Evidence against the reactive rotamer explanation of the gem-dialkyl effect

Parrill, Abby L.; Dolata, Daniel P.

doi:10.1016/0040-4039(94)85303-7

Cited by 31 publications

(17 citation statements)

References 13 publications

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“…An extensive series of links of the type shown in eqn. (6) below has now been quantitatively investigated for ring-chain tautomerism in keto-carboxylic acid systems. 3-5*8* '' The order of increasing tendency to form ring tautomers for the links (keto-link-carboxylic acid) is: CH,CH, 4 1 ,2-CH,C6H, < C(CH3) < l,2-C6H, < cis-C(CH,)=CH < cis-C(CH3)=C-H, < 4,5-C14H8 < cis-CPh=CPh.…”

Section: Ring-chain Tautomerismmentioning

confidence: 99%

Ring-chain tautomerism. Part 8. Substituted 2-(2-oxopropyl) and 2-(2-oxo-2-phenylethyl)benzoic and 2-(2-acetyl and 2-benzoylphenyl)acetic acids

Bowden¹,

Byrne²

1996

J. Chem. Soc., Perkin Trans. 2

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Section: Ring-chain Tautomerismmentioning

confidence: 99%

Ring-chain tautomerism. Part 8. Substituted 2-(2-oxopropyl) and 2-(2-oxo-2-phenylethyl)benzoic and 2-(2-acetyl and 2-benzoylphenyl)acetic acids

Bowden¹,

Byrne²

1996

J. Chem. Soc., Perkin Trans. 2

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“…In addition to the Thorpe-Ingold explanation, other hypotheses have emerged focusing on medium and larger ring formations 11-14. Shifts in conformer populations upon methylation can help favor ring formation, and the significance of the small change in bond angles, ca.…”

Section: Introductionmentioning

confidence: 99%

Thorpe−Ingold Acceleration of Oxirane Formation Is Mostly a Solvent Effect

Kostal

Jorgensen

2010

J. Am. Chem. Soc.

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The Thorpe-Ingold hypothesis for the gem-dimethyl effect in the cyclization reactions of 2-chloroethoxide derivatives has been investigated computationally in the gas phase and in aqueous solution. Ab initio MP2/6-311+G(d,p) and CBS-Q calculations reveal little intrinsic difference in reactivity with increasing α-methylation for the series of reactants 1 -3. However, inclusion of continuum hydration or of explicit hydration through mixed quantum and statistical mechanics (MC/FEP) simulations does reproduce the substantial, experimentally observed rate increases with increasing α-methylation. Analysis of the MC/FEP results provides clear evidence that the rate increases stem primarily from increased steric hindrance to hydration of the nucleophilic oxygen atom with increasing α-methylation. Thus, the gem-dimethyl acceleration of oxirane formation for 1 -3 is found to be predominantly a solvent effect.

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“…Thus, the piperidine derivatives are conformationally [10] restricted in a way that favours lactonization. [11] The equilibrium constant for the lactonization of -proline derivatives and the pipecolic acid derivatives must be nearly the same as the cyclic strain and it is not expected to change for either type of equilibrium that exists between the bicy- We explored the possibility of converting bicyclic lactones 14a,b and 15a into the desired piperidine derivatives. Whereas the use of BH 3 ·SMe 2 resulted in only the recovery of the starting material (20 or 60°C), the reduction of 14a,b and 15a with LiAlH 4 (3 h, 60°C) gave inseparable tarry materials.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Glycosidase Inhibitory Activities of Pyrrolidines and Piperidines with N‐(Polyhydroxyalkyl) Side Chains

et al. 2007

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Amidification of L‐proline (3) with (+)‐(R,R)‐6 and (–)‐(S,S)‐tartaric anhydride diacetate (7) gave N‐substituted L‐proline derivatives 8a,b, respectively. Acids 8a,b were transformed into diesters 9a,b with MeOH/HCl. Similar reactions with methyl (2S,4R)‐4 and (2R,4S)‐4‐acetoxypipecolate (5) led to bicyclic lactams 14a,b and 15a. Compounds 8a,b were converted into N‐(trihydroxybutyl)pyrrolidine derivatives 8c,d, 10a,b and 11a,b. Methyl (2S,4R)‐20a and (2R,4S)‐4‐acetoxy‐N‐[(2S,3S)‐1,2,3‐trihydroxybutyl]pipecolate (20b) were obtained by displacement of (–)‐(2S,2S)‐2‐O‐benzyl‐3,4‐O‐isopropylidene‐1‐deoxy‐1‐iodothreitol (19) by 4 and 5. Compounds 20a,b were converted into (2S,4R,2′S,2′S)‐21a and(2R,4S,2′S,3′S)‐4‐hydroxy‐2‐hydromethyl‐N‐(2‐benzyloxy‐3,4‐isopropylidenedioxy)piperidine (21b) and finally into unprotected pentols 22a,b. Nonprotected (2S,2′S,3′S)‐11a and (2S,2′R,3′R)‐N‐(1,2,3‐trihydroxybutyl)prolinol (11b), as well as 22a,b, did not inhibit any of the 13 glycosidases assayed. However, a triacetoxy derivative, (2S,3S)‐2,3‐diacetoxy‐4‐[(2R,4S)‐4‐acetoxy‐2‐(methoxycarbonyl)piperidin‐1‐yl]‐4‐oxobutanoic acid (13b) is an inhibitor (IC50 = 157 μM) of α‐L‐fucosidase from bovine kidney.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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Evidence against the reactive rotamer explanation of the gem-dialkyl effect

Cited by 31 publications

References 13 publications

Ring-chain tautomerism. Part 8. Substituted 2-(2-oxopropyl) and 2-(2-oxo-2-phenylethyl)benzoic and 2-(2-acetyl and 2-benzoylphenyl)acetic acids

Ring-chain tautomerism. Part 8. Substituted 2-(2-oxopropyl) and 2-(2-oxo-2-phenylethyl)benzoic and 2-(2-acetyl and 2-benzoylphenyl)acetic acids

Thorpe−Ingold Acceleration of Oxirane Formation Is Mostly a Solvent Effect

Synthesis and Glycosidase Inhibitory Activities of Pyrrolidines and Piperidines with N‐(Polyhydroxyalkyl) Side Chains

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