A Synthesis of 9-Methoxy-1-Methyl-1H,6H-Pyrazolo[4,3-c]Carbazole

The synthesis of 9-Methoxy-1-methyl-1H,6H-pyrazolo[4,3-c]carbazole is reported in four steps from 6-nitroindazole. Palladium acetate mediated cyclization gave only the “bent” tetracyclic derivative.     

Fluorénacènes et fluorénaphènes Synthèses dans la série des indéno-fluorènes XIV [1] Nouvelle synthèse du trans-fluorénacène

A new synthesis of 6, 12-dihydro-indeno [1,2-b] fluorene (trans-fluorenacene) in 9 steps starting from fluorene (overall yield 24,5%) is recorded. By partial oxidation of the hydrocarbon its 6-oxo derivative is also obtained.     

Brønsted acid promoted intramolecular cyclization of O-alkynyl benzoic acids: Concise total synthesis of exserolide F

Herein we report the stereoselective total synthesis of Exserolide F. The key step involves triflic acid catalyzed highly regioselective intramolecular cyclization of an O-alkynyl benzoic acid derivative to accomplish the core isocoumarin skeleton of the natural product via 6-endo-dig mode of cyclization. The other important steps are: Sharpless asymmetric epoxidation, Barbier propargylation, Sonogashira coupling en route to access the O-alkynyl benzoic acid derivative.     

Synthèses dans la série des bis-indéno-fluorènes,VIII. Méthyl-6-dihydro-9,15-7H-bis-indéno[2.1-b;2′.1′-g]fluorène

Starting from 5-benzoyl-2,4-dibromobenzoic acid and 3-methyl-fluorene, the 6-methyl-9,15-dihydro-7H-diindeno[2.1-b; 2′,1′-g]fluorene, a derivative of a mono-angular diindenofluorene has been synthesized in 5 steps (overall yield 1,5%).     

Synthesis of 2-aza analog of rosoxacin

Diazotization of 2-nitro-4-(4-pyridinyl)aniline ( 4 ) in hydrobromic acid gave the corresponding bromo derivative 5 which was treated with cuprous cyanide to give the benzonitrile derivative 6 which in turn was converted to 2-nitroacetophenone derivative 9 . Reduction of 9 followed by diazotization of the resulting amine 10 gave 7-(4-pyridinyl)cinnolin-4(1H)-one ( 11 ) which was subsequently converted to 1 -ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)cinnoline-3-carboxylic acid ( 14 ) in three steps.     

Imidazo[1,2-α]pyridine anthelmintics. Synthesis of 6-phenylaminoimidazo[1,2-α]pyridine-2-carbamate and 5-acylaminopyridines by a chapman rearrangement

The title compound, a potential anthelmintic agent, was prepared in seven steps from 5-hydroxy-2-picoline. The intermediate 5-(N,-phenylbenzamido)-2-picoline was prepared by a facile Chapman rearrangement of the corresponding benzimidoyl ester. Oxidation and Curtius rearrangement of the substituted picoline gave 5-(N-phenylbenzamido)-2-aminopyridine which underwent ring closure and debenzoylation to furnish methyl 6-phenylaminoimidazo[1,2-α]pyridine-2-carbamate. Fries rearrangement of the penultimate N-benzoyl derivative gave a 6-(p-benzoylphenylamino)imidazo[1,2-α]pyridine derivative, whose structure was confirmed by cmr study. The title compound lacked significant anthelmintic activity.     

Synthesis of the N,N'-Dibenzoyl Derivative of the Ornithine Decarboxylase Inhibitor (2R,5R)-Hept-6-Yne-2,5-Diamine from D-Glucosamine.

ABSTRACT

The N,N'-dibenzoyl derivative of (2R,5R)-hept-6-yne-2,5-diamine, a very powerful inhibitor of the enzyme ornithine decarboxylase, was prepared from D-glucosamine in fourteen steps.     

Non-steroidal antiinflammatory agents. VI. Synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic Acid,a conformationally restricted analogue of tolmetin

The synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic acid 4 , a tricyclic analogue of tolmetin which might show significant analgesic-antiinflammatory activity, has been accomplished in four steps. Alkylation of ethyl 2-pyrrolylglyoxylate ( 15 ) with 2-cyanobenzyl bromide afforded derivative 16 , which was transformed by the Huang-Minion reaction into the dicarboxylic acid 6 . Cyclization of this key intermediate to 17 , followed by alkaline hydrolysis, afforded 10-oxo-5H-pyrrolo[1,2–6]isoquinoline-3-acetic acid ( 4 ). Various attempted syntheses of 6 are also discussed.     

Preparation of large macrocyclic tetra-amines consisting of a methylene backbone and a cyclophane type skeleton

Efficient synthetic routes to 1,10,19,28-tetraazacyclohexatriacontane, a 36-membered ring compound with a methylene backbone, and bis(N,N-octamethylene-4,4′-diaminodiphenylmethane), a 38-membered tetra-amine with a cyclophane skeleton, have been developed via reduction of tetralactam and via a double condensation reaction, respectively. Overall yields are 51% with 5 steps for the former, and 46% with 6 steps for the latter, while the corresponding 2 + 2 cyclization gave the cyclic compounds in poor yields, 9% and 4%, respectively, for the 36-membered tetra-aza ring and for the 38-membered cyclophane derivative.     

Synthèses dans la série des bis-indéno-fluorènes IV [1] Hydroxy-8-dihydro-9, 15-7H-bis-indéno[2, 1-b;2′, 1′-g]fluorène

8-Hydroxy-9, 15-dihydro-7H-diindeno [2, 1-b;2′, 1′-g] fluorene, a derivative of a new mono-angular diindenofluorene system, has been synthesised in 6 steps (overall yield 42%) starting from 9-oxo-fluorene-1-carbaldehyde and acetophenone. The corresponding hydrocarbon could not be obtained by reductive scission of the hydroxyl group.     

Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac‐α‐2,3‐LacNPhth Trisaccharide

A concise approach to a Neu5Ac‐α‐2,3‐LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2‐NPhth group and the C6‐OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated‐α‐galactopyranosyl trichloroacetimidate and p‐methoxyphenyl 6‐O‐tert‐butyldiphenylsilyl‐2‐deoxy‐2‐phthalimido‐β‐d ‐glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d ‐glucosamine hydrochloride, the target Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.     

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.     

Expanding the Genetic Alphabet: Pyrazine Nucleosides That Support a Donor?Donor?Acceptor Hydrogen‐Bonding Pattern

The 6‐aminopyrazin‐2(1H)‐one, when incorporated as a pyrimidine‐base analog into an oligonucleotide chain, presents a H‐bond donor? donor? acceptor pattern to a complementary DNA or RNA strand. When paired with the corresponding acceptor? acceptor? donor purine in oligonucleotides, the heterocycle selectively contributes to the stability of the duplex, presumably by forming a base pair of Watson? Crick geometry joined by a nonstandard H‐bonding pattern, expanding the genetic alphabet. Reported here is a short, high yielding, β‐D ‐selective synthesis of a 6‐aminopyrazin‐2(1H)‐one nucleoside via the glycine riboside derivative 28 . The key steps include a Wittig? Horner reaction of an appropriately protected ribose derivative (Scheme 10, 19 → 21 ) followed by a Michael‐like ring closure (Scheme 12, 30 → 1a and 32 → 1b ). Thus, a variety of pyrazine nucleosides (Scheme 13) including the target 6‐aminopyrazin‐2(1H)‐one riboside 1a , and its 5‐methyl derivative 1b , 6‐amino‐5‐methylpyrazin‐2(1H)‐one riboside, are obtained.     

Facile access to 6‐substituted 1,4,5,7‐tetrahydropyrrolo[3,4‐b]‐pyridines via hantzsch type dimethyl 4‐aryl‐2‐formyl‐6‐methyl‐1,4‐dihydropyridine‐3,5‐dicarboxylates

Efficient assembly of 6‐substituted 4‐aryl‐5‐oxo‐1,4,5,7‐tetrahydropyrrolo[3,4‐b]pyridines (7a‐f) is described according to a Hantzsch type reaction from formyl‐ester 4 by imination, borohydride reduction and intramolecular thermal amino‐ester cyclization. The starting compound 4 was prepared in three steps from the readily available formyl derivative 1, methyl 4,4‐dimethoxy‐3‐oxobutanoate and methyl 3‐aminocrotonate.     

Synthesis of the penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-propyl]amino]benzoyl]-L-glutamic acid (5-DACTHF). An acyclic analogue of tetrahydrofolic acid

The penta-glutamyl derivative of N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]-benzoyl)-L-glutamic acid (1, 5-DACTHF, 543U76) was synthesized by a convergent route. L-γ-Glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis t-butyl ester ( 20 ) was prepared in ten steps from L-glutamic acid di-t-butyl ester and N-(benzyloxycarbonyl)-L-glutamic acid α-t-butyl ester. 4-[N-[3-(2,4-Diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]trifluoroacetamido]benzoic acid ( 6 ), which was synthesized from pyrimidinylpropionaldehyde 3 in three steps, was condensed with 20 , followed by deprotection to provide N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl]-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid ( 2 ). Hexaglutamate 2 is a potent inhibitor of glycinamide ribonucleotide transformylase.     

Syntheses of 6-fluoro-7-piperazin-1-yl-9-cyclopropyl-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione and 6-fluoro-7-piperazin-1-yl-9-p-fluorophenyl-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione

The syntheses of 6-fluoro-7-piperazin-1-yl-9-cyclopropyl (or 9-p-fluorophenyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-diones as well as novel synthesis of isothiazolo-3(2H)-one system are described. Key steps include the regiospecific displacement of a sulfinyl group and the amination of the resultant mercapto derivative followed by an intramolecular nucleophilic displacement cyclization reaction to generate the novel 2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione nucleus.     

A Stereoselective Synthesis of (±)-cis-γ-Irone

(±)-cis-γ-Irone( 1 ), a main constitutent of natural iris oil, has been stereoselectively synthesized from methyl (2E)-3 -[(2,2,4-trimethyl-3-cyclohexen-1-yl)methoxy]-2-propenoate (3) (6 steps, overall yield 14%). The cis-configuration as the exocyclic position of the double bond of 1 were secured by the thermal ene reaction of the β-(alkenyloxy)acrylate 3 yielding the 3-oxabicyclo [3,3,1] nonane derivative 5 .     

Pteridines. Part XCVII. Synthesis and properties of 6-thioxanthopterin and 7-thioisoxanthopterin

6-Thioxanthopterin ( 13 ) was synthesized in four steps starting from 2-amino-4-(penthyloxy)pteridine ( 3 ) via the 8-oxide 4 , its subsequent interconversion to the 6-chloro ( 7 ) and 6-thio derivative ( 12 ) and final hydrolysis of the pentyloxy group. 7-Thioisoxanthopterin ( 15 ) was derived analogously from 2-amino-4-(pentyloxy)pteridine-7(8H)-thione ( 14 ) by alkaline hydrolysis. The various 6- and 7-thiopteridines were methylated to give the corresponding 6- ( 10, 11 ) and 7-(methylthio) derivatives ( 16, 17 ). The newly synthesized compounds have been characterized by elemental analyses, their UV spectra, and the determination of the acidic and basic pK_a values. The spectral relationships are discussed in detail.     

Synthesis of O-(2-Acetamido-2-Deoxy-β-D-Glucopyranosyl)-(l→2)-O-α-D-Mannopyranosyl-(l→6)-O-β-D-Glucopyranosyl-(1→4)-2-Acetamido-2-Deoxy-D-Glucopyranose. A Potential Acceptor-Substrate for N-Acetylglucosaminyltransferase-V (GnT-V)

Abstract

The reaction of phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthaIimido-l-thio-β-D-glucopyranoside with methyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside catalysed by iodonium ion (TfOH-NIS) followed by deacylation-acetylarion afforded disaccharide 11. which was readily converted (in four steps) to bromide 12. A similar glycosylarion with phenyl 2,3,4,6-tetra-O-acetyl-l-thio-D-glucopyranoside of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside 16 followed by O-deacetylation of the resulting intermediate gave disaccharide 18. The 4,6-O-benzylidene derivative of 18 was acetylated then deacetaled to give diol 21. This diol acceptor was condensed with bromide 12 (promoted by mercuric cyanide) to give the partially protected tetrasaccharide derivative 22 which was O-deacetylated and then subjected to catalytic hydrogenation to furnish the title tetrasaccharide 6. The structure assigned to 6 was supported by ¹H and ¹³C NMR spectral data and FAB mass spectroscopy.     

A convenient synthesis of a permethyl-substituted β-cyclodextrin-containing polysiloxane stationary phase using an amide linking group

A novel amide-linked permethyl-substituted β-cyclodextrin-bound polysiloxane stationary phase was prepared in only four steps. First, mono(6-O-toluenesulfonyl)-β-cyclodextrin was treated with sodium azide. Second, the resulting azide derivative was treated with methyl iodide and base followed by reduction with hydrogen to give amine-substituted permethylcyclodextrin 3 . Third, cyclodextrin 3 was treated with p-(allyloxy)benzoyl chloride to form 6^A-(p-allyloxybenzamido)-substituted permethyl-β-cyclodextrin 4 . Lastly, β-cyclodextrin 4 was hydrosilylated onto a polysiloxane backbone containing hydrogen, methyl, and p-tolyl substituents. This new phase separated the enantiomers of certain chiral lactones and alcohols in capillary supercritical fluid chromatography.