Bioisosteres Technical Note #1.

Bicyclo[1.1.1]pentane (BCP)

In 2012, Stepan and co-workers demonstrated that the bicyclo[1.1.1]pentane (BCP) motif could be employed as a bioisostere of para-substituted phenyl rings. [i] They showed that the replacement of a para-substituted phenyl ring with BCP could improve the biopharmaceuticfusedal properties (e.g., microsomal stability, solubility, permeability) of the compound whilst minimizing changes to its overall size, shape and potency. Both motifs possess similar spatial features (compared in Figure 1) with identical dihedral angles and similar distance between substituents, the main caveat being that BCP cannot be used to replace a para-substituted phenyl ring where the ring itself is forming a specific interaction (e.g., cation-pi, pi-pi or dipole-pi) to its intended biological target.

Stepan and co-workers showed that replacement of the central para-substituted fluorophenyl ring in γ-secretase inhibitor 1a (see Figure 2) with the BCP moiety resulted in comparable IC50 (Aβ42) values of 0.225 nM (1a) and 0.178 nM (1b). Additionally, significant improvements in aqueous solubility and passive permeability were observed, presumably due to the increase in Fsp3 (fraction of sp3 as described in ‘Escape from Flatland’) [ii], greatly improving its oral absorption characteristics.

BCP has also been shown to be useful as a bioisostere of both tert-butyl and alkynyl groups. Bioisosteric replacement of the tert-butyl group, in the dual endothelin receptor antagonist Bosentan (2a – see Figure 2), with the BCP moiety was investigated by Westphal et al in 2015. [iii] The biological activity and properties of the analogues containing trifluoromethyl, pentafluorosulfanyl, cyclopropyl-trifluoromethyl and BCP moieties were compared to the tert-butyl containing parent. The BCP containing derivative 2b possessed a slightly improved IC50 value (11 nM for 2a, 4 nM for 2b). No increase in CYP inhibition was observed and it possessed an equivalent permeability value as well as a slightly increased metabolic stability.

The BCP containing analogue of topical retinoid Tazarotene (3a – see Figure 2), in which an internal alkyne was replaced, was investigated by Makarov and co-workers more recently. [iv] They found that incorporation of a BCP moiety into 3a caused little change to its non-specific binding (measured by the chromatographic hydrophobicity index on immobilized artificial membranes) and was also found to increase the basicity and melting point of the compound.

The most commonly used intermediate in the synthesis of BCP derivatives is [1.1.1]propellane (5). [v] The initial synthesis of Wiberg and Walker, [vi] which involved treating 1,3-dibromo-BCP with tBuLi, has since been improved upon by several groups. The current, optimized method (used within the groups of Baran [vii] and Anderson, [viii] among others) involves the treatment of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (4) with two equivalents of phenyl lithium. This is then followed by co-distillation of the [1.1.1]propellane product with diethyl ether (see Figure 3a). This enables the production of stock solutions of 5, through large scale (often >100 g) syntheses, which are stable to storage in the fridge for extended periods of time. A method of synthesizing BCP derivatives, not requiring 5 as an intermediate, was published by Applequist and co-workers in 1982. [ix] They observed that dichlorocarbene could add to certain 1,3-disubstituted-bicyclo[1.1.0]butanes to give 1,3-disubstituted-bicyclo[1.1.1]pentanes in moderate yields (see Figure 3b).

For a summary of the reactions discussed below, see Figure 4. An early example of the direct synthesis of 1,3-unsymmetrically substituted BCP derivatives was published by Messner and co-workers in 2000. [x] The addition of a variety of Grignard reagents to 5  (to form organo-magnesium intermediates of the type highlighted by 9) and subsequent quenching, with a variety of electrophiles (including water, allyl bromide, N-chlorosuccinimide, bromine and aryl-nitriles), afforded a variety of 1,3-unsymmetrically substituted BCP derivatives (with general structure 10). This publication also demonstrated the reaction of a variety of organo-iodides with 5, using either methyl lithium or irradiation by a mercury lamp. The resulting iodo-BCP compounds could then be lithiated and further derivatized. A milder procedure to obtain iodo-BCP compounds (of general structure 11) has been developed recently by Caputo et al.8They use a ‘triethylborane initiated atom transfer radical addition ring opening reaction’ of 5. Normally not requiring heating, and using as little as 1 mol% triethylborane, they demonstrate a broad substrate scope and obtain good yields. The resultant iodo-BCP compounds were then further functionalized, in a similar manner to that of Messner et al. Lithium-halogen exchange of the iodide enabled reaction with a variety of electrophiles (aldehydes, ethyl formate or iPrO-Bpin/sodium perborate) as well as transmetalation with zinc and subsequent Negishi coupling. Proto-deiodination could be achieved using triethylborane, as the initiator, with a silane.

An indirect route to 1,3-unsymmetrically substituted BCP derivatives is via the symmetrical opening of 5, followed by subsequent de-symmetrization. An example of this can be seen in a recent publication from Kokhan and co-workers, [xi] in which 5 is reacted with acetylacetone with irradiation from a mercury lamp. This affords 1,3-diacyl-BCP (12) which was then subsequently oxidized to the di-carboxylic acid and bis-esterified. Selective hydrolysis of one ester enabled a Curtius rearrangement to afford a now unsymmetrical BCP derivative possessing both a methyl-ester and boc-amino moiety.

An extremely facile method of generating amino-BCP derivatives (of general structure 13) was developed in the Baran group. [vii] They reacted a ‘turbo-amide’ (generated from turbo-Grignard, iPrMgCl·LiCl, and the corresponding secondary amine) with 5, to generate a wide range of tertiary amines possessing a BCP group. A slightly more circuitous route towards amino-BCP derivatives (of general structure 15), possessing the advantage that it generates 1,3-unsymmetrically substituted amino-BCP derivatives, was recently published by Kanazawa and co-workers. [xii] They demonstrated that the multi-component reaction between 5, di-tert-butyl-diazodicarboxylate and a variety of acyl-hydrazide derivatives could be facilitated using an iron(II) salt, oxidant and base. This afforded BCP-hydrazides (of general structure 14) which could be converted to amino-BCP 15 via deprotection and hydrogenation.

In summary, the bicyclo[1.1.1]pentane (BCP) motif has proven useful as a bioisostere for para-substituted phenyl rings as well as tert-butyl and alkynyl groups. With minimal changes to the size and shape of a range of compounds, their biophysical properties could be improved by incorporation of the BCP moiety. Numerous syntheses of a range of BCP derivatives have been published, many of which proceed via the readily accessible [1.1.1]propellane as an intermediate. A range of orthogonally protected functional groups can be incorporated onto the BCP moiety by a range of different mild or simple methods. These provide reactive handles with which BCP can be incorporated into potential pharmaceuticals in a quick and simple manner.


[i] A. F. Stepan et al, J. Med. Chem. 2012, 55, 3414-3424.

[ii] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756.

[iii] M. V. Westphal, B.T. Wolfstädter, J. Plancher, J. Gatfield, E. M. Carreira, ChemMedChem 2015, 10, 461-469.

[iv] I. S. Makarov, C. E. Brocklehurst, K. Karaghiosoff, G. Koch, P. Knochel, Angew. Chem. Int. Ed. 2017, 56, 12774-12777.

[v] J. Kanazawa, M. Uchlyama, SynLett 2018, 29, A-K.

[vi] K. B. Wiberg, F. H. Walker, J. Am. Chem. Soc. 1982, 104, 5239.

[vii] R. Gianatassio et al, Science, 2016, 351, 241-246.

[viii] D. F. J. Caputo, C. Arroniz, A. B. Dürr, J. J. Mousseau, A. F. Stepan, S. J. Mansfield, E. A. Anderson, Chem. Sci. 2018, 9, 5295-5300.

[ix] D. E. Applequist, T. L. Renken, J. W. Wheeler, J. Org. Chem. 1982, 47, 4985-4995.

[x] M. Messner, S. I. Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 2000, 1137-1155.

[xi] S. O. Kokhan, Y. B. Valter, A. V. Tymtsunik, I. V. Komarov, O. O. Grygorenko, Eur. J. Org. Chem. 2017, 6450-6456.

[xii] J. Kanazawa, K. Maeda, M. Uchiyama, J. Am. Chem. Soc.2017, 139, 17791-17794.