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Synlett 2011(18): 2697-2700  
DOI: 10.1055/s-0031-1289536
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Highly Efficient Conversion of a Simple Derivative of the Amino Acid Proline into a Nearly Enantiomerically Pure N-Protected Allyl Amine: Use of Thionyl Chloride to Promote the Peterson Olefination

Guoqing Wei*, Theodore Cohen*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax: +1(412)6248611; e-Mail: guoqing_wei@yahoo.com; e-Mail: cohen@pitt.edu;
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Publication History

Received 15 July 2011
Publication Date:
19 October 2011 (online)

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Abstract

A novel two-step conversion of an N-Boc methyl ester of the natural amino acid proline into highly enantioenriched N-Boc 2-vinylpyrrolidine is described. Key steps include (1) an SNi displacement of a methoxy group of the DIBAL-H adduct of the starting ester by the TMSCH2 group of the corresponding Grignard reagent, and (2) the use of thionyl chloride to promote the Peterson olefination of the resulting β-hydroxysilane bearing a stereocenter adjacent to the alcohol function. The overall transformation occurs with remarkable facility and virtually without loss of stereochemical integrity under mild conditions. The use of thionyl chloride in the elimination step is necessary because both basic and acidic conditions are incompatible with the Boc protecting group. In stark contrast to the standard Wittig olefination of the corresponding N-protected amino aldehyde, where 8-10% racemization (80-84% ee) occurs, only about 1% racemization (98% ee) was observed in this novel process.

Key words

allylamines - amino acids - chiral pool - pyrrolidines - olefination

    References and Notes

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12

The configuration of the newly formed chiral carbinol in β-hydroxysilane 3 was tentatively assigned as R based on ref. 10 and 11, although this assignment is inconsequential given that the newly created stereogenic center is destroyed in the next olefination step.

13

( S )- tert -Butyl 2-[( R )-1-Hydroxy(trimethylsilyl)ethyl]-pyrrolidine-1-carboxylate (3) To a solution of 1 (113 mg, 0.50 mmol, 99.8% ee) in CH2Cl2 (2.5 mL) was added DIBAL-H (1.0 M in toluene, 0.6 mL, 0.6 mmol) dropwise at -78 ˚C under an argon atmosphere. After the mixture had been stirred for 1 h at -78 ˚C, TMSCH2MgCl (1.0 M in Et2O, 6.0 mL, 6.0 mmol) was added, and the reaction mixture was stirred at -78 ˚C for an additional 10 min. The reaction mixture was then moved to a -33 ˚C bath and stirred for 48 h. After treatment with 1.0 M HCl (10 mL), the reaction mixture was extracted with EtOAc (3 × 10 mL). The combined extracts were washed successively with H2O (10 mL), sat. NaHCO3 (10 mL),
and brine (2 × 10 mL), and dried over anhyd Na2SO4. Concentration and purification of the crude by chroma-tography (6% EtOAc-hexanes) provided 81.8 mg (57%) of analytically pure 3 as a semisolid. [α]D ²0 -95.1 (c 0.82, CHCl3). IR (neat): 3328, 2980, 2951, 2923, 1648, 1411, 1244, 1160, 846 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 0.07 (s, 9 H), 0.71 (d, J = 3.0 Hz, 1 H), 0.73 (s, 1 H), 1.47 (s, 9 H), 1.57-1.71 (m, 1 H), 1.72-2.03 (m, 3 H), 3.25-3.35 (m, 1 H), 3.43-3.54 (m, 1 H), 3.61-3.71 (m, 2 H), 3.72-3.81 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = -0.6, 23.7, 23.9, 28.5, 29.0, 47.2, 65.5, 74.1, 80.2, 158.2. ESI-HRMS: m/z calcd for C14H29NNaO3Si [M + Na]+: 310.1814; found: 310.1822.

19

( S )- tert -Butyl 2-Vinylpyrrolidine-1-carboxylate (4) To a solution of 3 (57.4 mg, 0.20 mmol) in THF (4 mL) was added pyridine (0.05 mL, 0.6 mmol) and SOCl2 (0.02 mL, 0.3 mmol) sequentially at -50 ˚C. After being stirred for 30 min, the reaction mixture was allowed to slowly warm to 0 ˚C. After 2 h, the reaction was quenched with H2O (5 mL) and 1.0 M HCl (1 mL). The mixture was extracted with EtOAc (3 × 10 mL), and the combined extracts were washed with 1.0 M HCl (2 mL), H2O (5 mL), sat. NaHCO3 (5 mL), and brine (2 × 5 mL) and dried over anhyd MgSO4. After removal of the solvent, the crude was purified by chroma-tography (5% EtOAc-hexanes) to give 35.1 mg (89%) of analytically pure 4 as a colorless oil. [α]D ²0 -15.7 (c 0.55, CHCl3). IR (neat): 1700, 1367 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9 H), 1.62-1.74 (m, 1 H), 1.75-2.07 (m, 3 H), 3.31-3.43 (m, 2 H), 4.19-4.34 (br s, 1 H), 4.97-5.11 (m, 2 H), 5.64-5.81 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 23.0, 28.4, 31.7, 46.2, 59.0, 79.0, 113.6, 138.8, 154.6. Chiral GC analysis [Varian CP-Chiralsil-DEX CB column (25 m × 0.25mm), isothermal at 60 ˚C for 300 min and temperature programming to 100 ˚C at a rate of 5 ˚C/min and then isothermal at 100 ˚C for 20 min]: t R = 310 min for (R)-4 and t R = 313 min for (S)-4; er (S)-4/(R)-4 = 98.8:1.2 (97.6% ee).

20

1% Racemization may have occurred in the process of nucleophilic addition of the Grignard reagent to the aluminoxy acetal intermediate.