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

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

References and Notes

• 1a Ireland RE. Mueller RH. J. Am. Chem. Soc.  1972,  94:  5897 
• For recent reviews, see:
• 1b Ilardi EA. Stivala CE. Zakarian A. Chem. Soc. Rev.  2009,  38:  3133 
• 1c Martin Castro AM. Chem. Rev.  2004,  104:  2939 
• 1d Chai Y. Hong S. Lindsay HA. McFarland C. McIntosh MC. Tetrahedron  2002,  58:  2905 
• A creative alternative approach to the formation of stereodefined α,α-disubstituted enolates from cyclic precursors has been described:
• 2a Manthorpe JM. Gleason JL. J. Am. Chem. Soc.  2001,  123:  2091 
• 2b Tiong EA. Gleason JL. Org. Lett.  2009,  11:  1725 
• 3 Qin Y. Stivala CE. Zakarian A. Angew. Chem. Int. Ed.  2007,  46:  7466 
• Selected methods:
• 4a Schmierer R. Grotemeier G. Helmchen G. Selim A. Angew. Chem., Int. Ed. Engl.  1981,  20:  207 
• 4b Helmchen G. Selim A. Dorsch D. Taufer I. Tetrahedron Lett.  1983,  24:  3213 
• 4c Oppolzer W. Moretti R. Thomi S. Tetrahedron Lett.  1989,  30:  5603 
• 4d Evans DA. Ennis MD. Mathre DJ. J. Am. Chem. Soc.  1982,  104:  1737 
• 5a Shirai R. Tanaka M. Koga K. J. Am. Chem. Soc.  1986,  108:  543 
• 5b For a detailed, large-scale synthesis of Koga bases, see: Frizzle MJ. Caille S. Marshall TL. McRae K. Nadeau K. Guo G. Wu S. Martinelli MJ. Moniz GA. Org. Process Res. Dev.  2007,  11:  215 
• 6a Stivala C. Zakarian A. J. Am. Chem. Soc.  2008,  130:  3774 
• 6b Lu C.-D. Zakarian A. Org. Lett.  2007,  9:  3161 
• 6c Stivala CE. Zakarian A. Tetrahedron Lett.  2007,  48:  6845 
• 6d Pelc MJ. Zakarian A. Tetrahedron Lett.  2006,  47:  7519 
• 6e Pelc MJ. Zakarian A. Org. Lett.  2005,  7:  1629 
• 6f Recent application toward the synthesis of spirolide C: Stivala CE. Zakarian A. Org. Lett.  2009,  11:  839 
• 7a Chen C. Namba K. Kishi Y. Org. Lett.  2009,  11:  409 
• 7b Gul S. Schoenebeck F. Aviyente Houk KN. J. Org. Chem.  2010,  75:  2115 
• Examples:
• 8a Wallace GA. Scott RW. Heathcock CH. J. Org. Chem.  2000,  65:  4145 
• 8b Ireland RE. Vevert J.-P. J. Org. Chem.  1980,  45:  4259 
• 9a Bartlett PA. Pizzo ChF. J. Org. Chem.  1981,  46:  3896 
• 9b For a comprehensive study, see: Ireland RE. Wipf P. Xiang J.-N. J. Org. Chem.  1991,  56:  3572 
• 10a Wang Y.-F. Lalonde JJ. Momongan M. Bergbreiter DE. Wong C.-H. J. Am. Chem. Soc.  1988,  110:  7200 
• 10b Carea G. Danieli B. Palmisano G. Riva S. Santagostina M. Tetrahedron: Asymmetry  1992,  3:  775 
• For recent structural studies on lithium enolate aggregates, see:
• 14a Li D. Sun C. Williard PG. J. Am. Chem. Soc.  2008,  130:  11726 
• 14b Godenschwager PF. Collum DB. J. Am. Chem. Soc.  2008,  129:  12023 

11

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.

12

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.

13

Lithium diisopropylamide gives an equimolar ration of 9 and 10.