A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion

Abstract

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.

Figure 1. Macrocyclic natural products and overall strategy for the diversity-oriented synthesis of macrolactones and macrolactams

(a) Examples of macrocyclic natural products with diverse chemical structures and biological activities. (b) Overall approach to the diversity-oriented synthesis of functionalized macrocycles using oxidative ring expansion reactions. Polycyclic substrates are prepared using concise, modular reactions that allow for the introduction of chemical diversity both prior to and after ring expansion.

Figure 2. Modular approach to diverse polycyclic substrates for oxidative ring expansion

Average yields en route to 13 and 14 are shown in brackets (cf. Table 2). a) LDA (inverse addition), THF, −78°C, 1 h; AcCl (inverse addition), −78°C, 1 h or Ac₂O, BF₃(AcOH)₂, 4.5 h; NaOAc, MeOH, H₂O, 85 °C, 2.5 h; [85%]. b) LDA, THF, −78 °C, 1 h; TMSCl, −78 °C → rt, 1.5 h; LDA, −78°C, 1 h; TMSCl, −78 °C → rt, 1.5 h; [96%]. c) R¹CHX, Yb(OTf)₃, 4 Å MS, THF, 12 h; TFA, CH₂Cl₂, rt, 20 min; [86%]. d) NaBH₄, CeCl₃, CH₂Cl₂, MeOH, −78°C, 2 h or LiEt₃BH, toluene, −78°C, 40 min; [94%]. e) TBSCl, imidazole, DMF, 50°C; [87%]. LDA = lithium diisopropylamide; MS = molecular sieves; Ns = 2-nitrobenzenesulfonyl; TBS = tert-butyldimethylsilyl; TFA = trifluoroacetic acid; TMS = trimethylsilyl. (See Supplementary Methods for full details).

Figure 3. Functionalization of macrocyclic scaffolds

a) TBSOCH₂CH₂C≡CH, Pd(PPh₃)₄, CuI, Et₃N, DMF, 60°C, 18 h, 81%. b) 4-MeOPhZnCl, Pd(PPh₃)₄, THF, rt, 16 h, 72%. c) Bu₃SnCH=CH₂, Pd₂(dba)₃, AsPh₃, THF, 50°C, 18 h, 81%. d) NaBH₄, CeCl₃, MeOH, CH₂Cl₂, −78°C, 2 h; 27a: 86%, ≥98:2 dr, 27b: 93%, 1:1 dr; 27c: 99%, 90:10 dr; 27d: 55%, ≥98:2 dr; 27e: 73%, 96:4 dr; 27f: 67%, ≥98:2 dr. e) Cp₂TiMe₂, toluene, 65°C, 12 h; 23a: 55%; 23b: 55%; 23c: 50%; 23d: 71%. f) 9-BBN, THF, 0°C→ rt, 12 h, then NaOH, H₂O₂, 0°C→ rt, 1.5 h, 70%, ≥98:2 dr. g) DMDO, CH₂Cl₂, 0°C→ rt, 12 h, 88%, 63:37 dr. h) TBAF, AcOH, THF, rt, 3.5 h, 72%. i) AcCl, pyridine, CH₂Cl₂, 0°C, 10 min, 79%. 9-BBN = 9-bora-bicyclo[3.3.1]nonane; DMDO = dimethyldioxirane; DMF = N,N-dimethylformamide; TBAF = tetrabutylammonium fluoride; TBS = tert-butyldimethylsilyl; THF = tetrahydrofuran.

Figure 4. Cheminformatic analyses of macrocycle library

Principal component analysis (PCA) and principal moment of inertia (PMI) plots of 32 macrocycle library members, 24 macrocyclic natural products, and established reference sets of 40 top-selling brand name drugs, 60 diverse natural products, and 20 ChemBridge and ChemDiv drug-like library members. (a) PCA plot of PC1 vs. PC2 generated from 20 structural and physicochemical parameters. (b) PCA plot of PC3 vs. PC2. (c) PCA plot of PC1 vs. PC3. (d) PMI plot and representative macrocycle library members with lowest energy conformations having characteristic shapes. Structures 15f′, 16c′, 20′, and 26′ are derived from macrocycles 15f, 16c, 20, and 26, respectively, via in silico desilylation (see Supplementary Fig. 2). See Supplementary Figs. 5 and 6 for expanded PCA and PMI plots and Supplementary Datasets 1 and 2 for complete data. See Supplementary Fig. 7 for PMI plots with additional conformers within 3 kcal/mol of the minimum.