Synthetic studies on nogalamycin congeners [3]1,2 total syntheses of (+)-nogarene, (+)-7-deoxynogarol,and (+)-7-con-o-methylnogarol

According to the retrosynthetic perspective, the title total syntheses were accomplished by employing the regioselective Diels-Alder reactions of the (+)-naphthoquinone (5), the CDEF-ring system of nogalamycin congeners, with various structural types of dienes (8, 16, and 26). The highly functionalized dienes (16 and 26) incorporating all the functionalities present in the A-rings of (+)-7-deoxynogarol (3) and (+)-7-con-O-methylnogarol (2), were prepared efficiently by way of the 1 ,4-cyclohexadiene and 2-cyclohexanone derivatives (6 and 21), respectively. Reaction mechanism of the key Diels-Alder reaction was also discussed in terms of its stereoselectivity.     

An unprecedented methylene oxidation accompanying the aza Diels-Alder reactions of acyclic unactivated alkenes: synthesis of novel quinolin-3-one substituted pyrimidinone derivatives

The regioselective aza Diels-Alder reactions of isopropenyl pyrimidinone with N-arylimines in the presence of Y/Sc triflates as catalyst are described. An unprecedented oxidation of methylene to carbonyl occurred resulting in exclusive formation of 6-oxo-1,6-dihydropyrimidin-5-yl-4H-quinolin-3-one derivatives.     

Chromone-3-carboxaldehydes in Diels-Alder reactions with indole-o-quinodimethane. Synthesis of tetrahydrochromeno[2,3-b]carbazoles

An efficient route to a new class of indole derivatives, tetrahydrochromeno[2,3-b]carbazoles, has been developed. The cycloaddition reactions of chromone-3-carboxaldehydes with indole-o-quinodimethane gave a diastereomeric mixture of Diels-Alder cycloadducts in good yields after in situ deformylation.     

Lewis acid promoted aza Diels-Alder reactions of acyclic unactivated 5-dienyl pyrimidinones with N-arylimines: synthesis of novel quinoline derivatives

The chemo- as well as regioselective aza Diels-Alder reactions of 5-dienyl pyrimidinones with N-arylimines in the presence of a Lewis acid catalyst resulting in novel quinoline derivatives are reported.     

A dimethylsulfonium methylide mediated highly regioselective olefination of conjugated polyolefin 1,1-dioates to conjugated polyene-2-yl-malonates and their applications in Diels-Alder reactions

The reactions between dimethylsulfonium methylide and 1,3-diene- or 1,3,5-triene-1,1-dioates under specific conditions enable the highly regioselective tandem ylide addition-eliminative olefination to provide 1,3-butadien-2-yl- or 1,3,5-hexatriene-2-yl-malonates. Alkylation at malonate methine carbon of 1,3-butadien-2-ylmalonates with a suitable alkyl halide having in-built functionalities for a dienophile generation led to quick assembly of precursors for type 2 intramolecular Diels-Alder reaction. Syntheses of functionalized bicyclo[n.3.1] alkenes (n=5 or 6) with the double bond at the bridgehead position have been achieved via the IMDA. An asymmetric version of this reaction has been developed using a MacMillan's imidazolidinone catalyst, which provided a bicyclo[5.3.1] alkene with very high enantioselectivity. In situ methylation at malonate methine carbon of 1,3,5-hexatriene-2-yl-malonates followed by intermolecular Diels-Alder reaction with N-methylmaleimide provided the cycloadduct with complete regiocontrol and high diastereoselectivity.     

Lewis acid promoted imino Diels-Alder reactions of 5-dienyl pyrimidinones with N-aryl/naphthyl imines: synthesis of novel quinoline/benzoquinoline derivatives

The chemo- as well as regioselective imino Diels-Alder reactions of 5-dienyl pyrimidinones with N-aryl as well as N-naphthyl imines in the presence of a different Lewis acid catalysts resulting in novel quinoline and benzoquinoline derivatives are reported.     

Organocatalytic multicomponent alpha-methylenation/Diels-Alder reactions: a versatile route to substituted cyclohexenecarbaldehyde derivatives

This article describes the design and optimization of an effective organocatalytic three-component domino alpha-methylenation/Diels-Alder reaction to produce vinyl-substituted cyclohexenecarboxaldehydes in a highly regioselective fashion. In these one-pot transformations, 2-formyl-1,3-butadienes (4) were prepared in situ from alpha,beta-unsaturated aldehydes and formalin and were subsequently trapped with a variety of buta-1,3-dienes. The outcomes of the reactions were dependent on the electronic properties of the dienes. 1-Vinylcyclohexenecarbaldehydes 6 were formed by use of acyclic electron-rich dienes, while the initially formed cycloadducts of 4 with cyclopentadiene underwent Cope rearrangements, leading to the formation of tetrahydro-3H-indene-5-carbaldehyde compounds 7. The mechanisms involved in these reactions were deduced from experimental findings. Furthermore, the method was also extended to one-pot domino methylenation/Diels-Alder reactions of dihydrofurans and dihydropyrans to yield spirocyclic lactols 22. In these reactions, the unstable intermediate hydroxyethyl and hydroxypropyl acroleins behaved as dienophiles, undergoing cycloaddition reactions with dienes with good yields and selectivities. The wide variety of functionalized 1-vinylcyclohex-3-enecarbaldehydes 6, 4-vinylcyclohex-1-enecarbaldehydes 7, and spiro lactols 22 generated through the use of these organocatalytic domino processes as a diversity-oriented synthesis provided useful intermediates for the construction of novel odorants.     

Stereoselective Synthesis and Diels-Alder Reactions of (Z)- and (E)-1,2-bis(Phenylthio)-1,3-Butadiene

Bromination of 3-phenylthio-2-sulfolene (2) with N-bromosuccinimide gave 2-bromo-3-phenylthio-2-sulfolene (3) which was converted mainly to 2,3-bis(phenylthio)-2-sulfolene (4) by treatment with sodium phenylthiolate. Thermal desulfonylation of 4 at different temperatures in the presence of a base (DBU) yielded stereoselectively the (Z)- and (E)-1,2-bis(phenylthio)-1,3-butadiene (6). These two geometric isomers could be thermally interconverted. The Diels-Alder reactions of 6 were also investigated. Only the (Z)-diene 6a could undergo the Diels-Alder reaction; the (E)-diene 6b was in situ converted to the Z isomer before undergoing (he Diels-Alder reaction. The reaction of 6a with N-phenylmaleimide gave the cycloaddition product 7 with complete endo selectivity, but under daylight or during chromatography it readily underwent a thioallylic rearrangement to yield 8 with inversion of configuration. The cycloaddition of 6a with methyl acrylate proceeded regiospecifically, but generating a mixture of endo and exo isomers. The endo/exo ratio could be increased by using ZnCl₂ as the catalyst.     

Facile, completely regioselective 1,4-hydrogenations of C(60)-diaryltetrazine monoadducts

Thermal Diels-Alder reactions between C(60) and electron-deficient 3, 6-diaryl-1,2,4,5-tetrazines yield monoadducts possessing a diaryldihydropyridazine function nested atop the fullerene. The diaryldihydropyridazine functions direct a completely regioselective 1,4-hydrogenation, resulting in a racemic mixture of bifunctional bisadduct (+/-)-3.     

One pot three-component regioselective and diastereoselective synthesis of halogenated pyrido[2,1-b][1,3]oxazines

Three-component reactions of 3-substituted pyridines, dimethyl acetylenedicarboxylate (DMAD), and α-halo ketones led to regioselective and stereoselective synthesis of pyrido[2,1-b][1,3]oxazines in high to excellent yields under mild conditions. All the reactions gave the pyrido[2,1-b][1,3]oxazine derivatives without formation of any indolizine products.     

Domino 6pi-electrocyclization/Diels-Alder reactions on 1,6-disubstituted (E,Z,E)-1,3,5-hexatrienes: versatile access to highly substituted tri- and tetracyclic systems

The (E,Z,E)-1,3,5-hexatrienes 1a, 2a,b and 3b undergo 6pi-electrocyclization within 15-30 min upon heating to 200-215 degrees C. While the cyclohexene-annelated products 8a,b were stable, the analogous cyclopentene- and cycloheptene-annelated derivatives 7a and 9b easily underwent dehydrogenation to the corresponding aromatic compounds 10a and 12b during the work-up. The cyclohexadiene derivatives 8a,b were employed in thermal Diels-Alder reactions with 4-phenyl-3H-1,2,4-triazoline-3,5-dione (PTAD) and tetracyanoethylene (TCNE) to give the expected [4+2] cycloadducts 13a and 14a in good yields (60 and 78%). The initially formed cycloadduct of 8a and dimethyl acetylenedicarboxylate (DMAD) underwent a subsequent retro-Diels-Alder reaction to give the tetrahydronaphthalene 11b (47%). Under high pressure (10 kbar), the cycloadduct 15a was formed at room temperature and could be isolated in 44% yield. TCNE and N-phenylmaleimide with 8a under high pressure also led to the [4+2] cycloadducts 14a and 16a in good yields (60 and 77%). The 6pi-electrocyclization and subsequent Diels-Alder reaction, when performed as a one-pot domino process, provided direct access to Diels-Alder products of intermediately formed 6pi-electrocyclization products, for example from the 1,3,5-hexatrienes 1a,b, 2a,b, 3b and TCNE to the corresponding tricyclic products 17a,b, 14a,b, 18b in moderate to good yields (27-80%) depending on the nature of the alkoxycarbonyl group. Such sequential reactions with N-phenylmaleimide, maleic anhydride, dimethyl maleate and fumarodinitrile, the latter two under high pressure (10 kbar), worked as well to yield 16b (70%), 19a,b (19, 32%) and 20b (39%) and 21b (76%), respectively. With PTAD, however, the hexatrienes 2a,b reacted at ambient temperature without 6pi-electrocyclization to give the formal [4+2] cycloadducts 27a,b (48 and 46%), most probably via zwitterionic intermediates 23a,b and 25a,b.     

Synthesis and Reactions of a Stable Precursor to Dienes Containing Both Silicon and Sulfur Substituents

3-(Phenylthio)-4-(trimethylsilyl)-3-sulfolene (2) was readily prepared by chlorosulphenylation-dehydrochlorination of 3-(trimethylsilyl)-3-sulfolene (4b) . Treatment of 2 with n-butyllithium at ?105 °C followed by an alkylating agent gave only C5 alkylation products 6 demonstrating the stronger carbanion stabilizing ability of phenylthio group than that of trimethylsilyl group. 2-(Phenylthio)-3(trimethylsilyl)-1,3-butadiene (3a) was readily prepared by thermal extrusion of sulfur dioxide from 2 . Selective oxidation of 3a with MCPBA gave the sulfinyl (3b) and sulfonyl (3c) derivatives. The Diels-Alder reactions of 3a-c were studied, and the regiocontrolling power of the substituents follows the order PhS >PhSO ～ PhSO₂ >Me₃Si.     

The synthesis of 6-deoxyanthracyclinones: (±)α-citromycinone and (±)4-demethoxy-6-deoxydaunomycinone

Two synthetic approaches have been explored to prepare 6-deoxyanthracyclinones in general and α-citromycinone in particular. The first approach employed as starting materials 1,4,5-trimethoxynaphthalene and the Diels-Alder product from butadie regioselective carbon acylation of 4-hydroxy-l,5-dimethoxynaphthalene with the half-ester acid chloride of cis-4,5-dicarboxycyclohexene. The resulting product was converted to 7,10-dideoxy-α-citromycinone; however, even the C-7—OH group required for glycosylation could not be introduced satisfactorily into this product. The second strategy employed as the key step the coupling of a highly functionalized metallated quinol equivalent with the monoketal of a benzocyclobutenedione. This route gave (± )-α-citromycinone and (±)-4-demethoxy-6-deoxydaunomycinone in quantities suitable for biological testing.     

Synthesis of haloconduritols from an endo-cycloadduct of furan and vinylene carbonate

A method for preparing haloconduritols having a conduritol-A construction is described. A mixture of endo- and exo-cycloadduct derivatives prepared from the Diels-Alder reaction of furan and vinylene carbonate was converted into diacetate derivatives by hydrolysis (K₂CO₃/MeOH) followed by acetylation (Ac₂O/pyridine). Boron trihalide (BBr₃ or BCl₃)-assisted ring-opening of the endo-diacetate in CH₂Cl₂ at −78°C gave (1α,2α,3β,6β)-6-halogeno-4-cyclohexene-1,2,3-triol 1,2-diacetate from which the corresponding triacetate was prepared by acetylation (AcCl). trans-Esterification of the triacetate (MeOH/HCl) afforded (1α,2α,3β,6β)-6-halogeno-4-cyclohexene-1,2,3-triol (X=Br or Cl). BF₃-Assisted ring-opening of the endo-diacetate in CH₂Cl₂ gave (1α,2α,3β,6β)-6-chloro-4-cyclohexene-1,2,3-triol 1,2-diacetate by means of halogen exchange.     

1,4-Difluoro-2,5-dimethoxybenzene as a precursor for iterative double benzyne-furan Diels-Alder reactions

[reaction: see text] The use of 1,4-difluoro-2,5-dimethoxybenzene as a novel precursor for iterative two-directional benzyne-furan Diels-Alder reactions, using a range of 2- and 3-substituted furans, is reported. Substituted oxabenzonorbornadienes were synthesized following the initial Diels-Alder reaction, which upon ring opening under acidic conditions gave substituted naphthol derivatives. Highly substituted anthracenols were generated in the second benzyne-furan Diels-Alder reaction following acid-catalyzed isomerization of the cycloadducts.     

Microwave-mediated intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives

The synthetic utility of biodihydroxylated benzoic acid derivatives for the construction of bridge bicyclo scaffolds was investigated. Biodihydroxylation of benzoic acid using Ralstonia eutropha B9 gave (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylic acid (DCD) in high optical purity (>95% ee). Protection of the intermediate and subsequent functional group transformation gave the required cyclization precursors in moderate to excellent overall yields. Subsequent intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives was carried out using either thermal or microwave conditions. Enantiomerically pure products with five chiral centers were obtained in 4-6 steps from achiral starting material.     

Total synthesis of (±)-heliannuol C and E via aromatic Claisen rearrangement

The total synthesis of heliannuol C and E from a common intermediate are described. Key steps in the synthesis include a regioselective aromatic Claisen rearrangement to install the (1-vinyl)-4-methyl-3-pentenyl substituent and regioselective biomimetic 7-endo and 6-exo phenol epoxide cyclizations to form the cyclic ether moieties.     

Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.     

Facile and regioselective synthesis of functionalized benzenes via cascade reactions of 1,2-allenic ketones with 4-sulfonyl crotonates

An efficient and regioselective synthesis of functionalized benzenes via the cascade reactions of 1,2-allenic ketones with 4-sulfonyl crotonates under mild reaction conditions has been established. Mechanistically, the formation of the title compounds involves a cascade procedure consisting of an intermolecular regioselective Michael addition followed by an intramolecular condensation and aromatization. Compared with those of α,β-unsaturated aldehydes/ketones, the reactions of 1,2-allenic ketones with 4-sulfonyl crotonates demonstrated contrary regio-selectivity and distinct reaction conditions. Moreover, the functionalized benzene products obtained herein were found to be ready intermediates for the synthesis of fluorenone and anthracenone derivatives.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.