The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

Highly diastereoselective Henry reaction of nitro compounds with chiral derivatives of glyoxylic acid

N-Glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate react stereoselectively with simple nitro compounds giving diastereoisomeric nitroalcohols with high asymmetric induction. N-Glyoxyloyl-(2R)-bornane-10,2-sultam 1a is shown to be a highly efficient chiral inducer, superior to (1R)-8-phenylmenthyl glyoxylate 1b. In all cases, the absolute (2S) configuration at the center bearing the hydroxy group and the relative syn configuration for the major diastereoisomers were determined.     

Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.     

Regioselective electrophilic additions to 2-alkoxy- and 2-alkoxymethyl-7-oxabicyclo [2.2.1] hept-5-ene derivatives

The influence of the stereochemistry at C-2 on the selectivity of the reaction between PhSeBr and 2-alkoxymethyl substituted oxanorbornenes has been studied. All endo isomers displayed complete regio- and stereocontrol with incorporation of the electrophile on C-5.     

Highly diastereoselective synthesis of bicyclo[4.2.0]octanone derivatives by the [2+2] photocycloaddition of chiral cyclohexenonecarboxylates to ethylene

The diastereoselective [2+2] photocycloaddition of a cyclohexenonecarboxylate containing (−)-8-(4-nitrophenyl)menthyl as a chiral auxiliary to ethylene gave the photocycloadduct, a bicyclo[4.2.0]octanone derivative, with a high degree of diastereoselectivity. A photoreaction, conducted in CH₂Cl₂ at −78 °C gave the corresponding photocycloadduct in 88% de. In the presence of Ti(OR)₄ or Me₃SnCl, the diastereoselectivity was increased up to 92% de.     

Synthesis and ring opening reactions of 2-glyco-1,4-dimethyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes

The high-pressure asymmetric Diels-Alder reactions of d-galacto- (1a) and d-manno-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-nitrohept-1-enitol (1b) with 2,5-dimethylfuran (2) afforded mixtures of cycloadducts, from which the (2S,3R)-3-exo-nitro (3a and 3b), (2R,3S)-3-exo-nitro (4a and 4b), and (2R,3S)-1′,2′,3′,4′,5′-penta-O-acetyl-1′-C-(1,4-dimethyl-3-endo-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl)-d-galacto-pentitol (5b) were isolated pure. Deacetylation of these compounds led to new chiral mono-, bi-, and tricyclic ethers, being their asymmetric centers arising from the chiral inductor used in the cycloaddition reaction. A ring opening mechanism through a 1-nitro-1,3-cyclohexadiene intermediate has been proposed.     

N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected, N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b). In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has been carried out to explain the results observed in this work.     

3-Oxo-3-thia-2-azabicyclo[2.2.1]hept-5-en-2-carboxylates: the first isolation and characterization

Methyl and benzyl 3-oxo-3-thia-2-azabicyclo[2.2.1]hept-5-en-2-carboxylate were isolated at rt and characterized for the first time. Both endo and exo-isomers were observed. Under suitable experimental conditions (stoichiometric amount of sodium acetate, −40 °C or sodium borohydride/methyl iodide) ring opening of these compounds gave the corresponding thiosulfonates or methyl sulfides, respectively.     

(5R,6R)-6-苯基-5-(苯磺酰基乙酰基)二环[2.2.1]-2-庚烯的合成及结构表征

报道了一种制备4-苯基-1-苯磺酰基-3-丁烯-2-酮的新合成方法. 4-苯基-3-丁烯-2-酮与溴化试剂Ph₃P^＋CH₂CH₂- COOHBr 作用, 得到1-溴-4-苯基-3-丁烯-2-酮, 不经分离直接与苯亚磺酸钠发生亲核取代反应, 得到4-苯基-1-苯磺酰基-3-丁烯-2-酮. 将此反应产物作为亲双烯体与环戊二烯在手性钛金属催化剂催化下进行不对称Diels-Alder反应, 得到了＞99% ee 的环加成产物(5R,6R)-6-苯基-5-(苯磺酰基乙酰基)二环[2.2.1]-2-庚烯. 用X衍射法对产物的晶体结构进行了测定, 讨论了反应机理, 通过元素分析, NMR, MS对产物的结构进行了表征.     

v-Triazolines. part XXI. Spiro[bicyclo[2.2.1]hept-2-ene[54']1',2'.s'-triazole]derivatives from cyclopentadiene and 5-amino-4-methylene-v-triazolines

1R^*, 4R^*, 5S^*, 5'S^*-5'-Amino-1'-(4-nitrophenyl)-4',5'-dihydrospiro[bicyclo [2.2. 1]hept-2-ene[5.4]-1',2',3'-triazoles]$\text{2}$ have been obtained both by ?4 +2]-cycloaddition of cyclopentadiene to amino-methylene-1-(4-nitrophenyl)-4,5-dihydro-v-triazoles $\text{1}$ and by [3+2]-cycloaddition of 4-nitrophenylazide to 5-aminomethylene-2-norborenes $\text{4}$. The configuration has been fully established by X-ray crystallographic analysis. The course of the cycloaddition and the thermal behaviour of $\text{2}$ are discussed.     

Heteropoly acid catalyzed synthesis of 8-methyl-2-aryl/alkyl-3-oxabicyclo[3.3.1]non-7-ene derivatives through (3,5)-oxonium-ene reaction

A variety of aldehydes undergo a smooth coupling with (4-methylcyclohex-3-en-1-yl)methanol in the presence of 2 mol % of phosphomolybdic acid in dichloromethane to afford 3-oxabicyclo[3.3.1]non-7-ene in good yields through 3,5-oxonium-ene cyclization under mild conditions. The use of inexpensive, nontoxic, and readily available heteropoly acid catalyst makes this method simple, convenient, and environmental-friendly.     

Intramolecular hydrogen abstraction promoted by N-radicals: synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems

Homochiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems can be synthesized by reaction of specifically protected phosphoramidate derivatives of carbohydrates with (diacetoxyiodo)benzene or iodosylbenzene and iodine. The reaction mechanism goes through homolytic fragmentation of a hypothetical iodoamide intermediate. The N-radicals so generated participate in an intramolecular hydrogen abstraction reaction (IHA) to give the aforementioned bicycles.     

Short diastereoselective synthesis of cis- and trans-hexahydropyrido[2,1-a]isoindole derivatives

A new and highly stereoselective access to 4,10b-trans or 4,10b-cis hexahydropyrido[2,1-a]isoindole derivatives is reported, both requiring an intramolecular Mannich-type reaction as key step. The cis diastereoisomer is obtained in three steps from a 2-alkyl benzaldehyde through the stereoselective formation of a 2,6-cis-disubstituted piperidine, while the trans stereomer is efficiently obtained, in a single step, if a 2-formyl benzoic acid is involved in the Mannich cyclization process.     

Design of chiral boronate-substituted acrylanilides.: Self-activation and boron-transmitted 1,8-stereoinduction in [4+2] cycloaddition

The [4+2] cycloaddition of ortho-boronoanilide dienophile 4 with cyclopentadiene was found to proceed faster than both its para isomer 8 and the unsubstituted derivative 6, thereby confirming that self-activation by internal coordination is operative in the case of 4. Chiral boronic esters derivatives 9–13 provided a small level of remote 1,8-stereoinduction transmitted through a putative tetrahedral stereogenic boronate complex. These results show that dialkoxyboronic esters can operate as weak, internal Lewis acids and activate carbonyl-containing functionalities in cycloaddition reactions.     

Regio- and stereoselective ring openings of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene systems with copper catalyst-modified grignard reagents: application to the synthesis of an inhibitor of 5-lipoxygenase

Treatment of acylnitroso hetero Diels-Alder cycloadducts 2 with organomagnesium reagents in the presence of a catalytic amount of copper induces ring opening to afford predominantly monocyclic anti-1,2-hydroxamic acids 12. Alkylmagnesium reagents were found to give superior regio- and stereoselectivities compared with vinyl and arylmagnesium reagents. This cycloadduct ring opening methodology was applied to the synthesis of a unique cyclopentenyl hydroxamic acid-based inhibitor of 5-lipoxygenase.     

Photochemical studies on exo-bicyclo[2.1.1]hexyl and bicyclo[3.1.0]hexyl aryl ketones: two approaches for synthesis of enantiomerically enriched cyclopentene derivatives

Two approaches for the photochemical synthesis of cyclopentene derivatives through the Norrish type II cleavage reaction were described. Asymmetric studies using ionic chiral auxiliaries afforded enantiomeric excesses of up to 98% at the conversion of 85%. The results were rationalized by single X-ray crystal structures.     

Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study

A series of Bronsted acidic ionic liquids(ILs) were prepared and used for Biginelli-type condensation reaction among aromatic aldehydes, urea or thiourea and cyclopentanone. Through this reaction, the synthesis of various pyrimidinones could be achieved. Of interest, it was found that the reaction was efficiently catalyzed by a novel, eco-friendly functionalized IL [C_3SO_3HDoim]HSO_4, which could be reused for at least 7 times without significantly loss of catalytic activity. The reaction proceeded efficiently at 80℃ to afford the desired products in good yield(up to 96%). In addition, a possible mechanism that accounted for the IL [C_3SO_3HDoim]HSO_4-catalyzed reaction was proposed.     

Understanding the nature of the molecular mechanisms associated with the competitive Lewis acid catalyzed [4+2] and [4+3] cycloadditions between arylidenoxazolone systems and cyclopentadiene: a DFT analysis

The molecular mechanisms of the reactions between aryliden-5(4H)-oxazolone 1, and cyclopentadiene (Cp), in presence of Lewis acid (LA) catalyst to obtain the corresponding [4+2] and [4+3] cycloadducts are examined through density functional theory (DFT) calculations at the B3LYP/6-31G* level. The activation effect of LA catalyst can be reached by two ways, that is, interaction of LA either with carbonyl or carboxyl oxygen atoms of 1 to render [4+2] or [4+3] cycloadducts. The endo and exo [4+2] cycloadducts are formed through a highly asynchronous concerted mechanism associated to a Michael-type addition of Cp to the beta-conjugated position of alpha,beta-unsaturated carbonyl framework of 1. Coordination of LA catalyst to the carboxyl oxygen yields a highly functionalized compound, 3, through a domino reaction. For this process, the first reaction is a stepwise [4+3] cycloaddition which is initiated by a Friedel-Crafts-type addition of the electrophilically activated carbonyl group of 1 to Cp and subsequent cyclization of the corresponding zwitterionic intermediate to yield the corresponding [4+3] cycloadduct. The next rearrangement is the nucleophilic trapping of this cycloadduct by a second molecule of Cp to yield the final adduct 3. A new reaction pathway for the [4+3] cycloadditions emerges from the present study.     

Tandem [2+2] cycloaddition and Cope rearrangement in reactions of cross-conjugated azatrienes with conjugated ketenes: a facile single step synthesis of novel azocinone derivatives

A facile single step synthesis of novel azocinone derivatives involving tandem [2+2] cycloaddition and Cope rearrangement in the reactions of cross-conjugated azatrienes with vinyl/isopropenyl ketenes supported by theoretical calculations is reported.