Metathesis for catalyst design: Metacatalysis

Article abstract of DOI:10.1016/j.tet.2013.12.040

Prior studies have shown an effective way to produce diverse ligand sets for catalyst discovery is by using mixtures of monodentate forms to generate catalysts in situ. Research described here was performed to illustrate that alkene-functionalized monodentate ligands could be used in this way and in another that increases the diversity of the ligand library in an interesting way. Specifically, we hypothesized that as well as being used as monomers, these alkenes could be cross metathesized in situ immediately before the catalysis step. This combination of metathesis to form ligands in situ, then catalysis is referred to here as metacatalysis. In the event, a library of quinidine and quinine alkaloid-derived phosphites were tested as mixtures of monomers and dimers formed via metathesis in situ. The data obtained illustrated that metacatalysis can be used to identify ligands that positively and negatively modulate enantioselectivities in iridium-mediated hydrogenations of α,β-unsaturated carboxylic acid derivatives, relative to the mixtures of the monomeric forms used.

Full text of DOI:10.1016/j.tet.2013.12.040

Accepted Manuscript
Metathesis For Catalyst Design: Metacatalysis
Sakunchai Khumsubdee, Kevin Burgess
PII:
S0040-4020(13)01908-X
10.1016/j.tet.2013.12.040
TET 25124
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 October 2013
Revised Date: 10 December 2013
Accepted Date: 13 December 2013
Please cite this article as: Khumsubdee S, Burgess K, Metathesis For Catalyst Design: Metacatalysis,
Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.040.
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ACCEPTED MANUSCRIPT
S1
Metathesis For Catalyst Design: Metacatalysis
Supporting Information
Sakunchai Khumsubdee and Kevin Burgess*
Texas A & M University, Chemistry Department, P.O. Box 30012, College Station, Texas
7
7842, USA
E-mail: burgess@tamu.edu
Copies of NMR spectra----------------------------------------------------------------------------S7
Copies of GC data-------------------------------------------------------------------------------- S17

ACCEPTED MANUSCRIPT
S2
a
O
O
0
.003 A, 0.066 1g
Ph
OH
Ph
OH
CH Cl , 50 bar H
2
2
o
2
2
5 C, 12 h
B
<2 %
b
O
P
O
O
0
.05 A, CH Cl
2
2
N
crude metathesis
product
o
N
40 C, 12 h
OMe
1
g
crude metathesis product
O
O
(contain only 0.003 A)
Ph
OH
Ph
OH
CH Cl , 50 bar H
2
2
o
2
2
5 C, 12 h
B
<2 %
nd
Figure S1. Hydrogenation of α-methylcinnamic acid B using 2 Generation Hoveyda-
Grubb’s catalyst with 1g.

ACCEPTED MANUSCRIPT
S3
a
0
.003 A, 0.066 1g
HO
CO Me
no hydrogenation
product
2
CH Cl , 50 bar H
2
2
o
2
2
5 C, 12 h
C
b
O
P
O
O
0
.05 A, CH Cl
2
2
N
crude metathesis
product
o
N
40 C, 12 h
OMe
1
g
crude metathesis product
(
contain only 0.003 A)
HO
CO Me
no hydrogenation
product
2
CH Cl , 50 bar H
2
2
o
2
C
25 C, 12 h
nd
Figure S2. Hydrogenation of hydroxyl-ester C using 2 Generation Hoveyda-Grubb’s
catalyst with 1g.

ACCEPTED MANUSCRIPT
S4
a
0
.003 A, 0.066 1g
AcO
CO H
AcO
CO H
2
2
CH Cl , 50 bar H
2
2
o
2
2
5 C, 12 h
E
<1 %
b
O
P
O
O
0
.05 A, CH Cl
2
2
N
crude metathesis
product
o
N
40 C, 12 h
OMe
1
g
crude metathesis product
(contain only 0.003 A)
AcO
CO H
AcO
CO2H
2
CH Cl , 50 bar H
2
2
o
2
E
25 C, 12 h
<
1 %
nd
Figure S3. Hydrogenation of acetoxy-acid E using 2 Generation Hoveyda-Grubb’s
catalyst with 1g.

ACCEPTED MANUSCRIPT
S5
Catalytic Hydrogenation Using Chiral Ligand 1g with PPh
3
O
Ph
OH
B
0
.03 Ir(COD) BARF
2
0
.5 Cs CO , MeOH
2 3
o
5
0 bar H , 25 C, 24 h
2
0
.066 1g
0
.066 1g
0
.033 1g
+
+
0
.033 PPh3
0
.033 PPh3
O
O
O
Ph
OH
Ph
1
OH
Ph
OH
00 %, 0 % ee
100 %, 64 % ee
1
00 %, 60 % ee
Figure S4. Hydrogenation of α-methylcinnamic acid B using catalysts formed from 1g
with and without PPh3.

ACCEPTED MANUSCRIPT
S6
Catalytic Hydrogenation of Acetoxy Acid E Using Rh
a
0
.03 Rh(COD) BARF
2
AcO
CO H
AcO
CO H
2
2
0
.066 ligands
0
.5 Cs CO , MeOH, 50 bar H
2
3
2
E
100 %
o
2
5 C, 12 h
1
1
2
2
g + 1gꢀ
h + 1hꢀ
g + 2gꢀ
h + 2hꢀ
0
!
10!
20!
30!
40!
50!
ee!
60!
70!
80!
90!
100!
%
b
0
.03 Rh(COD) BARF
2
AcO
CO H
AcO
CO H
2
2
0
.033 ligand dimer
0
.5 Cs CO , MeOH, 50 bar H
2
3
2
E
100 %
o
2
5 C, 12 h
1g' − 1g'ꢀ
1h' − 1h'ꢀ
2g' − 2g'ꢀ
2h' − 2h'ꢀ
0
!
10!
20!
30!
40!
50!
ee!
60!
70!
80!
90!
100!
%
Figure S5. Hydrogenation of the acetoxy acid E using: a Rh catalysts from the
monodentate ligands 1g, 1h, 2g, and 2h; and b from the same ligands after metathesis (as
in Figure 3).

ACCEPTED MANUSCRIPT
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a
b
d
O
P
c
O
j
e
r
O
q
h
i
l
f
k
N
g
N
o
p
m
OMe
n
k
l
a + b + c
p
i + g + r
o
d
j
f
q
a
b
c
t
O
P
d
e
f
O
l
O
t
g
j
h
m
N
k
i
N
n
q
r
o
s OMe
p
a + b + c + d + e +
l + m + n + o + p
m
f
j
i
s
k
r
h
g

ACCEPTED MANUSCRIPT
S8
a
Ada
b
O
P
d
c
e
f
Ada
O
k
O
q
i
g
l
N
j
h
N
o
p
m
OMe
n
p
e + q
l
b + i + h
g
m + n + d
f
k
j
c
a
Ada
b
c
O
P
d
e
f
Ada
O
k
O
q
i
g
r
l
N
j
h
N
o
p
m
OMe
s
n
e + g
c + d + k + m +
n + o + r
s
p
i
h
f
l

ACCEPTED MANUSCRIPT
S9
a
Ada
b
c
O
P
d
Ada
O
O
e
h
k
f
l
N
j
g
i
N
o
p
m
OMe
n
p
j
a + d + f
+
h
l
k
g + i
m + o + c
b
e
a
Ada
b
c
O
P
d
Ada
O
O
e
h
k
f
l
N
j
g
i
N
o
q
p
m
OMe
n
l
b + c + k +
m + n + o
g
d+ e + f + h
i
q
e
j

ACCEPTED MANUSCRIPT
S10
d
c
a
b
iPrf
O
P
e
i
2
,6-Pr C H
2 6 3
O
O
h
g
m
i
n
N
l
j
k
a
N
q
r
o
OMe
p
c + d + o +
p + q
r
l
g
m
e
k + j
b + i + h
n
f
d
c
a
b
iPrf
O
P
e
i
2
,6-Pr C H
2 6 3
O
O
h
g
m
i
n
N
l
j
k
N
q
r
o
OMe
p
a + b + g +
h + i
c + d + e + f +
o + p + q
g
n
l
j + k

ACCEPTED MANUSCRIPT
S11
a
Ph
b
c
d
O
P
Ph
e
O
O
f
h
g
l
m
N
k
i
j
N
p
r
r
n
q
OMe
o
b + k
a + c + d + n +
o + p
m
f + g + h
l
d
j
i
a
Ph
b
c
d
O
P
Ph
e
O
O
f
h
g
l
r
m
N
k
i
j
b
N
p
r
n
q
OMe
o
a + c + d + l + n + o + p
m
f + g + h
j + i
q
k

ACCEPTED MANUSCRIPT
S12
a
Ph
b
c
d
O
P
Ph
e
O
O
f
h
j
g
l
m
N
k
i
N
p
r
n
q
OMe
o
r
a + c + d + n +
o + p
m
l
b + k
d
j
i + e
f + g + h
a
Ph
b
c
d
O
P
Ph
e
O
O
f
h
j
g
l
m
N
r
k
i
N
p
b
r
n
q
OMe
o
a + c + d + l + n + o + p
m
f + g + h
j + i
q
k

ACCEPTED MANUSCRIPT
S13
a
b
O
P
c
d
e
q
O
O
h
i
k
f
m
N
j
g
N
o
r
l
p OMe
n
a + b + k + l + n + o + p
r
e + f + h
i + g + d
m
b
j
a
b
O
c
d
e
P
q
O
O
h
i
k
f
m
N
j
g
N
o
r
l
p OMe
n
a + b + c + l + n + o
p
f + e + h + q
j + i + g
m
p
j
r

ACCEPTED MANUSCRIPT
S14
a
b
O
P
c
d
e
q
O
O
h
i
k
f
m
N
j
g
N
o
r
l
p OMe
n
a + b + c + k + l + n + o
f + e + h + q
r
d + i + g
m
j
c
a
b
q
O
c
d
e
f
P
O
O
h
i
k
m
N
j
g
N
o
r
l
p OMe
n
a + b + c + l + n + o
k
f + e + h + q
m
p
r
j
d + i + g

ACCEPTED MANUSCRIPT
S15
b
r
c
d
e
q
OMe
h
p
f
n
l
o
i
N
g
O
P
j
N
k
f + e + h + q
O
O
m
a
r
a + b + k + l + n + o
m
j + i + g
c
b
r
c
d
e
q
OMe
h
p
f
n
l
o
i
N
g
O
P
j
N
k
O
O
m
a
r
f + e + h + q
a + b + c + l + n + o
m
i + g
p
j

ACCEPTED MANUSCRIPT
S16
b
r
c
d
e
q
OMe
h
p
f
n
l
o
i
N
g
O
P
j
N
k
O
O
m
a
a + b + k + l + n + o
f + e + h + q
r
j + i + g
m
c
b
r
c
d
e
q
OMe
h
p
f
n
l
o
i
N
g
O
P
j
N
k
O
O
m
a
a + b + c + k + l + n + o
j + i + g
f + e + h + q
m
p
r
j

ACCEPTED MANUSCRIPT
S17
GC Data
Determination of enantiomer using known structure.
0
.02 Ir(COD) BARF
2
0
.044 1a - g
Ph
Ph
Ph
Ph
100 %
CH Cl , 50 bar H
2
2
2
o
2
5 C, 12 h
Hydrogenation using 1a

ACCEPTED MANUSCRIPT
S18
Hydrogenation using 1b
Hydrogenation using 1c
Hydrogenation using 1d

ACCEPTED MANUSCRIPT
S19
Hydrogenation using 1e
Hydrogenation using 1f
Hydrogenation using 1g

ACCEPTED MANUSCRIPT
S20
0
.03 Ir(COD) BARF
2
O
O
0
.066 ligands
Ph
OH
Ph
OH
0
.5 Cs CO , MeOH
2
3
o
5
0 bar H , 25 C, 24 h
2
1
00 %
B
Hydrogenation using 1g
Hydrogenation using 1h

ACCEPTED MANUSCRIPT
S21
Hydrogenation using 2g
Hydrogenation using 2h
Hydrogenation using 1g + 1h

ACCEPTED MANUSCRIPT
S22
Hydrogenation using 1g + 2h
Hydrogenation using 1h + 2g
Hydrogenation using 1h + 2h

ACCEPTED MANUSCRIPT
S23
Hydrogenation using 2g + 2h
Hydrogenation using 1g + 2g

ACCEPTED MANUSCRIPT
S24
0
.03 Rh(COD) BARF
2
O
O
0
.066 ligands
Ph
OH
Ph
OH
0
.5 Cs CO , MeOH
2
3
o
5
0 bar H , 25 C, 24 h
2
1
00 %
B
Hydrogenation using 1g
Hydrogenation using 1h

ACCEPTED MANUSCRIPT
S25
Hydrogenation using 2g
Hydrogenation using 2h
Hydrogenation using 1g + 1h

ACCEPTED MANUSCRIPT
S26
Hydrogenation using 1g + 2h
Hydrogenation using 1h + 2g
Hydrogenation using 1h + 2h

ACCEPTED MANUSCRIPT
S27
Hydrogenation using 2g + 2h
Hydrogenation using 1g + 2g

ACCEPTED MANUSCRIPT
S28
0
.03 Ir(COD) BARF
2
0
.033 1g
O
O
0
.033 PPh3
Ph
OH
Ph
OH
0
.5 Cs CO , MeOH
2
3
o
5
0 bar H , 25 C, 24 h
2
B
100 %
0
.03 Ir(COD) BARF
2
0
.066 1g
O
O
0
.033 PPh3
Ph
OH
Ph
OH
0
.5 Cs CO , MeOH
2 3
o
5
0 bar H , 25 C, 24 h
2
B
100 %

ACCEPTED MANUSCRIPT
S29
2
Stereoselectivities were determined using known structure.
0
.03 Ir(COD) BARF
2
0
.066 ligands
HO
CO Me
HO
CO Me
2
2
CH Cl , 50 bar H
2
2
o
2
2
5 C, 12 h
C
100 %
Hydrogenation using 1g
Hydrogenation using 1h