Cyclic Precursors Research Articles

ChemInform Abstract: Synthesis of a Stereoisomer of Frullanolide Utilizing the Intramolecular Cyclization of ω-Formyl-2-alkenylsilane.

Synthesis of 10-epi-frullanolide (3) is reported via the intramolecular cyclization of ω-formyl-α-trimethylsilylmethyl-α,β-unsaturated ester. The cyclization precursor, ethyl (Z)-5-(2-formyl-1,3-di...

Synthesis, Structure Determination, and Biological Evaluation of Destruxin E

The total synthesis of destruxin E (1) has been achieved for the first time, and the stereochemistry of its chiral center at the epoxide has been determined to be (S). The cyclization precursor 3a was synthesized by solid-phase peptide synthesis. Macrolactonization of 3a utilizing MNBA-DMAPO, followed by formation of the epoxide, then furnished destruxin E. Its diastereomer, epi-destruxin E (2), was also synthesized in the same manner. Furthermore, the biological evaluation indicated that destruxin E exhibits V-ATPase inhibitory activity 10-fold greater than that of epi-destruxin E.

Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A2 and B2

Development of the total syntheses of arylomycins A(1) and B(2) is detailed. Key features of our approach include 1) formation of 14-membered meta,meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A(2) was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13 % overall yield. Arylomycin B(2) was synthesized in 10 steps from L-3-nitro-Tyr, in 10 % overall yield.

ChemInform Abstract: Stereodivergent Synthesis of Highly Substituted Tetrahydropyrans.

Intramolecular oxa-conjugate addition has been employed in a stereoselective synthesis of enantiopure polyalkyl-substituted tetrahydropyrans, which are frequently found as substructures in many natural products. The requisite cyclization precursors, 7-hydroxy-2-enimides 3 and 7-hydroxy-2-enoates 6 were easily accessible by silyloxy Cope rearrangements of the appropriate chiral syn-aldols. It was found that the stereoselectivity of the cyclization could be controlled by judicious choice of the carboxylic acid derivative, resulting in a kinetically controlled reaction for the imides and a thermodynamically controlled process for the esters. Mechanistic considerations that could account for the stereocontrol of the process are outlined.

ChemInform Abstract: Synthesis of Bicyclic Lactams via Ring Closing Olefin Metathesis and Intramolecular Heck Reaction.

The application of the ring closing olefin metathesis and the intramolecular Heck reaction as key steps in the synthesis of 6,5- and 7,5-fused enantiomerically pure bicyclic lactams starting from a chiral pyrrolidone is shown. The diolefinic cyclization precursors can be obtained by a combined electrochemical oxidation- N- acyliminium coupling reaction and a subsequent N-alkylation using an unsaturated alkyl bromide.

Synthesis and evaluation of an Iejimalide-archazolid chimera

Even though the macrolides of the iejimalide family are of marine origin, whereas those of the archazolid series derive from terrestrial myxobacteria, a comparison of their constitution, stereochemistry, and biological activity suggests that these natural products are close structural and functional relatives. Guided by this perception, compound 5 was prepared, which hybridizes the macrolactone core of iejimalide B ( 2) with the tail of archazolid A ( 3). The cytotoxicity profile of this chimera, as determined with a panel of 12 human cancer cell lines, corresponds to that of the parent compound 2, although its potency is lower. This outcome may be interpreted on the basis of molecular dynamics calculations, which suggest that the low energy conformations of 2 and 5 are similar but the energetic barriers between the relevant conformers are distinctly higher for the hybrid structure. The synthesis of 5 hinged on a regioselective functionalization of 2,4-dibromothiazole 6, a highly selective CBS-reduction of ketone 8, a Suzuki cross coupling of vinyl boronate 17 with the elaborate alkenyl iodide 16, and a productive closure of the macrocycle by RCM, which requires the selective activation of two out of eight double bonds present in the cyclization precursor 20 by the second-generation Grubbs catalyst 21.

A novel route to substituted poly(vinyl pyrrolidone)s via simple functionalization of 1-vinyl-2-pyrrolidone in the 3-position by ring-opening reactions

A general synthetic approach is described that allows to obtain novel 1-vinyl-2-pyrrolidone (VP) derivatives with different kinds of functional groups in its 3-position in a one-pot reaction. The strategy used to achieve this goal is the reaction of the carboxamide anion of 1-vinyl-2-pyrrolidone with cyclic precursors of these functionalities. While the driving force for the reactions of three-membered rings is their high annular tension, it is shown here that larger heterocycles can be opened with good yield when additional electron-withdrawing groups are present in the ring. This leads to VP with longer spacer groups between the functionality and the future polymeric main chain. Furthermore, the high versatility of this procedure is demonstrated by the preparation, for the first time, of VP modified with amine or sulfonic functionalities that allow to prepare the corresponding aminated and sulfonated PVPs.

Intramolecular Diels–Alder cyclization of biodihydroxylated benzoic acid derivatives towards novel heterocyclic scaffolds

The potential of biodihydroxylated benzoic acid derivatives as versatile precursors for the construction of polycyclic scaffolds was investigated. Ralstonia eutropha B9 was used to biodihydroxylate sodium benzoate to sodium (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylate in high optical purity (>95% ee). The required cyclization precursors could be obtained in moderate to excellent yields after protection of the intermediate and subsequent functional group transformation. Intramolecular Diels–Alder cylizations were carried out under thermal or microwave conditions leading to enantiomerically pure products with five chiral centers.

New strategy in synthetic biology: from enzyme inhibition and natural products synthesis to PET imaging by 6π‐azaelectrocyclization

While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6pi-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling of biomolecules based on the rapid 6pi-azaelectrocyclization. Both DOTA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10(-8) m. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with (68)Ga to observe the receptor-mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time.

Enantioselective Chemoenzymatic Synthesis of cis- and trans-2,5-Disubstituted Morpholines

A versatile synthesis of enantiomerically pure cis- and trans-2,5-disubstituted morpholines is described. Hydroxynitrile lyase-mediated cyanide addition onto aldehydes provided cyanohydrins in virtually quantitative yield and excellent enantioselectivity. Subsequent formation of diastereomerically pure amino esters via a three-step, one-pot reduction-transimination-reduction sequence followed by reduction and simultaneous protection provided cyclization precursors. Finally, cyclization and SmI(2)-mediated reductive detosylation completed the synthesis of cis- and trans-2,5-disubstituted morpholines in good yields and excellent diastereoselectivities.

A concise formal synthesis of diazonamide A by the stereoselective construction of the C10 quaternary center.

Protecting groups are overrated! A formal total synthesis of diazonamide A is described. The key step in this synthesis is an intramolecular SNAr reaction between an oxindole and a bromooxazole. Interestingly, this reaction proceeds best using the mild base Na2CO3, and with no protecting groups on the oxindole nitrogen atom or phenol groups of the cyclization precursor.

Thermodynamic equilibration in Pd(0)-catalyzed interconversion of highly constrained [2.1.2] bicyclic lactones: its mechanistic investigation

Mechanistic study on the stereoselective construction of [2.1.2] bicyclic lactone skeleton via Pd(0)-catalyzed intramolecular allylic alkylation was described. The observed excellent stereoselectivity is likely due to Pd(0)-catalyzed equilibration of highly strained [2.1.2] bicyclic lactone framework via π-σ-π isomerization of π-allylpalladium complex. An efficient synthetic route to allylic carbonate as a requisite cyclization precursor has also been developed by employing a sequence of ring-closing metathesis, followed by epoxidation/desilylation of the resulting substituted oxasilepene intermediate.

Synthesis and biological evaluation of anti-1-amino-2-[ 18F]fluoro-cyclobutyl-1-carboxylic acid ( anti-2-[ 18F]FACBC) in rat 9L gliosarcoma

A new [ 18F] labeled amino acid anti-1-amino-2-[ 18F]fluoro-cyclobutyl-1-carboxylic acid 9 ( anti-2-[ 18F]FACBC) was synthesized in 30% decay-corrected yield with high radiochemical purity over 99%. The cyclic sulfamidate precursor was very stable and highly reactive towards nucleophilic radiofluorination. Cell uptake assays with rat 9L gliosarcoma cells showed that [ 18F] 9 was transported into tumor cells via multiple amino acid transport systems, including L and A systems. Biodistribution study in rats with intracranial 9L gliosarcoma tumors demonstrated that [ 18F] 9 had a rapid and prolonged accumulation in tumors with 26:1 tumor to brain ratio at 120 min post-injection. In this model, [ 18F] 9 is a potential PET tracer for brain tumor imaging.

The reversible macrocyclization of Tyrocidine A aldehyde: a hemiaminal reminiscent of the tetrahedral intermediate of macrolactamization

In spite of the important role of peptide macrocyclizations for the generation of conformationally constrained biological ligands, our knowledge of factors that determine the inclination of a substrate to cyclize is low. Therefore, methods that give access to the thermodynamic characterization of these processes are desirable. In this work, we present the isosteric substitution of the amide ligation site of a cyclopeptide by an imine. Applied to the decapeptide antibiotic Tyrocidine A (TycA), the reversible cyclization of the linear aldehyde TycA-CHO resulted in the unexpectedly stable hemiaminal Psi[CH(OH)NH]-TycA, which is equivalent to the tetrahedral intermediate of macrolactamization, and which is observed for the first time in a peptidic structure. On the basis of NMR spectroscopy and molecular modeling, we discuss the observed high stereoselectivity of hemiaminal formation, as well as its reluctance to be dehydrated to the imine. As required for thermodynamic analysis, it is possible to establish a pH- and temperature-dependent cyclization equilibrium, which allows determination of the entropy loss of the peptide chain, and quantification of the extent of preorientation of the cyclization precursor.

Synthesis of chiral polyazamacrocycles of variable ring size

Synthesis and structure elucidation of optically active tri-, tetra-, and penta-azamacrocycles having 4-methoxyphenyl pendants are described. Regioselective ring opening of a nosylaziridine with secondary benzyl amines was repeatedly performed to afford the cyclization precursors. Intramolecular N-alkylation of N-(omega-haloalkyl) nosylamide provided tri-, tetra-, and penta-azamacrocycles. On the basis of our study of the tetra-azamacrocycle previously elucidated by X-ray single-crystal analysis and in solution by NMR analysis, we conclude that the tri-azamacrocycle does not mainly have a vase-type conformation because of the steric hindrance of the 4-methoxyphenyl groups but the penta-azamacrocycle has a vase-type conformation in CDCl(3) and in CD(2)Cl(2). The vase-type conformation of the penta-azamacrocycle is, however, not as much stable as that observed in the tetra-azamacrocycle because conformational flexibility of the penta-azamacrocycle was observed in deuterated benzene.

Genetic interception and structural characterization of thiopeptide cyclization precursors from bacillus cereus

Genetic interception and structural characterization of thiopeptide cyclization precursors from bacillus cereus

Synthesis, Radiolabeling, and Biological Evaluation of (R)- and (S)-2-Amino-3-[18F]Fluoro-2-Methylpropanoic Acid (FAMP) and (R)- and (S)-3-[18F]Fluoro-2-Methyl-2-N-(Methylamino)propanoic Acid (NMeFAMP) as Potential PET Radioligands for Imaging Brain Tumors

The non-natural amino acids (R)- and (S)-2-amino-3-fluoro-2-methylpropanoic acid 5 and (R)- and (S)-3-fluoro-2-methyl-2-N-(methylamino)propanoic acid 8 were synthesized in shorter reaction sequences than in the original report starting from enantiomerically pure (S)- and (R)-alpha-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[(18)F]5 and (R)- and (S)-[(18)F]8 in fewer steps than in the original report. (R)- and (S)-[(18)F]5 and(R)- and (S)-[(18)F]8 were synthesized by no-carrier-added nucleophilic [(18)F]fluorination in 52-66% decay-corrected yields with radiochemical purity over 99%. The cell assays showed that all four compounds were substrates for amino acid transport and enter 9L rat gliosarcoma cells in vitro at least in part by system A amino acid transport. The biodistribution studies demonstrated that in vivo tumor to normal brain ratios for all compounds were high with ratios of 20:1 to115:1 in rats with intracranial 9L tumors. The (R)-enantiomers of [(18)F]5 and [(18)F]8 demonstrated higher tumor uptake in vivo compared to the (S)-enantiomers.

Enantioselective Fujiwara–Moritani Indole and Pyrrole Annulations Catalyzed by Chiral Palladium(II)–NicOx Complexes

AbstractThe catalytic asymmetric Fujiwara–Moritani ring closures of several indole‐ and pyrrole‐based cyclization precursors are reported. These unprecedented oxidative palladium(II)‐catalyzed annulations allow for the formation of a stereogenic quaternary carbon atom, and decent levels of enantiocontrol are seen in 5‐exo‐trig cyclizations (54 % ee for an indole and 76 % ee for a pyrrole) while 6‐exo‐trig ring closures afford essentially racemic material. Novel oxazoline ligands with a nicotine platform (NicOx) are pivotal for good catalytic turnover as conventional PyOx ligands failed to produce acceptable chemical yields. The preparation of these NicOx ligands as well as the syntheses of the cyclization precursors are described in detail.

“One‐pot” Synthesis of 1‐Vinyl‐2‐pyrrolidone with Protic Functional Groups in 3‐Position

AbstractA synthetic route that allows modification of 1‐vinyl‐2‐pyrrolidone with an alcohol or thiol group in its 3‐position in a one‐pot reaction without using protecting groups is described. The strategy used to achieve this goal is the reaction of the carboxamide anion of 1‐vinyl‐2‐pyrrolidone with cyclic precursors of these functionalities. It is furthermore shown that VP‐monomers functionalized with OH groups are suitable for the preparation of the corresponding copolymers with pure VP. As a second application of the new compounds, we also describe the synthesis of the first asymmetric crosslinker based on VP.magnified image

Asymmetric and diastereodivergent approach to key intermediates for the synthesis of homopumiliotoxin 223G and epiquinamide isomer

A stereoselective reaction followed by a sequential cyclization route has been used in the divergent synthesis of 1-hydroxyquinolizidione isomers. Sharpless asymmetric dihydroxylation afforded hydroxyl lactone and the following mesylation provided the required precursor for cyclization.