Recent advances in iridium-catalyzed asymmetric hydrogenation: New catalysts, substrates and applications in total synthesis

Article abstract of DOI:10.2533/chimia.2012.187

Iridium-catalyzed asymmetric hydrogenation has emerged as a highly efficient method for the synthesis of enantiomerically pure compounds. This account summarizes our recent efforts in this field. We have developed a new type of P,O-ligand that was success

Full text of DOI:10.2533/chimia.2012.187

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CHIMIA 2012, 66, No. 4 187
doi:10.2533/chimia.2012.187
Chimia 66 (2012) 187–191 © Schweizerische Chemische Gesellschaft
Recent Advances in Iridium-Catalyzed
Asymmetric Hydrogenation: New
Catalysts, Substrates and Applications in
Total Synthesis
Adnan Ganic´§*, Denise Rageot, Lars Tröndlin, and Andreas Pfaltz
§SCS-Metrohm Foundation Award for best oral presentation
Abstract: Iridium-catalyzed asymmetric hydrogenation has emerged as a highly efficient method for the
synthesis of enantiomerically pure compounds. This account summarizes our recent efforts in this field. We
have developed a new type of P, O-ligand that was successfully applied to the asymmetric hydrogenation of α,β-
unsaturated carbonyl compounds. Furthermore we have demonstrated the potential of known iridium catalysts
in the hydrogenation of α,β-unsaturated boronic esters. And finally we could demonstrate the utility of iridium-
catalyzed asymmetric hydrogenation in the formal synthesis of the natural product Platensimycin.
Keywords: Asymmetric catalysis · Boron · Hydrogenation · Iridium · Natural products · P, O-Ligands
hydrogenated with high enantioselectivity families was investigated aiming to broad-
is limited. In general, both rhodium und en the substrate scope. In our group several
Introduction
ruthenium complexes require substrates heterocyclic ligand systems (oxazolines,
bearing a coordinating functional group imidazolines and pyridines) containing a
next to the C=C bond in order to achieve phosphine or a phosphinite unit were de-
Asymmetric hydrogenation is a pow-
erful tool to convert prochiral substrates
into chiral products with high enantio-
high levels of ee.[3] While Rh and Ru cata- veloped and used for iridium-catalyzed
meric purity. The reaction fulfills all the
lysts show only low reactivity toward un- asymmetric hydrogenation. The classes
requirements for modern asymmetric
synthesis, such as perfect atom economy,
mild conditions, low catalyst loading and
functionalized tri- or tetrasubstituted C=C of ligands providing excellent results for
bonds, Crabtree’s group showed already in the hydrogenation of terminal, tri- and
high conversion.[1] The importance of this
the 1970s that cationic iridium complexes even tetrasubstituted olefins are shown in
bearing a pyridine and phosphine ligand Fig. 1.[9]
transformation has been recognized by
awarding the pioneering work of Knowles
and Noyori with the Nobel Prize in 2001.[2]
While Knowles used chiral rhodium
complexes for the hydrogenation of α,β-
dehydroamino acids, which finally resulted
in the well-known l-Dopa process imple-
mented at Monsato,[2a] Noyori introduced
ruthenium-BINOL complexes as catalysts
for the reduction of functionalized C=C
and C=O bonds.[2b] Despite the vast variety
of chiral Rh and Ru catalysts developed so
far (many of them are commercially avail-
able), the range of substrates that can be
can promote the hydrogenation of tri- or
During the last ten years many further
tetraalkyl-substituted olefins with high ligands for this particular transformation
efficiency.[4]
have been introduced by other research
In search of a chiral version of groups as well.[10] Most noteworthy are
Crabtree’s catalyst, phosphineoxazoline thiazole-, aminophosphine- and pyrano-
(PHOX) ligands were evaluated in the irid- side P,N-based systems, developed by
ium-catalyzed asymmetric hydrogenation Andersson and coworkers.[11] Besides P,N-
of imines and olefins.[5] However, catalyst ligands, C,N-ligands having a coordinat-
deactivation during the reaction led to in- ing N-heterocyclic carbene unit also gave
complete conversions, therefore relatively promising results.[12] All these new ligands
high catalyst loadings (>4 mol%) were re- enhanced the substrate scope to various
quired. After extensive experimental stud- types of C=C bonds, allowing asymmet-
ies, a relatively simple solution to avoid ric hydrogenations of vinyl fluorides,[13]
catalyst deactivation was found, by chang- vinyl ethers,[14] enol phosphinates,[15] vi-
ing the counter ion.[6] By using a bulky, nyl diphenylphosphine oxides,[16] vinyl
apolar, weakly coordinating anion like boronates,[17] chromenes,[18] furanes,[19]
tetrakis[3,5-bis(trifluoromethyl)phenyl] indoles,[20] enamines,[21] protected and un-
−
borate (BAr ),[7] full conversions could protected allylic alcohols,[22] and unsatu-
be achieved Feven at low catalyst loadings rated carbonyl compounds.[22b,22c,23]
(>0.02 mol%). Iridium complexes contain-
ing BArF− as counter ion proved to be less
*Correspondence: A. Ganic´
Department of Chemistry
University of Basel
sensitive to moisture and oxygen than the Development of New Catalysts
corresponding hexafluorophosphates and
moreover, purification by column chroma-
tography was possible.[8]
Having solved the deactivation prob- of various olefins are depicted in Fig. 1.
lem, the development of new P,N-ligand All these bidentate ligands were designed
Representative P,N-ligands for the irid-
ium-catalyzed asymmetric hydrogenation
St. Johanns-Ring 19
CH-4056 Basel
Tel.: +41 61 267 1140
Fax: +41 61 267 1013
E-mail: adnan.ganic@unibas.ch

188 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
drance around the carbonyl functionality
of amido- or ureaphosphines (12 and 14),
3
3
R R
X
1
X
2
X
X
O
gave the highest enantioselectivities (Table
1, entries 4 and 8) for 21. For substrate 20
the best enantiomeric excess of 91% was
O
1
1
1
(R ) P
N
(R ) P
N
2
(R ) P
N
2
2
B
Ar
B
Ar
BAr
F
2
Ir
F
Ir
F
Ir
2
R
2
R
R
achieved with the tetrasubstituted urea 18
(Table 1, entry 13).
The β-methyl-substituted α,β-unsat-
urated carboxylic ester (24) was reduced
1
2
1,X=O(P
H
OX)
3,X=H(SerP
H
OX)
5,X =O,X =O(SimpleP
H
OX)
2,X=N 3
R (PHIM)
1
2
6,X =N 3
R,X =O(SimplePHIM)
4,X=CH3 (ThreP
H
OX)
1
2
7,X =O,X =C 2
H (NeoPHOX)
with generally higher enantioselectivities
(Fig. 3). Amidophosphine 11 as well as
the urea-phosphines 16 and 18 achieved
OMe
enantioselectivities ≥98%. All of these cat-
alysts bear a sterically demanding substitu-
ent at the carbonyl functionality in com-
bination with a stronger electron donating
n
2
∗
O
1
O
P
O
(R ) P
2
N
N
1
N
Ir
N
N
B
Ar
(R ) P
F
2
B
Ar
Ir
F
BAr
F
Ir
2
R
dialkyl phosphine. The reduction of α,β-
Ph
R
unsaturated carboxylic esters 25 and 26
proceeded with complete conversion but
lower enantioselectivities. Remarkably the
α-substituted ester 26 was reduced with up
to 91% ee, whereas its β-methyl substitut-
ed analog 25 was only reduced with up to
77% ee (Fig. 3). Surprisingly, in this case
the diphenylphosphine substituted ligand
14 allowed the highest selectivity.[24]
8
9
10
OMe
Fig. 1. Iridium catalysts for enantioselective hydrogenation developed in the Pfaltz group.
esters (20 and 21) with excellent enantio-
meric excess (ee) up to 97% and respec-
to bind to the metal through a heterocyclic
sp2-nitrogen donor in combination with
a trisubstituted phosphorus atom. In the
course of our ongoing efforts to identify
other active and selective catalysts, we dis-
covered new proline-based iridium com-
tively 99%.[25] The proline-based P,O-
The α,β-unsaturated ketones 27 and
28 were previously reduced by iridium
type of substrate (Table 1, entries 4 and 8).
ligands allow for ees up to 95% for this
catalysts with sulfoximine-derived P,N-
ligands with enantioselectivities of up to
81% ee.[23c] Our P,O-ligands showed enan-
Conversion was complete after 2 h with al-
most all P,O-ligands. Increased steric hin-
plexes. These complexes are formed by
bidentate chelation of P,O-proline-based
ligands to the metal center with a phos-
phorus atom, and a carbonyl oxygen atom
(Fig. 2).
Thanks to their modular synthesis these
P,O-ligands are readily accessible in few
steps and in good yields starting from pro-
Table 1. Iridium-catalyzed asymmetric hydrogenation of α-substituted,
α,β-unsaturated estersa
[Ir(cod) ]BAr (1 mol%)
then L (1 mol%)
2
F
O
O
*
O 3
R
O 3
R
H (50 bar), CH2Cl2,rt, 2h
2
line. This allows the preparation of cata-
3
3
22,R =Et
20,R =Et
lysts whose steric and electronic charac-
teristics can be tuned with ease. In order
to evaluate the results depending on the
structural motif of both catalyst and sub-
strates, we carried out a broad screening
using functionalized and unfunctionalized
3
3
23,R =iPr
21,R =iPr
Entry
R3
Ligand
Yield [%]b ee [%]c
1
2
Et
11
11
> 99
> 99
90 (R)
89 (R)
iPr
olefins.[24] These catalysts proved to be
3
4
Et
12
12
13
13
14
14
15
15
17
17
18
18
19
19
> 99
> 99
> 99
> 99
> 99
> 99
> 79
> 87
> 99
> 99
> 99
> 96
> 99
> 99
87 (R)
95 (R)
90 (R)
92 (R)
86 (R)
95 (R)
84 (R)
87 (R)
81 (R)
88 (R)
91 (R)
94 (R)
83 (R)
87 (R)
particularly well-suited for the reduction
of C=C bond of α,β-unsaturated ketones
and carboxylic esters.
PyridylphosphinitebasedP,N-catalysts
(9) have previously been reported to re-
duce α-methyl substituted α,β-unsaturated
iPr
Et
5
6
iPr
Et
7
8
iPr
Et
9
10
11
12
13
14
15
16
iPr
Et
1
2
(S)-11 R =PhC,
R = tBu
3
1
2
(S)-12 R =PhC,
R =Cy
3
iPr
Et
1
2
(S)-13 R =1-AdmNH, R = tBu
1
2
(S)-14 R =PhCNH, R =Ph
3
1
2
iPr
Et
iPr
2
(S)-15 R =PhCNH, R = tBu
N
3
P(R )
2
1
2
(S)-16 R =PhCNH, R =Cy
3
O
1
1
2
R
(S)-17 R = iPr N,
R = tBu
2
1
2
(S)-18 R =CyN,
R = tBu
aReaction conditions: [Ir(cod)2]BArF (1 mol%), ligand (1 mol%), CH2Cl2
(0.5 m), substrate (250 μmol). bYields were determined by GC analysis
of the reaction mixture after removal of the catalyst. cEnantioselectivities
were determined by HPLC analysis using a chiral stationary phase.
2
1
2
(S)-19 R =CyN,
R =Cy
2
Fig. 2. Proline-based P, O-ligands.

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 189
Table 2. Iridium-catalyzed asymmetric hydrogenation of β-substituted,
α,β-unsaturated ketonesa
Table 3. Iridium-catalyzed asymmetric hydrogenation of α,β-unsaturated
boronic estersabc
[Ir(cod) ]BAr (1 mol%)
then L (1 mol%)
2
F
O
O
*
9a (1 mol%)
O
O
O
3
O O
3
(t-Bu) P
N
R
B
∗
R
2
H (50 bar), CH2Cl2,rt, 2h
2
B
BAr
F
Ir
H (50 bar),
2
R'
R'
CH2Cl2,rt, 12-15 h
Ph
R
3
3
R
29,R =Me
30,R =Ph
27,R =Me
28,R =Ph
3
3
9a
Entry
R3
Ligand
Yield [%]b ee [%]c
1
2
Me
Ph
11
11
12
12
13
13
14
14
15
15
16
16
18
18
19
19
98 (98e)
96 (R) (94 (R)e)
O
O
O O
O
O
O
O
B
O
B
B
O
B
O
B
O
B
99
94 (R)
96 (R) (89 (R)e)
B
B
O
O
O
O
3
Me
Ph
95 (98e)
98
3
1
3
2
3
3
34
4
95 (R)
[b]
>
9
9
% c
o
nv.
97
% c
o
nv.
e
>
9
9
% c
onv.
>
9
9
% c
onv.
% e [c]
e
7
2% e
e
8
5
% e
9
8
% ee
95
5
Me
Ph
87
86 (R)
6
98
82 (R)
93 (R) (91 (R)e)
7
Me
Ph
98 (99e)
> 99
86d
O
O
O
O
O O
CF
OMe
3
O
O
B
B
B
B
8
95 (R)
79 (R)d
9
Me
Ph
3
5
3
6
3
7
38
10
11
12
13
14
15
16
86
80 (R)
9
8
% c
o
nv.
e
>
9
9
% c
o
nv.
>
9
9
% c
o
nv.
>
9
9
% c
onv.
>
9
9
% e
9
5% e
e
9
8% e
e
9
7
% ee
Me
Ph
95
82 (R)
98
68d (94e)
90 (R)
92 (R)d (94 (R)e)
Me
Ph
O
O
O
B
O
O
O O
B
B
B
O
94
88 (94e)
96
84 (R)
87 (R) (87 (R)e)
82 (R)
F
Me
Ph
3
9
4
0
4
1
o
42
>
9
9
% c
o
nv.
>
9
9
% c
o
nv.
>
9
9
% c
nv.
e
9
9
% c
o
nv.
e
9
9% e
e
9
6% e
e
9
7% e
9
0% e
aReaction conditions: [Ir(cod)2]BArF (1 mol%), ligand (1 mol%),
CH2Cl2 (0.5 M), substrate (250 μmol). bYields were determined by GC
analysis of the reaction mixture after removal of the catalyst. cEnantiose-
lectivities were determined by HPLC analysis using a chiral stationary
phase. dAverage result of 3 experiments. eResults obtained with isolated
precatalyst [(L*)Ir(cod)]BArF (1 mol%).
aReaction conditions: Ir-9a (1 mol%), CH2Cl2 (0.2 M), substrate (50–
100 μmol), 50 bar H2, 12–15 hours. bConversion determined by
GC analysis of the reaction mixture after removal of the catalyst.
cEnantioselectivity determined by GC or HPLC analysis on chiral
stationary phase.
quired.[28] On the other hand, iridium cata-
lysts were reported to be more active, since
only 0.5 mol% of catalyst is generally suf-
ficient to reach full conversions.[17] In this
case though, high enantioselectivities were
only achieved with certain substrates.
Overall, the scope of rhodium- and
iridium-catalyzed hydrogenation of α,β-
unsaturated boronic esters is still limited,
and this prompted us to screen our cata-
tioselectivities of up to 96% ee for these
Hydrogenation of α,β-Unsaturated
substrates, with again complete conversion
after shorter reaction times. Even though
the conversions obtained were good to ex-
cellent, the reduction of the C=C double
bond was sometimes accompanied by the
undesired reduction of the carbonyl bond
of the substrate 27. Nevertheless, this over
reduction could be suppressed by using the
precatalyst in its isolated form instead of
Boronic Esters
Chiral boronates are highly versatile
compounds,[26] since the C−B bond can
be converted into C−O, C−N or even C−C
bondsinastereospecificmanner.[27] Oneat-
tractive method to access these compounds
in a catalytic and enantioselective fashion
is by hydrogenation of alkenylboronic es-
ters. Indeed, experiments using rhodium
catalysts derived from ferrocenyl ligands
led to chiral secondary boronates, which
are not accessible in high enantiomeric
purity via hydroboration. However, rela-
tively high catalyst loading (up to 5 mol%
catalyst) and long reaction times were re-
forming the catalyst in situ (Table 2, entries
lysts (see Fig. 1) in the hydrogenation of
31.[29] To our delight, catalyst 9a gave
1, 3, 7, 13 and 15). For the α,β-unsaturated
ketones 27 and 28, again P,O-ligands,
amido- and ureaphosphines, bearing dia-
kylphosphines in combination with a steri-
cally demanding carbonyl moiety proved
to be the most efficient (entries 1-4).
already under screening conditions full
conversion and 95% enantiomeric excess
(Table 3). Moreover, a series of differ-
ent bisboronic esters having various sub-
stituents at the C=C bond (31–34) was
hydrogenated with good to excellent ees.
Bisboronic esters (31–34) also gave ac-
cess to alkenyl-monoboronic esters, given
O
O
O
the higher reactivity of the terminal boron
group allowing chemoselective Suzuki-
Ph
Ph
Ph
O
O
O
Miyaura couplings. Therefore, several
24
25
26
alkenyl boronates were prepared (35–42)
in which the terminal boron was replaced
by various residues. Subjecting substrates
35–40 to the iridium-catalyzed hydroge-
nation excellent selectivities ranging from
95% to 99% ee were achieved. Moreover,
(S)-11:>99% y, 98% ee (R)
(S)-16:>99% y, 98% ee (R)
(S)-17:>99% y, 97% ee (R)
(S)-18:>99% y, 99% ee (R)
(S)-19:>99% y, 97% ee (R)
(S)-13:>99% y, 70% ee (S)
(S)-14:>99% y, 77% ee (S)
(S)-15:>99% y, 68% ee (S)
(S)-16:>99% y, 68% ee (S)
(S)-18:>99% y, 76% ee (S)
(S)-13:>99% y, 87% ee (-)
(S)-14:>99% y, 89% ee (-)
(S)-15:>99% y, 86% ee (-)
(S)-18:>99% y, 91% ee (-)
(S)-19:>99% y, 86% ee (-)
Fig. 3. Selected hydrogenation results of various α,β-unsaturated esters.

190 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
the electronic and steric properties of the
residues introduced had no significant ef-
fect on the stereoselectivity of the reaction.
Substrates 40 and 41 demonstrate that aryl
groups at C=C bond are not essential in or-
der to achieve high ee values. Substrate 42,
bearing the boronic ester group at the less
substituted olefinic carbon, reacted with
lower, but still very good enantioselectiv-
ity (90% ee).
Furthermore, we sought to examine the
relative reactivity of these new substrates
compared to unfunctionalized olefins. As
model substrates for this study we selected
E-α-methylstilbene, bisboronic ester deri-
vate 34 and a mono boronic ester derivate
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
35. This study showed surprising results.
While E-α-methylstilbene was expected
0%
[h]
to be reduced very rapidly, substrate 34
0
5
10
15
34
20
25
reacted even faster. Using 1 mol% of cata-
lyst full conversion was achieved already
E-α-methylstilbene
35
within 5 min. This is remarkably fast, con-
Fig. 4. Conversion over time for the hydrogenation of α,β-unsaturated boronic esters 34, 35 and
E-methylstilbene.
sidering that E-methylstilbene requires
under the same conditions 1 h to be fully
reduced. Therefore, we were able to re-
duce the catalyst loading for substrate 34
to 0.1% still achieving full conversion. On
the other hand, substrate 35 displayed re-
duced reactivity, as it reacted considerably
slower than 34 and E-α-methylstilbene, as
mono-hydrogenation of 46 failed, a selec-
OH
tive preparation of 48 was attempted. The
O
twofold 1,4-reduction of 46 proved chal-
lenging due to the poor diastereoselectiv-
ity of the reaction in favor of the desired
O
Me
HOOC
N
H
OH
shown in Fig. 4. These observations indi-
ketone 48.
O
cate that besides the steric properties of
the substrates, electronic effects also play
a crucial role.
In order to address this issue, we tested
our chiral iridium complexes for this par-
ticular hydrogenation. A thorough screen-
ing of catalysts and reaction conditions
revealed again 10 as an effective catalyst
in terms of both, conversion and diastereo-
selectivity. Using this catalyst the diaste-
reomeric ketones were obtained in 84%
Me
Fig. 5. Platensimycin.
Applications in the Synthesis of
Complex Molecules
10 afforded the desired compound with full
conversion and 99% ee. Notably, the cata-
lyst loading could be reduced to 0.2 mol%,
The power of iridium-catalyzed asym-
metrichydrogenationhasbeendemonstrat- so the hydrogenation could be easier per-
edintheenantioselectivesynthesisofsever- formed on a multigram scale.
isolated yield and 40:1 ratio in favor of
the desired ketone 48,[38c] providing an ef-
ficient route to 49, a key intermediate for
[36]
al biologically important natural products,
The second hydrogenation step in-
the preparation of Platensimycin.
such as (+)- and (−)-Mutisianthol,[30] (R)- volves the diastereoselective reduction of
(+)-7-demethyl-2-methoxycalamenene,[31] the tetracyclic dienone 46 (Scheme 2).
MacrocidinA,[32] (−)-Spongidepsin,[33] and Since all experiments to obtain the key
(+)-Torrubiellone C.[34]
Herein we would intermediate 49 directly through selective
like to highlight our contribution to the for-
mal synthesis of Platensimycin (Fig. 5) in
Scheme 1. Hydro-
genation of the bicy-
clic compound 44.
collaboration with the Mulzer group. This
O
Me
O
Me
O
Me
O
natural product recently received much at-
tention because of its unique structural fea-
tures and its potent activity as a new type
of antibiotic.[35]
After Nicolaou reported the first to-
tal synthesis of racemic Platensimycin in
2006,[36] several research groups have been
involved in an asymmetric approach to
it.[37] Among them the Mulzer group has
recently reported an elegant approach,[38]
which involves two hydrogenation reac-
tions as key synthetic transformations.
10 (0.2 mol%)
H (50 bar),
CH22Cl2,20h,rt
99% conv.
O
Me
O
*
43
C
O
Me
46
COMe
99% ee
44
45
O
O
O
H
O
Ir-10 (2 mol%)
H
+
O
H (50 bar),
CH2Cl2,65h,rt
O
2
O
O
The first hydrogenation step is an asym-
Me
Me
46
Me
Me
metric hydrogenation of the unsaturated
ester 44 (Scheme 1). After an extensive
screening of our iridium catalysts (Fig. 1)
we were delighted to observe that complex
47
48
49
key intermediate
1:40(84% isolated yield)
Scheme 2. Hydrogenation of the tetracyclic substrate 46.

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 191
[9] a) D. H. Woodmansee, A. Pfaltz, Top.
M. Lu, C. Bolm, Angew. Chem. Int. Ed. 2008,
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Organomet. Chem. 2011, 34, 31; b) D. H.
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