Asymmetric synthesis of all eight seven-carbon dipropionate stereotetrads

Enantiopure cycloheptadienyl sulfones 6 and 7 are diastereoselectively epoxidized to yield epoxyvinyl sulfones 8, 9, 14, and 16 in high yields and diastereomeric ratios. Syn and anti methylation of epoxides 8, 9, 14, and 16 enables access to all eight possible diastereomeric stereotetrads, seven of which are commonly found in polypropionate natural products. Anti methylations of the above epoxides are possible by either the reaction of methyl organometallics promoted by copper(I), or via reaction with trimethylaluminum to yield stereotetrads 11, 12, 22, and 24. Syn methylations are achieved via Lawton SN2' reaction in the case of stereotetrads 10, 15, and 38, while stereotetrad 13 is accessed by an oxidation/reduction alcohol inversion sequence from stereotetrad 11. All stereotetrads were obtained in high diastereomeric ratios and yields, and their relative stereochemistry was confirmed by X-ray crystallography. Oxidative cleavage of the cyclic stereotetrads yields termini-differentiated acyclic heptanyl stereotetrads ready for use in building larger fragments in the course of target syntheses.     

First examples of oxaphosphirane pentacarbonylchromium(0) and -molybdenum(0) complexes: synthesis, structures and reactions

Synthesis of the first oxaphosphirane chromium(0) and molybdenum(0) complexes of the type [{(R(1)PCH(R(2))-O}M(CO)(5)] (R(1) = C(5)Me(5)) (8a-e, 15a-e) and (R(1) = CH(SiMe(3))(2)) (9a-e, 16a-e) via reaction of dichloro(organo)- (1, 2, 10, 11) and chloro(organo)phosphane complexes (3,4,12) with lithium bases and aldehydes 7a-e is reported. Furthermore, bicyclic 1,3-oxaphospholane complexes 17 and 18 have been obtained via O-protonation of oxaphosphirane complexes 8a and 15a with HCl. All complexes were characterized by NMR, IR spectroscopic, mass spectrometric investigations and, in addition, single-crystal X-ray structures of complexes 8a-e, 9a,c, 15a,b,e, 16a-c, 17, 18 are presented and discussed.     

Functionalized chloroenamines in aminocyclopropane synthesis - V. synthesis and reactions of aminocyclopropylketones

Conjugated acylated chloroenamines 5A,C were available by chlorination of mixtures of acylated enamines 8A,C/9A,C by NCS at 0°C. Nonconjugated chloroenamines 10Aa and 10Ba could be obtained by NCS-chlorination of the conjugated acylenamines 9A,B at low temperature. Reaction of 5Aa-5Ac,5Ae, 5Af with cyanide produced morpholinocyclopropylketones 11A. In two cases aminofurans 12Ad and 12Ca resulted as products of this reaction. More generally amino-aryl-furans 12 were formed by thermolysis of the aryl-cyclopropyiketones 11. Amino-alkyl-furans as 12Ae and 12Af only could be trapped by a Diels-Alder reaction leading to 16Ae and 16Af. Epoxyenamines 29A,B unexpectedly were produced from the interaction of cyanide with the chloroenamines 10Aa and 10Ba.     

Studies on Organophosphorus Compounds: Synthesis and Reactions of Some New 5′-Cyano-2′-(4-methoxyphenyl)spiro[cycloalkane-1,6′-[1,3,2]thiazaphosphixane]-2′,4′-disulfide Derivatives

2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent, LR, 1 ) reacts with cycloalkylidenecyanothioacetamides ( 2 and 3 ) to give 5'-cyano-2'-(4-methoxyphenyl)spiro [cyclopentane(cyclohexane)-1,6'-perhydro-[1,3,2]thiazaphosphixane]-2',4'-disulfide ( 4 and 5 ). The reaction of compounds 4 and 5 with f -halo compounds led to the formation of the substituted thio-compounds 6a-e and 7a-e , respectively, these compounds, upon treatment with sodium ethoxide, produce the corresponding thienothiazaphosphixine derivatives 8a-e and 9a-e respectively. Compounds 8a-e and 9a-e react with LR under different reaction conditions to give polyfused heterocyclic compounds 10a-d and 11a-d respectively. Treatment of compounds 8b and 9b with CS 2 and (CH 3 ) 2 SO 4 gave the corresponding dithiocarbamate methyl ester derivatives 12 and 13 , respectively, which on treating with hydrazine hydrate yielded compounds 14 and 15 respectively. Compounds 14 and 15 reacted with LR to yield compounds 16a , b and 17a , b respectively.     

Efficient synthesis of peptides by extension at the N- and C-terminii of arginine

L-N(omega)-nitroarginine and L-arginine were coupled with N-(Cbz-alpha-aminoacyl)benzotriazoles and N-Cbz-dipeptidoylbenzotriazoles to provide arginine LL-dipeptides 9a-e, 11a-d; LLL-tripeptides 18a-c, 20; and diastereomeric mixtures (9b+9b'), (9c+9c'), (11b+11b') and (18c+18c') [compound numbers written within parentheses represent a diastereomeric mixture or racemate; compound numbers without parentheses represent an achiral compound or a single enantiomer] by extension at the N-terminus of arginine, in isolated yields of 66-95% with complete retention of chirality as evidenced by NMR and HPLC analysis. Arginine LL-dipeptides 15a-d were synthesized by extension at the C-terminus of arginine in isolated yield of 66-80%, using benzotriazole activated arginine L-(omega)NO2-Arg-Bt, 13. Our methodology has also been used to synthesize the protected RGD peptide (Cbz(alpha)-L-(omega)NO2-Arg-Gly-L-Asp-(OH)2) 21.     

Concise synthesis of cyclic ethers via the palladium-catalyzed coupling of ketene acetal triflates and organozinc reagents. Application to the iterative synthesis of polycyclic ethers

The reaction of the ketene acetal triflates 9a-e and a zinc homoenolate 10 in the presence of a catalytic amount of Pd(PPh(3))(4) gave the enol ethers 11a-e in good yields. The products were converted to the corresponding cyclic ethers 14a and 14b by hydroboration and lactonization. The present methodology allowed us to synthesize the DE and GH ring segment of gambierol in a concise manner. Iterative syntheses of the polycyclic ethers 26 and 32 are also described.     

A convenient synthesis of 2-amino-4H-1,3,4-oxadiazino[5,6-b]-quinoxaline derivatives

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with a 2-fold molar amount of ethyl chloroglyoxalate gave ethyl 8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline-2-carboxylate 6 , whose reaction with hydrazine hydrate afforded the C₂-hydrazinocarbonyl derivative 7 . The reaction of compound 7 with nitrous acid provided the C₂-acylazide derivative 8 , which was converted into the C₂-amino 9 , C₂-carbamate 11a-c, 12a,b , and C₂-ureido 13a-c, 14 derivatives. The mass spectral fragmentation patterns were examined for compounds 10–14 , wherein the molecular ion peak did not appear in the mass spectra of compounds 10c, 11a-c, 12a,b, 13c , and 14.     

Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a-e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a-f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a-e and 10a-f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.     

1,4-Benzoxazin-2-ones,benzo[d]oxazoles and 2H-1,4-benzoxazines from the reaction of 2-(methoxyimino)benzen-1-ones with arylacetates,arylacetic acids and trans- stilbene

10-(Methoxyimino)phenanthrene-9-one 1 reacts thermally with the arylacetic derivatives 2(a-j ) to yield the corresponding 1,4-benzoxazin-2-ones 4(a-d,f ) and benzo[d]oxazoles 5(a-e,g ). Similarly, reaction of the monoximes 7a, 7b with compounds 2a, 2d respectively affords 8a, 8b , while action of trans-stilbene on the monoximes 1, 7a, 7b leads to the 1,4-benzoxazines 10, 11, 13 , obtained along with the corresponding 2-phenyloxazoles 5a, 8a, 8c and compound 12 .     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.     

Efficient peptide coupling involving sterically hindered amino acids

Hindered amino acids have been introduced into peptide chains by coupling N-(Cbz- and Fmoc-alpha-aminoacyl)benzotriazoles with amino acids, wherein at least one of the components was sterically hindered, to provide compounds 3a-e, (3c +3 c'), 5a-d, (5a + 5a'), 6a-c, (6b + 6b'), 8a-c, 9a-e, 10a-d, and (10a + 10a') in isolated yields of 41-95% with complete retention of chirality as evidenced by NMR and HPLC analysis. The benzotriazole activation methodology is a new route for the synthesis of sterically hindered peptides. (Note: compound numbers written within brackets represent diastereomeric mixtures or racemates; compound numbers without brackets represent enantiomers.).     

Chelate-controlled synthesis of racemic ansa-zirconocenes

The reaction of Zr[PhN(CH(2))(3)NPh]Cl(2)(THF)(2) (5) with lithium ansa-bis-indenyl reagents Li(2)[XBI](Et(2)O) (XBI = (1-indenyl)(2)SiMe(2) (SBI, 7a), (2-methyl-1-indenyl)(2)SiMe(2) (MSBI, 7b), (2-methyl-4,5-benz-1-indenyl)(2)SiMe(2) (MBSBI, 7c), (2-methyl-4-phenyl-1-indenyl)(2)SiMe(2) (MPSBI, 7d), and 1,2-(1-indenyl)(2)ethane (EBI, 7e)) affords rac-(XBI)Zr[PhN(CH(2))(3)NPh] (8a-e) in high yield. The meso isomers were not detected by (1)H NMR. X-ray crystallographic studies show that the Zr[PhN(CH(2))(3)NPh] rings in 5, 8a, 8c, and (C(5)H(5))(2)Zr[PhN(CH(2))(3)NPh] (10) adopt twist conformations that position the N-Ph groups on opposite sides of the N-Zr-N plane. This conformation complements the metallocene structures of rac-8a-e but would destabilize the corresponding meso isomers. It is proposed that the Zr[PhN(CH(2))(3)NPh] ring adopts a similar twist conformation in the stereodetermining transition state for addition of the second indenyl ring in these reactions, which leads to a preference for rac products. The results of metallocene syntheses from other Zr amide precursors support this proposal. 8a-e are converted to the corresponding rac-(XBI)ZrCl(2) complexes (9a-e) by reaction with HCl.     

Chemistry of phosphorus ylides 21 new route for the synthesis of azetidinones. Reaction of phosphonium ylides with benzil-, o-naphthoquinone-, and triketonemonoanils

Active vinylidenetriphenylphosphoranes are nucleophilic reagents which can be con- sidered as versatile synthons for the synthesis of new heterocycles. The active phosphacumulene ylides, namely N-phenylimino- 2a , 2-oxo- 2b or 2-thioxo-vinylidenetriphenylphosphoranes ( 2c ), react with benzil- ( 1a,b ), o-naphthoquinone- ( 8 ), or triketone-monoanils ( 11 ), to give the corresponding phenylimino- ( 3a, d, 9a, 12a ), oxo- ( 3b, e, 9b, 12b ), or thioxoazetidinones ( 3c, f, 9c, 12c ), respectively, which constitute an important class of organic compounds with medicinal and biological importance. On the other hand, quinone monoanils 1a, 8, 11 can be converted by reaction with the stabilized alkylidenephosphoranes ( 5a–d ), namely acetylmethylene- 5a , methoxycarbonylmethylene- 5b , ethoxycarbonylmethylene- 5c , and benzoylmethylene-triphenylphosphorane 5d , into the phosphoranylidenes ( 7a–d, 10a–d, 13a–d ). No reaction was observed between iminophosphorane ( 14 ) and the monoanil ( 11 ). The structures of the new products were assigned according to consistent analytical and spectroscopic data. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:476–483, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20144     

Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,Pyridazines, and Their Fused Derivatives

Phenacylmalononitriles 8a , 8b react with hydrazines under dry conditions to afford the pyrazole derivatives 9a , 9b , 9c , 9d and in refluxing dioxane to afford the pyrazolo[3,4‐c]pyridazine derivatives 11a , 11b , 11c , 11d and the pyridazine‐6‐imine derivatives 12a , 12b , 12c , 12d . Compounds 12a , 12b were transformed into their oxo analogs 13a , 13b upon reflux in ethanolic HCl, whereas 12c , 12d were transformed into the furan derivatives 14a , 14b under the same reaction conditions (reflux in ethanolic HCl). Compounds 8a , 8b could be transformed directly into the benzoyl‐pyrazole derivatives 16a , 16b , 16c , 16d upon coupling with diazotized aromatic amines in pyridine. The structures of the new compounds were substantiated by elemental analyses and spectral data as well as x‐ray crystallographic analysis. Plausible mechanisms for the unexpected transformations are suggested.     

Dimethylformamide dimethyl acetal in heterocyclic synthesis: Synthesis of polyfunctionally substituted pyridine derivatives as precursors to bicycles and polycycles

Polysubstituted pyridines 11a,c and 12 were prepared by the reaction of benzoylacetone with dimethylformamide dimethyl acetal followed by treatment with cyanothioacetamide 9a , cyanoacetamide 9b and the anion of malononitrile dimmer 9c in dry DMF. When the reaction was carried out in ethanol as a solvent and piperidine as a base afforded 14a,b . Thienopyridines 16a,b were prepared by the reaction of pyridinethiones 11a and 14a with 2‐chloro‐N‐p‐tolyl‐acetamide ( 15 ). Further reaction of thienopyridines 16a,b with either DMFDMA or nitrous acid to gave 17a,b and 18a,b respectively. The reaction of pyridine derivative 11c with hydrazine and phenylhydrazine afforded the tricyclic compounds 19a,b .     

First synthesis of a alpha-trifluoromethyl allenol ether via the Julia-Lythgoe process

Alpha-trifluoromethyl allenol ethers 9a-e were prepared in moderate to good yields by the Julia-Lythgoe process using beta-ethoxy-beta-trifluoromethyl vinylic sulfone 3. Several reactions of 9c were examined to give alpha,beta-unsaturated trifluoromethyl ketone derivatives 11 and 12.     

Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

8-phenyl-10,10a-dihydropyrido

Base treatment of the pyridinium bromides 11a-e gives rise to the formation of the dihydropyridoazepines 14a-e as the only monomolecular products. The reaction takes place by initial deprotonation to the ylides 12, which undergo 8pi-electrocyclization affording the seven-membered-ring systems; no products of a dipolar 6pi-cyclization were detected. On the basis of quantum mechanical calculations a rationalization of the periselectivity of the electrocyclization process is given.     

Studies with enaminones: The reaction of enaminones with aminoheterocycles. A route to azolopyrimidines,azolopyridines and quinolines

The enaminones 1b,d,f react with 4‐phenyl‐3‐methyl‐5‐pyrazoleamine 3a to yield the pyrazole derivatives 4a‐c that cyclised readily on reflux in pyridine solution in presence of hydrochloric acid to yield the pyrazolo[1,5‐a]pyrimidines 5a‐c. Similarly 3(5)‐amino‐1H‐triazole (3b) reacted with 1b,d,f to yield the triazolo[1,5‐a]pyrimidines 5d‐f. In contrast attempted condensation of the 5‐tetrazoloamine (3c) with 1a,d,e resulted in its trimerisation and only triaroylbenzene 8a,d,e was isolated. The reaction of 1a,b,d with anthranilonitrile 9a and the reaction of 1a‐c with the 2‐aminocyclohexene thiophene‐3‐nitrile 10a afforded the cis enaminones 11a‐c and 12a‐c. Similarly, reaction of 1a‐c with the methylanthranilate 9b and reaction of 1b,e with ethyl 2‐aminocyclohexene thiophene‐3‐carboxylate 10b afforded the cis enaminones 11d‐f and 12d,e respectively. Attempted cyclization of 11a‐c into quinoline failed. Successful cyclization of 11d into the quinolinone 13 could be affected, on heating for five minutes in a domestic microwave oven at full power. The reaction of 1a‐c,f with piperidine afforded the trans enaminones 14a‐d. Similarly, trans 14e was formed from the reaction of 1b with morpholine. The coupling reaction of 1b with excess of benzene diazonium chloride afforded the formazane 16. The enaminone 2 reacted with heterocyclic amines to yield the pyridones 17,18.