Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions

A synthesis of anthracycline aglycone derivatives is described. The key step utilizes a powerful domino carbopalladation approach and subsequent ring closure. During this process two of the four rings of the anthracycline scaffold are formed. Differently substituted carbohydrates and dialkyne chains serve as versatile and simple starting materials for the reaction sequence. Diverse building blocks lead to a variety of different products and a broad range of structural diversity.

S3 splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; s br , broad singlet; m, multiplet and as combination of that kind. Undefined assignments of hydrogen and carbon atoms are marked by * sign.
Mass spectra: ESIMS and HRMS-ESI mass spectrometry was carried out on a FTICR instrument by Finnigan LCQ and on an APEX IV 7T FTICR by Bruker Daltonic. EIMS and HRMS-EI mass spectrometry was performed on an EI-TOF (Accu TOF) by Jeol and a sector instrument (MAT 95) by Finnigan. IR (ATR) and UV Spectra: IR (ATR) spectra were measured on a conventional ATR spectrometer (FT/IR-4100) by JASCO. UV spectra were measured with a common photometer (V630) by JASCO in acetonitrile or methanol as solvent.
Optical rotation values were measured at 20 °C using a polarimeter by Perkin-Elmer 241 in respective suitable solvents (e.g. chloroform, methanol and dimethyl sulfoxide).
X-ray analysis: For the X-ray crystal structures a single crystal was mounted in an inert oil.
The data was collected from cooled crystals at 100 K on a Bruker Smart ApexII with Incoatec micro focus source using monochromatic MoK  radiation,  = 0.71073 Å. Data reduction was done with SAINT, 1 and an empirical absorption correction with SADABS 2 or TWINABS 3 was applied. The structure was solved by direct methods   4 and refined by full-matrix least-squares methods against F 2 (SHELXL-97). 5 All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were refined isotropically on calculated positions using a riding model with their U iso values constrained to 1.5 times the U eq of their pivot atoms for terminal sp 3 carbon atoms and 1.2 times for all other carbon atoms. 4. Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, 64, 112-122. 5. Flack, H. D. Acta Crystallogr. Sect. A 1983

General procedures
Common aqueous workup: The reaction was stopped by addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution, dried over Na 2 SO 4 and the solvent was removed by rotary evaporation.

GP1: Appel reaction
The alcohol (1.0 equiv), triphenylphosphine (1.5-2.0 equiv) and imidazole (1.5-2.0 equiv) were dissolved in a mixture of Et 2 O and MeCN and cooled to 0 °C. Iodine (1.5-2.0 equiv) was added portionwise over a period of 45 min and the reaction was allowed to stir for further 15 min (monitored by TLC). After completion of the reaction, the mixture was poured into pentane and was immediately purified by silica gel column chromatography (pentane) to afford the desired product.

GP2: Silylacetylene coupling
To a solution of silylacetylene (2.0-3.0 equiv) in THF was added ethyl magnesium bromide (3.0 mol/L in Et 2 O) at room temperature. The solution was heated to reflux for 2 h and then cooled to ambient temperature. CuCl (25-40 mol %) and the corresponding iodide (1.0 equiv), dissolved in THF, were successively added to the reaction mixture and heated to 75 °C for 16 h. The reaction was stopped by addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography to afford the desired product.

GP3: TBS-cleavage
The protected alcohol (1.0 equiv) was dissolved in MeOH at 0 °C and AcCl was added dropwise. The reaction mixture was stirred for 3 h and then stopped by slow addition of NaHCO 3 solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography to afford the desired product.

GP4: Silyl ether formation
Dialkyne (1.0-1.2 equiv) was dissolved in dry CCl 4 and cooled to 0 °C. A freshly prepared solution of bromine in dry CCl 4 (0.976 mol/L, 1.0-1.2 equiv) was added over a period of 1 h S5 via syringe pump and stirred for further 2 h at 0 °C. To a solution of glycal (1.0 equiv), NEt 3 (2.0 equiv) and DMAP (10 mol %) in dry CCl 4 and dry Et 2 O was added the solution of the alkyne at 0 °C over a period of 30 min via syringe pump. The reaction was stirred for at least 2 h and stopped by the addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography to afford the desired product.

GP5: Domino reaction
The alkynylated bromoglycal (1.0 equiv) was dissolved in a mixture of DMF/MeCN/NMP (8:8:1). Pd(PPh 3 ) 4 (10 mol %), t-Bu 3 PH⋅BF 4 (20 mol %) and diisopropylamine (5.0 equiv) were added. The reaction was stirred in a microwave reactor for 3-5 h at 120 °C. The absorption level was set as very high and the prestirring time at 10 s. The reaction was stopped by the addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution, dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography to afford the desired product.

Compound 12a
To a solution of 26a (20 mg, 0.049 mmol, 1.0 equiv) in THF (0.1 mL) was added TBAF  The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed three times with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was

Compound 23b
To a solution of dimethylphenylsilylacetylene (3.32 g, 20.7 mmol, 1.5 equiv) in THF (120 mL) was added ethyl magnesium bromide (3.0 mol/L in diethyl ether, 6.90 mL, 20.7 mmol, 1.5 equiv) at room temperature. The solution was heated to reflux for 2 h and then cooled to ambient temperature. CuCl (342 mg, 3.45 mmol, 25 mol %) and 20 (5.00 g, 13.8 mmol, 1.0 equiv) were added to the reaction mixture and heated to 75 °C for 16 h. The reaction was stopped by addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation.

Compound 23c
The crude product 22c was dissolved in MeOH (8 mL) at 0 °C and AcCl (0.8 mL) was added dropwise. The reaction mixture was stirred for 3 h and then stopped by slow addition of saturated aq. NaHCO 3 solution. The aqueous layer was extracted three times with EtOAc.
The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography (pentane/EtOAc = 7:1) to afford 224 mg (62% over two steps) of compound 23c as a colorless oil: R f : 0.08 (hexane/EtOAc = 8:1

Compound 23d
The protected alcohol 22d (
The reaction was stirred for 2 h and stopped by the addition of saturated aq. NH 4 Cl solution.
The aqueous layer was extracted three times with CH 2 Cl 2 . The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography (pentane/EtOAc = 60:1) to afford 285 mg (56%) of compound 14e as a yellow oil:

Compound 28b
Compound 12b (29 mg, 0.099 mmol, 1.0 equiv), TBSCl (224 mg, 1.48 mmol, 15.0 equiv), imidazole (303 mg, 4.45 mmol, 45.0 equiv) and DMAP (19 mg, 0.148 mmol, 1.0 equiv) were dissolved in DMF (8.0 mL). The reaction mixture was heated in a sealed vial at 90 °C for 68 h. TLC still showed no complete conversion. The mixture of products was purified and the crude product was again set to reaction according the described procedure for 18 h. The reaction was stopped by the addition of saturated aq. NH 4 Cl solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed three times with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography (pentane/EtOAc = 100:1) to afford 18 mg (30%) of compound 27b as a colorless oil.

Compound 11b
To a solution of 28b (8 mg, 0.012 mmol, 1.0 equiv) in MeOH (1.0 mL) and water (0.1 mL) was added HCl (0.3 mol/L, 0.4 mL). The mixture was stirred for 17 h at 75 °C and stopped by the addition of saturated aq. NaHCO 3 solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aq. NaCl solution and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation and the residue was filtered over a small plug of celite (CH 2 Cl 2 : 20 mL and CH 2 Cl 2 /MeOH = 5:1: 250 mL). The product-containing fractions were collected, the solvent was removed by rotary evaporation and the residue was washed with water (50 mL). 3.5 mg (90%) of compound 11b were obtained as a yellow solid: R f : 0.16 (CH 2 Cl 2 /MeOH = 10:1). = -10.0° (c = 0.30, DMSO).