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.