ABSTRACT
The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization-deprotection reaction sequence, used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in-depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14â h, and revealed a favorable competing pathway for formation of the desired product.
Subject(s)
Bayes Theorem , CyclizationABSTRACT
The continuous flow synthesis of butane-2,3-diacetal protected derivatives has been achieved using commercially available flow chemistry microreactors in concert with solid supported reagents and scavengers to provide in-line purification systems. The BDA protected products are all obtained in superior yield to the corresponding batch processes.
Subject(s)
Acetals/chemical synthesis , Butanes/chemical synthesis , Microchemistry/instrumentation , Acetals/chemistry , Butanes/chemistry , Equipment Design , Microchemistry/methodsABSTRACT
The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.
Subject(s)
Acetals/chemical synthesis , Rheology/methods , Tartrates/chemical synthesis , Acetals/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Esters/chemical synthesis , Esters/chemistry , Rheology/instrumentation , Spectroscopy, Fourier Transform Infrared , Tartrates/chemistryABSTRACT
For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biological Products/chemical synthesis , Immunosuppressive Agents/chemical synthesis , Sirolimus/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Cyclization , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Molecular Structure , Sirolimus/chemistry , Sirolimus/pharmacologyABSTRACT
The 5'-triphosphates of 2'-hydroxymethyluridine (2'-homouridine) and 2'-hydroxyethyluridine were prepared from the corresponding acetyl-protected nucleosides by initial phosphitylation with 2-chloro-5,6-benzo-1,2,3-dioxaphosphorin-4-one. 2'-Acetamidouridine 5'-triphosphate was prepared in an analogous fashion from uridine 2'-C-, 3'-O-gamma-butyrolactone, in which the 3'-hydroxyl group is internally protected as the lactone. Subsequent treatment with ammonia gave the required acetamido triphosphate. All three triphosphates were investigated as substrates for T7 RNA polymerase and a Y639F mutant of this enzyme. 2'-Homouridine triphosphate was found to be a substrate for the wild-type enzyme in the presence of manganese and was specifically incorporated into short RNA transcripts (20 and 21 nucleotides in length). The presence of the analogue within the transcripts was confirmed through its resistance to alkaline hydrolysis. Gel electrophoretic analysis also showed that 2'-homouridine could be multiply incorporated into a transcript with a length of 75 nucleotides. This is the first report of a 2'-deoxy-2'-alpha-C-branched nucleoside 5'-triphosphate acting as a substrate for T7 RNA polymerase. The 2'-hydroxyethyl- and 2'-acetamido -uridine triphosphates were not substrates for the enzymes.