Direct C-2 arylation of alkyl 4-thiazolecarboxylates: new insights in synthesis of heterocyclic core of thiopeptide antibiotics

The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4-thiazolecarboxylates which are components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-coupling sequence.     

General synthesis route to benanomicin-pradimicin antibiotics

A general approach to the regio- and stereoselective total synthesis of the benanomicin-pradimicin antibiotics (BpAs) is described. Construction of the aglycon has been achieved by 1) the diastereoselective ring-opening of a biaryl lactone by using (R)-valinol as a chiral nucleophile and 2) the stereocontrolled semi-pinacol cyclization of the aldehyde acetal by using SmI(2) in the presence of BF(3)OEt(2) and a proton source to afford the ABCD tetracyclic monoprotected diol. This strategy enabled us to control the two stereogenic sites in the B ring (C-5 and C-6) and the regioselective introduction of the carbohydrate moiety. The ABCD tetracycle could serve as an ideal platform for the divergent access to various BpAs. The amino acid (D-alanine) was introduced onto the ABCD tetracycle. Glycosylation was promoted by the combination of Cp(2)HfCl(2) and AgOTf (1:2 ratio). Construction of the E ring followed by deprotection completed the first total synthesis of benanomicin A (2 a), benanomicin B (2 b), and pradimicin A (1 a). The route is flexible enough to allow the synthesis of other congeners differing in their amino acid and carbohydrate moieties.     

Reactivity and synthesis inspired by the Zincke ring-opening of pyridines

The century-old Zincke process for ring-opening of pyridinium salts produces 5-amino-2,4-pentadienals, a type of donor-acceptor dienes known as Zincke aldehydes. Inspired by this reasonably general and often efficient process for dearomatization, my laboratory has used pyridines as a starting point for heterocycle synthesis, which resulted in unusual syntheses of indoles, pyrrolines, and a formal synthesis of the natural product porothramycin A. Furthermore, our study of the reactivity of Zincke aldehydes has led to accidental discoveries of pericyclic cascade reactions that produce Z-α,β-unsaturated amides or polycyclic lactams, depending upon the identity of the substituents on nitrogen. Finally, a base-mediated formal cycloaddition reaction of tryptamine-derived Zincke aldehydes has served as the key step in concise syntheses of the indole alkaloids norfluorocurarine and strychnine.     

Hetero Diels-Alder synthesis of 3-hydroxypyridines: access to the nosiheptide core

The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation. Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with exceptional regioselectivity (>95:5). This methodology was applied to a scaleable synthesis of the core structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a racemization-free seven-step synthesis of the key building block.     

Toward the total synthesis of maoecrystal V: an intramolecular Diels-Alder route to the maoecrystal V pentacyclic core with the appropriate relative stereochemistry

A diastereoselective route to the maoecrystal V core compound (6) has been achieved. Key transformations include an intramolecular Diels-Alder cyclization and an exo-glycal epoxide rearrangement sequence.     

A practical synthesis of 2,3-dihydro-2-benzofurancarboxylic acid: A general route to 2,3-dihydrobenzofurans

A practical synthesis of 2,3-dihydro-2-benzofurancarboxylic acid is reported in five steps and approximately 40% overall yield. The methodology offers a useful new route to 2-substituted-2,3-dihydrobenzofurans.     

Total synthesis of the thiopeptide amythiamicin D

The first total synthesis of the thiopeptide antibiotic amythiamicin D is described.     

Recent approaches to the synthesis of thieno[2,3-b]pyridines (microreview)

Chemistry of Heterocyclic Compounds - This microreview describes recent approaches to the synthesis of thieno[2,3-b]pyridine derivatives. Selected works published in 2015–2019 are reviewed.     

A facile synthesis of 2,3-disubstituted furo[2,3-b]pyridines

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.     

Synthesis of the tetracyclic core of anthracycline antibiotics by an intramolecular dehydro Diels-Alder approach

[reaction: see text] A conceptually new approach to the tetracyclic core of the anthracycline antibiotics is reported. With use of this approach, the 7,8,9,10-tetrahydronaphthacene-5,12-dione skeleton has been synthesized in three steps, from commercially available reagents, in yields of up to 85%.     

Recent advances in the chemistry of thieno[2,3-b]pyridines 1. Methods of synthesis of thieno[2,3-b]pyridines

Russian Chemical Bulletin - The recent data (2007–2018) on the synthesis of thieno[2,3-b]pyridines are summarized and systematized.     

A biogenetically inspired heterodimerization approach to the synthesis of the core structure of the alkaloid fissoldhimine

A biogenetically inspired heterodimerization reaction of N-substituted 2-pyrroline equivalents leads to the tricyclic core of the alkaloid fissoldhimine. Thus, pyrrolidin-2-ol derivatives, in which the nitrogen atom is substituted either with urea or thiourea functionality, serve as equivalents of the corresponding N-substituted 2-pyrrolines. Reaction of these compounds under Lewis acidic (e.g., lanthanide triflate) or Brønsted acid conditions leads to a diastereomeric form of the tricyclic core of fissoldhimine. The reaction can be envisaged to occur either via an asynchronous intermolecular inverse electron demand hetero-Diels-Alder reaction, or through a tandem Mannich/ring-closure reaction.     

Homo Diels-Alder chemistry in the synthesis of portulal: construction of the functionalized hydroazulene core

A highly stereoselective synthesis of the functionalized hydroazulene skeleton of portulal (1), has been achieved using the newly developed cobalt catalyzed [4+2+2] homo Diels-Alder chemistry.     

Methodology for regioselective synthesis of substituted pyridines via intramolecular oximino malonate hetero Diels-Alder reactions

[structure] Various substituted pyridines can be prepared regioselectively by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of an oximino malonate dienophile tethered to a dienic carboxylic acid, followed by mild aromatization of the resulting cycloadduct with cesium carbonate in DMF at room temperature.     

Total synthesis of macquarimicins using an intramolecular Diels-Alder approach inspired by a biosynthetic pathway

A total synthesis of the macquarimicins A-C (1-3), novel natural products with intriguing tetra- or pentacyclic frameworks, has been achieved. The synthesis features an extensive investigation of the biosynthesis-based intramolecular Diels-Alder (IMDA) reactions of (E,Z,E)-1,6,8-nonatrienes. Considering possible biosynthetic sequences, four types of substrates were synthesized, and their IMDA reactions were examined. From one of the four substrates, the total synthesis was achieved via a transannular Diels-Alder reaction, which led to the stereoselective construction of the unique molecular framework. The convergent and efficient synthetic pathway afforded (+)-1 in 27 linear steps with 4.3% and 9.9% overall yields from readily available ethyl (2E,4S)-4,5-(isopropylidene)dioxy-2-pentenoate (22) and (R)-epichlorohydrin (30), respectively. Furthermore, efficient syntheses of 2, 3, and the 9-epi-cochleamycins A (57) and B (58) were accomplished. Additionally, the present work established the absolute stereochemistry of macquarimicins and revised the C(2)--C(3) geometry of 1.     

Ruthenium-catalyzed cycloisomerization-6pi-cyclization: a novel route to pyridines

[reaction: see text] Herein we report a method for the synthesis of substituted pyridines. The unsaturated ketones and aldehydes derived from the cycloisomerization of primary and secondary propargyl diynols in the presence of [CpRu(CH3CN)3]PF6 (1) are converted to 1-azatrienes which in turn undergo a subsequent electrocyclization-dehydration to provide pyridines with excellent regiocontrol.     

A concise synthesis of Tamiflu: third generation route via the Diels-Alder reaction and the Curtius rearrangement

Our third generation synthesis of Tamiflu was achieved in 12 steps from commercially available starting materials, using the Diels-Alder reaction and Curtius rearrangement as key steps.     

Mapping the binding site of thiopeptide antibiotics by proximity-induced covalent capture

Proximity-induced covalent capture (PICC) has been established for the investigation of ligand binding to composite protein/oligonucleotide target complexes. The RNA-induced attachment of the thiopeptides Thiostrepton and Nosiheptide to engineered Cys mutants of the ribosomal protein L11 was highly position selective and allowed mapping of their binding site at amino acid resolution.     

Total synthesis of the thiopeptide antibiotic amythiamicin D

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.