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

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.

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

References and Notes

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2 Joshi N, Bhirud SB, Chandrasekhar B, Rao KE, and Damle S. inventors; US  7312329.  ; Chem. Abstr. 2005, 143, 26633

3 Satyanarayana Reddy M, Thirumalai Rajan S, and Sahadeva Reddy M. inventors; WO  2007125547.  ; Chem. Abstr. 2007, 147, 522015

4 Hiyama T. Minami T. Takahashi K. Bull. Chem. Soc. Jpn.  1995,  68:  364 

5 For a highlight on the chemoenzymatic synthesis of statin side chains, see: Müller M. Angew. Chem. Int. Ed.  2005,  44:  362 

6 Wess G. Tetrahedron Lett.  1990,  31:  2545 

7 Nishiyama A, Horikawa M, Yasohara Y, Ueyama N, and Inoue K. inventors; US  7094594.  ; Chem. Abstr. 2001, 136, 904153

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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).

18 Blacker AJ, Reeve CD, and Holt RA. inventors; US  7157255. Immobilized lipase was used for regioselective acetylation of 4. See: ; Chem. Abstr. 2001, 136, 356851

19

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].

20 Chen K.-M. Hardmann GE. Prasad K. Repic O. Shapiro MJ. Tetrahedron Lett.  1987,  28:  155 

21

(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.