Highly enantioselective asymmetric isomerization of primary allylic alcohols with an iridium-N,P complex

Article abstract of DOI:10.1002/chem.201101524

Access to chiral aldehydes: The asymmetric isomerization of primary allylic alcohols was studied with a bicyclic phosphine-oxazoline iridium catalyst. This method displays a broad substrate scope and leads to the desired chiral aldehydes with excellent enantioselectivities (see scheme; R¹, R ²=Ar or alkyl). Copyright

Full text of DOI:10.1002/chem.201101524

COMMUNICATION
DOI: 10.1002/chem.201101524
Highly Enantioselective Asymmetric Isomerization of Primary Allylic
Alcohols with an Iridium–N,P Complex
[
a]
[a]
[a, b]
Jia-Qi Li, Byron Peters, and Pher G. Andersson*
The asymmetric transformation of allylic amines to opti-
cally active enamines, catalyzed by rhodium-BINAP com-
plexes, has been well studied and even applied in industry.
The related transition-metal-catalyzed isomerization of pri-
mary allylic alcohols is an atom-economical route to the cor-
responding aldehydes (Scheme 1). Various catalysts have
stituted and 3,3-dialkyl allylic alcohols. The similarities be-
tween Mazetꢀs catalysts and those that perform well in the
[1]
[7]
asymmetric olefin hydrogenation, prompted us to apply
+
À
the iridium-N,P complexes [(L*)Ir
ACHTUNGTNERUNNG( cod)] ACTHUNGTRENNU[GN BAr ] (L*=A–
F
F, Table 1), which were developed in our group for that pur-
[8]
pose, to the asymmetric isomerization of allylic alcohols.
The result was a highly enantioselective isomerization of
both E- and Z-trisubstituted primary allylic alcohols to the
corresponding chiral aldehydes.
We chose (E)-4-methyl-3-phenylpent-2-en-1-ol for the test
substrate with which to screen our catalysts (Table 1). Cata-
lysts with ligands A–D showed little activity for asymmetric
isomerization (Table 1, entries 1 to 4). Surprisingly, a moder-
ate yield and high enantioselectivity were delivered with the
catalyst bearing Ligand E (Table 1, entry 5), despite its simi-
Scheme 1. Asymmetric isomerization of a primary allylic alcohol.
Table 1. Screening of catalysts for the asymmetric isomerization of
(
E)-4-methyl-3-phenylpent-2-en-1-ol.
[2]
been developed for this reaction, however, only a few
asymmetric examples have been reported. Fu and co-work-
ers obtained appreciable results using planar-chiral phospha-
[3]
ferrocene-based rhodium catalysts. In 2009, Mazet and co-
workers showed that Crabtreeꢀs catalyst isomerized a wide
[
a]
[b]
[c]
Entry
L*
Yield
%]
ee
[%]
[
[4]
range of primary allylic alcohols. They later developed
three generations of chiral phosphine-oxazoline-based iridi-
um-N, P catalysts that displayed high activities and selectivi-
[
[
d]
d]
1
2
3
A
B
C
<5
<5
n.a.
[5]
ties in the asymmetric version of this reaction. Recently,
Quintard, Alexakis, and Mazet used the iridium-catalyzed
asymmetric isomerization of primary allylic alcohols in se-
quence with the chiral-enamine-catalyzed functionalization
of aldehydes to access a,b-chiral aldehydes with excellent di-
n.a.
[6]
astereo- and enantioselectivity.
[d]
[d]
<5
<5
n.a.
n.a.
The N,P-ligated iridium catalysts developed by Mazet and
co-workers give excellent selectivities in the asymmetric iso-
merizations of E-trisubstituted primary allylic alcohols, but
only moderate enantiomeric excess (ee) values for Z-trisub-
4
5
6
D
E
F
[
a] J.-Q. Li, B. Peters, Prof. Dr. P. G. Andersson
Department of Biochemistry and Organic Chemistry
Uppsala University, Box 576, 75123, Uppsala (Sweden)
Fax : (+46)18-471-3818
43
>99 (S)
>99 (S)
88
E-mail: pher.andersson@biorg.uu.se
[
b] Prof. Dr. P. G. Andersson
School of Chemistry, University of KwaZulu-Natal
Durban (South Africa)
[
a] Each result is the average from two reactions. [b] Isolated product
yields. [c] Determined by chiral GC/MS. Absolute configurations were
determined by comparing optical rotations to literature values (see
Ref. [3b]). [d] Not applicable.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101524.
Chem. Eur. J. 2011, 17, 11143 – 11145
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11143

larities with C and D. Ligand E differs from C by virtue of
its bulky bicyclic backbone, and from D in that it bears a
bulkier phenyl group rather than a methyl group on the
thiazole moiety. This is consistent with the observations of
Mazet and co-workers that the reaction is highly sensitive to
the catalyst structure, hence the steric accessibility of the
catalysts could be crucial to our system. A catalyst made
from an even bulkier ligand F gave high yield while main-
taining a high enantioselectivity (>99% ee, Table 1, entry 6)
and was therefore tested in the isomerization of a broad
range of primary allylic alcohols.
Table 3. Asymmetric isomerization of Z-trisubstituted primary allylic al-
cohols.
[
a]
1
2
[b]
[c]
[9]
Entry
R
R
Yield
%]
ee
[
[%]
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Me
Et
iPr
Cy
Me
Me
14
38
42
50
n.a.
50
>99 (S)
>99 (S)
>99 (R)
>99 (R)
n.a.
98 (S)
[d]
[d]
A
H
U
G
R
N
U
G
3
2
A
H
U
G
R
N
U
G
2 2
(CH )
Cy
E-trisubstituted allylic alcohols were evaluated first
(
Table 2). Aromatic allylic alcohols with bulky alkyl sub-
[a] Each result is the average from two reactions. No E/Z isomerization
of the allylic alcohols was detected. [b] Isolated product yields. [c] Deter-
mined by chiral GC/MS. Absolute configurations were determined by
comparing the optical rotations of the product to literature values (for
details, see the Supporting Information). [d] Not applicable.
1
stituents (R =iPr and Cy) gave excellent yields, as well as
high enantioselectivities (Table 2, entries 1 and 2). An aro-
matic allylic alcohol with a linear alkyl group on the double
1
bond (R =Et) was isomerized with a similar enantioselec-
tivity (97% ee), but the yield decreased dramatically
(
(
Table 2, entry 3). When the substituent was even smaller
R =Me), the enantioselectivity was only marginally affect-
merization of 3,3-dialkyl allylic alcohols was also attempted.
Nerol was a challenging substrate (Table 3, entry 5), but a
substrate with a larger substituent (Z)-3-cyclohexylbut-2-en-
1-ol was isomerized to the corresponding aldehyde in mod-
erate yield and with excellent enantioselectivity (Table 3,
entry 6).
1
ed, but the aldehyde was recovered in poor yield (Table 2,
entry 4). Thus the catalytic asymmetric isomerization of an
allylic alcohol was significantly impacted by the size of its
1
substituents (R ). An aromatic group was not required, as a
+
À
series of 3,3-dialkyl allylic alcohols were isomerized as well.
Just as was the case for aromatic allylic alcohols, 3,3-dialkyl
allylic alcohols with larger substituents were isomerized
more effectively (Table 2, entries 5–8).
More challenging Z-trisubstituted allylic alcohols were
isomerized using the same catalyst (Table 3). Aromatic allyl-
ic alcohols, interestingly, supplied the desired aldehydes in
uniformly high enantioselectivities, regardless of the steric
properties of their substituents (Table 3, entries 1–4). Yields
were moderate for these substrates except when a very
In summary, [(F)Ir ACHTUNGTREUNNNG( cod)] ACHTUNGERTNNUNG[ BAr ] catalyzed a highly
F
enantioselective asymmetric isomerization of a range of
E- and Z- trisubstituted primary allylic alcohols to the corre-
sponding chiral aldehydes. Notably, the selectivity of this
catalyst was less sensitive to steric effects in the asymmetric
isomerization of Z-trisubstituted allylic alcohols than E-tri-
substituted compounds.
Experimental Section
2
small substituent was present on the double bond (R =Me,
General procedure: A 10 mL microwave tube containing the iridium cat-
Table 3, entry 1), the yield was observed to be poor. The iso-
+
À
alyst [(L*)Ir
A
H
U
G
R
N
U
(cod)]
A
H
U
G
R
N
N
[BAr
F
]
(8 mg) and sealed with a septum was evacu-
three times. Thereafter, dry THF (2 mL) was
ated and refilled with N
2
added. The septum was pierced with a needle and the vessel was sealed
in a hydrogenation bomb. After eight cycles of applying and venting
Table 2. Asymmetric isomerization of E-trisubstituted primary allylic al-
cohols.
2
3 bar of argon, the tube was pressured to 3 bar with H and allowed to
react for 10 min, during which time the orange solution became yellow.
The vessel was vented and removed from the bomb, and the solution was
degassed through three freeze-pump-thaw cycles. Allylic alcohol
(
0.1 mmol) was then added as a stock solution (0.33m) in dry THF, and
[
a]
1
2
[b]
[c]
[10]
Entry
R
R
Yield
%]
ee
2
the reaction was stirred under N for 17 h.
[
[%]
1
2
Cy
iPr
Et
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
86
88
21
>99 (S)
>99 (S)
97 (R)
91 (R)
94 (S)
95 (S)
96 (R)
>99 (R)
[
[
[
[
d]
d]
d]
d]
3
4
5
6
7
8
Acknowledgements
<5
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
)
2
C=CH
A
H
U
G
R
N
U
G
2
)
2
11
24
79
40
This work was supported by the Swedish Research Council (VR), the
Knut and Alice Wallenberg Foundation, AstraZeneca, VR/SIDA, Nord-
Forsk & Nordic Energy Research, the Swedish energy agency and SYN-
FLOW (FP7). We also would like to thank Dr. T. L. Church for careful
reading of the manuscript. J.-Q.L. thanks the China Scholarship Council
for a fellowship.
tBuCH
Cy
tBu
2
[
a] Each result is the average from two reactions. No E/Z isomerization
of the allylic alcohols was detected. [b] Isolated product yields. [c] Deter-
mined by chiral GC/MS. Absolute configurations were determined by
comparing the optical rotations of the product to literature values (for
details, see the Supporting Information). [d] Trace amounts of the a,b-un-
saturated aldehyde were observed (ref. [3b]).
Keywords: aldehydes
·
allylic alcohols
·
asymmetric
catalysis · iridium · isomerization · N, P ligands
11144
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11143 – 11145

Highly Enantioselective Asymmetric Isomerization
COMMUNICATION
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[
9] Mazet and co-workers reasoned that a bulky trialkylphosphine
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variation of the Crabtree catalyst that combines a trialkylphosphine
[
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2
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[
10] It was observed that if the solution containing the catalyst was not
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strate, competing hydrogenation took place resulting in trace
amounts of saturated alcohols.
5
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[
6] A. Quintard, A. Alexakis, C. Mazet, Angew. Chem. 2011, 123, 2402–
Received: July 5, 2011
Published online: August 23, 2011
2
406; Angew. Chem. Int. Ed. 2011, 50, 2354–2358.
Chem. Eur. J. 2011, 17, 11143 – 11145
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11145