Systematic studies using 2-(1-adamantylethynyl)pyrimidine-5-carbaldehyde as a starting material in soai's asymmetric autocatalysis

Article abstract of DOI:10.1002/chem.200900634

Herein, we present a new substrate for the Soai reaction, which has an adamantylethynyl residue (1g) and exhibits asymmetric autocatalysis, yielding products with enantiomeric excesses above 99%. For the first time, all reactions were performed on a parallel synthesizer system to ensure identical reaction conditions. A detailed systematic study of reaction parameters was performed and we report the highest enhancements of enantiomeric excess reported so far in the Soai reaction in one reaction cycle (7.2→94.1% ee or 3.1→92.1% ee). Our results led to a set of reaction parameters that yield reproducible results. Therefore, our new starting material 1g is suitable for systematic and mechanistic studies on this remarkable reaction. A series of experiments designed to quantify the amplification of enantiomeric excess demonstrated that the reaction can be used in principle as a tool for the detection of low enantiomeric excesses: under definite conditions, an unknown low enantiomeric excess (0.1-7%) was amplified to a detectable one. A back calculation to the original value offers a new method for the determination of small enantiomeric excesses.

Full text of DOI:10.1002/chem.200900634

FULL PAPER
DOI: 10.1002/chem.200900634
Systematic Studies using 2-(1-Adamantylethynyl)pyrimidine-5-carbaldehyde
as a Starting Material in Soaiꢀs Asymmetric Autocatalysis
Mark Busch, Martin Schlageter, Daniel Weingand, and Timo Gehring*[a]
Abstract: Herein, we present a new
substrate for the Soai reaction, which
has an adamantylethynyl residue (1g)
and exhibits asymmetric autocatalysis,
yielding products with enantiomeric ex-
cesses above 99%. For the first time,
all reactions were performed on a par-
allel synthesizer system to ensure iden-
tical reaction conditions. A detailed
systematic study of reaction parameters
was performed and we report the high-
est enhancements of enantiomeric
excess reported so far in the Soai reac-
tion in one reaction cycle (7.2!94.1%
ee or 3.1!92.1% ee). Our results led
to a set of reaction parameters that
yield reproducible results. Therefore,
our new starting material 1g is suitable
for systematic and mechanistic studies
on this remarkable reaction. A series
of experiments designed to quantify
the amplification of enantiomeric
excess demonstrated that the reaction
can be used in principle as a tool for
the detection of low enantiomeric ex-
cesses: under definite conditions, an
unknown low enantiomeric excess
(0.1–7%) was amplified to a detectable
one. A back calculation to the original
value offers a new method for the de-
termination of small enantiomeric ex-
cesses.
Keywords: asymmetric amplifica-
tion
·
autocatalysis
·
chirality
·
systems chemistry
reagents
·
organozinc
Introduction
able chiral initiators includes virtually any class of chiral
compounds and also chiral crystals of achiral molecules
have been shown to serve as chiral initiators in this reac-
tion.[3] Soai and co-workers demonstrated unambiguously
that even circularly polarized light can induce the formation
of nonracemic product.[4] Without the addition of chiral
sources, the reaction shows spontaneous symmetry break-
ing.[5] So far, the Soai reaction has proven to be an outstand-
ing example of the incorporation of an asymmetric autocata-
lytic process into a classical chemical reaction. New findings
suggest that such processes might also occur in organocata-
lytic aldol and Mannich reactions.[6]
Asymmetric autocatalytic processes are a central part of
the evolving field of systems chemistry and are believed to
play an important role in the origin of homochirality and
life. In particular, the self-replication of biological molecules
and the amplification of ee in the prebiotic environment are
favored research topics.[7] Therefore, the detailed knowledge
of a reaction mechanism and the influence of reaction pa-
rameters as well as the structure of the starting material on
the enhancement of ee is important for the discovery and
understanding of asymmetric autocatalytic processes.
The Soai reaction is a remarkable example of asymmetric
autocatalysis. In this reaction, which was first discovered by
Soai and co-workers in 1990, a pyrimidine-5-carbaldehyde
reacts with diisopropylzinc, leading to chiral secondary alco-
hols (Table 1).[1a] A substoichiometric addition of the prod-
uct (itself with only a low enantiomeric excess (ee)) as auto-
catalyst at the beginning of the reaction leads to a significant
enhancement of the ee during the reaction.[1b] So far, the
best-performing starting material, discovered by Soaiꢀs
group in 1999, is 2-(tert-butylethynyl)pyrimidine-5-carbalde-
hyde (1c), which leads to ee values above 99.5% in only a
few reaction cycles.[2a,b] The nonracemic product is also ob-
tained when a chiral compound other than the product is
added at the beginning of the reaction. The plethora of suit-
[a] M. Busch, M. Schlageter, D. Weingand,
Dipl.-Chem. Dipl.-Math. T. Gehring
Institut fꢁr Organische Chemie, Universitꢂt Karlsruhe (TH)
Karlsruher Institut fꢁr Technologie (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-608-7652
All previously published substrates that provide a high en-
hancement of ee in this reaction have been synthesized by
Soai and co-workers.[2] In this context, the crucial influence
of the residue R in 1 (at the 2-position of the pyrimidine
E-mail: mail@timogehring.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900634.
Chem. Eur. J. 2009, 15, 8251 – 8258
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8251

ring) on the asymmetric autocatalytic activity has been em-
phasized in many publications, but has not yet been suffi-
ciently studied.[8]
In Table 1, the enhancement of ee is summarized for a
range of selected substrates and reveals some interesting ob-
servations: When R is hydrogen (1a), methyl (1b), or n-bu-
All of these substrates show typical autocatalytic behavior.
Although the temperature was varied over a range of 708C
in the published measurements, the influence of tempera-
ture itself on the reaction rate or the ee has not been studied
in detail. Taking into account that substrates 1b, 1c, and 1d
exhibit considerable differences in asymmetric autocatalytic
activity, it is still not clear whether they (and other sub-
strates) follow the same mechanistic pathway, thus there is
still a considerable knowledge gap. Blackmond and Buono
published heat-flow measurements with substrate 1b at
258C and varied reaction parameters in four different ex-
periments, which led to a preliminary result concerning the
Table 1. Different substrates and their asymmetric autocatalytic activity
in the Soai reaction.[8]
influence of ZnACTHNUTRGNEUNG(iPr)2 (1.8 vs. 3.6 equiv) and initial ee (6 vs.
22%).[9a,c] This resulted in an improvement of a previously
published rate law proposal by Blackmond and co-work-
ers.[9d] Considering the limited amount of published data,
this suggested rate law is the best so far because the pro-
posed kinetic model predicts the observed time evolution in
the experiment.[9a] The influence of the amount of enantio-
pure autocatalyst used was investigated by Brownꢀs group
for substrate 1d.[5b] This group also performed extensive
NMR spectroscopy studies and DFT calculations, which sup-
ported a postulated {Zn-O}2 square structure for the resting
state and clarifying the necessity of the always used isopro-
Added autocatalyst
ee mol% ee
Entry Compound
R
Reference
[%]
product
[%]
[1b]
[9h]
[9a]
[9a]
1
2
3
4
1a
1b
1b
1b
H
10
94.8
6
20
20
10
10
57
Me
Me
Me
95.7
~42[a]
~76[a]
22
[2]
[2]
5
1c
5.5
8.4
20
69.6
pyl group in ZnACTHNUTRGNEUNG
(iPr)2.[9b,f,g] In summary, important experi-
ments have been performed and yield a preliminary under-
standing of this reaction, although a full explanation is still
lacking. The use of different conditions and substrates
makes it particularly difficult to compare the published
data.
6
1d
20
74.2
[2]
[2]
7
8
1e
1 f
8.6
5.8
20
20
8.8
To resolve the mechanism of the Soai reaction and to
make this reaction valuable for possible applications, further
experiments have to be performed. Studies on the influence
of reaction parameters such as temperature, molar ratio of
added reactants, ee of the added autocatalyst, and variation
of substrate structures on both the ee of the newly formed
product and on the detailed kinetic behavior of this reaction
will lead to reliable data for the elucidation of a mechanism.
Since the Soai reaction is sensitive to impurities and slight
changes in reaction conditions, systematic studies should be
carried out in a reaction setup that ensures reproducibility.
Furthermore, repeat determinations of experiments should
be performed to determine whether the reaction parameters
used have been chosen in such a way as to provide reprodu-
cible results or not.[12] In our opinion, this natural require-
ment of every scientific experiment demands special men-
tion in the case of the Soai reaction, because this reaction
shows bifurcation and chaotic behavior phenomena. Experi-
mental data from previous kinetic studies usually lack ex-
plicit information on repeat determinations. Considering the
Soai reaction as an ee amplification tool, it should be of in-
terest for practical applications. Possibly it can even be used
as a quantitative amplification instrument for the detection
of small ee values. Even though it has been shown that the
reaction is able to amplify undetectable deviations from rac-
emic mixtures into high ee values, no detailed quantitative
experiments have yet been published.
21.2
[a] Taken from Figure 2 from reference [9a].
tylethynyl (1 f), moderate asymmetric autocatalytic activity
is observed, whereas when R is tert-butylethynyl (1c) or tri-
methylsilylethynyl (1d), significantly higher activities are
achieved. A triisopropylsilylethynyl group (1e) leads to stag-
nation of the enhancement. A mechanistic or structural
reason for this different behavior is still lacking and no ki-
netic data for the different substrates under identical condi-
tions are available. Over the last decade only one attempt to
synthesize other substrates has been published.[2c]
Even though several groups have tried to address mecha-
nistic questions, a detailed model of the reaction mechanism
and its underlying asymmetric autocatalysis on a molecular
level is still incomplete and is the subject of ongoing re-
search.[9] Ercolani and Schiaffino recently proposed a reac-
tion mechanism for the moderately active substrate 1b,
based on theoretical calculations in the gas phase.[10] Howev-
er, the kinetic and mechanistic understanding of the Soai re-
action is still not satisfactory. Rate measurements were re-
corded at ꢀ45, ꢀ25, and 08C with substrate 1c,[11] at 08C
with substrate 1d,[5b] and at +258C with substrate 1b.[9c,d]
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Asymmetric Autocatalysis
FULL PAPER
To address the above open questions, we planned to syn-
thesize a new starting material and to study its behavior in
the Soai reaction by varying the reaction conditions in
detail. To ensure identical reaction conditions and to make
the reaction appropriate for use in applications, we intended
to carry out reactions on a parallel synthesizer so that the
quantitative behavior of the amplification can be addressed.
synthesizer to ensure an identical reaction setup. Random
repeat determinations of experiments were performed to ex-
amine the reproducibility of the reactions. All reactions
were carried out in toluene on a 100 mg scale. It should be
noted that all of our experiments were performed by the
single addition of reactants and not in multistep procedures
consisting of repeating enhancement cycles in one reaction,
as used in most studies by Soai.[15,16]
Results and Discussion
Influence of reaction temperature: The temperature de-
pendency (ꢀ35 to +458C) of the ee obtained after one reac-
tion cycle is shown in Figure 1a for (S)-2g and in Figure 1b
Synthesis of the adamantyl starting material 1g: We aimed
to perform the Soai reaction with 2-(1-adamantylethynyl)-
pyrimidine-5-carbaldehyde (1g; reaction shown above Table
2). This new compound was synthesized through Sonoga-
shira cross-coupling of the building blocks 3 and 4 followed
by subsequent formylation (Scheme 1). A similar sequence
was used in the syntheses of most known Soai substrates.[2]
Compound 4 was synthesized in two steps from commercial-
ly available 2-hydroxypyrimidine hydrochloride[13] and 3 was
accessible from 1-acetyladamantane by elimination of the
corresponding vinyl phosphate.[14]
Scheme 1. Synthesis of adamantyl starting material 1g. Reagents and
conditions: a) Br2, H2O, then POCl3, N,N-dimethylaniline; b) HI, CH2Cl2,
46% (two steps); c) ꢀ788C, LDA (1 equiv), ClPO
ACHTUNGTRENNUNG
Figure 1. Influence of reaction temperature on ee of product (S)-2g (a)
and (R)-2g (b). Conditions: eeinitial =7.2% (S) (a), 7.4% (R) (b), ratio
ZnACHTNURTGNE(UNG iPr)2/1g/2g=1.5:1:0.15. For data sets and details see the Supporting
ꢀ788C, LDA (2 equiv), ꢀ788C to RT, 77%; d) [Pd
AHCTUNGTRENNUNG
CuI (3.4 mol%), (iPr)2NH (4 equiv), THF, 08C, 24 h, 91–99%;
e) ꢀ1108C, nBuLi (2 equiv), TMEDA (1 equiv), 30 min, then HCO2Et
(1 equiv), 20 min, then HCl in dioxane (3 equiv), THF, ꢀ1108C to RT,
54%. Abbreviations: TMEDA=N,N,Nꢀ,Nꢀ-tetramethylethylenediamine,
LDA=lithium diisopropylamide.
Information.
for (R)-2g, and reveals interesting facts not reported before.
Repeat determinations led to reproducible results (Dee<
3.3%). Between ꢀ20 and +258C, no significant change in
ee was observed (69–74% ee, Figure 1a). It is reasonable to
assume that higher reaction temperatures shift underlying
equilibrium processes or favor an uncatalyzed racemic addi-
Formylation (5!1g) was performed through bromine–
lithium exchange at ꢀ1108C followed by the addition of
ethyl formate. In our system, these reaction conditions were
extensively varied and optimized up to 54% yield. Use of
other formylation conditions (Grignard reaction, Pd-cata-
lyzed with CO/H2, 30 bar) led to lower yields.
tion of ZnACHTUNGRTENNG(U iPr)2, and accordingly, a considerable decrease in
ee was observed above +258C (+458C, 22.5% ee, (S)-2g).
Interestingly, a decrease in ee was also observed at lower
temperatures (ꢀ358C, 45.1% ee, (S)-2g).
Systematic studies on the influence of reaction parameters:
Our main goal was to study the influence of reaction param-
eters such as temperature, equivalents of ZnACTHNURGTNEUNG(iPr)2, and the
ee and the amount of autocatalyst added at the beginning of
the reaction on the ee of the newly formed product. There-
fore, product 2g (with a definite ee) was used as asymmetric
autocatalyst and all reactions were performed in a parallel
A plot of ln(er) against 1/T (er=enantiomeric ratio) ex-
hibited nonlinear Eyring behavior (see the Supporting Infor-
mation for this plot). Therefore, an explanation involving
the isoinversion principle[17] is not simply applicable also
due to the still unknown reaction mechanism. The nonlinear
behavior could suggest multiple reaction pathways with
Chem. Eur. J. 2009, 15, 8251 – 8258
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8253

T. Gehring et al.
complex temperature dependencies. Even at ꢀ358C the re-
action proceeded with complete conversion still indicating
the presence of catalytic processes but with significantly
lower selectivity. Further experiments are required to clarify
this temperature influence. The observed temperature de-
pendency is quite challenging for mechanistic and kinetic
studies and implies a more complex picture for the Soai re-
action. Detailed temperature studies on substrates other
than 1g are lacking. For further studies we propose experi-
ments at the temperatures yielding the highest ee values to
ensure that the phenomenon of asymmetric autocatalysis is
studied at the level of highest activity. In our system, the
highest ee values were obtained between ꢀ15 and +108C.
Further experiments were conducted at ꢀ58C.
lower amounts of autocatalyst results in dispersive ee values
as shown by Brown et al. for enantiopure autocatalyst 1d.[5b]
A determination of the optimum amount of a low ee autoca-
talyst required to yield high ee values has not been reported
so far and our study shows interesting results for substrate
2g (Table 2): The highest ee of the newly formed product
(S)-2g was obtained when 2.0 mol% of (S)-2g (7.2% ee)
was added at the beginning of the reaction (Table 2,
entry 9). This reaction outcome was reproducible in multiple
experiments and held also for (R)-2g (Table 2, entry 20).
Even 0.2% (S)-2g (7.2% ee) yielded (S)-2g with an ee of
89% (Table 2, entry 5). In summary, we observed that when
leaving all other reaction parameters constant, a change in
the number of equivalents of autocatalyst added (over two
orders of magnitude, 0.2 to 20%) has no crucial influence
on the ee of the newly formed product. Further reduction of
the amount of (S)-2g added at the beginning of the reaction
results in lower ee values, but still with enhancement of the
major enantiomer. Even an extremely small amount of (S)-
2g is capable of amplifying the ee: the ee value was en-
hanced to 17 and 40% using just 0.0004 mol% of (S)-2g
(Table 2, entries 1 and 2).[18] Here it seems that statistical ef-
fects come to the fore, or the system is very sensitive to
small changes. Brown et al. observed this trend using enan-
tiopure (R)-2d at similar amounts of added autocatalyst
(~0.002% catalyst).[5b] Hence, below this concentration, dis-
persive ee values are obtained for both low (7.2%) and high
(99%) ee of the autocatalyst used.
Influence of amount of low ee autocatalyst added: Varying
the equivalents of autocatalyst 2 used has great influence on
the ee of newly formed product (Table 2). On addition of
large amounts of low ee autocatalyst one might expect a de-
crease in ee because a larger amount of the minor enantio-
mer was added at the beginning of the reaction. Addition of
Table 2. Influence of amount of autocatalyst added on the ee of newly
formed product 2g.[a]
About 20 mol% of enantiopure (S)-2g (99.1% ee) is re-
quired to maintain or even enhance the ee value up to
99.7% ee. This is consistent with reported results for the
substrates 1a–1d.[2,5b,9b] Blackmond et al. observed higher ee
values when 10 mol% of enantiopure 1b was used.[19] Com-
paring the enhancement in ee of our substrate 1g with those
of 1a–1 f, we describe conditions leading to the highest am-
plification of ee observed so far in the Soai reaction in one
reaction cycle (Table 2, entry 9).[20] Therefore, our starting
material 1g is suitable for systematic studies.
Chiral additive
Entry compound ee
[%]
mol%
T
Zn
G
ee newly
[8C] [equiv] product formed
product
[%]
1
2
3
4
5
6
7
8
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
0.00041 ꢀ5 1.5
0.00043 ꢀ5 1.5
16.7
40.5
40.3
63.5
89.6
92.3
91.9
93.1
95.8
95.1
95.8
92.0
89.8
87.7
84.4
0.0042
0.022
0.23
0.68
0.99
0.98
2.0
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
Influence of concentration of Zn
ACHTUNGRTEN(NUNG iPr)2 and total reaction
volume: Blackmond et al. showed that the number of equiv-
alents of ZnACHTNUGTRENUNG(iPr)2 used has no influence on the reaction rate
at +258C in the Soai reaction of 1b (1.8 vs. 3.6 equiv).[9a,c]
We only observed small changes in the ee of 2g when the
9
10
11
12
13
14
15
2.5
2.5
5.6
amount of ZnACTHUNRGTNEUNG(iPr)2 was varied from one to three equiva-
lents (using 2.5 mol% autocatalyst, Table 3). Lowering the
amount of autocatalyst to 0.25 mol% led to differing results.
7.2 10.9
7.2 15.3
7.2 20.3
Whereas 1.5 equivalents of ZnACHTNUTRGNENG(U iPr)2 led to reproducible re-
sults at both catalyst concentrations (Table 3, entries 1, 2, 7,
and 8), the use of two or three equivalents led to dispersive
ee enhancement at low catalyst concentration, which indi-
cates that these conditions exhibit complex and chaotic be-
havior in the amplification of ee.
16
17
18
(S)-2g
(S)-2g
(S)-2g
99.1 0.87
99.1 2.4
99.1 22.1
ꢀ5 1.5
ꢀ5 1.5
ꢀ5 1.5
98.5
98.3
99.7
98.5
98.3
99.7
19
(S)-2g
99.7 20.5
ꢀ5 1.5
99.7
99.7
The influence of the total reaction volume on ee was
checked using half, respectively double amount of the other-
wise used solvent amount (Table 4). Only small changes in
ee enhancement were obtained in the concentration range
20
21
(R)-2g
(R)-2g
6.0
7.4 14.8
2.0
ꢀ5 1.5
93.8
73.1
95.6
82.8
ꢀ11 1.5
[a] Selection of collected data, see Supporting Information for full list of
experiments performed. [b] Containing the added catalyst.
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Chem. Eur. J. 2009, 15, 8251 – 8258

Asymmetric Autocatalysis
FULL PAPER
Table 3. Influence of the amount of Zn
above Table 2).
ACHTUNGRTEN(NUNG iPr)2 on ee (reaction shown
Chiral additive
Entry Compound ee [%] mol% ZnACHTNUGRTNEUNG
(iPr)2 [equiv] ee product [%][a]
1
2
3
4
5
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
7.2
7.2
7.2
7.2
7.2
2.5
2.5
2.6
2.5
2.6
1.5
1.5
2
2
3
92.8
93.6
84.9
91.4
89.7
6
7
8
9
10
11
12
13
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
(S)-2g
7.2
7.2
7.2
7.2
7.2
7.2
7.2
7.2
0.25
0.25
0.23
0.25
0.25
0.25
0.25
0.25
1
73.1
88.8
89.4
83.1
11.4
73.0
62.3
14.9
1.5
1.5
2
2
2
Figure 2. Amplification of ee after addition of low ee (S)-2g. All reactions
performed in toluene at ꢀ58C, ratio Zn
ACHTUNGERTN(NUNG iPr)2/1g/2g=1.5:1:0.02. See the
Supporting Information for details and data.
3
3
[a] Containing the added catalyst. All reactions were carried out at
ꢀ58C, see Supporting Information for details.
is evident that repeat determinations are necessary to
ensure that the measured probe is within the area of repro-
ducibility (0.1–7% ee). A concrete calculation example for a
logarithmic fit in the area 0.1–7% ee in Figure 2 for a mea-
sured ee value eey1 =(75.0ꢁ5.0)% affords an original value
of eex1 =(0.35ꢁ0.28)%. Compared with the result obtained
in our study that an ee value of eex2 =0.5% is amplified to
eey1 =(75.0ꢁ5.0)% the determination of ee values with
eex <4% with the given accuracy is quite remarkable (the
model in the given reaction conditions has a lower boundary
of 0.1% ee). The collection of more data will clearly reduce
the error and lead to more accurate results.
Table 4. Influence of the total reaction volume on the ee (reaction shown
above Table 2).
Chiral additive
Entry
Compound
ee
c (1g)
Vtotal (toluene)
ee product
[%]
N
]
[%][a]
1
2
3
4
5
6
(R)-2g
(R)-2g
(R)-2g
(R)-2g
(R)-2g
(R)-2g
7.4
7.4
7.4
7.4
7.4
7.4
0.089
0.089
0.045
0.044
0.022
0.022
4.2
4.2
8.5
8.5
17
92.3
88.8
93.4
91.8
94.8
95.0
17
Because the Soai reaction is sensitive to various added
sources of chirality, the reaction could be used as a general
tool for the determination of small ee values for other pure
compounds under standardized conditions. The determina-
tion of whether tuning of the reaction parameters (e.g.,
higher amount of used catalyst) will lead to reproducible en-
hancement of still smaller ee values will be the subject of
future experiments.
[a] Containing the added catalyst. All reactions were carried out at
ꢀ58C, ratio Zn(iPr)2/1g/2g=1.5:1:0.020, see the Supporting Information
for details.
ACHTUNGTRENNUNG
studied to indicate a slightly better enhancement when the
initial concentration of 1g was 0.022m.
We have investigated the ability of chiral initiators to
induce chirality in 1g, as studied frequently by Soai et al. for
Enhancement of low ee catalyst in the Soai reaction: A tool
for determination of small ee values: Having established the
optimum reaction conditions to yield product 2g with high
ee values, we started varying the ee of autocatalyst 2g in the
low ee range (Figure 2). Lowering the ee from 7 to 0.1% led
to an almost linear decrease in the ee of the obtained prod-
uct (in a logarithmic plot). In the range of 1 to 0.1% ee, the
results became slightly dispersive (Dee<12%). Below
0.1% ee, the results were scattered quite strongly but all still
show enhancement and the same handedness. Adding cata-
lyst with 0.001% ee yielded (in two experiments) 40.3 and
84.6% ee. Adding 2 mol% of rac-2g resulted in spontaneous
symmetry breaking to give 2g with both R and S configura-
tions.[21] In summary, we have studied the character of the
amplification of small ee values and demonstrated in princi-
ple the use of the Soai reaction as a tool for the detection of
small ee values. Under definite conditions, an unknown
small ee value (eex) could be amplified to a detectable one
(eey) and a back calculation yields the original value (eex). It
compound 1c.[22] Treatment of 1g with Zn
ACHTNUTRGNE(UNG iPr)2 in the pres-
ence of (S)-1-phenylethylamine as chiral initiator
(21 mol%) yielded (R)-2g with 92% ee. The use of (R)-1-
phenylethylamine (21 mol%) resulted in an ee of 92% for
(S)-2g. By using the chiral bis-sulfoxide (1R,3R)-2-benzyli-
dene-[1,3]dithian-1,3-dioxide[23] (20 mol%) as chiral initiator
yielded (S)-2g with an ee of 77%. Sulfoxides have not previ-
ously been tested as chiral initiators and we hereby show
that they also serve as excellent molecules for this purpose.
Again, our implementation in a parallel synthesizer system
yielded reproducible results in repeat determinations (Dee<
3%). Compared with the laborious multistep reaction setup
used by Soaiꢀs group for their studies with chiral initiators,[16]
our procedure (consisting of mixing reagents, adding
ZnACTHUNTRGENNG(U iPr)2, and stirring) to yield high ee values is quite a
simple approach. An expansion of our work would be to at-
tempt to transfer the determination of small ee values of 2g
to the determination of small ee values of any chiral com-
Chem. Eur. J. 2009, 15, 8251 – 8258
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8255

T. Gehring et al.
ried out by using Merck silica gel 60 (230–400 mesh) and TLC was car-
ried out by using commercially available Merck F254 pre-coated sheets.
1H and 13C NMR spectra were recorded on Bruker Cryospek WM-250,
AM-400, and DRX 500 spectrometers. The spectra were measured at
room temperature unless noted otherwise. Chemical shifts are given in
ppm downfield of tetramethylsilane or calibrated to the CHCl3 solvent
signal. 13C NMR spectra were recorded with broadband proton decou-
pling and were assigned using DEPT experiments. Melting points were
measured on a Bꢁchi 530 melting point apparatus and are not corrected.
IR spectra were recorded on a Bruker IFS-88 spectrophotometer. Ele-
mental analyses were performed on an Elementar Vario MICRO instru-
ment. Electron-ionization and high-resolution mass spectra were record-
ed on a Finnigan MAT-90 spectrometer. Determination of ee values by
HPLC was performed using a Chiralcel OD-H column and hexane/2-
propanol as solvent (HPLC-grade quality, Fisher scientific). Flow rate,
solvent ratio, and retention time are given in the particular procedures.
Optical rotations were recorded on a Perkin–Elmer 241 polarimeter and
specific optical rotations [a]2D0 are given in units of 10ꢀ1 degcm2 gꢀ1. The
Soai reactions were performed in a Heidolph Synthesis Liquid 16 parallel
synthesizer. Temperature tuning was achieved by connecting the parallel
synthesizer to a Lauda PROLINE RP890 cryostat.
pound, and this will be a challenging subject of our further
research.
Conclusions
The Soai reaction offers a chance to study the phenomenon
of asymmetric autocatalysis in the form of a chemical reac-
tion. To perform detailed studies, a setup that ensures iden-
tical reaction conditions was necessary. This was accom-
plished by performing the reaction in a parallel synthesizer
system. We present a new starting material 1g for the Soai
reaction, which shows high asymmetric autocatalytic activity,
together with a detailed study that led to the highest en-
hancement of ee reported so far in the Soai reaction in one
reaction cycle (3.1!92.1%). We emphasize the important
influence of the residue at the 2-position in 1 for the asym-
metric autocatalytic activity. Comparative studies of the dif-
ferent substrates are not yet available and should be useful
for mechanistic investigations. Compound 1g exhibits typical
behavior in the Soai reaction as observed for other starting
materials 1a–1 f. It was shown that high ee values can be in-
duced by different chiral initiators and in the absence of a
chiral source the reaction shows spontaneous symmetry
breaking. Beyond the confirmation of known facts, we have
demonstrated that the reaction parameters have to be
chosen carefully to yield reproducible results. On the other
hand, the parameters can be tuned in such a way that defi-
nitely scattered ee values are obtained. The consideration of
this boundary between reproducible and scattered results is
important for all mechanistic studies. The influence of the
reaction temperature on ee amplification reveals a decrease
at lower temperatures, indicating a still more complex mech-
anism for the Soai reaction. The transfer of our findings to
an application as a general tool for the determination of
small ee values of any chiral compound might be possible
and will be the subject of further investigations.
Synthesis of 5: THF (140 mL) and diisopropylamine (16.7 mL, 119 mmol)
were added to a heat-gun-dried Schlenk tube charged with 4 (8.47 g,
29.7 mmol),
tetrakis(triphenylphosphane)palladium
(584 mg,
0.505 mmol), and CuI (192 mg, 1.01 mmol). The resulting milky solution
was degassed (three freeze–thaw cycles with liquid nitrogen under
vacuum). Compound 3 (5.00 g, 31.2 mmol) was added at 08C and the re-
action mixture was stirred at 08C until complete conversion was observed
(typically 24 to 48 h reaction time; 0.1 mL samples of the reaction mix-
ture were removed, filtered over Celite, and analyzed by 1H NMR).
After filtration through Celite, the solvents were removed in vacuo and
the residue was purified by column chromatography (cyclohexane/EtOAc
20:1) to yield 5 as a white crystalline solid (8.54 g, 26.9 mmol, 91%). Rf =
0.55 (hexanes/EtOAc 5:1); m.p. 175–1768C; 1H NMR (400 MHz, CDCl3,
TMS): d=1.65 (s, 6H), 1.94 (s, 9H), 8.65 ppm (s, 2H; aromatic-H);
13C NMR (101 MHz, CDCl3, TMS): d=27.5 (d), 29.9 (s), 36.0 (t), 41.7 (t),
78.1 (s), 99.0 (s), 118.3 (s), 151.1 (s), 157.6 ppm (d); IR (KBr): n˜ =3026,
2927, 2900, 2853, 2220 (alkyne), 1526, 1417, 1368, 1239, 1109, 1013, 933,
790, 653, 542 cmꢀ1; MS (EI, 70 eV): m/z (%): 316 (100) [M+], 301 (3),
275 (12), 261 (15), 55 (23), 41 (56); HRMS (EI): m/z calcd for
C16H17BrN2: 316.0575; found 316.0578; elemental analysis calcd (%) for
C16H17BrN2: C 60.58, H 5.40, N 8.83; found: C 60.30, H 5.59, N 8.74.
Synthesis of 1g: nBuLi (11.8 mL of
18.9 mmol) was added over 20 min using a syringe pump to a solution of
(3.00 g, 9.46 mmol) and N,N,Nꢀ,Nꢀ-tetramethylethylenediamine
a 1.60m solution in hexane,
5
The Soai reaction is one of the most successful asymmet-
ric autocatalytic reactions. Our present study on the new
substrate 1g expands our understanding of this remarkable
reaction and offers a means for possible application of the
reaction. Our work should therefore stimulate further re-
search in this field.
(1.45 mL, 9.46 mmol) in THF (150 mL) at ꢀ1108C (temperature of the
ethanol/N2 (l) cooling bath). After complete addition the yellow solution
was stirred for 30 min at ꢀ1108C. At this time the bromine–lithium ex-
change is complete as shown by TLC or GC-MS. Then, a solution of
ethyl formate (1.52 mL in 5 mL THF, 18.9 mmol) was added dropwise
over 5 min by using a syringe pump. After 15 min of stirring at ꢀ1108C a
solution of HCl in dioxane (7.03 mL, 4.03m, 28.4 mmol) was added drop-
wise within 5 min, the cooling bath was removed, and the solution was al-
lowed to warm to 08C. Water (40 mL) and a saturated aqueous solution
of NaHCO3 (40 mL) were added followed by extraction with EtOAc (3ꢄ
70 mL). The combined organic extracts were dried over Na2SO4, filtered
through Celite, and the solvents were removed in vacuo. The crude
yellow product was subjected to column chromatography (cyclohexane/
EtOAc 20:1) to yield 1g as a white to slight yellowish solid, which was
sometimes contaminated with a side product (2-(1-adamantylethynyl)pyr-
imidine). Recrystallization from hot cyclohexane yielded pure 1g as a
white crystalline solid (1.35 g, 5.07 mmol, 54%). Rf =0.50 (hexane/EtOAc
2:1); m.p. 160–1628C; 1H NMR (400 MHz, CDCl3, TMS): d=1.69 (s,
6H), 1.99 (s, 9H), 9.06 (s, 2H; aromatic-H), 10.08 ppm (s, 1H; -CHO);
13C NMR (101 MHz, CDCl3, TMS): d=27.5 (d), 30.2 (s), 36.0 (t), 41.7 (t),
79.3 (s), 102.6 (s), 126.1 (s), 156.4 (s), 158.1 (d), 188.2 ppm (d); IR (KBr):
n˜ =2931, 2854, 2215 (alkyne), 1710 (aldehyde), 1579, 1542, 1423, 1367,
1344, 1216, 797 cmꢀ1; MS (EI, 70 eV): m/z (%): 266 [M+] (14), 58 (38),
43 (100); HRMS (EI): m/z calcd for C17H18N2O: 266.1419 [M+]; found:
Experimental Section
General: Toluene, pentane, tetrahydrofuran, and diisopropylamine were
freshly distilled over sodium/benzophenone ketyl before use. Syntheses
of 3[14] and 4[13] are published elsewhere, and Zn
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tion was determined by titration versus iodine in a LiCl solution (0.5m in
THF) until the violet color vanished (mean value over three independent
titrations).[25] The concentrations of commercial nBuLi (Sigma–Aldrich)
solutions were determined by performing titration with diphenylacetic
acid or salicyl aldehyde phenylhydrazone.[26] All moisture-sensitive reac-
tions were carried out under oxygen-free argon using heat-gun-dried
glassware and a vacuum line. Flash column chromatography[27] was car-
8256
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Chem. Eur. J. 2009, 15, 8251 – 8258

Asymmetric Autocatalysis
FULL PAPER
266.1417; elemental analysis calcd (%) for C17H18N2O: C 76.66, H 6.81, N
10.52; found: C 76.26, H 6.91, N 10.37.
S. Ishiguro, T. Shibata, K. Soai, Angew. Chem. 2003, 115, 329–331;
Angew. Chem. Int. Ed. 2003, 42, 315–317; c) F. Lutz, T. Kawasaki,
K. Soai, Tetrahedron: Asymmetry 2006, 17, 486–490.
Representative experimental procedure for a Soai reaction in a parallel
synthesizer: Full experimental details of all runs can be found in the Sup-
porting Information. An oven-dried Heidolph Synthesis Liquid-16 tube
was charged with 1g (100 mg). A chiral initiator can be added now as a
solid or later in the form of a stock solution (noted for each experiment
in the Supporting Information). The tube containing all solids was evacu-
ated and flushed with argon (three times) followed by the addition of
freshly distilled toluene in an amount such that the final reaction volume
[3] a) K. Soai, T. Shibata, I. Sato, Bull. Chem. Soc. Jpn. 2004, 77, 1063–
1073; b) J. Podlech, T. Gehring, Angew. Chem. 2005, 117, 5922–
5924; Angew. Chem. Int. Ed. 2005, 44, 5776–5777; c) T. Kawasaki,
K. Suzuki, Y. Hakoda, K. Soai, Angew. Chem. 2008, 120, 506–509;
Angew. Chem. Int. Ed. 2008, 47, 496–499; d) T. Kawasaki, Y.
Harada, K. Suzuki, T. Tobita, N. Florini, G. Pꢅlyi, K. Soai, Org. Lett.
2008, 10, 4085–4088.
[4] T. Kawasaki, M. Sato, S. Ishiguro, T. Saito, Y. Morishita, I. Sato, H.
Nishino, Y. Inoue, K. Soai, J. Am. Chem. Soc. 2005, 127, 3274–3275.
The racemic product is irradiated with circularly polarized light to
yield a non-detectable deviation from the racemate, which then
serves as an autocatalyst for a consecutive Soai reaction to yield
products with ee values over 99.5%.
[5] a) D. A. Singleton, L. K. Vo, Org. Lett. 2003, 5, 4337–4339; b) I. D.
Gridnev, J. M. Serafimov, H. Quiney, J. M. Brown, Org. Biomol.
Chem. 2003, 1, 3811–3819; c) K. Soai, I. Sato, T. Shibata, S. Komiya,
M. Hayashi, Y. Matsueda, H. Imamura, T. Hayase, H. Morioka, H.
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185–188; d) B. Barabas, L. Caglioti, C. Zucchi, M. Maioli, E. Gꢅl,
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9268179, 1997; f) T. Kawasaki, K. Suzuki, M. Shimizu, K. Ishikawa,
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(including the ZnACHTUNGTRENNUNG(iPr)2 solution to be added later) is 8.5 mL. The reaction
was carried out at ꢀ58C (unless noted otherwise). The temperature
tuning with the connected cryostat took about one hour. Upon reaching
the exact temperature (measured with a temperature sensor inside the re-
action vessel) the required amount of ZnACHTNUTRGNEUNG(iPr)2 (c=0.5–2.0m in toluene)
was added by syringe in a single shot into the shaking reaction mixture.
The reaction was performed for 12–15 h at ꢀ58C under vigorous shaking.
The solution was quenched by addition of a 1m aqueous solution of HCl
(7 mL) followed by careful addition of an ice-cold saturated solution of
NaHCO3 (20 mL), and extraction with EtOAc (2ꢄ20 mL). The combined
organic phases were dried over Na2SO4 and filtered over Celite. The sol-
vents were removed in vacuo and the crude product was obtained as a
pale-yellowish solid. The ee value was determined by using chiral HPLC
of the crude reaction product (retention time (ꢀ)-(S)-2g 13 min, (+)-(R)-
2g 26 min, hexane/isopropyl alcohol (93:7) 1.5 mLminꢀ1). For determina-
tion of the absolute configuration of the product, compound (S)-2g was
synthesized through asymmetric addition of Zn
(iPr)2 to 1g in the pres-
[6] M. Mauksch, S. B. Tsogoeva, I. M. Martynova, S. Wei, Angew.
Chem. 2007, 119, 397–400; Angew. Chem. Int. Ed. 2007, 46, 393–
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2007, 19, 816–825.
ence of (1S,2R)-(ꢀ)-2-(dibutylamino)-1-phenyl-1-propanol ((ꢀ)-DBNE),
which then allowed an assignment of HPLC peaks to the absolute config-
uration of 2g.[28] All reactions proceeded with complete consumption of
the starting material and yielded pure product (purity checked by HPLC
analysis of the crude product with the integrated chromatogram 240–
261 nm; in the majority of the runs the sum of the peak areas of both en-
antiomers was in the range 95–99.5%; details are given in the complete
list of all runs in the Supporting Information).
(S)-2g: Rf =0.46 (hexanes/EtOAc 1:1); m.p. 176–1788C; [a]2D0 =ꢀ27.4
(c=1.01 in CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d=0.84 (d, J=
6.8 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H), 1.68 (s, 6H), 1.97 (s, 9H), 1.89–2.00
(m, 1H), 3.17 (s, 1H), 4.47 (d, J=5.5 Hz, 1H), 8.54 ppm (s, 2H);
13C NMR (101 MHz, CDCl3, TMS): d=17.4 (q), 18.3 (q), 27.7 (d), 29.9
(s), 35.1 (d), 36.1 (t), 42.0 (t), 75.0 (d), 78.7 (s), 97.5 (s), 134.4 (s), 152.0
(s), 155.5 ppm (d); IR (KBr): n˜ =3300, 2906, 2851, 2221 (alkyne), 1543,
1427, 1019, 809, 666 cmꢀ1; MS (FAB): m/z: 311 [M+H+]; HRMS (FAB):
m/z calcd for C20H27ON2: 311.2123 [M+H+]; found: 311.2120; elemental
analysis calcd (%) for C20H27ON2: C 77.38, H 8.44, N 9.02; found: C
77.10; H 8.12, N 8.92.
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We use it in the sense that the higher the ee enhancement of a given
system under identical starting conditions the higher is the asymmet-
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Acknowledgements
We are deeply grateful to Joachim Podlech for theoretical discussions
and support of this research project. We thank Pierre Keller and Julian
Stiller for their help in the laboratory work; the Eilbracht group for help
in the Pd-catalyzed formylation reaction; and Moritz Biskup, John M.
Brown, and Julian Stiller for theoretical discussions. This work was sup-
ported by the Stiftung der deutschen Wirtschaft (stipend for T.G.). The
“Feasibility Study for Young Scientists 1-03” received financial support
by the “Concept for the Future” of Karlsruhe Institute of Technology
within the framework of the German Excellence Initiative (FYS 1-03:
The Soai reaction).
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stock solution handled with utmost care and have to be considered
as theoretical concentrations. Due to adsorption phenomena the
real concentration could be different.
[19] In reference [9d] the authors state, “It should also be noted that this
system displays condition-dependent complexities. Contribution
from a slow but significant background reaction triggering racemic
autocatalysis may be minimized only by employing higher catalyst
concentrations.” Our findings suggest that this conclusion is not true
in general, but only for enantiopure catalyst 1d as used in referen-
ce [9b].
[20] There are no data available on the influence of the concentration of
a low ee catalyst for substrates 1a–1 f.
[21] The addition of rac-2g is not necessary for spontaneous symmetry
breaking. If no catalyst was added at all, spontaneous symmetry
breaking yielding (R)- and (S)-2g was also observed in preliminary
experiments; this will be subject of ongoing research.
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studies, in the majority of the reaction tubes a milky product solu-
tion was obtained. Except for extreme temperatures and high cata-
lyst concentrations, the clouding mostly occurred after a considera-
ble reaction time (one to several hours; monitoring by TLC and
HPLC showed that the clouding appeared after the reactions were
completed). A considerable number of our reactions stayed clear
throughout. We observed no correlation between this fact and the
enhancement of ee in our study.
[22] For an overview of chiral initiators, see: K. Soai, T. Kawasakin,
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[25] A. Krasovshiy, P. Knochel, Synthesis 2006, 890–891.
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Published online: July 8, 2009
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