Regiospecific synthesis of isogabaculine

Hershenson, Fred M.

doi:10.1021/jo01321a040

Cited by 28 publications

(8 citation statements)

References 3 publications

(3 reference statements)

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“…Reaction took place only at the terminal diene system of (11) to give mainly (12) with highly selective endo addition to the less-hindered face of the double bond of the dienophile. Further manipul ation led stereoselectively to (13) and thence after several steps to cytochalasin (14).…”

Section: Methodsmentioning

confidence: 99%

Intermolecular Diels-Alder Reactions

1990

Cycloaddition Reactions in Organic Synthesis

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Section: Methodsmentioning

confidence: 99%

Intermolecular Diels-Alder Reactions

1990

Cycloaddition Reactions in Organic Synthesis

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“…The other gabaculine isomer, 4-amino-1,4-cyclohexadienylcarboxylic acid (143), was synthesized, but no biochemical studies were reported. 161 Following inactivation of GABA-AT by gabaculine, the activity could be restored by treatment with PLP. 162 were found using m-carboxyphenylpyridoxamine 5-phosphate (139, Scheme 32) as the active site titrant, except that the affinity for 139 was 10 times greater than that of PLP.…”

Section: Aromatization Mechanismsmentioning

confidence: 99%

“…This is how α-difluoromethylornithine (160, eflornithine, DFMO) was designed to inactivate ornithine decarboxylase. The reaction catalyzed by the PLP-dependent enzyme ornithine decarboxylase is the conversion of ornithine (161) to putrescine (163, Scheme 42); putrescine is further converted to spermidine (164) and then to spermine (165), but ornithine decarboxylase is the rate-determining step in the polyamine biosynthetic pathway. These polyamines are regulators of cell growth, differentiation, and division and can enhance tumor cell and parasite growth; 184 Eflornithine is, in fact, a FDA-approved drug (Ornidyl) for the treatment of African sleeping sickness 185 and is in clinical trials for the treatment of relapsed or refractory neuroblastoma.…”

Section: Selected Examples Of How Gaba-at Inactivation Mechanisms Can...mentioning

confidence: 99%

Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions

Silverman

2018

Chem. Rev.

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When the brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) diminishes below a threshold level, the excess neuronal excitation can lead to convulsions. This imbalance in neurotransmission can be corrected by inhibition of the enzyme γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. It also has been found that raising GABA levels can antagonize the rapid elevation and release of dopamine in the nucleus accumbens, which is responsible for the reward response in addiction. Therefore, the design of new inhibitors of GABA-AT, which increases brain GABA levels, is an important approach to new treatments for epilepsy and addiction. This review summarizes findings over the last 40 or so years of mechanism-based inactivators (unreactive compounds that require the target enzyme to catalyze their conversion to the inactivating species, which inactivate the enzyme prior to their release) of GABA-AT with emphasis on their catalytic mechanisms of inactivation, presented according to organic chemical mechanism, with minimal pharmacology, except where important for activity in epilepsy and addiction. Patents, abstracts, and conference proceedings are not covered in this review. The inactivation mechanisms described here can be applied to the inactivations of a wide variety of unrelated enzymes.

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“…[2][3][4][5][6][7][8][9][10] The usual protection of the terminal dienyl amine involves amide, lactam and carbamate functions; 11-13 such dienes react readily with various olefins bearing an electron-withdrawing group (NO 2 , CHO, CO 2 R, CN) to furnish exclusively the ortho-cycloadducts with a moderate to good endo-selectivity. [13][14][15][16][17][18] On the other hand, the use of N-1,3dienylimides in Diels-Alder reactions is poorly documented. 19 In connection with studies of biologically active phosphonic derivatives, we required a flexible route towards orthoaminophosphonocyclohexane derivatives which could be further functionalized on the six-membered ring.…”

Section: Introductionmentioning

confidence: 99%

Diels–Alder reactivity of trialkyl 2-phosphonoacrylates with N-buta-1,3-dienylsuccinimide

Defacqz¹,

Touillaux²,

Tinant³

et al. 1997

J. Chem. Soc., Perkin Trans. 2

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N-Buta-1,3-dienylsuccinimide 1 reacts quantitatively with trimethyl 2-phosphonoacrylate 2a to furnish the ortho-[4 ϩ 2]-cycloadduct 3a as a single stereoisomer. The cis axial/equatorial relationship between the succinimido and phosphonate groups respectively has been established by NMR and X-ray diffraction analyses. Triethyl 2-phosphonoacrylate 2b similarly undergoes cycloaddition with the diene 1 to give a 55 : 45 mixture of ortho stereoisomers 3b (cis axial/equatorial) and 4b (trans axial/axial). The activating and directing effect of the phosphonate group is discussed on the basis of a theoretical approach considering the van der Waals complexes.

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Regiospecific synthesis of isogabaculine

Cited by 28 publications

References 3 publications

Intermolecular Diels-Alder Reactions

Intermolecular Diels-Alder Reactions

Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions

Diels–Alder reactivity of trialkyl 2-phosphonoacrylates with N-buta-1,3-dienylsuccinimide

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