Biocatalytic Conversion of Cyclic Ketones Bearing α‐Quaternary Stereocenters into Lactones in an Enantioselective Radical Approach to Medium‐Sized Carbocycles

Abstract Cyclic ketones bearing α‐quaternary stereocenters underwent efficient kinetic resolution using cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus. Lactones possessing tetrasubstituted stereocenters were obtained with high enantioselectivity (up to >99 % ee) and complete chemoselectivity. Preparative‐scale biotransformations were exploited in conjunction with a SmI2‐mediated cyclization process to access complex, enantiomerically enriched cycloheptan‐ and cycloctan‐1,4‐diols. In a parallel approach to structurally distinct products, enantiomerically enriched ketones from the resolution with an α‐quaternary stereocenter were used in a SmI2‐mediated cyclization process to give cyclobutanol products (up to >99 % ee).


General Information
Experiments (excluding biotransformations) were performed under an atmosphere of nitrogen using anhydrous solvents, unless otherwise stated. THF and CH 2 Cl 2 were freshly distilled before use. THF was distilled over sodium wire and benzophenone; CH 2 Cl 2 was distilled over calcium hydride. All other solvents and reagents used were purchased from commercial suppliers and used according to relevant guidelines. The gene of Cyclohexanone Monooxygenase from Acinetobacter Calcoaceticus was supplied by GeneArt. 1 H-NMR spectra were obtained at room temperature on a Bruker 400 or 500 MHz spectrometer. 13 C-NMR were obtained at 101 or 126 MHz respectively. 19 F-NMR were obtained at 376 MHz. All NMR spectra were processed using Mestrenova© NMR software. Chemical shifts are reported in parts per million (ppm), relative to residual chloroform (δH = 7.27 and δC = 77.0) as internal standards, and coupling constants (J) are reported in Hz. Splitting patterns are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), double of doublets (dd), doublet of triplets (dt), doublet of quartets (dq), doublet of doublets of doublets (ddd), doublet of doublets of triplets (ddt) and multiplet (m).
Column chromatography was carried out using 35 -70 m, 60Å silica gel. TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness and visualised using potassium permanganate solution and/or UV light at 254 nm.
The solution was concentrated under vacuum and extracted with EtOAc (3 x 20 mL), washed with brine (15 mL), dried (MgSO 4 ) and concentrated. The crude reaction mixture was used in the next step without further purification.

General procedure D: CHMO-Catalysed Biotransformations
For a detailed description of the procedure for analytical scale biotransformations, see the preparation of 2a. For a detailed description of the procedure for preparative scale biotransformations, see the preparation of 2i.

rac-2b
(R)-2b S19 The remaining starting material from the reaction could be isolated and was obtained as a pale yellow oil (18 mg, 0.079 mmol, 39%). Enantiomeric purity of (S)-1b was determined by HPLC analysis

Additional Unreactive Substrates
Seven-membered ketones S6 and S7 were prepared from literature procedures [12] and were exposed to the biotransformation conditions described in general procedure D. The crude reaction mixture was analysed by 1 H NMR, which indicated that no starting material had been converted to the desired products.

S42
The major diastereomer could be isolated and was obtained as a pale yellow oil. 1