Concise Formation of 4-Benzyl Piperidines and Related Derivatives Using a Suzuki Protocol

Vice, Susan F.; Bara, Thomas; Bauer, Annette; Evans, Carla A.; Ford, John; Josien, H; McCombie, Stuart W.; Miller, Michael J.; Nazareno, Dennis V.; Palani, Anandan; Tagat, Jayaram R.

doi:10.1021/jo0007682

Cited by 45 publications

(16 citation statements)

References 20 publications

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“…1989; Chemler et al. 2001; Vice et al. 2001), prepared in situ by hydroboration of N ‐ tert ‐butoxycarbonyl ( N ‐Boc)‐protected 1‐methylene‐1,2,3,4‐tetrahydroisoquinoline 2 with 9‐borabicyclo[3.3.1]nonane, which afforded N ‐Boc‐protected 1DAzBnTIQ 4 .…”

Section: Resultsmentioning

confidence: 99%

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Kohta¹,

Kotake²,

Hosoya³

et al. 2010

Journal of Neurochemistry

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Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and the appearance of Lewy bodies in the substantia nigra, leading to clinical symptoms of rigidity, resting tremor, and bradykinesia. A few percent of PD is of genetic origin, and over ten genes have been identified as causes of familial PD so Received October 9, 2009; revised manuscript received November 27, 2009; accepted December 1, 2009. Address correspondence and reprint requests to Dr Y. Kotake, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. E-mail: yaichiro@hiroshima-u.ac.jp Abbreviations used: 1BnTIQ, 1-Benzyl-1,2,3,4-tetrahydroisoquinoline; 1DAzBnTIQ, 1-(3-azido-5-azidomethylbenzyl)-1,2,3,4-tetrahydroisoquinoline; 1MeTIQ, 1-methyl-1,2,3,4-tetrahydroisoquinoline; 3¢,4¢ DHBnTIQ, 1-(3,4-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline; AR-JP, autosomal recessive juvenile parkinsonism; BSA, bovine serum albumin; CBB, Coomassie Brilliant Blue; GST, glutathione-S-transferase; IP, immunoprecipitation; N-Boc, N-tert-butoxycarbonyl; Pael-R, parkinassociated endothelin receptor-like receptor; PBS, phosphate-buffered saline; PD, Parkinson's disease; PVDF, polyvinylidene difluoride; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TIQ, 1,2,3,4-tetrahydroisoquinoline; TNE, tris-NaCl-EDTA; TOF, time of flight; Tris, tris(hydroxymethyl)aminomethane; TTBS, Tween 20-containing tris-buffered saline; WB, western blotting. AbstractSubstances that mimic the actions of causative gene products of familial Parkinson's disease (PD) are candidate as causative agents of idiopathic PD. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is present at three times higher levels in CSF of PD patients than in CSF of control subjects. However, the mechanism of 1BnTIQ's neurotoxicity is unclear. In this study, we tried to identify 1BnTIQ-binding proteins by using a diazido-functionalized 1BnTIQ analog, 1-(3-azido-5-azidomethylbenzyl)-1,2,3,4-tetrahydroisoquinoline, designed and synthesized as a probe for radioisotope-free photoaffinity labeling. One major photolabeled protein identified using this probe was tubulin b, which has been reported to be a substrate of parkin, a ubiquitin E3 ligase and a causative gene product of familial PD. Loss of function mutation of parkin is reported to result in loss of tubulin b ubiquitination. Therefore, we examined the effect of 1BnTIQ on ubiquitination of tubulin b. The polyubiquitinated tubulin b level in human neuroblastoma SH-SY5Y cells was reduced in the presence of 1BnTIQ, even at concentrations as low as those detected in parkinsonian CSF. In vitro ubiquitination assay gave similar results. It is suggested that 1BnTIQ has the same effect on tubulin ubiquitination as does mutant parkin in familial PD. Taken together, substances which reduce polyubiquitination of tubulin such as 1BnTIQ are supposed to be candidates of etiological factors of PD.

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Section: Resultsmentioning

confidence: 99%

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Kohta¹,

Kotake²,

Hosoya³

et al. 2010

Journal of Neurochemistry

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“…263 The hydroboration of N -Boc-4-methylene piperidine, followed by reaction with aryl bromides, iodides, and triflates in the presence of a catalytic amount of PdCl 2 (dppf)/AsPh 3 produced a series of biologically relevant coupling products. Interestingly, 2,5-dibromopyridine underwent cross-coupling regioselectively at the 2-position, producing the corresponding coupling product in high yield.…”

Section: Cross-coupling With Alkylboron Reagentsmentioning

confidence: 99%

Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners

2011

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Introduction 1418 1.1. List of Common Ligands 1419 2. Alkylzinc Reagents 1419 2.1. Synthesis of Alkylzinc Reagents 1419 2.2. Stability of Alkylzinc Reagents 1420 2.3. Cross-Coupling Reactions of Alkylzinc Reagents 1421 2.4. Palladium-Catalyzed Cross-Coupling Reactions of Alkylzinc Reagents 1423 2.4.1. Palladium-Catalyzed C(sp 2 )-C(sp 3 ) Negishi Coupling with Alkylzinc Reagents 1423 2.4.2. Palladium-Catalyzed C(sp 3 )-C(sp 3 ) Negishi Coupling with Alkylzinc Reagents 1427 2.4.3. Palladium-Catalyzed C(sp)-C(sp 3 ) Negishi Coupling with Alkylzinc Reagents 1428 2.4.4. Formation of Ketones via Palladium-Catalyzed Negishi Coupling with Alkylzinc Reagents 1429 2.5. Nickel-Catalyzed Cross-Coupling Reactions of Alkylzinc Reagents 1429 2.5.1. Nickel-Catalyzed C(sp 2 )-C(sp 3 ) Negishi Coupling with Alkylzinc Reagents 1429 2.5.2. Nickel-Catalyzed Carboxylations with Alkylzinc Reagents 1430 2.5.3. Nickel-Catalyzed C(sp 3 )--(sp 3 ) Negishi Coupling with Alkylzinc Reagents 1430 2.5.4. Mechanistic Insights in Nickel-Catalyzed Cross-Couplings 1433 3.

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“…5-Hydroxyindoline compound (23) 8) was converted to its trifluoromethanesulfonate 24. 15) This compound was subjected to a SuzukiMiyaura cross coupling reaction 16,17) with N-Boc-4-methyl-enepiperidine (25) 18) to give compound 26, which has a methylene chain between the indoline ring and piperidine ring. By the same method as described in Chart 2, compound 26 was converted to corresponding 5-alkylindoline derivative 27.…”

Section: Indoline Derivatives Ii: Synthesis and Factor Xa (Fxa) Inhibmentioning

confidence: 99%

Indoline Derivatives II: Synthesis and Factor Xa (FXa) Inhibitory Activities

Noguchi¹,

Tanaka²,

Nishimata³

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Intravascular clot formation is a serious event which leads to a number of ischemic diseases, such as myocardial infarction, stroke and venous thromboembolism. At present, warfarin is the sole oral anticoagulant that is being widely used for prophylaxis and treatment of thrombosis. However, many reports have mentioned the limitations of warfarin. [2][3][4] Indeed, warfarin requires frequent international normalized ratio (INR) monitoring because of its narrow therapeutic window and the large inter-and intraindividual variability in its effect. In addition, its onset of anticoagulant action is considerably slow and it interacts with many foods and conventional agents. Accordingly, novel oral anticoagulants with high efficacy and without INR monitoring are desired.Factor Xa (FXa) has been thought of as a particularly promising target for effective anticoagulation because it acts at the convergence point of the intrinsic and extrinsic coagulation pathways. Moreover, one molecule of FXa generates more than 100 thrombin molecules.5) It is thought that inhibition of FXa effectively blocks thrombin formation, thereby diminishing thrombin-mediated fibrin clot formation. Recent research has focused on the identification of orally available small-molecule FXa inhibitors that do not require routine coagulation monitoring. 6,7)In a previous paper, we reported that compound (R)-1 ( Fig. 1), which has the (R)-configuration at the 2-position of the indoline ring, showed potent inhibitory activity against FXa in vitro.8) However, orally administered (RS)-1 had high toxicity in mice. We intended to explore new indoline compounds with potent FXa inhibitory activity and diminished toxicity by further structural optimization of (RS)-1. In this study, we examined substituents on the indoline ring in order to identify more desirable compounds. Herein, we describe the synthesis and structure-activity relationships (SARs) of these compounds. ChemistryKey intermediates 8a-g and i were synthesized as shown in Chart 1. After reduction of the nitro group of alcohol 2 by catalytic hydrogenation, 8) aniline 3 was reacted with acyl reagents or sulfonyl reagents to give anilides 4a-g. An intramolecular Mitsunobu reaction 9) of 4a-g with n-Bu 3 P and 1,1Ј-(azodicarbonyl)dipiperidine (ADDP) afforded corresponding indolines 5a-g. After removing the methoxymethyl (MOM) group of 5a-g by treatment with HCl, phenols 6a-g was converted to intermediates 8a-g by means of a Mitsunobu reaction 10) with alcohol 7. Furthermore, after removing the benzyloxycarbonyl (Z) group of compound 8h 8) by catalytic hydrogenation, the resulting indoline derivative was acylated with ethyl malonyl chloride to give ethyl malonate intermediate 8i.The syntheses of the amidine derivatives from intermediates 8a-g, i are outlined in Chart 2. Compounds 8a-g, i were converted to the corresponding amidines 9a-g, i by bubbling HCl gas into a mixture of ethanol and dichloromethane, followed by amination of the resulting imidates (Method A), or by treatment with hydroxylamine, foll...

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Concise Formation of 4-Benzyl Piperidines and Related Derivatives Using a Suzuki Protocol

Cited by 45 publications

References 20 publications

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners

Indoline Derivatives II: Synthesis and Factor Xa (FXa) Inhibitory Activities

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