Straightforward and Efficient Synthesis of (4R,6S)-4-(tert-Butyldimethyl­siloxy)-6-(hydroxymethyl)tetrahydropyran-2-one

Abstract

A novel synthetic approach to (4R,6S)-4-(tert-butyldi­methylsiloxy)-6-(hydroxymethyl)tetrahydropyran-2-one, a key precursor of statin side chain, is described. A prime feature of the presented strategy is the transformation of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(iodomethyl)tetrahydropyran-2-one to an acetate ester derivative and subsequent cleavage of an acetate protection by applying homogeneous tin catalysis. Iodolactone used in the study is accessible by a new route in five steps from (S)-ethyl 4-chloro-3-hydroxybutanoate. This method overcomes many of the drawbacks associated with previously reported approaches. It gives the title compound in 21% over seven steps, which is the highest attained overall yield yet. The disclosed approach was realized in convenient and economical manner suitable for industrial use.

drugs - lactones - stereoselective synthesis - homogeneous catalysis - tin

References and Notes

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Data for ( R )-4-( tert -Butyldimethylsiloxy)-6-methylene-tetrahydro-2 H -pyran-2-one (10)
IR (KBr): 2956, 2930, 2897, 2857, 1760, 1663, 1210, 1130, 1089 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 4.75 (s, 1 H), 4.33 (s, 1 H), 4.21 (m, 1 H), 2.78-2.52 (m, 4 H), 0.87 (s, 9 H), 0.08, 0.08 (2 s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 152.2, 95.6, 62.7, 39.5, 35.6, 25.5, 17.7, -5.0. HRMS (EI): m/z calcd for C₁₂H₂₃O₃Si [M + H]⁺: 243.1416; found: 243.1414. [α]_D ^²0 -3.0 (c 1, CHCl₃).

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Procedure for the Preparation of [(2 S ,4 R )-4-( tert -Butyldimethylsiloxy)-6-oxotetrahydro-2 H -pyran-2-yl]methyl Acetate (11)
To the solution of (4R,6S)-4-(tert-butyldimethylsiloxy)-6-(iodomethyl)-tetrahydropyran-2-one (2, 40.00 g, 108.0 mmol) in AcOH (660 mL) was added AgOAc (20.03 g, 118.8 mmol). The resultant mixture was then heated at 120-125 ˚C for 6 h. The reaction mixture was filtered through diatomite filter medium (Celite^®). The obtained filtrate was evaporated to afford the residue. To this residue EtOAc (500 mL) and H₂O (600 mL) were added. The organic layer was separated and the aqueous layer was washed again with EtOAc (5 × 150 mL). The combined organic layers were washed with H₂O (4 × 300 mL), brine (5 × 300 mL) and dried over anhyd MgSO₄, filtered, and concentrated under reduced pressure to afford 30.28 g (92.6%) of [(2S,4R)-4-(tert-butyldimethylsiloxy)-6-oxotetrahydro-2H-pyran-2-yl]methyl acetate (11) as a pale yellow oil (HPLC purity 98%). IR (liquid film): 2955, 2930, 2897, 2857, 1742, 1226, 1089 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 4.93 (m, 1 H), 4.37 (m, 1 H), 4.30 (dd, J = 12, 3 Hz, 1 H), 4.21 (dd, J = 12, 5 Hz, 1 H), 2.62 (d, J = 4 Hz, 2 H), 2.11 (s, 3 H), 1.84-1.80 (m, 2 H), 0.89 (s, 9 H), 0.09, 0.09 (2 s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 170.4, 169.1, 73.3, 65.5, 63.0, 38.9, 32.2, 20.5, 17.7, -5.1, -5.2. HRMS (EI): m/z calcd for C₁₄H₂₇O₅Si [M + H]⁺: 303.1628; found: 303.1629. [α]_D ^²0 +11.0 (c 1, CHCl₃).

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