Diastereodivergent synthesis of 4-oxocyclohexanecarbaldehydes by using the modularly designed organocatalysts upon switching on their iminium catalysis

Article abstract of DOI:10.1039/d1cc01020d

The cinchona thiourea moiety in the self-assembled modularly designed organocatalysts (MDOs) switches off the iminium catalysis of these catalysts. In this study, it was found that the inhibited iminium catalysis could be switched on by using an appropriate weak acid and that, once the iminium catalysis was switched on, these catalysts could be applied for the highly stereoselective and diastereodivergent synthesis of 4-oxocyclohexanecarbaldehydes via a domino reaction between ketones and α,β-unsaturated aldehydes. This journal is

Full text of DOI:10.1039/d1cc01020d

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Diastereodivergent synthesis of
4-oxocyclohexanecarbaldehydes by using
the modularly designed organocatalysts upon
switching on their iminium catalysis†
Cite this: DOI: 10.1039/d1cc01020d
Received 23rd February 2021,
Accepted 25th April 2021
Pranjal Bora, Satish Jakkampudi,‡ Ramarao Parella,‡ Nagaraju Sakkani, Qipu Dai,
DOI: 10.1039/d1cc01020d
Manisha Bihani, Hadi D. Arman and John C.-G. Zhao
*
rsc.li/chemcomm
The cinchona thiourea moiety in the self-assembled modularly enamine catalysis.4 However, when we tried to apply these
designed organocatalysts (MDOs) switches off the iminium catalysis catalysts in activating an a,b-unsaturated aldehyde via the
of these catalysts. In this study, it was found that the inhibited iminium catalysis, we had not much success. After careful
iminium catalysis could be switched on by using an appropriate examination of the reported mechanism of proline catalysis,5
weak acid and that, once the iminium catalysis was switched on, we realized that the formation of MDO promoted two pathways
these catalysts could be applied for the highly stereoselective and that could inhibit its iminium catalysis (Scheme 1, pathways a
diastereodivergent synthesis of 4-oxocyclohexanecarbaldehydes and b), since the deprotonation of the L-proline by QDT will
via
a domino reaction between ketones and a,b-unsaturated make the iminium intermediate 2 more prone to the formation
aldehydes.
of the parasitic intermediate 35 and the 1,3-dipolar intermedi-
ate 4.5b,6 Thus, while QDT activates the enamine catalysis of
In a living cell, numerous reactions occur simultaneously. To L-proline, it switches off the iminium catalysis simultaneously.
ensure that all these reactions are not interfering with each Since protonation of the iminium intermediate 2 (pathway c)
other, the enzymes that catalyze these reactions are often should make it less prone to the formation of intermediate 3
regulated by feedback loops or triggers in order to allow them and 4, we hypothesized that an acid that is strong enough to
to proceed with exact spatial and temporal control.1 Simple protonate iminium intermediate 2, but weak enough to keep
chemical systems that mimic the enzyme reactivities, which are the self-assembled MDO intact should behave as an activator to
reversibly switchable, have been actively pursued by chemists switch on the iminium catalysis of the MDO.7 Herein we report
in the past decades with the goals of understanding the that the iminium catalysis mode of the MDOs can indeed be
fundamental questions regarding enzyme activation and developing switched on by adding an acid7 and that we are able to con-
synthetically useful catalysts inspired by the enzymes.1 In the past duct a diastereodivergent catalysis for a domino Mannich
two decades, an exponential growth has been witnessed in the
amine-mediated organocatalysis via the iminium and/or the ena-
mine mechanisms.2 Nonetheless, amine-based switchable organo-
catalytic systems are still very limited.3
In the past a few years, our group has developed the modular
designed organocatalysts (MDOs),4a which are self-assembled
from amino acids and cinchona alkaloid thiourea derivatives
[such as quinidine thiourea (QDT)] in the reaction media, for
various asymmetric enamine-mediated reactions, including
diastereodivergent catalysis.4 Formation of MDO greatly
enhances the reactivity and stereoselectivity of L-proline in
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698, USA. E-mail: cong.zhao@utsa.edu
† Electronic supplementary information (ESI) available. CCDC 1976271, 2043408
and 859678. For ESI and crystallographic data in CIF or other electronic format
Scheme 1 Potential pathways that switch off the MDO iminium catalysis
by QDT (9e) and proposed switch-on.
see DOI: 10.1039/d1cc01020d
‡ These two authors contribute equally.
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condensation/Michael/Michael reaction of ketones and a,
b-unsaturated aldehydes8,9 and obtained both diastereomers
of the desired 4-oxocyclohexanecarbaldehydes.
Despite the advances in organocatalysis, the organocatalytic
asymmetric Michael addition of ketones or aldehydes to a,
b-unsaturated aldehydes via the enamine/iminium catalysis
remains a challenging task,8,9 and only a few examples are
available.8,10 In 2013, Kong and coworkers reported
a
pyrrolidine-catalyzed domino reaction between ketones 6 and
cinnamaldehydes (such as 1a), which yields the racemic cyclo-
hexanecarbaldehydes 7 in low to mediocre yields (Scheme 2,
upper equation).8a Unfortunately, an asymmetric version of this
reaction was not possible because the chiral amine catalysts
tried failed to catalyze this reaction.8a Moreover, the reaction
between acetone (6a, R = H) and 1a yielded the condensation
product 8 instead (Scheme 2).8a We adopted this reaction as a
model reaction to test our hypothesis since this domino reac-
tion would require the simultaneous enamine and iminium
activations. It should be pointed out that, while this manuscript
was under preparation, Appayee and coworkers reported an
enantioselective synthesis of this diastereomer (ent-7a)10 using
a two-catalyst system similar to those of Hayashi’s, which was
reported to work through an enolate/iminium activation9
(Scheme 2, lower equation). In comparison, as our results
shown below, we were able to obtain both diastereomers in
high stereoselectivities using the reactivated MDOs.
Fig. 1 Structure of selected precatalyst modules and acids used in this study.
Table 1 Selected results of catalyst screening and reaction condition
optimizationsa
As usual, cinchona alkaloid derivatives (9) and amino acid
derivatives (10) were adopted to form the MDOs. Some weak
acids (11) were adopted as the activator to switch on the
iminium catalysis. Some representative examples of these
compounds are collected in Fig. 1 and the representative results
of catalyst screening and reaction condition optimizations are
collected in Table 1 (For detailed catalyst screening and opti-
mizations, please see Section S3 of the ESI†).
As the results in Table 1 show, when the MDO formed from 9a/
10a was employed without the addition of any acid, no formation
the expected product was observed. Instead, a 60% yield of the
mono-condensation product 12 was obtained (entry 1).11
Entry
9
10
11
Yieldb (%)
drc (7a/7a0)
eed (%)
1
2
3
4
5
6
7
8
9a
9a
9a
—
9b
9c
9d
9e
9f
9a
9a
9a
9a
9a
9a
9e
9a
10a
10a
—
—
0e
—
75 : 25
—
—
95
—
—
39
54
86
499
40
37
72
71
90
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
11c
11d
11a
11a
11a
11a
77
0
10a
10a
10a
10a
10a
10a
10b
10a
10a
10a
10a
10a
10a
10a
0f
—
70
70
65
83
60
51
67
42
50
86
90
91
Trace
91 : 9
71 : 29
63 : 37
8 : 92
32 : 68
70 : 30
76 : 24
70 : 30
70 : 30
84 : 16
90 : 10
6 : 94
—
9
10
11
12
13
14g
15gh
16i
17j
97
499
499
—
a
Unless otherwise indicated, all reactions were carried out with 1a
and 10
(0.10 mmol), 6a (0.10 mL), the precatalyst modules
9
(0.010 mmol each, 10 mol%), and the acid cocatalyst 11 (0.010 mmol,
b
10 mol%) in dry toluene (1.0 mL) at room temperature for 24 h. Yield
c
of the isolated product after column chromatography. Determined by
d
1H NMR analysis of the crude product. Determined by HPLC analysis
e
for the major diastereomer. The condensation product 12 was
f
g
obtained in 60% yield. Product 12 was obtained in 29% yield. EtOH
h
i
was used as the solvent. Carried out at ꢀ5 1C. Carried out with
j
0.5 mL toluene at 0 1C. Water was used as solvent.
However, when a weak acid such as trans-cinnamic acid (11a)
was employed together with 9a/10a, the desired domino product
7a was obtained in 77% yield with a dr of 75 : 25 and ee value of
Scheme 2 Organocatalyzed domino reaction between 1a and 6.
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95% (entry 2). These results clear demonstrate that a weak acid
like 11a is required to switch on the iminium catalysis for the
Michael addition step. In addition, the combination of the MDO
and 11a yielded very decent stereoselectivities for 7a, which
indicates this weak acid doesn’t affect the self-assembly of the
MDO. The results of the other control reactions reveal that all
three components of this catalytic system are required to achieve
the desired domino reaction (entries 3 and 4). Further screening
of different cinchona derivatives against L-proline (10a) (entries
5–9) revealed that, while the MDO of 9a/10a yielded the best
results for diastereomer 7a (entry 2), the MDO of 9e/10a produced
high dr and ee values for the other diastereomer 7a0 (entry 8). On
the other hand, screening of the other amino acids against 9a
showed that, except for amino acid 10b (entry 10), which gave a
much inferior results than L-proline, all the other amino acids
were not reactive at all (Section S3 of the ESI†). Finally, the acid
was screened (entries 11–13), and the results indicate that trans-
cinnamic acid (11a) is the best in terms of stereoselectivities
(entry 2). Next the solvent and reaction temperature were further
optimized (please see Section S3 of the ESI† for details). In
summary, for obtaining diastereomer 7a, the use of 9a/10a/11a
in EtOH at ꢀ5 1C gives the best results (entry 15). For obtaining
the other diastereomer 7a0, the best outcome was obtained by
using 9e/10a/11a in toluene at 0 1C (entry 16). While protic solvent
EtOH is a good solvent for these reactions, especially for obtaining
diastereomer 7a, a similar reaction conducted in water failed to
yield the desired product (entry 17).
Once the reaction conditions were optimized, the scope of
this domino reaction was then established for both catalytic
systems to obtain either one of the two product diastereomers
(Scheme 3). As the results in Scheme 3 show, both catalytic
systems have very similar substrate tolerance, while catalyst
system 9e/10a/11a normally produces slightly higher stereose-
lectivities for product 70 than 9a/10a/11a does for diastereomer 7.
In terms of the cinnamaldehydes used, the substituent on the
phenyl has almost no influence on the reactions, except for Scheme 3 Substrate scope study.
slight lower product yields were normally obtained for substi-
tuted cinnamaldehydes. 1-Naphthyl and 2-thiophenyl-sub-
stituted enals also worked well for both catalytic systems
(Scheme 3). Nonetheless, crotonaldehyde (an alkyl-substituted
aldehyde) gave a complex mixture of products (data not shown).
In addition, both reactions are very sensitive toward the ketone
substrate. For example, when 2-butanone was applied in this
reaction, the yield and diastereoselectivities of 7n and 7n0
were much worse (Scheme 3), while the other ketones (2- and
3-pentanones, and 4-phenylbutan-2-one) we tried all failed to
give the desired product. This is most likely due to steric
reasons.
The absolute stereochemistry of the diastereomeric products
was determined by the X-ray crystallographic analysis of com-
pounds 7c and 7h0 (please see Section S4 of the ESI†).12
To show the utility of this method, we conducted some
derivatizations of reaction product 7c0. As shown in Scheme 4,
the selective reaction of the aldehyde group of 7c0 with phos-
phorane 13 gave product 14 in 86% yield with complete reten-
Scheme 4 Derivatizations of the reaction product 7c0.
tion of the stereochemistry. Moreover, a selective reduction of
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catalysis mode is switched on, these catalysts can be used for
catalyzing a domino Mannich condensation/Michael/Michael
reaction between ketones and a,b-unsaturated aldehydes and
achieving a highly stereoselective and diastereodivergent synthesis
of 4-oxocyclohexanecarbaldehydes.
The authors thank the Welch Foundation (Grant No.
AX-1593) and the National Science Foundation (Grant No.
CHE-1664278) for the financial support of this project.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 For reviews, see: (a) U. Lu¨ning, Angew. Chem., Int. Ed., 2012, 51,
8163–8165; (b) V. Blanco, D. A. Leigh and V. Marcos, Chem. Soc. Rev.,
2015, 44, 5341–5370.
2 (a) Comprehensive Enantioselective Organocatalysis: Catalysts, Reac-
tions and Applications, ed. P. I. Dalko, Wiley-VCH, Weinheim, 2013;
¨
(b) A. Erkkila, I. Majander and P. M. Pihko, Chem. Rev., 2007, 107,
5416–5470; (c) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List,
Chem. Rev., 2007, 107, 5471–5569.
3 For some leading examples of switchable amine catalysts, see:
¨
(a) V. Blanco, A. Carlone, K. D. Hanni, D. A. Leigh and
B. Lewandowski, Angew. Chem., Int. Ed., 2012, 51, 5166–5169;
(b) V. Blanco, D. A. Leigh, U. Lewandowska, B. Lewandowski and
V. Marcos, J. Am. Chem. Soc., 2014, 136, 15775–15780; (c) C.-S. Kwan,
A. S. C. Chan and K. C.-F. Leung, Org. Lett., 2016, 18, 976–979For an
example of switchable thiourea catalyst, see: (d) N. Hayama,
Y. Kobayashi, E. Sekimoto, A. Miyazaki, K. Inamoto, T. Kimachi
and Y. Takemoto, Chem. Sci., 2020, 11, 5572–5576.
Scheme 5 Proposed reaction mechanism and favored transition states.
4 For selected examples, see: (a) T. Mandal and C.-G. Zhao,
Angew. Chem., Int. Ed., 2008, 47, 7714–7717; (b) N. K. Rana,
H. Huang and J. C.-G. Zhao, Angew. Chem., Int. Ed., 2014, 53,
7619–7623; (c) H. Huang, S. Konda and J. C.-G. Zhao, Angew. Chem.,
Int. Ed., 2016, 55, 2213–2216; (d) S. Jakkampudi, S. Konda, H. Arman
and J. C.-G. Zhao, Adv. Synth. Catal., 2020, 362, 2419–2426For a
review on diastereodivergent catalysis, see: (e) M. Bihani and
J. C.-G. Zhao, Adv. Synth. Catal., 2017, 359, 534–575.
the aldehyde group in 7c0 was achieved with NaBH4 at ꢀ90 1C,
and an ensuing reaction of the alcohol product with NBS in
CH2Cl2 at 0 1C yielded the octahydro-6H-isochromen-6-one
derivative 15 in a good diastereoselectivity (80 : 20) with com-
plete retention of the stereochemistry.
´
5 (a) J. E. Hein, J. Bures, Y.-H. Lam, M. Hughes, K. N. Houk,
In order to understand the reaction mechanism, we con-
ducted some control experiments (please see Section S5 of the
ESI†). Based on the results of these control experiments, we
propose a domino Mannich condensation13/Michael/Michael
reaction mechanism for the observed catalysis (Scheme 5).
From the structural difference of these two diastereomers, it
is evident that the diastereodivergence is created in the last-
step intramolecular Michael reaction. The two proline moieties
and the cinchona thiourea are most likely assembled with each
other through hydrogen bonding in the transition state of this
step. To account for the observed diastereodivergence in the
product, two different favored transition states (Scheme 5,
bottom structures) are proposed for this step on the basis of
our previous study of the MDO enamine catalysis4d and a
computational study14 of the MDO catalysis.
A. Armstrong and D. G. Blackmond, Org. Lett., 2011, 13,
5644–5647; (b) N. Zotova, A. Franzke, A. Armstrong and
D. G. Blackmond, J. Am. Chem. Soc., 2007, 129, 15100–15101.
6 We successfully trapped a similar 1,3-dipolar intermediate 22,
please see Section S5 of the ESI† for details.
7 Using weak acids as cocatalysts in organocatalytic reactions is
known from the very beginning of organocatalysis, see:
(a) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001,
123, 4370–4371; (b) N. Mase, R. Thayumanavan, F. Tanaka and
C. F. Barbas, Org. Lett., 2004, 6, 2527–2530.
8 (a) F.-Z. Bao, X.-B. Wang and L.-Y. Kong, Tetrahedron Lett., 2013, 54,
1405–1408; (b) Z.-L. Jia, Y. Wang, G.-Q. Xu and P.-F. Xu, Chem.
Commun., 2017, 53, 4938–4941.
9 N. Umekubo, T. Terunuma, E. Kwon and Y. Hayashi, Chem. Sci.,
2020, 11, 11293–11297.
10 V. Maurya, M. S. Kutwal and C. Appayee, Org. Lett., 2021, 23,
1566–1571.
11 Formation of 12 indicates that the enamine catalysis mode of the
MDO is still functioning.
12 CCDC deposition numbers 1976271, 2043408, 859678† contain the
X-ray crystallographic data for compounds 7c, 7h0, and 20,
respectively.
In summary, we have demonstrated that the iminium cata-
lysis mode of the MDOs inhibited by the cinchona alkaloid
thiourea component of the MDOs is switchable and can be
13 For
a mechanistic study, see: M. B. Schmid, K. Zeitler and
R. M. Gschwind, J. Org. Chem., 2011, 76, 3005–3015.
easily restored by using an appropriate acid. After the iminium 14 B. Bhaskararao and R. B. Sunoj, Chem. Sci., 2018, 9, 8738–8747.
Chem. Commun.
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