Total synthesis of (-)-brevenal: a streamlined strategy for practical synthesis of polycyclic ethers

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)(2)-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by Suzuki-Miyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through Suzuki-Miyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.     

Total synthesis of (-)-21-isopentenylpaxilline

[structure: see text] The total synthesis of (-)-21-isopentenylpaxilline (1) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (-)-5, a highly efficient union of the eastern and western fragments (-)-5 and 4, respectively, exploiting our 2-substituted indole synthesis, and a new protocol for the construction of ring C.     

Total synthesis of (+)-thiazinotrienomycin E

[formula: see text] The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. The synthesis features a highly efficient construction of the aromatic fragment 3 incorporating TBS protection of the aniline, a significantly improved synthesis of (-)-19, an intermediate employed in our trienomycins A and F total syntheses, application of the Kocienski modified Julia protocol to elaborate the E,E,E-triene subunit, an efficient union of 3 and (+)-4, and Mukaiyama macrolactamization to access the thiazinotrienomycin macrolide.     

A one-pot chemoenzymatic synthesis of (2S, 4R)-4-methylproline enables the first total synthesis of antiviral lipopeptide cavinafungin B

We report an efficient ten-step (longest linear sequence) synthesis of antiviral natural product cavinafungin B in 37% overall yield. By leveraging a one-pot chemoenzymatic synthesis of (2S,4R)-4-methylproline and oxazolidine-tethered (AT (Boc)G-Rink resin) SPPS methodology, the assembly of our molecular target could be conducted in an efficient manner. This general strategy could prove amenable to the construction of other natural and unnatural linear lipopeptides. The value of incorporating biocatalytic steps in complex molecule synthesis is highlighted by this work.     

First diastereoselective synthesis of (-)-methyl thyrsiflorin A, (-)-methyl thyrsiflorin B acetate, and (-)-thyrsiflorin C

An efficient procedure for the synthesis of scopadulan diterpenes, using (+)-podocarp-8(14)-en-13-one 13 as starting material, is reported. This procedure has been used for the diastereoselective synthesis of (-)-methyl thyrsiflorin A (8), (-)-methyl thyrsiflorin B acetate (9), and (-)-thyrsiflorin C (7). Key steps in our strategy are the intramolecular cyclopropanation of diazoketone 19 and the regioselective cleavage of the cyclopropane ring.     

Total synthesis of the ansamycin antibiotic (+)-thiazinotrienomycin E

The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. Key features of the synthetic strategy include (a) the efficient construction of sulfone 7 incorporating TBS protection of the aniline, (b) an improved synthesis of allyl chloride (-)-6, the advanced intermediate employed in our trienomycins A and F total syntheses, (c) application of the Kocienski modified Julia protocol to elaborate the E,E,E-triene subunit in a stereo-controlled fashion, (d) an efficient union of sulfone 7 with advanced iodide 62, and (e) Mukaiyama macrolactamization to access the thiazinotrienomycin macrocyclic ring.     

Monomers for preparation of amide-linked RNA: asymmetric synthesis of all four nucleoside 5'-azido 3'-carboxylic acids

[reaction: see text] Recent discovery of RNA interference as an efficient and naturally occurring mechanism of gene regulation has reinvigorated the interest in chemically modified RNA. For potential in-vivo applications small interfering RNAs require chemical modifications to fine-tune the thermal stability and increase the cellular delivery and potency and in vivo half-life of the RNA duplexes. From this perspective, amides as neutral and hydrophobic internucleoside linkages in RNA are highly interesting modifications for RNA interference. Amides are remarkably good mimics of the phosphodiester backbone of RNA and can be prepared using a relatively straightforward peptide coupling chemistry. However, the progress in the field has been hampered by the shortage of efficient methods to synthesize the monomeric building blocks for such couplings, the nucleoside amino acid equivalents. Herein, we report enantioselective synthesis of 5'-azido 3'-carboxylic acid derivatives of all four natural ribonucleosides. The key transformations in our synthesis are a double asymmetric ene reaction and a stereoselective iodolactonization that form the basic carbon skeleton of the modified ribose. Standard nucleoside synthesis is followed by a short and highly efficient protecting group manipulation to give the enantiomerically pure (>98%) title compounds in 9-10 steps and 15-19% overall yields starting from small achiral molecules. The present results are a significant improvement over our first-generation racemic synthesis and compare favorably with the previously reported synthesis from nucleoside and carbohydrate precursors.     

A new approach to difficult Fischer synthesis: the use of zinc chloride catalyst in triethylene glycol under controlled microwave irradiation

[reaction: see text]. Application of triethylene glycol with catalytic quantity of zinc chloride (ZnCl2/TEG) is described as a new and efficient reaction medium for a difficult Fischer synthesis, leading to sensitive indoles. Transformation of the 3-acetyl-1-methylthiocycloalka[c]pyridine phenylhydrazones and p-methoxyphenylhydrazones into the 2-(2-pyridyl)indoles and 5-methoxy-2-(2-pyridyl)indoles, which are the synthons in our total synthesis of the sempervirine-type alkaloids, is carried out under controlled microwave irradiation in dry zinc chloride solution (0.16 M) in TEG. This protocol produces indoles from acetophenone or cyclohexanone via their phenylhydrazones in excellent yields.     

Construction of eight-membered ether rings by olefin geometry-dependent internal alkylation: first asymmetric total syntheses of (+)-3-(E)- and (+)-3-(Z)-pinnatifidenyne

The first and highly stereoselective asymmetric total syntheses of eight-membered ring ether marine natural products (+)-3-(E)-pinnatifidenyne and (+)-3-(Z)-pinnatifidenyne have been accomplished. Notable features of our syntheses include a novel and efficient construction of oxocene 5 by a highly stereo- and regioselective internal alkylation and direct ketone synthesis of ketone 16 from the alpha-alkyloxy amide moiety in oxocene 5.     

A short, efficient, and stereoselective total synthesis of a pyrrolidine alkaloid: (-)-codonopsinine

An efficient total synthesis of antibiotic (-)-codonopsinine 1 with an overall yield of 44% was achieved from d-alanine as a chiral template. The key steps in our strategy are modified Sharpless asymmetric dihydroxylation reaction and the highly stereoselective intramolecular acid-catalyzed amidocyclization.     

Multigram Synthesis of a Chiral Substituted Indoline Via Copper-Catalyzed Alkene Aminooxygenation

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its bis(allyl)aniline by-product by distillation under reduced pressure.     

Synthesis of a New Family of Aminocyclitols from D-(-)-Quinic Acid

In continuation of our interest in the synthesis of glycosidase inhibitors, we report herein an efficient synthesis of three new polyhydroxylated amino cyclohexane derivatives (aminocyclitols) that may potentially possess important biological activities. The key step involved the highly stereoselective dihydroxylation of protected azido cyclohexene derivatives 5, 9, and 15, which were easily red from D-(-)-quinic acid. The subsequent hydrogenation step was conducted under acidic conditions to provide the target molecules in an efficient manner with high overall yields.     

Microwave-assisted Green and Efficient Synthesis of N^6-（2-Hydroxyethyl）adenosine and its Analogues

Nucleoside analogues generally possess outstanding biological activity, mainly as antitumor and antiviral agents. Many works have been done for the synthesis of natural nucleosides and their analogues1-5. N6-(2-Hydroxyethyl)adenosine (HEA), which behaves …     

An efficient synthesis of 2,2-bis(1H-indol-3-yl)-2H-acenaphthen-1-one catalyzed by recyclable solid superacid SO_4~(2-)/TiO_2 under grinding condition

<正>An efficient synthesis of symmetrical 2,2-bis(1H-indol-3-yl)-2H-acenaphthen-1-one is achieved via a reaction of acenaphthe-nequinone and indoles catalyzed by solid superacid SO_4~(2-)/TiO_2 under solvent-free conditions at room temperature by grinding, which provides an efficient route to the synthesis of symmetrical 2,2-bis(1H-indol-3-yl)-2H-acenaphthen-1-one.This procedure offers several advantages including solvent-free conditions,excellent yields of products,simple work-up as well as reuse of catalysts which makes it a useful and attractive protocol for the synthesis of these compounds.     

Total synthesis of natural (+)-sesbanimide a and (-)-sesbanimide b

The first total synthesis of natural (+)-sesbanimide A (1) and (-)-sesbanimide B (2), potent antitumor alkaloids isolated from the seeds of the leguminous plant, Sesbania drummondii, has been accomplished starting from D-(+)-xylose. This total synthesis involves efficient construction of the optically active AB-ring system from D-(+)-xylose, introduction of the C₅-unit into the AB-ring system in a form of exo-methylene-γ-lactone, and elaboration of the labile C-ring system at the last stage of the synthesis. The absolute configurations of natural 1 and 2 could be obviously established by our total synthesis.     

Continuous-flow synthesis of activated vitamin D3 and its analogues

An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH)(2)-vitamin D(3) (activated vitamin D(3)) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions.     

Diastereoselective total synthesis of (+)-morusimic acid B, an amino acid from Morus alba

An efficient, flexible and diastereoselective synthesis of the naturally occurring pyrrolidine amino acid, (+)-morusimic acid B, has been accomplished. Starting from chiral, optically active (+)-(3S)-hydroxy butyric acid methyl ester the key steps of our synthesis are diastereoselective α-alkylation of its dianion to introduce the main part of the side chain, Curtius rearrangement of the hydrazide derivative to a 2-oxazolidinone followed by N→π-cyclization with mercury(II) acetate to generate the cis-2,5-disubstituted pyrrolidine ring. The remote C-3 stereocentre is established after chain elongation with the dianion of methyl acetoacetate and asymmetric hydrogenation of the resulting β-oxoester with Noyori's Ru(II)-(R)-BINAP catalyst.     

Highly Efficient and Practical Syntheses of Lavendamycin Methyl Ester and Related Novel Quinolindiones

The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.     

An expedient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide

[reaction: see text] A highly convergent and efficient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide is reported.