A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings

Abstract

The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. Since natural products are the most valuable source for the discovery of therapeutics, the derivatization of natural products has been extensively investigated to generate molecules for biological screenings. However, most previous approaches only modified a limited number of functional groups, which resulted in a limited number of skeleta. Here we show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry - the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings. This library occupies a unique chemical space compared to selected diverse reference compounds. The diversification strategy developed herein for steroids can also be expanded to other types of natural products.

Fig. 1

Two Phases of Diversification. Starting from a polycyclic scaffold, we are able to oxidize then functionalize various natural products to produce modified scaffolds

Fig. 2

Ring expansion of polycyclic natural products based on native C–O bonds. a A-ring expansion of dehydroepiandrosterone and cholesterol. b D-ring expansion of isosteviol. c D-ring expansion of estrone. d D-ring expansion of dehydroepiandrosterone. (i) (a) TPAP, NMO, 4 Å MS, CH₂Cl₂, (b) LDA, THF, then CNCO₂Et, −78 °C; (ii) (a) NaH, HMPA, THF, rt, then 1-Chloro-3-iodopropane, rt, (b) NaN₃, DMF, 80 °C, (c) CF₃COOH, rt; (iii) NaBH₄, MeOH, −78 °C; (iv) NaH, toluene, then DMAD, rt; (v) HCl, AcOH, 120 °C; (vi) (a) Me₂SO₄, LiOH, THF, 65 °C, (b) Ethyl diazoacetate, BF₃•Et₂O, Et₂O/CH₂Cl₂, rt; (vii) (a) LiCl, DMSO, H₂O, 120 °C, (b) NH₂OH•HCl, KOAc, 70 °C, (c) TsCl, DMAP, Py, 60 °C; (viii) Dibal-H, CH₂Cl₂, −78 °C; (ix) (a) NaOH, Me₂SO₄, acetone, 60 °C, (b) LDA, THF, −78 °C, then CNCO₂Et; (x) (a) MgCl₂, Py, NHCbz(CH)₂COCl, CH₂Cl₂, (b) Pd/C, H₂, EtOAc, rt; (xi) (a) TBSCl, imidazole, CH₂Cl₂, rt, (b) LDA, THF, then CNCO₂Et, −78 °C; (xii) 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate, CsF, MeCN, 80 °C, 18:1 d.r.; (xiii) TBAF, THF, rt; (xiv) (a) NaH, THF, methyl phenylpropiolate, 65 °C, (b) TsOH, THF, rt. Full details are in the Supplementary Figures 5–7

Fig. 3

Diversification of polycyclic natural products by sequential C–H oxidation and ring expansion. a Electrochemical C–H oxidation/B-ring expansion of DHEA, cholesterol and Diosgenin. b Electrochemical C–H oxidation/A-ring expansion of isosteviol. c Copper-mediated C–H oxidation/C-ring expansion of DHEA and estrone. d Benzylic C–H oxidation/C-ring expansion of estrone. (i) TBSCl, imidazole, CH₂Cl₂, rt; (ii) LiClO₄, Py, t-BuOOH, Cl₄NHPI, acetone, rt; (iii) (a) Pd/C, H₂, EtOAc, rt, (b) NH₂O•HCl, KOAc, 70 °C, (c) TsCl, DMAP, Py, 60 °C; (d) TsOH, THF/H₂O or Pd/C, MeOH, rt; (iv) (a) Pb(OAc)₄, Cu(OAc)₂, Py, toluene, 90 °C, (b) I₂, toluene, 120 °C (c) glycol, toluene, TsOH, 120 °C; (v) (a) PtO₂, H₂, rt, (b) NaOMe, MeOH, rt, (c) NH₂OH•HCl, KOAc, 70 °C, (d) TsCl, DMAP, Py, 60 °C; (vi) (a) Me₂SO₄, K₂CO₃, acetone, (b) TsOH, toluene, (4-methylpyridin-2-yl)methanamine, 120 °C, (c) [Cu(MeCN)₄PF₆], O₂, (+)-sodium-(L)-ascorbate, acetone/MeOH, 50 °C, 6 h, then, Na₄EDTA, rt; (vii) glycol, toluene, TsOH, 120 °C; (viii) (a) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 °C (b) NH₂OH•HCl, KOAc, 70 °C, (c) TsCl, DMAP, Py, 60 °C, (d) TsOH, THF/H₂O, rt, for 27c, 60 °C, 5 days; (ix) (a) TsOH, toluene, (4-methylpyridin-2-yl)methanamine, 120 °C, (b) [Cu(MeCN)₄PF₆], O₂, (+)-sodium-(L)-ascorbate, acetone/MeOH, 50 °C, 6 h, then, Na₄EDTA, rt; (x) (a) glycol, toluene, TsOH, 120 °C, (b) TBSCl, imidazole, CH₂Cl₂, rt; (xi) Cr(CO)₆, tBuOOH, MeCN, 70 °C; (xii) (a) K^tOBu, LDA, (MeO)₃B, THF, (b) H₂O₂, NaOH, (c) (COCl)₂, DMSO, Et₃N, CH₂Cl₂; (xiii) (a) NH₂OH•HCl, KOAc, EtOH, (b) TsCl, DMAP, Py, (c) CF₃COOH. Full details are in the Supplementary Figures 8–11

Fig. 4

Application of the two-phase C–H oxidation/ring expansion strategy to picfeltarraegenin and kirenol. a Electrochemical allylic C–H oxidation/ring expansion of picfeltarraegenin. b Allylic C–H oxidation/ring expansion of kirenol. (i) MOMCl, DIPEA, DMAP, CH₂Cl₂, rt; (ii) (a) NaBH₄, EtOH, rt, (b) MOMCl, DIPEA, DMAP, CH₂Cl₂, 50 °C; (iii) LiClO₄, Py, t-BuOOH, Cl₄NHPI, acetone, rt. (iv) Pd/C, H₂, MeOH, rt; (v) NH₂OH•HCl, KOAc, (c) TsCl, DMAP, Py, 60 °C; (vi) (a) CDI, toluene, 90 °C, (b) MOMCl, DIPEA, DMAP, CH₂Cl₂, rt; (vii) (a) SeO₂, dioxane, (b) (COCl)₂, DMSO, Et₃N, CH₂Cl₂; (viii) (a) Pd/C, H₂, EtOAc, (b) NH₂OH•HCl, KOAc, 70 °C, (c) TsCl, DMAP, Py, 60 °C. Full details are in Supplementary Figure 12

Fig. 5

Further diversication of medium-sized ring scaffolds. a Formation of carbamates. b Formation of azide. c. Formation of imide 47. d Formation of imide 48. e Ring-cleavage of medium ring scaffold. A total of 150 polycyclic final products, most of which have >90% purity (LC-MS, ultraviole detector at 254 or 210 nm) and >10 mg quantities, were prepared. (i) (a) CDI, Et₃N, CH₂Cl₂, rt, (b) R¹R²NH, DMAP, toluene, 90 °C; (ii) NaH, HMPA, THF, then RI, rt; (iii) R¹R²NH, toluene/CH₂Cl₂, rt, then 90 °C; (iv) (a) 5 M NaOH, THF, 60 °C, then NaBH₄, rt, then HCl, (b) RNH₂, toluene, rt, then 90 °C, (c) Dess-Martin oxidant, NaHCO₃, CH₂Cl₂; (v) (a) NaOH, EtOH/H₂O, 100 °C, (b) DMSO, HCl, 120 °C; (vi) (a) NaN₃, DMF, 80 °C, (b) Sodium ascorbate, CuSO₅•H₂O, HCCR, THF/H₂O, rt, (c) TsOH, THF/H₂O, rt; (vii) DPPA, Et₃N, R²NH₂, DMF, rt. Full details are in the Supplementary Figures 13–16

Fig. 6

Cheminformatic analyses of polycyclic compounds with a medium-sized ring library. PCA and PMI plots of 30 medium-membered ring library (Med Lib) members, established reference sets of 40 brand-name drugs (without including the top-selling steroid drugs), 25 steroid drugs, 25 diverse steroids and terpenoid natural products and 25 diverse medium-membered ring natural products. The hypothetical average structure for each series (−AVG) is also shown. a PCA plot of PC1 versus PC2. b PCA plot of PC1 versus PC3. c PCA plot of PC2 versus PC3. The first three principal components account for 72% of the variance in the complete dataset, with individual contributions of 29.6%, 27.9%, and 14.4%, respectively. More than 90% of the variance in the complete 20-dimensional dataset is accounted for by the first six principal components (PC1–PC6). d PMI plot showing the three-dimensional shape of the lowest-energy conformations of each compound. Expanded PCA and PMI plots are in Supplementary Figures 4, and complete data are in Source Data