Super Acid-Induced Pummerer-Type Cyclization Reaction: Improvement in the Synthesis of Chiral 1,3-Dimethyl-1,2,3,4-tetrahydroisoquinolines

Saitoh, Toshiaki; Shikiya, Kentaro; Horiguchi, Yuji; Sano, Takehiro

doi:10.1248/cpb.51.667

Cited by 18 publications

(5 citation statements)

References 10 publications

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“…19 , Scheme ) might be doubly charged. Nevertheless, some precedent for this type of doubly cationic intermediate is known, and so Pummerer-based oxidative cyclizations with 24a − 24c were explored. These dihydrooroidin derivatives in particular were selected with the expectation that the bromination pattern on the pyrrole ring might influence the nucleophilicity at C(3) in an exploitable manner.…”

Section: Resultsmentioning

confidence: 99%

Extending Pummerer Reaction Chemistry: (±)-Dibromoagelaspongin Synthesis and Related Studies

Feldman

Fodor

2009

J. Org. Chem.

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Section: Resultsmentioning

confidence: 99%

Extending Pummerer Reaction Chemistry: (±)-Dibromoagelaspongin Synthesis and Related Studies

Feldman

Fodor

2009

J. Org. Chem.

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“…We previously reported that deprenyl, a monoamine oxidase (MAO) inhibitor, and its structural analogue could selectively block the nuclear GAPDH cascade in cells by inhibiting GAPDH-Siah1 protein interaction ( 15 ). We performed extended screening of structural analogues of deprenyl, and identified more potent and selective blockers of GAPDH-Siah1 binding ( 16 ). One of the most promising compounds was (1R, 3R)-1, 3-dimethyl-2-propargyl-1, 2, 3, 4-tetrahydroisoquinoline (designated RR in the present manuscript) ( Fig.…”

Section: Main Textmentioning

confidence: 99%

Nuclear GAPDH cascade mediates pathological cardiac hypertrophy

Zhang¹,

Kariya²,

Numata³

et al. 2019

Preprint

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One-sentence summary:This study shows a novel function of GAPDH in homeostatic control of the heart, which is disturbed and results in cardiac hypertrophy with pathological stressors. Abstract:Pathological stressors disrupt cellular and organ homeostasis, causing various diseases. We discovered a novel role for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathological growth response of the heart, independent of its functions in glycolysis and cell death. In a cellular model for cardiac hypertrophy, endothelin-1 elicited nuclear translocation of GAPDH and activation of p300 histone acetyl-transferase (HAT), followed by activation of myocyte enhancer factor 2 (MEF2). GAPDH nuclear translocation and p300 HAT activation was also identified in rodent pathological hypertrophied hearts. The hypertrophy was markedly ameliorated by molecular and pharmacological interventions that antagonize the nuclear GAPDH pathway, including a novel antagonist selective to its nuclear function. This pathway may be the key to stress response/homeostatic control, and thus the potential therapeutic target for stressassociated diseases. Main Text:Besides glycolytic function, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) translocate to the nuclei in response to stress where it has been described to mainly regulate cell death (1-4).The nuclear GAPDH pathway is triggered by a specific oxidation/S-nitrosylation of GAPDH at cysteine-150, which enables the interaction of the pool of GAPDH with Siah1 (5, 6). The protein complex translocates to the nucleus where GAPDH can affect p300, p53 and p53 upregulated modulator of apoptosis (PUMA) resulting in cell death; in this cascade, only a small fraction of GAPDH is converted to a signaling molecule, and the overall change in cytosolic and glycolytic GAPDH is negligible (5, 7). Despite it is involvement in cell death, it remains unclear whether and how this cascade plays general and diverse roles.The heart is among the organs with the highest expression of GAPDH (8), which has been simply thought to play a "house keeping" glycolytic role in this organ. The heart develops hypertrophy or abnormal growth in response to pathological stress, which can ultimately result in the organ failure (9). Indeed, cardiac hypertrophy and failure is a leading cause of death worldwide, imposing an enormous burden on society (10). Although p300 has been implicated in this pathophysiology (11,12), the overall significance and its regulatory mechanism remain elusive. We hypothesize that nuclear GAPDH-p300 signaling may mediate this stress response, which disrupts critical homeostasis of cardiac myocytes and causes hypertrophic growth.To address this question, we used a mouse model of pressure-overload cardiac hypertrophy induced by transverse aortic constriction (TAC) (13). In this model, cardiac hypertrophy is developed at 7 to 10 days after TAC, transitioning to failure in 63 days after TAC.The histone acetyl transferase (HAT) activity of p300 was markedly increased in TAC hearts at Reagents and RR compound...

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“…Homochiral β-amino sulfoxides and derivatives of them represent a set of sulfoxides that have been used in organocatalysis, − as ligands in organometallic chemistry, − and as valuable precursors of larger synthetic targets. − Furthermore, the β-amino sulfoxide unit has been recognized and assembled as a constituent of many biologically and/or medicinally important compounds. − …”

Section: Introductionmentioning

confidence: 99%

“…The oxidation of homochiral β-amino sulfides has been employed the most extensively, presumably since the protocol gives the most rapid access to sulfoxide by way of a readily accessible amino sulfide ( D ). ,,− ,,− ,− Surprisingly, despite the presence of the stereogenic carbon, the diastereoselection of oxidation protocols has only rarely exceeded dr values of 90%. ,, In most cases, ratios range from 1:1 to 3:2, ,,,,,,− , and on many occasions, diastereoselectivities are not even reported or acknowledged. ,,,,− In the few instances when an asymmetric oxidizing agent was employed to complement the stereogenic carbon in the substrate, selected de values reach 95% but only for particular substrates and conditions. ,− …”

Section: Introductionmentioning

confidence: 99%

Sulfenate Substitution as a Complement and Alternative to Sulfoxidation in the Diastereoselective Preparation of Chiral β-Substituted β-Amino Sulfoxides

Söderman

Schwan

2013

J. Org. Chem.

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Building from a previous communication, the reaction of sulfenate anions with chiral N-Boc-protected β-substituted β-amino iodides was evaluated as a conceptually different synthetic approach to chiral β-substituted β-amino sulfoxides. Using arenesulfenates, yields typically ranged from 71% to 92%, and dr's were often near 9:1. Alkanesulfenates proved less reactive, delivering lower yields and dr's. 1-Alkenesulfenates demonstrated high reactivity, returning chemical yields of 60-86% and dr's often close to 9:1 and as high as 95:5. (S)-β-Amino iodide electrophiles yielded (R(S),S(C))-β-amino sulfoxides, whereas (R)-amino iodides afford (S(S),R(C))-β-amino sulfoxides. The absolute configuration of the products makes the sulfenate protocol complementary to other existing preparations, including the commonly employed sulfoxidation of β-amino sulfides. The reactivity of N-Boc-protected 2-benzyl-2-aminoethyl iodide was found to be superior to the less sterically encumbered n-butyl iodide. A transition state model is proposed to account for the stereochemistry of the products and also for the high reactivity of the electrophile. Overall, the chemistry represents a new means of introducing sulfur stereogenicity in a molecule.

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Super Acid-Induced Pummerer-Type Cyclization Reaction: Improvement in the Synthesis of Chiral 1,3-Dimethyl-1,2,3,4-tetrahydroisoquinolines

Cited by 18 publications

References 10 publications

Extending Pummerer Reaction Chemistry: (±)-Dibromoagelaspongin Synthesis and Related Studies

Extending Pummerer Reaction Chemistry: (±)-Dibromoagelaspongin Synthesis and Related Studies

Nuclear GAPDH cascade mediates pathological cardiac hypertrophy

Sulfenate Substitution as a Complement and Alternative to Sulfoxidation in the Diastereoselective Preparation of Chiral β-Substituted β-Amino Sulfoxides

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