Conformational analysis of sulfur-containing 6-deoxy-l-hexose derivatives by molecular modeling and NMR spectroscopy. A theoretical study and experimental evidence of intramolecular nonbonded interactions between sulfur and oxygen

6-Deoxy-l-mannose diphenyldithioacetal (1) unexpectedly gave the rearranged products phenyl 3,4-di-O-acetyl-2-S-phenyl-1,2-dithio-6-deoxy-beta-l-glucopyranoside (9) and 3,4-di-O-acetyl-2,5-anhydro-6-deoxy-l-glucose diphenyldithioacetal (10) upon treatment with acetyl chloride, while 6-deoxy-l-mannose ethylenedithioacetal (3) yielded (4aR,6S,7S,8R,8aS)-7,8-diacetyloxy-6-methylhexahydro-4aH-[1,4]dithiino[2,3b]pyran (11), whose structure was further confirmed by X-ray diffraction, and 3,4-di-O-acetyl-2,5-anhydro-l-rhamnose ethylenedithioacetal (12). The geometry of the four rearranged products as well as that of 1-thio-6-deoxy-l-mannopyranosides 5 and 7 and their acetyl derivatives 6 and 8 was studied by density functional theory (B3LYP/6-31G) molecular models, in combination with a Karplus-type analysis of the NMR vicinal coupling constants, revealing that the six-membered ring of pyranosides 5-9 and 11 exists in a slightly distorted chair conformation (6-13% distortion) and that the conformational behavior of the 2,5-anhydro-6-deoxy-l-glucose dithioacetals 10 and 12 is strongly influenced by the presence of stabilizing intramolecular nonbonded sulfur-oxygen 1,4- and 1,5-interactions. Compounds 9-12 were formed by a molecular rearrangement via sulfonium ion intermediates followed by stereoselective intramolecular cyclizations as formulated by the quantum chemical calculations performed in the present study.     

Reaction of alicyclic reformatsky reagents with 2,5-bis(arylmethylidene)cyclopentanones

Reformatsky reaction of methyl 1-bromocyclobutane-, 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates with 2,5-bis(arylmethylidene)cyclopentanones gave the corresponding 4??-aryl-7??-arylmethylidene-4??,5??,6??,7??-tetrahydro-2??H-spiro[cycloalkane-1,3-cyclopenta[b]pyran]-2??-ones.     

Studies on pyrazines. 14 The syntheses of 2,5-dihydroxypyrazines and their derivatives

Reaction of phenylglycinamide ( 1c ) with ethyl benzoylformate ( 2c ) in the presence of refluxing ethanolic sodium ethoxide gave 2,5-dihydroxy-3,6-diphenylpyrazine ( 3i ) in 19% yield. This synthetic method, however, was limited to the preparation of 3i . On the other hand, α-aminoamides 1 condensed with α-ketoesters 2 to give the intermediates 5 , which were also prepared by condensation of 1 with α-ketalesters 6 , followed by hydrolysis of the ketal moeity. Cyclization of 5 with refluxing methanolic sodium methoxide gave only disubstituted 2,5-dihydroxypyrazines 3 . Acetylation of 5 with refluxing acetic anhydride/acetic acid led to direct formation of 2,5-diacetoxypyrazines 9 . Similarly, compounds 5 could be converted into 2,5-dichloropyrazines 4 .     

Total stereoselective synthesis of (+)-goniothalesdiol

[reaction: see text] The stereoselective synthesis of (+)-goniothalesdiol (1) was accomplished in nine steps starting from commercially available (-)-(2S,3S)-dimethyl D-tartrate (3). The key features were a completely diastereoselective reduction of a beta-ketosulfoxide to generate the stereogenic center at C-5 in 7 and formation of the 2,5-cis-substituted tetrahydrofuran ring in 10 from a stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization/deoxygenation.     

One-Pot synthesis of photochromic naphthopyrans in the solid state

p-TsOH-catalyzed condensation reactions of 1,1-diaryl-2-propyn-1-ol (1) and 2-naphthol (2) in the solid state gave 3, 3-diaryl-3H-naphtho[2,1-b]pyran (6) via Claisen rearrangement. Similar reactions of 1 with 2,6- (7) and 2,7-dihydroxynaphthalenes (8) afforded naphthodipyrane derivatives 9 and 10, respectively. Bis-naphthopyran derivatives 12 were also obtained by the reaction of 1,1,6,6-tetraaryl-2,5-hexadiyn-1,6-diol (11) and 2-naphthol (2) in the solid state.     

Biomimetic synthesis of the tetracyclic core of berkelic acid

Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 degrees C, followed by CH2N2 esterification, gave a 4:1:4:1 mixture of diastereomers 15b-18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83% yield) with the complete skeleton of berkelic acid. A similar condensation at 0 degrees C afforded 15b-18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift.     

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine

Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1,10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22. Unsubstituted 12H-benzo[b][1,10]phenanthrolin-7-ones 16, 17, 20, and 21 were devoid of significant cytotoxic activity, whereas 18 and 22, bearing a nitrogen substituent at position 11, were significantly active. Unsubstituted 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 19, which include a pyridine nitrogen in the same 4-position as the pyran oxygen of acronycine exhibited cytotoxic activities within the same range of magnitude as acronycine itself.     

Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin

A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin from l-ascorbic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM deprotection and bicyclic ketal formation was carried under Pd/C, H₂ followed by acid treatment.     

Synthetic studies toward the pyran core and the amide side chain of psymberin

A synthetic approach to the polysubstituted pyran core and amide side chain of psymberin (irciniastatin A) using stereoselective organoboron methodology is described. An advanced oxyranyl pyran intermediate was prepared using a catalytic enantioselective and diastereoselective three-component reaction involving first an inverse electron-demand hetero [4+2] cycloaddition between 3-boronoacrolein pinacolate and 1-ethoxy-2-methylpropene, followed by an allylboration of ethyl glyoxylate. The amide side chain was prepared highly efficiently using the first example of a doubly diastereoselective allylboration of a chiral α-alkoxy aldehyde under the Lewis acid-catalyzed reaction manifold.     

Stereoselective synthesis of chiral oxepanes and pyrans through intramolecular nitrone cycloaddition in organized aqueous media

[reaction: see text] A highly stereoselective surfactant-catalyzed intramolecular nitrone (formed by dehydration in water) cycloaddition in aqueous media leading to exclusive formation of a single isomer is reported. Either oxepane or pyran is formed from 3-O-allyl furanoside derivatives, which constitute the framework of a large number of biologically active compounds. Therefore, the environmentally friendly, efficient, and highly stereoselective syntheses of these chiral intermediates are still a meaningful pursuit.     

Photochemical access to tetra- and pentacyclic terpene-like products from R-(+)-sclareolide

Fused tetracyclic oxetanes 4, highly substituted cyclobutenes 6, and the pentacyclic derivatives 7 and 8 were obtained by irradiation of derivatives 3 that were prepared from commercial R-(+)-sclareolide (1) in three steps. Compounds 4 are formed through a Paterno-Büchi reaction, while tricyclic derivatives 6 are the fragmentation products of the first formed oxetanes. In clear contrast, cyclopentenyl and 3-furyl derivatives, 3e and 3f, gave the [2+2] adducts, namely pentacyclic derivatives 7 and 8. All the reported reactions are totally regio- and stereoselective, with the exception of the cyclization of furyl derivative 3f, which gave the mixture of both the crossed (7b) and the right (8) isomers.     

Synthesis of 4-aminotropones from [(sulfinyl or sulfonyl)methyl]-substituted p-quinamines

An efficient synthesis of 4-aminotropones has been achieved in excellent yields by simple treatment of 4-amino-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienones (p-quinamines) with NaH. The method allowed regiocontrolled access to 3-methyl, 5-methyl- and 3,5-dimethyl-substituted derivatives starting from p-quinamines with adequate substituents at the cyclohexadienone moiety and/or at the carbon linked to the sulfur function. The p-quinamines in turn were easily accessible from N-Boc p-anisidines (Boc=tert-butoxycarbonyl) by electrochemical oxidation in MeOH to quinone imine monoketals, followed by addition of a alpha-lithium sulfinyl carbanion to the imino group, and ketal hydrolysis. Oxidation of the sulfoxide gave the sulfonyl-substituted p-quinamines that, upon basic treatment, behave similarly. The p-quinamine 55 and bis-p-quinamine 56, resulting in the addition of the anion derived from dimethyl sulfone to the p-quinonimine ketal 14, also gave the 4-aminotropone. The mechanism involves the initial formation of a alpha-sulfonyl carbanion, which intramolecularly attacks the cyclohexadienone giving a norcaradiene-like enolate intermediate, the evolution of which through a ring-expansion process, pushes off a methyl sulfinate anion or SO2. This efficient process fulfils the criteria of atom economy. The introduction of a proline substituent in the nitrogen of the starting p-quinamine allowed the synthesis of an enantiopure 4-aminotropone, the asymmetric Diels-Alder reactions of which with maleimide occurred in a highly endo and pi-facial diastereoselective manner.     

Stereoselective synthesis of tetrahydrofuran lignans via BF(3) x OEt(2)-promoted reductive deoxygenation/epimerization of cyclic hemiketal: synthesis of (-)-odoratisol C, (-)-futokadsurin A, (-)-veraguensin, (+)-fragransin A(2), (+)-galbelgin, and (+)-talaumidin

A versatile route to the synthesis of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans, (-)-odoratisol C (1), (-)-futokadsurin A (2), (-)-veraguensin (3), (+)-fragransin A2 (4), (+)-galbelgin (5), and (+)-talaumidin (6), is described. Central to the synthesis of the lignans is BF(3) x OEt(2)-promoted deoxygenation/epimerization of the hemiketal 9a followed by stereoselective reduction of the oxocarbenium ion intermediates 8a,b.     

Stereoselective reactions of a (-)-quinic acid-derived enone: application to the synthesis of the core of scyphostatin

[reaction: see text] A (-)-quinic acid-derived enone, with the trans-1,2-diol protected as a 2,3-dimethoxybutanediyldioxy ketal, provides an excellent template for further highly stereoselective elaboration as exemplified by its conversion into the core of scyphostatin, a potent inhibitor of neutral sphingomyelinase.     

Electroreductive intramolecular coupling of aromatic imino esters: is four-membered cyclization much more favorable than six-membered cyclization?

[reaction: see text] The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine afforded a four-membered cyclized product, a mixed ketal of cis-2,4-disubstituted azetidine-3-one, stereospecifically. Calculations for the transition states by the DFT method support the predominant formation of the azetidine. The electroreduction of an aromatic imino ester prepared from (S)-aspartic acid gave almost equal amounts of a diastereomerically pure mixed ketal of cis-2,4-disubstituted azetidine-3-one and a diastereomeric mixture of 2,5-disubstituted pyrollidine-3-one.     

Bis(2-bromoethyl) selenium dibromide as the selenium-introducing reagent: One-pot preparation of 2,5-bis(alkoxymethyl)tetrahydroselenophenes by the cyclization of 1,5-hexadiene

The reaction of bis(2-bromoethyl)selenium dibromide (1a) with 1,5-hexadiene (2) in methanol or ethanol affords 2,5-bis(alkoxymethyl)tetrahydroselenophene-1,1-dibromides (R = CH₃ (3b), R = C₂H₅ (3c)) via 2,5-bis(bromomethyl)tetrahydroselenophene-1,1-dibromide (3a). The reaction of 1a with 2 in 1-propanol, 2-methyl-1-propanol or 1-butanol in the presence of sodium carbonate gave 2,5-bis(alkoxymethyl)tetrahydroselenophene (R = C₃H₇ (4a), R = (CH₃)₂CHCH₂ (4b) and R = C₄H₉ (4c)) via 3a. The ratios of the trans and cis isomers of 3a–3c are 3:2. In addition, the structure of trans-2,5-bis(methoxymethyl)tetrahydroselenophene-1,1-dibromide (trans-3b) was determined by X-ray crystallography.     

Allylsilane and diallylsilane reactions with functionalized ethylene ketals or benzodioxoles

The bis-allylation of ethylene ketal and catechol ketal derivatives of 2,5-hexanedione occurred with a great stereoselectivity. The tetraallylation of bis-catechol ketal derivatives of 2,5-hexanedione and 2-methyl-1,3-cyclohexanedione or the diallylation of 4-phenylbutan-2-one derivatives arise in good yields and these compounds were suitable substrates for ring-closing metathesis leading to 4,4-dialkylcyclopentenes. Condensation of 1,8-bistrimethylsilyl-2,6-octadiene (Bistro) with 4-phenylbutan-2-one catechol ketal derivatives or 2-methylcyclohexan-1,3-dione mono catechol ketal afforded in good yields cyclic and tricyclic products 12 or 23, respectively.     

Dithiolopyranthione Synthesis,Spectroscopy, and an Unusual Reactivity with DDQ

The bicyclic pyran thiolone tetrahydro‐3αH‐[1,3]dithiolo[4,5‐β]pyran‐2‐thione ( 3a ) engages in a highly unusual fragmentation in the presence of DDQ. The pyran thiolone, 3a , was synthesized by chlorination of 3,4‐dihydro‐2H‐pyran ( 1 ) followed by condensing with CS₂ and NaSH. Reaction of 3a with DDQ generates the isomerized pyran thiolone tetrahydro‐3αH‐[1,3]dithiolo[4,5‐β]pyran‐2‐thione ( 3b ) and 4‐benzyl‐5‐(3‐hydroxypropyl)‐1,3‐dithiole‐2‐thione ( 4 ) via a deep‐seated rearrangement. The identity of 3b was confirmed by single crystal X‐ray analysis: P2₁/c, a = 5.807(9) Å, b = 12.99(2) Å, c = 11.445(15), β = 113.23(6)°. Mechanistic experiments and computational insight is used to explain the likely sequence of events in the highly unusual formation of 4 . Collectively, these results establish fundamental reactivity patterns for further research in this area.     

Stereoselective Substrate‐Controlled Asymmetric Syntheses of both 2,5‐cis‐ and 2,5‐trans‐Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation

The concise, highly stereoselective, substrate‐controlled asymmetric total syntheses of both 2,5‐cis‐ and 2,5‐trans‐tetrahydrofuranoid nematocidal oxylipids from the Australian brown algae Notheia anomala have been accomplished in a stereodivergent fashion. The highly stereoselective intramolecular amide enolate alkylation strategy provides access to both stereoisomers of the 3‐hydroxy‐2,5‐disubstituted tetrahydrofuran core of these marine natural products through chelate and nonchelate control, which is driven by the C3‐hydroxy protecting group. This approach offers an optional and highly stereoelective access to any of the eight possible stereoisomers of the 2,5‐disubstituted‐3‐oxygenated tetrahydrofuran skeleton, an important structural feature which is present in many biologically active natural products.     

First comprehensive investigation of Suzuki couplings of alkenyl nonaflates with aryl and alkenyl boronic acid derivatives by using classical conditions and microwave heating

Alkenyl nonaflates (nonafluorobutanesulfonates) are excellent substrates in a variety of palladium-catalysed coupling reactions. We herein demonstrate that bicyclic nonaflates generated from 8-heterobicyclo[3.2.1]octan-3-one derivatives can be coupled with aryl or alkenyl boronic acids in a very efficient manner. The resulting densely functionalised bicyclic skeletons are highly suitable for further synthetic elaboration. The thermal Suzuki couplings provided the expected products in moderate to good yields. Microwave (MW) irradiation dramatically shortened reaction times and gave superior results. Bisboronic ester 19 was also coupled with bicyclic nonaflates, for example, with 14, and double Suzuki-coupling products, such as 22, were isolated in good yields. We demonstrated the great synthetic potential of aryl-substituted 8-heterobicyclo[3.2.1]octene derivatives, such as 15, by the stereoselective conversion of this compound into highly substituted furanose 31 or substituted pyran derivative 33, which were obtained in short and efficient reaction sequences.