Efficient and highly enantioselective formation of the all-carbon quaternary stereocentre of lyngbyatoxin A

Indole 25, an advanced intermediate in a projected enantioselective total synthesis of lyngbyatoxin A 1, was prepared from allylic alcohol 11 in 9 steps and >95% ee, key transformations being the enantiospecific rearrangement of vinyl epoxide 14 and the Hemetsberger-Knittel reaction of azide 24.     

The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.     

A chiral molecular recognition approach to the formation of optically active quaternary centres in aza-Henry reactions

An approach to asymmetric catalysis based on chiral molecular recognition by the combination of chiral Lewis acids and chiral organocatalysis for the formation of optically active quarternary centers in the aza-Henry reaction is presented; this procedure leads to products with up to 98% ee and a diastereomeric ratio of 14 : 1 in excellent yields with catalyst loadings of 5 mol%.     

Highly enantioselective hydrovinylation of alpha-alkyl vinylarenes. an approach to the construction of all-carbon quaternary stereocenters

The highly enantioselective hydrovinylation of alpha-alkyl vinylarenes was realized by using nickel complexes of chiral spiro phosphoramidite ligands. The method provided a new approach to the construction of chiral all-carbon quaternary centers.     

A cascade reaction sequence en route to 7-substituted 2-aminopyrrolo[1,2-a]pyrimidine-4,6-diones and the corresponding acrylic acid derivatives

Reaction of α-bromo ketones with 6-amino-2-methylpyrimidin-4(3H)-one under basic conditions and in the presence of atmospheric oxygen affords novel 7-substituted 2-amino-pyrrolo[1,2-a]pyrimidine-4,6-diones that are readily hydrolyzed to afford the corresponding acrylic acid derivatives. The reaction sequence consists of an initial alkylation, followed by an unexpected condensation, elimination, and oxidation sequence to afford the products. This cascade reaction sequence represents a rapid and unprecedented route to the described small molecules.     

A directed metalation route to the zwitterionic indole alkaloids. : Synthesis of sempervirine

A synyhesis protocol involving beta-lithiation of 2-(2-pyridinyl)indoles (4 → 5) and subsequent reaction with bromoacetaldehyde leads to the indol[2,3-a]quinolzine(1)ring system. Application of this methodology to 2-(2-pyridinyl)indole 17, which is prepered via Taylor-Boger triazine Dieis-Alder annulation chemistry, affords the zwitterionic indole alkaloid sempervirine (3).     

Concise route to the key intermediate for divergent synthesis of C7-substituted fluoroquinolone derivatives

A concise route to ethyl 7-bromo-1-cyclopropyl-6,8-difluoro-4-quinolone-3-carboxylate has been developed. This compound is a key intermediate for divergent synthesis of various C7-substituted fluoroquinolones, a group of potent topoisomerase II inhibitors with promising clinical applications.     

Probing the formation and chemistry of enoxyoxirane derivatives in the C-ring en route to guanacastepene

Enol acetate and silyl enol ether, derivatives of 2 and 3 undergo stereoselective epoxidation from the β-face of the C13-C14 olefin. The progression of these compounds to the C13 acetoxy C14 ketones is described.     

Carbon dioxide: A reagent for the simultaneous protection of nucleophilic centres and the activation of alternative locations to electrophilic attack: Part 11. A new synthetic route to the 2-substituted thiazolidines

Thiazolidine is readily converted into a range of 2-substituted derivatives in a one-pot lithiation procedure, using carbon dioxide both for N-protection and as an intermediate carbanion stabilizing group.     

A highly convergent cascade cyclization to cis-hydrindanes with all-carbon quaternary centers and its application in the synthesis of the aglycon of dendronobiloside A

An efficient and versatile ZnBr(2)-catalyzed Diels-Alder/carbocyclization cascade reaction has been developed for construction of highly functionalized cis-hydrindanes (70-96% yields with high diastereoselectivity), and it has been successfully utilized in the synthesis of the aglycon of dendronobiloside A.     

Directed ortho metalation-cross coupling strategies. N-cumyl arylsulfonamides. Facile deprotection and expedient route to 7- and 4,7-substituted saccharins

By using the powerful N-cumylsulfonamide directed metalation group (DMG), a series of 2-substituted derivatives were prepared according to the directed ortho metalation (DoM) tactic (Table 1). Mild conditions for N-decumylation and other simple transformations of the products have been achieved (Scheme 2). The 3-silyloxy sultam 12 undergoes further DoM to give formyl, thiomethyl, iodo, and amide derivatives 13a-g of potential value for saccharin synthesis (Table 2). An effective route to target 7-aryl saccharins via Suzuki cross coupling (Table 3) followed by further metalation-carbamoylation and cyclization (Table 5) is described. 4,7-Disubstituted saccharins have been obtained by similar sequences (Scheme 3). Mild TFA-mediated N-decumylation furnishes substituted primary arylsulfonamides (Table 4).     

A directed metalation route to the zwitterionic indole alkaloids. Syntheses of indolo[2,3-a]quinolizine,flavopereirine, flavocarpine,and dihydroflavopereirine

A protocol involving beta-lithiation of 2-(2-pyridinyl)indoles (4 → 5) and subsequent reaction with bromoacetaldehyde or oxirane has led to syntheses of the alkaloids indolo[2,3-a]quinofizine (1), flavopereirine (2), flavocarpine (21), and dihydroflavopereirine (24).     

A model study for the synthesis of the tumor promoting agents lyngbyatoxin a and teleocidin b—further aspects of a new isoxazoline-based indole synthesis.

A new indole synthesis developed in our laboratories has been shown to be applicable to the preparation of 4-amino-7-carbon substituted indoles, a result of some relevance to the preparation of the title compounds.     

Freidel-crafts acylation of 1-tert-butyldimethylsilylpyrrole,a very short and simple route to 3-substituted pyrroles.

1-tert-Butyldimethylsilylpyrrole undergoes Freidel-Crafts acylation almost exclusively at β-position giving after sodium flouride supported hydrolysis the 3-pyrroloketones.     

Stereospecific conjugate addition of organolithium reagents to naphthylimines. A facile route to 1,1,2- and 1,2-substituted dihydroronaphthalenes

Addition of organolithium reagents at low temperature to the cyclohexylimine of 1-naphthaldehyde followed by electrophilic trapping of the intermediate gives rise to high yields of the title compounds.     

A new route toward 4-substituted pyrazino[2,1-b]quinazoline-3,6-dione systems. Total synthesis of glyantrypine

Treatment of sodium N-(o-azidobenzoyl)aminoacylglycinates 8 with acetic anhydride afforded 1-acetyl-4-(o-azidobenzoyl)-2,5-piperazinediones 7, with complete retention of the stereochemistry. The intramolecular aza Wittig reactions of compounds 7 in the presence of tributylphosphine followed by deacetylation gave 1,2-unsubstituted pyrazino[2,1-b]quinazoline-3,6-diones 1. This route was adapted to the synthesis of both enantiomers of the alkaloid glyantrypine.     

A catalytic and stoichiometric approach to the synthesis of the steroid B-ring en route to estratrienes

Zirconocene catalyzed cyclization of 2-(5-methoxy-3-penten-1-yl)styrene in the presence of organomagnesium reagents was studied. The cyclization proceeded in high isolated yields (up to 84%) with excellent trans-selectivity (>98%), which is unusual for the formation of cyclohexane derivatives. Catalytic cyclization in the presence of Cp₂ZrCl₂ proceeded as well with similar results. The reaction with (R,R)-(EBTHI)₂ZrCl₂ gave a cis/trans mixture of 5 in low yield and poor ee.     

The structure of melinonine-E,a quaternary indole alkaloid from Strychnos melinoniana baillon. Part 190: Studies on organic natural products

The structure of melinonine-E ( 2 ) with relative configuration was established on the basis of spectral data for 2 and its acetate 3 .