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A traceless solid-phase synthesis of oxazoles 4 via Robinson−Gabriel reaction of solid-supported α-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield α-methoxyphenyl (MAMP) resin with an α-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with α-keto aldehydes; reaction of MAMP resin with α-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.

The availability of small organic molecules covering as much chemical space as possible is seen as the only means that guarantees potential modulation of the many biological targets that are ultimately being unveiled by genomics. Therefore diversity oriented organic synthesis is rapidly becoming one of the paradigms in the process of modern drug discovery. This has spurred research in those fields of chemical investigation that lead to the rapid assembly of not only molecular diversity, but also molecular complexity. As a consequence multi-component as well as domino or related reactions are witnessing a new spring. Coupling these one-pot processes with solid-phase synthesis offers new perspectives for the preparation of both primary and thematic libraries. The progresses recently made in this field that perfectly suits the needs of modern drug discovery are the subject of the present review.

SummaryThe effect of clenbuterol (NAB 365) in inhibiting exercise-induced asthma was compared with that of salbutamol in a single-blind, placebo-controlled, crossover study. Single doses of 20 μg clenbuterol and 200 μg salbutamol were given by inhalation 180 minutes before exercise to 9 patients. The exercise used was treadmill running. Clenbuterol offered complete protection to 7 patients, partial protection to 1 and no protection to 1 patient. Salbutamol offered complete protection to 5 patients, partial protection to 1 and no protection to 3 patients. One patient was not protected by any treatment. The protective effects of the two beta-adrenergic bronchodilator drugs were similar (p = 0.42 for FEV1and p = 0.10 for FEF25-75). Placebo failed to prevent exercised-induced asthma in any patient. No adverse reactions were manifested or reported by the patients.

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