Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: taurean on November 30, 2006, 11:13:57 PM
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How can we reduce a cyclic beta-ketoester to beta-hydroxy ester, diastereoselectively? Anyone know of any method other than biotransformation? Please pour in your comments.
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:'( I want to help, but I have no idea of how to do it. have you tried to google and see if any methods will pop up?
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What is controlling the stereoselectivity? If it's diastereoselective then you must have a stereocenter somewhere in your molecule already.
Also, is the ester in the ring, or outside the ring. If it's outside the ring like in 2-carboxymethyl cyclopentanone, there are excellent enantioselective methods for reducing the ketone carbonyl.
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What is controlling the stereoselectivity? If it's diastereoselective then you must have a stereocenter somewhere in your molecule already.
Also, is the ester in the ring, or outside the ring. If it's outside the ring like in 2-carboxymethyl cyclopentanone, there are excellent enantioselective methods for reducing the ketone carbonyl.
Please open the attachment. This is the ketoester I am trying to reduce.
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How about sodium borohydride?
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How about sodium borohydride?
The reaction with sodium borohydride results in the mixture of four diastereomers. I tried changing the solvent system from methanol to isopropanol, it gives me the same result in each case.
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Really?? How about L-Selectride?
Do you know what the diastereomers are?
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Really?? How about L-Selectride?
Do you know what the diastereomers are?
I will let you know shortly; working on that.
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Really?? How about L-Selectride?
Do you know what the diastereomers are?
I need a diequatorial beta-hydroxy ester or a diequatorial 1,3-diol. After reading through the literature, I came to a conclusion that use of sterically encumbered borohydride would give a thermodynamically less stable isomer.
Please let me know your comments as why did you think that L-selectride would work for my substrate?
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Well, usually bulky reducing agents give better levels of diastereoselectivity, although in this case I guess it would be in the wrong direction for your purposes. If you want the thermodynamic product, I would recommend a Meerwein-Ponndorf-Verley reduction (http://www.organic-chemistry.org/frames.htm?http://www.organic-chemistry.org/namedreactions/). That reaction is usually under thermodynamic control.
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Well, usually bulky reducing agents give better levels of diastereoselectivity, although in this case I guess it would be in the wrong direction for your purposes. If you want the thermodynamic product, I would recommend a Meerwein-Ponndorf-Verley reduction (http://www.organic-chemistry.org/frames.htm?http://www.organic-chemistry.org/namedreactions/). That reaction is usually under thermodynamic control.
Thanks for suggesting MPV reaction.
I would like to try someother stereoselective reductions along with MPV reaction. I was unsuccessful in digging out the literature for stereoselective (diastereoselective) carbonyl reduction of cyclic beta-ketoester. If possible can you let me know some good reading material for diastereoselective carbonyl reduction of cyclic beta-ketoesters.
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There should be lots of diastereoselective versions, certainly MPV has been used for this purpose as well as Selectrides and aluminum hydrides. There may not be a whole lot of obvious beta-ketoester versions that are exactly like your case, but I would look for diastereoselective ketone reductions with reagents that aren't powerful enough to reduce esters.
Have you tried Pd/C with hydrogen gas? You might be able to reduce the enol form and heterogeneous reductions often give pretty good dr.
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There should be lots of diastereoselective versions, certainly MPV has been used for this purpose as well as Selectrides and aluminum hydrides. There may not be a whole lot of obvious beta-ketoester versions that are exactly like your case, but I would look for diastereoselective ketone reductions with reagents that aren't powerful enough to reduce esters.
Have you tried Pd/C with hydrogen gas? You might be able to reduce the enol form and heterogeneous reductions often give pretty good dr.
I cannot reduce with Pd/C-H2. I want the double bond in the reactant to be retained in the product.
I would look for diastereoselective ketone reductions, thanks.
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Sorry, I forgot what the rest of the molecule looks like and the picture seems to be gone now.
You might be able to reduce with dissolving metals like Na/EtOH. Those are kinda strange reactions, but they really work sometimes. You might reduce off the sulfone you have, however. I'm not sure.
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Movies,
After reading different papers, I feel that there is no set rule that diastereoselective reduction of ketone with L-selectride or any other sterically hindered hydride would give kinetically stable product (axial alcohol in case of cyclic ketone).
What is your opinion?
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The selectivity for axial versus equatorial alcohol is highly dependent on the system in question. I forget exactly what your system looks like, however, so it might favor the equatorial alcohol. In general, very bulky hydride sources are controlled by the steric hindrance associated with the approach of the hydride onto the carbonyl, that is to say, the hydride will approach from the sterically less hindered face of the carbonyl. I don't know if that will work for you or not.
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The selectivity for axial versus equatorial alcohol is highly dependent on the system in question. I forget exactly what your system looks like, however, so it might favor the equatorial alcohol. In general, very bulky hydride sources are controlled by the steric hindrance associated with the approach of the hydride onto the carbonyl, that is to say, the hydride will approach from the sterically less hindered face of the carbonyl. I don't know if that will work for you or not.
Here is my substrate. Please let me know your opinion.
I guess it also depends on the reactive conformation of the substrate.
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I would predict that most reducing agents will come from the convex face of your molecule. In this system it might be really difficult to get the other diastereomer because the other face is so significantly hindered. If sodium borohydride gave some reasonable level of selectivity, my guess would be that one of the Selectride reagents would give the same major product, but in a higher ratio. I suspect that two of your stereoisomers are resulting from epimerization of the stereocenter next to the ester in the reduced product. It might be very difficult to control that.
In simple systems, Selectride definitely does give axial alcohols when it is favorable. For example, consider the reduction of 4-tert-butylcyclohexanone. Small reducing agents like LiAlH4 generally give mostly equatorial alcohol (92:8 e:a), whereas large reducing agents like Selectride give mostly axial alcohol (7:93 e:a). See: Brown, JACS 1972, 94, 7159.
One other system to consider is the Noyori Ru-BINAP system for hydrogenation of beta-ketoesters. As I recall, it is selective for the reduction of beta-ketoesters over other alkenes in the molecule. You might be able to squeeze some selectivity out of the system with a chiral ligand as well.
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I would predict that most reducing agents will come from the convex face of your molecule. In this system it might be really difficult to get the other diastereomer because the other face is so significantly hindered. If sodium borohydride gave some reasonable level of selectivity, my guess would be that one of the Selectride reagents would give the same major product, but in a higher ratio. I suspect that two of your stereoisomers are resulting from epimerization of the stereocenter next to the ester in the reduced product. It might be very difficult to control that.
In simple systems, Selectride definitely does give axial alcohols when it is favorable. For example, consider the reduction of 4-tert-butylcyclohexanone. Small reducing agents like LiAlH4 generally give mostly equatorial alcohol (92:8 e:a), whereas large reducing agents like Selectride give mostly axial alcohol (7:93 e:a). See: Brown, JACS 1972, 94, 7159.
One other system to consider is the Noyori Ru-BINAP system for hydrogenation of beta-ketoesters. As I recall, it is selective for the reduction of beta-ketoesters over other alkenes in the molecule. You might be able to squeeze some selectivity out of the system with a chiral ligand as well.
Thanks for your suggestions. Sodium borohydride gives some amount of selectivity. I obtained four diastereomers (1,3-diols) with sod.borohydride, of which two are formed from the epimerization of the stereocenter next to the ester, as you expected. I would try hindered hydrides in the next few days and will let you know the result.
I am doing diastereoselective synthesis. By doing enantioselective hydrogenation, using Ru-BINAP, I would loose half of the material. ???