Aziridine-Modified Amino Alcohols as Efficient Modular Catalysts for Highly Enantioselective Alkenylzinc Additions to Aldehydes

Abstract

N-Tritylaziridino alcohols have been easily synthesized in a straightforward synthetic route from an inexpensive and easily available chiral pool. They were used in the enantioselective alkenylzinc additions to aldehydes furnishing the products in excellent yields and stereoselectivities up to 97%.

Key words

asymmetric synthesis - allylic alcohols - vinyl addition - alkenylzinc - aziridino alcohols

References and Notes

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8

Braga, A. L.: Paixao, M. W.; Westermann, B.; Schneider, P. H.; Wessjohann, L. A.; Chem. Eur. J., in press.

9

General Procedure for the Synthesis of Ligands 1-3 The Grignard reagent (25 mmol) in THF (10 mL, 2.5 M solution) was added dropwise over a period of 10 min to a solution of the appropriate aziridine ester (5 mmol) in 10 mL of THF. After 1.5 h the reaction was quenched with sat. aq NH₄Cl (30 mL) followed by the evaporation of the organic solvents. The residue was extracted with Et₂O (3 × 50 mL) and the combined organic layers were dried (MgSO₄) and concentrated to give the product. The crude product was purified by flash column chromatography on silica (hexane-EtOAc, 12:1); Et₃N was added to the eluent to prevent detritylation of the product during the purification procedure. Recrystallization was achieved from MeOH-Et₃N by a hot solution.

10

Compound 1: yield 70%; mp 133.5-134.5 °C; [α]_D ²² -78.8 (c 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.45-7.34 (d, 2 H, J = 7.3 Hz), 7.32-7.12 (m, 8 H), 7.09-7.04 (m, 15 H), 4.44 (br s, 1 H), 2.38 (dd, 1 H, J = 6.2, 3.1 Hz), 2.08 (d, 1 H, J = 3.1 Hz), 1.32 (d, 1 H, J = 6.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 146.79, 145.25, 143.44, 129.04, 127.77, 127.59, 127.22, 126.62, 126.55, 126.50, 126.04, 125.72, 73.95, 73.89, 41.46, 23.80. ESI-HRMS: m/z calcd for C₃₄H₂₉NO + Na⁺: 490.2147; found: C₃₄H₂₉NO + Na⁺: 490.2141.
Compound 2: yield 74%; pale yellow oil; [α]_D ²² -82.8 (c 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.51-7.18 (m, 15 H), 3.05 (br s, 1 H), 1.94 (d, 1 H, J = 3.3 Hz), 1.62-1.43 (m, 1 H), 1.41-1.29 (m, 4 H), 1.14 (d, 1 H, J = 6.4 Hz), 0.73 (q, 6 H, J = 7.5 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 144.03, 129.37, 127.40, 126.68, 73.97, 70.82, 40.18, 31.93, 28.23, 23.51, 8.13, 7.73. ESI-HRMS: m/z calcd for C₂₆H₂₉NO + Na⁺: 394.2141; found: C₂₆H₂₉NO + Na⁺: 394.2147
Compound 3: yield 82%; mp 174-176 °C; [α]_D ²² +22 (c 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.46-6.98 (m, 25 H), 3.05 (s, 1 H), 2.20 (d, 1 H, J = 6.7 Hz), 1.66 (q, 1 H, J = 6.0 Hz), 1.19 (d, 3 H, J = 5.8 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 148.39, 146.04, 143.80, 143.68, 129.34, 128.60, 127.80, 127.74, 127.29, 126.79, 126.64, 126.03, 125.52, 75.17, 73.50, 45.21, 31.99, 1376. ESI-HRMS: m/z calcd for C₃₅H₃₁NO + Na⁺: 504.2303; found: C₃₅H₃₁NO + Na⁺: 504.2297.

11

General Procedure for the Alkenylzinc Addition to Aldehydes
Cyclohexene (608 µL, 3.0 mmol) was added under argon at 0 °C to a magnetically stirred solution of borane dimethyl-sulfide complex (142 µL, 1.5 mmol) in toluene (1 mL). After 2 h at 0 °C the alkyne (1.5 mmol) was added and the mixture was stirred for 30 min at r.t. The mixture was cooled to
-78 °C and a solution of Et₂Zn (2 mL, 1 mmol, 1.0 M in toluene) or Me₂Zn solution (1.5 mL, 3 mmol, 2 M in toluene) was added slowly to this and after 1 h at -78 °C, a toluene solution of ligand (0.1 mL, 1 M in toluene, 0.1 mmol) was added. After warming from -78 °C to -30 °C over a period of 1 h, toluene (1 mL) and the aldehyde (1 mmol) were added and the mixture was stirred for 18 h at -20 °C. The reaction mixture was quenched with H₂O, Et₂O was added and the organic layer was subsequently extracted with brine. The organic layer was dried over MgSO₄ and the solvent was removed in vacuo. The residue was purified through column chromatography on silica gel to provide the enantio-merically pure allyl alcohol. Conditions for Determining Enantiomeric Excess by HPLC Analysis All measurements were performed at a 20 °C column temperature using a UV detector at 219 nm. ( S , E )-1-Phenylhept-2-en-1-ol (Table [1] , entries 1-10): Chiralcel OD-H column eluted with hexane-2-PrOH (99:1) at 1.0 mL/min; t _R = 22.0 min for R and t _R = 32.3 min for S.
( S , E )-1-Phenylnon-2-en-1-ol (Table [2] , entry 1): Chiralcel OD-H column eluted with hexane-2-PrOH (99:1) at 1.0 mL/min; t _R = 20.7 min for R and t _R = 32.3 min for S.
( S , E )-4,4-Dimethyl-1-phenylpent-2-en-1-ol (Table [2] , entry 2): Chiralcel OD-H column eluted with hexane-2-PrOH (99:1) at 1.0 mL/min; t _R = 14.1 min for R and t _R = 22.3 min for S.
( S , E )-3-Cyclohexyl-1-phenylprop-2-en-1-ol (Table [2] , entry 3): Chiralcel OD-H column eluted with hexane-2-PrOH (99:1) at 1.0 mL/min; t _R = 21.9 min for R and t _R = 33.2 min for S.
( S , E )-(4-Tolylphenyl)-4,4-dimethylpent-2-en-1-ol (Table [2] , entry 4): Chiralcel OD-H column eluted with hexane-2-PrOH (98:2) at 0.5 mL/min; t _R = 18.3 min for R and t _R = 20.5 min for S.
( S , E )-1-(4-Methoxyphenyl)-4,4-dimethylpent-2-en-1-ol (Table [2] , entry 5): Chiralcel OD-H column eluted with hexane-2-PrOH (99:1) at 1.0 mL/min; t _R = 25.5 min for R and t _R = 32.5 min for S.
( S , E )-(4-Chlorophenyl)-4,4-dimethylpent-2-en-1-ol (Table [2] , entry 6): Chiralcel AD-H column eluted with hexane-2-PrOH (95:5) at 1.0 mL/min: t _R = 7.15 min for R and t _R = 8.14 min for S.
( S , E )-(4-Bromophenyl)-4,4-dimethylpent-2-en-1-ol (Table [2] , entry 7): Chiralcel AD-H column eluted with hexane-2-PrOH (95:5) at 1.0 mL/min: t _R = 7.64 min for R and t _R = 9.07 min for S.

( S , E )-Methyl 4-(1-hydroxy-4,4-dimethylpent-2-enyl)benzoate (Table [2] , entry 8): Chiralcel OD-H column eluted with hexane-2-PrOH (95:5) at 1.0 mL/min; t _R = 13.7 min for S and t _R = 14.8 min for R.
( S , E )-(2-Bromophenyl)-4,4-dimethylpent-2-en-1-ol (Table [2] , entry 9): Chiralcel OD-H column eluted with hexane-2-PrOH (97:7) at 1.0 mL/min: t _R = 13.2 min for R and t _R = 15.7 min for S.