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Synlett 2009(7): 1144-1148  
DOI: 10.1055/s-0028-1088152
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Zdenko Časar*a, Janez Košmrljb
a Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis, Kolodvorska 27, 1234 Mengeš, Slovenia
Fax: +386(1)7237382; e-Mail: zdenko.casar@sandoz.com;
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
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Publication History

Received 22 December 2008
Publication Date:
20 March 2009 (online)

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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

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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.