Pyridine 2,3,5-trisubstituted pyridines

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

When the 4-position is substituted, Grignard addition occurs at the 2-position, to eventually give a 2,4,6-trisubstituted pyridine via the 6-lithiated species (Scheme 145) (88TL1751). Alternatively, if the 4-substituent is a chloro (88TL1751) or methoxy group (89TL5053), the initial product can be hydrolyzed to an enone rather than being aromatized to a pyridine. 

Cycloaddition of 2-amino-3-cyano-4,5,6-trisubstituted pyridine 360 with formamidine acetate in the presence of diglyme produced the 4-pyridopyrimidinylamine 361 as its hydrochloride salt (Equation 30) <2000USP6030969>. 

As broadly demonstrated in aromatic DoM chemistry (90CRV879), iterative metalation of pyridyl O-carbamates are synthetically useful processes. Thus, sequential metalation reactions of 3- and 4-pyridyl O-carbamates with electrophiles that provide incipient DMGs afford 3,4,5-trisubstituted pyridines 327, 328, and 329, respectively (Scheme 99) (85JOC5436). 

Nucleophilic addition at the 2-position of pyrylium salts (223) occurs readily under mild conditions and when ammonia or primary amines are used the subsequent ring-opening/ring-closure sequences give pyridines (224) and pyridinium salts (222), respectively (Section 3.2.1.6.4.iii). The process is most useful for the synthesis of 2,4,6-trisubstituted pyridine derivatives. Thiinium salts (226) are conveniently prepared from pyrylium salts (225) by treatment with sodium sulfide (Section 3.2.1.6.5), Thiinium salts (226) react with ammonia and amines similarly to their pyrylium analogues. 

SynPhase Crowns with a Rink amide linker were used by Linn et al.38 at Glaxo-Wellcome to synthesize a library of 1,3,5-trisubstituted pyridin-2-ones (Scheme 12). The solid bound amide 38 was treated with 3-amino-5-methoxycarbonyl-l/f-pyridin-2-one with CS2CO3 in DMF to afford pyridine-2-one 39. Coupling of diphenylacetic acid FIATU and DIEA in... 

Vinylogous iminium salts, e.g. (7), cyclize with P-aminocrotonitriles to form trisubstituted pyridines, e.g. (8), (Scheme 5) <95T(51)1575>. 

Microwave reaction conditions have been reported for the synthesis of 2-pyridones in a modern version of the traditional three-component condensation reaction (Scheme 108) <2004T8633>. A library of 18 3,5,6-trisubstituted pyridines was generated and includes aryl, alkyl, and fused derivatives. 

In the total synthesis of ( )-WS75644B 360, a biaryl endothelin converting enzyme inhibitor, pyrone 357 derived from kojic acid was converted to pyridone 358 by reaction with concentrated ammonium hydroxide in a sealed flask at 90 °C. The resulting pyridine was subsequently converted to 2,4,5-trisubstituted pyridine 359 and ultimately elaborated to complete the total synthesis (Scheme 54) <1997TL1297>. 

Consistent with this picture, reaction of pure metallacycles with the 2,4-disubstitution pattern with nitriles gives isomerically pure 2,4,6-trisubstituted pyridines Y. Wakatsuki and H. Yamazaki, 7. Chem. Soc., Dalton Trans., 1978, 1278. 

The Lewis acid-promoted reaction of our oximinosulfonate with dienes and the conversion of the resulting cycloadducts to pyridines comprises a new annulation method for the synthesis of substituted pyridines from conjugated dienes. As illustrated in the Table, very good overall yields are obtained in reactions of 2-substituted dienes, providing 5-substituted pyridine-2-carboxylates. Reactions with 1-substituted dienes yield 3-substituted pyridines, and disubstituted dienes react smoothly to afford trisubstituted pyridines in good yield. Polycyclic systems are obtained when dienes such as 1-vinyl-1-cyclohexene are employed in the annulation. 

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived l-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesis-inspired hetero-Diels-Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization <2005JA15644, 2004CC946>. 

GE2270A 394 is an antibiotic produced by Planobispora rosea ATCC 537731. It inhibits Gram-positive bacteria and anaerobes by acting on the protein synthesis elongation factor (EF) <1991JAN693, 1995T4867>. It contains proline, serine, glycine, two thiazolyl amino acids, and a heterocyclic centerpiece of a trisubstituted pyridine, all in a macrocyclic array. 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

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