A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Abstract

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.

Keywords: diversity-oriented synthesis; macrocycles; molecular diversity; synthesis design; synthetic methods.

Scheme 1

Outline of the multidimensional DOS concept applied to macrocycles. Multiple arrows represent many branching reactions, but only one representative product is shown at each stage.

Scheme 2

The couple phase of the DOS. Reagents and conditions: i) PBu₃ or PPh₃, 4 Å molecular sieves, THF, RT; ii) THF, RT, then quenched with MeOH‐H₂O; iii) CO₂, DIPEA, THF, RT; iv) CO₂, THF, RT; v) Lindlar catalyst, HO(CH₂)₂S(CH₂)₂S(CH₂)₂OH, H₂, MeOH, RT; vi) 40 °C, THF; vii) 8‐azidooctanoic acid, 60 °C, 1.5 h, then isocyanocyclohexane, 60 °C, MeOH; viii) methoxyacetyl chloride, NEt₃, 0 °C then 40 °C, CH₂Cl₂; ix) Danishefsky's diene, Yb(OTf)₃, 40 °C, THF; x) 2‐cyclohexen‐1‐one, Yb(OTf)₃, 40 °C, THF; xi) 3,4‐dihydro‐2H‐pyran, Yb(OTf)₃, 40 °C, THF; xii) TMS‐CN, Yb(OTf)₃, 55 °C, THF. R_F=CH₂COO(CH₂)₂C₈F₁₇. Stereochemistry of 20 detemined by NOESY (see Figure S1; DIPEA=diisopropylethylamine, OTf=triflate, and TMS=trimethylsilyl).

Scheme 3

Representative examples of the macrocyclizations utilized in the pair phase. Regiochemistry of 35 determined by NOESY (see Figure S6).

Scheme 4

Some examples of the divergent transformations used in the modify stage of the DOS. Regiochemistry of 61 determined by NOESY (see Figure S7).

Figure 1

PMI plots of some selected compounds. a) Compounds which differ only in the linking motif installed at the secondary branching point. b) Three different groups of macrocycles (groups 1–3), the members of which differ only in the pairing motif present. Members of each group are linked together by a solid line. c) Three different series of compounds (Series 1–3) whose members differ only in the nature of any post‐pairing modification. d,e) Macrocycles shown in Figure 1 a and b. Macrocycles in Figure 1 c are shown in Scheme 4.