Chem 634 Introduction to Protecting Groups
Reading: CS B 3.5!
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Announcements
Announcements
Thesis Defense:
Transition Metal Catalysis of Acetals & Pivalates:
Enantioselective & Enantiospecific Methods
for C–C and C–B Bond Formation
Hari Srinivas (M Watson Group)
Mon, 9/8, 9:30am
219 BRL
Announcements
Mary’s Homework: Yamaguchi Macrolactonization?
Cl
O
O
O
O
Cl
R
Cl
R
Cl
pKa ~ 16.5
HO Me
NEt3
HO Me
CO2H
pKa (Et3
NH+)
R
vs.
= 10.8
O
O
O
R
+
HO Me
O
Et3NH
O
more nucleophilic
O Me
O
O
Cl
observed
pKa ~ 4.8
Cl
Cl
Cl
Cl
Cl
not observed
CO2H
Mary’s Homework: Elimination w/ PPh3/Br2?
HBr generated...
Elimination?
Epimerization?
Ts
DEAD, PPh3
H2NTs
NH
OH
NH
OBn
OBn
OBn
Less acidic alternative conditions:
PPh3, Br2, imidazole
PPh3, CBr4
PPh3, DEAD, CH3I
1) TsCl; 2) LiBr
Ts
OBn
OBn
OMe
1. PPh3, Br2
2. H2NTs, Cs2CO3
OBn
OMe
OMe
OH
CH3
Ph
O
N
Bn
H
Br
PBr3
CH3
CH2Cl2, rt
Ph
(95%)
Synth. Commun. 2005, 35, 2795
OH
Ph
Ph3PBr2
CH2Cl2, 50 °C
(95%)
O
H
Br
Ph
N
Bn
J. Org. Chem. 2013, 78, 8396
Ideal Synthesis
“The ideal chemical process is that which a one-armed operator can perform by
pouring the reactants into a bath tub and collecting pure product from the drain
hole.”
– Sir John Cornforth
“The ideal synthesis creates a complex skeleton from simpler starting
materials…in a sequence only of successive construction reactions involving
no intermediary refunctionalization, and leading directly to the structure of the
target, not only its skeleton but also its correctly placed functionality.”
– James Hendrickson
JACS 1975, 97, 5786
Protecting Groups
Protecting groups are groups of atoms that are attached to (and later removed
from) a functional group to mask it from competitive undesired reactions.
Without Protection:
R FG
Chemistry
to modify R
R FG P
Chemistry
to modify R
R' Y
With Protection:
R FG
R'
FG P
R'
FG
Advantages: Allows reactions that otherwise would not be possible.
Disadvantages: extra steps (at least 2 - protection and deprotection), lowered
yield, low atom economy, added mass of PG on substrate.
Considerations: protecting group and both protection / deprotection sequences
must be compatible with all other desired steps and other functional groups.
Protecting Groups
Bible of protecting groups:
Protective Groups in Organic Synthesis
by Theodora Green & Peter Wuts
Published by Wiley
Make sure you have access to this book
Disclaimer on Today’s Lecture
This lecture has a lot of different reactions… most of the mechanisms are
very simple, or will be once we have covered a little more material in the
class.
For the sake of time, I have not included many mechanisms in this
lecture. However, do not mistake this for me thinking that they are not
important.
You need to be able to draw out every mechanism for every reaction in
this lecture.
Not only will this help you understand the material more deeply, but by
knowing what each reaction is doing, it will help you remember the
reagents needed for it.
ROH Protecting Groups
Silyl Protecting Groups
R O SiR3
Most Common:
SiR3 Name Abbrevia.on SiMe3 trimethylsilyl "TMS" SiEt3 triethylsilyl "TES" SitBuMe2 tertbutyldimethylsilyl "TBDMS" or "TBS" Si(iPr)3 triisopropylsilyl "TIPS" SitBuPh2 tert-­‐butyldiphenylsilyl "TBDPS" ROH Protecting Groups
Silyl Ether Formation
R OH
R'3SiCl
R OSiR'3
imid or Et3N
R OH
R'3SiOTf
2,6-lutidine
R OSiR'3
N
imid = imidazole =
HN
Corey, JACS, 1972, 94, 6190
2,6-lutidine =
Me
N
Me
Corey, TL, 1981, 22, 3455
Note: Formation becomes harder as substitution of alcohol increases, and
size of silyl group increases. For example, TMS ethers are difficult to form
on 3° alcohols, others are nearly impossible.
ROH Protecting Groups
Stability of Silyl Ethers
Basic:
OH (5% NaOH/MeOH)
T1/2: TMS < TES < TBS < TIPS < TBDPS
≤ 1 min
24 h
Acidic:
H
(1% HCl/MeOH)
T1/2: TMS < TES < TBS < TIPS < TBDPS
<1 min
<1 min ~1 h
~4 h
R OSiR3'
R OH
(1°)
•  Note: This data is for silyl ethers of
primary alcohols, gives relative
stabilities.
•  Also note: TMS is not a protecting
group for 1° alcohols. Too unstable!
ROH Protecting Groups
Deprotection of Silyl Ethers With Fluoride:
Fluoride:
F- (TBAF 0.06 M)
R OSiR3'
TBAF = Bu4NF
R OH
(1°)
R OSiR3'
F
R OH2 + F SiR3'
Driven by strength of Si-F bond
– strongest σ bond known.
T1/2: TMS < TES < TBS < TIPS < TBDPS
2.5 h
6.5 h
Other F- Sources:
Protic: TBAF (contains water), HF·Py, Et3N·HF, HF(aq), HOAc/CsF
Aprotic: (anhydrous)
TSAF= Me3SiF2 S(NMe)3
TBAT= Bu4N Ph3SiF2
ROH Protecting Groups
Esters:
O
O
=
RO
CF3
(TFA)
R'
O
Ph
(Bz)
why ?
Formation:
Deprotection:
O
O
X
R'
base
O
RO
Me
Me
(Piv) Me
Me
(Ac)
Increasing Stability
ROH
O
O
NaOH
R'
RO
R'
O
RO
or
H
LiAlH4
R'
ROH
ROH
ROH Protecting Groups
Carbonates:
O
RO
OR'
Me
CH3
R'=
Me
methyl carbonate
Me
tBu
tert-butyl carbonate
(Boc)
allyl
(alloc)
9-Fluorenyl methyl carbonate
(Fmoc)
Cl
Cl
benzyl
(Cbz)
Cl
2,2,2-trichloroethyl
(Troc)
OTMS
(TEOC)
ROH Protecting Groups
Carbonate Formation:
O
R OH
Cl
or
O
O
OR'
O
R'O
O
OR'
base, (DMAP)
RO
OR'
ROH Protecting Groups
Carbonate Deprotection:
O
RO
K2CO3/MeOH
R OH
OMe
R O(Fmoc)
R O(Troc)
R O(Teoc)
R O(alloc)
R O(Cbz)
R O(Boc)
Et3N or Py
Zn/AcOH
F
Pd0‚ Et2NH
Pd/C, H2
H or Δ
R OH
R OH
R OH
R OH
R OH
R OH
Carbonates (like many classes of protecting groups) have different conditions for
deprotection depending on the exact carbonate involved. This is advantageous
because many of the conditions are orthogonal, meaning you can remove one
without effecting the others. You need to learn the conditions for removing all of these
protecting groups. By the end of the course, you should be able to draw mechanisms
for each.
ROH Protecting Groups
Acetals:
RO
OMe
methoxy methyl ether
(MOM)
RO
O
Benzyoxy methyl ether
(BOM)
Me
RO
O
β-Methoxyethoxymethyl ether
(MEM)
RO
O
TMS
2-trimethyl silyl ethoxy methyl ether
(SEM)
ROH Protecting Groups
Acetals:
Formation:
R OH
R'O
Cl
NaH, etc
RO
O
R'
Cleavage:
HCl
R OMOM
R OBOM
R OSEM
or Lewis acid
Na/NH3
or H2, Pd/C
F
R OH
R OH
R OH
ROH Protecting Groups
Cyclic Acetals:
tetrahydropyran
Formation:
O
R OH
H+
RO
H
O
tetrahydropyran "THP"
Note! mixture of epimers
Cleavage:
dilute H
R OTHP
H2O
R OH
ROH Protecting Groups
Ethers:
RO
RO
allyl
benzyl (Bn)
RO
OMe
p-methoxyl benzyl
"PMB"
Formation:
R OH
R'X
NaH, etc
RO R'
RO CPh3
trityl (Tr)
ROH Protecting Groups
Ethers:
Cleavage:
R
O
L4Pd0
HCO2Na
R OBn
R OPMB
R OH
or other reductant
H2, Pd/C
or Na/NH3
or DDQ (hard to do)
DDQ
R OH
R OH
O
DDQ= 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone =
(mild oxidant)
NC
Cl
NC
Cl
O
Protecting Groups for Diols
All ROH protecting groups work, but 1,2- or 1,3- can be protected in unique ways.
Acetals:
O
OH
OH
n=1 or 2
n
R
R'
cat. H+
can also use:
n
O
R
O
R'
R=R'=Me
"acetonide"
What is the mechanism?
MeO
MeO OMe
R
or
R
R
OMe
Me
Common:
O
Ph
Me
O
O
R
R
acetonide
R
O
R
benzylidine
acetal
O
R
O
R
p-methoxybenzyidine acetal
ROH Protecting Groups
Acetal Cleavage:
Me
Me
O
O
H
MeOH
HO
OH
n
n
Ph
O
O
Pd/C
or Na/NH3
HO
OH
n
n
OMe
DDQ
HO
OH
n
O
O
Protecting Groups for Carbonyls
O
R
O
R'
R
H
Common:
MeO OMe
R
O
R'
dimethyl acetal
MeS SMe
R
R'
R R'
1,3 dioxane
S
O
O
S
O
R
R'
1,3 dioxalane
S
S
Me Me
R R'
1,3 dithiane 1,3 dithiolane
Protecting Groups for Carbonyls
Acetal Formation:
MeOH
O
R
MeO OMe
or
R'
R
n
O
O
Me
Me
or
R'
n
HO
OH
anhydrous HCl
or Lewis acid
TMSOMe
O
R
MeO OMe
cat TMSOTf
R'
R'
R
Acetal Cleavage:
MeO OMe
R
R'
TsOH, acetone
or
HCl, H2O
O
R
R'
Protecting Groups for Carbonyls
Thioacetals:
Formation :
R'SH
O
R
SR'
SR'
R
R'
or
R
n
S
S
Me
Me
or
n
HS
SH
HCl
or Lewis acid
Cleavage:
SR'
SR'
R
R'
O
cond.
R
R'
(Generally
Oxidative)
Difficult!
Conditions: Hg(ClO4)2, CuCO3; NBS, AgNO3;
CuCl2, CuO, Δ; H2O2, NaOH; DDQ, BF3
Do not worry about these mechanisms.
Thioacetals are robust
protecting groups, but often
very hard to remove. The
oxidative conditions for
removal often destroy
complex molecules. Use
only with proper planning
and foresight.
Note about Thioacetals
SR'
SR'
R
H
useful nucleophile,
synthetic equiv for
SR'
nBuLi
R
O
SR'
R
mildy acidic
Li
SR'
R1
X
R2
SR'
SR'
SR'
R2
R1
O
R2
R1
Note: As carbonyls are normally electrophilic, this is known as an “umpolung” strategy
(from German verb “umpolen” meaning “reversed polarity”).
Protecting Groups for Amines
RNH2, R2NH
Carbamates (very common):
O
R2'N
R'= Me, tBu, etc.
OR'
formation and removal same as for corresponding with carbonates
Protecting Groups for Amines
Alkyl Protecting Groups
Formation:
RNH2
P X , base
or
1° and 2°:
R2NH P= Bn, allyl, Tr
RNHP
or
R2NP
note: over alkylation is a probelm with primary amines
O
1°: RNH2
H
PG
RHN
NaBH4
prevents over alkylation
OAc
RR'NH
Pd(0)
RR'N
Removal is the same as with the alkyl ether PG's.
Protecting Groups for Amines
Amides
O
R'
N
R
Most common
(others hard to remove)
CF3
trifluoroacetomide
Formation:
O
R'
N
R
H
F3C
O
O
CF3
O
R'
Et3N
N
R
1° or 2 °
Removal:
O
R'
N
R
NaOH
CF3
R'
N
R
H
CF3
Protecting Groups for Amines
Sulfonamides (Avoid where possible)
O
N S
R O
R'
Me
Tosyl- "Ts'
Formation (easy):
R'
N H
R
TsCl
py
R'
N Ts
R
Removal (typically very hard with destroying substrate):
R'
Li/NH3
or SmI3
N Ts
R
strong reducing
conditions
R'
N H
R
Protecting Groups for Amides
(not a lot of options)
Alkyl Protecting Groups
Formation:
O
Cl
O
R
R
NHR
N
R
NaH or
C2CO3
O
BnBr or PMBCl
O
R
NHR
NaH or
C2CO3
R
N
R
R'
R' = H or OMe
Protecting Groups for Amides
Removal of Alkyl Protecting Groups from Amides
O
R
Pd (0)
N
R
red.
O
R
NHR
usually best option
O
R
N
R
H2, Pd/C
O
ΔΔ
or tBuLi, O2 R
NHR
(Hard to remove from amides)
O
R
N
R
CAN
O
R
NHR
OMe
CAN = ceric ammonium nitrate = strong oxidant
Protecting Groups for Amides
Indirect Methods:
formation
Me
Me
Me
O
R
removal
NH2
O
R
Cl
O
TfOH
N
H
tBu
R
NH2
NHR'
O
R
MeO
Cl
OMe
O
R
N
R'
O
CAN
R
N
H
R'
para-methoxyphenyl
(PMP)
Note: these protecting groups are hard to install from an existing amide