A diastereoselective approach to cis- and trans-1,3-disubstituted bicyclo[2.1.0]pentanes (housanes) was recently reported by our chemists in The Journal of Organic Chemistry. The article included preparation of 35 derivatives on up to 100 g scale. Moreover, pKa’s and conformational features of selected examples of housanes (e.g. GABA analogues) were also studied and compared to that of the corresponding 1,3-disubstituted cyclopentanes. For an extended list of novel housanes check the Enamine Store page.
In a recent JOC paper, Enamine chemists reported a comprehensive study of regioselective [3 + 2] cycloaddition reactions – an efficient approach towards 3,5-disubstituted isoxazole building blocks bearing mono-, di- or trifluoromethyl substituents. More than 100 derivatives were obtained on up to 130 g scale, and multigram quantities of representative examples are available from EnamineStore at the isoxazole library.
Enamine’s EurJOC paper on the scalable and regioselective preparation of all isomeric (cyclo)alkyl piperidines and the corresponding amino alcohols was featured on the cover of the issue. The multigram quantities of these derivatives are available from EnamineStore at the piperidine library
Recent Enamine’s paper disclosed novel heteroaryl difluoroacetates and the corresponding carboxylic acids, amides, nitriles and alcohols as promising building block in drug design. Known literature example of metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitor 1 led to the the corresponding 2,2-difluoro-2-pyridin-2-yl derivative 2, which is not prone to metabolic oxidation at the α-methylene group next to the aromatic moiety.
The review mentioned in the title was published in Chemistry – A European journal and emerged from a collaboration of scientists from Enamine Ltd. (including myself) and Duncan Judd from Awridian Ltd. Despite some “symbiotic” hype in the title (as it was pointed out by one of the reviewers), the paper provides a comprehensive overview of concepts which appeared at the edge of these disciplines recently. Initially, we have aimed at tutorial review that might help synthetic chemists to become familiar with state-of-the-art in the field. Thus, genesis of concepts like “…-oriented” syntheses (DOS, LOS, BIOS, FOS, DTS), as well as related “abbreviated” strategies (BBs, FBDD, DEL, REAL) has been discussed, together with recent advances focusing mainly on chemical aspects.
However, the paper exceeded the initial “tutorial” goal, and in my opinion, it might be of interest not only to beginners in the field, but also to highly qualified specialists in medicinal chemistry and related sciences. Although we attempted to be as neutral as possible, one might feel that we advocated for the compound selection models taking into account physico-chemical properties of the compounds, and hence concepts like lead-oriented-synthesis (LOS). Despite recent criticism and numerous successful exceptions, we believe that if used properly, such strategies might be step at the right direction for early drug discovery. In particular, LOS-like concepts seem to be dominating for building blocks, and majority of the Enamine’s building block collection have been designed by the corresponding criteria such as “the smaller, the better”.
The title picture (which was also used as a frontispiece for the paper) shows one of the most beautiful examples of symbiosis found in Nature – a hummingbird pollinating an ornithophilous flower. These two families co-evolved together, changing their features (i.e. the bill shape of the bird, as well as color spectrum and nectar composition of the plant) to get maximum benefit from their interaction. This is a good illustration of the main concept of the paper: similar symbiotic relationship between synthetic organic chemistry and early drug discovery exists.
(This article originally appeared at Sciencetrends.com)
Modern drug discovery relies heavily on the ability of chemists to produce good starting points for producing high-quality lead compounds. Several concepts were established in the last two decades to aim synthetic organic chemistry onto the proper areas of chemical space, in particular, the so-called lead-oriented approach which describes paradigm shift towards low-molecular-weight, relatively hydrophilic, conformationally restricted, sp3-enriched structures.