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Synlett 2010(11): 1717-1722  
DOI: 10.1055/s-0029-1219965
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© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Construction of Adjacent Quaternary Chiral Centers by the Ireland-Claisen Rearrangement: Stereoselection with Esters of Cyclic Alcohols

Zhenhua Gu, Aaron T. Herrmann, Craig E. Stivala, Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Fax: +1(805)8934241; e-Mail: zakarian@chem.ucsb.edu;
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Publication History

Received 7 May 2010
Publication Date:
10 June 2010 (online)

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Abstract

This work describes a study of the Ireland-Claisen rearrangement of α,α-disubstituted enolates derived from esters of cyclic alcohols. Highly stereoselective enolizaitions could be generally achieved using N-benzyl Koga-type bases by matching chirality of the ester and the base. The [3,3]-sigmatropic rearrangement took place in good yields and moderate diastereoselectivity forming two adjacent quaternary stereogenic centers, and generally proceeding through a chairlike transition state.

Key words

diastereoselectivity - rearrangement - esters - sigmatropic - chirality - stereoselective synthesis

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General Procedure for Esterification - Synthesis of ( S )-[( S )-3-Methylcyclohex-2-enyl] 2-Methyl-butanoate (6)
EDCI (0.345 g, 1.80 mmol) was added to a mixture of (S)-3-methyl-2-cyclohexen-1-ol (0.100 g, 0.89 mmol), (S)-2-methylbutyric acid (0.153 g, 1.50 mmol) in CH2Cl2 (4.0 mL), and the resultant mixture was stirred at r.t. for 2 h.
After evaporation, the residue was purified by column chromatography (3% EtOAc-hexanes) to give the ester 6 (0.143 g, 82%); [α]D ²² -112 (c 1.0, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 5.44 (s, 1 H), 5.25 (s, 1 H), 2.40-2.28 (m, 1 H), 2.06-1.84 (m, 2 H), 1.82-1.58 (m, 8 H), 1.52-1.39 (m, 1 H), 1.13 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl3): δ = 176.5, 140.7, 120.2, 68.3, 41.2, 29.9, 28.0, 26.8, 23.7, 19.1, 16.7, 11.6 ppm. HRMS (FI): m/z calcd for C12H20O2 [M+]: 196.1463; found: 196.1455.

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General Procedure for the Ireland-Claisen Rearrangement - ( S )-2-Methyl-2-[( R )-1-Methylcyclohex-2-enyl]butanoic acid (9)
n-BuLi (1.96 M in hexanes, 0.105 mL, 0.20 mmol) was added to a solution of (S)-7 (60 mg, 0.20 mmol) in THF (0.25 mL) at -78 ˚C. After 5 min, the flask was removed from the ice bath and stirring was continued at r.t. The solution was allowed to stir for 20 min before being cooled down to
-78 ˚C, at which point a solution of 6 (19.6 mg, 0.10 mmol) in THF (0.50 mL) was added dropwise to the reaction vessel. After 1.5 h, TMSCl (25 µL, 0.20 mmol) was added. The mixture was stirred at -78 ˚C for 20 min, then at 0 ˚C for 10 min. The reaction mixture was diluted with hexanes (20 mL). The organic layer was washed with 1 M HCl (2 × 2 mL), followed immediately by sat. aq NaHCO3 (10 mL), dried with Na2SO4, and concentrated. The residue was dissolved in THF (1.0 mL) and heated in a sealed flask at 70 ˚C. After 3 h, the reaction vessel was cooled to r.t. and THF (2.0 mL) was added followed by the addition of 1 M HCl (3.0 mL). The progress of the silyl ester hydrolysis was monitored by TLC. After dilution with CH2Cl2 and H2O, the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were dried with Na2SO4, concentrated, and the residue was purified by column chromatography (silica, 10% EtOAc-hexanes w/0.1% AcOH then 40% EtOAc-hexanes w/0.1% AcOH) delivering a 70:30 mixture of carboxylic acids 9 and 10 (16.7 mg, 85 µmol, 85%), respectively. ¹H NMR (300 MHz, CDCl3): δ (major isomer) = 5.66 (dd, J 1 = 10.8 Hz, J 2 = 0.8 Hz, 1 H), 5.61 (ddd, J 1 = 10.4 Hz, J 2 = J 3 = 3.2 Hz, 1 H), 2.10-2.10 (m, 1 H), 1.75-1.68 (m, 3 H), 1.51-1.40 (m, 3 H), 1.34-1.27 (m, 1 H), 1.14 (s, 3 H), 1.09 (s, 3 H), 0.87 (dd, J 1 = J 2 = 7.6 Hz, 3 H) ppm.

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Lithium diisopropylamide gives an equimolar ration of 9 and 10.