Asymmetric Amplification Coupling Enantioselective Autocatalysis and Asymmetric Induction for Alkylation of Azaaryl Aldehydes

Article abstract of DOI:10.1002/ejoc.201500508

Herein, we describe a chemical system combining asymmetric amplification of Soai's autocatalyst alongside a catalytic addition of Zn(iPr)₂ to azaaryl aldehydes. Thus, Soai autocatalyst is amplified in situ from 11 to > 98% ee and concomitantly

Full text of DOI:10.1002/ejoc.201500508

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500508
Asymmetric Amplification Coupling Enantioselective Autocatalysis and
Asymmetric Induction for Alkylation of Azaaryl Aldehydes
Carlo Romagnoli,[a] Bora Sieng,[a] and Mohamed Amedjkouh*[a]
Dedicated to the memory of Professor Per Ahlberg
Keywords: Asymmetric synthesis / Alkylation / Autocatalysis / Chirality
Herein, we describe a chemical system combining asymmet- vide alkanols with up to 99% ee. Also, exceptional amplifi-
ric amplification of Soai’s autocatalyst alongside a catalytic
cations of ee in one cycle are observed for both compounds
addition of Zn(iPr)2 to azaaryl aldehydes. Thus, Soai autocat- produced throughout the reaction, probably as a result of in-
alyst is amplified in situ from 11 to Ͼ 98% ee and concomi-
tantly catalyzes the alkylation of pyridine aldehydes to pro-
teractions in a reaction network coupling enantioselective
autocatalysis and asymmetric induction.
closed system to give rise to absolute asymmetric synthesis
under kinetic control. Such a system requires an efficient
irreversible enantioselective autocatalysis and a fast hetero-
dimerization, which are key for the observed non-linear am-
plification of ee.[6]
Thus, asymmetric autocatalytic amplification, if coupled
to asymmetric induction, might become a powerful process
to access chiral molecules in the future.
Also, inspired by the work of Soai et al., we herein report
on a reaction network combining simultaneous enantiose-
lective autocatalysis with asymmetric induction in the alkyl-
ation of azaaryl substrates, which are unable of such asym-
metric amplification on their own.
Introduction
Research has been intensive to develop methods for cata-
lytic asymmetric synthesis of highly enantioenriched com-
pounds with enzyme-like chemo- and stereoselectivity.
These strategies make use of optically pure catalysts only
available from the chiral pool. In parallel, low ee catalysts
are believed to be of limited interest in asymmetric synthe-
sis, since a linear relationship of the ee values between the
chiral catalyst and the product is expected.
The pioneering work of Soai on a practically perfect
asymmetric amplification in the asymmetric autocatalysis
of (5-pyrimidyl)alkanol 2 by addition of Zn(iPr)2 to (5-pyr-
imidyl)aldehyde 1,[1] introduced a new entry into optically
pure compounds.[2] Despite the structure requisite of a rigid
γ-imino aldehyde, the extreme sensitivity of this reaction to
any variation in chirality made it the perfect tool for the
detection of minute imbalance of asymmetry.[3]
Because autocatalysis may contribute to understanding
the origins of homochirality, several groups have investi-
gated the chemical mechanism of the Soai reaction.[4] While
the exact details remain under investigation, results ob-
tained in kinetic studies proposed the involvement of homo-
and heterochiral dimers of Zn-2.[5] However, this chemical
model alone cannot rationalize such marked ee amplifi-
cation as in the Soai reaction.
Results and Discussions
We describe a process whereby asymmetric autocatalytic
amplification of 2 operates in one single cycle alongside
enantioselective addition of Zn(iPr)2 to azaaryl aldehydes.
We also demonstrate that high enantiopurity through asym-
metric amplification of 2 is not a prerequisite for high en-
antioselctivity in the asymmetric catalysis.
Scheme 1 introduces the proposed catalytic process con-
sisting of an asymmetric autocatalytic loop where the low
ee pyrimidyl alcohol 2 undergo a self-replication process
with amplification of ee, and a second loop with asymmet-
ric catalysis where 2 should act as the catalyst for the dialk-
ylzinc addition to a different set of pyridine-3-carbal-
dehydes.
An interesting and more integrative model describes the
Soai reaction as Frank-like reaction network operating in a
[a] Department of Chemistry, University of Oslo,
Postboks 1033, Blindern, 0315 Oslo, Norway
E-mail: mamou@kjemi.uio.no
Interestingly, Soai reported an elegant and efficient one-
pot asymmetric alkylation method where a chiral catalyst
self improves its ee by asymmetric autocatalysis and then
acts as a chiral catalyst to give very high ee products.[7]
www.kjemi.uio.no
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500508.
Eur. J. Org. Chem. 2015, 4087–4092
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Romagnoli, B. Sieng, M. Amedjkouh
SHORT COMMUNICATION
pyridine derived carbaldehydes with various electron-rich
and -deficient substituents were investigated as depicted in
Table 1.[8]
Table 1. Enantioselective addition of Zn(iPr)2 to aldehydes using
(R)-pyrimidyl alcohol 2 as chiral catalyst.
Scheme 1. Asymmetric autocatalysis with amplification of ee of the
pyrimidyl alcohol and its use as a chiral catalyst.
However, the use of autocatalyst 2 required a self-improve-
ment to high ee prior to its use in a subsequent asymmetric
reaction.
Besides, two substrates reported by Soai, namely quinol-
ine-3-carbaldehyde and 5-(diisopropylcarbamoyl)pyridine-
3-carbaldehyde are capable of autocatalytic amplification of
ee in their alkylation with Zn(iPr)2.[8,9] Therefore it is not
clear whether the high ee of the product is due to the cata-
lytic effect of autocatalyst 2 or to own amplification of com-
pound 4. It is also conceivable to attribute this amplifi-
cation of ee to a combined effect of 2 and 4.
Surprisingly, this new concept of asymmetric catalysis
went overlooked and no further studies on the subject have
been published since. Moving in this direction, we also ap-
plied this concept to the asymmetric alkynylation of azaaryl
aldehydes.[10]
[a] Reactions were performed under nitrogen at 0 °C using
2.2 equiv. of (iPr)2Zn and 10 mol-% of (R)-2. [b] Isolated product
after column chromatography. [c] ee were determined by HPLC
and/or GC analysis on chiral stationary phases.
Even if certain levels of ee were reached with all sub-
To test our approach, we began our survey by evaluating strates studied, the reaction proved to be clearly sensitive to
the reactivity of a series of azaaryl aldehydes as substrates substituent effect. Substitution at 4- and 5-positions pro-
in the presence of highly enantioenriched (R)-1-(2-tert-bu- vided poor to moderate enantioselectivity although good
tylethynyl-5-pyrimidyl)-2-methylpropanol (R)-2, following yields could be obtained (Table 1, entries 1–3). For example,
experimental conditions originally reported by Soai. The the enantioselectivity increased drastically from 20% ee
synthesis of chiral pyrimidyl alcohol (R)-2 was achieved in with (R)-4a to 68% ee for (R)-4b (Table 1, enty1 vs. 2). A
high yield and Ͼ 98% ee by autocatalytic asymmetric am- MeO at 5-position delivered alkanol (R)-4c with 68% ee
plification as described previously by Soai and subsequently (Table 1, entry 3). Remarkably, the nature of the substituent
used to catalyse the asymmetric addition of Zn(iPr)2 to dif- at the 6-position on the pyridine ring proved to have a more
ferent azaaryl aldehydes 3.[11] The zinc alkoxide of (R)-2 profound influence on the enantioselectivity. While methyl
was generated by premixing autocatalyst (R)-2 (10 mol-%) and phenyl groups gave poor ee for alkanols (R)-4d,e, sub-
with Zn(iPr)2 (2.2 equiv.) and subsequently followed by stituted alkynyls all provided excellent ee. Whether the alk-
slow addition of aldehyde 3 (Table 1). The current limita- ynyl provides an electronic effect or only acts as a spatial
tion lies with the high reactivity of 2- and 4-pyridine alde- stretch to avoid an excessive strain of the complex is still
hydes which exhibited extremely fast and non-enantioselec- unclear.
tive reactions to produce racemic mixtures of alkanols. For
It is important to note that control reactions showed that
example, nicotinaldehyde reacted with dialkylzinc in few substrates such as 3a, 3b and 3f can undergo autocatalysis
seconds even in absence of any ligand. Thus, a range of 3- but with a pronounced loss of ee (Supporting Information,
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Asymmetric Amplification and Asymmetric Induction for Alkylation
Table S1). This confirms the influence of the Zn-alkoxide Table 2. Enantioselective addition (reverse mode) of Zn(iPr)2 to al-
dehydes with (R)-pyrimidyl alcohol 2.
(R)-2-Zn in the asymmetric alkylation of aldehydes 3.
Among the substrates investigated we paid a particular
attention to the behavior of compound (R)-4f, a pyridine
reminiscence of the Soai’s autocatalyst 2. Reaction of alde-
hyde 3f in presence of autocatalyst (R)-2 provided very high
yield of alkanol (R)-4f with 89% ee (Table 1, entry 6). In
contrast, when alkanol (R)-4f, with initial ee of 92%, was
used to perform an autocatalytic reaction, the ee of the final
product dropped to 33% (Supporting Information, Table
S1). This represents a very significant observation with re-
gard to the structure similarity of 3f and 2. This result
clearly shows the beneficial contribution of autocatalyst 2
to achieve high ee in systems unable themselves of amplifi-
cation of ee.
Entry[a]
Aldehyde
Prod.
Yield [%][b]
ee [%][c]
1
2
3
4
3f
3g
3h
3i
4f
4g
4h
4i
88
91
93
95
98
95
91
99
[a] Reactions were performed under nitrogen at 0 °C using
2.2 equiv. of (iPr)2Zn, 10 mol-% of (R)-2 (99% ee). [b] Yield deter-
mined by H NMR spectroscopy. [c] ee were determined by HPLC
analysis on chiral stationary phases.
1
After these preliminary results, aldehyde 3f was then cho-
sen as a model for some systematic studies regarding this
procedure.
relevant interaction between autocatalysts (R)-2 and (R)-4.
Indeed, while (R)-2 is a catalyst for the formation of (R)-
4 – as we originally assumed – the newly formed (R)-4
might interfere with the reactivity of (R)-2 and become a
concern for the overall outcome of the reaction. Thus, if
(R)-2 and (R)-4 are generated in the reaction without prior
amplification of (R)-2, the process of coupling asymmetric
autocatalysis with asymmetric induction would become of
major interest. To evaluate such an opportunity, we set out
to investigate a system combining asymmetric amplification
of autocatalyst (R)-2 alongside a catalytic addition of
Zn(iPr)2 to aldehydes 3. The results are shown in Table 3.
Early studies demonstrated the influence of the tempera-
ture on the enantioselectivity in the Soai reaction.[12] Natu-
rally, we wondered whether the temperature influenced the
enantioselectivity induced by 2 in the addition of Zn-
(iPr)2 to other azaaryl aldehydes. These experiments show
the temperature dependency of the ee of product (R)-4f in
the alkylation reaction of 3f (Supporting Information, Fig-
ure S1), and the system reveals a dramatic erosion of ee just
above 0 °C (+10 °C, 22% ee). The plot shows retention of
high ee at 82–89% over a wide range of low temperatures
(–30 °C, 82% ee). It is therefore reasonable to assume that
the temperature is a critical factor in the formation of the
intermediate complexes that are responsible for the enantio-
selectivity of the reaction. Although uncatalyzed racemic
alkylation that would resolve into a great loss of ee remain
plausible, this behaviour may also stem from an improved
stability for the active species favouring the catalytic step at
lower temperature.
Another interesting aspect is the strong amplification ob-
served when (R)-4f is generated under a reverse mode of
addition of Zn(iPr)2 to aldehyde 3f. Thus, Zn-alkoxide was
generated by mixing (R)-2 (10 mol-%) in 99% ee and
Zn(iPr)2 (10 mol-%) at 0 °C for 30 min. Then, aldehyde 3f
was added in a single portion, followed by slow addition of
Zn(iPr)2 (2.1 equiv.) at 0 °C over 3 h. Under these condi-
tions, which are different from those usually employed by
Soai et al., (R)-4f was obtained with 98% ee. Furthermore,
this strong amplification is retained when Zn(iPr)2 was
added over 3 h to a mixture of (R)-2 (10 mol-%) in 99% ee
Table 3. One-pot asymmetric autocatalysis and enantioselective ad-
dition of Zn(iPr)2 to aldehydes using low ee (R)-pyrimidyl alcohol
2 as chiral catalyst.
Entry[a] Aldehyde Cat. (R)-2
(R)-2
[%] ee
final
Product (R)-4
[%] ee
yield[b]
[%]
ee[c]
initial
[%]
[d]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
15
15
11
11
11
11
11
11
11
–
4a
4b
4c
4d
4e
4f
4g
4h
4i
47
65
59
60
62
81
96
93
92
3
40
42
41
39
97
80
84
96
15
30
12
26
98
95
82
98
[a] Reactions were performed under nitrogen at 0 °C using
2.2 equiv. of (iPr)2Zn, 10 mol-% of aldehyde 1 and 1 mol-% (R)-2.
[b] Yield determined by 1H NMR. [c] ee values were determined
by HPLC and/or GC analysis on chiral stationary phases. [d] The
and aldehyde 3f at 0 °C. Except for compound 4h, alkanols soai alcohol 2 could not be isolated.
4f,g,i show a significant amplification of ee in the range of
95–99%, as shown in Table 2.
In a first attempt, to a mixture containing alkanol (R)-2
This might suggest that (R)-2, when generated in situ, is (1 mol-%.) with an initial 53% ee and aldehydes 1 (10 mol-
a much better catalyst for the alkylation of 3. Also, notice %) and 3f in toluene was added dialkylzinc slowly over 3 h.
that the slow addition of Zn(iPr)2 may contribute to sup- To our surprise, we observed the formation of alkanol (R)-
press a possibly competing background and non-enantiose- 4f in Ͼ 98% ee and in good yield. Moreover, under these
lective alkylation of 3.
conditions (R)-2 showed high autocatalytic activity and was
Because of the structural similarity of (R)-2 and alkyl- amplified to a final 98% ee. This suggests that compound
ation product 4f, together with such a remarkable asymmet- 2 is not operating just as an autocatalyst, but might be part
ric amplification, we became intrigued by the potentially of an improved catalytic system.
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C. Romagnoli, B. Sieng, M. Amedjkouh
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Next, we decided to evaluate the performance of this
combination starting from a lower enantiopurity. Under
similar conditions, even (R)-2 (1 mol-%.) with initially only
11% ee was still able to perform with high asymmetric am-
plification. The reaction could deliver high yields of (R)-2
in a final Ͼ 97% ee together with (R)-4f in Ͼ98% ee. The
results indicate that autocatalyst (R)-2 had also achieved a
high asymmetric amplification in-situ in one cycle.
This transformation was also applicable to a series of
azaaryl aldehydes even when Soai autocatalyst (R)-2 was
employed initially with only 11% ee as shown in Table 3.
Aldehydes 3a–e do not seem to have the necessary elec-
tronic or steric properties to interact with the autocatalysis
of (R)-2, and thus have failed to exhibit the expected ampli-
fication of ee. Although we observe clearly that (R)-2 was
generated with asymmetric amplification from 11% to
about 39–42% ee, this resulted in poor final ee for products
4a–e (Table 3, entries 1–5). With a striking difference, sub-
strates 3f–i reacted efficiently to afford high yields of 4f–i,
and exhibited remarkable amplification of ee. Again, over-
expression of autocatalyst (R)-2 reached high values of 80–
95% ee after just one cycle (Table 3, entries 6–9). Com-
pounds (R)-4g–i were isolated in up to 98% ee. More inter-
estingly, alkanol (R)-4g is isolated with 95% ee though (R)-
2 had only reached a final 80% ee.
These findings prompted us to get more insight into the
amplification of ee. For this purpose, we started continuous
monitoring over time of ee progress in the formation of 2
and 4f. Examination of the correlation between the ee of
the catalyst derived from (R)-2 and ee of product (R)-4f
revealed clear time dependence and pronounced asymmet-
ric amplification. As depicted in Figure 1 (a), the enantio-
meric excess of autocatalyst (R)-2 increased steadily to
Ͼ 90% ee from the initial condition (53% ee) in ca 45 min-
Figure 1. Variation of ee of product (R)-4f and Soai alcohol (R)-2
as a function of time. Reactions were performed under nitrogen at
0 °C using experimental conditions as above (Table 3, entry 6). ee
were measured by HPLC analysis using chiral stationary phases.
The ee values for Soai alcohol (R)-2 are reported as measured from
the HPLC traces and include the initial catalyst.
utes, reaching the maximum value of Ͼ 98% after 2 hours (R)-4f in a single reaction step, which is a breach to the
(a plot of ee/conv. is also provided, see Supporting Infor- essential feature of the Soai reaction, i.e. a sequential pro-
mation, Figure S2). For autocatalyst (R)-2 with low initial cedure of 3–4 reactions.
11% ee, the plot shows a similar trend but with a stronger
This behaviour could be attributed to a process whereby
amplification of ee (Figure 1, b).
(R)-2 and (R)-4f promote a reaction network of enantiose-
Surprisingly, both plots show a rapid increase of the en- lective autocatalysis coupled to asymmetric induction. It is
antiomeric excess of the newly forming alkanol (R)-4f to its also reasonable to assume the presence in this network of a
maximum of 98% ee (Figure 1), instead of increasing fast equilibrium of heterodimers of 2 and 4f, which can be
slowly, as it would be expected, following the amplification seen as mutual enantiomeric inhibition.[6a–6c] If faster than
of the catalyst (R)-2. Intriguingly, a strong amplification of enantioselective autocatalysis, this equilibrium may lead to
(R)-4f could be observed already in the early amounts of the generation of non-linear effect in catalysis. Also, the
product.
eventuality of a cross catalysis must not be disregarded and
In addition, the progress of the reaction exhibits an un- this is the subject of further investigations. Nevertheless,
usual amplification-time profile,[13] and suggests two strong these findings support our assumption of a potential inter-
NLE for both autocatalysts (R)-2 and (R)-4f in interdepen- action between the Soai autocatalyst and pyridinyl-alkanol
dent relationship. Also, to the best of our knowledge, no products. This is confirmed by recalling the inhibition of
case of such two NLE that operate in parallel has been asymmetric amplification of (R)-2 during formation of
reported to date.
products 4a–e (Table 3, entries 1–5).
Although tempting, the observed non-linear asymmetric
Of course, it remains very intriguing that this new ap-
amplification cannot be attribute solely to the formation of proach gave great results for pyridine systems, which closely
dimeric or oligomeric catalytic species as described in pre- resemble the structure of the Soai autocatalyst, but unable
vious reports.[5]
of such performance on their own. In particular the bulky
Such behaviour could be rationalized by a kinetically alkynyl moiety in the 6-position seems to be a key feature,
controlled amplification that leads to high ee for (R)-2 and crucial to form a new complex, which exhibits a higher
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Asymmetric Amplification and Asymmetric Induction for Alkylation
catalytic activity responsible for this unexpected behaviour.
Such profound effect can be illustrated by considering the
striking asymmetric amplification for compound (R)-4f
when compared to (R)-4e under identical reaction condi-
tions (Table 3, entries 5,6).
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Conclusions
In summary, we have presented a new chemical system
combining asymmetric amplification of autocatalyst 2
alongside a catalytic addition of Zn(iPr)2 to aldehydes 3.
Probably most important, even starting from very low en-
antiopurity, autocatalysts (R)-2 and (R)-4 exhibit efficient
cooperation and reveal a strong non-linear relationship.
Also, this catalytic system provides exceptional amplifi-
cation up to Ͼ98% ee in one reaction cycle for both com-
pounds (R)-2 and (R)-4, which adds complexity to the Soai
reaction when it is coupled to asymmetric induction, and
suggests a more advanced reaction network. Currently we
are conducting further investigations to delineate the nature
and the key role of reactive species in such a novel reaction
network.
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Experimental Section
General Procedures for the Asymmetric Alkylation: Standard pro-
cedures for the asymmetric alkylation catalysed by 2 in two step
one-pot: In an oven dried flask (R)-1-[2-(3,3-dimethylbut-1-yn-1-
yl)pyrimidin-5-yl]-2-methylpropan-1-ol (R)-2 (0.027 mmol, 99%
ee), is dissolved in 0.4 mL of dry toluene under nitrogen and di-
isopropylzinc 1 m (0.583 mmol) is added drop wise at 0 °C and
stirred for 30 min. The pyrimidyl aldehyde 3 (0.265 mmol) is dis-
solved in 1.6 mL of dry toluene and added slowly over three hours
at 0 °C to the reaction mixture. The advancement of the reaction
is monitored by HPLC. The reaction is quenched by the addition
of HCl 1 m in dioxane (0.265 mmol) and neutralized with saturated
aqueous NaHCO3. The mixture is extracted with ethyl acetate,
dried with anhydrous Na2SO4 and the solvents evaporated to dry-
ness under reduced pressure. The crude is further purified by flash
chromatography on silica gel to give the pure alcohol 4.
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Valero, J. M. Ribó, A. Moyano, Chem. Eur. J. 2014, 20, 17395–
17408; c) J. Crusats, D. Hochberg, A. Moyano, J. M. Ribó,
ChemPhysChem 2009, 10, 2123–2131; d) R. Plasson, A. Brand-
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8073–8085; A similar model was applied to Mannich and aldol
reactions: e) M. Mauksch, S. B. Tsogoeva, S. Wei, I. M. Mar-
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Standard Procedure for the One-pot Asymmetric Autocatalysis of 2
and Asymmetric Alkylation: In an oven dried flask soai alcohol (R)-
2 (0.002 mmol, 11% ee), soai aldehyde 1 (0.02 mmol) and aldehyde
3 (0.200 mmol) are dissolved in 2 mL of dry toluene under nitrogen
atmosphere. A solution of diisopropylzinc 1 m in toluene (0.51 mL,
0.51 mmol) is added slowly over 3 h to the mixture, and is moni-
tored by TLC. The reaction is quenched by the addition of HCl 1 m
in dioxane (0.210 mmol) and neutralized with saturated aqueous
NaHCO3. The mixture is extracted with ethyl acetate, dried with
anhydrous Na2SO4 and the solvents evaporated to dryness under
reduced pressure. The crude was further purified by flash
chromatography on silica gel to give the pure alcohol 4.
[7]
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Acknowledgments
This work was supported by the Research Council of Norway
(FRIPRO program 205271), the University of Oslo, and COST Ac-
tion, Emergence and Evolution of Complex Chemical Systems
(CM 1304).
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Received: April 21, 2015
Published Online: May 27, 2015
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4087–4092