Download O V O O RO OH t-BuOOH, CH2Cl2, Ti(OPr-i)4(cat), 20 oC (L)

Enantioselective Catalysis
Asymmetric Epoxidation.
You have already seen in 59-331 that a very common method for converting alkenes to epoxides
involves the reaction of the former with peracids.
O
R
O
1
R
R2
CH2Cl2
O
H
O
R2
R1
There is a well-known alternative to this, which employs metal complex catalyzed oxidation by a alkyl
hydroperoxide. The original method involved a V(O)(OR)3 complex and t-BuOOH; it is selective for allylic
alcohols, because the VV alkoxide (shown below) is likely a critical intermediate in the epoxidation. That
leaves the OR’s for potential sources of making a chiral catalyst, using some kind of chiral alcohol.
O
-O
V
O
RO O
Other transition metal based compounds (i.e., Mo, Ti) are known for this process, too, and in particular
the TiIV catalysts can be made to operate enantioselectively. The overwhelmingly employed set of
reagents are:
OH
t-Bu
O
O
H
+ Ti( OPr-i)4
+
O
EtO
OEt
O
(L)-(+)-(R,R)diethyl tartate
(or diisopropyl)
OH
This is particularly useful in that the naturally occurring enantiomer (shown) of diethyl tartrate is pretty
cheap (100 g, $65, 2012 dollars), and even the unnatural enantiomer ((S,S)-) isn’t too bad (25 g, $122,
2012 dollars). Furthermore, 3 Å molecular sieves are added to make the reaction reliably catalytic in TiIV
and tartrate. Typical loadings of the catalysts are anywhere from 5 mol% TiIV + 6 mol% tartrate to 10
mol% TiIV + 12 mol% tartrate. This process is called the Katsuki-Sharpless epoxidation (older books tend
to leave out Katsuki). Here’s a simple example:
OH
t -BuOOH, CH2Cl2,
Ti(OPr-i)4(cat), 20 oC
O
OH
H
(L)-(+)-diethyl tartrate(cat)
95% ee
(97.5:2.5) er
This first thing to notice is that the stereosepecific with respect to alkene geometry; cis- alkene
substitutents on the alkene give cis- substituents on the epoxide and trans- gives trans-. The direction of
asymmetric induction, is also stereospecific (depending upon the tartrate enantiomer), and a model is
useful that is totally empirical. In it, of you lay out the allylic alcohol such that the alcohol is out from and
to the right, the natural tartrate based complex attacks from the bottom face, while the unnatural
tartrate based reagent attacks from the top face.
(D)-(-)-(S,S)-tartrate
O
"O"
unnatural
R1
R2
OH
R3
R2

R1
O
R2
OH
H
R1
R3
OH
R2
natural
R1

R2
R1
R2
OH
O
OH
H
O
"O"
(L)-(+)-(R,R)-tartrate
In addition, it is possible to accomplish a kinetic resolution on alcohols that have a chiral centre but are
racemic (in other words, have one enantiomer react faster than the other), and as a result you can get
enantiomerically enriched epoxide and unreacted allylic alcohol (recovered starting material) if the
reaction is stopped at ca. 50% conversion. Here’s schematic showing why….
(D)-(-)-(S,S)-tartrate - SLOW
(D)-(-)-(S,S)-tartrate - FAST
"O"
"O"
R2
R4
OH
R3
R2
R1
H
OH
R3
R4
H
"O"
(L)-(+)-(R,R)-tartrate - FAST
R1
"O"
(L)-(+)-(R,R)-tartrate - SLOW
The rate difference between the two (diastereotopic) faces are large to massive (16:1 = 82% ee to 700:1)
at -20 oC, often giving excellent results.
Ti(OPr-i)4(cat),
t -BuOOH,
OH
OH
H
(L)-(+)-DET(cat),
CH2Cl2
~ 50% conversion
racemic
O

OH
+
OH
H
O
H
enantiomerically
enriched
enantiomerically
enriched
The functional group tolerance turns out to be pretty good. Of the common functional groups, only
amines (-NR2), carboxylic acids (-CO2H), thioethers (-SR), phenols (Ar-OH), and phosphines (-PR2) are not
tolerated. For carboxylic acids and phenols, there are fairly simple protections available (esters and
phenolic ethers, respectively).
Not every alkene that is an allylic alcohol undergoes epoxidation under these conditions equally well,
however, as there is some steric hindrance issues when too many R groups get in the way of the alcohol
function. As a general rule.
R1
R1
R2
R2
OH
OH
R2
R3
OH
R5
OH
R3
limited #
generally good
 90% ee
R4
OH
R3
great
great
OH
R1
too slow
a bit of a problem - slowest
variable ee's but still  80% ee
This was all developed empirically, so the mechanism is proposed rather than unequivocal, but the
proposed ‘loaded catalyst’ is
R4
R5
E O
OR
RO
O
E
RO
O
Ti
EO
Ti
O
E
O
'loaded catalyst"
R2
Comprehensive Organic Synthesis
1991, V 7, Ch. 3.2
O
O
t-Bu
Selected examples: mostly taken from Gawley, Aube, Principles of Asymmetric Synthesis, Elsevier, 2012
Ti(OPr-i)4(cat),
O
OH
OH
(-)-DIPT(cat),
t -BuOOH, CH2Cl2
55%, 95:5 er
O
Ti(OPr-i)4(cat),
OH
OH
(+)-DET(cat),
t-BuOOH, CH2Cl2
Ti(OPr-i)4(cat),
( )9
OH
(-)-DET(cat),
t -BuOOH, CH2Cl2
J. Am. Chem. Soc. 1987, 109, 5765.
85%, 97:3 er
( )9
( )9
O
OH
(+)-DET(cat),
t -BuOOH, CH2Cl2
Ti(OPr-i)4(cat),
OH (+)-DET(cat),
t -BuOOH, CH2Cl2
O
(+)-disparlure
80%, 91% ee
(95.5:4.5 er)
Ti(OPr-i)4(cat),
OH
Masamune, Sharpless et al
J. Am. Chem. Soc. 1987, 109, 5765.
O
OH
(gypsy moth insect sex pheromone)
77%
J. Am. Chem. Soc. 1987, 109, 5765.
96:4 er
O
OH
95%
95:5 er
J. Am. Chem. Soc. 1987, 109, 5765.
Asymmetric Dihydroxylations
See Kolb, H.C.; VanNieuwenzhe, M. S; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
Recall that alkenes can be converted to 1,2- (vic-) diols by the use of OsO4, followed by a workup that
breaks up the osmate ester.
It has been known for many years that pyridine accelerates the rate of this reaction; so a reasonable
approach to creating an enantioselective dihydroxylation reagent would be to make a chiral pyridine, or
at least a chiral amine. Before we get to what would serve appropriately….
There are a couple of problems with this process:
i)
OsO4 is expensive, so it would be very preferable to use it catalytically, and a have a cheap
stoichiometric oxidant bring the OsVI back to OsVIII
The best choice for this oxidant is K3Fe(CN)6 with a two phase oxidation (K3Fe(CN)6 is water
soluble; OsO4 is the only oxidant in the organic phase.
The 2nd best choice is N-methylmorpholine-N-oxide (NMO), which you have
O
seen before in other contexts as a stoichiometric oxidant.
NMO
ii)
The catalytic cycle has a bottleneck, which is the hydrolysis of the osmate
VI
ester product to free Os and free diol. This break-up is accelerated by
methanesulfonamide, MeSO2NH2, which increases the overall reaction rate
by a factor of 50x, except for terminal alkenes.
N
CH3
O
O O
S
H3C
NH2
So what chiral amines (or pyridines)? They are two or three piece combinations of one of two naturally
occurring cinchona alkaloid ‘ligands’, link with a tether. The ligands are most commonly…
Et
Et
N
RO
N
(R)(S)-
H
(S)-
OR
H
(R)-
MeO
OMe
N
R = H dihydroquinine
(DHQ)
N
R = H dihydroquinidine
(DHQD)
These are not actually enantiomers of each other, but rather diastereomers, because the chirality of the
C bearing the ethyl is the same in each case ((R)-). For the dihydroxylations, however, they function as
the complementary systems to get enantiomeric products; the unofficial term pseudoenantiomers is
commonly used. It should also be noticed that it is likely the aliphatic nitrogen atom, and not the
aromatic one, that is involved in coordination to Os.
So what’s that ‘R’ in the structure? The dihydroxylations are most commonly successful when there are
two of these units in the same molecule, and they are hooked together with an ether tether, which is
normally one of…
Ph
N N
alk-O
O-alk
O-alk
O-alk
O
N N
alk-O
O-alk
O-alk
N
N
phthalazine (PHAL)
historically the best
O
alk-O
N
Ph
diphenylpyrimidine
(PYR)
sterically hindered
cases
N
O
O-alk
anthraquinone (AQN)
2nd best
Ph
N
Ph
DPP
similar to PHAL
IND
best for cisdisubst. alkenes
The way the reagent combinations are presented is shown by the following example: using the PHAL
spacer with the DHQD ligand is termed (DHQD)2-PHAL. This is sold as AD-mix-β. (DHQ)2-PHAL is sold as
AD-mix-α.
Like the epoxidation reactions, there is a mnemonic for how each of the reagents direct addition to
alkenes. If one puts the alkene in a plane with the largest substituent towards the left and towards the
reader. DHQD attacks from the top (or β- face), DHQ from the bottom face (or α- face), such as in:
DHQD derivs
-face
OH
HO
OH
RS
RL
RS
RL
RM
H
OH
RS
RL
OH
DHQ derivs
 -face
-
-
RM
H
RM
H
often*
(R)-left
(R)-right
often*
(S)-left
(S)-right
OH
Not every alkene is dihydroxylated equally well. The following is a rough schematic; you’ll notice
that cis- disubstituted cases are the toughest, and really the only case where the IND spacer is
used.
90-99.8% ee
PHAL
DPP
AQN
-
HO
OH
great
90-99% ee
PHAL
AQN
DPP
80-97% ee
PHAL
PYR
AQN
DPP
pretty good
70-97% ee
PHAL
PYR
AQN
DPP
20-80%
IND
moderate
20-97% ee
PHAL
PYR
limited #
In general, the higher end of the ranges have RL as aromatic groups, and the lower end has RL as
aliphatic groups. The newer spacers (AQN especially) have helped out with aliphatic cases.
Typical conditions are as follows. Notice that OsO4 is most often replaced by an osmate salt,
K2OsO2(OH)4, a non-volative,w ater soluble form of OsVIII.
T = 0-25 oC
ligand 1-5 mol%
osmate K2OsO2(OH)4 0.2-1 mol%
Stoichiometric oxidant K3Fe(CN)6
solvent t-BuOH/H2O
And the mechanism? Firstly, it was originally proposed that OsO4 dihydroxylation of alkenes was a
[3+2] cycloaddition. This view has been replaced that the initial addition is a [2+2] cycloaddition
(reminiscent of a Wittig reaction), followed by a ring expansion/rearrangement.
O
O
[3+2]
O
O
OsO4 + L
+ alkene
Os
O
O
O
O
L
L
[2+
2]
nt
e
m
ge
n
a
a rr
re
O
O
Os
Os
O
O
L
The proposed source of enantioselectivity stems from minimization of repulsive steric interactions
between osmaoxetane and the benzylic carbon of cinchona alkaloid. Attractive π- stacking interactions
between aryl groups on the alkene and the electron poor aromatic of the linker are the proposed source
of great selectivity with aryl substituted alkenes.
O
RS
O
RM
O
H minimal repulsion
Os
RL
O
H
stabilizing -stacking
N
RO
O
RS
O
Os
RL
O
N H
(S)- Ar
RO
(S)- Ar
with DHQD
good
O
R
H M severe repulsion
bad