Benzodiazepine-2,5-diones

For the preparation of the 2,5-diketopiperazines 9-57 and 1,4-benzodiazepine-2,5-diones 9-58, respectively, the isocyanide 9-54 was either treated with an aldehyde and an amino acid, or with an aldehyde and an anthranilic acid, to give either 9-55 or 9-56, using the conditions depicted in Scheme 9.11. Further transformations include liberation from the resin with KOtBu forming N-acyloxazolidones and treatment with NaOMe to afford the corresponding esters, which are then cy-clized to the desired products 9-57 and 9-58 under acidic conditions. 

In this context it must be mentioned that the procedure by Kennedy and coworkers, in which a novel resin-bound isonitrile is applied in an Ugi multicomponent reaction for the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones, was discussed earlier, in Chapter 9. 

Kennedy AL, Fryer AM, Josey JA (2002) A new resin-hound universal isonitrile for the ugi 4CC reaction preparation and applications to the synthesis of 2,5-diketopiperazines and 1, 4-benzodiazepine-2, 5-diones. Org Lett 4 1167-1170... 

Keating TA, Armstrong RW (1996) A remarkable two-step synthesis of diverse 1, 4-benzodiazepine-2, 5-diones using the Ugi four-component condensation. J Org Qiem... 

Hulme C, Peng J, Tang S-Y, Bums CJ, Morize I, Labaudiniere R (1998) Improved procedure for the solution phase preparation of 1, 4-benzodiazepine-2, 5-dione libraries via Armstrong s convertible isonitrile and the Ugi reaction. J Org Chem 63 8021-8023... 

Cuny G, Bois-Choussy M, Zhu JP (2004) Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1, 4-benzodiazepine-2, 5-diones. Control of reaction pathway by metal-switching. J Am Chem Soc 126 14475-14484... 

Boojamra, C. G. Burow, K. M. Ellman, J. A. An Expedient and High-Yielding Method for the Solid-Phase Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones, J. Org. Chem. 1995, 60, 5742-5743. 

The most selective example is represented by the synthesis of 1,4-benzodiazepin-2,5-diones 37 via Ugi reaction with different a-aminoesters. The use of aromatic aldehyde 35 leads in some cases to very high stereoselectivity in the preparation of intermediate 36, and a single diastereoisomer is isolated after crystallization (Scheme 1.15) [43]. 

An alternative procedure for the solution-phase preparation of 1,4-benzodiaze-pine-2,5-diones was reported by Hulme et al. [85]. This method combines the UDC strategy and the use of the convertible 1-isocyano-l-cyclohexene 1. The Ugi-4CR between 1, N-Boc-protected anthranilic acids, amines, and aldehydes afforded the N-Boc-protected Ugi adducts 150 which, on treatment with HCl/MeOH or 10% TFA in DCE underwent N-deprotection, cyclohexenamide cleavage, and cydi-zation to the desired l,4-benzodiazepine-2,5-diones 151 (Scheme 2.55). Hulme and Cherrier [74a] reported another high-yield one-pot solution-phase synthesis of 1,4-benzodiazepine-2,5-diones that used ethyl glyoxylate in a Ugi-4CR to give 152 and then 153 (Scheme 2.55). 

Moroder L, Lutz J, Grams F, Rudolph-Bohner S, Osapay G, Goodman M, Kolbeck W, A new efficient method for the synthesis of 1,4-benzodiazepine-2, 5-dione diversomers, Biopolymers, 38 295-300, 1996. 

The reaction of cyclohexenamides with nucleophiles such as water, alcohols, or thiols, produced carboxylic acid, esters, or thioesters. Reaction with acetylenic dipolarophiles in acidic conditions produced highly functionalized pyrroles via a complex mechanism, implying as intermediates 1,3-dipoles and bycyclic cycloaddition products. Reaction of cyclohexenamides containing protected hydroxylic functions with AcCl/MeOH produced < -lactones, while cyclohexenamides, bearing in Ri an o-aminophenyl group, easily cyclized to 1, 4-benzodiazepine-2, 5-diones. 

C Boojamra, K Burow, L Thompson, J. Ellman. Solid-phase synthesis of 1,4-benzodiazepine-2,5-diones. Library preparation and demonstration of synthesis generality. J Org Chem 62 1240-1256, 1997. 

Cummings, M. D., Schubert, C., Parks, D. J., Calvo, R. R., LaFrance, L. V., Lattanze, J., Milkiewicz, K. L., and Lu, T. (2006) Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction. Chem. Biol. Drug Des. 67, 201-205. 

The importance of l,4-benzodiazepine-2,5-diones (BZDs) has increased due to their valuable pharmacological properties in the treatment of cancer, AIDS, hypertension, inflammation, pain, muscle tension, and depression. The green reaction of isatoic anhydrides with a-amino acids in the presence of the IL l-butyl-3-methyli-midazolium bromide gave 1,4- benzodiazepine-2,5-diones in excellent yields with no catalyst (Equation 4.45). The reaction work-up is simple and the IL was easily separated from the reaction and reused. The methodology was fairly general and numerous cyclic and acyclic a-amino acids were used to produce 1,4-benzodiaze-pine-2,5-diones [87]. 

Cyclisation was achieved by intramolecular substitution as exemplified by the synthesis of 1,4-benzodiazepine-2,5-diones 18. 

Benzodiazepine-2,5-diones represent a versatile pharmacophore with a wide range of pharmaceutical utility which can function as opiate receptor antagonist, anticonvulsant agents ° and glycoprotein mimics. Goff et alT developed a solid-phase synthesis of 1,4-benzodiazepine-... 

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