Pyrrolo -l,4-benzodiazepines

Isatoic anhydride can be condensed with proline in polar aprotic solvents at high temperature, or in a reaction catalyzed by the enzyme catalase, to yield a pyrrolo[l,4]benzodiazepine ring, a structural pattern found in some antineoplasic antibiotics188 (Scheme 40). 

There is a group of antibiotics that possess the pyrrolo[l,4]benzodiazepine skeleton and show antimicrobial activity against Gram-positive bacteria, along with antiviral, antiphage, and antitumor activities. Anthramycin and tomaymycin are typical alkaloids in this group. 

Giiesbeck AG, Kramer W, Lex J (2001) Diastereo- and enantioselective synthesis if pyrrolo [l,4]benzodiazepines through decarboxylative photocyclization. Angew Chem Int Ed 40 577-579... 

Sibanomycin (10) is a new pyrrolo [l,4]benzodiazepine antitumour antibiotic produced by a Micromonospora strain it contains 4,6-dideoxy-3-C-methyl-4-methylamino- -L-mannopyranose linked to a tricyclic aglyconea very closely related compound DC 102 (11) has... 

An interesting application (Scheme 15) was the diastereoselective synthesis of [1,4]benzodiazepines and pyrrolo[l,4]benzodiazepines (41). The photolysis of chiral, a-amino-acid-derived substrates proceeded with high diastereoselectivity and the fra s-diastereoisomers were formed exclusively. Additionally, for two substrates derived from proline and a proline analogue, remarkably high memory of chirality effects were determined with ee values of 86% and >98%, respectively. 

Pyrrolo[2,1 -c][l, 4]benzodiazepines synthesis, 7, 614 Pyrrolo[l, 6]benzodiazocines synthesis, 7, 515 Pyrrolo[3,4-c]benzopyrazoles reactions, 6, 1034 Pyrrolobenzothiazoles synthesis, 4, 785 Pyrrolo[l, 2-c]benzotriazines synthesis, 4, 240 Pyrrolo[3,4-c]cinnolines synthesis, 4, 240... 

New routes to pyrrolo[2,l-c][l,4]benzodiazepines and their thiazolo[4,3-c] analogues have been reported <96CC385, 96TL6803, 96JHC275>. A number of new routes to pyrrolo[l,2-a]thieno[3,2 [l,4]diazepines have also been published <96JHC75,96JHC87>. 

The carbinolamine-containing pyrrolo[2,l-c][l,4]benzodiazepine family of antitumor antibiotics is produced by various Streptomyces species well-known members include abthramy-cine, tomay mycine, and DC-81,138 Various approaches to the synthesis of these compounds have been investigated over past years reductive cyclization of suitably substituted nitroaldehydes is the frequently used method (Eq. 10.81).139... 

The thermal cyclization of N-(5//-pyrrolo[2,l-c]-l,4-benzodiazepin-ll-yl)aminomethylenemalonates (97) by heating in boiling Dowtherm A for 1-2 hr gave 10//-pyrimido[l,2-a]pyrrolo[2,l-c]-l,4-benzodiazepine-3-car-boxylates (1161) in 68-86% yields (85CP1197242, 85JHC305). Compound 97 (R = R = H) was also cyclized in ethanol in the presence of sodium ethoxide at ambient temperature to afford tetracyclic compound 1161 (R = R1 = H) in 87% yield (85CP1197242, 85JHC305). 

Reductive ring closure of l-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,l-c][l,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R = H) or ester (R = Et) 205 followed by CDI or thermal cyclization (1992JHC1005). 

Intramolecular cyclization is the final step in the preparation of the scaffold for a 66-member C2-aryl pyrrolo[2,l-c][l,4]benzodiazepine library (2007JCC437). 

Reaction of 10,n-dihydro-5H-pyrrolo[2,l-c][l,4]benzodiazepines 202 with trichloroacetylchloride results in trichloromethyl keto derivatives 382 (Scheme 78 (2000BMCL783)). 

Arylmethyl-4H-pyrrolo[l,2-fl][l,4]benzodiazepines 236 can be transformed with sodium borohydride to corresponding derivatives reduced at the imine double bond (Scheme 50, Section 3.1.1.3 (1995EJM593)). 

The iodo benzamide derivative of pyrrolo[2,l-c][l,4]benzodiazepine 367 (R = I, Scheme 75, Section 5.1.1) reacts with bis(tributyl)tin, lithium chloride and tetrakis(triphenylphosphine) palladium(O) in refluxing dioxane to yield the stannyl derivative 370. The latter couples with substituted aryl bromides in the presence of... 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

The C(2)-C(3) olefin of a l,4-benzodiazepin-5-one regiospecifically captured an alkyl radical intramolecularly in a 5-f vo-/r/g-proccss that is the critical step in an approach to the constmction of the fused tricyclic system found in the pyrrolo[2,l-f][l,4]benzodiazepine class of antitumor antibiotic. Treatment of the alkyl bromide 46 with Bu3SnH afforded the tricyclic product 47 in 90% yield, a reaction that proceeded with equal efficiency with the alkoxy aryl ring substituents found in the naturally occurring ( )DC-81 (Scheme 18) <19990L1835>. 

Chemical Name 2-Propenamide, 3-(5,10,ll,lla-tetrahydro-9,ll-dihydroxy-8-methyl-5-oxo-lFI-pyrrolo[2,l-c][l,4]benzodiazepin-2-yl)-, (11R-[2(E),llallap])-... 

Chemical Name 2H,10H-Parazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine, l,3,4,14b-tetrahydro-2-methyl-, maleate (1 1)... 

To the suspension of 12.8 g of 2-methyl-3,4-dioxo-l,3,4,14b-tetrahydro-10H-pyrazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine in 460 ml of tetrahydrofuran, 200 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling with ice. The mixture is refluxed for one hour, again cooled and combined with 25 ml of acetic acid. It is evaporated, the residue taken up in 50 ml of 30% aqueous sodium hydroxide and the mixture extracted with methylene chloride. The extract is dried, evaporated, the residue dissolved in diethyl ether, the solution filtered and the filtrate evaporated, to yield the crude 2-methyl-l,3,4,14b-tetrahydro-10H-pyrazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine. It is triturated with ethyl acetate-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1 9). The eluate is evaporated and the residue salified. 

The solution of 500 mg thereof in 35 ml of ethanol and 5 ml of glacial acetic acid is hydrogenated over 250 mg of 5% palladium on charcoal at 2.7 atm and 40°C for 7 hours. The mixture is filtered, the filtrate evaporated and the residue taken up in methylene chloride. The solution is washed with saturated aqueous sodium carbonate, the aqueous phase extracted with methylene chloride and the combined organic solutions dried and evaporated, to yield the ll-(N-methylaminomethyl)-10,ll-dihydro-5H-pyrrolo[2,l-c][l,4]benzodiazepine. 

The mixture of 300 mg thereof and 232 mg of diethyl oxalate is slowly heated to 140°C during 45 minutes and to 180°C during 15 minutes, at which temperature it is maintained for 30 minutes. It is cooled, diluted with benzene, chromatographed on silica gel and eluted with methanol-chloroform (1 9), to yield the 2-methyl-3,4-dioxo-l,3,4,14b-tetrahydro-10H-pyrazino[l,2-a]pyrrolo[2,l-c][l,4]benzodiazepine melting at 178°-179°C. 

A suspension of 29.8 mmol of sodium hydride (55 percent oil dispersion) in 40 ml of dry dimethylformamide is treated at 20-30°C with 27.1 mmol of (S)-6-bromo-1,2,3, lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepine-5,11 (10H)-dione, the mixture is stirred in the above temperature range for 45 min and then at -35°C 27.1 mmol of diethylchlorophosphate are added dropwise thereto. 

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