Route to three-dimensional fragments using diversity-oriented synthesis

Abstract

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp(2)-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp(3)-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.

Fig. 1.

Building blocks 1, 2, and 3 were synthesized for the preparation of a 3D fragment library.

Fig. 2.

Application of a B/C/P approach starting from proline 1 yielding bicyclic compounds 4–7: (i) 2-chlorosulfonyl chloride, Et₃N, CH₂Cl₂, 46%; (ii) Grubbs II, CH₂Cl₂, reflux, 80%; TFA; (iii) prop-2-ene-1-sulfonyl chloride, Et₃N, CH₂Cl₂, 48%; (iv) Grubbs II, CH₂Cl₂, reflux, 90%; TFA; (v) (S)-N-Boc-allylglycine, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), Oxyma, Et₃N, CH₂Cl₂, 98%; (vi) Grubbs I, CH₂Cl₂, reflux, 87%; TFA; (vii) N-Boc-N-allylglycine, EDCI, Oxyma, Et₃N, CH₂Cl₂, 97%; (viii) Grubbs I, CH₂Cl₂, reflux, 60%; TFA.

Fig. 3.

Application of a B/C/P approach starting from proline 3/3^′ to give compounds 8–14. From 3^′, (i) (S)-allylglycine methyl ester, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), Oxyma, Et₃N, CH₂Cl₂, 89%; NaH, MeI, DMF, 89%; (ii) Grubbs II, CH₂Cl₂, reflux, 34%; TFA; (iii) allylamine, EDCI, Oxyma, Et₃N, CH₂Cl₂, 91%; NaH, MeI, dimethylformamide (DMF), 72%; (iv) Grubbs II, toluene, 60%; TFA. From 3, (v) allyl isocyanate, Et₃N, CH₂Cl₂, 70%; (vi) NaH, DMF, 93%; (vii) 2-chlorosulfonyl chloride, Et₃N, CH₂Cl₂, 62%; (viii) Grubbs II, CH₂Cl₂, reflux, 92%; LiOH, THF, 53%; (ix) prop-2-ene-1-sulfonyl chloride, Et₃N, CH₂Cl₂, 44%; (x) Grubbs II, CH₂Cl₂, reflux, 96%; LiOH, THF, 71%; (xi) LiAlH₄, THF; tert-butyldimethylsilylchloride, Et₃N, CH₂Cl₂ (24% over two steps); 2-chlorosulfonyl chloride, Et₃N, CH₂Cl₂, 33%; (xii) tetrabutylammonium fluoride, THF, 45%; (xiii) (S)-N-Boc-allylglycine, EDCI, Oxyma, Et₃N, CH₂Cl₂, 48%; (xiv) Grubbs II, CH₂Cl₂, reflux, 41%; TFA.

Scheme 1.

Synthesis of spirocyclic enamide 9b and 35b from building block 3^′.

Fig. 4.

Using a B/C/P approach to obtain the full matrix of all possible diastereomeric products.

Fig. 5.

Reducing the olefin groups in a postpairing phase to generate a new set of fragments.

Fig. 6.

Molecular shape analysis. Each corner on the triangular PMI plot indicates compounds with certain shape characteristics. The top left-hand corner of the PMI represents compounds with rod-like features (e.g., acetylene), the top right corner represents compounds with spherical features (e.g., adamantane), and the bottom corner represents compounds with disc-like features (e.g., benzene). (A) PMI plot depicting 35 3D fragments from this study (red) and 18,534 fragments obtained from ZINC database (gray). The darker-blue region represents 75% of the 18,534 fragments. (B) PMI plot depicting 35 3D fragments and 62 best-matched fragments from ZINC (gray), based on heavy atom count similarity. (C) PMI plot depicting 35 3D fragments and 76 of best-matched fragments from ZINC based on physiochemical descriptors.