Efficient Synthesis of Glycosylated Matijin‐Su Derivatives via Ultrasonic Irradiation

Matijin‐Su ( 1 ) is a phenylalanine dipeptide compound with anti‐hepatitis B virus (HBV) activity. Previous reports suggest that the synthesis of glycosylated Matijin‐Su derivatives needs at least 10 steps. To simplify the synthetic procedure, we have developed a shorter and more efficient method for the preparation via ultrasound irradiation. Two galactopyranosylated ( 2 ) and two glucopyranosylated ( 3 ) derivatives were synthesized in 6 or 7 steps. The overall yields for the total synthesis of galactopyranosylated derivatives were markedly increased to 39% ( 2a ) or 22% ( 2b ). And the yields for glucopyranosylated derivatives also reached 29% ( 3a ) or 16% ( 3b ).     

A new general access to either type of Securinega alkaloids: synthesis of securinine and (-)-allonorsecurinine

The syntheses of securinine and (-)-allonorsecurinine have been achieved starting from easily available alpha-amino acid derivatives and using as key steps a RCM and a Heck reaction for the formation of rings D and C, respectively. [reaction: see text]     

The Tricyclooctanone Approach to the Total Synthesis of Steroids. The Cyclization of the A-CD Unit

The first steps of a novel approach to the total synthesis of 9, 11-dehydroestrone via tricyclo[3.3.0.0^2,8]octan-3-one (2) are described. One route involves a tandem-type transformation of the key intermediate 3 (A-CD unit) consisting of cyclopropane cleavage and ring B closure to afford C, 18-bisnor-13 α, 17 α-estradiol derivatives. E.g. the 3-methoxy-9 ζ-hydroxy-17 α-methanesulfonyloxy derivative (-)- 6 has been synthesized in 8 steps and 10% overall yield from 1,3-cyclohexadiene. As an alternative, the A-CD type intermediate 4b has been prepared and could be used for a ring C enlargement prior to cyclization.     

Total synthesis of Akuammiline alkaloid (-)-vincorine via intramolecular oxidative coupling

An asymmetric total synthesis of the Akuammiline alkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key steps include Pd-catalyzed direct C-H functionalization of indole derivatives, organocatalyzed asymmetric Michael addition of aldehydes to alkylidene malonates, and intramolecular oxidative coupling between indole and malonate moieties.     

Synthesis of myo-inositol derivatives required for the total synthesis of surugatoxin, prosurugatoxin, and neosurugatoxin

Two myo-inositol derivatives (4) and (5), required for the total synthesis of surugatoxin, prosurugatoxin, and neosurugatoxin, were prepared. Synthesis of (+/-)-2,3-O-cyclohexylidene-4,5-O-isopropylidene-1-O-methoxymethyl-myo-i nositol (4) was achieved from (+/-)-1-O-benzoyl-2,3-O-cyclohexylidene-4,5-O-isopropylidene-myo-inosito l (6) in 4 steps, and (-)-2,3-O-cyclohexylidene-1,4-di-O-methoxymethyl-5-O-[2',3',4'-tri-O-ace tyl- beta-D-xylopyranosyl]-myo-inositol (5) was synthesized from (+/-)-1-O-benzoyl-2,3-O-cyclohexylidene-5,6-O-isopropylidene-myo-inosito l (12) in 7 steps.     

Synthesis of 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine

We have synthesized 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine 1 in five steps from 1-(2-amino-methylphenyl) pyrrole 4 . Amidino derivatives 11-12 have also been prepared.     

Utility of polymer-supported reagents in the total synthesis of lamellarins

Four solid-supported reagents have been utilized in the multistep synthesis of lamellarins. The use of Amberlyst A-26 Br(3)(-) and polymer bound pyridine hydrobromide perbromide (PVPHP) for keto alpha-bromination of the less studied ortho-substituted acetophenone derivatives selectively furnished the corresponding monobromination products (phenacyl bromide derivatives), which were used directly in condensation reactions with benzyldihydroisoquinoline mediated by Amberlyst A-26 NaCO(3)(-). The 2H-pyrrole carbonates subsequently underwent intramolecular Friedel-Crafts transacylation followed by lactonization to provide the lamellarin skeleton. Alternatively, Amberlyst A-26 NaCO(3)(-) effectively served as base in condensation reaction of benzyldihydroisoquinoline with alpha-nitrocinnamate derivatives to provide the corresponding 2-ethoxycarbonyl pyrroles, which smoothly underwent O-debenzylation reaction followed by lactonization to furnish the lamellarin skeleton. The novel Amberlyst-15 mediated lactonization reactions effectively combined the otherwise two separate steps into a single transformation.     

Synthesis of large macrocyclic tetraaza compounds with a methylene backbone: Cyclo[-NH- (CH2)n-]4, (n = 6, 7, 8, 9 and 10). The formation of 28-, 32-, 36-, 40- and 44-membered rings

A series of macrocyclic tetraamines with 28-, 32-, 36-, 40- and 44-membered rings have been efficiently prepared from the corresponding ditosylamide and monobromoalcohol derivatives in 6 steps via a double condensation reaction. Overall yields were: 41, 41, 46, 29, and 33%, respectively, for 1,8,15,22-tetraazacyclooctacontane ( 11a ), 1,9,17,25-tetraazacyclodotriacontane ( 11b ), 1,10,19,28-tetraazacyclohexatriacontane ( 11c ), 1,11,21,31-tetraazacyclotetracontane ( 11d ) and 1,12,23,34-tetraazacyclotetratetracontane ( 11e ).     

Extreme conformational constraints in pi-extended tetrathiafulvalenes: unusual topologies and redox behavior of doubly and triply bridged cyclophanes

Doubly and triply bridged 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (ex-TTF) derivatives have been synthesized. Key steps are the generation and macrocyclization reactions of ex-TTF-dithiolate reagents. The X-ray crystal structures of the doubly bridged cyclophanes 15 and 16 and the triply bridged system 23 show that the saddle-like conformation of the ex-TTF framework is enhanced by the short bridges between the dithiole rings. Unlike all previous ex-TTF derivatives (which display a single quasi-reversible two-electron oxidation wave, D0 --> D2+), cyclic voltammetry of the cyclophanes reveals two reversible, one-electron oxidation steps (D0 --> D*+ --> D2+), with differences between the half-wave potentials (E2(1/2) - E1(1/2)) of 0.22-0.26 V. The conformational changes and gain in aromaticity which drive the second oxidation process in unrestricted ex-TTF systems (including singly bridged cyclophanes) have been prevented by multiple bridging. The radical cation species gives rise to a very broad, low-energy band (lambdamax = 2175 and 2040 nm for 15 and 21, respectively), assigned to an intramolecular interaction. The steric constraints imposed by multiple bridging have become so extreme that the pi-framework of 15, 16, 21, and 23 exhibits remarkable optical and redox behavior which is not characteristic of ex-TTF systems.     

Design,synthesis and antibacterial activity evaluation of novel 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives

In this paper, a novel series of 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives are synthesized in two steps. The first step involved Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and isocyanide derivatives. The product of this step, underwent a click 1,3-dipolar cycloaddition reaction with benzyl azide derivatives. The 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide product was characterized and their antibacterial activities were evaluated against various G-positive (Staphylococcus aureus and Bacillus subtilis) and G-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria, using minimal inhibition concentration. The compounds showed very good antimicrobial activity and a number of products have been more active than ciprofloxacin.     

A highly efficient total synthesis of (R)-(+)-muscopyridine by intramolecular [4+2] cycloaddition of bisketene

A highly efficient total synthesis of (R)-(+)-muscopyridine 1 has been accomplished in 12 steps with 40% overall yield. A highlight of the synthesis is the intramolecular [4+2] cycloaddition of bisketene to afford a bridged pyrone and ring transformation of the pyrone to afford pyridine derivatives.     

Solid-Phase Synthesis of 2-Arylamino-5-(4-hydroxyphenyl)-1,3,4-thiadiazole Derivatives Based on Resin-Bound Acylhydrazines

A highly efficient, solid-phase synthesis of 2-arylamino-5-(4-hydroxy-phenyl)-1,3,4-thiadiazole derivatives under mild conditions has been developed. The 1,3,4-thiadiazole derivatives were synthesized from resin-bound acylhydrazines in several steps, which gave 78–88% overall yields and excellent purities of the products.     

A carbohydrate-based total syntheses of (+)-pyrenolide D and (-)-4-epi-pyrenolide D

Efficient total syntheses of (+)-pyrenolide D (5) and (-)-4-epi-pyrenolide D (6) have been achieved from a known 5-deoxy-d-xylose derivative 9 in ten steps with 19% overall yield either exclusively as 5 or as pure 5 and 6 in a 3:2 ratio. Key steps involved are one-pot epoxidation-cyclization by Corey-Chaykvosky reagent, reductive Barton-McCombie deoxygenation, and per-acid mediated oxidative spiroketalization.     

2,3-Dihydroimidazo[1,2-a]pyridines: a new class of enantioselective acyl transfer catalysts and their use in kinetic resolution of alcohols

The long-known, but previously unexplored 2,3-dihydroimidazo[1,2-a]pyridine (DHIP) has been shown to be a competent acyl transfer catalyst. Its chiral 2-phenyl derivatives obtainable in two steps from commercially available starting materials have proved to be effective acylation catalysts, giving high levels of enantioselectivity (s = 20-85) in kinetic resolution of secondary benzylic alcohols. A transition state model explaining the observed selectivity has been proposed.     

Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1beta converting enzyme, and biological properties of their derivatives

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.     

SYNTHESIS OF NOVEL BITHIOPHENE-SUBSTITUTED HETEROCYCLES BEARING CARBONITRILE GROUPS

Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene. Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium bisulfite furnishes the unsymmetrical bithiophene derivative 6. The bis-benzimidazole derivative 8 was obtained via hexabutylditin-mediated homocoupling of 5-bromothiophene-2-carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic protocols for the aryl/hetaryl-2,2'-bithiophene derivative 14 have also been presented. In addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-n-butylstannyl)-2,2'-bithiophene through a Stille coupling reaction followed by a condensation step.     

Improved Synthesis of 5,5-Diamino BINAP and Application to Asymmetric Hydrogenation

5,5-Diamino BINAP has been synthesized via three steps using BINAPO as starting material with high reaction yield. Present method needed only a stoichiometric quantity of nitric acid in the step of nitration of BINAPO, giving almost quantitative reaction yield. Based on 5,5-diamino BINAP, other three new BINAP derivatives have been synthesized. These modified BINAP ligands showed better catalytic properties as compared to BINAP itself in the asymmetric hydrogenation of 2-(6‘-methoxyl-2‘-naphthyl)acrylic acid.     

Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives

The design and synthesis of spiroketal structures and their chemical modification, leading to a collection of new small molecules for biological evaluation as orally-bioavailable lead compounds is described. Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski's guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and with high purity.     

Total synthesis of (-)-leuconicine A and B

Concise asymmetric total syntheses of Strychnos alkaloids (-)-leuconicine A (14 steps, 9% overall yield) and B (13 steps, 10% overall yield) have been accomplished. Key steps include (1) our sequential one-pot spiro-cyclization/intramolecular aza-Baylis-Hillman method to prepare the ABCE framework; (2) a novel domino acylation/Knoevenagel cyclization to prepare the F-ring; and (3) a Heck cyclization to access the D-ring.     

3-(2-Pyridyl)-[1,2,3]triazolo[1,5-a]pyridines. An experimental and theoretical (DFT) study of the ring-chain isomerization

An experimental ((1)H NMR) and theoretical (DFT) study of the ring-chain-ring isomerization of 3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]pyrid-7-yl derivatives (A) into 6-{[1,2,3]triazolo[1,5-a]pyrid-3-yl}-2-pyridyl derivatives (B) has been carried out. Based on the calculations, a mechanism of several steps will be proposed. The experimental results as well as the calculations lead to the conclusion that the A-B ratio depends on the electronic properties of the substituents.