Synthesis of the pyridine core of cyclothiazomycin

A highly convergent synthesis of the pyridine core of the thiopeptide antibiotic cyclothiazomycin has been developed based on a [2+2+2] cyclotrimerization key step. The regioselective assembly of the heterocyclic center of this important class of antibiotics takes advantage of a temporary silicon tether and the ruthenium-catalyzed cyclotrimerization reaction of a diyne and an electron-poor thiazole nitrile.     

Total Synthesis of Nosiheptide

Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3‐hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity.     

Biosynthesis inspired Diels-Alder route to pyridines: synthesis of the 2,3-dithiazolylpyridine core of the thiopeptide antibiotics

Reaction of serine derived 1-alkoxy-2-azadienes with dehydroalanine derived dienophiles results in Diels-Alder reaction and aromatisation to give 2,3,6-trisubstituted pyridines, thereby establishing the viability of the proposed biosynthetic route to the pyridine ring of the thiopeptide antibiotics originally proposed by Bycroft and Gowland.     

One-pot multistep Bohlmann-Rahtz heteroannulation reactions: synthesis of dimethyl sulfomycinamate

[reaction: see text] The synthesis of dimethyl sulfomycinamate, the acidic methanolysis product of the sulfomycin family of thiopeptide antibiotics, from methyl 2-oxo-4-(trimethylsilyl)but-3-ynoate is achieved in a 2,3,6-trisubstituted pyridine synthesis that proceeds with total regiocontrol in 13 steps by the Bohlmann-Rahtz heteroannulation of a 1-(oxazol-4-yl)enamine or in 12 steps and 9% yield by three-component cyclocondensation with N-[3-oxo-3-(oxazol-4-yl)propanoyl]serine and ammonia in ethanol.     

Total synthesis and complete structural assignment of thiocillin I

The total synthesis of the thiopeptide antibiotic, thiocillin I, is described. This work unequivocally defines the full structure (constitution and configuration) of the natural product as 1.     

Synthesis of dimethyl sulfomycinamate

[reaction: see text] Dimethyl sulfomycinamate, the oxazole-thiazole-pyridine product generated in the methanolysis of the thiopeptide antibiotic sulfomycin I, is prepared in 13 steps and 8% overall yield by the Bohlmann-Rahtz heteroannulation of 1-(oxazol-4-yl)enamines and methyl 4-(trimethylsilyl)-2-oxobut-3-ynoate.     

Total Synthesis of Dimethyl Sulfomycinamate

Dimethyl sulfomycinamate (1), a methanolysis product from the natural antibiotic sulfomycin I, is synthesized in 11 steps (Scheme 19). The chemistry of various pyridine, thiazole, and oxazole heterocycles and their coupling reactions under palladium catalysis are examined. The key transformations in the synthesis are the selective palladium-catalyzed coupling reactions on doubly activated pyridine 62 and the condensation reaction between bromo ketone 69 and amide 28 to form the oxazole moiety 76. The first preparation of oxazole triflates is described, as are some of their chemical properties.     

Total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis

We describe the first synthesis of amiclenomycin, a natural product that has been found to inhibit biotin biosynthesis and, as a consequence, to exhibit antibiotic properties. Structure 1, with a trans relationship between the ring substituents. had previously been proposed for amiclenomycin on the basis of its 1H NMR spectrum. We have prepared the trans and cis isomers 1 and 2 by unequivocal routes and we conclude that the natural product is in fact the cis isomer 2. The properly substituted cyclohexadienyl rings were constructed first. A cycloaddition reaction between 1,2-di(phenylsulfonyl)ethylene and the N-allyloxycarbonyl diene 13, followed by reductive elimination of the phenylsulfinyl groups, gave the cis isomer 15. To obtain the trans isomer, the O-trimethylsilyl diene was used to give the cis hydroxylated Diels-Alder adduct 33, which was transformed into the corresponding trans amino derivative by means of a Mitsunobu reaction. The L-alpha-amino acid functionality was introduced by means of a Strecker reaction on the aldehydes 16 and 42, followed by enzymatic hydrolysis with immobilised pronase.     

Asymmetric total synthesis of ent-(-)-roseophilin: assignment of absolute configuration

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.     

Stereoselective synthesis of the gamma-lactam hydrolysate of the thiopeptide cyclothiazomycin

[reaction: see text] Bohlmann-Rahtz pyridine synthesis of a chiral nonracemic enamine and thiazolylpropynone gives a terminal-protected pyridine-containing gamma-amino acid in high optical purity in a sequential one-pot multicomponent reaction that proceeds with total control of regiochemistry and with minimal racemization. Further elaboration has established the synthesis of the gamma-lactam acidic hydrolysate of the macrocyclic thiopeptide antibiotic cyclothiazomycin, a selective renin inhibitor, in only four steps and 30% overall yield and has confirmed its structure.     

Synthesis of (+/-)-phloeodictine A1

The antitumor antibiotic phloeodictine A1 (2) has been synthesized by a convergent seven-step route in 8% overall yield. The key step was the Eguchi aza-Wittig reaction of 6 to give 13 followed by a retro Diels-Alder reaction to liberate 5. Addition of 11-dodecenylmagnesium bromide to 5 to give 4b, alkylation with 18b, and deprotection completed the first synthesis of 2.     

Synthesis, structure and reactivity of 1-(4-nitrobenzyl)-2-chloromethyl benzimidazole

The synthesis of 1-(4-nitrobenzyl)-2-chloromethyl benzimidazole, which undergoes a nucleophilic substitution with pyridine in the absence of additional base, is reported. The key steps are the reaction of 1,2-phenylenediamine to give exclusively the mono-substituted product and the avoidance of minor by-products via the use of glycolic acid for the cyclisation step. The X-ray structures of 1-(4-nitrobenzyl)-2-chloromethyl benzimidazolium chloride and 1-[1-(4-nitrobenzyl)benzimidazol-2-ylmethyl]pyridinium chloride are presented.     

Ligand coupling through σ-sulfurane — complete retention of configuration of 1-phenylethyl group in the reaction of 1-phenylethyl 2-pyridyl sulfoxide with grignard reagent1

The reaction of benzyl or 1-phenylethyl 2-pyridyl sulfoxide with Grignard reagent proceeds via a σ-sulfurane as an intermediate to give the coupling product, 2-benzylpyridine or 2-(1-phenylethyl)pyridine in quantitative yield. Stereochemistry for this reaction is complete retention at the benzylic carbon atom.     

聚苯乙烯基N-甲基-N-酰基磺酰胺树脂的制备及其作为酰基转移试剂在酰胺合成中的应用

聚苯乙烯基磺酰氯树脂(树脂1)与甲胺水溶液在吡啶的催化作用下反应，制备了N—甲基磺酰胺树脂(树脂2)．用酰氯在吡啶中与树脂2反应，得到N—酰基—N—甲基磺酰胺树脂(树脂3)．树脂3作为胺底物的酰基转移试剂，用来制备N—取代的酰胺，收率14～81％．树脂3可以有选择性地酰化乙醇胺中的氨基而不会使羟基酰化。     

Total synthesis of piericidin A1 and B1

The first total syntheses of piericidin A1 and B1 are disclosed and unambiguously establish the relative and absolute stereochemistry of the natural products by an approach that will facilitate the synthesis of a series of analogues. Central to the approach is an inverse electron demand Diels-Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene with tetramethoxyethene followed by Lewis acid-promoted aromatization used to assemble the functionalized pyridine core. Additional key elements in the convergent approach include the use of an anti-aldol reaction to install the C9 and C10 relative and absolute stereochemistry, a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chain, and a penultimate heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain.     

Synthesis of unsymmetrical annulated 2,2'-bipyridine analogues with attached cycloalkene and piperidine rings via sequential Diels-Alder Reaction of 5,5'-bi-1,2,4-triazines

Synthesis of bisfunctionalized unsymmetrical 2,2'-bipyridines 8 or their sulfonyl derivatives 12a,b are described. They were prepared via the Diels-Alder reaction of 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6) with 3,3'-bis(methyl- sulfanyl)-5,5'-bi-1,2,4-triazine (1). The reaction leads to the single cycloaddition product 7 which undergoes Diels-Alder reaction with cyclic enamines 2a,b to give unsymmetrical 2,2'-bipyridine derivatives 8, consisting of the two different heterocyclic units: cycloalkeno[c]pyridine and 2,6-naphthyridine.     

Carbon(sp(3) )Fluorine Bond-Forming Reductive Elimination from Palladium(IV) Complexes

Pd(IV) -fluoride complexes, some of which are remarkably insensitive to water, have been synthesized and used in the title reaction, which proceeds with high selectivity to give the product of the C(sp(3) )?F coupling (see scheme, TfO=trifluoromethanesulfonate). Preliminary mechanistic studies implicate a pathway involving dissociation of pyridine followed by direct C?F coupling at the Pd center.     

苯磺酸贝他斯汀的合成新方法

探索了一条合成苯磺酸贝他斯汀的新路线。以2-吡啶甲酸、氯苯为原料，经过9步反应合成苯磺酸贝他斯汀，其中关键消旋中间体(4-氯苯基)(2-吡啶基)甲氧基哌啶，经过D-DBTA拆分，可得到光活性(S)-(4-氯苯基)(2-吡啶基)甲氧基哌啶(>99% ee)。同时，(R)-(4-氯苯基)(2-吡啶基)甲氧基哌啶经过消旋化后再次拆分得到(S)-构型产物。该合成方法反应条件温和，具有工业化生产前景。最终产物结构由¹H NMR， ¹³C NMR和HR-MS(ESI)确证。      

Intramolecular nonbonded S...N interaction in rabeprazole

Intramolecular nonbonded S...N interactions in the crystal structures of the derivatives (7a-d) of sodium rabeprazole (1) and an intermolecular nonbonded S...N interaction between ethylmethylsulfoxide and pyridine in a solution were recognized. These results made us estimate that the intramolecular nonbonded S...N interaction existed in 1 and its derivatives in a solution, and formed the 4-membered quasi-ring in 2 (Fig. 1) followed by the increase of the reactivity of 2 to give the putative spiro sulfoxide 3, which is the key intermediate in the reaction cascade of 1 (Chart 1).     

Total synthesis of (±)-spiniferin-1 via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction

A facile total synthesis of marine natural product (±)-spiniferin-1 has been accomplished in eight steps with 28.9% overall yield, involving a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to construct the 1,6-methano[10]annulene core of the natural product as a key step.