Ring Expansion via One-Pot Conversion of Lactone Acetals to Cyclic Enones. Synthesis of (±)-1--Xerantholide.

Baeyer-Villiger oxidation of α-alkoxy ketones provides lactone acetals , which react with the lithium salts of dimethyl(alkyl) phosphonates in the presence of LaCl·2LiCl to provide cyclic enones in good to excellent yields after treatment with dilute aqueous potassium carbonate. Thus, five-, six-, and seven-membered lactones are converted to five-, six-, and seven-membered cyclic enones. The utility of this two-step ring expansion method is demonstrated in the synthesis of (±)-1--xerantholide from 5-methyl-2-cyclohexen-1-one.

[3,3]-Sigmatropic rearrangements of propargyl alkynyl ethers. Synthesis of complex dienoates and unsaturated lactones.

In an extension of our studies on low-temperature rearrangements of 1-alkynyl ethers, we describe herein the [3,3]-sigmatropic rearrangement of formed propargyl alkynyl ethers to allenyl ketenes, which furnish complex -butyl-(2,4)-dienoates 2 in good yields upon -butanol addition. Similarly, sigmatropic rearrangements of formed propargyl lithioalkynyl ethers yield methyl-(2,4)-dienoates 4 upon methanol addition or unsaturated lactones 6 upon aldehyde or ketone addition to the allenyl ynolate intermediate.

Butyllithium-Induced Tandem [3,3]-Sigmatropic Rearrangement and Carbonyl Olefination of Allyl-1,1-dichlorovinyl Ethers.

Exposure of dichlorovinyl ethers to butyllithium and addition of saturated or unsaturated aldehydes, ketones, or esters at ambient temperature furnishes rearranged α,β-unsaturated carboxylic acids, isolated as their corresponding methyl esters in 48-91% overall yields. Exposure of dichlorovinyl ethers to butyllithium, addition of aldehydes, ketones, dialdehydes, or diketones at -78 °C, and warming to 80 °C in the presence of SiO provide 1,4-dienes or cycloalken-1-ols (or their dehydration products) in 45-72% overall yields.

Total Syntheses and Absolute Configuration Assignment of (+)-Sootepdienone, (-)-Jambolanin C, (-)-Jambolanin I, and (-)Gibberodione.

Total syntheses of the sesquiterpenes (+)-sootepdienone, (-)-jambolanin C, (-)-jambolanin I, and (-)-gibberodione have been accomplished in 10 steps each from -(+)-pulegone, allowing assignment of the absolute configuration of the natural products. A key step in the synthetic pathways involves the one-carbon ring expansion of a cyclic allylic phosphonate to a substituted cycloheptenone by a tandem oxidative cleavage/intramolecular Horner-Wadsworth-Emmons reaction.

Total Synthesis of Alvaradoins E and F, Uveoside, and 10-epi-Uveoside.

Concise total syntheses of the anthracenone -glycosides alvaradoins E and F, uveoside, and 10-epi-uveoside (-) have been accomplished from chrysophanic acid and bromosugar . Key steps in the syntheses include the DBU-induced coupling of and to produce β--glycoside , and a Pb(OAc)-mediated Kochi reaction to introduce the C-1' oxygen atom of the natural products. Isothermal titration calorimetry and fluorescence binding studies reveal that compounds and have good affinity for the plasma protein HSA.

Ring Expansion, Ring Contraction, and Annulation Reactions of Allylic Phosphonates under Oxidative Cleavage Conditions.

Oxidative cleavage of cycloalkenylalkylphosphonates 1 followed by treatment with base gives rise to homologated cycloalkenones 2 in good to excellent yields. Subjecting cycloalk-2-enylphosphonates 3 to identical conditions provides the one-carbon ring-contracted compounds 4 in excellent yields. Oxidative cleavage of γ,δ-unsaturated ketophosphonates 6 followed by treatment with base affords 2-cyclopenten-1-ones 7 in good overall yields.

Dimeric and trimeric derivatives of the azinomycin B chromophore show enhanced DNA binding.

To explore the utility of the azinomycin B chromophore as a platform for the development of major-groove binding small molecules, we have prepared a series of 3-methoxy-5-methylnaphthalene derivatives containing diamine, triamine, and carbohydrate linker moieties. All bis- and tris-azinomycin derivatives are intercalators that display submicromolar binding affinities for calf-thymus DNA, as revealed by viscometry measurements and fluorescent intercalator displacement (FID) assays, respectively. Although the tightest binding ligand 1d (K = 2.

A protecting group-free synthesis of (-)-hortonones A-C from the Inhoffen-Lythgoe diol.

A synthesis of hortonones A-C has been accomplished from vitamin Dvia the Inhoffen-Lythgoe diol without the use of protective groups. Key steps in the syntheses include a TMS-diazomethane mediated regioselective homologation of the cyclohexanone ring to a cycloheptanone moiety and a sodium naphthalenide-mediated allylic alcohol transposition. It has been found that the absolute configuration of the natural hortonones is opposite that of the synthetic material prepared from vitamin D.

A Single-Flask Synthesis of Morita-Baylis-Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and E.

Sequential treatment of (ethoxyethynyl)lithium with aldehydes and/or ketones (2 and 4) and BF3·OEt2 gives rise to β-hydroxyenoates 5 in good to excellent overall yields. Similarly, the combination of 1 (M = Li) and dicarbonyl compounds 6 (X = O) or keto/aldehyde acetals (X = OMe) followed by the addition of a Lewis acid leads to five-, six-, and seven-membered hydroxycycloalkene carboxyates. The utility of this method is demonstrated in the synthesis of the α-alkylidene lactone natural products subamolide D and E.

Tandem Bond-Forming Reactions of 1-Alkynyl Ethers.

Electron-rich alkynes, such as ynamines, ynamides, and ynol ethers, are functional groups that possess significant potential in organic chemistry for the formation of carbon-carbon bonds. While the synthetic utility of ynamides has recently been expanded considerably, 1-alkynyl ethers, which possess many of the reactivity features of ynamides, have traditionally been far less investigated because of concerns about their stability. Like ynamides, ynol ethers are relatively unhindered to approach by functional groups present in the same or different molecules because of their linear geometry, and they can potentially form up to four new bonds in a single transformation.

Synthesis and DNA binding profile of N-mono- and N,N'-disubstituted indolo[3,2-b]carbazoles.

A series of N-monosubstituted and N,N'-disubstituted derivatives of the indolo[3,2-b]carbazole chromophore have been prepared, and their binding affinity for duplex DNA has been evaluated by ultraviolet and fluorescence spectroscopies. It has been found that indolo[3,2-b]carbazoles bearing basic N-alkyl substituents are intercalators that bind DNA with affinities in the micromolar and submicromolar range and a preference for associating with sequences of mixed composition and purine-pyrimidine steps.

Total synthesis of the antitumor natural product polycarcin V and evaluation of its DNA binding profile.

The convergent total synthesis of polycarcin V, a gilvocarcin-type natural product that shows significant cytotoxicity with selectivity for nonsmall-cell lung cancer, breast cancer, and melanoma cells, has been achieved in 13 steps from 7, 8, and 22; the sequence features a stereoselective α-C-glycosylation reaction for the union of protected carbohydrate 7 and naphthol 8. The association constant for the binding of polycarcin V to duplex DNA is similar to that previously reported for gilvocarcin V.

Synthesis of 3,3'-di-O-methyl ardimerin and exploration of its DNA binding properties.

The 3,3'-di-O-methyl derivative (15) of the bis-C-aryl glycoside natural product ardimerin (1) has been synthesized in 11 steps from 2,3,4,6-tetrabenzylglucose (2) and 1,2,3-trimethoxybenzene (3). Key steps in the synthesis involve a Lewis acid mediated Friedel-Crafts type glycosylation and a Yamaguchi lactonization under Yonemitsu conditions. 3,3'-Di-O-methyl ardimerin aggregates in aqueous solutions at concentrations greater than 1 μM, and both UV and fluorescence binding studies indicate that 15 has a low affinity for duplex DNA.

Low temperature n-butyllithium-induced [3,3]-sigmatropic rearrangement/electrophile trapping reactions of allyl-1,1-dichlorovinyl ethers. Synthesis of β-, γ- and δ-lactones.

Treatment of allyl-1,1-dichlorovinyl ethers with n-BuLi at -78 °C, followed by quenching with ketones, epoxides, and oxetanes, leads to highly substituted β-, γ-, and δ-lactones in good to excellent yields.

Anti-peroxyl radical quality and antibacterial properties of rooibos infusions and their pure glycosylated polyphenolic constituents.

The anti-peroxyl radical quality of two aqueous rooibos infusions and solutions of their most abundant glycosylated polyphenols was evaluated using pyrogallol red and fluorescein-based oxygen radical absorbance ratios. It was observed that the artificial infusions, prepared using only the most abundant polyphenols present in rooibos and at concentrations similar to those found in the natural infusions, showed greater antioxidant quality than the latter infusions, reaching values close to those reported for tea infusions. Additionally, the antimicrobial activity of the natural and artificial infusions was assessed against three species of bacteria: Gram (+) Staphylococus epidermidis and Staphylococcus aureus and Gram (-) Escherichia coli.

Lewis acid catalyzed intramolecular condensation of ynol ether-acetals. Synthesis of alkoxycycloalkene carboxylates.

Treatment of ynol ether-tethered dialkyl acetals with catalytic quantities of scandium triflate in CH(3)CN gives rise to five-, six-, and seven-membered alkoxycycloalkene carboxylates in good to excellent yields. Tri- and tetrasubstituted carbocyclic and heterocyclic alkenes may be formed by this method, and the products obtained may serve as useful intermediates for natural product synthesis.

Total synthesis of indole-3-acetonitrile-4-methoxy-2-C-β-D-glucopyranoside. Proposal for structural revision of the natural product.

Indole-3-acetonitrile-4-methoxy-2-C-β-D-glucopyranoside (1), a novel C-glycoside from Isatis indigotica with important cytotoxic activity, has been prepared in ten steps from ethynyl-β-C-glycoside 3 and 2-iodo-3-nitrophenyl acetate 6. Key steps in the synthesis include a Sonogashira coupling and a CuI-mediated indole formation. NMR spectroscopic data for synthetic 1 differs from that reported for the natural product.

Intramolecular [2 + 2] cycloaddition reactions of alkynyl ether derived ketenes. A convenient synthesis of donor-acceptor cyclobutanes.

Mild thermolysis of tert-butyl alkynyl ethers furnishes aldoketenes, which undergo facile [2 + 2] cycloaddition reactions with pendant di- and trisubstituted alkenes. A wide variety of cis-fused cyclobutanones are produced in moderate to high diastereoselectivity and good to excellent yields by this method, and free hydroxyl groups are tolerated in the ene-ynol ether starting materials. Enol-ynol ethers also undergo efficient reaction to produce donor-acceptor cyclobutanes in high yields.

[3,3]-Sigmatropic rearrangement/5-exo-dig cyclization reactions of benzyl alkynyl ethers: synthesis of substituted 2-indanones and indenes.

Substituted benzyl alkynyl ethers, prepared from the corresponding α-alkoxy ketones in a two-step sequence involving enol triflate formation and KOtBu-induced E2 elimination, undergo [3,3]-sigmatropic rearrangement/intramolecular 5-exo-dig cyclization at 60 °C to form substituted 2-indanones in good overall yields. 1,3-cis-Disubstituted-2-indanones are formed preferentially when the benzylic substituent R(1) is bulky. Substituted indenes may be prepared from 2-indanones in high yields by Horner-Wadsworth-Emmons reaction.

Indium-mediated allylation of aldehydes, ketones and sulfonimines with 2-(alkoxy)allyl bromides.

2-(Alkoxy)propenyl bromides are readily prepared from 1,3-dibromo-2-propanol in a two-step sequence involving hydroxyl protection and sodium hydride-induced dehydrobromination. Indium-mediated allylation of aldehydes, ketones, and sulfonimines with 2-(alkoxy)propenyl bromides furnishes the corresponding homoallylic alcohols and sulfonamines in good yields. The products can be easily transformed into β-hydroxy ketones and esters, as well as substituted dihydropyrans and protected β-amino acids.

Concise total syntheses of aspalathin and nothofagin.

Syntheses of the C-glycosyl flavone natural products aspalathin and nothofagin have been accomplished in eight steps from tribenzyl glucal, tribenzylphloroglucinol, and either 4-(benzyloxy)phenylacetylene or 3,4-bis(benzyloxy)phenylacetylene. The key step of the syntheses involves a highly stereoselective Lewis acid promoted coupling of 1,2-di-O-acyl-3,4,6-tribenzylglucose with tribenzylphloroglucinol, which gives rise to the corresponding beta-C-aryl glycoside in 30-65% yields.

A sequential indium-mediated aldehyde allylation/palladium-catalyzed cross-coupling reaction in the synthesis of 2-deoxy-beta-C-aryl glycosides.

Indium-mediated allylation of aldehydes with 2-chloro-3-iodopropene, followed by a palladium-catalyzed cross-coupling reaction with triarylindium reagents or arylboronic acids, leads to aryl-substituted homoallylic alcohols in good to excellent yields and diastereoselectivities. The products obtained from reactions conducted with d-glyceraldehyde acetonide can be transformed into 2-deoxy-beta-C-aryl ribofuranosides in high overall yields. Similarly, 2-deoxy-beta-C-aryl allopyranosides may be prepared efficiently from 2,4-O-benzylidene erythrose.

Synthesis of alkynyl ethers and low-temperature sigmatropic rearrangement of allyl and benzyl alkynyl ethers.

Alpha-alkoxy ketones 3 can be transformed into 1-alkynyl ethers 5 by a two-step procedure involving formation of the enol triflate or phosphate and base-induced elimination. Performing the same reaction sequence with allylic alcohols (R2OH, R2 = allyl) furnishes instead gamma,delta-unsaturated carboxylic acid derivatives 6, derived from [3,3]-sigmatropic rearrangement of the intermediate allyl alkynyl ethers at -78 degrees C and trapping of the subsequently formed ketene with nucleophiles (Nu-H). Benzyl alkynyl ether 5 (R2 = benzyl) rearranges to indanone 7 upon heating to 60 degrees C.

An environmentally benign synthesis of cis-2,6-disubstituted tetrahydropyrans via indium-mediated tandem allylation/Prins cyclization reaction.

In the presence of indium metal, 3-iodo-2-[(trimethylsilyl)methyl]propene (1) reacts with sequentially added aldehydes to provide cis-2,6-disubstituted tetrahydropyrans in good yields. Evidence suggests that InI, formed upon aldehyde (R1CHO) allylation in aqueous media, acts as a promoter for the silyl-Prins reaction with the second equivalent of added aldehyde (R2CHO). The preparation of cyclohexenyl-fused pyrans via this one-pot, three-component coupling process is presented, as is a short formal synthesis of (+/-)-centrolobine.

Revised Structure of Tolyporphin A.

Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.