ABSTRACT
The single-step construction of various densely oxygenated carboskeletons was achieved by radical-based two- and three-component coupling reactions of sugar derivatives, without the need for light or heat. Et3B/O2-mediated decarbonylation readily converted α-alkoxyacyl tellurides to α-alkoxy carbon radicals, which intermolecularly added to glyoxylic oxime ether or enones to provide the two-component adducts. Furthermore, the three-component adducts were produced by an intermolecular aldol reaction between the aldehyde and the boron enolates generated by capture of the two-component radical intermediates by Et3B. This powerful coupling method serves as a novel strategy for the convergent synthesis of polyol natural products.
ABSTRACT
Et3B-mediated three-component coupling reactions between O,Te-acetal, α,ß-unsaturated ketones, and aldehydes/ketones were developed. Et3B promoted the generation of the potently reactive bridgehead radical from the O,Te-acetal of the trioxaadamantane structure and converted the α-carbonyl radical of the resultant two-component adduct to the boron enolate, which then underwent a stereoselective aldol reaction with the aldehyde/ketone. This powerful, yet mild, radical-polar crossover reaction efficiently connected the hindered linkages between the three units and selectively introduced three new stereocenters.
Subject(s)
Aldehydes/chemistry , Boranes/chemistry , Ketones/chemistry , Tellurium/chemistry , Acetals , Molecular Structure , StereoisomerismABSTRACT
Various analogues of the marine alkaloids, discorhabdins, have been synthesized. The strategy contains spirocyclization with phenyliodine(III) bis(trifluoroacetate) (PIFA), oxidative fragmentation of the ß-amino alcohols with the hypervalent iodine reagent C(6)F(5)I(OCOCF(3))(2), the detosylation and dehydrogenation reaction of the pyrroloiminoquinone unit in the presence of a catalytic amount of NaN(3) and the bridged ether synthesis with HBr-AcOH as the key reactions. All the synthesized compounds were evaluated by in vitro MTT assay for cytotoxic activity against the human colon cancer cell line HCT-116. Furthermore, the discorhabdin A oxa analogues were also evaluated against four kinds of tumor model cells, a human colon cancer cell line (WiDr), a human prostate cancer cell line (DU-145) and murine leukemia cell lines (P388 and L1210). For the identification of the target, discorhabdin A and the discorhabdin A oxa analogue were evaluated by an HCC panel assay. In the test, discorhabdins could have a novel mode of action with the tumor cells.
Subject(s)
Quinones/chemical synthesis , Thiazepines/chemical synthesis , Animals , Cell Line, Tumor , Cell Survival/drug effects , Humans , Mice , Mice, Inbred BALB C , Molecular Structure , Neoplasms/drug therapy , Quinones/pharmacology , Quinones/therapeutic use , Structure-Activity Relationship , Thiazepines/pharmacology , Thiazepines/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Discorhabdin A (1) exhibits a strong cytotoxic activity in vitro, but it is difficult to synthesize and handle due to the instability of its highly strained N,S-acetal structure. We then designed the analogues of discorhabdin A which also have strong cytotoxic activity and stability. The synthesis and examination of the biological activity of various types of stable discorhabdin A oxa analogues (2) were achieved.
Subject(s)
Alkaloids/chemical synthesis , Drug Screening Assays, Antitumor , Marine Biology , Oxytocin/analogs & derivatives , Quinones/chemical synthesis , Spiro Compounds/chemical synthesis , Thiazepines/chemical synthesis , Acetals , Alkaloids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Oxytocin/chemical synthesis , Oxytocin/chemistry , Quinones/chemistry , Quinones/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Thiazepines/chemistry , Thiazepines/pharmacologyABSTRACT
Hypervalent iodine(III) reagents are readily available, easy to handle, and have a low toxicity and similar reactivities to those of heavy metal reagents, and hence they are used for various oxidative reactions. The oxidative cleavage of alkynes or carbonyl compounds by using bis(trifluoroacetoxy)iodo(III) pentafluorobenzene (C(6)F(5)I(OCOCF(3))(2)) has been reported. Herein, the efficient direct synthesis of N,O-acetal compounds as key intermediates of discorhabdin A, by the oxidative fragmentation reaction of alpha-amino acids or beta-amino alcohols by using C(6)F(5)I(OCOCF(3))(2), is described.
Subject(s)
Amino Acids/chemistry , Amino Alcohols/chemistry , Hydrocarbons, Halogenated/chemistry , Quinones/chemical synthesis , Spiro Compounds/chemical synthesis , Thiazepines/chemical synthesis , CatalysisABSTRACT
The concise total synthesis of marine alkaloids, (-)-flustramines A and B, and (-)-flustramides A and B has been achieved through the domino olefination/isomerization/Claisen rearrangement (OIC) for highly enantioselective construction of the asymmetric quaternary carbon center and the chemoselective reduction-cyclization (RC) for pyrrolidine formation as key steps.
Subject(s)
Alkaloids/chemical synthesis , Alkenes/chemistry , Indole Alkaloids/chemical synthesis , Alkaloids/pharmacology , Cyclization , Indole Alkaloids/pharmacology , Isomerism , Models, Chemical , Oxidation-Reduction , Pyrrolidines/chemistry , StereoisomerismABSTRACT
The use of hypervalent iodine(III) reagents allowed us to develop the novel and efficient direct synthesis of N,O-acetal compounds via the oxidative fragmentation reaction of alpha-amino acids or alpha-amino alcohols; furthermore, we succeeded in developing an improved synthesis of the key intermediate of discorhabdins.