Mechanism of the conversion of inverted CB[6] to CB[6

Inverted cucurbit[n]urils (iCB[n]) form as intermediates during the synthesis of cucurbit[n]urils from glycoluril and formaldehyde in HCl (85 degrees C). Product resubmission experiments establish that the diastereomeric iCB[6] and iCB[7] are kinetic products that are less stable thermodynamically than CB[6] or CB[7] (>2.8 kcal mol(-1)). When iCB[6] or iCB[7] is heated under aqueous acidic conditions, a preference for ring contraction is noted in the formation of CB[5] and CB[6], respectively. Interestingly, under anhydrous acidic conditions ring size is preserved with iCB[6] delivering CB[6] cleanly. To establish the intramolecular nature of the iCB[6] to CB[6] conversion under anhydrous, but not aqueous, acidic conditions we performed crossover experiments involving mixtures of iCB[6] and its (13)C=O labeled isotopomer (13)C(12)-iCB[6]. An unusual diastereomeric CB[6] with a M?bius geometry (13) is proposed as a mechanistic intermediate in the conversion of iCB[6] to CB[6] under anhydrous acidic conditions. The improved mechanistic understanding provided by this study suggests improved routes to CB[n]-type compounds.     

Synthesis of [4,5-Bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides as Potential Inhibitors of HIV via Stereospecific Base-Induced Rearrangement of a 2,3-Epoxy Thioacetate(1)

The synthesis of [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides is described. 2,3-Epoxy alcohol 10 was converted in one pot into thioacetate 11. Treatment of 11 under mild alkaline conditions gave thiirane 12 with inversion of configuration at C-2. We also found that thioacetate 11 rearranges into thiirane 14 under mild acidic conditions. This rearrangement reaction was shown by independent synthesis to proceed with net retention of configuration at C-2. We have proposed a tentative mechanism which may explain the results obtained. Opening of thiiranes 12 and 14 followed by deprotection gave (2R,3R)-2-thiothreitol (23) and (2S,3R)-2-thioerythritol (25), respectively. Regioselective silylation of the primary hydroxyl groups of 23 followed by treatment with trimethyl orthoformate gave 2-methoxy-1,3-oxathiolanes 26 and 27. Condensation with silylated bases followed by deprotection and separation of the anomers gave the oxathiolanylnucleosides. Compounds 29-31, 34, and 35 were found to be inactive when tested for inhibition of HIV-1 activity in vitro.     

Efficient microwave-assisted two-step procedure for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones

A general method has been developed for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones. This process involves initial microwave-assisted quinazolinone formation between anthranilamide and various Boc- or acylamino acids, followed by intramolecular cyclodehydration under acidic conditions. In the case of 3-monosubstituted-imidazoquinazolinones, the procedure needs the formation of the formamide derivatives by deprotection and formylation of the Boc-intermediates.     

Preparation of diamines by lithiation-substitution of imidazolidines and pyrimidines

The synthesis of chiral 1,2-diamines and 1,3-diamines was achieved from the unsubstituted diamines by way of N-tert-butoxycarbonyl (Boc) substituted imidazolidines (tetrahydroimidazoles) and pyrimidines (hexahydro-1,3-diazines), which were treated with sec-butyllithium to effect deprotonation alpha- to the N-Boc group, followed by addition of an electrophile to give substituted products that could be hydrolysed under acidic conditions to give the substituted 1,2- or 1,3-diamines. Use of the chiral ligand (-)-sparteine promoted asymmetric deprotonation of the imidazolidine substrates to give, after hydrolysis, enantiomerically enriched 1,2-diamines.     

Synthesis of terpinyl acetate using octadecylamine ethoxylate ionic liquids as catalysts

Terpinyl acetate, an important natural flavor, can be synthesized by esterification of α-pinene with acetic acid under acidic conditions. In this work, seven acidic ionic liquids were first synthesized, using octadecylamine ethoxylates (AC 1810, AC 1815, AC 1820, and AC 1830) as the cations, and characterized by FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. The ionic liquids were then used as catalysts in the synthesis of terpinyl acetate. The effect of preparation conditions on catalyst performance was examined. It was found that the acidic ionic liquid 1-(3-sulfonic acid)propyl-3-poly(ethylene glycol) octadecylamine polyoxyethylene ether tetrafluoroborate ([PAC1815]⁺[BF₄]^?) was an excellent catalyst for synthesis of terpinyl acetate. The effects of the conditions used for preparation of terpinyl acetate were examined in detail, and the optimum preparation conditions were obtained. Under the optimum conditions, the yield of terpinyl acetate reached 35.70 %. When the catalyst was reused for the 5th time, the yield of terpinyl acetate was still 32.00 %. The results showed that effective separation and recycling of catalyst could contribute to developing a new strategy for synthesis of terpinyl acetate.     

A divergent synthesis of functionalized unsaturated delta-lactones from alpha-alkenoyl-alpha-carboxyl ketene dithioacetals

A divergent synthesis of functionalized unsaturated delta-lactones 2, 3, 4, and 5 has been developed starting from the readily available alpha-alkenoyl-alpha-carboxyl ketene dithioacetals 1 in high to excellent yields under mild reaction conditions. Thus, 6-substituted 3-(1,3-dithiolan/dithian-2-ylidene)-3H-pyran-2(6H)-ones 2, obtained from a consecutive reduction with NaBH4 and acidic workup of 1 via a novel vinylogous Pummerer cyclization, can be further transformed into alpha-pyranones 3, 4, and 5 upon a sequential isomerization catalyzed by triethylamine (to give 3), followed by dethioacetalization (to give 4) or a formylation with Vilsmeier reagent (to give 5).     

Synthesis of a capillarisin sulfur-analogue possessing aldose reductase inhibitory activity by selective isopropylation

We describe the synthesis of 2-[(4-hydroxyphenyl)thio]-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2 from 3,4,5-trimethoxyphenol 6 via the key intermediate, 3-iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 3. An important feature of this synthetic scheme involves selective alkylation, which can be achieved by two different routes. One route involves the selective isopropylation of a triacetate derivative 4 under basic conditions. The second route employs the selective demethylation of a trimethoxy derivative 5 under acidic conditions followed by isopropylation. The product of these alternative routes, compound 3, is then converted to a capillarisin sulfur analogue 2 in a one-pot reaction via the imidazolyl intermediate 22.     

Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition

[reaction: see text]. The total synthesis of the potent immunosuppressant FR901483 is described. In a key step, the intermolecular Diels-Alder cycloaddition of an amidoacrolein with 2-(triisopropylsilyloxy)-1,3-butadiene produced the desired 3-cyclohexene-1-carboxaldehyde. This compound was subjected to basic followed by acidic conditions which effected two sequential aldol cyclizations to deliver the tricyclic ring system of the natural product, suitably functionalized for completion of the total synthesis.     

A two step route to indoles from haloarenes--a versatile variation on the Fischer indole synthesis

In a new variation on the Fischer indole synthesis, readily available haloarenes are converted into a wide range of indoles in just two steps by halogen-magnesium exchange, quenching with di-tert-butyl azodicarboxylate, followed by reaction with ketones under acidic conditions.     

Synthesis of aldehyde building blocks protected as acid labile N-Boc N,O-acetals: toward combinatorial solid phase synthesis of novel peptide isosteres

The synthesis of (RS)-3'-tert-butoxycarbonyl-perhydro-1', 3'-oxazine-2'-yl acetic acid and the syntheses of the simple and C-2 substituted 3'-tert-butoxycarbonyl-perhydro-1',3'-oxazine-2'(RS)-yl propionic acids from simple starting materials are presented. The simple compounds were prepared from 1,3-propanediol and 1, 4-butanediol, respectively, via a short series of facile steps, in 70% overall yield in both cases. For the syntheses of the C-2 substituted compounds of the longer homologue, (RS)-3'-tert-butoxycarbonyl-perhydro-1',3'-oxazine-2'-yl propionic acid, a malonic ester route was selected, thus allowing easy incorporation of various side chains. The stability of the novel aldehyde protection group, the N-Boc N,O-acetal moiety, under various acidic conditions was investigated, and it was found to cleanly and rapidly yield the aldehyde under strong acidic conditions or, if desired, slower under less harsh conditions. As a demonstration of the use of the building blocks, one building block was coupled to a solid support and, after unmasking of the aldehyde, submitted to three different types of nucleophilic reactions (Pictet-Spengler condensation, reductive amination, Horner-Wadsworth-Emmons olefination) followed by further chemical modification, and the identity of the structures were verified after cleavage from the resin.     

Two-step route to indoles and analogues from haloarenes: a variation on the Fischer indole synthesis

In a new variation on the Fischer indole synthesis, readily available haloarenes are converted into a wide range of indoles in just two steps by halogen-magnesium exchange and quenching with di-tert-butyl azodicarboxylate, followed by reaction with aldehydes or ketones under acidic conditions. The protocol, which is readily extended to the preparation of indole isosteres, 4- and 6-azaindoles and thienopyrroles, obviates the need to prepare potentially toxic aryl hydrazines, simultaneously avoiding undesirable anilines such as naphthylamines.     

Short synthesis of the 6,6-spiroketal cores of spirofungins A and B

[reaction: see text] Initial efforts toward the total synthesis of the antifungal antibiotics spirofungins A and B are reported. A short and efficient synthesis of the C9-C20 6,6-spiroketal fragments of both compounds is described. This asymmetric approach uses a very efficient alkylation of a lithiated N,N-dimethylhydrazone followed by spiroketal formation under acidic conditions.     

Purines. LI. Synthesis and biological activity of hypoxanthine 7-N-oxide and related compounds.

A detailed account is given of the first chemical synthesis of hypoxanthine 7-N-oxide (5), which started from coupling of 6-chloro-5-nitro-4(3H)-pyrimidinone (7) with N-(4-methoxybenzyl)phenacylamine, generated in situ from the hydrochloride (8), and proceeded through cyclization of the resulting phenacylaminopyrimidinone (9) and removal of the 4-methoxybenzyl group. The results of catalytic hydrogenolysis, methylation followed by catalytic hydrogenolysis, and rearrangement under acidic conditions of 5 supported the correctness of the assigned structure. An ultraviolet spectroscopic approach suggested that the neutral species of 5 exists in H2O mainly as the N(7)-OH tautomer (21). In the in vitro bioassay of antileukemic activity against murine L5178Y cells, 5 was weakly cytotoxic, with IC50 of 100 micrograms/ml. It did not show any antimicrobial activity even at 1000 micrograms/ml. None of the 9-(4-methoxybenzyl) (11) and O-methyl (12, 13, and 14) derivatives was found to be antileukemic or antimicrobial.     

1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquid catalyzed Skraup synthesis of quinolines under microwave heating

1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquids are shown as excellent catalysts and reaction mediums for Skraup synthesis of quinolines under microwave conditions without the use of nitrobenzene as an oxidant and metal catalysts.     

Synthesis of (±)-7-hydroxylycopodine

A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (±)-7,8-dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)(3) and to an amino phenol with KHMDS and oxygen.     

A diastereoselective route to 2,6-syn-disubstituted tetrahydropyrans: synthesis of the civet compound (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid

A diastereoselective synthesis of 2,6-syn-disubstituted tetrahydropyrans has been developed based on the ability of furanyl-ether chiral centres to epimerise readily under acidic conditions. This novel methodology was applied to the synthesis of (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid, a component of the African civet cat's glandular marking secretion.     

1,5-Dimethyl-4-phenylimidazolidin-2-one-derived iminic glycinimides: useful new reagents for practical asymmetric synthesis of alpha-amino acids

New 1,5-dimethyl-4-phenylimidazolidin-2-one-derived acyclic chiral iminic glycine reagents have been prepared and diastereoselectively alkylated with activated alkyl halides and electrophilic olefins in the presence of lithium chloride under (a) strong bases (LHMDS, KOBu(t)) and low temperature (-78 degrees C) conditions, (b) solid-liquid phase-transfer catalysis reaction (LiOH, TBAB, -20 degrees C) conditions, and (c) in the presence of organic bases (DBU, BEMP, TMG, -20 degrees C). In the case of dielectrophiles C- and N-alkylation takes place to afford heterocyclic derivatives. Hydrolysis of alkylated products has been carried out (a) in two-step procedures with LiOOH or LiOH followed by acidic hydrolysis or Dowex purification, (b) in one single-step under refluxing water to give the corresponding alpha-amino acid, (c) in the presence of DBU in methanol to provide N-protected alpha-amino acids methyl esters, or (d) by a protection-hydrolysis procedure to afford N-Boc-protected alpha-amino acids. The chiral imidazolidinone has generally been recovered in good yield. This methodology has been shown to be useful for the synthesis of acyclic and heterocyclic (S)- and (R)-alpha-amino acids.     

Chromophores from hexeneuronic acids (HexA): synthesis of model compounds and primary degradation intermediates

Hexeneuronic acid (HexA) is formed under pulping conditions from 4-O-methyl-glucuronic acid residues in xylans by methanol elimination. It is usually removed by an acidic washing treatment (A-stage) within the pulp bleaching sequence. Hexeneuronic acid has long been recognized as a source of color generation in pulps, but the chemical structure of the actual chromophoric compounds remained elusive. We report the synthesis of isotopically (¹³C) labeled HexA model units carrying a label at any of the six carbon atoms. Confirming pertinent literature accounts, it is shown that HexA forms three primary degradation intermediates, 2-furancarboxylic acid, 5-formyl-2-furancarboxylic acid, and formic acid, under mildly acidic conditions, and their formation mechanism is discussed. 2-Furancarboxylic acid is demonstrated to be deformylation product of 5-formyl-2-furancarboxylic acid. The three primary intermediates are colorless and do not represent chromophores themselves. Their mixture, upon thermal or acidic treatment, gives rise to the same chromophores that are also directly formed from HexA.     

An efficient synthesis of the taxane-derived anticancer agent ABT-271

ABT-271, 1, has been identified as a promising anticancer agent. ABT-271 is a novel taxane possessing a C9-(R)-hydroxyl group as opposed to a C9-ketone which is present in Taxol and Taxotere. To further evaluate ABT-271 as a potential anticancer agent, an efficient synthesis was developed which allows the large scale synthesis of ABT-271. Ketalization of the 7,9-diol of 9-DHAB-III, 2, allows selective removal of the C13-acetate with phenyllithium. The resulting C13-hydroxyl group is then acylated using LiHMDS and beta-lactam 22 to give ABT-271 in protected form. The protecting groups were removed first by acidic hydrolysis followed by basic hydrolysis to provide ABT-271. Application of this synthetic sequence provided over 600 g of ABT-271, 1.     

Novel approach towards one pot stereospecific synthesis of carbohydrate derived substituted imidazolines

A simple synthetic approach has been developed towards one pot synthesis of 2-imidazolines under mild acidic conditions from N-acetyl glucosamine via reductive amination followed by dehydrative cyclization. Synthetic studies were explored in detail with different amines and sugar derivatives. While the conversion was good, the corresponding substituted imidazolines were obtained in moderate yields.