Recent developments concerning the application of the Mannich reaction for drug design

Abstract

The versatile multicomponent Mannich reaction occupies a salient position in organic chemistry and drug design. Sound knowledge of its scope and variations and of the biological activities of Mannich bases is crucial for the development and improvement of drugs for various diseases. Areas covered: The following article provides an overview of the latest developments in the field of drugs based on the Mannich reaction. Web-based literature searching tools such as PubMed and SciFinder were applied to obtain useful articles. In addition, pertinent literature that was recently published by the authors is discussed in this manuscript. The chemical structures of bioactive Mannich bases are also given. Expert opinion: The Mannich reaction represents a feasible and cost-effective procedure with great potential for drug development. Several newly discovered Mannich bases exhibit sound activities against various human diseases as well as favorable pharmacokinetics. Thus, scientific research about Mannich bases is prospering and appears very attractive both for chemists and for clinicians.

Stereodivergent access to all four stereoisomers of chiral tetrahydrobenzo[f][1,4]oxazepines, through highly diastereoselective multicomponent Ugi–Joullié reaction

“…The results reported in Scheme 3 show that it is possible to synthesize enantiopure trans tetrahydrobenzo[f] [1,4]oxazepines 10, introducing up to four diversity inputs: the salicylaldehyde 1, the amino alcohol 7, the isocyanide, and the carboxylic acid. The methodology is operationally simple (just two chromatographies) and highly diastereoselective.…”

“…Finally, both enantiomeric series are accessible, thanks to the easy availability of 1,2amino alcohols or a-amino acids in either enantiomeric form. Tetrahydrobenzoxazepines 10 may be useful in the medicinal chemistry realm, since several N-acylated tetrahydrobenzo[f] [1,4]oxazepines have been reported to be endowed with very interesting pharmacological properties. [51][52][53][54][55] On the other hand, the 5-substituted compounds are largely unexplored from this point of view, although some stimulating examples can be found in the literature.…”

“…In conclusion we have developed a concise and diversityoriented methodology to obtain both N-acylated, and N-free tetrahydrobenzo[f] [1,4]oxazepines with a high control of conguration of the two stereogenic centres. The enantiomeric purity is granted by the starting materials (1,2-amino alcohols of a-amino acids), which are easily accessible from the chiral pool.…”

“…1 Thanks to their high step economy and to the possibility to introduce several diversity inputs in a single step, they are considered a very powerful tool for the construction of libraries of drug-like entities. [2][3][4] While the use of MCRs in medicinal chemistry is well assessed, their application in other elds is less pronounced. Recently, MCRs were found to be successful in the synthesis of functionalized uorophores.…”

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Starting from easily accessible chiral enantiopure 1,2-amino alcohols and salicylaldehydes, a concise route to cyclic imines has been developed. These chiral cyclic imines undergo a highly diastereoselective Ugi-Joullié reaction to give trans tetrahydrobenzo[f] [1,4]oxazepines with the introduction of up to 4 diversity inputs. The cis isomer may also be attained, thanks to a thermodynamically controlled base catalysed epimerization.

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