Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

Monique Lüthy, Mary C. Wheldon, Chehasnah Haji-Cheteh, Masakazu Atobe, Paul S. Bond, Peter O'Brien*, Roderick E. Hubbard, Ian J S Fairlamb

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) -1 ≤ A log P ≤ 3; (ii) 14 ≤ number of heavy atoms ≤ 26; (iii) total polar surface area ≥ 50 Å<sup>2</sup>. The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.

Original languageEnglish
Pages (from-to)2680-2694
Number of pages15
JournalBioorganic and Medicinal Chemistry
Issue number11
Publication statusPublished - 1 Jun 2015


  • 3-D shape analysis
  • Lead-like library
  • Lead-oriented synthesis
  • Nitrogen heterocycles
  • Organolithium-mediated synthesis

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