A simple and efficient synthesis of novel 14-membered macrocycles from a resin-bound orthogonally... more A simple and efficient synthesis of novel 14-membered macrocycles from a resin-bound orthogonally protected lysine residue is described. Reductive alkylation of the lysine alpha-nitrogen introduces the first diversity element. Acylation of the resultant secondary amine with an Fmoc-amino acid introduces the second diversity element providing a resin-bound protected di-peptide precursor. Removal of the Fmoc-group is followed by acylation with a succinic anhydride to introduce the final diversity elements. Removal of the methyltrityl-group from the amino group followed by macrocyclization provides the desired macrocycles, after TFA cleavage, in excellent yield and purity.
ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene... more ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.
Abslracl: A procedure for preparing substituted arninosulfooylureas on solid support is described... more Abslracl: A procedure for preparing substituted arninosulfooylureas on solid support is described. Chemoselectivereactionof chlorosulfonylisocyanatewith the Wangresin followedby reactionwith an amineprovidesresin-boundsubstitutedaminosulfonylcarbamates.Heatingof the resultantresin irrTHF with a secondamineprovidesthe desiredsubstitutedaminosulfonylureas in good yield rural purity.
ABSTRACT Colored glass beads and caps provide a simple color-coding strategy adapted to porous pl... more ABSTRACT Colored glass beads and caps provide a simple color-coding strategy adapted to porous plastic containers and allow visual identification of the individual constituents of combinatorial libraries.
... the Orally Active Hypocholesterolemic Agent Breynin At Amos B. Smith III,* James R. Empfield,... more ... the Orally Active Hypocholesterolemic Agent Breynin At Amos B. Smith III,* James R. Empfield, Ralph A. Rivero, Henry A. Vaccaro, James J.-W. Duan, and Michelle M. Sulikowski ... 1989, 30, 105. (7) Witliams, DR; Jass, P.; Tse, H.; Gaston, R. J. Am. Chem. Soc. 1990, 112, 4552. ...
Bioorganic Medicinal Chemistry Letters, Mar 15, 2012
A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationa... more A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
... AN EFFICIENT SYNTHESIS OF GLYCOSYL ESTERS EXPLOITING THE MITSUNOBU REACTION. Amos B. Smith Ii... more ... AN EFFICIENT SYNTHESIS OF GLYCOSYL ESTERS EXPLOITING THE MITSUNOBU REACTION. Amos B. Smith Iii,*1 Karl J. Hale and Ralph A. Rivero. ... 2. (a) Bugiaesi, R. and Shen, TY, Carbohydr. ~., 19.11, .11, 179; (b) Kornhauser, A. and Keglevic, D., Carbohydr. ...
The antineoplastic glycoside (+)phyllanthostatin 3 (4) has been synthesized for the ftrst time. t... more The antineoplastic glycoside (+)phyllanthostatin 3 (4) has been synthesized for the ftrst time. together with its aglycone (+)~phyllanthooindiol (5).
Breynins A and B, novel sulfur-containing glycosides isolated from the Taiwanese woody shrub Brey... more Breynins A and B, novel sulfur-containing glycosides isolated from the Taiwanese woody shrub Breynia officinalis Hemsl, possess significant oral hypocholesterolemic activity.I Although the complete structures of the breynins remain unknown, exhaustive hydrolysis of breynin A afforded breynolide ( l ) , along with D-ghCOSe, L-rhamnose, and p-hydroxybenzoic acid.lb The structure of 1 was then secured via single-crystal X-ray analysis.IC Our interest in the breynins stems from their potent pharmacological properties and the remarkable structural similarity of 1 with phyllanthocin," the aglycon methyl ester of the phyllanthoside family of antitumor agents.2b Not surprisingly, others in the synthetic community have also been attracted to this arena,3 and in 1990 Williams et al. reported the first total synthesis of (+)-l.3b
ABSTRACT The solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-... more ABSTRACT The solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-2-ones 8 is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the resin-bound aryl fluoride with an α-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group with SnCl2·H2O and subsequent intramolecular cyclization result in the formation of the core quinoxalinone. Selective alkylation at the N-4 position of the quinoxalinone is accomplished with alkyl halides in the presence of K2CO3. The desired products are cleaved from solid supports and obtained in from 32 to 93% isolated yields.
Non-peptide ligands for peptide receptors of the G-protein-coupled type are generally antagonists... more Non-peptide ligands for peptide receptors of the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells ...
ABSTRACT Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Ra... more ABSTRACT Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Radiolabeled Losartan (DuP 753)1,2, L-158,641 (EXP3174)3 and L-158,8094,5 were prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl. Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl
A simple and efficient synthesis of novel 14-membered macrocycles from a resin-bound orthogonally... more A simple and efficient synthesis of novel 14-membered macrocycles from a resin-bound orthogonally protected lysine residue is described. Reductive alkylation of the lysine alpha-nitrogen introduces the first diversity element. Acylation of the resultant secondary amine with an Fmoc-amino acid introduces the second diversity element providing a resin-bound protected di-peptide precursor. Removal of the Fmoc-group is followed by acylation with a succinic anhydride to introduce the final diversity elements. Removal of the methyltrityl-group from the amino group followed by macrocyclization provides the desired macrocycles, after TFA cleavage, in excellent yield and purity.
ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene... more ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.
Abslracl: A procedure for preparing substituted arninosulfooylureas on solid support is described... more Abslracl: A procedure for preparing substituted arninosulfooylureas on solid support is described. Chemoselectivereactionof chlorosulfonylisocyanatewith the Wangresin followedby reactionwith an amineprovidesresin-boundsubstitutedaminosulfonylcarbamates.Heatingof the resultantresin irrTHF with a secondamineprovidesthe desiredsubstitutedaminosulfonylureas in good yield rural purity.
ABSTRACT Colored glass beads and caps provide a simple color-coding strategy adapted to porous pl... more ABSTRACT Colored glass beads and caps provide a simple color-coding strategy adapted to porous plastic containers and allow visual identification of the individual constituents of combinatorial libraries.
... the Orally Active Hypocholesterolemic Agent Breynin At Amos B. Smith III,* James R. Empfield,... more ... the Orally Active Hypocholesterolemic Agent Breynin At Amos B. Smith III,* James R. Empfield, Ralph A. Rivero, Henry A. Vaccaro, James J.-W. Duan, and Michelle M. Sulikowski ... 1989, 30, 105. (7) Witliams, DR; Jass, P.; Tse, H.; Gaston, R. J. Am. Chem. Soc. 1990, 112, 4552. ...
Bioorganic Medicinal Chemistry Letters, Mar 15, 2012
A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationa... more A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
... AN EFFICIENT SYNTHESIS OF GLYCOSYL ESTERS EXPLOITING THE MITSUNOBU REACTION. Amos B. Smith Ii... more ... AN EFFICIENT SYNTHESIS OF GLYCOSYL ESTERS EXPLOITING THE MITSUNOBU REACTION. Amos B. Smith Iii,*1 Karl J. Hale and Ralph A. Rivero. ... 2. (a) Bugiaesi, R. and Shen, TY, Carbohydr. ~., 19.11, .11, 179; (b) Kornhauser, A. and Keglevic, D., Carbohydr. ...
The antineoplastic glycoside (+)phyllanthostatin 3 (4) has been synthesized for the ftrst time. t... more The antineoplastic glycoside (+)phyllanthostatin 3 (4) has been synthesized for the ftrst time. together with its aglycone (+)~phyllanthooindiol (5).
Breynins A and B, novel sulfur-containing glycosides isolated from the Taiwanese woody shrub Brey... more Breynins A and B, novel sulfur-containing glycosides isolated from the Taiwanese woody shrub Breynia officinalis Hemsl, possess significant oral hypocholesterolemic activity.I Although the complete structures of the breynins remain unknown, exhaustive hydrolysis of breynin A afforded breynolide ( l ) , along with D-ghCOSe, L-rhamnose, and p-hydroxybenzoic acid.lb The structure of 1 was then secured via single-crystal X-ray analysis.IC Our interest in the breynins stems from their potent pharmacological properties and the remarkable structural similarity of 1 with phyllanthocin," the aglycon methyl ester of the phyllanthoside family of antitumor agents.2b Not surprisingly, others in the synthetic community have also been attracted to this arena,3 and in 1990 Williams et al. reported the first total synthesis of (+)-l.3b
ABSTRACT The solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-... more ABSTRACT The solid phase synthesis of 3,4-disubstituted-7-carbamoyl-1,2,3,4-tetrahydroquinoxalin-2-ones 8 is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the resin-bound aryl fluoride with an α-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group with SnCl2·H2O and subsequent intramolecular cyclization result in the formation of the core quinoxalinone. Selective alkylation at the N-4 position of the quinoxalinone is accomplished with alkyl halides in the presence of K2CO3. The desired products are cleaved from solid supports and obtained in from 32 to 93% isolated yields.
Non-peptide ligands for peptide receptors of the G-protein-coupled type are generally antagonists... more Non-peptide ligands for peptide receptors of the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells ...
ABSTRACT Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Ra... more ABSTRACT Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared. Radiolabeled Losartan (DuP 753)1,2, L-158,641 (EXP3174)3 and L-158,8094,5 were prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl. Selective radioligands of the angiotensin II AT1 receptor subtype have been prepared from a common bromobiphenyl intermediate. The key step in the synthesis is the selective aromatic monobromination of 2-cyano-4′-methylbiphenyl
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Papers by Ralph Rivero