A Further Improved Synthesis of a Dibenzodioxocinone CETP Inhibitor

Abstract

A newly improved synthesis of a dibenzodioxocinone CETP inhibitor is described. Key features of the synthetic route include a chiral ligand induced alkyl addition to aldehyde and the use of triethylborane for improved selective alkylation of brominated phenyl ring.

Key words

total synthesis - asymmetric synthesis - natural products - inhibitors - drugs

References and Notes

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• 2 inventors; WO  1994012175. Taisho Pharmaceutical Ltd.;
• 3 Tomoda H. Nishida H. Masuma R. Cao J. Okuda S. Omura S. J. Antibiot.  1990,  44:  136 
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• 5a inventors; DE  4039860. Bayer AG;
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10

Experimental Procedure To a stirred solution of 4c (74.1 mg, 0.4 mmole) in dry toluene at 15 ˚C under argon, a solution of 2,2-dimethyl-propyl zinc (4.76 g, 23 mmole) in toluene was added. After 15 min, the temperature was lowered to -78 ˚C, followed by the addition of a toluene solution (10 mL) of compound 3 (10.4 g, 18.8 mmol). The mixture was allowed to slowly warm to 0 ˚C, and stirred for another 6 h. The reaction was slowly quenched by a sat. solution of NH₄Cl, and then extracted three times with EtOAc. The combined organic phase was washed by H₂O and brine, dried over anhyd MgSO₄, filtered and concentrated. The product 5 was purified using silica gel chromatography (CH₂Cl₂-EtOAc, 50:1). Yield 7.06 g, 60%, [a]_D ^²0 +22.5 (c 1.0, CHCl₃; >99% ee, as analyzed by chiral HPLC, see Figure  [²] ). ESI-MS:
m/z = 627.1 [M + H]⁺. ^¹H NMR (400 MHz, CD₃Cl): δ = 1.01 (s, 9 H), 1.20-1.70 (m, 8 H), 2.02 (s, 1 H), 2.37 (s, 3 H), 3.45 (m, 1 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 4.50 (dd, 1 H), 4.65 (m, 1 H), 4.93 (dd, 1 H), 5.02 (s, 2 H), 5.08 (m, 1 H), 6.38 (d, 1 H), 6.90 (s, 1 H), 7.18-7.35 (m, 6 H) ppm. ^¹³C NMR (100 MHz, CD₃Cl): δ = 20.4, 20.5, 25.4, 27.1, 30.1 (3 C), 30.5, 51.5, 52.4, 58.6, 62.3, 63.3, 66.5, 71.1, 114.5, 116.9, 118.8, 121.3, 123.6, 127.1 (2 C), 127.6, 128.9 (2 C), 131.0, 131.6, 131.8, 136.7, 138.3, 142.3, 144.1, 151.1, 154.2, 168.2 ppm.

11

Under argon, compound 10 (18.0 g, 36 mol), CsOAc (35.2 g, 108 mmol), and Pd(dppf)₂Cl₂ (0.54 g, 0.72 mmol) was dissolved in dry THF. To this was added a solution of Et₃B (1 M, 108 mL, 108 mmol) in THF. The mixture was heated to reflux for 4 h. Then it was cooled to 0 ˚C, and the reaction was quenched with 10% NaOH and 30% H₂O₂. After stirring at r.t. for 30 min, the mixture was neutralized with diluted HCl, followed by extraction with EtOAc for three times. The combined organic phase was washed with brine, dried over anhyd MgSO₄, and concentrated. Purification using silica gel chromatography (PE-EtOAc, 8:1 to 1:1) afforded 11. Yield 10.5 g (65%). HRMS (MALDI/DHB): m/z = 471.1550 [M + Na]⁺. ^¹H NMR (400 MHz, CD₃Cl): δ = 1.03 (s, 9 H), 1.15 (t, 3 H), 1.57 (m, 1 H), 1.61 (m, 1 H), 1.93 (d, 1 H), 2.31 (s, 3 H), 2.77 (q, 2 H), 3.99 (s, 3 H), 5.16 (m, 1 H), 5.37 (dd, 1 H), 5.48 (dd, 1 H), 6.26 (s, 1 H), 6.84 (d, 1 H), 6.95 (s, 1 H), 7.59 (d, 1 H) ppm. ^¹³C NMR (100 MHz, CD₃Cl): δ = 13.3; 16.2; 20.7, 30.1 (3 C), 30.8, 52.4, 62.3, 65.9, 66.6, 116.9, 118.8, 121.3, 123.6, 131.0, 131.6, 131.8, 138.3, 142.3, 144.1, 151.1, 154.2, 167.4 ppm.