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1.
Chemistry ; 27(16): 5171-5179, 2021 Mar 17.
Article in English | MEDLINE | ID: mdl-33300620

ABSTRACT

1,2,3,4-Tetrahydroquinolines should be applicable to the development of new pharmaceutical agents. A facile synthesis of 1,2,3,4-tetrahydroquinolines that is achieved by a photoinduced formal [4+2] cycloaddition reaction of acyclic α,ß-unsaturated amides and imides with N,N-dialkylanilines under visible-light irradiation, in which a new IrIII complex photosensitizer, a thiourea, and an oxidant act cooperatively in promoting the reaction, is reported. The photoreaction enables the synthesis of a wide variety of 1,2,3,4-tetrahydroquinolines, while controlling the trans/cis diastereoselectivity (>99:1) and constructing contiguous stereogenic centers. A chemoselective cleavage of an acyclic imide auxiliary is demonstrated.

2.
Bioorg Med Chem Lett ; 30(12): 127176, 2020 06 15.
Article in English | MEDLINE | ID: mdl-32299730

ABSTRACT

We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.


Subject(s)
Antidepressive Agents/pharmacology , Depression/drug therapy , Drug Discovery , Receptors, Opioid, delta/agonists , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Mice , Molecular Structure , Structure-Activity Relationship
3.
J Org Chem ; 84(18): 11474-11481, 2019 09 20.
Article in English | MEDLINE | ID: mdl-31309833

ABSTRACT

Ligand-dependent Suzuki cross-coupling of 4-bromopyrazol-5-yl triflates has been developed. This approach enabled selective introduction of an aryl substituent at the C4 or C5 position in pyrazoles. This protocol is the first example in which the cross-coupling proceeded predominantly at the C4 position in pyrazoles, which is generally recognized as the least reactive position. The selection of phosphine ligands switched the order of arylation. This method should be highly useful for preparing diverse poly-substituted pyrazole derivatives.

4.
ACS Chem Neurosci ; 10(5): 2237-2242, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30913383

ABSTRACT

The cyclopropylmethyl group in classical δ opioid receptor (DOR) antagonist NTI, BNTX, and NTB was replaced with various electron-withdrawing groups to develop DOR inverse agonists. N-Benzyl NTB derivative SYK-657 was a potent DOR full inverse agonist and its potency was over 10-fold potent than that of a reference compound ICI-174,864. Intraperitoneal administration of SYK-657 induced the short-term memory improving effect in mice without abnormal behaviors.


Subject(s)
Analgesics, Opioid/pharmacology , Behavior, Animal/drug effects , Cognition/drug effects , Cognitive Dysfunction , Memory, Short-Term/drug effects , Receptors, Opioid, delta/agonists , Animals , Drug Inverse Agonism , Male , Mice , Restraint, Physical , Stress, Psychological
5.
RSC Adv ; 9(22): 12365-12369, 2019 Apr 17.
Article in English | MEDLINE | ID: mdl-35515875

ABSTRACT

A novel asymmetric photodimerization reaction of coumarin derivatives bearing the (S)-4-benzyl-2-oxazolidinone auxiliary provides only the syn-head-to-tail (syn-HT) dimer with moderate diastereoselectivity (up to 75 : 25). The mechanism of complete syn-HT selectivity and moderate diastereoselectivity is proposed based on the result of density functional theory (DFT) calculation. The benzyl group of the (S)-4-benzyl-2-oxazolidinone auxiliary in combination with a Lewis acid exerts effective diastereofacial shielding of the reaction site.

6.
Chem Commun (Camb) ; 55(11): 1552-1555, 2019 Jan 31.
Article in English | MEDLINE | ID: mdl-30560972

ABSTRACT

The first example of asymmetric 1,3-dipolar cycloadditions between diazo imine-derived cyclic azomethine ylides and acryloylpyrazolidinone using a rhodium(ii) complex/chiral Lewis acid binary system is reported. The asymmetric cycloadditions afforded optically active 8-oxabicyclo[3.2.1]octanes with high diastereo- and enantioselectivities (up to >99 : 1 dr, 99% ee). A switch of exo/endo-selectivity was observed depending on the diazo substrates.

7.
Org Biomol Chem ; 16(33): 6155, 2018 08 22.
Article in English | MEDLINE | ID: mdl-30090886

ABSTRACT

Correction for 'Dibenzofuran-4,6-bis(oxazoline) (DBFOX). A novel trans-chelating bis(oxazoline) ligand for asymmetric reactions' by Kennosuke Itoh et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob01010 b.

8.
Org Biomol Chem ; 16(31): 5551-5565, 2018 08 08.
Article in English | MEDLINE | ID: mdl-29947634

ABSTRACT

The trans-chelating bis(oxazoline) ligand (R,R)-4,6-dibenzofurandiyl-2,2'-bis(4-phenyloxazoline) [(R,R)-DBFOX/Ph] coordinates metal ions to give C2-symmetric complexes which effectively catalyze a variety of asymmetric reactions. (R,R)-DBFOX/Ph·Ni(ClO4)2·3H2O, whose crystal structure is octahedral with three aqua ligands, can be stored under air for several months without loss of catalytic activity and promotes highly enantioselective reactions even in the presence of excess amounts of water, alcohols, amines, and acids. The complex shows remarkable chiral amplification in asymmetric Diels-Alder (DA) reactions. This review focuses on enantioselective reactions catalyzed by (R,R)-DBFOX/Ph·metal complexes.

9.
Org Lett ; 20(9): 2659-2662, 2018 05 04.
Article in English | MEDLINE | ID: mdl-29671597

ABSTRACT

A dual catalytic system, dirhodium tetrapivalate/ytterbium(III) triflate, enables the three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and N-benzylidenebenzylamine derivatives to afford the corresponding ß-amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts, whereas no ß-amino alcohols are obtained in the absence of ytterbium(III) triflate. A similar dual catalytic system, dirhodium tetraacetate/ytterbium(III) triflate, is found to be effective in accelerating the reactions of α-aryl-α-diazoesters in high yields. Furthermore, the reactions using dimethyl diazomalonate are described.

10.
Chem Pharm Bull (Tokyo) ; 65(10): 920-929, 2017.
Article in English | MEDLINE | ID: mdl-28966276

ABSTRACT

Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the µ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.


Subject(s)
Analgesics, Opioid/chemistry , Morphinans/chemistry , Analgesics, Opioid/chemical synthesis , Animals , Buprenorphine/analogs & derivatives , Buprenorphine/chemistry , CHO Cells , Cricetinae , Cricetulus , Cyclization , Humans , Kinetics , Molecular Conformation , Morphinans/chemical synthesis , Protein Binding , Receptors, Opioid/chemistry , Receptors, Opioid/genetics , Receptors, Opioid/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification
11.
Bioorg Med Chem ; 24(10): 2199-205, 2016 05 15.
Article in English | MEDLINE | ID: mdl-27079125

ABSTRACT

As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds.


Subject(s)
Morphinans/chemistry , Morphinans/pharmacology , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid/metabolism , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacology , Animals , Benzylidene Compounds/chemical synthesis , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacology , CHO Cells , Cricetulus , Humans , Ligands , Models, Molecular , Morphinans/chemical synthesis , Naltrexone/analogs & derivatives , Naltrexone/chemical synthesis , Naltrexone/chemistry , Naltrexone/pharmacology , Narcotic Antagonists/chemical synthesis , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Opioid, delta/metabolism , Structure-Activity Relationship
12.
Org Biomol Chem ; 13(33): 8919-24, 2015 Sep 07.
Article in English | MEDLINE | ID: mdl-26205235

ABSTRACT

Photoexcited nitrones serve as excellent electron acceptors as well as radical acceptors in the presence of tertiary amines to give ß-amino hydroxylamines via photochemically-induced direct sp(3) C-H functionalization of the tertiary amines. The combined use of an organophotosensitizer and photoirradiation was highly effective in accelerating addition reactions. Several nitrones and tertiary amines were successfully utilized to give ß-amino hydroxylamines in good yield. Highly regioselective generation of primary α-aminoalkyl radicals based on Lewis's stereoelectronic rule and diastereoselective addition reactions of primary α-aminoalkyl radicals with nitrones were successfully achieved. Furthermore, a highly diastereoselective reaction of an α-aminoalkyl radical with a chiral (E)-geometry-fixed α-alkoxycarbonylnitrone was performed.


Subject(s)
Amines/chemistry , Nitrogen Oxides/chemistry , Photochemical Processes , Photosensitizing Agents , Proton Magnetic Resonance Spectroscopy , Solvents/chemistry , Stereoisomerism , Ultraviolet Rays
13.
J Org Chem ; 80(13): 6687-96, 2015 Jul 02.
Article in English | MEDLINE | ID: mdl-26106799

ABSTRACT

Asymmetric 1,3-dipolar cycloaddition reactions between N-methylindoles and several cyclic carbonyl ylides that were derived from diazodiketone or diazoketoester precursors in the presence of both achiral Rh and chiral lanthanoid metal catalysts are described. For the six-membered cyclic carbonyl ylides derived from 1-diazo-5-aryl-2,5-pentanedione precursors, the cycloaddition reactions were carried out using Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Lu(OTf)3 complex (10 mol %) as catalysts, resulting in high enantioselectivities (83% to >98% ee (exo)) along with relatively good exo-selectivities (exo:endo = 65:35 to 94:6) and yields (63-85%). For the five-membered cyclic carbonyl ylide derived from 1-diazo-2,4-pentandione precursor, the cycloaddition reaction with 5-bromo-1-methylindole was carried out in the presence of Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Er(OTf)3 complex (30 mol %) as catalysts, resulting in relatively good enantioselectivity (78% ee) and endo-selectivity (endo:exo = 81:19).


Subject(s)
Azo Compounds/chemical synthesis , Indoles/chemistry , Lewis Acids/chemistry , Azo Compounds/chemistry , Catalysis , Cycloaddition Reaction , Molecular Structure , Stereoisomerism
14.
J Org Chem ; 78(21): 10840-52, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24099422

ABSTRACT

Highly enantioselective 1,3-dipolar cycloaddition reactions, catalyzed by chiral Lewis acids, between several 3-(2-alkenoyl)-2-oxazolidinones and carbonyl ylides that were generated from N-diazoacetyl lactams are described. Reactions of N-diazoacetyl lactams that possess 5-, 6-, and 7-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes with good to high enantioselectivities. Regio- and stereoselective ring-opening of the epoxy-bridged indolizidine cycloadduct gave the corresponding alcohol as a single diastereomer. The sequence of asymmetric cycloaddition followed by ring-opening was applied to the syntheses of several chiral indolizidine derivatives, including (+)-tashiromine.

15.
J Org Chem ; 78(12): 6182-95, 2013 Jun 21.
Article in English | MEDLINE | ID: mdl-23758193

ABSTRACT

The effects of including metal salts for three-component reactions involving α-alkyl-α-diazo esters, aromatic aldehydes, and 3-(2-alkenoyl)-2-oxazolidinones are described, in terms of yields and diastereoselectivities. Metal tetrafluoroborates (10-30 mol %) such as Co(BF4)2·6H2O, Ni(BF4)2·6H2O, and AgBF4 were effective in delivering high yields and diastereoselectivities (93:7 to 99:1) of the corresponding tetrahydrofuran derivatives while suppressing the competitive formation of 1,3-dioxolane. Using (S)-3-(2-alkenoyl)-4-isopropyl-2-oxazolidinones as the dipolarophiles in the three-component reactions, in the presence of Ni(BF4)2·6H2O or Co(ClO4)2·6H2O (10-30 mol %), optically active tetrahydrofurans that possess four successive asymmetric centers were synthesized in high diastereoselectivities (99:1). On the basis of the configuration of the cycloadduct using the X-ray analysis, the high diastereoselectivity could be explained by the unusual Re-face approach to the dipolarophile in the presence of the Lewis acid, proceeding through the s-cis conformer of the 3-(2-alkenoyl)-2-oxazolidinone with the two carbonyls in opposing directions (dipole-dipole interaction).

16.
J Org Chem ; 76(18): 7377-87, 2011 Sep 16.
Article in English | MEDLINE | ID: mdl-21797207

ABSTRACT

The catalytic activity of chiral binaphthyldiimine (BINIM)-Ni(II) complexes for asymmetric enantioselective diazoalkane cycloadditions of ethyl diazoacetate with 3-acryloyl-2-oxazolidinone and 2-(2-alkenoyl)-3-pyrazolidinone derivatives was evaluated. The cycloadditions of 3-acryloyl-2-oxazolidinone and its 5,5-dimethyl derivative, in the presence of the BINIM-Ni(II) complex (10 mol %; prepared from (R)-BINIM-4Ph-2QN (ligand C) and Ni(ClO(4))(2)·6H(2)O) afforded 2-pyrazolines having a methine carbon substituted with an oxazolidinonyl group in moderate ratios (70:30 to 72:28), along with high enantioselectivities (90-92% ee) via 1,3-proton migration. On the basis of the investigations on the counteranions of the Ni(II) complex, the N-substituent of pyrazolidinone, and reaction temperatures, the optimal enantioselectivity (97% ee) and ratio (85:15) of 2-pyrazoline were obtained for the reaction of 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-Ni(II) ((R)-C/Ni(II)) complex prepared using Ni(BF(4))(2)·6H(2)O. In the cases of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, 1-benzyl-2-(2-butenoyl)-5,5-dimethyl-3-pyrazolidinone, and 1-benzyl-5,5-dimethyl-2-(3-ethoxycarbonyl)propenoyl-3-pyrazolidinone, the use of the (R)-BINIM-2QN-Ni(II) ((R)-A/Ni(II)) complex gave good to high enantioselectivities (85-93% ee) with the sole formation of the 2-pyrazoline having a methine carbon substituted with a pyrazolidinonyl group. Relatively good enantioselectivity (77% ee) was observed for the reaction between 2-acryloyl-5,5-dimethyl-1-naphthylmethyl-3-pyrazolidinone and an α-substituted diazo ester, ethyl 2-diazo-3-phenylpropanoate, which has yet to be employed as a diazo substrate in asymmetric cycloaddition reactions catalyzed by a chiral Lewis acid.

17.
Chem Pharm Bull (Tokyo) ; 58(11): 1502-10, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21048344

ABSTRACT

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3',4':4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl3) is also discussed.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Nitrogen Compounds/chemical synthesis , Thienopyridines/chemical synthesis , Heterocyclic Compounds/chemistry , Nitrogen Compounds/chemistry , Thienopyridines/chemistry
19.
Org Lett ; 7(12): 2349-52, 2005 06 09.
Article in English | MEDLINE | ID: mdl-15932195

ABSTRACT

[reaction: see text] The use of N-H imide templates provides a solution to the problem of rotamer control in Lewis acid catalyzed reactions of alpha,beta-disubstituted acryloyl imides. Reactions proceed through the s-cis rotamer and with improved reactivity because A(1,3) strain is avoided. Enantioselective nitrone, nitrile oxide, and Diels-Alder cycloadditions demonstrate the principle.

20.
Org Lett ; 7(6): 979-81, 2005 Mar 17.
Article in English | MEDLINE | ID: mdl-15760118

ABSTRACT

[reaction: see text] The reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles in THF, catalyzed by catalytic amounts of both DBFOX/Ph-nickel(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine, in the presence of acetic anhydride in THF produces the corresponding enol lactones in high enantioselectivities through enantioselective Michael additions followed by cyclization with removal of the pyrazole auxiliary. Other related nucleophile precursors can be successfully applied in the enantioselective enol lactone synthesis under the double catalytic conditions.

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