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

The Baran group at The Scripps Research Institute (http://www.scripps.edu/baran/html/publications.html) 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.

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.

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).

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 http://openflask.blogspot.co.uk/ and read the primary reference [1].

Blog written by Scott Henderson

References

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).