Highly Enantioselective Total Synthesis of (+)-Isonitramine

A new efficient enantioselective synthetic method of (+)-isonitramine is reported. (+)-Isonitramine was obtained in 12 steps (98% ee and 43% overall yield) from δ-valerolactam <i>via</i> enantioselective phase-transfer catalytic alkylation, Dieckman condensation, and diastereoselective reduction as key steps

Role of the C(1) Triol Group in Bicyclomycin: Synthesis and Biochemical and Biological Properties

Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the essential cellular protein transcription termination factor rho. The bicyclomycin binding domain in rho is unknown; however, enzyme irreversible inactivators that modify rho upon activation may identify the site. In this study, we investigated the importance for rho binding of the C(1) triol group in 1. Twelve bicyclomycin derivatives were prepared, and the C(1) triol group was modified at the C(1‘), the C(2‘), and the C(3‘) sites. The compounds were evaluated by rho-dependent ATPase and transcription termination assays and their antimicrobial activities assessed using a filter disc assay. Bicyclomycin inhibited both rho-dependent ATPase (I50 = 60 μM) and rho-dependent transcription termination (I50 ∼ 5 μM) processes and had a minimum inhibitory concentration value of 0.25 mg/mL against E. coli W3350 cells. None of the 12 C(1) triol bicyclomycin derivatives significantly inhibited rho-dependent ATPase (I50 > 400 μM) and transcription termination (I50 > 100 μM) activities or exhibited antibiotic activity at a 32 mg/mL concentration. These results indicated that there was a strong molecular complement between the C(1) triol group and its rho binding site. We concluded that the C(1) triol group in 1 is a critical structural element necessary for drug binding to rho and that an enzyme irreversible inactivating unit placed at this site would prohibit the bicyclomycin derivative from efficiently binding to rho

Enantioselective Synthesis of (−)-<i>cis</i>-Clavicipitic Acid

An enantioselective synthetic method for (−)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps

First Asymmetric Total Synthesis of (−)-Antofine by Using an Enantioselective Catalytic Phase Transfer Alkylation

The first asymmetric total synthesis of a potential antitumor phenanthroindolizidine alkaloid, (−)-antofine, is described. An important feature of this synthesis is the creation of a stereogenic center by using enantioselective catalytic phase transfer alkylation, affording an unnatural α-amino acid derivative, together with a ring closing metathesis for pyrrolidine ring construction

Role of the C(5)−C(5a) Exomethylene Group in Bicyclomycin: Synthesis, Structure, and Biochemical and Biological Properties

Thirty-two C(5)−C(5a) exomethylene-modified bicyclomycin derivatives were prepared to determine the effect of structural modification of this unit on bicyclomycin (1) function. The compounds were grouped into three categories:  the C(5)-unsaturated bicyclomycins, the C(5a)-substituted C(5)−C(5a)-dihydrobicyclomycin derivatives, and the C(5)-modified norbicyclomycins. An efficient three-step procedure was developed to synthesize C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins. Bicyclomycin was converted to bicyclomycin C(2‘),C(3‘)-acetonide (36) and then treated with a nucleophile in 50% aqueous methanol (“pH” 10.5) to give the C(5a)-substituted C(5),C(5a)-dihydrobicyclomycin C(2‘),C(3‘)-acetonide. Removal of the acetonide group (trifluoroacetic acid in 50% aqueous methanol) in the final step provided the desired bicyclomycin derivative. All the compounds were evaluated using the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay. Most of the compounds were also tested in the transcription termination assay. We observed that many of the C(5)-unsaturated bicyclomycins effectively inhibited ATP hydrolysis at 400 μM and inhibited the production of rho-dependent transcripts at 100 μM. The biochemical activities of C(5a)-bicyclomycincarboxylic acid (5), methyl C(5a)-bicyclomycincarboxylate (6), ethyl C(5a)-bicyclomycincarboxylate (7), and bicyclomycin C(5)-norketone O-methyloxime (11) were all similar to 1. Compounds 6, 7, and 11 exhibited diminished antibiotic activity compared to 1, and 5 displayed no detectable activity. Several C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins showed significant inhibition of rho-dependent ATPase and transcription termination activities. The inhibitory properties of C(5),C(5a)-dihydrobicyclomycin C(5a)-methyl sulfide (18), C(5),C(5a)-dihydrobicyclomycin C(5a)-phenyl sulfide (23), and C(5)−C(5a)-dihydrobicyclomycin-5,5a-diol (31) approached those of 1. Compounds 18, 23, and 31 did not exhibit antibiotic activity. Two of the four C(5)-modified norbicyclomycin adducts showed moderate inhibitory activities in the ATPase assay, and none showed significant antibiotic activity. Our findings showed that the C(5)−C(5a) exomethylene unit retention in 1 was not essential for inhibition of in vitro rho activity. The structure−activity relationship data indicated that bicyclomycins that contained a small unsaturated C(5) unit or C(5),C(5a)-dihydrobicyclomycins that possessed a small, nonpolar C(5a) substituent effectively inhibited rho function in in vitro biochemical assays. We concluded that the C(5)−C(5a) unit in 1 was not a critical structural element necessary for drug binding to rho and that irreversible, inactivating units placed at this site would permit the bicyclomycin derivative to bind efficiently to rho

First Asymmetric Total Synthesis of (−)-Antofine by Using an Enantioselective Catalytic Phase Transfer Alkylation

The first asymmetric total synthesis of a potential antitumor phenanthroindolizidine alkaloid, (−)-antofine, is described. An important feature of this synthesis is the creation of a stereogenic center by using enantioselective catalytic phase transfer alkylation, affording an unnatural α-amino acid derivative, together with a ring closing metathesis for pyrrolidine ring construction

An Unusual Electronic Effect of an Aromatic-F in Phase-Transfer Catalysts Derived from <i>Cinchona</i>-Alkaloid

Various N-benzylcinchonidinium salts were prepared to study electronic factors in the catalytic enantioselective phase-transfer alkylation of glycine anion equivalent. An ortho-fluoro substituent on the benzyl group in the quaternary ammonium salt dramatically increased the enantioselectivity in the alkylation. O(9)-Allyl-N-2‘,3‘,4‘-trifluorobenzylhydrocinchonidinium bromide (27), which gave the highest enantioselectivity of the catalysts studied, was used to prepare 12 α-alkylated amino acid derivatives in 94∼>99% ee

An Enantioselective Synthesis of (+)-Polyoxamic Acid via Phase-Transfer Catalytic Conjugate Addition and Asymmetric Dihydroxylation

A new enantioselective synthetic method of (+)-polyoxamic acid is reported. (+)-Polyoxamic acid could be obtained in 7 steps with 46% overall yield from diphenylmethyl-glycineimine tert-butyl ester via an enantioselective phase-transfer conjugate addition (99% yield, 96% ee) and an asymmetric dihydroxylation (98% yield, 94% de) as the key reactions

Role of the C(5)−C(5a) Exomethylene Group in Bicyclomycin: Synthesis, Structure, and Biochemical and Biological Properties

Thirty-two C(5)−C(5a) exomethylene-modified bicyclomycin derivatives were prepared to determine the effect of structural modification of this unit on bicyclomycin (1) function. The compounds were grouped into three categories:  the C(5)-unsaturated bicyclomycins, the C(5a)-substituted C(5)−C(5a)-dihydrobicyclomycin derivatives, and the C(5)-modified norbicyclomycins. An efficient three-step procedure was developed to synthesize C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins. Bicyclomycin was converted to bicyclomycin C(2‘),C(3‘)-acetonide (36) and then treated with a nucleophile in 50% aqueous methanol (“pH” 10.5) to give the C(5a)-substituted C(5),C(5a)-dihydrobicyclomycin C(2‘),C(3‘)-acetonide. Removal of the acetonide group (trifluoroacetic acid in 50% aqueous methanol) in the final step provided the desired bicyclomycin derivative. All the compounds were evaluated using the rho-dependent ATPase assay and their antimicrobial activities determined using a filter disc assay. Most of the compounds were also tested in the transcription termination assay. We observed that many of the C(5)-unsaturated bicyclomycins effectively inhibited ATP hydrolysis at 400 μM and inhibited the production of rho-dependent transcripts at 100 μM. The biochemical activities of C(5a)-bicyclomycincarboxylic acid (5), methyl C(5a)-bicyclomycincarboxylate (6), ethyl C(5a)-bicyclomycincarboxylate (7), and bicyclomycin C(5)-norketone O-methyloxime (11) were all similar to 1. Compounds 6, 7, and 11 exhibited diminished antibiotic activity compared to 1, and 5 displayed no detectable activity. Several C(5a)-substituted C(5),C(5a)-dihydrobicyclomycins showed significant inhibition of rho-dependent ATPase and transcription termination activities. The inhibitory properties of C(5),C(5a)-dihydrobicyclomycin C(5a)-methyl sulfide (18), C(5),C(5a)-dihydrobicyclomycin C(5a)-phenyl sulfide (23), and C(5)−C(5a)-dihydrobicyclomycin-5,5a-diol (31) approached those of 1. Compounds 18, 23, and 31 did not exhibit antibiotic activity. Two of the four C(5)-modified norbicyclomycin adducts showed moderate inhibitory activities in the ATPase assay, and none showed significant antibiotic activity. Our findings showed that the C(5)−C(5a) exomethylene unit retention in 1 was not essential for inhibition of in vitro rho activity. The structure−activity relationship data indicated that bicyclomycins that contained a small unsaturated C(5) unit or C(5),C(5a)-dihydrobicyclomycins that possessed a small, nonpolar C(5a) substituent effectively inhibited rho function in in vitro biochemical assays. We concluded that the C(5)−C(5a) unit in 1 was not a critical structural element necessary for drug binding to rho and that irreversible, inactivating units placed at this site would permit the bicyclomycin derivative to bind efficiently to rho

Synthesis of (−)-Paroxetine via Enantioselective Phase-Transfer Catalytic Monoalkylation of Malonamide Ester

A new enantioselective synthetic method of (−)-paroxetine is reported. (−)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps