Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones.

A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, alpha-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. Alpha-alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other alpha-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different alpha-acidic esters.

A novel, versatile D-->BCD steroid construction strategy, illustrated by the enantioselective total synthesis of estrone.

A general steroid synthesis is presented that relies on prior formation of three stereogenic centers (C8, C13, and C14) on a D ring template, followed by C- and B-ring cyclizations. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation process, allows introduction of structural variety as required. The method is illustrated by the total synthesis of estrone via a C-ring closing metathesis and a B-ring Heck cyclization.

Synthesis of conformationally constrained peptidomimetics using multicomponent reactions.

A novel modular synthetic approach toward constrained peptidomimetics is reported. The approach involves a highly efficient three-step sequence including two multicomponent reactions, thus allowing unprecedented diversification of both the peptide moieties and the turn-inducing scaffold. The turn-inducing properties of the dihydropyridone scaffold were evaluated by molecular modeling, X-ray crystallography, and NMR studies of a resulting peptidomimetic. Although modeling studies point toward a type IV beta-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.

Synthesis of 5,10-seco analogs of testosterone.

A number of 5,10-seco analogs of testosterone has been synthesized starting from products of the radical oxidation of 3beta,17beta-diacetoxy-5alpha-androstan-5alpha-ol. The obtained compounds possess a flexible 10-membered ring with substituents (O, -OH) at C-3 and C-5. Similar derivatives with an (E)- and (Z)-Delta(1(10))-double bond have been prepared also. X-ray analysis and a combination of NMR experiments have been used for their structure elucidation and conformation analysis.

A tissue-selective nonsteroidal progesterone receptor modulator: 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4-f]quinoline.

The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.

Selective formation of 2-imidazolines and 2-substituted oxazoles by using a three-component reaction.

Selective formation of 2H-2-imidazolines and 2-substituted oxazoles by using a multicomponent reaction of amines, either aldehydes or ketones, and alpha-acidic isocyano amides or esters is described. By selecting the appropriate solvent, Ag(I) or Cu(I) catalyst, or by employing a weak Brønsted acid, the product formation can be fully controlled and directed quantitatively to the desired heterocyclic scaffold. The described experimental procedures not only significantly increase the scope of compatible inputs for this complexity-generating three-component reaction, but also allow for considerable chemical diversity: At least four diversity points in two distinct scaffolds can be exploited in this way.

Efficient C2 functionalisation of 2H-2-imidazolines.

Alkylation and oxidation of 2H-2-imidazolines, followed by regioselective deprotection, thionation and microwave-assisted Liebeskind-Srogl reaction, efficiently led to 2-aryl-2-imidazolines as new analogues of p53-hdm2 interaction inhibitors (Nutlins).

A multicomponent synthesis of triazinane diones.

An efficient, one-pot synthetic protocol toward triazinane diones, a rather unexplored class of heterocyclic scaffolds combining phosphonates, nitriles, aldehydes, and isocyanates is described. The optimization of the reaction, synthesis of a small library of different triazinane diones, as well as alternative routes toward the triazinane dione scaffold are discussed.

A flexible six-component reaction to access constrained depsipeptides based on a dihydropyridinone core.

Highly functionalized and conformationally constrained depsipeptides based on a dihydropyridin-2-one core are prepared by the combination of a four- and a three-component reaction. The synthesis combines a one-pot Horner-Wadsworth-Emmons/cyclocondensation sequence leading to isonitrile-functionalized DHP-2-ones with an isonitrile-based Passerini multicomponent reaction (MCR). Substituents could be independently varied at six different positions. The two MCRs could also be performed as a one-pot procedure, simplifying the protocol and leading to a new and highly variable six-component process.

A resource-efficient and highly flexible procedure for a three-component synthesis of 2-imidazolines.

A multicomponent reaction between alpha-acidic isonitriles, primary amines, and carbonyl compounds was studied using 14 different solvents. Depending on the isocyanide that was used, optimal yields for the three-component synthesis of 2H-2-imidazolines were observed in different solvents. The solvents could be used as purchased, and in situ preformation of the imine was not required. By selecting the appropriate solvent, it was possible to considerably expand the range of compatible isocyanides toward less alpha-acidic isocyanides. Further process simplification was achieved by performing the reaction at higher concentrations and avoiding purification by column chromatography, resulting in a fast, easy to perform, and resource-efficient protocol for this three-component reaction.

Diastereoselective multicomponent synthesis of dihydropyridones with an isocyanide functionality.

[Structure: see text] In a search for new multicomponent strategies leading to valuable small heterocycles, a new highly diastereoselective four-component reaction (4CR) was found in which a phosphonate, nitriles, aldehydes, and isocyanoacetates combine to afford functionalized 3-isocyano-3,4-dihydro-2-pyridones. In this strategy, initially a 1-azadiene is generated, which is trapped in the same pot by an isocyanoacetate as the fourth component. Multicomponent reactions (MCRs) that lead to heterocycles containing isocyano substituents are unprecedented and offer many possibilities for further differentiation.

Multicomponent synthesis of dihydropyrimidines and thiazines.

A broad range of differently substituted dihydropyrimidines and thiazines can be efficiently prepared by using a four-component reaction between phosphonates, nitriles, aldehydes, and iso(thio)cyanates. The scope and limitations of this multicomponent reaction are fully described. Variation of all four components has been investigated. The nitrile and aldehyde inputs can be varied extensively, but variation of the phosphonate input remains limited. An interesting rearrangement leading to phosphoramidates has been observed. Furthermore, the multicomponent reaction seems to be restricted to the use of isocyanates with strongly electron-withdrawing substituents, but an interesting additional exchange reaction under microwave conditions leads to dihydropyrimidines with less electron-withdrawing substituents at N3. In addition, a diastereoselective formation of dihydropyrimidines has been observed when using a chiral aldehyde as the input. Finally, by changing the isocyanate component to an isothiocyanate, thiazines are efficiently formed instead of the corresponding thio-dihydropyrimidines.

A new type of steroids with a cyclobutane fragment in the AB-ring moiety.

The synthesis of a 5,10-seco steroid containing two double bonds in a AB-macrocycle as well as the preparation of a steroidal skeleton with a cyclobutane fragment is described. The structures of these compounds are different from those of natural steroids, but they are very similar with respect to conformation of the carbon skeleton.

Isolation and structure elucidation of new radical oxidation products of 5-hydroxy steroids.

Three new products have been isolated from the lead-tetraacetate version of the hypoiodite oxidation of 3beta,17beta-diacetoxy-5-hydroxy-5 alpha-androstane. Along with the expected 1(10)-unsaturated 5,10-seco steroidal 5-ketones, the fragmentation reaction gave two epimeric C-4 iodides. Their structural assignment was based on X-ray data of one of them ((4R,10S)-4-iodo-3beta,17beta-diacetoxy-5,10-secoandrostan-5-one). The third new product was found to be the 5 beta,6 beta-epoxide resulting from the dehydration of the tertiary alcohol followed by epoxidation of the intermediate Delta(5)-olefin.

Multicomponent synthesis of 2-imidazolines.

[reaction: see text] A multicomponent reaction (MCR) between amines, aldehydes, and isocyanides bearing an acidic alpha-proton gives easy access to a diverse range of highly substituted 2-imidazolines. The limitations of the methodology seem to be determined by the reactivity of the isocyanide and by the steric bulk on the in situ generated imine rather than by the presence of additional functional groups on the imine. Less reactive isocyanides, for example p-nitrobenzyl isocyanide 25a, react successfully with amines and aldehydes, using a catalytic amount of silver(I) acetate. Some of the resulting p-nitrophenyl-substituted 2-imidazolines undergo air oxidation to the corresponding imidazoles. Differences in reactivity of the employed isocyanides are explained with use of DFT calculations. Difficult reactions with ketones instead of aldehydes as the oxo-compound in this MCR are promoted by silver(I) acetate as well.

The synthesis of functionalized 13,14-seco-steroids via Grob fragmentation.

A synthetic methodology for the synthesis of 13,14-seco-steroids with substituents at C-14 and C-17 is described. The approach involves Grob fragmentation of 14beta-hydroxy-17beta-tosylates, hydroboration-oxidation of the intermediate delta13(17)-olefin, and hydride reduction of the 14-ketone. An unambiguous structural assignment of (13R,14S,17S)-14,17-diacetoxy-3-methoxy-7alpha-methyl-13,14-secoestra-1,3,5(10)-triene was determined by X-ray analysis.

Synthesis of 13,14-secotestosterone derivatives.

A number of testosterone analogs with a 13,14-secosteroidal fragment have been prepared from (13S)-13-iodo-6beta-methoxy-3alpha, 5-cyclo-13,14-seco-5alpha-androstan-14,17-dione. The key steps involved stereoselective deiodination of the starting compound with triphenylphosphine and selective protection of the 17-keto group with trimethylsilylcyanide. Removal of iodine at C-13 proceeded with inversion of the configuration at C-13, which has been established by X-ray crystallography. 13,14-Secotestosterone analogues substituted and non-substituted at C-14 have been prepared. The obtained compounds containing flexible CD ring fragments are of great interest for comparative studies in biological tests together with testosterone and other steroids with a rigid tetracyclic skeleton.

Reaction of (13S)-13-iodo-6beta-methoxy-3alpha,5-cyclo-13,14-seco-5alpha-androstane-14,17-dione with hydroxylamine and its application to the synthesis of new 13,14-seco steroids.

The synthesis of 13,14-seco steroids starting from easily available (13S)-13-iodo-6beta-methoxy-3alpha,5-cyclo-13,14-seco-5alpha-androsta-14,17-dione is described. The C-17 ketone was converted regioselectively into its oxime with simultaneous stereoselective deiodination at C-13. The remaining C-14 carbonyl group was then reduced stereoselectively with Ca(BH4)2. The configurations at the relevant stereocenters of the thus obtained hydroxy oxime were determined by X-ray analysis. Successful regeneration of the C-17 carbonyl group was achieved by treatment of the corresponding oxime acetate with TiCl3.