Intramolecular palladium mediated π-allyl cyclisation of bis-Cbz- and bis-Boc-protected guanidines

The Pd-mediated π-allyl cyclisation of bis-Cbz- and bis-Boc-protected guanidines 4 and 14b led to the formation of five- and six-membered heterocycles 5 and 17 in high yields.     

A rapid and efficient synthesis of a new pyrrolobenzodiazocines via an intramolecular Friedel-Crafts reaction

New pyrrolobenzodiazocines 3 have been prepared by an intramolecular Friedel-Crafts process from pyrrolobenzoacrylamides 2. The cyclisation process involving a 1,4-intramolecular addition of a pyrrole onto acrylamide led to the formation of an eight-membered ring.     

A connective approach to the tetrahydropyran subunit of polycavernoside A via a novel 1,1-dianion equivalent

Racemic tetrahydropyran 3 was efficiently synthesised from allylsilane 6 and aldehyde 7 via an intramolecular Sakurai cyclisation. In a single step, the relative configuration of three chiral centres was established. Allylsilane 6 was readily assembled from 1-iodo-1-selenopropene 10, a synthetic equivalent of a propene 1,1-dianion.     

Synthesis of the alkenyl-substituted tetracyclic core of the bisabosquals

HCl-catalyzed deprotection and cyclization of benzylic alcohol 15 cleanly provided tricycle 16 by a cis-selective intramolecular Diels-Alder reaction. Acetylation of the phenol, bis epoxidation, and base-catalyzed hydrolysis and cyclization afforded tetracycle 19 with the bisabosqual skeleton, but the opposite stereochemistry at the tertiary alcohol stereocenter. Selective dehydration of the tertiary alcohol to form the exocyclic alkene, ozonolysis, reductive deoxygenation of the side chain epoxide, and addition of MeMgBr to the ketone from the less hindered face gave tertiary alcohol 24 with the tetracyclic core of bisabosqual A (1).     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Surprising 1,7-cyclization of vinyl carbonyl ylides generated from reaction of indanetrione with vinyl diazo compounds

Reactions of tricarbonyl compounds with vinyl diazo compounds 2 were carried out. Reaction of 1,2,3-indanetrione with 2a,b,c gave the spiroindan-1,3-dione-2,2′-benzodihydrooxepin 7a,b,c, but not normal products oxirane and dihydrofuran derivatives expected from intermediate vinyl carbonyl ylides 4. Formation of 7 requires isomerization of vinyl carbonyl ylides 4 bearing a (Z)-cyanostyryl group to unstable (E)-form 5 and subsequent cyclization to oxepin 6 followed by a 1,5-hydrogen shift. However, reaction of 2 with six-membered cyclic tricarbonyl compounds 1,2,3-trioxo-2,3-dihydrophenalene 11 and dimethylalloxane 13 gave the dioxole 12 and the dihydrofuran 14, respectively, typical products expected from vinyl carbonyl ylides.     

Synthesis of polycyclic and 4,5-diacylthiophene-2-carboxylates via intramolecular Friedel-Crafts alkylations and unusual autooxidative fragmentation of the derivatives obtained from the samarium diiodide-promoted coupling reactions of thiophene-2-carboxylate with carbonyl compounds

Our present study provides an expedient method for the synthesis of novel polycyclic and multi-substituted thiophene derivatives. A series of 4,5-di(hydroxyalkyl)-4,5-dihydrothiophene-2-carboxylates (e.g., 4a-c and 10) were prepared by the SmI₂-promoted three-component coupling reactions of thiophene-2-carboxylate with aromatic aldehydes and 4-methoxyacetophenone. Diol 4a was oxidized by DDQ or pyridinium dichromate to give 5-acyl-4-hydroxyalkyl-4,5-dihydrothiophene-2-carboxylate 6a, which was subjected to dehydration to give either alkene 7 with terminal CC double bond or alkene 15a having conjugation with the ester group, depending on the reaction conditions using different quantities of p-toluenesulfonic acid. Alkene 7 underwent an intramolecular Friedel-Crafts alkylation to give a tetralone-fused thiophene-2-carboxylate 9. By the similar procedure, a carbazole-fused thiophene 14 was also prepared. Alkenes 15a-c underwent autooxidative fragmentation to give 4,5-diacylthiophene-2-carboxylates 5a-c that were elaborated to pyridazine-fused thiophenes.     

Formal synthesis of (+)-lactacystin based on a novel radical cyclisation of an α-ethynyl substituted serine

A diastereoselective 5-exo-dig radical cyclisation of the bromoamide 7 produced from the enantiopure α-ethynyl substituted amino alcohol 5 led to the pyrrolidinone 8 (2:1 α:β epimers) in 70% yield. Oxidative cleavage of the alkene bond in 8, followed by a stereoselective α-methylsulfanylation of the resulting 4-keto derivative 9, next led to the methylsulfanyl derivative 10. Finally, the pyrrolidinone derivative 10 was converted into the key intermediate 12 used previously in an enantioselective synthesis of (+)-lactacystin.     

Stereocontrolled total syntheses of (±)-clovan-3-one and (±)-epi-clovan-3-one and a facile total synthesis of (±)-pseudoclovene-A

Stereocontrolled total syntheses of the bridged tricyclic ketones (±)-clovan-3-one (5) and (±)-epi-clovan-3-one (6) and a facile total synthesis of the tricyclic sesquiterpene (±)-pseudoclovene-A (3) have been successfully accomplished involving participation of an aryl intramolecular cyclisation of the bromophenol 11 as a key step.     

Synthesis of C1- and C8a-epimers of (+)-castanospermine from d-glucose derived γ,δ-epoxyazide: intramolecular 5-endo epoxide opening approach

A concise synthesis of two diastereomers of (+)-castanospermine namely 1- and 8a-epi-castanospermine 1b and 1c, respectively, is reported from d-glucose. The methodology involves stereoselective cross metathesis of d-glucose derived alkene 2 with 4-bromo-1-butene followed by azide displacement and m-CPBA oxidation to afford diastereomeric γ,δ-epoxyazides 5a/5b. The Staudinger reaction of epoxyazide 5a followed by reaction with benzylchloroformate (CbzCl) unexpectedly furnished 1,3-oxazinan-2-one derivative 7 whose stereochemistry was establish by single crystal X-ray. This helps to assign the stereochemistry in the epoxidation reaction. The reduction of 5a/5b was then carried out by transfer hydrogenation to provide γ,δ-epoxyamine that concomitantly undergoes intramolecular 5-endo-tet cyclization to afford hydroxypyrrolidine ring skeleton with sugar framework-a precursor to castanospermine analogues 1b/1c.     

Synthesis of substituted (S)-2-aminotetralins via ring-opening of aziridines prepared from l-aspartic acid β-tert-butyl ester

This paper describes the total synthesis of the hydrochloride salts of (2S)-2-amino-7-methoxytetralin (21-HCl) and (2S)-2-amino-6-fluoro-7-methoxytetralin (ST1214), from a common enantiomerically pure aziridine 4b, which was available from l-aspartic acid β-tert-butyl ester. The synthesis of 21-HCl and ST1214 proceeded in nine steps and 5 and 6% overall yields, respectively. Key steps are the regioselective ring-opening of 4b with ArMgBr/CuBr·SMe₂ and the intramolecular Friedel-Crafts cyclisation providing α-tetralone. Substituted naphthalenes were formed as side products in the latter reaction.     

First synthesis of pyrrolo[1,2:1′,2′]azepino[5,6-b]indole derivatives

A new family of pyrrolo[1,2:1′,2′]azepino[5,6-b]indole derivatives 8,15 related to anthramycin skeleton was prepared in good yield from indole-2-carboxylic acid and β-aminoesters 4 through intramolecular cyclisation.     

First construction of 12H-thiochromeno[2,3-b]quinolines and 5H-benzo[7,8]thiocino-[2,3-b]quinolines via intramolecular Friedel-Crafts reaction of Morita-Baylis-Hillman adducts

An acid-promoted intramolecular Friedel-Crafts reaction of the Morita-Baylis-Hillman adducts 3 derived from 2-arylthioquinolin-3-carbaldehydes 2 was investigated. Interestingly, promoted by sulfuric acid, the substrates with electron-donating groups on the aromatic ring gave six-membered fused-ring 12H-thiochromeno[2,3-b]quinolines 4 with good yields, while those with electron-withdrawing groups afforded eight-membered fused-ring 5H-benzo[7,8]thiocino[2,3-b]quinolines 5 in moderate yields. Using triflic acid instead of sulfuric acid, only products 4 could be obtained under the similar condition.     

Lewis acid-catalyzed intramolecular amination via 1,3-chirality transfer

Direct intramolecular amination of the chiral non-racemic allylic alcohol 1 conjugated with a benzene ring afforded the tetrahydroisoquinoline 2 possessing a newly formed alkene in the presence of a catalytic amount of Lewis acid.     

A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles

N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized five- and six-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,β-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15.     

Synthetic studies towards oxygenated and unsaturated furanocembranoid macrocycles. Precursors to plumarellide, rameswaralide and mandapamates

A new approach to the synthesis of oxygenated furanocembranoids, exemplified by danielid 3, is described. The approach features an intermolecular Knoevenagel-type condensation together with an intramolecular aldolisation to elaborate the furan and the lactone rings, respectively, in the initial target compound 14. Efforts to isomerise the C13-C14 double bond, or to introduce an alkene bond at C11-C12 in 14, leading to structures 3 and 8, respectively, are described.     

A new 3-methylidenepentane-1,5-dianion synthon: synthesis of perhydropyrano[2,3-b]pyrans and 1,7-dioxaspiro[4.5]decanes

4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) has proved to be an appropriate and new 3-methylidenepentane-1,5-dianion synthon. The reaction of 2 with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbonyl compound in THF at 0 °C, leads, after hydrolysis, to the expected methylidenic diols 3. These diols when subjected to successive hydroboration-oxidation and final oxidation, undergo spontaneous cyclisation to furnish a series of cis-perhydropyrano[2,3-b]pyrans (4) in a highly diastereoselective manner (>99% de). Additionally, diols 3 also undergo double intramolecular iodoetherification promoted by a silver salt, to furnish the corresponding 1,7-dioxaspiro[4.5]decanes (6) in very high yields.     

Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.     

Synthesis of (−)-pinidinone

The diastereoselective PdCl₂/CuCl₂-catalysed intramolecular methoxyaminocarbonylation of N-benzyl protected alkenyl amine 4 was used as a key step in the total synthesis of the naturally occurring piperidine alkaloid (−)-pinidinone. Commercially available (S)-propylene oxide was employed as starting material, delivering the key substrate 4 in three steps and 68% overall yield. Subsequently, the influence of various reaction parameters on the diastereoselectivity of the key cyclisation of 4 was scrutinised. Copper(II) chloride proved to be the optimum reagent and/or co-catalyst for the successful aminocyclisation-methoxycarbonylation tandem transformation of alkenyl amine 4 into the desired methyl esters 3 and 8. The latter were subsequently transformed into the title natural product.     

Stereoselective total syntheses of (±)-1,14-herbertenediol and (±)-tochuinyl acetate and facile total syntheses of (±)-α-herbertenol, (±)-β-herbertenol and (±)-1,4-cuparenediol

Stereoselective total syntheses of (±)-1,14-herbertenediol (7) and (±)-tochuinyl acetate (10) and facile total syntheses of (±)-α-herbertenol (2), (±)-β-herbertenol (3) and (±)-1,4-cuparenediol (8) have been successfully accomplished involving intramolecular cyclisation of 3-aryl-3-methyl-6-bromohexanoates and in situ methylation of the resulting cyclopentanecarboxylates as the key reactions.