ABSTRACT
An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.
Subject(s)
Antiviral Agents/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Humans , Molecular Structure , Stereoisomerism , Viral Nonstructural Proteins/metabolismABSTRACT
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/chemistry , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular NâC benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of ß3-AR agonists is synthesized in 38% overall yield.
Subject(s)
Adrenergic beta-3 Receptor Agonists/chemical synthesis , Pyrrolidines/chemical synthesis , Adrenergic beta-3 Receptor Agonists/chemistry , Adrenergic beta-3 Receptor Agonists/pharmacology , Amino Alcohols/chemistry , Catalysis , Hydrogenation , Imines/chemistry , Molecular Structure , Oxidation-Reduction , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , StereoisomerismABSTRACT
A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.
Subject(s)
Carbolines/chemical synthesis , Alkenes/chemistry , Alkynes/chemistry , Carbolines/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.
Subject(s)
Azepines/chemical synthesis , Ruthenium/chemistry , Triazoles/chemical synthesis , Amination , Catalysis , Hydrogenation , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Kinetics , Neuropeptides/antagonists & inhibitors , Orexins , StereoisomerismABSTRACT
A novel synthesis of 3-methylindoles from chlorotriflates through a Heck reaction, carbamate/aryl chloride coupling, and isomerization sequence is presented. The three-step sequence is highly efficient and general, enabling the regiocontrolled synthesis of substituted indoles in short order.
Subject(s)
Hydrocarbons, Chlorinated/chemistry , Mesylates/chemistry , Skatole/analogs & derivatives , Skatole/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Molecular Structure , Skatole/chemistryABSTRACT
Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.
Subject(s)
Benzothiazoles/chemical synthesis , Benzoxazoles/chemical synthesis , Hydrocarbons, Halogenated/chemistry , Amination , Benzothiazoles/chemistry , Benzoxazoles/chemistry , Catalysis , Magnetic Resonance Spectroscopy/methods , Molecular Structure , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , TemperatureABSTRACT
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Subject(s)
Insecticides/chemical synthesis , Limonins/chemical synthesis , Insecticides/chemistry , Limonins/chemistry , Molecular Conformation , StereoisomerismABSTRACT
Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Sesquiterpenes, Guaiane/chemical synthesis , Thapsigargin/chemical synthesis , Alkenes/chemistry , Biological Factors/chemical synthesis , Biological Factors/chemistry , Biological Factors/pharmacology , Cyclization , Dose-Response Relationship, Drug , Endoplasmic Reticulum/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Nanotechnology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/pharmacology , Stereoisomerism , Thapsigargin/analogs & derivatives , Thapsigargin/pharmacologyABSTRACT
Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.
Subject(s)
Chlorohydrins/chemistry , Cyclopropanes/chemistry , Epoxy Compounds/chemistry , Aldehydes/chemistry , Bridged Bicyclo Compounds/chemistry , Catalysis , Heptanes/chemistry , Hexanes/chemistry , Isomerism , Molecular Structure , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistryABSTRACT
The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4-C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-O. A selective esterification approach completes the total synthesis in a total of 42 steps and 0.61% overall yield (88.6% average yield per step). [reaction: see text].
Subject(s)
Enzyme Inhibitors/chemical synthesis , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Thapsigargin/chemical synthesis , Alcohols/chemistry , Alkenes/chemistry , Chelating Agents/chemistry , Indicators and Reagents , Oxidation-Reduction , StereoisomerismABSTRACT
The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines.
Subject(s)
Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Molecular ConformationABSTRACT
The thapsigargins are a family of complex guaianolides with potent and selective Ca(2+)-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton.
Subject(s)
Thapsigargin/analogs & derivatives , Apiaceae/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Chemistry, Organic/methods , Molecular Structure , Stereoisomerism , Thapsigargin/chemical synthesis , Thapsigargin/chemistryABSTRACT
A two-step selenocyclisation-oxidative deselenaton sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.
ABSTRACT
The synthesis of the germination self-inhibitor (-)-Gloeosporone is reported. The embedded 1,7-diol motif in the product is constructed by an ironcarbonyl tether controlled Mukaiyama aldol reaction. The key step in the synthesis is the reductive removal of the ligating iron species by treatment of an acetoxycomplex 6 with lithium naphthalenide.