Combination of enantioselective metal catalysis and organocatalysis: Enantioselective sequential hydroformylation/ aldol reactions

Article abstract of DOI:10.1002/adsc.200900780

This work reports the possibility of con-trolling the sense of enantio- and diastereoinduc-tions in the sequential hydroformylation and aldol reactions via the judicious combination of a chiral metal catalyst with a chiral organocatalyst. The dia-stereoselectivity of the reaction between styrene, syngas and acetone can be increased by using a matched pair of catalysts, [rhodium/(25, 4S)-Chira-phite]/(S)-organocatalyst and decreased, but not in-verted, by using a mismatched pair of catalysts, [rhodium/(2/R, 4/R)-Chiraphite]/(S)-organocatalyst.

Full text of DOI:10.1002/adsc.200900780

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DOI: 10.1002/adsc.200900780
Combination of Enantioselective Metal Catalysis and
Organocatalysis: Enantioselective Sequential Hydroformylation/
Aldol Reactions
Serghei Chercheja,a Sailendra K. Nadakudity,a and Peter Eilbrachta,*
a
Fakultꢀt Chemie, Organische Chemie, Technische Universitꢀt Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
Fax : (+49)-231-755-5363; e-mail: peter.eilbracht@udo.edu
Received: November 9, 2009; Published online: March 4, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900780.
Abstract: This work reports the possibility of con-
trolling the sense of enantio- and diastereoinduc-
tions in the sequential hydroformylation and aldol
reactions via the judicious combination of a chiral
metal catalyst with a chiral organocatalyst. The dia-
stereoselectivity of the reaction between styrene,
syngas and acetone can be increased by using a
matched pair of catalysts, [rhodium/ACTHNUGRTENUNG(2S,4S)-Chira-
phite]/(S)-organocatalyst and decreased, but not in-
verted, by using a mismatched pair of catalysts,
metal-ligand complex and the configuration of anoth-
er stereogenic center is controlled by a chiral organo-
catalyst has not been very successful so far.[6g] Consid-
ering the multitude of enantioselective reactions cata-
lyzed by either metal catalysts (reductions, oxidations,
s-bond insertions, p-bond activation, Lewis acid reac-
tions)[8] or organocatalysts (enamine, iminium, hydro-
gen-bonding, SOMO, counter ion catalysis)[9] we envi-
sion a tremendous potential for the creation of
unique multicatalytic systems to influence chirality in
reaction products.
[rhodium/ACHTUNGTRENNUNG(2R,4R)-Chiraphite]/(S)-organocatalyst.
In this report we present the combination of a
chiral rhodium catalyst with a chiral organocatalyst in
an enantioselective sequential hydroformylation fol-
lowed by an aldol reaction (Scheme 1).
Keywords: aldol reaction; asymmetric catalysis; hy-
droformylation; organocatalysis; tandem reactions
The sequential conversion of styrene with syngas
and acetone to aldol product 3 was chosen as a model
reaction. We presumed that exposure of styrene to a
In order to achieve the highest possible efficiency in chiral Rh catalyst under hydroformylation conditions
enantioselective chemical transformations, the would generate an enantioenriched aldehyde 2, which
number of steps must be kept to a minimum and the can be intercepted in the second catalytic cycle by the
yield, regio-, enantio- and diastereoselectivities of chiral enamine derived from acetone and (S)-proline.
each step should approach 100%. To meet this enor- We envisioned that control of the sense of enantio-
mous challenge, several reactions can be combined in and diastereoinductions (e.g., S vs. R, anti vs. syn)
tandem reaction sequences.[1] Moreover, multiple could be achieved via judicious selection of the chiral
chiral catalysts operating simultaneously could cir- catalysts involved in each catalytic cycle. The synthet-
cumvent the time and yield losses associated with the ic plan relied on finding optimal conditions for both
isolation and purification of stereoisomers in multi- enantioselective hydroformylation and enantioselec-
step sequences.
tive aldol reactions and then combining these reac-
In contrast to the major progress made in asymmet- tions into a tandem sequence.
ric multicatalysis using multimetallic,[2] multiorganoca-
Our starting point was the Rh-catalyzed enantiose-
talytic[3] or metal-enzyme systems,[4] very few reports lective hydroformylation of styrene. Styrene was
exist on the combination of metal with organocata- chosen as a substrate in order to avoid the regioselec-
lysts to accomplish an asymmetric reaction.[5] Recent- tivity problems of hydroformylation reactions. It is re-
ly, achiral metal catalyst/chiral organocatalyst[6] and ported that Rh complexes modified with bidentate
chiral metal catalyst/achiral organocatalyst catalytic phosphorus ligands such as (R,S)-BINAPHOS[10] and
systems have been reported.[7] However, a methodolo- (R,S)-YanPhos[11] give the best enantioselectivities
gy where the absolute configuration of one stereogen- and excellent regioselectivities in styrene hydroformy-
ic center in the product is controlled by a chiral lation. However, we did not consider them suitable
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Scheme 1. Enantioselective sequential hydroformylation and aldol reactions.
for a tandem reaction, since they usually operate at
temperatures higher than 608C.[12] Loss of steric infor-
mation via formation of the a,b-unsaturated ketones
in the subsequent aldol reaction at these temperatures
might be a problem. In contrast, Rh catalysts modi-
fied with Chiraphite ligands 4 were reported to be
used under relatively mild reaction conditions (25–
408C, 9 bar of CO/H2 1:1 pressure, toluene) achieving
good enantioselectivities (up to 76%) at reasonable
conversion (50%).[13]
First, the [Rh/ACHTUNGTRENNUNG(2R,4R)-Chiraphite]-catalyzed enan-
tioselective hydroformylation of styrene was adapted
to be combined with an aldol reaction. The reaction
was performed at 20/20 bar pressures of CO/H2 (re-
ported to be the optimal pressure for tandem hydro-
formylation and enantioselective aldol reactions)[6a] in
acetone (in the subsequent aldol reaction acetone
would serve both as the enamine component and as
solvent) (Scheme 2).
Scheme 2. Enantioselective hydroformylation of styrene.
According to GC analysis, styrene was fully con-
sumed after 72 h at 408C. (S)-2-Phenylpropanal (S)-
2[14] was obtained with excellent regioselectivity in line-tetrazole (S)-8[18] and (S)-proline[19] gave excellent
73% ee (Scheme 2). GC analysis revealed that during aldehyde conversions within 7 h and 72 h, respectively
the enantioselective hydroformylation, racemization (entries 3 and 5). The diastereomeric ratio and ee of
of the aldehyde by the Rh catalyst does not occur. the aldol products[20] (syn/anti=1.3:1, with 76% and
With all these findings in hand we could now proceed 98% ee, respectively) proved to be identical for all
to the organocatalyzed enantioselective aldol reaction conversions independent of the type of the catalyst
(Table 1).
used.
These results are not only interesting with respect
A range of organocatalysts was therefore tested in
the reaction between (S)-2-phenylpropanal (96% ee) to the different activities and identical selectivities of
(S)-2[15] and acetone (Table 1). The catalytic efficiency the organocatalysts chosen, but also informative if
of sulfonamides (S)-6[16] and (S)-7[16b,17] proved to be looking at the stereochemical outcome. Starting with
very low (Table 1, entries 1 and 2). In contrast, pro- 98% of the (S)-aldehyde 2 [96% ee, vs. 2% of the
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Combination of Enantioselective Metal Catalysis and Organocatalysis
Table 1. Enantioselective organocatalyzed aldol reactions.
Entry
Catalyst
Time [h]
Conversion [%][a]
3 [%][b]
1
2
3
4
5
(S)-6
(S)-7
(S)-proline
(S)-proline
(S)-8[c]
72
72
72
7
55
60
96
38
98
10
12
87
25
88
7
[a]
Determined by GC using dodecane as an internal standard.
Isolated yield.
5 mol% of catalyst was used.
[b]
[c]
(R)-configuration] the isolated aldol products have a slowly racemize aldehyde (S)-2 at similar rates. A
total of 50% of the former (S)-configuration and 50% drop in ee from 96% to 75–83% was observed after
of the (R)-configuration in the 5-position (stemming 5 h (Figure 1). In contrast, with dichloromethane as
from the aldehyde).[21] Thus the (S)-aldehyde must the solvent relatively fast aldehyde racemization was
have been racemized under the reaction conditions to observed. Here, after 5 h the aldehyde was almost
preferentially form the (4R,5R)-syn-aldol product completely racemized. In addition we investigated
(>49%), and only traces of the (4S,5R)-anti-aldol which part of the organocatalyst is responsible for the
product (<1%). Obviously, in the conversion of the racemization. Here, we found very fast racemization
(R)-aldehyde with acetone and the (S)-proline orga- (<2 min) in the presence of pyrrolidine and no race-
nocatalyst to the syn-aldol product both chiral units mization in the presence of acetic acid. These results
are directing towards the (4R)-configuration in the can be interpreted as an aldehyde deprotonation or
aldol product, thus representing the matched case of a the formation of the corresponding enamine from pyr-
double stereodifferentiation.[21] Conversion of the (S)- rolidine.
aldehyde with (S)-proline preferably leading to
We presumed that in a sequential hydroformyla-
(4R,5S)-anti-aldol product (43%) is accompanied by tion/aldol reaction it would be possible to adjust the
7% of the (4S,5S)-diastereoisomer.[21] This is obvious- hydroformylation and racemization rates relative to
ly representing the mismatched case with (S)-proline
overriding the opposite directing effect of the chiral
centre in the aldehyde. Thus racemization of the start-
ing (S)-aldehyde must play an important role under
the conditions of this organocatalyzed cross-aldol re-
action.
Indeed, with GC monitoring we observed that all
four organocatalysts racemize aldehyde (S)-2 at simi-
lar rates. For a better understanding of this phenom-
enon we performed control experiments of proline-
catalyzed racemization of the aldehyde (S)-2 (96%
ee) in different solvents (dichloromethane, 3-penta-
none and cyclohexanone) (Figure 1).
3-Pentanone and cyclohexanone were chosen as
solvents because they are similar to acetone but do
not react with (S)-2 in the presence of proline. In
Figure 1. Proline-catalyzed racemization of (S)-2-phenylpro-
these acetone-like solvents both proline enantiomers panal (S)-2 in different solvents.
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the aldol addition rate in such a way as to increase
A combination of achiral PACTHUNGTRENNU(G OPh)3-modified Rh cat-
the aldol reaction rate and minimize accumulation of alyst with an (S)-organocatalyst affords low syn/anti-
the aldehyde during the reaction. Thus, keeping the diastereoselectivities (1.8:1 in favour of the syn prod-
stationary concentration of the aldehyde at a low uct, Table 2, entries 1 and 2). When a chiral Rh cata-
level should minimize the contact of the aldehyde lyst is combined with an (S)-organocatalyst, a two-
with the organocatalyst and consequently lead to sup- fold asymmetric induction is expected.[22] This means
pression of the undesired racemization.
that the stereoselectivity of the aldol addition step is
In order to confirm this hypothesis, tandem reac- not only controlled by the configuration of the orga-
tions of chiral rhodium complex-catalyzed hydrofor- nocatalyst, but also by the aldehyde configuration
mylation and organocatalyzed aldol addition (both formed via enantioselective hydroformylation.
catalysts present from the beginning of the reaction)
and one-pot versions (the organocatalyst is added pair of catalysts, [Rh/AHCTNUGTRENNNUG
In the mismatched case mediated by a mismatched
(2R,4R)-4] [preferentially lead-
after enantioselective hydroformylation is completed) ing to the (S)-aldehyde] and (S)-organocatalyst [di-
were carried out starting from styrene as the substrate recting towards the (4R)-configuration in the aldol
and acetone as a substrate and also as a solvent product], formation of the anti isomer (4R,5S)-3
(Table 2).
should be enhanced. Indeed, with the chiral Rh cata-
When using the best organocatalysts, as shown in lyst the diastereoselectivity is lowered (1.3:1 dr in
Table 2, the yields of the aldol product 3 were good favour of syn, entries 3, 4 and 5) as compared with
(63–83%). It is important to note that the presence of the achiral rhodium catalyst (entries 1 and 2), but it is
the organocatalysts affects the rate of enantioselective not reversed. Despite the fact that the enantioselectiv-
hydroformylation in this tandem reaction. Thus sty- ity for the anti product is very high (98% ee), the
rene is not fully converted after 72 h (entries 3, 4, 6 major product is the syn isomer (4R,5R)-3 with 76%
and 7). Analysis of the results assembled in Table 2 ee.
indicate that the stereoselectivities of the sequential
In contrast, with a combination of the [Rh/ACTHNGUTRENNU(G 2S,4S)-
reactions are controlled by a complex series of factors 4] and an (S)-organocatalyst much higher diastereo-
amongst which are the rates of enantioselective hy- and enantioselectivities for aldol product (4R,5R)-
droformylation, aldehyde racemization and double syn-3 are observed. The selectivities in favour of
stereodifferentiation in the aldol addition. In an ideal (4R,5R)-syn-3 could be improved from 3:1 dr (84%
tandem reaction, the aldol reaction should have much ee) to 6.6:1 dr (93% ee) by changing (S)-proline to
higher rates than aldehyde racemization.
(S)-8 and from tandem reaction to one-pot version
Table 2. Enantioselective sequential hydroformylation and aldol reactions.
Entry Type of reaction[a]
Ligand
Organocatalyst Styrene conversion [%][b] 3 [%][c] syn:anti[d]
ee 3 [%][e]
4R,5R 4R,5S
1[6a]
2
3
4
5
6
7
8
Tandem
Tandem
P
P
ACHTUNGTRENNUNG
T
N
N
N
E
N
(S)-proline
(S)-8
>99
>99
87
84
>99
88
83
83
64
63
68
65
64
69
1.8:1
1.8:1
1.3:1
1.3:1
1.3:1
3:1
72
72
76
76
76
84
83
93
>99
>99
98
98
98
80
49
69
Tandem (mismatched)
Tandem (mismatched)
One-pot (mismatched)
Tandem (matched)
Tandem (matched)
One-pot (matched)
87
>99
4:1
6.6:1
[a]
Tandem=chiral metal catalyst and chiral organocatalyst are present from the beginning of the reaction; one-pot=chiral
organocatalyst is added after hydroformylation is completed and the reaction mixture is stirred at room temperature and
atmospheric pressure for an additional 16 h.
[b]
[c]
[d]
[e]
Determined by GC using dodecane as an internal standard.
Isolated yield.
Determined by H NMR analyses.
1
Determined by chiral HPLC.
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Combination of Enantioselective Metal Catalysis and Organocatalysis
(S)-8[18e] were synthesized according to the literature proce-
(entries 6, 7 and 8). This can be attributed to a
matched case of double stereodifferentiation establish-
ing a strong improvement in stereoselectivity, espe-
cially if considering the fact that the ee of the alde-
hyde obtained in the hydroformylation step cannot
exceed 73% (Scheme 2).
dures. Column chromatography was carried out using MN
Kieselgel 60 (0.063–0.2 mm/70–230 mesh). TLC was per-
formed on Merck Silica gel 60 F254 plates. Visualization of
the developed chromatograms was performed by ultraviolet
irradiation (254 nm) or by anisaldehyde stain. For gas chro-
matographic analyses, a Carlo Erba HRGC Mega2 Series
MFC 800 chromatograph with a Carlo Erba EL 580 flame-
ionization detector (FID) was used. Separations were per-
formed on the Supelco Beta Dex 225 column. Semi-prepara-
tive HPLC was performed using a SUPELCOSILTM LC-SI
5 mm (25 cmꢃ21.2 mm) column. Analytical HPLC was per-
formed on a Hewlett–Packard 1050 Series chromatograph
using CHIRALCEL OJ-H (250ꢃ4.6 mm) and CHRALPAK
AD (250ꢃ4.6 mm) columns as noted.
Moreover, in entry 8, the calculated ratio of the
carbon stereocenters bearing the Ph group [(5S)/
(5R)=86:14][21] is very similar to that from the (S)-al-
dehyde obtained in enantioselective hydroformylation
[(S)/(R)=86.5:13.5][21] from Scheme 2. This means
that in the one-pot reaction, for the matched case, rac-
emization of the aldehyde during the aldol reaction is
almost completely suppressed. From these results, we
conclude that, in contrast to our initial presumption,
keeping the stationary concentration of aldehyde at a
low level has a smaller effect on asymmetric induction
during the subsequent aldol addition step, as com-
pared with the one-pot version. In the mismatched
case, however, the ratio (5S)/(5R)=50:50[21] (entries 4,
5 and 6). This implies that aldehyde racemization
during the aldol addition here has a greater impact on
the asymmetric induction (see Figure 1).
In conclusion, the work reported here shows that it
is possible to control the sense of enantio- and dia-
stereoinductions in sequential hydroformylation and
aldol reactions via the judicious combination of a
chiral metal catalyst with a chiral organocatalyst
under suitable reaction conditions. The diastereoselec-
tivity of the reaction between styrene, syngas and ace-
tone can be considerably increased by using a
Enantioselective Hydroformylation of Styrene
(Scheme 2)
To
0.005 equiv.) in 2 mL of acetone in a vial, was added
(2R,4R)-Chiraphite (2R,4R)-4 (9 mg, 0.0097 mmol,
a solution of [RhACHTUNTGERNUGN(acac)(CO)2] (1 mg, 0.0039 mmol,
0.0125 equiv.). The solution was stirred with magnetic stirrer
for 5 min and then charged with styrene (81 mg, 0.78 mmol,
1 equiv.) and dodecane (40 mg, 0.234 mmol, 0.3 equiv.). The
vial was transferred to the autoclave, pressurized with 20/
20 bar CO/H2 and heated to 408C. After the reaction was
completed, the autoclave was cooled down to room temper-
ature, depressurized, flushed with argon and opened to
obtain a sample for GC analysis. GC conditions: carrier gas
50 kPa He, temperature program of 1008C for 5 min, then
48C/min to 1608C and 208C/min to 2008C; retention times:
8.69 min for styrene, 16.26 min for dodecane, 18.02 min for
(R)-2-phenylpropanal, 18.28 min for (S)-2-phenylpropanal
and 21.8 min for 3-phenylpropanal, in accord with the litera-
ture data.[14]
matched pair of catalysts [Rh/
ACHTUNGTNER(NUNG 2S,4S)-Chiraphite]/(S)-
organocatalyst and decreased, but not inverted, by
using a mismatched pair of catalysts [Rh/
Chiraphite]/(S)-organocatalyst.
Moreover in the matched case the easily racemized
aldehyde obtained after the hydroformylation step is
converted to an aldol product without loss of its
chiral information.
The cooperation of chiral metal catalysts and chiral
organocatalysts offers many other possibilities for
asymmetric transformations. This approach is likely to
lead to the development of powerful methods for the
generation of complex optically active molecules from
simple starting materials.
ACHTUNGTRENN(UNG 2R,4R)-
Enantioselective Organocatalyzed Aldol Reactions
(Table 1)
To a stirred suspension of (S)-organocatalyst (0.3 mmol,
0.3 equiv.) in 5 mL of acetone was added dodecane (51 mg,
0.3 mmol, 0.3 equiv.) and (S)-2-phenylpropanal (134 mg,
1 mmol, 1 equiv.). The resulting mixture was stirred at room
temperature until the reaction was completed. Then, the re-
action mixture was filtered through a column filled with
silica gel. Additionally the column was washed with 50 mL
of diethyl ether. The filtrate was concentrated under
vacuum and the crude product was purified by column chro-
matography (EtOAc/cyclohexane 1:4) to afford the mixture
of syn/anti diastereomers of the compound 3 as a colourless
oil. Diastereomers were separated on a semi-preparative
HPLC column (EtOAc/cyclohexane, 1:6).
Experimental Section
General Remarks
Proline-Catalyzed Racemization of (S)-2-
Phenylpropanal in Different Solvents (Figure 1)
Enantioselective hydroformylation and tandem reaction ex-
periments were carried out in a BERGHOF HR-200 high-
pressure reactor with magnetic stirring and electrical heat-
ing. The inside part of the cover was made from Teflonꢂ to
protect the solution from direct contact with the stainless
steel. Commercial reagents were used as received. (2R,4R)-
Chiraphite,[13a] (2S,4S)-Chiraphite,[13a] (S)-6,[18e] (S)-7[18e] and
To a solution of (S)-2-phenylpropanal (96% ee) (20 mg,
0.15 mmol) in 1 mL of solvent in a flask, was added proline
(5 mg, 0.045 mmol). The suspension was stirred with a mag-
netic stirrer at room temperature. A sample for GC analysis
was taken every hour and analyzed immediately.
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temperature and atmospheric pressure. After that the reac-
tion mixture was filtered through a column filled with silica
gel. Additionally the column was washed with 50 mL of di-
ethyl ether. The filtrate was concentrated under vacuum and
the crude product was purified by column chromatography
(EtOAc/cyclohexane 1:4) to afford the mixture of syn/anti
diastereomers of the compound 3 as a colourless oil. Diaste-
Tandem Hydroformylation and Enantioselective
Aldol Addition (Table 2, entries 1 and 2)
To
a solution of [RhACHTUNTGERNUGN(acac)(CO)2] (5 mg, 0.019 mmol,
0.005 equiv.) in 2 mL of acetone in a vial, was added tri-
phenyl phosphite (24 mg, 0.078 mmol, 0.02 equiv.). The solu-
tion was stirred with a magnetic stirrer for 5 min and then
charged with styrene (395 mg, 3.8 mmol, 1 equiv.), dodecane
(199 mg, 1.17 mmol, 0.3 equiv.) and (S)-organocatalyst
(1.17 mmol, 0.3 equiv.). The vial was transferred to the auto-
clave, pressurized with 20/20 bar CO/H2 and heated to 408C.
After the reaction was completed, the autoclave was cooled
down to room temperature, depressurized, flushed with
argon and opened to obtain a sample for GC analysis. Then
the reaction mixture was filtered through a column filled
with silica gel. Additionally the column was washed with
50 mL of diethyl ether. The filtrate was concentrated under
vacuum and the crude product was purified by column chro-
matography (EtOAc/cyclohexane 1:4) to afford the mixture
of syn/anti diastereomers of the compound 3 as a colourless
oil. Diastereomers were separated on a semi-preparative
HPLC column (EtOAc/cyclohexane, 1:6) and analyzed by
chiral HPLC.
reomers were separated on
a semi-preparative HPLC
column (EtOAc/cyclohexane, 1:6) and analyzed by chiral
HPLC.
A
(Table 2,
entry 1): 1H NMR (500 MHz, CDCl3): d=7.32- 7.29 (m,
2H), 7.24–7.16 (m, 3H), 4.09 (ddd, 1H, J=7.9, 5.8, 5.8 Hz),
2.74 (qd, 1H, J=7.9, 7.0 Hz), 2.42–2.40 (m, 2H), 2.07 (s,
3H), 1.36 (d, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3):
d=17.6, 30.7, 45.4, 47.9, 72.1, 126.6, 127.6, 128.6, 143.8,
210.1; HRMS (FAB+): m/z 193.1236, exact mass calculated
for [M+H]+ (C12H17O2): 193.1229; elemental analysis (%),
calcd. for C12H16O2: C 74.97, H 8.39; found: C 74.48, H 8.50;
IR (film): nmax =3461, 2965, 1708, 1493, 1452, 1361, 1164,
702 cmÀ1; [a]2D0: +13.8 (c 1.23, n-heptane); HPLC (CHIR-
ALPAK AD, n-heptane/i-PrOH, 98:2, 1.0 mLminÀ1,
254 nm): ee=72%, tR [(4R,5R)-3]=18.6 min; tR [(4S,5S)-3]=
20.3 min. All the spectral and HPLC data are in accord with
the literature data.[6a]
Tandem Enantioselective Hydroformylation and
Aldol Addition (Table 2, entries 3, 4, 6 and 5)
A
(Table 2,
entry 1): 1H NMR (500 MHz, CDCl3): d=7.34–7.31 (m,
2H), 7.26–7.22 (m, 3H), 4.20 (ddd, 1H, J=9.3, 6.1, 2.6 Hz),
2.82 (qd, J=7.0, 6.1 Hz), 2.58 (dd, 1H, J=17.2, 2.6 Hz), 2.47
(dd, 1H, J=17.2, 9.3 Hz), 2.14 (s, 3H), 1.31 (d, 3H, J=
7.0 Hz); 13C NMR (125 MHz, CDCl3): d=17.0, 30.8, 45.0,
47.3, 71.7, 126.6, 128.1, 128.4, 142.8, 209.4; HRMS (FAB+):
m/z 193.1236, exact mass calcd. for [M+H]+ (C12H17O2):
193.1229; elemental analysis (%), calcd. for C12H16O2: C
74.97, H 8.39; found: C 74.62, H 8.60; IR (film): nmax =3461,
2965, 1708, 1493, 1452, 1361, 1164, 702 cmÀ1; [a]D20: +32.7 (c
1.97, n-heptane); HPLC (CHIRALCEL OJ-H, n-heptane/i-
PrOH, 90:10, 1.0 mLminÀ1, 254 nm): ee=>99%, tR
[(4R,5S)-3]=16.5 min, tR [(4S,5R)-3]=22.99 min. All the
spectral and HPLC data are in accord with the literature
data.[6a]
To
a solution of [RhACHTUNTGERNUGN(acac)(CO)2] (1 mg, 0.0039 mmol,
0.005 equiv.) in 2 mL of acetone in a vial, was added 4
(9 mg, 0.0097 mmol, 0.0125 equiv.). The solution was stirred
with a magnetic stirrer for 5 min and then charged with sty-
rene (81 mg, 0.78 mmol, 1 equiv.), dodecane (40 mg,
0.234 mmol, 0.3 equiv.) and organocatalyst (0.234 mmol,
0.3 equiv.). The vial was transferred to the autoclave, pres-
surized with 20/20 bar CO/H2 and heated to 408C. After the
reaction was completed, the autoclave was cooled down to
room temperature, depressurized, flushed with argon and
opened to obtain a sample for GC analysis. Then the reac-
tion mixture was filtered through a column filled with silica
gel. Additionally the column was washed with 50 mL of di-
ethyl ether. The filtrate was concentrated under vacuum and
the crude product was purified by column chromatography
(EtOAc/cyclohexane 1:4) to afford the mixture of syn/anti
diastereomers of the compound 3 as a colourless oil. Diaste-
reomers were separated on
column (EtOAc/cyclohexane, 1:6) and analyzed by chiral
HPLC.
a semi-preparative HPLC
Acknowledgements
The authors thank Dr. Hon Wai Lam for valuable discus-
ˇ
sions and Mr. Ales Marek for the assistance in synthesis of
Chiraphite ligands.
One-Pot Enantioselective Hydroformylation and
Aldol Addition (Table 2, entries 5 and 8)
To a solution of [RhACHTNUGRTNE(NUG acac)(CO)2] (1 mg, 0.0039 mmol) in
2 mL of acetone in a vial, was added 4 (9 mg, 0.0097 mmol, References
0.0125 equiv.). The solution was stirred with a magnetic stir-
rer for 5 min and then charged with styrene (81 mg,
0.78 mmol, 1 equiv.) and dodecane (40 mg, 0.234 mmol,
0.3 equiv.). The vial was transferred to the autoclave, pres-
surized with 20/20 bar CO/H2 and heated to 408C. After the
reaction was completed, the autoclave was cooled down to
room temperature, depressurized, flushed with argon and
opened to obtain a sample for GC analysis. Then organoca-
talyst (0.234 mmol, 0.3 equiv.) was added to the vial and the
reaction mixture was stirred for an additional 18 h at room
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The Supporting Information contains the information
presented in Table 1 and Table 2 in an alternative
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asc.wiley-vch.de
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