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Synlett 2008(10): 1523-1525  
DOI: 10.1055/s-2008-1078428
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of (3R,5S)-3,5,6-Trihydroxyhexanoic Acid Derivative as a Chiral Side Chain of Statins

Hyeong-wook Choi, Hyunik Shin*
Chemical Development Division, LG Life Sciences, Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Fax: +82(42)8665754; e-Mail: hisin@lgls.com;
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Publication History

Received 19 March 2008
Publication Date:
16 May 2008 (online)

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Abstract

Efficient synthesis of tert-butyl [(3R,5S)-6-hydroxy­methyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate (1) has been accomplished. Unprecedented hydration of 3 in the presence of lithium chloride provided 4a,b, the primary hydroxyl group of which reacted with pivaloyl- and 1-naphthoyl chloride, respectively, in pyridine to give 7a or 7d in improved selectivity. Diastereoselective reduction of 7a and protection-deprotection sequence provided 1.

Key words

statins - chiral side chain - 3,5,6-trihydroxy heptanoic acid - selective protection - hydration

    References and Notes

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17

Preparation of 4a,b
A solution of 2 (1.6 g, 6.8 mmol) in THF (30 mL) was treated with DBU (1.3 mL, 8.6 mmol) at ambient temperature. After 20 h, the reaction mixture was quenched with 0.5 N HCl (30 mL). The organic phase was separated and the aqueous phase was re-extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with aq NaHCO3 solution, dried with MgSO4, and concentrated in vacuo. The crude 3 was dissolved in 9:1 mixture of H2O and THF (40 mL), and treated with LiCl (1.8 g, 42.6 mmol) and PTSA (81 mg, 0.42 mmol). The mixture was stirred for 20 h at ambient temperature and quenched by solid NaHCO3 (71 mg, 0.85 mmol). The organic phase was separated and the aqueous phase was re-extracted with EtOAc (5 × 10 mL). The combined organic layer was dried with MgSO4 and concentrated. Column chromatography provided a mixture of 4a and 4b (1.28 g, 86% over two steps).

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Preparation of 7a and 7d
A cooled (ca. 0 °C) solution of 4a,b (10 mmol) in pyridine (5 mL) was treated with protecting agent (10-11 mmol). The resulting solution was stirred at the same temperature for 1 h and diluted with EtOAc (20 mL). The organic phase was washed twice with 1 N H2SO4 (2 × 30 mL). The separated organic layer was dried over MgSO4, and concentrated. Column chromatography (EtOAc-hexane = 1:20 to 1:3) of the residue provided 7a and 7d in 85% yield, respectively.
Spectroscopic Data of 7a
1H NMR (300 MHz, CDCl3): δ = 4.34 (m, 1 H), 4.09-4.24 (m, 2 H), 3.42 (s, 2 H), 2.96 (d, 1 H), 2.76 (d, J = 5.55 Hz, 2 H), 1.48 (s, 9 H), 1.23 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 196.9, 172.9, 160.9, 76.4, 61.8, 60.2, 45.6, 40.7, 33.3, 22.5, 21.7. ESI-MS: m/z = 320 [M + NH4].
Spectroscopic Data of 7d
1H NMR (300 MHz, CDCl3): δ = 7.33-8.90 (m, 7 H), 4.49 (m, 1 H), 4.35-4.39 (m, 2 H), 3.36 (s, 2 H), 2.71-2.87 (m, 2 H), 1.38 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 197.4, 162.0, 161.1, 128.5, 128.3, 126.1, 125.2, 123.3, 122.6, 121.4, 121.0, 120.5, 119.2, 76.9, 62.6, 60.6, 45.8, 40.9, 22.6. ESI-MS: m/z = 395 [M + Na].

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(3 R ,5 S )-{2,2-Dimethyl-6-trimethylacetoxymethyl-[1,3]dioxan-4-yl}-acetic Acid tert -Butyl Ester (1) Compound 7a (2.7 g, 9 mmol) was dissolved in a 5:1 mixture of THF and MeOH (18 mL), cooled to -78 °C and treated with Et2BOMe (10 mL, 10 mmol, 1 M in THF). After stirring for 30 min, the resulting solution was treated with NaBH4 (380 mg, 10 mmol) and stirred at -78 °C for 5 h. The reaction was quenched with AcOH (5 mL) and solvent was evaporated in vacuo. The residue was dissolved in methanolic AcOH soln (50 mL, 3% v/v) and evaporated again. The resulting mixture was dissolved in EtOAc (20 mL), and washd twice with a sat. NaHCO3 solution. The organic phases were dried over anhyd MgSO4 and concentrated. Column chromatography (EtOAc-hexane = 1:10 to 1:2) of the residue gave diol compound (2.3 g, 85%), 1.3 g (4.3 mmol) of which was dissolved in acetone (5 mL) and treated with 2,2-dimethoxypropane (667 mg, 6.4 mmol) and PTSA (4 mg, 0.02 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with Et3N. The reaction mixture was evaporated in vacuo, and diluted with hexane (10 mL). The organic phase was washed with a sat. NaHCO3 solution (2 × 10 mL). The organic phases were dried over anhyd MgSO4 and concentrated. Column chromatography (EtOAc-hexane = 1:20 to 1:3) of the residue gave 8 (1.34 g, 91%). Compound 8 (1.20 g, 3.5 mmol) was dissolved in EtOH (5 mL) and treated with NaOEt (1.6 g, 5.2 mmol). After stirring at ambient temperature for 15 h, the reaction mixture was quenched with solid NH4Cl. The reaction mixture was evaporated in vacuo, and diluted with EtOAc (10 mL). The separated organic layer was washed with H2O (10 mL) and brine (10 mL), dried over anhyd MgSO4. After evaporation of solvent, the crude product was purified by column chromatography (EtOAc-hexane = 1:10 to 1:3) to give 1 (0.73 g, 81%). 1H NMR (300 MHz, CDCl3):δ = 4.29 (m, 1 H), 4.01 (m, 1 H), 3.45-3.65 (m, 2 H), 2.65 (br s, 1 H), 2.38 (dd, J 1 = 22.9 Hz, J 2 = 7.1 Hz), 1.49 (s, 3 H), 1.45 (s, 9 H), 1.38 (s, 3 H), 1.26-1.61 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 164.8, 93.5, 75.2, 64.4, 60.4, 37.3, 26.7, 24.6, 22.7, 14.4. MS: m/z = 261 [M + H]+. [α]D -3.7 (c 2.0 in MeOH); lit.: [α]D -3.7 (c 14.9 in MeOH); see: Wess G., Kesseler K., Baader E., Beck G.; US 4977279, 1990; Chem. Abstr. 1990, 112, 55602.