New Year, New Chemistry – “Any-stage functionalisation” via strain-release amination

The Baran group at The Scripps Research Institute ( have recently reported an interesting reagent-based methodology to enable “any-stage functionalisation” of both simple and complex amines with small cyclic motifs such as bicyclo[1.1.1] pentanes, azetidines and cyclobutanes [1].

The strategy employs a turbo-amide to break a “spring-loaded” C-C or C-N bond, and in doing so directly aminates a strained species (Fig 1), enabling simpler syntheses and expanding retrosynthetic logic of some traditionally challenging targets.

Scott 01-02-2015 Picture 1

Fig 1. A – Strain-release amination using turbo amide and “strain-release reagent”, propellane, to afford bicyclo[1.1.1]pentan-1-amine on large scale after deprotection. B – Strain-release amination using turbo amide of late stage intermediate and “strain release” reagent, propellane, to afford a “propellerized” tertiary amine. Image taken directly from [1] without permissions

These small heterocyclic and bicyclic motifs can serve as bioisosteres in medicinal chemistry with the potential to bypass structural liabilities and navigate intellectual property space [2]. The incorporation of such structures into molecules using traditional methods (Fig 2), and from a late stage intermediate, can involve multiple FGIs and may involve the synthetic route being altered significantly to accommodate the small cyclic structure.

Scott 01-02-2015 Picture 2

Fig 2. Conventional and ‘new’ retrosynthetic analysis to obtain Pfizer’s precursor, bicyclo[1.1.1]pentan-1-amine. Image adapted from [3] and [1] without permissions

Pfizer’s urgent requirement of the costly precursor, bicyclo[1.1.1]pentan-1-amine (3 kg ~ $150 k)(Fig 2), in kilogram quantities for the synthesis of a clinical candidate, was the driving force behind this innovative methodology. Fortuitously, the strategy developed was then successfully demonstrated on a variety of secondary amines including commercial drugs, highlighting the applicability of strain-release amination. The ‘strain-release reagent’, propellane, used in direct amination was then substituted to include azetidines and cyclobutanes (B and C from Fig 3 respectively).

Scott 01-02-2015 Picture 3

Fig 3. The concept of strain-release amination: using the turbo amide of a lead with “strain-release reagent” A, B or C to append a strained ring system at “any stage” of synthesis onto the lead. Image taken directly from [1] without permissions

It will be interesting to see how this methodology develops; what other “strain-release reagents” can be employed, and how strain-release amination will be realised by academia and industry.

For a more complete account of the development of strain-release amination, further applications and in-depth details of the methodology (> 400 pages of supporting info!) visit and read the primary reference [1].

Blog written by Scott Henderson


  1. Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego, N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu, P. S. Baran. Science. 351, 6270, 241 (2016)
  2. A. Meanwell. J. Med. Chem. 54, 2529 (2011)
  3. D. Bunker, N. W. Sach, Q. Huang, P.F. Richardson. Org. Lett. 13, 4746 (2011).


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