Base-promoted regioselective synthesis of 1,2,3,4-terahydroquinolines and quinolines from N-boc-3-piperidone

An efficient synthesis of 1,2,3,4-tetrahydroquinolines with donor and acceptor group has been delineated by base mediated ring transformation of 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles by N-boc-3-piperidone followed by consecutive deprotection of Boc group under acidic conditions. This reaction involves 2 new bond formations namely C4a-C5 and C8a-C8 in order to create the nucleus. Various donor and acceptor functional groups like aryl, heteroaryl, nitrile, methylsulfanyl and secondary amine were installed in 1,2,3,4-tetrahydroquinolines. We extended our approach to synthesize the fused 1,2,3,4-tetrahydroquinolines by using 2-oxobenzo[h]chromenes as precursor. Further, we synthesized fused and isolated quinolines through aromatization of 1,2,3,4-tetrahydroquinolines by DDQ in excellent yields. Single-crystal X-ray analysis of the Boc protected tetrahydroisoquinoline 6t showed the steric hindrance between N-Boc and aryl group.     

A Flexible Approach to the γ－Amino－β－hydroxy Acid Moiety of Hapalosin

A flexible approach to ethyl (3R,4S)-N-Boc-4-amino-3-hydroxy-5-phenylpentanoate (N-Boc-AHPPA-OEt), the γ-amino-β-hydroxy acid moiety of hapalosin is described. The synthetic method features a ring-opening ethanolysis of an activated N-Boc-lactam, which is obtained via a diastereoselective reductive-alkylation of (R)-malimide derivative. The flexibility of the method resides in the introduction of the alkyl side chain by Grignard reagent addition.     

Synthesis of N,N-Ac,Boc laurylthio sialoside and its application to O-sialylation

The combination of the 5-N-tert-butoxycarbonyl (Boc) group of laurylthio sialoside and cyclopentyl methyl ether (CPME) as a solvent enhanced the reactivity and α-selectivity of the sialyl donor during sialylation. Selective deprotection of the N-Boc group of sialoside, including an acid-sensitive isopropylidene function, was successfully achieved by Yb(OTf)₃-SiO₂. Transformation of N,N-Ac,Boc into an N-acetylglycolyl group of sialoglycoside was easily performed via selective N-deacylation of the mixed Ac-N-Boc carbamate, subsequent Boc group removal, and acylation.     

Synthesis of bivalent ligands of β-carboline-3-carboxylates via a palladium-catalyzed homocoupling process

The first synthesis of bivalent ligands of β-carboline-3-carboxylates has been achieved from β-carboline-3-carboxylate tert-butyl ester (βCCt) via Sonogashira and palladium-catalyzed homocoupling processes. The Boc protected intermediate, an iodo-β-carboline-3-carboxylate, was employed to provide a general entry into a series of bivalent ligands structurally similar to βCCt.     

BF3·Et2O and trifluoroacetic acid/triethyl amine-mediated synthesis of functionalized piperidines

A two-step short and efficient strategy for the synthesis of substituted piperidones and piperidines in high diastereoselectivity (only trans-configuration), by employing cascade type reaction using BF₃·Et₂O or by carrying out one pot deprotection of ^tBoc group followed by intramolecular aza-Michael addition of α,β-unsaturated beta keto esters has been developed. Using a similar strategy a short access to hydroxy pipecolic acid is also described. Very simple and rapid experimental procedures involving mild conditions and only one or two chromatographic purifications are the main features of the process.     

Enzymatic resolution of N-protected-β3-amino methyl esters,using lipase B from Candida antarctica

Racemic β³-amino methyl esters bearing the amine function protected with Bz, Cbz, Boc, Fmoc and as aminobenzamide, were resolved by enantiospecific transesterifications catalyzed by lipase B from Candida antarctica. The reactions proceeded with a high conversion and yielded enantiomerically pure enantiomers.     

Synthesis of 4-unsubstituted dihydropyrimidines having acyl and alkoxycarbonyl groups at 5- and 6-positions by cyclization–elimination reactions using 1,3-diaza-1,3-butadienes

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by ¹H NMR spectroscopy.     

Structural characterization of folded pentapeptides containing centrally positioned β(R)Val, γ(R)Val and γ(S)Val residues

A cylindrical pore of ～7.5 Å diameter containing a one-dimensional water wire, within the confines of a hydrophobic channel lined with the valine side chain, has been observed in crystals of the peptide Boc–d-Pro-Aib-Val-Aib-Val–OMe (1) (Raghavender et al., 2009, 2010). The synthesis and structural characterization in crystals of three backbone homologated analogues Boc–d-Pro-Aib-β³(R)Val-Aib-Val–OMe (2), Boc–d-Pro-Aib-γ⁴(R)Val-Aib-Val–OMe (3), Boc–d-Pro-Aib-γ⁴(S)Val-Aib-Val–OMe (4) are described. Crystal structures of peptides 2, 3 and 4 reveal close-packed arrangements in which no pore was formed. In peptides 2 and 3 the N-terminus d-Pro-Aib segment adopted conformations closely related to Type II′ β-turns, while residues 2–4 form one turn of an αβ right-handed C₁₁ helix in 2 and an αγ C₁₂ helix in 3. In peptide 4, a continuous left-handed helical structure was observed with the d-Pro-Aib segment forming a Type III′ β-turn, followed by one turn of a left-handed αγ C₁₂ helix.     

Copper nanoparticles catalyzed N-H functionalization: An efficient solvent-free N-tert-butyloxycarbonylation strategy

A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives (NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate, mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino acid esters and amino alcohols were performed without racemization.     

Size‐Controlled Fabrication of Polyaniline Microfibers Based on 3D Hydrodynamic Focusing Approach

Owing to the relatively high conductivity and unique redox behavior, polyaniline (PANI) has been one of the most technologically promising conducting polymers. Although various methodologies have been developed, fabrication of PANI microfibers has been a challenging task owing to the poor solubility in most organic solvents. By taking advantage of a microfluidic technology and organic soluble acid labile t‐Boc‐protected PANI (t‐Boc‐PANI) as the conducting polymer precursor, fabrication of PANI microfibers in a size‐controlled manner is possible. Introduction of a THF solution containing t‐Boc‐PANI, and dodecylbenzenesulfonic acid (DBSA) as a core flow, and water as a sheath flow into a microfluidic channel with a 3D hydrodynamic focusing effect results in crystallization of the polymer fiber. By changing the flow rate, linear PANI microfibers that range from 16.2 to 39.4 μm in diameter are readily obtained.

     

Differentiation of Boc‐protected α,δ‐/δ,α‐ and β,δ‐/δ,β‐hybrid peptide positional isomers by electrospray ionization tandem mass spectrometry

Two new series of Boc‐N‐α,δ‐/δ,α‐ and β,δ‐/δ,β‐hybrid peptides containing repeats of L ‐Ala‐δ⁵‐Caa/δ⁵‐Caa‐L ‐Ala and β³‐Caa‐δ⁵‐Caa/δ⁵‐Caa‐β³‐Caa (L ‐Ala = L ‐alanine, Caa = C‐linked carbo amino acid derived from D ‐xylose) have been differentiated by both positive and negative ion electrospray ionization (ESI) ion trap tandem mass spectrometry (MS/MS). MSⁿ spectra of protonated isomeric peptides produce characteristic fragmentation involving the peptide backbone, the Boc‐group, and the side chain. The dipeptide positional isomers are differentiated by the collision‐induced dissociation (CID) of the protonated peptides. The loss of 2‐methylprop‐1‐ene is more pronounced for Boc‐NH‐L ‐Ala‐δ‐Caa‐OCH₃ (1), whereas it is totally absent for its positional isomer Boc‐NH‐δ‐Caa‐L ‐Ala‐OCH₃ (7), instead it shows significant loss of t‐butanol. On the other hand, second isomeric pair shows significant loss of t‐butanol and loss of acetone for Boc‐NH‐δ‐Caa‐β‐Caa‐OCH₃ (18), whereas these are insignificant for its positional isomer Boc‐NH‐β‐Caa‐δ‐Caa‐OCH₃ (13). The tetra‐ and hexapeptide positional isomers also show significant differences in MS² and MS³ CID spectra. It is observed that ‘b’ ions are abundant when oxazolone structures are formed through five‐membered cyclic transition state and cyclization process for larger ‘b’ ions led to its insignificant abundance. However, b₁⁺ ion is formed in case of δ,α‐dipeptide that may have a six‐membered substituted piperidone ion structure. Furthermore, ESI negative ion MS/MS has also been found to be useful for differentiating these isomeric peptide acids. Thus, the results of MS/MS of pairs of di‐, tetra‐, and hexapeptide positional isomers provide peptide sequencing information and distinguish the positional isomers. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis and structural studies of a novel scaffold for drug discovery: a 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4-piperidine]

We describe the three-step synthesis of a novel 4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4^′-piperidine] scaffold from ortho-hydroxyacetophenone and N-benzylpiperidone. The structure of one disubstituted derivative, studied by NOESY NMR in an aqueous medium and X-ray diffraction, demonstrates that this scaffold presents side chains in a well-defined orientation. The Boc protected derivative represents a key intermediate for the combinatorial synthesis of drug-like molecules.     

Catalytic Asymmetric Synthesis of 3‐Indolyl Methanamines Using Unprotected Indoles and N‐Boc Imines under Basic Conditions

A chiral imidazolidine‐containing NCN/Pd‐OTf catalyst ( C4 ) promoted the nucleophilic addition of unprotected indoles to N‐Boc imines. Using sulfinyl amines as the N‐Boc imine precursors, the combined use of C4 with K₂CO₃ activated the NH indoles to give chiral 3‐indolyl methanamines with up to 98 % ee. Compared with conventional acid‐catalyzed Friedel–Crafts reactions, this reaction proceeds under mildly basic conditions and is advantageous for the use of acid‐sensitive substrates.     

Efficient synthesis of substituted quinolines through intramolecular addition of aryl anion to carbonyl carbon

Substituted quinolines were synthesized in three steps from the Boc amides of substituted 2-iodoanilines and alkyl vinyl ketones. This method consists of (1) N-Michael addition of the Boc amide of 2-iodoaniline to alkyl vinyl ketone in the presence of Cs₂CO₃ in MeCN; (2) I-Mg exchange of the adduct with 3.5 equiv of i-PrMgCl·LiCl, and (3) acid-catalyzed reaction (excess AcCl in EtOH) of the resulting alcohol. Six examples are given with good yields.     

cis‐trans Peptide‐Bond Isomerization in α‐Methylproline Derivatives

α‐Methyl‐L ‐proline is an α‐substituted analog of proline that has been previously employed to constrain prolyl peptide bonds in a trans conformation. Here, we revisit the cis‐trans prolyl peptide bond equilibrium in derivatives of α‐methyl‐L ‐proline, such as N‐Boc‐protected α‐methyl‐L ‐proline and the hexapeptide H‐Ala‐Tyr‐αMePro‐Tyr‐Asp‐Val‐OH. In Boc‐α‐methyl‐L ‐proline, we found that both cis and trans conformers were populated, whereas, in the short peptide, only the trans conformer was detected. The energy barrier for the cis‐trans isomerization in Boc‐α‐methyl‐L ‐proline was determined by line‐shape analysis of NMR spectra obtained at different temperatures and found to be 1.24 kcal/mol (at 298 K) higher than the corresponding value for Boc‐L ‐proline. These findings further illuminate the conformationally constraining properties of α‐methyl‐L ‐proline.     

Base-labile tert-butoxycarbonyl (Boc) group on phenols

Phenols are deprotected with weak bases from their tert-butoxycarbonyl (Boc) derivatives. Boc deprotection with bases can avoid side reactions during the deprotection with acids. We note the lability of the Boc to bases and are able to utilize it as a new cleavage condition for synthetic studies.     

Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or ¹H NMR spectroscopy and X-ray diffraction.     

A highly chemoselective Boc protection of amines using sulfonic-acid-functionalized silica as an efficient heterogeneous recyclable catalyst

A facile and versatile method for the chemoselective Boc protection of amines has been developed by a treatment with (Boc)₂O in the presence of sulfonic-acid-functionalized silica as a catalyst. The method is general for the preparation of N-Boc derivatives of aliphatic (acyclic and cyclic), aromatic, and heteroaromatic amines; primary and secondary amines; aminols, amino-esters; and sulfonamides. The catalyst works under heterogeneous conditions and can be recycled.     

Synthesis of N-glycyl-β-glycopyranosylamines, human milk fucooligosaccharide derivatives

The action of ammonium carbamate in aqueous methanol in the presence of NH₃ on three-, penta-, hexa-, octa-, and nonasaccharides of human milk and on decasaccharide (N-glycan from human immunoglobulin (IgG)) containing one or two a-l-fucose residues led to the corresponding β-glycopyranosylamines. After their N-acylation upon treatment with N-hydroxysuccinimide ester of N-Boc-glycine or N-Boc-glycine anhydride (Boc is the tert-butyloxycarbonyl) with subsequent removal of the Boc group, N-glycyl-β-glycopyranosylamines were obtained in up to 75% yield.     

N6-tert-Butoxycarbonyl derivatives of sydnone imines: Preparation and synthetic use

A highly efficient gram-scale method for the C(4)-functionalization of sydnone imine hydrochloride derivatives was developed. This new approach was realized through consecutive reactions including the preparation of a C(3)-substituted N₆-tert-butoxycarbonyl sydnone imine derivative, deprotonation with n-BuLi and reaction of the lithiated-intermediate with an electrophilic agent, and removal of the Boc protecting group.