Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

Formation of cyclic sulfonamides via an unusual 8-endo-trig Heck olefination reaction

The synthesis of the novel benz[c]azocines, 11a and 11b was achieved following an 8-endo-trig selective intramolecular Heck reaction. Optimisation of this reaction demonstrated that inclusion of both tetra-n-butylammonium sulfate and water was essential for its success. No products from the corresponding 7-exo-trig process were encountered under these conditions.     

Manganese(III)-mediated facile synthesis of 3,4-dihydro-2(1H)-quinolinones: selectivity of the 6-endo and 5-exo cyclization

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1H)-quinolinones 2 were easily synthesized by the oxidative 6-endo-trig cyclization of 2-[2-(N-arylamino)-2-oxoethyl]malonates 1 with manganese(III) acetate in good to excellent yields. The same reaction of N-(2,4-dimethoxyphenyl)-substituted malonate 1t exclusively produced the 5-exo-cyclized 4,4-bis(ethoxycarbonyl)-1-azaspiro[4,5]deca-6,9-diene-2,8-dione 5t instead of the corresponding dihydroquinolinone. The regioselectivity during the cyclization could be explained by the difference in the activation energy of the transition state of the 6-endo/5-exo cyclization.     

Sodium dithionite initiated regio- and stereoselective radical addition of polyfluoroalkyl iodide with norbornene analogs

Sodium dithionite initiated free-radical addition of polyfluoroalkyl iodides (2m-2s) with norbornene 1a and its derivatives, such as norbornene-2-carboxylates 1b and 1c, and norbornene-2-carboxylic acids 1d and 1e was investigated. In all the cases, the addition of R_F group was stereoselectively delivered at exo-position and the predominant configuration of products was trans. Under the similar condition, norbornene-2-carboxylic ethyl ester 1b reacted with 2p to give 6-exo-R_F-5-endo-iodo adduct 3bp and 5-exo-R_F-6-endo-iodo adduct 5bp in the ratio of 4:1. While 1c, which has a heavy crowded group in the 2-endo-position, gave 6-exo-R_F-5-endo-iodo adduct 3cp and polyfluoroalkylated product 4cp retaining the trans-configuration and the exo-orientation of R_F group. The fluoroalkylation-lactonization reaction occurred in the reaction of norbornene-2-endo-carboxylic acids 1d and 1e with polyfluoroalkyl iodides to afford the corresponding fluoroalkylated γ-lactone products (7dp-7ds, and 7em-7er). The configuration of the products was further confirmed by 2D NMR and X-ray diffraction analyses for the first time.     

The fragmentation of exo-5-norbornenyl-2-oxychlorocarbene: stereochemistry and mechanism

The fragmentation of (S)-exo-5-norbornenyl-2-oxychlorocarbene (3) affords (S)-exo-5-norbornenyl-2-chloride (4), (R)-endo-5-norbornenyl-2-chloride (5), and (S)-3-nortricyclyl chloride (6) with varying degrees of enantiomeric excess. A weighted blend of S_Ni fragmentation and escape to norbornenyl/nortricyclyl ion pairs rationalizes the stereochemical results.     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Asymmetric 1,3-dipolar reactions of 3-sulfinylfuran-2(5H)-ones with 11H-dibenzo[b,e]azepine 5-oxide. Synthesis of pyrroloazepines via isoxazoloazepines

The addition of morphanthridine N-oxide (1) to homochiral 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) under mild conditions affords furoisoxazoloazepines (3a and 3b) in high yields and with complete regioselectivity. The π-facial and endo-selectivities are also complete from 2a, which yields anti-3a-endo as the only diastereoisomer, whereas cycloreversion determines that the anti-3b-endo adduct can be almost exclusively isolated from 2b. Proper manipulation of the furoisoxazoloazepines allows the synthesis of the optically pure isoxazoloazepines and pyrroloazepines.     

The first entry to 5,6-dihydroxy-3-mercaptoindole, 5-hydroxy-3-mercaptoindole and their 2-carbomethoxy derivatives by a mild thiocyanation/reduction methodology

The hitherto unknown 5,6-dihydroxy-3-mercaptoindole (4a) and its 2-carbomethoxy derivative (4b), as well as the analogous 5-hydroxy 3-mercaptoindoles, have been conveniently obtained as O,S-acetyl derivatives 3a-d by thiocyanation of the corresponding acetoxyindoles 1a-d with the NH₄SCN/oxone system followed by SmI₂ reduction and acetylation.     

The 5-exo-trig radical cyclization reaction under reductive and oxidative conditions in the synthesis of optically pure GABA derivatives

Free radical precursors 4a and 4b were synthesized and treated under reductive or oxidative conditions to obtain the corresponding optically pure pyrrolidinones 5-8, which were subsequently transformed into corresponding optically pure GABA derivatives 9-11. When reductive radical conditions (4a→7 and 8) were used, a Ph_1-5 migration product 14 was obtained; presumably depending upon the specific conformation of the rotamer precursor and also 14 was found to be a kinetic product.     

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.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Synthesis and pharmacological evaluation of 6a,7-dihydro-6H,13H-pyrazino[1,2-a;4,5-a′]diindole analogs as melatonin receptor ligands

The synthesis of two melatonin-derived analogs of the novel 6a,7-dihydro-6H,13H-pyrazino[1,2-a;4,5-a′]diindole ring system is described. The non-methoxy and methoxy analogs, 4a and 4b were prepared in seven steps starting from indoline-2-carboxylic acid 5a and 5-methoxyindoline-2-carboxylic acid 5b, respectively. While 4a exhibited micromolar affinities for both melatonin receptors, the methoxy analog 4b displayed moderate affinity for MT₂ receptors (K_i=0.41 μM) being 4.4-fold higher than for the MT₁ subtype.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

A versatile approach to pyrrolidine azasugars and homoazasugars based on a highly diastereoselective reductive benzyloxymethylation of protected tartarimide

A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was developed based on SmI₂-mediated benzyloxymethylation of O,O′-dibenzyltartarimide. The versatility of 13a and its antipode as the key building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive ring-opening product 35.     

Synthesis and chemistry of tricyclic cyclopropene-tricyclo[3.2.2.0]nona-2(4),6-diene

The 1,2-bridged tricyclic cyclopropene, tricyclo[3.2.2.0^2,4]nona-2(4),6-diene (1), has been synthesized by the elimination of 2-bromo-4-chlorotricyclo[3.2.2.0^2,4]-non-6-ene (5). Cyclopropene 1 will undergo different isomerizations in ether solution and in neat conditions. Compound 1 rearranged to an anti-Bredt compound 4 via diradical mechanism in ether and tricyclic compound 6 via vinyl carbene mechanism in neat conditions. Compound 1 can be trapped with DPIBF at different temperatures yielding different results: the exo-endo adduct 2 (exo-addition from the view of the cyclopropene and endo-addition from the view of bicyclo[2.2.2]octene) is a sole product at 0°C by slowly addition of methyllithium, and the exo-endo adduct 2, endo-endo adduct 9, anti-Bredt adduct 3, and styrene 8 are isolated at ether refluxing temperature. Styrene 8 is proposed to be formed from endo-endo adduct 9 by diradical mechanism. The chemistry of exo-endo adduct 2 and endo-endo adduct 9 is as well studied. The exo-endo adduct 2 undergoes hydration in trifluoroacetic acid to generate 1,3-cis-diol 11 followed by eliminations of water and formaldehyde to give naphthalene 12. The endo-endo adduct 9 reacts with water in tetrahydrofuran-containing silica gel to yield 1,4-cis-diol 10. Both 9 and 10 react with trifluoroacetic acid to form trans-3-hydroxy trifluoroacetate 13. Compound 13 will undergo hydrolysis and isomerization to generate 1,3-cis-diol 11 in trifluoroacetic acid.     

Benzoazabicyclo[4.3.1] derivatives by intramolecular Michael addition of piperidinone enolates to enoates

Piperidinones with a 2-bromobenzyl substituent in the 5-position were subjected to a Heck coupling reaction with ethyl acrylate resulting in the highly functionalized cinnamates 9a-d. A subsequent deprotonation of the piperidinones using NaN(SiM₃)₂ in THF induced an intramolecular Michael addition of the enolate to the cinnamate part. In this way, a range of novel 2,6-methano-4H-4-benzazonines 10-13 were obtained. In each case, a separable mixture of endo/exo-diastereomers was obtained.     

The regioselectivity of the addition of benzeneselenyl chloride to 7-azanorborn-5-ene-2-yl derivatives is controlled by the 2-substituent: new entry into 3- and 4-hydroxy-5-substituted prolines

The electrophilic addition of benzeneselenyl chloride to the alkene moiety of 7-azabicyclo[2.2.1]hept-5-en-2-yl derivatives has been studied. With camphanates 8 and 9N-Boc-5-endo-chloro-6-exo-phenylseleno-7-azanorborn-2-yl camphanates 10 and 11 are obtained with high regioselectivity due to a steric control. With N-Boc-7-azanorbor-5-en-2-one (2) the corresponding 6-endo-chloro-5-exo-phenylseleno derivative 15 is obtained in high yield due to a kinetic control attributed to the electron-releasing ability of the homoconjugated carbonyl group. Bicyclic adducts 10 and 11 and 15 are readily converted into 4-hydroxy-(14) and 3-hydroxy-5-substituted proline derivatives 19, respectively.     

Samarium diiodide-mediated reductive couplings of chiral nitrones with aldehydes/ketones and acyl chlorides

The SmI₂-mediated and H₂O-promoted reductive cross-coupling reactions of the l-tartaric acid derived nitrone (3S,4S)-8 with aldehydes/ketones, and the l-malic acid derived nitrone (S)-6 with aliphatic acyl chlorides have been investigated, respectively. (2R,3S,4S)-1,3,4-Trihydroxyprolinol derivatives 9a-f were obtained with high C-2/C-3 trans-selectivities, and 72:28-85:15 diastereoselectivities at the carbinol center from aromatic ketones/aldehydes, while low diastereoselectivities for aliphatic aldehydes. Conditions have been established for the syntheses of (2R,3S,4S)-3,4-dihydroxyprolinol derivatives such as 18, by N-O bond cleavage of the corresponding N-hydroxyprolinol derivatives 9b-f, or more conveniently by a one-pot reductive coupling of nitrone 8 and in situ N-O bond cleavage of the resultant coupling product. The 2-acyl-3-benzyloxy-1-hydroxypyrrolidines 10a-f were formed in 48-82% yields, and in 74:26-78:22 diastereoselectivities. It was revealed that the amount of water required for the reaction is substrate-depending.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

Stereoselective tandem synthesis of oxazolo-fused pyrroloquinolines from o-alkynylaldehydes via Ag(I)-catalyzed regioselective 5-exo-dig ring closure

A tandem approach for the regio- and stereoselective synthesis of oxazolo-fused pyrroloquinolines 3a–l via the reaction of o-alkynylaldehydes 1a–i with chiral amino alcohols 2a–c under mild reaction conditions is described. The possible participation of the pyridine ring in the regioselective formation of 5-exo-dig cyclized products was supported by the controlled experiments. The structures and stereochemistry of the products were confirmed by NOESY and X-ray crystallographic studies.