13949-95-6Relevant academic research and scientific papers
On the mechanism of ylide-mediated cyclopropanations: Evidence for a proton-transfer step and its effect on stereoselectivity
Riches, Samantha L.,Saha, Chandreyee,Filgueira, Noelia Fontan,Grange, Emma,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
supporting information; experimental part, p. 7626 - 7630 (2010/07/09)
In this paper, we describe studies on the cyclopropanation of Michael acceptors with chiral sulfur ylides. It had previously been found that semi-stabilized sulfonium ylides (e.g., Ph-stabilized) reacted with cyclic and acyclic enones and substituted acrylates with high ee and that stabilized sulfonium ylides (e.g., ester-stabilized) reacted with cyclic enones again with high ee. The current study has focused on the reactions of stabilized sulfonium ylides with acyclic enones which unexpectedly gave low ee. Furthermore, a clear correlation of ee with ylide stability was observed in reactions with methyl vinyl ketone (MVK): ketone-stabilized ylide gave 25% ee, ester-stabilized ylide gave 46% ee, and amide-stabilized ylide gave 89% ee. It is believed that following betaine formation an unusual proton transfer step intervenes which compromises the enantioselectivity of the process. Thus, following addition of a stabilized ylide to the Michael acceptor, rapid and reversible intramolecular proton transfer within the betaine intermediate, prior to ring closure, results in an erosion of ee. Proton transfer occurred to the greatest extent with the most stabilized ylide (ketone). When the same reactions were carried out with deuterium-labeled sulfonium ylides, higher ees were observed in all cases since proton/deuteron transfer was slowed down. The competing proton transfer or direct ring-closure pathways that are open to the betaine intermediate apply not only to all sulfur ylides but potentially to all ylides. By applying this model to S-, N-, and P-ylides we have been able to rationalize the outcome of different ylide reactions bearing a variety of substituents in terms of chemo- and enantioselectivity.
Catalytic cyclopropanation of electron deficient alkenes mediated by chiral and achiral sulfides: Scope and limitations in reactions involving phenyldiazomethane and ethyl diazoacetate
Aggarwal, Varinder K.,Smitha, Helen W.,Hynd, George,Jones, Ray V.H.,Fieldhouse, Robin,Spey, Sharon E.
, p. 3267 - 3276 (2007/10/03)
Phenyldiazomethane reacts with electron deficient alkenes in the presence of catalytic amounts of transition metal catalyst [Rh2(OAc)4 was better than Cu(acac)2] and catalytic amounts of sulfide to give cyclopropanes. Pentamethylene sulfide was found to be superior to tetrahydrothiophene and the optimum solvent was toluene. Under these optimised conditions a range of enones were cyclopropanated in high yields. Cyclic enones and acrylates were not successful in this process. The use of the chiral 1,3-oxathiane derived from camphorsulfonyl chloride in 2 steps in this process furnished cyclopropanes in good yield and very high enantiomeric excess (>97% ee). The absolute stereochemistry of cyclopropane 10 was proven by X-ray analysis and the origin of the stereochemical induction has been rationalised. Extension of this work to include diazoesters was partially successful. Again pentamethylene sulfide was found to be superior to tetrahydrothiophene, but this time both Rh2(OAc)4 and Cu(acac)2 were found to be equally effective. Enones, fumarates and unsaturated nitro compounds worked well but simple acrylates and unsaturated aldehydes were not effective substrates. Control experiments were conducted in which the stabilised ylide was isolated and reacted with the less successful substrates and, whilst unsaturated aldehydes still gave low yields, simple acrylates gave high yields of the corresponding cyclopropane. The use of the chiral 1,3-oxathiane was not successful with these more stable diazo compounds.
2-substituted-(2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 1. Effects of alkyl, arylalkyl, and diarylalkyl substitution
Ornstein, Paul L.,Bleisch, Thomas J.,Arnold, M. Brian,Wright, Rebecca A.,Johnson, Bryan G.,Schoepp, Darryle D.
, p. 346 - 357 (2007/10/03)
In this paper, we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxy-cyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a aeries of four isomers, i.e., two racemic diastereomers. We explored alkyl substitution, both normal and terminally branched; phenylalkyl and diphenylalkyl substitution; and a variety of aromatic and carbocyclic surrogates for phenyl. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin-stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. We found that while alkyl substitution provided no increase in affinity relative to 2, phenylethyl and diphenylethyl substitution, as in 105 and 109, respectively, were quite beneficial. The affinity of 109 was further enhanced when the two aromatic rings were joined by an oxygen or sulfur atom to form the tricyclic xanthylmethyl and thioxanthylmethyl amino acids 113 and 114, respectively. Amino acid 113, with an IC50 of 0.010 μM in the [3H]Glu binding assay, was 52-fold more potent than 2, whose IC50 was 0.47 μM.
