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A Quick Recap on Protecting Groups Three Steps Required: 1. “Hide” the incompatible group 2. Do what needs to be done elsewhere in the molecule 3. Remove the protecting group and return to the original group Two protecting groups for alcohols: • Trimethylsilyl ether formation using trimethylsilyl chloride (TMS-Cl) and triethylamine (NEt3) • Easily removed by aqueous acid (H3O+) or F- R-O-H TMS-Cl NEt3 R-O-TMS Two protecting groups for alcohols: • Dihydropyran (DHP) and an acid catalyst (H+) will react to form a tetrahydropyran protecting group (THP) • Easily removed by aqueous acid (H3O+) R-O-H DHP, H+ R-O-THP For more than one alcohol… … remember that there is an order in which alcohols are protected, beginning with primary alcohols (least sterically hindered), then secondary alcohols (more sterically hindered) and finally tertiary alcohols OH OH 1 equiv. TMS-Cl NEt3 OTMS OH • In most cases, when working with a single alcohol that needs to be protected, the two groups are INTERCHANGEABLE so it doesn’t matter which ones you use… OH OH 1 equiv. DHP H+ OTHP OH • Sometimes you will need to manipulate two alcohols… if you need to protect them both so they are both out of the way, use the same one… HO OH OH 2 equiv. DHP H+ THPO OTHP OH • Remember the order for protecting alcohols is always going to show reaction on the 1°, then 2° and then 3°: Thus: HO OH OH 2 equiv. DHP H+ THPO OH OTHP • Those problems that require you to protect the less hindered alcohol first are easier than those where the less hindered alcohol is the one you NEED for the chemistry… Example: OH OH OH O Quick and simple to protect the primary alcohol so the secondary can be oxidized, right? • Right! OH OH 1 equiv. DHP H+ OTHP OH PCC OH OH H3O+ OTHP O • When the the primary alcohol is the one you NEED for the chemistry, you will have to actually protect it FIRST and then use a different protecting group on the secondary alcohol… and deprotect the first alcohol so you can do your chemistry on it… O OH OH H OH • Be sure to use two protecting groups that can be taken off with different reagents • For alcohols, you have TWO protecting groups to use - one that comes off with aqueous acid and one that comes off with aqueous acid OR fluoride anion… • Just be sure not to START with the one that has to be removed using the SAME reagent as the second one… O OH OH H OH • Using TMS-Cl, NEt3 first and then DHP, H+ allows you to remove the TMS group easily with F-, thus allowing the THP to stay in place: OH OH 1 equiv. TMS-Cl NEt3 OTMS OH DHP, H+ OH OTHP HF OTMS OTHP • Using DHP, H+ first and then TMS-Cl, NEt3 won’t allow you to remove the THP group easily without also removing the TMS group: OH OH 1 equiv. DHP H+ OTHP OH TMS-Cl, NEt3 OH OH H3O+ OTHP OTMS • And hopefully you recognize that if you put the same protecting group on both alcohols, you cannot selectively REMOVE one over the other: OH OH 2 equiv. DHP H+ OTHP OTHP H3O+ OH OH • This concludes our review of alcohol protecting groups. Hopefully it helped eliminate any questions that may have been left in your mind after lecture.
