Gem-Dialkyl effect

The gem-dialkyl effect as a function of ring size relative EM s for the formation of small rings... 

The main problem a peptide chemist has to tackle with CMetrasubstituted a-amino acids is their rather poor reactivity in peptide-bond formation due to steric hindrance at the a-carbon. In addition, during the activation process of the carboxylic function of peptides and urethane or amide N-protected derivatives, an intramolecular reaction leading to the oxazoI -5 (4 //) -on e heterocyclic skeleton is greatly favored by the gem-dialkyl effect (Scheme... 

The oxazol-5(4//)-one coupling method (Scheme 4) is uniquely appropriate for C -tetra-substituted a-amino acids, since racemization or epimerization is unlikely to occur with these compounds. It represents the main methodology exploitable for fragment condensation of peptides based on C -tetrasubstituted a-amino acids. Due to the gem-dialkyl effect on the C°... 

A facilitated transition hypothesis has been suggested to replace the reactive rotamer hypothesis as an explanation for the gem-dialkyl effect in intramolecular cyclization reactions.59... 

Jung, M. E. Gervay, J. gem-Dialkyl effect in the intramolecular Diels-Alder reaction of 2-fur-furyl methyl fumarates the reactive rotamer effect, enthalpic basis for acceleration, and evi-... 

Asymmetric intramolecular Diels-Alder reaction.1 This chiral Ti catalyst system 4 is also effective for enantioselective intramolecular Diels-Alder reactions (equation I). In this particular case, a dithiane group accelerates the rate and enhances the em/o-selectivity, and is comparable to the gem-dialkyl effect. 

As already shown for hydride shifts, there are also cases, in which consecutive ir-cyclizations cannot be suppressed. For none of the reactions, described in Scheme 27, conditions could be found, under which acyclic products were isolable [99,103-105]. The gem-dialkyl effect [9] accelerated the cyclizations so much that these reactions afforded cyclized products exclusively. 

Comparison of equation (52) with Schemes 10 and 11 suggests diat substitution at C-4 confers substantial benefit in terms of lx>th yield and reaction time. This is most likely a result of a gem-dialkyl effect in which conformations placing the alkene and complexed-alkyne ends of the system in close proximity are rendered endialpically more favorable by increasing substitution on the intervening atoms. The reduced contribution of to AG associated with alkene complexation allows it to better compete with intermolecular side reactions (i.e. trimerization of the otherwise mote reactive alkyne moieties). Hua has made similar observations in simpler systems (equation 53). No stereocontrol at C-4 is available, however, the position being too remote from the reaction centers (equation 54). ... 

Since the electron inductive influence exerted by the methyl groups should result in bond weakening, i.e., a red-shift in absorption and, furthermore, substitution in the 4-position does not lead to any comparable stabilization, the observed effect in the 2-substituted species can, indeed, only been explained in terms of steric reasons specific to the C-2 position. It has been proposed that the shift in max reflects the gem-dialkyl effect which causes a structural distortion favoring p-orbital interactions with respect to 2a/la bond formation to a relatively larger extent. 23 xhis aspect is depicted in structures 12 and 13. 

The potency of Danheiser s pericyclic cascade was further demonstrated in the construction of pyridine cores, disclosing presumably the first example in which an unactivated nitrile function participates in a [4+2]-cycloaddition. Two examples with established mechanisms are depicted in Scheme 6.33. If the required hydrogen for the anticipated ene reaction is present, pathway A dominates and follows the common domino reaction sequence to pyridine 181. If, however, the crucial position is substituted, for instance by an amide moiety, the system is able to overcome this hurdle and utilize its nitrile group for the preluding ene reaction (pathway B). This time, the alkyne group eventually terminates the cascade in a cycloaddition to give the tricyclic pyridine 184. Some efforts has been made to prove that pathway A is usually faster a gem-dialkyl effect in the substrates 179 as well as 182 was shown to play a role in order to facilitate the reaction progress. 

J. The Ejfect of Intramolecularity—Ring Size and gem-Dialkyl Effects... 

Kennedy and Hall have reported a one-pot allylboration/lactonization using the tetra-substituted 2-alkoxycarbonyl aUylboronates 17 (Section 6.2.1.2) [39]. These allyl-boronates react with aldehydes, thermally and under Lewis acid catalysis, to first provide the hydroxy-ester intermediate 119 (Equation 58). This initial product cyclizes under the reaction conditions by lactonization to afford a-exomethylene y-lactones 120. This facile cyclization is probably a manifestation of the gem-dialkyl effect. In-... 

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