Mild addition of carbon nucleophiles to pyridine and quinoline N-oxides under different activation conditions

In the course of our syntheses of functionalised pyridine and quinoline derivatives, we examined the reactivities of pyridine and quinoline N-oxides towards the nucleophilic addition of acidic carbon derivatives. Different activating reagents were used, such as PyBroP, triflic anhydride and a combination of pyrrolidine phosphoramide and triflic anhydride.     

Enantioselective total synthesis of pyrroloquinolone as a potent PDE5 inhibitor

A concise enantioselective strategy for the synthesis of key PDE5 inhibitor 2 was developed in 5 and 6 steps using asymmetric hydrogenation and one-pot chiral auxiliary approaches, respectively. The synthesis features the use of imine 6 obtained through Bischler-Napieralsky reaction from amide 5. Absolute R configuration was introduced in (+)-7 by asymmetric transfer-hydrogenation reaction with Ru(II) catalyst followed by establishing the tricyclic pyrroloquinalone core using the Winterfeldt oxidation. Another alternative synthetic approach for the introduction of chirality in the molecule employed imine 6 and chloroformates of different chiral auxiliaries, which achieved N-acyliminium ion intermediates that were reduced in situ using PdCl₂/Et₃SiH protocol. These synthetic routes were applied in the total synthesis of promising male erectile dysfunction (MED) PDE5 inhibitor 1.     

Stereoselective formal synthesis of the potent proteasome inhibitor: salinosporamide A

(2R,3S)-α-Methylenelactam 3, the key intermediate in Corey’s syntheses of salinosporamide A, has been synthesized from (S)-methyl 2-hydroxymethylpyroglutamate through chemoselective O-protection, regio- and stereoselective N-methylnitrone cycloaddition and quaternarization-elimination reactions as the main steps.     

Studies toward the synthesis of salinosporamide A, a potent proteasome inhibitor

An α-methylenepyrrolidinone bearing all the functionalities and relative configurations of an advanced intermediate in the synthesis of salinosporamide A and analogues has been synthesized from methyl pyroglutamate through regio- and stereoselective N-methylnitrone cycloaddition.     

A new class of o-hydroxyaryl-substituted N-heterocyclic carbene ligands and their complexes with palladium

A facile synthesis of o-hydroxyaryl-substituted N-heterocyclic carbene ligands and their complexes with palladium is presented. This kind of salicylaldimine-like NHC ligands expands the class of available NHC ligands for organometallic catalysts.     

Regioselective synthesis of 2-unsubstituted 1-aryl-4- and 1-aryl-5-acylimidazoles

An efficient and simple method for the synthesis of 2-unsubstituted 1-aryl-4- and 1-aryl-5-acylimidazoles has been developed. It consists in the condensation of α-diketone monooximes with aromatic amines and formaldehyde on the presence of boron trifluoride etherate, leading to the formation of stable boron trifluoride complexes of N-oxides. Further reduction of these complexes led to the corresponding imidazoles. This method permits broad variations of substituents in the aryl part of these compounds.     

Peptoids bearing tertiary amino residues in the n-alkyl side chains: synthesis of a potent inhibitor of Semaphorin 3A

A study on the preparation of N-alkylglycines (peptoids) that contain tertiary amino residues on the N-alkyl side chains is reported. The appropriate combination of the submonomer strategy with N-alkylglycine monomer couplings depending upon the structure of the N-alkyl side chain that must be incorporated into the peptoid is determinant for the efficiency of the synthetic pathway. The application of this strategy to the preparation of SICHI, an N-alkyglycine trimer containing tertiary amino residues in the three N-alkyl branches, and that has been identified as a potent Semaphorin 3A inhibitor, is presented.     

A concise synthesis of asymmetrical N,N′-disubstituted guanidines

We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and triethylamine.     

Simple pyridylmethylamines: efficient and robust N,N-ligands for Suzuki-Miyaura coupling reactions

A series of pyridylmethylamines have been synthesized in one step from commercially available starting material and identified as effective ligands for Pd-catalyzed carbon-carbon bond formation through Suzuki-Miyaura coupling reaction. The N,N-pyridylmethylamine-Pd catalytic systems appeared as an interesting and robust compromise between catalytic efficiency, substrate compatibility, and practical aspects.     

A concise synthesis of novel naphtho[a]carbazoles and benzo[c]carbazoles

Starting from simple indole precursors the synthesis of naphtho[a]carbazoles and benzo[c]carbazoles is described. Key steps include the use of the Suzuki-Miyaura reaction to afford 2- or 3-aryl substituted indoles, as well as a potassium t-butoxide and light assisted aromatic ring-forming reaction.     

Solvent-controlled selective synthesis of a trans-configured benzimidazoline-2-ylidene palladium(II) complex and investigations of its Heck-type catalytic activity

Reaction of N,N′-dimethylbenzimidazolyl iodide (A) with Pd(OAc)₂ in DMSO gives selectively trans-bis(N,N′-dimethylbenzimidazoline-2-ylidene) palladium(II) diiodide (trans-2) in 77% yield. The selective formation of the trans-coordination isomer and thus the cis-trans rearrangement is driven by the insolubility of trans-2 in DMSO. X-ray single-crystal diffraction analysis and ¹³C NMR spectroscopy confirm the trans-geometry of the square planar Pd(II) complex. Catalytic studies show that cis-1 and trans-2 are highly efficient in the Mizoroki-Heck coupling reaction of aryl bromides and activated aryl chlorides both in DMF and [N(n-C₄H₉)₄]Br as ionic liquid. The catalytic activities of Pd(II) complexes with N-heterocyclic carbene ligands derived from benzimidazole are comparable to their imidazole-derived analogues.     

A new application of the Mitsunobu reaction in the synthesis of phosphonium salts

The condensation of methanol or primary alcohols with triphenylphosphonium tetrafluoroborate in the presence of ethyl azodicarboxylate and triphenylphosphine in THF at room temperature gives the respective alkyltriphenylphosphonium salts in good yields. The reaction also worked for the conversion of N-acyl-2-hydroxyglycinates into N-acyl-2-triphenylphosphonioglycinates.     

A new route to 2,2′,3,3′-tetrasubstituted binaphthyls

Based on an ortho-lithiation protocol of 2,2′-dibromo-1,1′-binaphthyl four tetrasubstituted binaphthyls, 2,2′-dibromo-3,3′-diiodo-, 3,3′-dibromo-2,2′-diiodo-, 2,2′,3,3′-tetrabromo-, and 2,2′,3,3′-tetraiodo-1,1′-binaphthyls have been prepared in excellent yield which in turn proved to be versatile key intermediates in the synthesis of various 2,2′,3,3′-tetrasubstituted 1,1′-binaphthyl derivatives.     

Efficient synthesis of new butenolides by subsequent reactions: application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones

We have developed the synthesis of twenty four new iminolactones, bis-iminolactones and bis-lactones by subsequent esterification-condensation or addition-condensation reactions according to two strategies from α-hydroxyketones. The X-ray diffraction data of a bis-iminolactone is described and present an interesting helical column packing.     

Highly efficient synthesis of spirocyclic (1R)-camphor-derived triazolium salts: application in the catalytic asymmetric benzoin condensation

New (1R)-camphor-derived triazolium salts, incorporating a spirocyclic system, are described. Benzoin condensation of aromatic aldehydes, mediated by these salts affords α-hydroxyketones in good yields and moderate enantiomeric excesses.     

Practical and efficient synthesis of N-halo compounds

A practical and efficient synthesis of N-halo compounds is described. Treatment of primary and secondary amines or amides with sodium hypohalite in the presence of tert-butanol and acetic acid afforded N-halo compounds in 90-100% yield.     

A novel reagent combination for the oxidation of highly electron deficient pyridines to N-oxides: trifluoromethanesulfonic anhydride/sodium percarbonate

A novel reagent combination, Tf₂O/Na₂CO₃·1.5H₂O₂, has been developed for the oxidation of highly electron deficient pyridines to their corresponding N-oxides. The N-oxidation reaction, utilizing the in situ generated peracid, proceeds under mild conditions that allow for a number of functional groups and substitution patterns on the pyridine ring.     

Intermolecular reductive coupling of hindered N-aryl imines towards the modular synthesis of chiral N-heterocyclic carbenes

We describe a simple method for the synthesis of hindered N-aryl diamines. The diastereoselectivity for these processes are relatively low but the diamines can be separated using either chromatography or selective crystallization. Separation of enantiomers can be accomplished using HPLC equipped with a chiral stationary phase.     

Convergent synthesis of the ABCDE ring fragment of ciguatoxins

Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent manner via the B-alkyl Suzuki-Miyaura coupling-based approach.     

Asymmetric synthesis of abietane diterpenoids via B-alkyl Suzuki-Miyaura coupling. Formal total asymmetric synthesis of 12-deoxyroyleanone and cryptoquinone

A convergent synthetic strategy for abietane diterpenoids via B-alkyl Suzuki-Miyaura coupling and Lewis acid-mediated cyclization reactions is established. Asymmetric total synthesis of 12-deoxyroyleanone, an antileishmanial diterpene, is described.