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Using PhI(O-Ac)2 as a co-catalyst is proved to be the key for performing the title reaction under mild conditions (35°C, absence of any Broensted acids).

This reaction uses mild conditions and yields the products in a short reaction time in high yields.

In the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), reaction of an α-isocyanoacetate 1, an aldehyde 2, an aniline 3 followed by addition of a toluene solution of α,β-unsaturated acyl chloride 5 afforded oxa-bridged tricycle 6 in excellent yield, diastereoselectivity and enantioselectivity. Six chemical bonds, five stereogenic centers, three cycles were formed in this one pot four-component reaction.

A three-component reaction of α-isocyanoacetates bearing an electron-withdrawing substituent at α-position (II) with o-alkynylanilines (I) and aromatic and aliphatic aldehydes (III), (V) proceeds smoothly without the need for additive or catalyst to afford title furoquinolines (IV) and (VI) in good yields.

A novel multicomponent synthesis of 5-alkoxyoxazoles, based on a new reactivity profile of a-isocyanoacetates, is described. Thus, simply heating a solution of amine, aldehyde, and a-(EWG-phenyl)-a-isocyanoacetate or a-(4-pyridyl)-a isocyano acetate (EWG=electron-withdrawing group) in toluene provided 5-alkoxyoxazoles in good to excellent yields. Reaction of the 5-alkoxyoxazoles with various a,b-unsaturated acyl chlorides led to the formation of epoxytetrahydropyrrolo- [3,4-b]pyridin-5-ones by a domino N-acylation/Diels–Alder cycloaddition sequence. Subsequent fragmentation under basic conditions provided 6,7-dihydro- 5H-pyrroloACHTUNGTRENUNG[3,4-b]pyridin-5-ones. A four-component synthesis of the pyridin-5-one compounds, without isolation of the 5-alkoxyoxazole, was subsequently developed.

Reaction of aromatic aldehydes and isocyanides in the presence of N-methylhydroxyamine, acetic acid, and zinc chloride affords the aryl α-ketoamides in moderate to good yields.

A new strategy is described to synthesize 19-norsteroids with substituents at C-6, C-11 and C-17. The strategy is applied to the synthesis of 11β-[4-(dimethylamino)phenyl]-6β-methyl-4′, 5′– -dihydrospiro[estra-4,9-diene-17,2′-(3′H)-furan]-3-one (15, Org 31710) and some related compounds. These compounds have been shown to have potent antiprogestational activity and, compared to previously described 11-aryl-19-norsteroids, much reduced affinity for the glucocorticoid receptor.

Reaction of 4-pentynyltriphenylphosphonium bromide 2 with oestrone methyl ether in the presence of potassium tert -butylate produced a spirobicyclo[3.1.0]hexane rather than the anticipated Wittig product. The reaction appears to be general for pinacolone-type ketones, as was demonstrated by several examples. A mechanism for this anomalous reaction is proposed.

A total synthesis of the title compound 2, a potential precursor of the progestagens desogestrel and 3-ketodesogestrel, is described. The backbone of the steroid was assembled by condensation of 1,2-dihydro-4,7-dimethoxynaphthalene (12) and [S-(Z)]-8,9-dihydroxy-7-ethyl-6-nonen-2-ynoic acid methyl ester 9-(tert-butyldimethyl)silyl ether (11), prepared from [R-(+ )]-glyceraldehyde acetonide (4), and subsequent Claisen rearrangement. Heating of the resulting disecosteroid (14) at 170°C gave a 1:1 mixture of 9,11-secosteroids, 15 and 16, having the 8α, 13β, 14α- and 8α, 13α, 14α-configuration, respectively. The 13β-epimer 15 was converted into 11-bromo-13-ethyl-3-methoxy-9,11-secogona-1,3,5(10)-triene-9,17-dione (21), which reacted with triphenylphosphine under high pressure conditions (12 kbar, 55°C) to give the corresponding phosphonium salt 22. The intramolecular Wittig reaction of 22 proceeded with epimerization at C-8 to give exclusively (8α)-13-ethyl-3-methoxygona-1,3,5,9(11)-tetraen-17-one (23) which, upon treatment with acid, isomerized to the title compound 2.

As 3-Ketodesogestrel and Gestodene differ in the conformation of the 13-ethyl group, a series of progestagens was devised in which this conformation is fixed. Thus, both epimers of a steroid with a methyl-substituted 11,13-ethano bridge were prepared and their biological activities compared. From the receptor binding activity, it was concluded that the “Desogestrel conformation” is the more active one.

11,13-Ethanopregnanes were prepared to assess the influence of the bending of the steroid skeleton on progestagenic activity. It was demonstrated that, contrary to previous assumptions, upward bending of the A ring has little overall effect on the activity.

The crystal structures of five follicular fluid meiosis-activating sterol-related Δ8,14-sterol compounds are presented. These are 4,4-di­methyl-23-phenyl-24-nor-5α-chola-8,14-dien-3β-ol, C31H44O, 4,4-di­methyl-22-phenyl-23,24-dinor-5α-chola-8,14-dien-3β-ol, C30H42O, (20R)-4,4-di­methyl-22-oxa-5α,20-chol­es­ta-8,14,24-trien-3β-ol, C28H44O2, 4,4-di­methyl-23-phenyl-22-oxa-24-nor-5α-chola-8,14-dien-3β-ol–water (4/1), 4C30H42O2·H2O, and 4,4-di­methyl-5α-cholesta-8,14-dien-3-one, C29H46O. Two of the derivatives are inactive and three are active as agonists. Preliminary structure–activity relationship studies showed that the positions of the double bonds in the skeleton and the structures of the side chains are important determinants for activity. The conformations of the skeletons were compared with double-bond isomers retrieved from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 1, 31–37]; no significant differences were found. Thus, conformational changes induced by the double bonds are not discriminative with respect to the activity of the compounds. Comparisons of the side-chain conformations of active and inactive structures revealed that the crystal structures were not conclusive as far as correlation of conformation and activity of the side chains were concerned.

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 β-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.

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 Bronsted 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.

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.

Cationic cyclization of the alcohols (VIII), prepared from the diester (I), yields the title compounds (IX) and (X) as major products.