S-substituted analogues are configurationally unstable.W en ow report that they can both be generated easily and trapped with arange of electrophiles with high enantioselectivity,p roviding ready access to ar ange of enantioenriched tertiary alcohols and thiols.T he configurational stability of the a-S-organolithium species was enhanced by using aless coordinating solvent and short reaction times.Chiral a-heteroatom (O,N ,a nd S)-substituted organolithium compounds are av ersatile class of nucleophiles that are useful in the asymmetric synthesis of chiral alcohols, amines,a nd thiols.[1] Although the use of secondary and mesomerically stabilized (e.g., benzylic and allylic) tertiary a-O-and a-S-substituted organolithium reagents in synthesis is well established, [1c-e] the use of non-mesomerically stabilized (i.e., dialkyl-substituted) tertiary reagents is not. This discontinuity is due to contrasting problematic features governing a-O-and a-S-substituted organolithium species. Nonstabilized tertiary a-O-organolithium compounds are configurationally stable but are difficult to generate owing to their reduced kinetic acidity (Scheme 1B); [1e, 2] tertiary a-Sorganolithium species are easily formed but are not configurationally stable (Scheme 1A). To apply a-O/S-substituted organolithium compounds in asymmetric synthesis,both ease of generation and configurational stability are essential requirements. [1a-d,3] Through variation of the directing group,b ase,s olvent, and additives we discovered reaction conditions enabling the stereospecific deprotonation of secondary dialkyl benzoates (TIB esters) [4] and demonstrated their configurational stability in lithiation-borylation reactions.[5] Herein, we report the broad applicability of these novel enantioenriched nucleophiles in reactions with ab road range of electrophiles.I n addition, we have discovered reaction conditions for the generation of enantioenriched, tertiary,n onstabilized a-Sorganolithium compounds and report their subsequent trapping with electrophiles in high enantioselectivity (Scheme 1C).Boronic esters represent an iche class of electrophiles, [6] and therefore,w ei nitially embarked on as tudy of the trapping of tertiary a-O-substituted organolithium species, which were generated by lithiation of the enantioenriched TIB esters 1a-1e,w ith ar ange of electrophile classes (Scheme 2). Upon exposure of av ariety of enantioenriched benzoates to sec-BuLi and TMEDAinCPME at À60 8 8C, the corresponding organolithium species Li-1a-1e were generated. Pleasingly,L i-1a-1e were successfully trapped with ar ange of electrophiles,i ncluding methyl chloroformate (2aa), benzoyl chloride (2ab), isocyanates (2ac and 2ad), aldehydes (2ae and 2af), and trialkyl tin chlorides (2ag, 2ah, 2ba-2ea). Reactions with aldehydes gave mixtures of diastereomers (see 2ae and 2af)b ut in the case of PhCHO,h igh Scheme 1. A, B) Previous studies regardingnonstabilized tert...

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Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

Degennaro¹,

Musio²,

Luisi³

2014

Lithium Compounds in Organic Synthesis

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IntroductionNitrogen-containing compounds are ubiquitous and are extremely important in synthesis. This chapter reports some general aspects of the generation, structure, and reactivity of nitrogen-bearing organolithiums showing the progress made over the last decade. The chapter does not cover comprehensively the field but the aim is to provide the reader with useful information on the generation, reactivity, and potential in synthesis of this kind of lithiated intermediates.Throughout the chapter, the name amino-organolithiums is used to describe reactive intermediates lithiated at sp 3 -hybridized carbon atoms adjacent (α) to a nitrogen atom that could be included also in a ring. Amino-organolithiums can be generated mainly in three different ways: (i) deprotonation of a parent amine or its derivative; (ii) transmetallation by using an alkyllithium; and (iii) reductive cleavage of C-heteroatom bond (e.g., C-S). Each way has advantages and disadvantages and in some cases they complement each other (Scheme 7.1).Direct deprotonation is a widely used strategy to generate amino-organolithiums even in chiral form, while tin-lithium exchange reactions are preferred when direct deprotonations are difficult (high kinetic barrier) or regiochemical issues apply. Concerning the direct deprotonation of amines, this is not a simple task because the corresponding lithiated intermediates suffer from destabilizing interactions that make this reaction very difficult unless a ''stabilizing group'' (SG) is introduced either on the nitrogen atom or on the lithium-bearing carbon (Scheme 7.2).The SG (Scheme 7.2) has a pivotal role, either reducing the kinetic barrier in the hydrogen/lithium permutation or stabilizing the organolithium mesomerically or by coordination. For these reasons, often, amino-organolithiums are classified as stabilized or unstabilized. The chemistry of unstabilized amino-organolithiums has been so far less developed however, lithiation of simple tertiary amines could be accomplished by two main strategies: (i) by tin/lithium exchange reaction and (ii) by deprotonation of quaternary ammonium complexes (Scheme 7.3).

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The barrier to enantiomerization and dynamic resolution of N-Boc-2-lithiopiperidine and the effect of TMEDA

Cited by 26 publications

References 27 publications

Dynamics of Catalytic Resolution of 2-Lithio-N-Boc-piperidine by Ligand Exchange

Dynamics of Catalytic Resolution of 2-Lithio-N-Boc-piperidine by Ligand Exchange

Asymmetric Synthesis of Tertiary Alcohols and Thiols via Nonstabilized Tertiary α‐Oxy‐ and α‐Thio‐Substituted Organolithium Species

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

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