| 76% |
With tert.-butylhydroperoxide In water; 1,2-dichloro-ethane at 40℃; for 40h; |
2.1
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
|
With tert.-butylhydroperoxide; triethylamine |
2
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
|
With tert.-butylhydroperoxide In nitromethane at 40℃; for 16h; |
2
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
|
With tert.-butylhydroperoxide In water at 40℃; for 16h; |
2
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
|
With tert.-butylhydroperoxide; sodium hydrogencarbonate |
2
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
|
With pyridine; tert.-butylhydroperoxide |
2
Example 2 Optimization of Aqueous Allylic Oxidation Conditions of Non-Steroidal CompoundsIn order to determine aqueous allylic oxidation reaction conditions for non-steroidal compounds, trans-3-nonene-2-one, whose fire bee toxin (Russell, G. A. (1957) “Deuterium-isotope Effects in the Autoxidation of Aralkyl Hydrocarbons. Mechanism of the Interaction of Peroxy Radicals,” J. Am. Chem. Soc. 79:3871-3877; Caudle, M. T. et al. (1996) “Mechanism for the Homolytic Cleavage of Alkyl Hydroperoxides by the Manganese(III) Dimer MnIII2(2-OHsalpn)2,” Inorg. Chem. 35:3577-3584) product trans-3-nonene-2,5-dione (1) has been previously prepared by anhydrous allylic oxidation (Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623) was selected for optimization: Using T-HYDRO as the oxidant and Rh2(cap)4 as the catalyst at 40° C., various solvents were examined for suitability. 1,2-Dichloroethane (DCE), nitromethane, and water all led to comparable conversions to product (1) after 16 hours when 8 equivalents of TBHP were employed. In contrast to previous reports of catalytic TBHP oxidations under anhydrous conditions (Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417; Blanksby, S. J. et al. (2003) “Bond Dissociation Energies Of Organic Molecules,” Acc. Chem. Res. 36:255-263) the addition of weak bases such as sodium bicarbonate, pyridine, or triethylamine lowered percent conversions. Two factors limited the efficiency of this allylic oxidation: (1) the slow rate of oxidation of the substrate relative to radical chain decomposition of TBHP (kP/kD, Scheme 1) (Timmons, D. et al. In METAL BONDS BETWEEN METAL ATOMS, 3rd Ed.; Cotton, F. A. et al. Eds.; Springer Science and Business Media: New York; (2005) Chapter 13) and (2) the decrease in the concentration of the catalytically active dirhodium species (FIG. 2). For the former, increasing the number of molar equivalents of TBHP increased percent conversion, and increasing the reaction temperature from room temperature to 40° C. increased the rate of oxidation. For the latter, adding Rh2(cap)4 in two portions, 0.5 mol % to initiate the reaction and the second 0.5 mol % portion after 16 h, ensured complete conversion and high product yield. Subsequent studies revealed that complete conversion could be achieved using as little as 0.1 mol % Rh2(cap)4 if applied twice, each with 5.0 molar equiv of TBHP, after the initial addition (22 and 44 h). The role of dirhodium caprolactamate in these oxidation reactions is suggested from the spectral observations revealed in FIG. 2. The conversion of Rh2(cap)4 to its oxidized Rh(cap)4RhOH form by TBHP has been reported by Choi, H. et al., (2007) “Optimal TBHP Allylic Oxidation of Δ5-Steroids Catalyzed by Dirhodium Caprolactamate,” Org. Lett. 9:5349-5352). One aspect of the present invention relates to the recognition that Rh(cap)4RhOH is converted back to Rh2(cap)4 via TBHP. The observation of Rh2(cap)4 in FIG. 2, combined with confirmation of its initial formation and presence throughout the course of oxidation through HPLC analysis, confirms the catalytic role for Rh2(cap)4 that is described in Scheme 2. Thus, the Example demonstrates that dirhodium caprolactamate is effective and efficient for the production of the tert-butylperoxy radical. Optimized conditions were selected for oxidation of α,β-unsaturated substrates (0.54 M in DCE) that included initial addition of 0.5 mol % Rh2(cap)4 and 4.0 or 5.0 equiv T-HYDRO followed by the same portion of catalyst and oxidant after 16 hours. Reactions were performed at 40° C. and terminated 40 hours after the initial catalyst/oxidant addition. Percent conversion at 16 hours was only half that at 40 hours, and using acetonitrile or nitromethane as solvent resulted in lower conversions than that achieved in DCE. Selected α,β-unsaturated carbonyl compounds were oxidized according to this methodology, and the results are reported in Table 3. Noteworthy are the relatively high yields of oxidized product obtained with acyclic compounds. For example, trans-4-oxo-2-nonenoic acid (3), reported to have antibiotic activity (Pfefferle, C. et al. (1996) “(E)-4-Oxonon-2-Enoic Acid, An Antibiotically Active Fatty Acid Produced By Streptomyces olivaceus Tü 4018,” J. Antibiotics 49:826-828), is efficiently prepared in one transformation (entry 3), improving upon the previously described multistep syntheses (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674; Shet, J. et al. (2004) “Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid,” Synthesis 11:1859-1863; Obrect, D. et al. (1989) “A New Method for the Preparation of (E)-3-Acylprop-2-enoic Acids,” Helv. Chim. Acta 72:117-122). Oxidation of methyl crotonate under the same conditions yielded monomethyl fumaric acid (entry 8) in modest isolated yield.Reactions were performed with 1.36 mmol of substrate in 2.5 mL of DCE to which was added 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 and the solution was heated at 40° C. After 16 hours an additional 4.0 or 5.0 equiv of TBHP (70% in water) and 0.50 mol % Rh2(cap)4 was added, and reaction was continued for an additional 24 hours. Isolated yield after column chromatography; carboxylic acids were purified by recrystallization from ethyl acetate and the mass yield after recrystallation is given.General Procedure for the Oxidation of α,β-Unsaturated Carbonyl Compounds. A 10 mL vial equipped with a stirbar was charged with substrate (1.36 mmol) and Rh2(cap)4 (5 mg, 0.007 mmol). Solvent (2.5 mL) was added followed by the addition of TBHP (0.75 mL, 5.5 mmol, 4 equiv). The vial was loosely capped and stirred for 16 hrs, then the second portion of Rh2(cap)4 (5 mg, 0.007 mmol) and TBHP (0.75 mL, 5.5 mmol, 4 equiv) was added. After an additional 24 hrs, the solution was concentrated and purified by column chromatography to obtain analytically pure compounds whose spectral characteristics were identical to those previously reported: trans-3-nonen-2,5-dione (1) (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233) ethyl (E)-4-oxo-2-decenoate (2) (Manfredini, S. et al. (1988) “A Convenient Synthesis Of λ-Oxo-Acrylates,” Tetrahedron Lett. 29:3997-4000), (E)-4-oxo-2-pentenamide (5) (Scheffold, R. et al. (1967) “Synthese Von Azaprotoanemoninen,” Helv. Chim. Acta. 50:798-808), 4-androsten-17-3,6-dione (28) (Jasiczak, J. (1988) “Oxidations Of Enone Systems In Steroids By Oxidizers With Reversible Redox Potential,” J. Chem. Soc. Perkin Trans. 1, 10, 2687-2692), 17β-acetoxyandrost-4-en-3,6-dione (29) (Marwah, P. et al. (2004) “An Economical And Green Approach For The Oxidation Of Olefins To Enones,” Green Chem. 570-577), 4-androstene-3,6,17-trione (30) (Kiran, I. J. (2004) “An Alternative Preparation Of Steroidal Δ4-3,6-Diones,” Chem. Res. 3:208-209), 4-cholesten-3,6-dione (31) (Hunter, C. A. et al. (2006) “An Efficient One-Pot Synthesis Generating 4-Ene-3,6-Dione Functionalised Steroids From Steroidal 5-En-3β-ols UsingA Modified Jones Oxidation Methodology,” Steroids 71:30-33) and acids were purified by recrystallization in ethyl acetate and matched with those in the literature: (E)-4-oxo-2-nonenoic acid (3) (Ballini, R. et al. (1998) “Synthesis of (E)-4-Oxonon-2-enoic Acid, a Natural Antibiotic Produced by Streptomyces olivaceus,” J. Nat. Prod. 61:673-674), (E)-4-oxo-2-pentenoic acid (4) (Lüüond, R. M. et al. (1992) “Assessment Of The Active-Site Requirements Of 5-Aminolevulinic Acid Dehydratase: Evaluation Of Substrate And Product Analogs As Competitive Inhibitors,” J. Org. Chem. 57:5005-5013), 2-cyclohexenone-1-carboxylic acid (7) (Webster, F. X. et al. (1987) “Control Of The Birch Reduction Of m-Anisic Acid To Produce Specific 3-Oxocyclohexenecarboxylic Acids,” Synthesis 10:922-923) and fumaric acid monomethyl ester (8) (Davis, R. A. (2005) “Isolation and Structure Elucidation of the New Fungal Metabolite (-)-Xylariamide A,” J. Nat. Prod. 68:769-772). |
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