Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium cyclization and O-N Smiles rearrangement

The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O-N Smiles rearrangement. The present cascade exhibited a different profile compared to the previously reported ones, which consisted of N-N Smiles rearrangement. Lewis acid (TiCl₄) under carefully controlled conditions was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives with potential biological activities.     

Experimental and quantum-mechanical investigation of the vinylsilane-iminium ion cyclization

A vinylsilane-ketiminium ion cyclization involving iminium species derived from amines 6 and 7 was investigated experimentally as a possible approach to some biologically interesting 1-azaspirocycles. However, even under conditions of microwave irradiation at high temperatures no such cyclization was observed whereas (in line with previous results) the corresponding vinylsilane-aldiminium ion cyclizations were more successful. Aldiminium species substituted alpha to nitrogen displayed no diastereoselectivity in the cyclization of precursors derived from 6 while high trans diastereoselectivity could be obtained for iminium species derived from 7. Quantum-mechanical investigations of the general reaction mechanism underlined the lack of reactivity of ketiminium species and also convincingly explained the observed diastereoselectivities of aldiminium species. The calculations further revealed that (Z)-vinylsilanes cyclize via a silicon-stabilized beta-carbocation, and that any formal aza-Cope rearrangement of the starting material to an allylsilane-iminium species does not take place in a concerted fashion. However, the calculations show that the aza-Cope rearrangement precedes cyclization for the corresponding (E)-vinylsilanes, the overall reaction being energetically slightly less favoured than cyclization of the (Z)-isomers.     

A cascade reaction consisting of Pictet-Spengler-type cyclization and Smiles rearrangement: application to the synthesis of novel pyrrole-fused dihydropteridines

[reaction: see text] Tandem Pictet-Spengler-type cyclization and Smiles rearrangement have been discovered in the synthesis of pyrimidine-fused heterocycles. The reaction of 4-chloro-5-pyrrol-1-ylpyrimidine amino aldehyde with an amine under an acidic condition yielded the Pictet-Spengler-type cyclization product diazepine, which readily underwent Smiles rearrangement to give a novel pyrrolo[1,2-f]pteridine derivative.     

Synthesis of pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives via tandem iminium cyclization and smiles rearrangement

The tandem iminium cyclization and Smiles rearrangement of pyridinyloxyacetaldehyde 1 and a primary amine generated a novel pyrido[2,3-e]pyrrolo[1,2-a]pyrazine scaffold. TFA was discovered to be an efficient catalyst in the reactions with aromatic amines, whereas TiCl4 was found to be superior in the case of aliphatic amines. This methodology proved to be efficient in the preparation of a library of diversified pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives.     

Diastereocontrol by a hydroxyl auxiliary in the synthesis of pyrrolidines via radical cyclization

[reaction: see text] Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone, and regioselective benzeneselenol ring opening of the aziridine. Reductive radical cyclization was highly selective, affording the corresponding trans-2,4-disubstituted pyrrolidine (cis/trans ca. 1/10) as the major diastereomer. Recrystallization afforded material that was substantially more enriched in the trans isomer (cis/trans < 1/25).     

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.     

A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach

A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.     

A New Benzotriazole‐Mediated Stereoflexible Gateway to Hetero‐2,5‐diketopiperazines

Open chain Cbz‐L ‐aa¹‐L ‐Pro‐Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans‐ or cis‐fused 2,5‐diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans‐DKPs (69–75 %). Complementarily, tandem deprotection/cyclization led to the cis‐DKPs (65–72 %). A representative set of proline‐containing cis‐ and trans‐DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

2-氯-2-氧代(硫代)-1, 3, 2-二氧磷杂环己烷的甲醇解及其开环 异构化反应

报道了trans-2-氧代-2-氯-4-苯基-5,5-二甲基-1,3,2-二氧磷杂环己烷以及cis-2-硫代-2-氯-4-苯基-5,5-二甲基-1,3,2-二氧磷杂环己烷甲醇解反应的立体化学。结果表明,反应体系的酸碱性对前者甲醇解反应的立体化学有着重要影响。而硫代环磷酰氯在碱性条件下的甲醇解反应存在一个开环异构化过程。     

α-三唑基查尔酮与苯肼的加成-关环反应研究

(Z)或(E)-1,3-二芳基-2-(1H-1,2,4-三唑-1-基)-2-丙烯-1-酮与苯肼在醋酸中反应均生成顺式和反式吡唑啉异构体混合物,但是在三乙胺催化下却只生成反式的异构体。制备了三对顺、反式的1-苯基-3,5-二芳基-4-(1H-1,2,4-三唑-1-基)-2-吡唑啉衍生物,其结构为^1HNMR和元素分析证实,初步论证了经α-氮原子的加成-环化反应机理。     

Comparative study of anionic and radical cyclization for the preparation of 1,3-dimethylindans: highly stereoselective preparation of cis-1,3-disubstituted indans via intramolecular carbolithiation

[reaction: see text] The preparation of 1,3-dimethylindans from 4-(2-bromophenyl)-1-pentene (1) and 2-(2-iodo-1-methylethyl)styrene (2) substrates via radical-mediated cyclization and intramolecular carbolithiation has been investigated. Although cyclization of the radical derived from either substrate proceeds with modest selectivity for the cis-isomer, as does cycloisomerization of the aryllithium derived from substrate 1 (cis/trans approximately 2), intramolecular cyclization of the alkyllithium derived from substrate 2 is a highly cis-selective process (cis/trans = 12).     

Probing highly efficient photoisomerization of a bridged azobenzene by a combination of CASPT2//CASSCF calculation with semiclassical dynamics simulation

Mechanism of phototriggered isomerization of azobenzene and its derivatives is of broad interest. In this paper, the S(0) and S(1) potential energy surfaces of the ethylene-bridged azobenzene (1) that was recently reported to have highly efficient photoisomerization were determined by ab initio electronic structure calculations at different levels and further investigated by a semiclassical dynamics simulation. Unlike azobenzene, the cis isomer of 1 was found to be more stable than the trans isomer, consistent with the experimental observation. The thermal isomerization between cis and trans isomers proceeds via an inversion mechanism with a high barrier. Interestingly, only one minimum-energy conical intersection was determined between the S(0) and S(1) states (CI) for both cis → trans and trans → cis photoisomerization processes and confirmed to act as the S(1) → S(0) decay funnel. The S(1) state lifetime is ～30 fs for the trans isomer, while that for the cis isomer is much longer, due to a redistribution of the initial excitation energies. The S(1) relaxation dynamics investigated here provides a good account for the higher efficiency observed experimentally for the trans → cis photoisomerization than the reverse process. Once the system decays to the S(0) state via CI, formation of the trans product occurs as the downhill motion on the S(0) surface, while formation of the cis isomer needs to overcome small barriers on the pathways of the azo-moiety isomerization and rotation of the phenyl ring. These features support the larger experimental quantum yield for the cis → trans photoisomerization than the trans → cis process.     

Light-driven molecular hinge: a new molecular machine showing a light-intensity-dependent photoresponse that utilizes the trans-cis isomerization of azobenzene

[reaction: see text] A new class of molecular machine exhibits a hingelike motion upon photoirradiation. The motion (close and open) can be operated by alternate irradiation with UV and visible light. The trans/trans and cis/cis isomers are thermally stable at 40 degrees C, and the photochemical closure reaction (from trans/trans to cis/cis isomer) is dependent on the intensity of the light used because of the short-lived intermediate (trans/cis isomer).     

A new convergent and stereoselective synthesis of 2,5-disubstituted N-acylpyrrolidines

A new synthesis of 2,5-disubstituted N-acylpyrrolidines through an S_N2′ reaction promoted by the nitrogen anion of a secondary amide onto an allylic bromide is reported. A moderate stereoselectivity, in favour of the trans heterocycle, was observed during the cyclization of a chiral precursor, while a good stereoselectivity, this time in favour of the cis one, was obtained when the second stereocentre was introduced after the cyclization step to give the same product.     

Diversity-oriented synthesis of novel polycyclic scaffolds using polymer-bound reagents

A concise sequence utilizing a Petasis three component reaction followed by a tandem aza-Cope-Mannich cyclization afforded novel polycyclic heterocycles in good yield; alternative iminium cyclization based on a Pictet-Spengler reaction or aminal formation led to divergent pathways affording skeletal diversity.     

Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin

Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than the cis isomer against AChE from two sources.     

Photoisomerization of cis,cis-1,4-diphenyl-1,3-butadiene in the solid state: the bicycle-pedal mechanism

The cis-trans photoisomerization of crystalline or powdered cis,cis-1,4-diphenyl-1,3-butadiene (cc-DPB) was studied at room temperature. The progress of the reaction was monitored by fluorescence spectroscopy, powder X-ray diffraction, 1H NMR and HPLC. High conversions (up to 90%) to the trans,trans isomer were observed in a crystal to crystal reaction. Formation of the cis,trans isomer, the sole product obtained in solution and in very viscous glassy media at 77 K is entirely suppressed in the solid state. The observed two-bond photoisomerization is explained by Warshel's bicycle-pedal photoisomerization mechanism (BP). The results are consistent with X-ray diffraction measurements, which have revealed that cc-DPB molecules exist in crystals in edge to face alternating arrays of two conformer structures whose phenyl rings deviate significantly from the plane of the central diene moiety ( approximately 40 degrees ). One of the conformers has the two phenyls in parallel planes and the other in roughly perpendicular planes. Least motion considerations suggest that the former should undergo the two-bond photoisomerization more easily, in agreement with observations that indicate that the reaction proceeds in discrete stages. Recently reported cis,cis- to trans,trans-muconate photoisomerizations in the solid state are proposed to also proceed via the BP mechanism. The reactions are consistent with the X-ray crystal structures of the cis,cis-muconate isomers.     

cis,cis- and trans,trans-ceratospongamide, new bioactive cyclic heptapeptides from the Indonesian red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica

Chemical investigation of the marine red alga (Rhodophyta) Ceratodictyon spongiosum containing the symbiotic sponge Sigmadocia symbiotica collected from Biaro Island, Indonesia, yielded two isomers of a new and bioactive thiazole-containing cyclic heptapeptide, cis,cis-ceratospongamide (1) and trans, trans-ceratospongamide (2). Isolation of these peptides was assisted by bioassay-guided fractionation using a brine shrimp toxicity assay (Artemia salina). The structures of the ceratospongamides, which each consist of two L-phenylalanine residues, one (L-isoleucine)-L-methyloxazoline residue, one L-proline residue, and one (L-proline)thiazole residue, were established through extensive NMR spectroscopy, including (1)H-(13)C HMQC-TOCSY, and (1)H-(15)N HMBC experiments, as well as chemical degradation and chiral analysis. cis,cis- and trans,trans-ceratospongamide are stable conformational isomers of the two proline amide bonds. Molecular modeling of these two ceratospongamide isomers showed the trans, trans isomer to be quite planar, whereas the cis,cis isomer has a more puckered overall conformation. trans,trans-Ceratospongamide exhibits potent inhibition of sPLA(2) expression in a cell-based model for antiinflammation (ED(50) 32 nM), whereas the cis,cis isomer is inactive. trans,trans-Ceratospongamide was also shown to inhibit the expression of a human-sPLA(2) promoter-based reporter by 90%.     

Synthesis of seven-membered carbocyclic rings via a microwave-assisted tandem oxyanionic 5-exo dig cyclization-claisen rearrangement process

Appropriately substituted 1-alkenyl-4-pentyn-1-ol systems, readily prepared from simple starting materials, serve as useful precursors to a number of substituted cyclohept-4-enone derivatives via a microwave-assisted tandem oxyanionic 5-exo cyclization/Claisen rearrangement sequence. The reactions involving terminally substituted 4-pentyn-1-ols were found to be highly stereoselective, with the alpha and beta groups in the final product showing a strong preference for the trans orientation.