The First Convenient Entry to δ-Formyl-δ-valerolactone Precursor for the Synthesis of Statins via Lactonized Side Chain

Abstract

(4R,6S)-4-(tert-Butyldimethylsilyloxy)-6-formyltetra-hydro-2H-pyran-2-one has been prepared for the first time by oxidation of alcohol (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one. The oxidation of the alcohol was performed with Dess-Martin periodinane in up to 95% yield. Because of limited stability of the aldehyde, it was isolated in the form of hydrate for isolation and storage purposes. The latter can be dehydrated back to the aldehyde quantitatively by simple dissolution in an apolar organic solvent followed by removal of volatiles. The aldehyde was demonstrated to undergo Wittig olefination in high yield. Presented findings set a key platform for statin synthesis via lactonized side chain.

Key words

lactones - aldehydes - oxidations - drugs - statins

References and Notes

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22

Synthesis of (4 R ,6 S )-4-( tert -Butyldimethylsilyloxy)-6-(dihydroxymethyl)tetrahydro-2 H -pyran-2-one (4) A mixture of 2 ^¹5 (500 mg, 1.92 mmol) and DMP (896 mg, 2.11 mmol) in CH₂Cl₂ (50 mL) was stirred at 26 ˚C for 30 min. The mixture was diluted with MTBE (35 mL) and washed with sat. NaHCO₃ (45 mL). The organic phase was separated. The water phase was additionally extracted with MTBE (3 × 25 mL). Combined organic layers were washed with sat. aq Na₂S₂O₃ (2 × 25 mL), sat. NaHCO₃ (2 × 25 mL), H₂O (70 mL), dried (MgSO₄), and concentrated under reduced pressure to give pure hydrate 4 (498 mg, 94%) as a white crystalline powder; mp 73-75 ˚C. ^¹H NMR (300 MHz, THF-d ₈): δ = 0.10 (s, 6 H, CH₃Si), 0.91 (s, 9 H, CH₃C), 1.80-2.00 (m, 2 H, H-5), 2.39 (dd, J = 17.1, 3.9 Hz, 1 H, H-3), 2.58 (dd, J = 17.1, 4.2 Hz, 1 H, H-3), 4.35-4.45 (m, 2 H, H-4, H-6), 4.83-4.91 [m, 1 H, CH(OH)], 5.14 (d, J = 6.0 Hz, 1 H, OH), 5.22 (d, J = 6.0 Hz, 1 H, OH). ^¹³C NMR (75 MHz, THF-d ₈): δ = -4.79 (CH₃Si), -4.74 (CH₃Si), 18.7 (CCH₃), 26.2 (CH₃C), 31.0 (C-5), 40.4 (C-3), 65.1 (C-4), 79.1 (C-6), 91.7 [CH(OH)], 168.8 (C-2). IR (KBr): ν = 1697 cm^-¹. MS (ES⁺): m/z (%) = 851.6 (10) [3 M + Na]⁺, 575.4 (58) [2 M + Na]⁺, 570.4 (13) [2 M + NH₄]⁺, 299.2 (35) [M + Na]⁺, 294.2 (100) [M + NH₄]⁺, 277.2 (88) [M + 1]⁺, 259.2 (73), 145.1 (8). Anal. Calcd (%) for C₁₂H₂₄O₅Si: C, 52.14; H, 8.75. Found: C, 52.45; H, 9.18.

25

(4 R ,6 S )-4-( tert -Butyldimethylsilyloxy)-6,7-dihydroxy-oxepan-2-one (5) Hydrate 4 (50 mg, 0.18 mmol) was dissolved in MeOH (2 mL) and left to stand at r.t. for 2.5 d. The solvent was evaporated to dryness to give 5 (50 mg, 100%) as a colorless solid. ^¹H NMR (300 MHz, CD₃OD): δ = 0.14 (s, 6 H, CH₃Si), 0.94 (s, 9 H, CH₃C), 1.87-2.06 (m, 2 H, H-5), 2.52 (ddd, J = 17.5, 2.9, 2.0 Hz, 1 H, H-3), 2.72 (dd, J = 17.5, 3.8 Hz, 1 H, H-3), 4.42-4.52 (m, 1 H, H-4), 4.56-4.70 (m, 2 H, H-6, H-7). ^¹³C NMR (75 MHz, CD₃OD): δ = -4.82 (CH₃Si), -4.76 (CH₃Si), 18.9 (CH₃C), 26.2 (CH₃C), 30.7 (C-5), 31.0 (C-5), 40.5 (C-3), 64.9 (C-4), 79.0, 79.5, 98.6, 98.8, 172.58 (C-2), 172.60 (C-2). Two sets of ^¹³C resonances are observed in the intensity ratio of 1:1. HRMS (ES⁺): m/z calcd for C₁₂H₂₄O₅SiNa⁺ [M + Na]⁺: 299.1291; found: 299.1299. Anal. Calcd (%) for C₁₂H₂₄O₅Si: C, 52.14; H, 8.75. Found: C, 52.35; H, 8.97.

26

(4 R ,6 S )-4-( tert -Butyldimethylsilyloxy)-6-formyltetra-hydro-2 H -pyran-2-one (1) A solution of hydrate 4 (500 mg, 1.81 mmol) in CH₂Cl₂ (30 mL) was left to stand for 1 d. The solvent was evaporated to afford quantitatively aldehyde 1 as a colorless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 0.11 (s, 6 H, CH₃Si), 0.90 (s, 9 H, CH₃C), 1.80-1.91 (m, 1 H, H-5), 2.13 (ddd, J = 14.0, 4.2, 4.2 Hz, 1 H, H-5), 2.55-2.70 (m, 2 H, H-3), 4.37 (m, 1 H, H-4), 5.07 (dd, J = 11.3, 3.9 Hz, 1 H, H-6), 9.83 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = -4.9 (CH₃Si), 17.9 (CCH₃), 25.6 (CH₃C), 31.4, 39.6, 63.0, 79.2, 167.9 (C-2), 199.3 (CHO). IR (NaCl): ν = 1739, 1697 cm^-¹. [α]_D ^²0 -12.2 (c 1, CHCl₃). MS (ES⁺): m/z (%) = 517.3 (20) [2 M + H]⁺, 259.1 (100) [M + 1]⁺, 246.1 (11), 233.1 (15), 221.1 (31), 205.1 (34), 183.1 (9), 169.1 (16), 153.1 (14), 129.1 (33), 127.0(27). HRMS (TOFMS⁺): m/z calcd for C₁₂H₂₂O₄Si⁺ [M + H]⁺: 259.1366; found: 259.1366.

27

β-Substituted δ-lactone ring is unstable and readily undergoes elimination to unsaturated compounds. For example, see ref. 13, 18.

29

(4 R ,6 S )-4-( tert -Butyldimethylsilyloxy)-6-styryltetra-hydro-2 H -pyran-2-one (7) Benzyltriphenylphosphonium bromide (0.130 g, 3.00 mmol) was dissolved in dry toluene (70 mL) and NaHDMS (5.25 mL, 3.15 mmol, 0.6 M in toluene) was added at r.t. The reaction mixture was stirred at r.t. for 2.25 h to give ylide 6. Then the solution of ylide 6 was warmed up to 65 ˚C within 10 min. At this temperature a solution of pre-dried aldehyde 1 (853 mg, 3.30 mmol) in toluene (25 mL), prepared from hydrate 4 (913 mg, 3.30 mmol) and toluene, was added. The resulting reaction mixture was stirred at 65 ˚C for 5 min quenched with EtOH and allowed to cool down to r.t. The solvent was evaporated, and the residue was subjected to flash chromatography with ARMEN INSTRUMENT Spot^® apparatus on SiO₂ [gradient elution; EtOAc-hexane (3:97) over 10 min; from 3:97 to 5:95 over 15 min, from 5:95 to 15:85 over 10 min, and from 15:85 to 100:0 over 5 min; flow rate 60 mL/min] to obtain a mixture of (E)-7/(Z)-7 in the ratio of 63:37 (740 mg, 74%). For analysis, the isomers were separated by the second flash chromatography under the same conditions as described above.
Data for Compound ( E )-7 White solid; mp 57.5 ˚C (DSC onset). ^¹H NMR (400 MHz, CDCl₃): δ = 0.00 (s, 6 H, CH₃Si), 0.81 (s, 9 H, CH₃C), 1.73-1.82 (m, 1 H), 1.87-1.95 (m, 1 H), 2.48-2.61 (m, 2 H), 4.22-4.29 (m, 1 H), 5.21-5.28 (m, 1 H), 6.12 (dd, J = 6.4, 15.9 Hz, 1 H), 6.59 (d, J = 15.9 Hz, 1 H, CHPh), 7.14-7.32 (m, 5 H, Ph). ^¹³C NMR (100 MHz, CDCl₃): δ = -5.0 (CH₃Si), -4.9 (CH₃Si), 17.9, 25.6, 36.9, 39.3, 63.4, 76.1, 126.6, 126.8, 128.1, 128.6, 132.0, 135.9, 169.8. IR (NaCl): ν = 2927, 1727, 1348, 1233, 1165, 1090, 1072, 693 cm^-¹. HRMS (CI⁺): m/z calcd for C₁₅H₁₉O₃Si⁺ [M - C₄H₉]⁺: 275.1104; found: 275.1110.
Data for Compound ( Z )-7
White solid; mp 65.8 ˚C (DSC onset). ^¹H NMR (400 MHz, CDCl₃): δ = 0.05 (s, 6 H, CH₃Si), 0.81 (s, 9 H, CH₃C), 1.80-2.00 (m, 2 H), 2.52-2.69 (m, 2 H), 4.29-4.35 (m, 1 H), 5.64-5.76 (m, 2 H), 6.67 (d, J = 10.5 Hz, 1 H, CHPh), 7.22-7.36 (m, 5 H, Ph). ^¹³C NMR (100 MHz, CDCl₃): δ = -5.1 (CH₃Si), -5.0 (CH₃Si), 17.8, 25.5, 36.6, 39.2, 63.6, 72.4, 127.6, 128.4, 128.5, 129.0, 133.0, 135.7, 169.8. IR (NaCl): ν = 2927, 1737, 1359, 1239, 1160, 1084, 1065, 697 cm^-¹. HRMS (CI⁺): m/z calcd for C₁₅H₁₉O₃Si⁺ [M - C₄H₉]⁺: 275.1104; found: 275.1110.