Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols Using MaxPHOX Ligands: Experimental and Theoretical Study

Article abstract of DOI:10.1002/cctc.202000442

The asymmetric isomerization of primary allylic alcohols to chiral aldehydes using iridium-catalysts bearing P,N-MaxPHOX ligands has been studied. These catalysts can be fine-tuned as they present three different stereogenic centers to modulate both the reactivity and enantioselectivity of a family of different substrates. The experimental part is supported by a DFT study of the reaction mechanism, which provides new insights into the key steps of this transformation.

Full text of DOI:10.1002/cctc.202000442

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic
Alcohols Using MaxPHOX Ligands: Experimental and Theoretical
Study
Authors: Antoni Riera, Albert Cabre, Martí Garçon, Albert Gallen,
Lorenzo Grisoni, Arnald Grabulosa, and Xavier Verdaguer
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10.1002/cctc.202000442
ChemCatChem
FULL PAPER
Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic
Alcohols Using MaxPHOX Ligands: Experimental and Theoretical
Study
Albert Cabré,[a,b]§ Martí Garçon,[a,b]§ Albert Gallen,[c] Lorenzo Grisoni,[a] Arnald Grabulosa,[c,d] Xavier
Verdaguer[a,b] and Antoni Riera*[a,b]
[a]
Dr. A. Cabré, M. Garçon, L. Grisoni, Prof. X. Verdaguer and Prof. A. Riera
Institute of Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac 10, Barcelona 08028, Spain
E-mail: antoni.riera@irbbarcelona.org
[b]
[c]
[d]
Dr. A. Cabré, Prof. X. Verdaguer and Prof. A. Riera
Departament de Química Inorgànica i Orgànica, Secció Orgànica. Universitat de Barcelona, Martí i Franquès 1, Barcelona 08028, Spain.
Dr. A. Gallen and Dr. Arnald Grabulosa
Departament de Química Inorgànica i Orgànica, Secció Inorgànica. Universitat de Barcelona, Martí i Franquès 1, Barcelona 08028, Spain.
Dr. Arnald Grabulosa
Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona 08028, Spain.
§
Authors contributed equally.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Later on, in 2009, Mazet and co-workers showed thhe capacity
Abstract: The asymmetric isomerization of primary allylic alcohols to
chiral aldehydes using iridium-catalysts bearing P,N-MaxPHOX
ligands has been studied. These catalysts can be fine-tuned as they
present three different stereogenic centers to modulate both the
reactivity and enantioselectivity of a family of different substrates.
The experimental part is supported by a DFT study of the reaction
mechanism, which provides new insights into the key steps of this
transformation.
of Crabtree’s catalyst (Figure 1, B) to isomerize a wide range of
primary allylic alcohols.[10] They later developed three
generations of chiral phosphine-oxazoline-based iridium-P,N
catalysts that displayed high activity and selectivity in the
asymmetric version of this reaction (Figure 1, D).[4b,9c] The
iridium catalysts with P,N-ligands developed by Mazet and co-
workers gave excellent selectivities in the asymmetric
isomerizations of E-trisubstituted primary allylic alcohols, but
only moderate enantiomeric excess (ee) values for Z-
trisubstituted and 3,3-dialkyl allylic alcohols.
Introduction
The need for chemical reactions with a lower environmental
impact has focused the attention on the twelve principles of
green chemistry.[1] The efficiency of a process can be defined in
terms of atom economy, complexity and selectivity.[2] In this
context, catalytic reactions are particularly desirable. Catalytic
isomerization reactions, which offer perfect atom economy and
minimal generation of waste, fulfill all these criteria.
Enantioselective versions of these catalytic isomerizations are
thus highly demanded. As a pioneering example, Noyori’s
asymmetric isomerization of allylic amines to optically active
enamines, catalyzed by rhodium-BINAP complexes stands out
as one of the most industrially relevant catalytic reactions.[3] In
contrast, although some studies have been reported in the last
decade,[4] the asymmetric isomerization of allylic alcohols still
lacks general and efficient synthetic protocols.
Figure. 1. State-of-the-art ligands and catalysts used in isomerization of
primary allylic alcohols.
The selective, metal-catalyzed isomerization of primary allylic
alcohols into the corresponding saturated carbonyl compounds
is an atom-economical route to the corresponding aldehydes.[5]
Allylic alcohols are therefore masked synthons for preparing
carbonyl compounds, including functionalized ones via tandem
processes.[5a,6] However, several drawbacks have prevented the
widespread use of this method: limited reaction scope, high
catalyst loadings or elevated temperatures, long reaction times
and poor catalyst accessibility. During recent decades, many
transition metals have been used, but ruthenium,[7] rhodium[8]
and iridium[4b,9] complexes dominate the field in the
enantioselective version.
To address this limitation, Andersson and co-workers
developed other P,N-ligands bearing aryl substituents at the
phosphorus atom (Figure 1, C).[9e] As a result, the asymmetric
isomerization of both E- and Z-trisubstituted primary allylic
alcohols gave the corresponding chiral aldehydes with high ee
values. However, the behavior of each substrate in terms of
reactivity
was
completely
different.
Although
high
enantioselectivity was achieved for most examples, the yields for
Z isomers were very low compared to their E-counterparts.
Moreover, in the scope of E-trisubstituted primary allylic
alcohols, excellent yields were afforded for bulky alkyl
substituents (such as cyclohexyl or isopropyl), whereas the
conversion was extremely low for small alkyl groups (such as
methyl).
In 2000, Fu and co-workers pioneered the research in this
field obtaining appreciable results
phosphaferrocene-based rhodium catalysts (Figure 1, A).
with planar-chiral
[8a]
7
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10.1002/cctc.202000442
ChemCatChem
FULL PAPER
At that point, we focused on studying the mechanism behind
the iridium-catalyzed version of this reaction. Various
mechanisms for this reaction are postulated in the literature.[4a]
These strongly depend on the nature of the catalyst and the
reaction conditions. However, and surprisingly, no computational
study of its mechanism has been done to date. We consider that
such a study would provide crucial knowledge that would allow
us to determine why the reactivity differs so greatly in function of
the substitution pattern. Moreover, this study paves the way to
designing and synthesizing new, modular iridium catalysts that
could improve the efficiency of this reaction.
out using (E)-5a as model substrate in THF at room temperature
using 5 mol% of the precatalyst (Table 1). The iridium
complexes were activated by slowly bubbling hydrogen directly
into a solution of the catalyst in anhydrous THF. After 5 min, the
vessel was fully degassed and the substrate in anhydrous THF
was added. This is the standard synthetic protocol used to avoid
competing hydrogenation processes in isomerization reactions.
After only 2 h, the reaction showed full conversion in all cases,
and aldehyde 6a was obtained as a single product (Table 1,
entries 1-4). Remarkably, when using precatalyst 3b the ee was
maximized (86% ee, Table 1, entry 3). We addressed whether
the high activity of these catalysts would allow the reactions to
run at low temperature. Taking (E)-5a and catalyst 3b, we
performed the reaction at -20 ºC overnight. Using the same
catalyst loading (5 mol%), the reaction gave 50% of conversion
and the enantioselectivity increased up to 90% ee (Table 1,
entry 5), compared to 86% when performed at room temperature
(Table 1, entry 3,).
Our research group has recently developed a new family of
iridium complexes bearing chiral P,N ligands (MaxPHOX),[11,12]
which present three distinct chiral centers, so up to four
diastereoisomers with completely different catalytic properties
can be tested (Figure 2). Moreover, the substituent in the
oxazoline ring can also be modified to modulate the steric effect.
These catalysts have been successfully applied in the
asymmetric hydrogenation of 2-aryl allyl phthalimides,[13] cyclic
enamides,[11b] and N-aryl[14] and N-alkyl imines[15] providing
excellent results. Moreover, they have also been used in the
asymmetric isomerization of a Boc-protected allyl amine to its
corresponding enamide achieving excellent enantioselectivity.[16]
Thus, we consider that a dual experimental-theoretical study
using MaxPHOX ligands would be highly complementary to this
field, providing valuable data.
We then proceeded to modify the oxazoline substituent.
Replacement of the isopropyl by a phenyl (catalyst 3a) afforded
the product with lower enantioselectivity (Table 1, entry 6).
Gratifyingly, when the size of the substituent was increased
using a tert-butyl group, the ee reached 95% ee (catalyst 3c,
Table 1 entry 7). Alternatively, and in order to facilitate the
synthetic protocol, the precatalyst was activated (with H2 for 2
min in the pressure reactor and then fully degassed three times)
in the presence of the substrate in CH2Cl2. No significant
differences in terms of yield and enantioselectivity were detected
(Table 1, entry 8).
Table 1. Iridium-catalyzed asymmetric isomerization of (E)-5a to 6a.
Entry
1
catalyst
Conv. (%)a
ee (%)b
32 (S)
18 (S)
86 (R)
56 (R)
90 (R)
61 (R)
95 (R)
95 (R)
1b-(SPRS)
2b-(SPSS)
3b-(SPRR)
4b-(SPSR)
3b-(SPRR)
3a-(SPRR)
3c-(SPRR)
3c-(SPRR)
99
99
99
99
50
99
98
99
2
3
4
5c
6
Figure 2. The 4 diastereoisomers of Ir-MaxPHOX pre-catalysts.
7d
8d,e
Herein, we report the application of the Ir-MaxPHOX catalysts
to the enantioselective isomerization of primary allylic alcohols.
The best substrate-catalyst match was found by fine-tuning the
stereochemistry and the steric hindrance of the oxazoline-
substituent of the catalyst. Thus the corresponding chiral
aldehydes were obtained in good to excellent ee values. In
addition, the first theoretical study on the reaction mechanism is
described.
The reaction was performed in a sealed vial with 0.1 mmol of (E)-5a and
using 5 mol% of catalyst loading, under stirring for 2 h. a Determined by 1H
NMR spectroscopy. b Measured by chiral HPLC. cThe reaction was performed
at -20ºC, overnight. d The reaction was left stirring overnight. eActivation of the
catalyst was performed in the presence of the substrate in dichloromethane.
The substrate scope was next examined. Using the best
catalyst 3c under the optimized conditions, we modified the aryl
group of the allyl alcohols, maintaining an isopropyl as R1
substituent (E-isomers, 5a-d). Excellent results were achieved
in all cases (Table 2, entries 1-4) both in terms of reactivity and
enantioselectivity (93-96% ee). Other alkyl substituents in the
R1 position of the allylic alcohols were then tested. The lower
reactivity of these substrates led us to re-optimize the catalyst.
Following our standard protocol, we first searched the best of
Results and Discussion
The four diastereoisomers of the MaxPHOX family of ligands
with an isopropyl as substituent in the oxazoline ring (1b-4b,
Figure 2) were synthesized and tested as precatalysts in allylic
alcohol isomerization reactions. These reactions were carried
7
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10.1002/cctc.202000442
ChemCatChem
FULL PAPER
the four diastereomers. We used the doubly substituted
isopropyl ligands (1b, 2b, 3b, 4b) to do this initial screening.
With the best diastereomer in hand, we then modified the
substituent of the oxazoline ring, selecting among phenyl,
isopropyl and tert-butyl depending of the steric requirements.
Thus, for large alkyl substituents, such as cyclohexyl (5e), the
isopropyl-substituted catalyst 3b gave excellent activity and
enantioselectivity (Table 2 entry 5). Conversely, the substrate
5g with a small methyl group afforded the aldehyde in low
yields and enantioselectivities. (Table 2 entry 6). The behavior
of the allylic alcohols with small substituents is consistent with
previous reports.[4b]
improve the ee by choosing the most appropriate diastereomer
in each case.
We then studied the more challenging substrates with dialkyl
substituents. The allylic alcohol with cyclohexyl and methyl
substituents (E)-5h gave poor results with catalyst 3b (table 2,
entry 11) which were improved to 88% by switching to catalyst
1c (Table 2, entry 12). Finally, geraniol was used as an
industrially important example of dialkyl allylic alcohol. Again,
catalyst 1b gave the best results (Table 2, entry 13) affording
the chiral aldehyde 6i with synthetically useful yield in 73% ee.
We then turned our attention to the mechanism of this
transformation. Various mechanisms have been proposed for
the isomerization of allylic alcohols catalyzed by organometallic
complexes. However, the mechanism catalyzed by iridium-
complexes has never been corroborated by calculations. A
general mechanistic picture was proposed by Mazet and co-
workers.[9c] After hydrogenation of the COD ligand of the
precatalyst, the actual catalyst, is proposed to be an iridium
dihydride species cat1. The allylic alcohol would coordinate to
the catalyst affording the intermediate Int1. This intermediate
would experience an olefin insertion into a Ir–H bond giving the
second intermediate Int2. The β-hydride elimination would
generate the coordinated enol species Int3 which can then
simply tautomerize to furnish the aldehyde as final product
(Figure 3).[4b,9] Using this proposal as the starting point, DFT
calculations were conducted on the key steps of the mechanism
(see Supporting Information for computational details).
We then moved to the Z isomers. Using catalyst 3b, substrates
(Z)-5a and (Z)-5e gave good results although with lower
enantioselectivity than the (E) isomers. In both cases, the
reactivity and enantioselectivity were synthetically useful (Table
2, entry 7 and 8). For these substrates, an increase in the
bulkiness of the oxazoline substituent (catalyst 3c) led to an
excessive lowering of reactivity, thus yielding low conversions.
Table 2. Scope of the asymmetric iridium-catalyzed isomerization of primary
allylic alcohols.
R-OH
R1
R2
cat.
yield
(%)a
ee (%)b
1c
2
(E)-5a
(E)-5b
(E)-5c
(E)-5d
(E)-5e
(E)-5g
(Z)-5a
(Z)-5e
(Z)-5f
(Z)-5f
(E)-5h
(E)-5h
(E)-5i
iPr
iPr
iPr
iPr
Cy
Me
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
3c
96
94
88
80
97
26
78
85
27
53
86
85
57
95 (R)
93 (R)
94 (R)
96 (R)
87 (S)
57 (R)
76 (S)
71 (R)
66 (S)
92 (S)
34 (R)
88 (S)
73 (S)
4-MePh
3-ClPh
3-MeOPh
Ph
3c
3
3c
4
3c
5
ent-3b
ent-3b
3b
6
Ph
7
iPr
8c
9
Cy
ent-3b
3b
tBu
10
11
12
13
tBu
ent-1b
3b
Cy
Cy
1c
(CH2)2CH
=C(Me)2
ent-1b
The reaction was performed in a sealed vial, using 5 mol% of catalyst loading
Figure 3. Proposed catalytic cycle for the isomerization.
a
b
for 17 h. 1H NMR yield using 1,4-dimethoxybenzene as internal standard.
Measured by chiral GC. c7 mol% of catalyst was used to completion.
First, the structure of the intermediates Int1 formed by
coordination of the catalytic species to the allylic alcohol was
studied. Using complex 3b as catalyst and 5a as allylic alcohol,
we fully optimized the structures at the DFT/B3LYP-D3 level. In
general, the cis-dihydride-Ir-complexes derived from catalyst 3b
can exist as four possible diastereomeric complexes that we
label A-D (Figure 4). Previous studies by Pfaltz and Mazet on
iridium dihydride phosphinooxazoline complexes showed that
the isomers with both hydrides in cis to the P atoms (C and D)
are the most energetically favorable isomers,[17] and hence they
Surprisingly, substrate (Z)-5f with a tert-butyl substituent as R2,
gave poor results using catalyst 3b (Table 2, entry 9).
Therefore, we had to use our catalyst-optimization protocol.
Gratifyingly, we found that catalyst 1b enhanced the
enantioselectivity, increasing it to 92% ee (Table 2, entry 10).
This is a good example of fine-tuning of the catalyst. Although
both cyclohexyl and tert-butyl groups can be considered large
alkyl groups, the modular nature of MaxPHOX ligands can
7
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10.1002/cctc.202000442
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proposed them to be the catalytically active species in the
isomerization of allylic alcohols.[9a].
coplanarity restraints, this approach will cause a steric clash
between the cis-phosphine substituents and the bulkier
substituents of the alkene in some cases. Therefore, there are
only two significant low-energy reaction pathways starting either
from Int1(5a)-A-si (path a) and Int1(5a)-B-re (path b). The
latter, that we considered the energy reference (0.0 kcal·mol-1),
being 5.1 kcal·mol-1 more stable than the former. Concerted
migratory insertion of the olefin then occurs with the coplanar
Ir–Htrans-to-P bond generating intermediates Int2(5a)-A-si and
Int2(5a)-B-re through transition states TS1(5a)-A-si (11.2
kcal·mol-1) and TS1(5a)-B-re (4.9 kcal·mol-1). These five-
coordinate Ir-alkyl intermediates already have the stereocenter
and thus the absolute configuration of the final product is
already determined, i.e. (S) for Int2(5a)-A-si and (R) for
Int2(5a)-B-re. The mechanism continues from these
intermediates via β-H elimination to generate the corresponding
enol intermediates.
Figure. 4. General structure of the four possible diastereomers of
Ir(MaxPHOX) cis-dihydride complexes.
The two enantiotopic faces (re and si) of the allyl alcohol 5a can
coordinate to each of the four diastereomeric complexes (A-D).
Of note, the generation of one enantiomer of the product or the
other only depends on which face of the alkene (re or si)
coordinates to Ir for a given alkene with a defined (E or Z)
stereochemistry.
Consistent with the results by Pfaltz and Mazet, Int1(5a)-C (re
and si) and Int1(5a)-D (re and si) were more stable than
Int1(5a)-A-si and Int1(5a)-B-re. However, to our surprise, all
our attempts to continue the mechanism from complexes
Int1(5a)-C and Int1(5a)-D with the alkene moiety at the
equatorial plane trans to P, by insertion of the olefin into an Ir–H
bond were unsuccessful. All possible insertions were
considered (insertion into the Ir–Htrans-to-N bond or the Ir–Hcis-to-N
bond, coordination from the re or si faces of the olefin, E and Z
isomers of the olefin), but none of the 16 possible pathways
calculated, i.e. 8 for Int1(5a)-C and 8 for Int1(5a)-D, were
feasible or energetically favorable. At this point, we looked for
the coordination to the less stable isomers Int1(5a)-A and
Int1(5a)-B. Since all these complexes are likely to be in
equilibrium it is feasible that the less stable intermediates were
the reactive ones, as in the classical mechanism of the
hydrogenation of functionalised olefins with [Rh(PP)(diene)]+. In
this respect, we located the corresponding transition states for
olefin insertion, i.e. TS1(5a)-A-si and TS1(5a)-B-re (Figure 5).
This is arguably the most important step of the mechanism
since it is when the chiral center is generated. Consequently,
close inspection is warranted. Both pathways will generate the
opposite enantiomer. Furthermore, the face that coordinates to
Ir also determines the most favorable pathway between
configurations A and B. This effect can be traced back to steric
clashes caused by the stereoelectronic constraints of the
migratory insertion step. For this step to happen, the Ir–H bond
has to be coplanar with the C=C bond, so that the orbitals can
overlap efficiently. Analysis of the MO and NBO showed
significant involvement of the Ir d orbitals as well as the σ(Ir–H),
σ*(Ir–H), π(C=C), π*(C=C) orbitals in the transition state during
the concerted bond breaking and forming process.
Figure 5. Relevant transition states for the migratory insertion.
Intermediates Int2(5a)-B-re and Int2(5a)-A-si possess
3
hydrogen atoms in the β-position that are prone to elimination.
However, one of these atoms is the hydrogen of the newly
formed stereocenter, and therefore its elimination would
regenerate the starting materials. The other two are in the CH2-
OH group (Figure 6). Since the two hydrogens are not
equivalent, β-elimination of one will produce the (E)-enol,
whereas the elimination of the other hydrogen will generate the
(Z)-enol. In order to align the C–H bonds with the Ir–C bond to
promote the β-H elimination (as the microscopic reverse of the
migratory insertion, this step also requires co-planarity), the
alcohol will decoordinate from the Ir center. This process
generates two vacant coordination sites in cis relative positions
from which β-elimination can occur. Depending on the site that
undergoes the β-elimination two different Ir dihydride
complexes are obtained, namely with a cis-dihydride or trans-
dihydride configuration. Decoordination of the enol from the cis-
dihydride complex closes the catalytic cycle. The trans-
dihydride pathway is usually less favorable, but with the present
data it cannot be ruled out as a competitive pathway (see SI for
details). In this case, an extra isomerization step would be
required to regenerate the catalytic species.
Despite the multiple pathways for β-hydride elimination, after
the tautomerization of the enol to the aldehyde and
regeneration of the initial catalytic species all these divergent
pathways converge and are irrelevant to the product formation.
Consequently, the simplest and most favorable pathway
It was observed that the Ir–Htrans-to-P bond is the most accessible
Ir-hydride bond and hence olefin insertion into this bond offers
the lowest energy barriers (Figure 7). Combined with the
7
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10.1002/cctc.202000442
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examined leads to Int3(5a)-B-re. From this intermediate,
coordination of 5a to the axial vacant site and displacement of
the enol would regenerate Int1(5a)-B-re, thus closing the
catalytic cycle. This step combined with the tautomerization of
the enol was found to be clearly exergonic (Figure 7, inset).
Our calculations show that the barriers for the two key steps of
the mechanism are relatively low. This finding is in agreement
with the experimental observation that the proposed catalytic
species Ir-H,H is active even at -20 ºC. While the β-hydride
elimination has the highest barriers, they are similar to the ones
for the backwards reaction from Int2(5a) to Int1(5a). This
observation might suggest that the first step is not in rapid
equilibrium and hence the Curtin-Hammett principle is not
applicable. Therefore, the selectivity is likely to be determined
earlier in the pathway, despite this second step being rate
determining. To further study this point, we can ponder an
extreme case in which the coordination of the alcohol was fast
and reversible. Under these conditions, the enantioselectivity
would be determined by the ΔΔGǂ between the two TSs of the
migratory insertion, as predicted by the Curtin-Hammett
principle.[18] Based on our data the most likely scenario is that
the coordination equilibria are not fast enough and the
enantioselectivity is quantitatively determined by the two
elemental steps, i.e. coordination and migratory insertion.
Nevertheless, the energy difference between the two transition
states TS1, can be used as
qualitatively explain the observed trends in enantioselectivity.
For 5a, this ΔΔGǂ is very high (6.3 kcal·mol-1). It should then
a convenient indicator to
TS1
be expected that the pathway leading to the (R)-enantiomer
would be preferred This fact is in good agreement with the high
enantioselectivity experimentally observed.
Figure 6. Relevant transition states for the β-H elimination.
Figure. 7. Free energy profiles (in kcal·mol-1) for the key steps of the two most favorable pathways of the conversion of 5a to 6a. The lowest energy path leads to
the experimentally favored enantiomer (R) of the product. Inset: Thermochemistry (in kcal·mol-1) for product formation and closure of the catalytic cycle.
The robustness of the proposed pathway was evaluated by
computing the mechanism using Z)-5a and (E)-5g substrates as
models. In both cases, a similar mechanistic pathway was
located. As expected, the lowest energy pathway for (Z)-5a led
to the (S)-enantiomer of the product, which is in good
agreement with the experimental observation and is the
opposite enantiomer of the product obtained from (E)-5a (See
SI for further details).
In the case of (E)-5g, a substrate with a methyl substituent,
subtle differences were observed (Figure 8). First, the energy
difference between both TS1, was much smaller (1.9 kcal·mol-1)
than in the case of (E)-5a (6.3 kcal·mol-1). This observation is in
agreement with the lower enantioselectivity found for (E)-5g.
The second difference was the low conversion found
experimentally. The energy barriers and thermodynamics of the
two key steps of the mechanism do not show any significant
difference that could explain the experimental yield. A plausible
7
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10.1002/cctc.202000442
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explanation can be found by considering the stability of the
different Int1 obtained upon coordination of the allylic alcohol to
the diastereomeric complexes A–D. Considering the most
favorable enantiotopic face (re or si) in each case (see SI for full
details), Int1(5a)-C-re (-5.5 kcal·mol-1) and Int1(5a)-D-si (-3.5
kcal·mol-1) were more stable than Int1(5a)-A-si (5.1 kcal·mol-1)
and Int1(5a)-B-re (0.0 kcal·mol-1). However, these energy
differences were easily overcome and the less stable isomers
Int1(5a)-A-si and Int1(5a)-B-re were the active species (vide
supra). On the other hand, for 5g these energy differences were
more pronounced, and it might be more energetically
demanding to access the active isomers, thereby leading to a
decrease in reactivity. For instance, the non-productive isomers
Int1(5g)-C-re (-7.9 kcal·mol-1) and Int1(5g)-D-si (-6.4 kcal·mol-
1) were markedly more stable than Int1(5g)-B-re (0.0 kcal·mol-1)
and Int1(5g)-A-si (3.3 kcal·mol-1).
Figure. 8. Free energy profiles (in kcal·mol-1) for the key steps of the two most favorable pathways for the conversion of (E)-5g to 6g. The lowest energy path
leads to the experimentally favored enantiomer (R) of the product. Inset: Thermochemistry (in kcal·mol-1) for product formation and closure of the catalytic cycle.
Experimental Section
Conclusion
General Methods. All reactions were carried out in anhydrous solvents
under nitrogen atmosphere. THF and CH2Cl2 were dried in a purification
system. Other commercially available reagents and solvents were used
without further purification. Thin layer chromatography was carried out
using TLC-aluminum sheets with silica gel. Flash chromatography was
performed by using an automated chromatographic system with
hexane/ethyl acetate gradients as eluent, unless otherwise stated. NMR
Here we have studied the use of the P-stereogenic ligands
MaxPHOX to the catalytic asymmetric isomerization of allylic
alcohols to aldehydes. This family of ligands has four possible
diastereomers (1-4) that can be fine-tuned by changing the
oxazoline substituent (a: Ph; b: iPr or c: tBu). The isomerization
of (E)-3,3-disubstituted allyl alcohols with aromatic and isopropyl
groups gave excellent yields and enantioselectivities (up to 96%
ee) using catalyst 3c. With less reactive substrates the reactivity
can be improved using catalyst 3b. With substrates with dialkyl
substituents the best catalysts were 1b or 1c.
1
spectra were recorded at 23 °C on a 400 MHz apparatus. H NMR and
13C NMR spectra were referenced either to internal TMS or to residual
solvent peaks. Chemical shifts are given in ppm. Optical rotations were
measured at room temperature (25 °C) and concentration is expressed
in g/100 mL. IR spectra were recorded in a FT-IR apparatus. HRMS
were recorded in a LTQ-FT spectrometer using the nanoelectrospray
technique. MaxPHOS catalysts were prepared as previously
described.[11,12] For the characterization data of catalyst 3c, see
Supporting Information.
DFT studies provided new insight into the mechanism of this
transformation. While the general picture of migratory insertion
and β-hydride elimination as the key steps is maintained, our
calculations showcase a significant mechanistic complexity that
has previously been overlooked. The structure of the main
transition states and intermediates was optimized. This
optimization has led to finding alternative isomeric pathways that
complement the understanding of this transformation. Further
mechanistic studies will be performed to allow for rational
catalyst design.
General Experimental Procedure for the Synthesis of Allylic
Alcohols. Step 1: Horner-Wadsworth-Emmons (HWE) olefination. To a
stirred solution of triethylphosphonoacetate (1.0 equiv., 20 mmol) in
hexane (20 mL) was added dropwise n-BuLi (1.0 equiv., 20 mmol, 2,5 M
in hexane) at -78°C. After stirring for 30 minutes at -78°C it was left stir at
0°C for other 30 minutes. The appropriate ketone (1.0 equiv., 20 mmol)
was then added dropwise and the reaction was refluxed overnight. The
7
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000442
ChemCatChem
FULL PAPER
mixture was cooled to ambient temperature, quenched with a saturated
aqueous Na2CO3 solution and extracted with Et2O. The ethereal organic
phase was washed with water and dried over MgSO4. After filtration the
crude mixture was purified by flash chromatography on silica gel
(hexanes : EtOAc = 20 : 1). The E-isomer eluted first than the more polar
Z-isomer. Step 2: The ester (1.0 equiv.) was dissolved in Et2O and
cooled down to -78°C. DIBAL-H (2.2 equiv., 1 M in hexane) was added
dropwise. The reaction mixture was stirred at -78°C for 3h. The cooling
bath was removed until the reaction reached room temperature. The
solution was quenched with a saturated solution of NH4Cl at 0°C and
stirred at room temperature for 1h producing a white precipitate. The
precipitate was filtered through a pad of Celite® and washed with Et2O,
the resulting solution was washed with brine and dried over MgSO4. After
concentration under vacuum, the residue was purified by flash
chromatography on silica gel (Et2O/pentane, 1 : 3) as colourless oils.
1.64 (d, J = 1.3 Hz, 3H), 1.43 (s, 1H), 1.29 – 1.15 (m, 5H). 13C NMR (101
MHz, CDCl3) δ 144.77, 121.47, 59.42, 47.12, 31.70, 26.63, 26.31, 14.62.
General Procedure for the Iridium-Catalyzed Asymmetric
Isomerization of Primary Allylic Alcohols (GP).
A vial containing 5 mol% of catalyst (5 mg) –unless otherwise indicated-
and a magnetic stirrer was sealed and purged with N2. Thereafter, allylic
alcohol (0.2 mmol, 1.0 equiv.) dissolved in 2 mL of anhydrous CH2Cl2
were added. The solution was bubbled with a balloon of H2 for 2 minutes,
until the orange solution became yellow. The balloon was removed and
the vessel was degassed and purged with N2. The reaction was stirred
under N2 for the indicated time. Afterwards, the solvent was evaporated
and the crude was analysed by 1H NMR to calculate conversion and yield
(%) using 1,4-dimethoxybenzene as internal standard. Enantiomeric
excesses (%) were determined by chiral GC.
(R)-4-methyl-3-phenylpentanal, (R)-6a. Following GP and using (E)-5a,
catalyst 3c-(SPRR) was used and the reaction was left stirring for 17
hours. The desired product was obtained as an oil (96% yield). [α]D25: -
16.1 (c 0.6, CHCl3), lit.[8b] [α]D24: +14.9 (c 1.04, dichloromethane, for S
enantiomer with 83% ee). 1H NMR (400 MHz, CDCl3) δ 9.60 (t, J = 2.2
Hz, 1H), 7.32 – 7.26 (m, 2H), 7.23 – 7.18 (m, 1H), 7.17 – 7.13 (m, 2H),
2.95 (ddd, J = 9.5, 7.5, 5.5 Hz, 1H), 2.82 – 2.71 (m, 2H), 1.91 – 1.82 (m,
1H), 0.95 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 202.50, 142.58, 128.35, 128.23, 126.51, 47.17, 46.93,
33.40, 20.53, 20.26. Chiral GC: 95% ee, retention times = 23.9 min (S,
minor), 24.3 min (R, major).
(E)-4-methyl-3-phenylpent-2-en-1-ol. (2-steps, 31% yield). 1H NMR
(400 MHz, CDCl3) δ 7.32 – 7.23 (m, 3H), 7.21 – 7.15 (m, 2H), 5.49 (td, J
= 6.7, 0.5 Hz, 1H), 4.37 (d, J = 6.7 Hz, 2H), 3.03 (pd, J = 7.0, 0.5 Hz, 1H),
1.45 (s, 1H), 1.06 (d, J = 7.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ
150.02, 142.18, 128.35, 127.59, 127.29, 126.59, 58.95, 29.74, 21.94.
(Z)-4-methyl-3-phenylpent-2-en-1-ol. (2-steps, 33% yield). 1H NMR
(400 MHz, CDCl3) δ 7.35 – 7.29 (m, 2H), 7.29 – 7.23 (m, 1H), 7.09 – 7.05
(m, 2H), 5.63 (td, J = 6.8, 1.3 Hz, 1H), 3.94 (dd, J = 6.8, 0.8 Hz, 2H), 2.65
– 2.49 (m, 1H), 1.03 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ
150.91, 140.15, 128.46, 127.92, 126.82, 123.12, 60.43, 35.66, 21.55.
(S)-4-methyl-3-phenylpentanal, (S)-6a. Following GP and using (Z)-5a,
1
(E)-4-methyl-3-(p-tolyl)pent-2-en-1-ol.[8b] (2 steps, 39% yield). H NMR
catalyst 3b-(SPRR) was used and the reaction was left stirring for 17
25
hours. The desired product was obtained as an oil (78% yield). [α]D
:
(400 MHz, CDCl3) δ 7.14 – 7.04 (m, 4H), 5.47 (t, J = 6.8 Hz, 1H), 4.35 (d,
J = 6.8 Hz, 2H), 3.02 (hept, J = 7.0 Hz, 1H), 2.34 (d, J = 0.6 Hz, 3H), 1.05
(d, J = 7.0 Hz, 6H).
+10.4 (c 0.3, CHCl3), lit. [8b] [α]D23: +14.9 (c 1.04, dichloromethane, for S
enantiomer with 83% ee). 1H NMR (400 MHz, CDCl3) δ 9.60 (t, J = 2.2
Hz, 1H), 7.32 – 7.26 (m, 2H), 7.23 – 7.18 (m, 1H), 7.17 – 7.13 (m, 2H),
2.95 (ddd, J = 9.5, 7.5, 5.5 Hz, 1H), 2.82 – 2.71 (m, 2H), 1.91 – 1.82 (m,
1H), 0.95 (d, J = 6.7 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 202.50, 142.58, 128.35, 128.23, 126.51, 47.17, 46.93,
33.40, 20.53, 20.26.Chiral GC: 76% ee, retention times = 23.9 min (S,
major), 24.6 min (R, minor).
(E)-3-(3-chlorophenyl)-4-methylpent-2-en-1-ol.[21] (2-steps, 38% yield).
1H NMR (400 MHz, CDCl3) δ 7.27 – 7.16 (m, 3H), 7.06 (dt, J = 6.6, 1.9
Hz, 1H), 5.48 (t, J = 6.7 Hz, 1H), 4.36 (d, J = 6.6 Hz, 2H), 3.01 (hept, J =
7.0 Hz, 1H), 1.05 (d, J = 7.0 Hz, 6H).
(E)-3-(3-methoxyphenyl)-4-methylpent-2-en-1-ol. (2-steps, 41% yield).
1H NMR (400 MHz, CDCl3) δ 7.20 (ddd, J = 8.1, 7.5, 0.4 Hz, 1H), 6.83 –
6.74 (m, 2H), 6.72 (dd, J = 2.6, 1.6 Hz, 1H), 5.50 (t, J = 6.7 Hz, 1H), 4.36
(d, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.08 – 2.95 (m, 1H), 1.06 (d, J = 7.0 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 158.90, 149.82, 143.64, 128.53,
127.23, 120.91, 114.36, 111.85, 58.92, 55.16, 29.74, 21.97.
(E)-3-cyclohexyl-3-phenylprop-2-en-1-ol. (2-steps, 29% yield). 1H NMR
(400 MHz, CDCl3) δ 7.30 – 7.24 (m, 3H), 7.17 – 7.14 (m, 2H), 5.47 (t, J =
6.8 Hz, 1H), 4.36 (d, J = 6.8 Hz, 2H), 2.62 (tt, J = 11.4, 3.2 Hz, 1H), 1.73
(dd, J = 9.3, 3.0 Hz, 2H), 1.67 – 1.61 (m, 3H), 1.42 (s, 1H), 1.37 – 1.29
(m, 2H), 1.28 – 1.21 (m, 2H), 1.11 – 1.02 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 149.74, 142.87, 128.31, 127.52, 127.44, 126.50, 58.95, 40.89,
32.18, 26.62, 25.87.
(R)-4-methyl-3-(p-tolyl)pentanal, (R)-6b.[8b] Following GP and using
(E)-5b, catalyst 3c-(SPRR) was used and the reaction was left stirring for
25
17 hours. The desired product was obtained as an oil (94% yield). [α]D
:
-12.0 (c 0.4, CHCl3), lit. [8b] [α]D23: -23.0 (c 0.81, dichloromethane, for R
enantiomer with 77% ee). 1H NMR (400 MHz, CDCl3) δ 9.60 – 9.57 (m,
1H), 7.10 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 2.96 – 2.88 (m,
1H), 2.78 – 2.68 (m, 2H), 2.31 (s, 3H), 1.85 (dq, J = 13.7, 6.7 Hz, 1H),
0.94 (d, J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). Chiral GC: 93% ee,
retention times = 26.9 min (S, minor), 27.7 min (R, major).
(R)-3-(3-chlorophenyl)-4-methylpentanal, (R)-6c. Following GP and
using (E)-5c, catalyst 3c-(SPRR) was used and the reaction was left
stirring for 17 hours. The desired product was obtained as an oil (88%
yield). [α]D25: -3.6 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.69 –
9.55 (m, 1H), 7.25 – 7.12 (m, 3H), 7.05 – 7.01 (m, 1H), 2.93 – 2.59 (m,
3H), 1.85 (dddd, J = 13.4, 7.8, 6.3, 1.1 Hz, 1H), 0.95 (d, J = 6.7 Hz, 3H),
0.78 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 201.88, 145.08,
134.38, 129.78, 128.40, 126.91, 126.66, 47.28, 46.69, 33.45, 20.66,
20.43. HRMS (ESI) calculated for C12H19ClNO 228.1150, found 228.1152
[M+NH4]+. IR (ATR-FTIR) νmax = 2956, 2926, 2869, 2359, 2320, 1722,
1276, 1124 cm-1. Chiral GC: 94% ee, retention times = 42.1 min (S,
minor), 43.5 min (R, major).
(R)-3-(3-methoxyphenyl)-4-methylpentanal, (R)-6d. Following GP and
using (E)-5d, catalyst 3c-(SPRR) was used and the reaction was left
stirring for 17 hours. The desired product was obtained as an oil (80%
yield). [α]D25: -9.5 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.60 (dd, J
= 2.5, 2.0 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.77 – 6.72 (m, 2H), 6.70 (t, J
= 2.1 Hz, 1H), 3.79 (s, 3H), 2.91 (ddd, J = 9.6, 7.6, 5.4 Hz, 1H), 2.84 –
2.67 (m, 2H), 1.85 (ddd, J = 13.3, 7.5, 6.6 Hz, 1H), 0.95 (d, J = 6.7 Hz,
3H), 0.79 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 202.48,
159.57, 144.38, 129.33, 120.64, 114.38, 111.38, 55.13, 47.17, 47.06,
33.39, 20.56, 20.39. HRMS (ESI) calculated for C13H22NO2 224.1645,
found 224.1654 [M+NH4]+. IR (ATR-FTIR) νmax = 2976, 2927, 2857, 2340,
(Z)-3-cyclohexyl-3-phenylprop-2-en-1-ol. (2-steps, 34% yield). 1H NMR
(400 MHz, CDCl3) δ 7.36 – 7.26 (m, 3H), 7.08 – 7.03 (m, 2H), 5.62 (td, J
= 6.9, 1.2 Hz, 1H), 3.95 (dd, J = 6.8, 0.8 Hz, 2H), 2.24 – 2.13 (m, 1H),
1.80 – 1.72 (m, 4H), 1.65 (dpd, J = 9.8, 3.1, 2.1, 1.6 Hz, 1H), 1.40 – 1.35
(m, 1H), 1.29 – 1.08 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 150.34,
140.43, 128.41, 127.89, 126.76, 123.48, 60.43, 45.77, 32.11, 26.63,
26.24.
(Z)-4,4-dimethyl-3-phenylpent-2-en-1-ol. (2-steps, 26% yield). 1H NMR
(400 MHz, CDCl3) δ 7.35 – 7.26 (m, 3H), 7.06 – 6.97 (m, 2H), 5.77 (t, J =
6.7 Hz, 1H), 3.75 (d, J = 6.7 Hz, 2H), 1.08 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 153.71, 139.57, 129.49, 127.78, 126.65, 123.38, 61.00, 36.13,
29.55.
(E)-3-phenylbut-2-en-1-ol. (2-steps, 61% yield). 1H NMR (400 MHz,
CDCl3) δ 7.41 (dq, J = 7.2, 1.2 Hz, 2H), 7.36 – 7.30 (m, 2H), 7.26 (dddd,
J = 8.6, 6.4, 2.6, 1.3 Hz, 1H), 5.98 (ddq, J = 6.8, 5.8, 1.3 Hz, 1H), 4.37
(dt, J = 6.7, 0.9 Hz, 2H), 2.08 (dt, J = 1.5, 0.9 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 142.84, 137.89, 128.26, 127.27, 126.45, 125.76, 59.95,
16.02.
(E)-3-cyclohexylbut-2-en-1-ol. (2-steps, 54% yield). 1H NMR (400 MHz,
CDCl3) δ 5.39 (tt, J = 6.8, 1.2 Hz, 1H), 4.15 (d, J = 6.8 Hz, 2H), 1.85 (tt, J
= 11.3, 3.3 Hz, 1H), 1.76 (dt, J = 12.0, 3.1 Hz, 2H), 1.72 – 1.66 (m, 3H),
7
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000442
ChemCatChem
FULL PAPER
2325, 1726, 1278, 1110 cm-1. Chiral GC: 96% ee, retention times = 21.3
min (S, minor), 21.7 min (R, major).
1H), 0.97 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 203.01,
131.75, 124.00, 50.98, 36.92, 27.76, 25.67, 25.37, 19.85, 17.64. Chiral
GC (from citronellol): 73% ee, retention times = 52.1 min (R, minor), 52.9
min (S, major).
(S)-3-cyclohexyl-3-phenylpropanal, (S)-6e Following GP and using (E)-
5e, catalyst ent-3b-(RPSS) was used and the reaction was left stirring for
25
17 hours. The desired product was obtained as an oil (97% yield). [α]D
:
-1.3 (c 0.8, CHCl3), lit.[19] [α]D23: +1.5 (c 1.08, benzene, for R enantiomer
with 84% ee). H NMR (400 MHz, CDCl3) δ 9.62 – 9.59 (m, 1H), 7.31 –
1
Acknowledgements
7.25 (m, 2H), 7.22 – 7.16 (m, 1H), 7.16 – 7.12 (m, 2H), 2.97 (ddd, J = 9.6,
7.5, 5.4 Hz, 1H), 2.83 (ddd, J = 16.4, 5.4, 1.9 Hz, 1H), 2.71 (ddd, J = 16.4,
9.5, 2.5 Hz, 1H), 1.83 – 1.72 (m, 2H), 1.61 (dddd, J = 9.1, 7.4, 5.9, 4.2 Hz,
2H), 1.52 – 1.44 (m, 2H), 1.20 (ddd, J = 12.6, 9.3, 3.4 Hz, 1H), 1.13 –
1.05 (m, 2H), 0.99 – 0.91 (m, 1H), 0.85 – 0.79 (m, 1H). 13C NMR (101
MHz, CDCl3) δ 202.61, 142.77, 128.34, 128.26, 126.45, 47.12, 46.16,
43.10, 31.05, 30.71, 26.30. Chiral GC: 87% ee, retention times = 34.8
min (S, major), 36.2 min (R, minor).
(R)-3-cyclohexyl-3-phenylpropanal, (R)-6e. Following GP and using
(Z)-5e, catalyst ent-3b-(RPSS) was used and the reaction was left stirring
for 17 hours. The desired product was obtained as an oil (85% yield).
[α]D25: +1.0 (c 0.6, CHCl3), lit.[19] [α]D23: +1.5 (c 1.08, benzene, for R
enantiomer with 84% ee). 1H NMR (400 MHz, CDCl3) δ 9.62 – 9.59 (m,
1H), 7.31 – 7.25 (m, 2H), 7.22 – 7.16 (m, 1H), 7.16 – 7.12 (m, 2H), 2.97
(ddd, J = 9.6, 7.5, 5.4 Hz, 1H), 2.83 (ddd, J = 16.4, 5.4, 1.9 Hz, 1H), 2.71
(ddd, J = 16.4, 9.5, 2.5 Hz, 1H), 1.83 – 1.72 (m, 2H), 1.61 (dddd, J = 9.1,
7.4, 5.9, 4.2 Hz, 2H), 1.52 – 1.44 (m, 2H), 1.20 (ddd, J = 12.6, 9.3, 3.4
Hz, 1H), 1.13 – 1.05 (m, 2H), 0.99 – 0.91 (m, 1H), 0.85 – 0.79 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 202.61, 142.77, 128.34, 128.26, 126.45,
47.12, 46.16, 43.10, 31.05, 30.71, 26.30. Chiral GC: 71% ee, retention
times = 34.7 min (S, minor), 36.2 min (R, major).
This work was supported by FEDER/Ministerio de Ciencia,
Innovación y Universidades-Agencia Estatal de Investigación
through grant CTQ2017-87840-P. We also acknowledge
institutional funding from Spanish Ministry of Economy, Industry
and Competitiveness (MINECO) through the Centres of
Excellence Severo Ochoa award given to IRB Barcelona and
from the Catalan Government through the CERCA Program. A.C
thank MINECO for a PhD fellowship (FPU). M.G. thanks “la
Caixa” Foundation (ID 100010434) for
a
postgraduate
scholarship (LCF/BQ/EU19/11710077) and Imperial College
Research Computing Service for access to computational
resources.
Keywords: asymmetric catalysis • iridium complexes •
isomerization • P,N-catalysts • DFT calculations
[1]
[2]
P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002, 35, 686-694.
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5f, catalyst ent-1b-(RPSR) was used and the reaction was left stirring for
25
17 hours. The desired product was obtained as an oil (53% yield). [α]D
:
[3]
a) S. Inoue, H. Takaya, K. Tani, S. Otsuka, T. Sato, R. Noyori, J. Am.
Chem. Soc. 1990, 112, 4897–4905; b) K. Tani, T. Yamagata, S.
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-42.0 (c 0.3, CHCl3), lit.[8b] [α]D23: +44.0 (c 1.29, dichloromethane, for R
enantiomer with 92% ee). 1H NMR (400 MHz, CDCl3) δ 9.53 (dd, J = 2.8,
1.7 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.23 – 7.19 (m, 1H), 7.18 – 7.14 (m,
2H), 3.03 (dd, J = 10.5, 4.8 Hz, 1H), 2.92 – 2.76 (m, 2H), 0.90 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 202.72, 141.15, 129.43, 127.91, 126.60,
50.33, 44.58, 33.72, 27.87. Chiral GC: 92% ee, retention times = 79.8
min (R, minor), 81.2 min (S, major).
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Matute, Dalton Trans. 2012, 41, 1660–1670; b) V. Cadierno, P. Crochet,
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(R)-3-phenylbutanal, (R)-6g. Following GP and using (E)-5g, catalyst
ent-3b-(RPSS) was used and the reaction was left stirring for 17 hours.
The desired product was obtained as an oil (26% yield). [α]D25: -17.0 (c
20
0.5, CHCl3), lit.[8a] [α]D
: +20.7 (c 0.31, dichloromethane, for S
enantiomer with 67% ee). 1H NMR (400 MHz, CDCl3) δ 9.71 (t, J = 2.0
Hz, 1H), 7.34 – 7.28 (m, 2H), 7.24 – 7.20 (m, 3H), 3.36 (h, J = 7.1 Hz,
1H), 2.76 (ddd, J = 16.6, 6.8, 1.8 Hz, 1H), 2.66 (ddd, J = 16.6, 7.7, 2.2
Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 201.82,
145.43, 128.66, 126.73, 126.51, 51.72, 34.29, 22.15. Chiral GC: 57% ee,
retention times = 14.1 min (R, major), 14.4 min (S, minor).
[6]
For selected examples of tandem processes involving isomerization of
allylic alcohols, see: a) A. Vázquez-Romero, A. B. Gómez, B. Martín-
Matute, ACS Catal. 2015, 5, 708–714; b) A. Bartoszewicz, B. Martín-
Matute, Org. Lett. 2009, 11, 1749–1752; c) A. B. Gõmez, E. Erbing, M.
Batuecas, A. Vázquez-Romero, B. Martín-Matute, Chem. Eur. J. 2014,
20, 10703–10709; d) N. Ahlsten, A. B. Gõmez, B. Martín-Matute,
Angew. Chem. Int. Ed. 2013, 52, 6273–6276; e) V. Bizet, X.
Pannecoucke, J. L. Renaud, D. Cahard, Adv. Synth. Catal. 2013, 355,
1394–1402; f) R. Wu, M. G. Beauchamps, J. M. Laquidara, J. R. Sowa,
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(S)-3-cyclohexylbutanal, (R)-6h. Following GP and using (E)-5h,
catalyst 1c-(SPRS) was used and the reaction was left stirring for 17
25
hours. The desired product was obtained as an oil (85% yield). [α]D
:
+11.0 (c 0.4, CHCl3), lit.[8a] [α]D20: +8.2 (c 1.15, dichloromethane, for S
enantiomer with 73% ee). 1H NMR (400 MHz, CDCl3) δ 9.75 (dd, J = 2.9,
1.9 Hz, 1H), 2.46 (ddd, J = 15.9, 4.9, 1.9 Hz, 1H), 2.19 (ddd, J = 15.9,
8.8, 2.9 Hz, 1H), 1.96 (dddt, J = 11.2, 6.9, 4.3, 2.0 Hz, 1H), 1.77 – 1.71
(m, 3H), 1.64 (ddt, J = 8.0, 3.0, 1.5 Hz, 3H), 1.20 – 1.13 (m, 3H), 1.01 –
0.96 (m, 2H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
203.51, 48.51, 42.74, 33.10, 30.24, 29.17, 26.52, 16.90. Chiral GC: 88%
ee, retention times = 33.9 min (S, major), 35.0 min (R, minor).
(S)-3,7-dimethyloct-6-enal ((S)-Citronellal), (S)-6i. Following GP and
using commercially available geraniol ((E)-5i), catalyst ent-1b-(RPSR)
was used and the reaction was left stirring for 17 hours. The desired
product was obtained as an oil (57% yield). The crude was treated with
NaBH4 to afford citronellol, from which the corresponding optical rotation
and enantiomeric excess were determined. [α]D25: -3.8 (c 0.4, CHCl3),
lit.[20] [α]D23: +5.14 (c 2.22, CHCl3, for R enantiomer). 1H NMR (400 MHz,
CDCl3) δ 9.76 (dd, J = 2.7, 2.1 Hz, 1H), 5.09 (tdt, J = 7.1, 2.9, 1.4 Hz,
1H), 2.41 (ddd, J = 16.0, 5.6, 2.1 Hz, 1H), 2.23 (ddd, J = 16.0, 8.0, 2.7
Hz, 1H), 2.12 – 2.05 (m, 1H), 2.03 – 1.94 (m, 2H), 1.69 (d, J = 1.3 Hz,
3H), 1.60 (dd, J = 1.4, 0.7 Hz, 3H), 1.41 – 1.31 (m, 1H), 1.30 – 1.21 (m,
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