Iridium-catalyzed asymmetric hydrogenation of 3,3-disubstituted allylic alcohols in ethereal solvents

Article abstract of DOI:10.1002/chem.201303915

Ir-phosphinomethyl-oxazoline complexes have been identified as efficient, highly enantioselective catalysts for the asymmetric hydrogenation of 3,3-disubstituted allylic alcohols and related homoallylic alcohols. In contrast to other N,P ligand complexes, which require weakly coordinating solvents, such as dichloromethane, these catalysts perform well in more ecofriendly THF or 2-MeTHF. Their synthetic potential was demonstrated with the formal total synthesis of four bisabolane sesquiterpenes. Particularly high enantioselectivity values in the asymmetric hydrogenation of 3,3-disubstituted allylic alcohols and related homoallylic alcohols have been achieved with Ir-phosphinomethyloxazoline catalysts. In contrast to other N,P-ligand complexes, which require weakly coordinating solvents, such as CH ₂Cl₂, these catalysts perform well in more ecofriendly THF or 2-MeTHF (see scheme; CODa =a 1,5-cyclooctadiene). Copyright

Full text of DOI:10.1002/chem.201303915

DOI: 10.1002/chem.201303915
Communication
&
Asymmetric Hydrogenation
Iridium-Catalyzed Asymmetric Hydrogenation of 3,3-Disubstituted
Allylic Alcohols in Ethereal Solvents
Maurizio Bernasconi, Vincenzo Ramella, Paolo Tosatti, and Andreas Pfaltz*[a]
Abstract: Ir-phosphinomethyl-oxazoline complexes have
been identified as efficient, highly enantioselective cata-
lysts for the asymmetric hydrogenation of 3,3-disubstitut-
ed allylic alcohols and related homoallylic alcohols. In con-
trast to other N,P ligand complexes, which require weakly
coordinating solvents, such as dichloromethane, these cat-
alysts perform well in more ecofriendly THF or 2-MeTHF.
Their synthetic potential was demonstrated with the
formal total synthesis of four bisabolane sesquiterpenes.
The asymmetric hydrogenation of prochiral allylic alcohols is
an attractive method for the synthesis of enantioenriched alco-
hols with a stereogenic center in the 2- or 3-position. The
Figure 1. Synthetic routes to enantioenriched 3,3-disubstituted primary alco-
hols.
products available by this route are versatile building blocks
for the synthesis of natural products and pharmaceuticals and
also play an important role in perfumery.[1] However, despite
boxylic acids,[9] esters[9] and aldehydes,[10] all give products that
the wide range of substrates that nowadays can be hydrogen-
ated efficiently with high enantioselectivity by using chiral
metal complexes, state-of-the-art methods for the enantiose-
lective reduction of allylic alcohols lack generality. Since
Noyori’s group seminal publication on the asymmetric hydro-
genation of geraniol and nerol with Ru–2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl (BINAP) catalysts,[2] many further studies
on asymmetric reductions of allylic alcohols have been report-
ed,[3–5] and in particular, 2-methyl cinnamyl alcohol has become
a standard substrate for the evaluation of new catalysts.[4] Nev-
ertheless, examples of highly enantioselective reductions of
3,3-disubstituted allylic alcohols are still scarce.[2,5]
require further redox transformations to yield the target mole-
cules. However, provided that a suitable catalyst can be found,
the more direct approach by asymmetric hydrogenation is
more attractive, as it affords the product in one step in the de-
sired oxidation state.
Herein, we report an efficient class of catalysts for this trans-
formation, giving high enantioselectivities (ee) for a wide range
of 3,3-disubstituted allylic alcohols and related homoallylic al-
cohols. Importantly, reactions could be performed in ecologi-
cally advantageous solvents, such as THF or 2-methyl-THF,
rather than dichloromethane, which is commonly used as
a standard solvent for iridium-catalyzed asymmetric hydroge-
nation.
Thus, currently used methods for the preparation of enan-
tioenriched alcohols with a stereogenic center in the 3-position
are generally based on multistep sequences involving an initial
enantioselective transformation carried out on a functionalized
substrate, followed by adjustment of the oxidation state of the
resulting product. As summarized in Figure 1, asymmetric SN2’
allylic alkylation,[6] 1,4-addition to a,b-unsaturated carbonyl
compounds,[7] asymmetric isomerization of allylic alcohols to
aldehydes,[8] asymmetric hydrogenation of a,b-unsaturated car-
In an initial screening of various iridium complexes derived
from chiral N,P ligands with alcohol 1a as substrate, the com-
plex derived from phosphinomethyloxazoline L4 performed
best, giving 98% ee and full conversion (Table 1). Other li-
gands, which in the past had been successfully used in the hy-
drogenation of various functionalized and unfunctionalized tri-
substituted olefins,[11] gave inferior results. Ligands, such as L4,
have proven to be particularly effective for the hydrogenation
of tetrasubstituted C=C bonds,[12] but have not found use for
the hydrogenation of other substrate classes to date. Catalysts
derived from L4 or related phosphinomethyloxazolines are at-
tractive, because the chiral ligands are readily accessible
through several short synthetic routes.[12–13]
[a] M. Bernasconi,+ V. Ramella,+ Dr. P. Tosatti, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056, Basel (Switzerland)
Fax: (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[+] These authors contributed equally to this work.
With a promising catalyst in hand, we examined the hydro-
genation of 1a with [Ir(cod)L4]BArF in different solvents
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303915.
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Table 1. Catalyst screening for the asymmetric hydrogenation of alcohol
1a.[a]
Table 3. Asymmetric hydrogenation of allylic alcohols 1.[a]
Entry R1, R2
THF
2-MeTHF
L, Conv. [%], ee [%][a]
L, Conv. [%], ee [%][a]
L4, >99, 97
L9, >99, 90
L9, >99, 95
L9, 41, 93
1
2
3
4
4-MeOC6H4, Me (a) L4, >99, 98, (À)-(R)
Ph, Me (b)
L9, >99, 95, (À)-(R)
4-MeC6H4, Me (c) L9, >99, 95, (À)-(R)
2-MeC6H4, Me (d) L9, >99, 97, (À)
L9, >99, 95[b]
L11, 98, 93
5
6
7
8
9
2-Naphthyl, Me (e) L11, 97, 95, (À)
4-ClC6H4, Me (f)
Me, 4-ClC6H4 (g)
Ph, Cy (h)
L11, >99, 92, (+)
L11, 14, 50, (À)
L11, 94, 92, (+)
L10, 43, 96, (+)-(R)
L11, >99, 90
L11, 8, 36
L11, >99, 90
L10, 10, n.d.
L11, 68, 90[c]
tBu, Ph,(i)
10
11
12
tBu, Me (j)
Cy, Me (k)
iBu, Me (l)
L11, >99, >99,[b] (À)-(S) L11, >99, 95[b]
[a] Conversion values were determined by GC analysis of the crude reac-
tion mixtures, whereas enantioselectivity values were determined by
HPLC analysis on a chiral stationary phase (see the Supporting Informa-
tion for further details). BArF =(tetrakis(3,5-bis(trifluoromethyl)phenyl)-
borate; cod=1,5-cyclooctadiene.
L12, >99, 88,[b] (+)-(R)
L11, >99, 80,[b] (+)
L13, >99, 60[b]
L9, >99, >99,[b] (À)
Table 2. Solvent screening for the asymmetric hydrogenation of alcohol
1a with [Ir(cod)L4]BArF.[a]
[a] Conversion was determined by GC analysis of the crude reaction mix-
tures, whereas enantioselectivity values were determined by HPLC analy-
sis on a chiral stationary phase (see the Supporting Information for fur-
ther details). [b] Catalyst (1 mol%) was used. [c] Reaction was carried out
for 20 h with catalyst (2 mol%).
Entry
Solvent
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
PhCl
n-hexane
EtOAc
acetone
iPrOH
>99
>99
82
93
92
<2
>99
>99
97
95
99
99
95
n.d.
98
97
they are less toxic and less volatile than dichloromethane and
do not produce chlorinated waste.[16] In particular, 2-MeTHF is
considered an ecofriendly solvent, as it can be obtained from
renewable resources[17] and has several advantages, such as
low miscibility with water and high stability under acidic and
basic conditions that render it attractive for industrial applica-
tions.[18]
THF
2-MeTHF
[a] Reaction conditions are similar to those given in Table 1, except for
the choice of solvent. [b] Conversions were determined by GC analysis of
the crude reaction mixtures. [c] Enantioselectivity values were determined
by HPLC analysis on a chiral stationary phase (see the Supporting Infor-
mation for further details); n.d. =not determined.
Therefore, we extended our hydrogenation studies in THF
and 2-MeTHF to a series of different 3,3-disubstituted allylic al-
cohols to evaluate the scope of the reaction. Table 3 summa-
rizes the results obtained with [Ir(cod)L4]BArF and related cata-
lysts derived from ligands L9–13. In general, slightly better re-
sults were observed in THF, although in most cases compara-
ble levels of conversion and enantioselectivity were achieved
in the two solvents (Table 3, entries 1, 3–7). Yet in one case
(entry 12), the reaction in 2-MeTHF gave significantly higher
enantioselectivity than in THF.
(Table 2). Reactions in 1,2-dichloroethane and chlorobenzene
proceeded with full conversion but slightly lower enantioselec-
tivity than in dichloromethane (entries 1 and 2). In n-hexane
and ethyl acetate, enantioselectivities reached 99% ee; howev-
er, at the expense of incomplete conversion under standard
conditions (entries 3 and 4). A somewhat lower ee of 95 and
92% conversion were observed in acetone, whereas in isopro-
panol the catalyst was not active (Table 2, entries 5 and 6). Sur-
prisingly, reactions in THF (Table 2, entry 7) and 2-methyltetra-
hydrofuran (entry 8) gave essentially the same results as reac-
tions in the standard solvent dichloromethane. The excellent
performance of the catalyst in these ethereal solvents contrasts
the general experience that coordinating solvents cause signifi-
cant inhibition of iridium catalysts.[11a,14,15] The use of THF and
2-MeTHF offers advantages from an ecological point of view as
(E)-3-Methylcinnamyl alcohol (1b) and related aryl/methyl-
substituted derivatives reacted with excellent enantioselectivi-
ties of 95–98% (Table 3, entries 1-5), except for the 4-chloro-
phenyl derivative 1 f, which gave slightly lower ee (entry 6).
The corresponding Z-configured alcohol 1g was considerably
less reactive than 1 f, affording the enantiomeric product in
14% conversion and 50% ee in THF (entry 7). The sterically
more hindered ortho-tolyl derivative 1d required a somewhat
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higher catalyst loading of 1 mol% instead of 0.5 mol% to
achieve full conversion in 2-MeTHF. Although high conversion
and good enantioselectivity could be achieved for the phenyl/
cyclohexyl-substituted substrate 1h (entry 8), a substantial de-
crease of conversion, but excellent ee value (99% in THF) was
observed for the bulky phenyl/tert-butyl derivative 1i (entry 9).
On the other hand, the tert-butyl/methyl analogue 1j gave full
conversion at 1 mol% catalyst loading (entry 10). The dialkyl-
substituted substrates 1k and 1l proved to be less reactive
than the corresponding aryl/alkyl-substituted compounds, but
at 1 mol% catalyst loading, full conversion was achieved. Al-
though the enantioselectivity was only moderate for the cyclo-
hexyl/methyl derivative 1k, up to 99% ee was recorded for 1j
and 1l by using the appropriate catalyst and solvent (en-
tries 10 and 12). Overall, the results show that proper choice of
the phosphinomethyloxazoline ligand and the solvent (THF or
2-MeTHF) is crucial for obtaining optimal results for a particular
substrate.
rated alcohols 7a and b with full conversion and excellent
enantioselectivity.
The asymmetric hydrogenation of homoallylic alcohols of
this type has considerable potential for application in organic
synthesis. In fact, the reduction of 6b to 7b is a key step in
the synthesis of four natural products, curcumene, nuciferal,
nuciferol, and erogorgiaene. All these bisabolane sesquiter-
penes can be accessed from 7b via the corresponding alde-
hyde 10.[19] Thus, the sequence leading to highly enantioen-
riched aldehyde 10 shown in Scheme 3 represents a formal
Two mechanistic pathways seem to be possible for these hy-
drogenations. Taking into account the work of Mazet and co-
workers on the iridium-catalyzed asymmetric isomerization of
allylic alcohols to the corresponding aldehydes,[8] a two-step
process involving a formal 1,3-H shift to the saturated alde-
hyde followed by reduction of the C=O function may be pro-
posed (Scheme 1, path A). Alternatively, the allylic alcohol
Scheme 2. Hydrogenation experiments in support of pathway B.
Scheme 1. Possible reaction pathways for the asymmetric reduction of allylic
alcohols catalyzed by iridium complexes.
could undergo direct hydrogenation of the C=C bond (path B).
To distinguish between the two pathways, we ran the hydro-
genation of substrate 1b with catalyst [Ir(cod)L9]BArF under
1
2
a 50 bar of D2 (Scheme 2, A). H and H NMR analysis of prod-
uct 3 revealed complete deuterium incorporation (>90%) at
C2 and C3, whereas no deuterium was detected at C1. This
result is consistent with pathway B (see the Supporting Infor-
mation for further details). Further support of pathway B came
from the hydrogenation of the tertiary allylic alcohol 4 under
the conditions previously used for primary allylic alcohols
(Scheme 2B). Judicious choice of the iridium complex was nec-
essary in this case to achieve full conversion and avoid the for-
mation of unidentified by-products. By using [Ir(cod)L14]BArF
as catalyst, alcohol 5 was formed with full conversion and 74%
ee. The successful hydrogenation of homoallylic alcohols 6a
and b as well rules out pathway A, because isomerization to
the corresponding aldehyde is not possible in this case
(Scheme 2C). Both 6a and b cleanly reacted to give the satu-
Scheme 3. Formal total synthesis of natural products through alcohol 6b.
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synthesis of these natural products.[20] We found that the ho-
moallylic alcohol 6b is readily accessible from commercially
available cyclopropyl methyl ketone 8 by a two-step transfor-
mation involving Grignard addition followed by acid-catalyzed
rearrangement of the tertiary alcohol 9.[21] After iridium-cata-
lyzed asymmetric hydrogenation of 6b, the resulting chiral al-
cohol 7b was converted to the aldehyde 10 by Parikh–Doering
oxidation in 97% yield.[22] Compared to the most efficient pub-
lished route to 10, which is based on the enantioselective cy-
clopropanation of para-methylstyrene, the sequence shown in
Scheme 3 is shorter, and the overall yield of 10 is higher (68%
vs. 30–36%).[23]
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In summary, we have identified an efficient ligand class for
the iridium-catalyzed asymmetric hydrogenation of 3,3-disub-
stituted allylic alcohols, a type of substrate for which generally
applicable catalysts were not available to date. The required li-
gands are structurally simple and readily accessible from enan-
tiopure aminoalcohols by several short syntheses. Importantly,
reactions can be carried out in THF or 2-MeTHF, which are eco-
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tions than dichloromethane that is commonly used for iridium-
catalyzed hydrogenation. In addition to 3,3-disubstituted allylic
alcohols, analogous homoallylic alcohols were also hydrogen-
ated with high enantioselectivities. The potential of this
method was illustrated by a short and efficient synthesis of
a highly enantioenriched precursor that has been used for the
synthesis of several bisabolane sesquiterpenes.
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Experimental Section
Procedure for the iridium-catalyzed asymmetric hydrogena-
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In a glove box, the allylic alcohol 1a (320 mg, 1.8 mmol) and [Ir-
(cod)L4]BArF (13 mg, 9 mmol, 0.5 mol%) were dissolved in THF
(3.6 mL, 0.5m) in a glass vial equipped with a magnetic stir bar.
The reaction vial was placed into a high-pressure steel autoclave
that was then sealed and brought outside the glove box. The auto-
clave was pressurized with H2, purged with H2 three times, and
sealed under 50 bar H2. The reaction was stirred for 15 h at RT.
After release of H2, the solution was concentrated in vacuo, and
the catalyst was removed by filtration of the crude mixture
through a plug of silica gel (2ꢁ0.5 cm) with n-hexane/MTBE 4:1
(15 mL). After washing with approximately 10 mL of the same sol-
vent mixture, the solution was concentrated in vacuo to give 2a
(321 mg, 99% yield, 96% ee) as a colorless liquid.
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Acknowledgements
[15] The potentially coordinating hydroxy group does not seem to be re-
sponsible for the high reactivity of this catalyst observed in THF. Hydro-
genation of (E)-1-(but-2-en-2-yl)-4-methoxybenzene, the analogue of
substrate 1a, possessing a methyl group instead of a hydroxymethyl
group, gave 98% conversion and 93% ee in this solvent (1.0 mol% [Ir-
(cod)L4]BArF, THF (0.2m), 50 bar H2; see the Supporting Information for
further details).
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Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
Keywords: allylic alcohols · green solvents · hydrogenation ·
iridium · natural products
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Received: October 7, 2013
Published online on January 30, 2014
Chem. Eur. J. 2014, 20, 2440 – 2444
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2444
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