Modified Cinchona Alkaloid-Zinc Complex Catalysts: Enantioselective Monoacetylation of Glycerol Derivatives with Acetic Anhydride

Abstract

Enantioselective monoacetylation of σ-symmetric glycerol derivatives with acetic anhydride catalyzed by modified cinchona alkaloid-zinc complexes was achieved in up to 86% ee at 5 mol% catalyst loading.

Key words

cinchona alkaloid - zinc complex - asymmetric synthesis - glycerol - acetylation

References and Notes

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9

The ^¹H NMR spectra of a mixture of chiral ligand 1 and Et₂Zn were complicated by multiple signals arising from rotamers of 1. In the case of our previous results, the structure of chiral sulfonamide-Zn complex (2:1) was determined by X-ray crystallographic analysis.⁵ However, attempts to crystallize the Zn complex of chiral ligand 1 were unsuccessful.

11

The authors reported the experimental results at the 126th annual meeting of the Pharmaceutical Society of Japan, Sendai, Japan, 2006, abstract No. 4, pp. 137.

14

General Experimental Procedure for a Modified Cinchona Alkaloid-Zinc Complex Catalyzed Desymmetrization of Glycerol Derivatives
To a solution of modified cinchona alkaloid 1 (6.0 mg, 0.01 mmol) in Et₂O (4 mL) was added Et₂Zn (1.0 M in n-hexane, 10 µL, 0.01 mmol) at r.t. The mixture was stirred at r.t. for 10 min, and diol 9a (51.3 mg, 0.2 mmol) and Ac₂O (28 µL, 0.3 mmol) were then added to the solution at 0 ˚C. After stirring at 0 ˚C for 20 h, the reaction mixture was treated with sat. aq NaHCO₃ (5 mL) followed by extraction with CHCl₃ (75 mL). The extract was dried over anhyd MgSO₄, filtered, and concentrated in vacuo. The oily residue was purified by silica gel column chromatography (EtOAc-n-hexane, 1:1) to afford 9aa (46.3 mg, 78% yield, 86% ee) as a colorless oil.
The ee (%) of (S)-9aa (Scheme  [²] ) was determined on a Chiralpak IA, n-hexane-EtOH (3:1), flow rate: 1 mL/min, detection: 254 nm]. The retention times were 9.4 min [minor product, (R)-9aa] and 12.2 min [major product, (S)-9aa], respectively. The absolute configuration of (S)-9aa was explicitly determined by its chemical conversion to acetonide (S)-15 {[α]_D ^²0 -3.1 (c 1.01, EtOH), lit.^¹6 (R)-15 [α]_D +5.8 (c 1.00, EtOH)}.

Scheme 2

15

Spectroscopic Data of 9aa-ea (Table 4)
Compound 9aa (R = Me): colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 1.28 (3 H, s), 2.10 (3 H, s), 2.15 (1 H, s), 3.56-3.59 (2 H, m), 3.79 (6 H, s), 4.17 (1 H, d, J = 11.7 Hz), 4.24 (1 H, d, J = 11.7 Hz), 4.48 (2 H, s), 6.38 (1 H, t, J = 2.2 Hz), 6.49 (2 H, d, J = 2.2 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 17.5, 20.9, 55.3, 64.6, 65.4, 65.7, 76.8, 99.4, 105.2, 141.1, 160.9, 171.1. IR (neat): 3471, 2939, 2843, 1738, 1599, 1464, 1244, 1205, 1155, 1053 cm^-¹. ESI-MS: m/z calcd for C₁₅H₂₂NaO₆: 321.1314; found: 321.1324 [M⁺ + Na].
Compound 9ba (R = Et): colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 0.96 (3 H, t, J = 7.7 Hz), 1.60-1.72 (2 H, m), 2.10 (3 H, s), 2.21 (1 H, s), 3.57 (1 H, d, J = 12.0 Hz), 3.62 (1 H, d, J = 12.0 Hz), 3.79 (6 H, s), 4.20 (1 H, d, J = 11.7 Hz), 4.25 (1 H, d, J = 11.7 Hz), 4.45 (2 H, s), 6.37 (1 H, t, J = 2.2 Hz), 6.51 (2 H, d, J = 2.2 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 7.0, 20.9, 22.6, 55.3, 62.8, 63.6, 63.9, 78.6, 99.4, 105.2, 141.0, 160.9, 171.2. IR (neat): 3481, 2968, 1741, 1599, 1462, 1238, 1205, 1155, 1063 cm^-¹. ESI-MS: m/z calcd for C₁₆H₂₄NaO₆: 335.1471; found: 335.1471 [M⁺ + Na].
Compound 9ca (R = i-Pr): colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 1.01 (3 H, d, J = 3.2 Hz), 1.03 (3 H, d, J = 3.2 Hz), 2.07-2.10 (4 H, m), 2.17-2.25 (1 H, m), 3.73-3.76 (2 H, m), 3.79 (6 H, s), 4.34 (1 H, d, J = 12.2 Hz), 4.36 (1 H, d, J = 12.2 Hz), 4.52 (1 H, d, J = 11.5 Hz), 4.54 (1 H, d, J = 11.5 Hz), 6.38 (1 H, t, J = 2.2 Hz), 6.52 (2 H, d, J = 2.2 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 17.06, 17.13, 21.0, 30.1, 55.3, 62.6, 64.5, 64.6, 79.7, 99.3, 105.0, 141.4, 160.9, 171.0. IR (neat): 3483, 2964, 1741, 1599, 1238, 1205, 1155, 1055 cm^-¹. ESI-MS: m/z calcd for C₁₇H₂₆NaO₆: 349.1627; found: 349.1597 [M⁺ + Na].
Compound 9da (R = CH₂=CHCH₂): colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 2.10 (3 H, s), 2.21 (1 H, br s), 2.44 (2 H, d, J = 7.3 Hz), 3.60 (1 H, d, J = 12.0 Hz), 3.64 (1 H, d, J = 12.0 Hz), 3.78 (6 H, s), 4.21 (1 H, d, J = 12.0 Hz), 4.26 (1 H, d, J = 12.0 Hz), 4.52 (2 H, s), 5.14-5.20 (2 H, m), 5.81-5.92 (1 H, m), 6.38 (1 H, t, J = 2.2 Hz), 6.50 (2 H, d, J = 2.2 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 20.9, 35.2, 55.3, 63.2, 63.9, 64.3, 78.3, 99.4, 105.3, 118.9, 132.2, 140.9, 160.8, 171.1. IR (neat): 3483, 2939, 1741, 1599, 1464, 1238, 1205, 1155, 1055 cm^-¹. ESI-MS: m/z calcd for C₁₇H₂₄NaO₆: 347.1471; found: 347.1494 [M⁺ + Na].
Compound 9ea (R = Ph): colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 2.06 (3 H, s), 2.22 (1 H, br s), 3.79 (6 H, s), 3.88-3.99 (2 H, m), 4.30 (1 H, d, J = 11.5 Hz), 4.35 (1 H, d, J = 11.5 Hz), 4.64 (2 H, s), 6.38 (1 H, t, J = 2.2 Hz), 6.50 (2 H, d, J = 2.2 Hz), 7.32-7.36 (1 H, m), 7.38-7.45 (4 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 20.9, 55.3, 65.0, 65.3, 65.5, 80.5, 99.4, 105.2, 126.7, 128.3, 128.7, 138.5, 140.7, 160.9, 170.9. IR (neat): 3481, 2939, 1741, 1599, 1462, 1238, 1205, 1155, 1053 cm^-¹. ESI-MS: m/z calcd for C₂₀H₂₄NaO₆: 383.1471; found: 383.1466 [M⁺ + Na].