Asymmetric supramolecular catalysis: A bio-inspired tool for the high asymmetric induction in the enamine-based Michael reactions

Article abstract of DOI:10.1002/chem.201200962

A new and efficient supramolecular catalysis was designed for the asymmetric Michael reaction of cyclohexanone with 2-(2-nitrovinyl)phenols to give the desired hexahydroxanthenols 5 with high yield, enantiomeric excess (ee) and diastereoisomeric excess (de) values. The reaction yielded the anticipated opposite enantiomer of (+)-6aa in 86% yield after two steps with a little compromise in enantioselectivity of 96% ee and 98% de. The lactols were isolated in 92-95% de at the Michael-reaction stage, but were found to get enriched to <99% de after the reductive etherification reaction may be due to the decomposition or hydrolysis of minor isomer of lactols. To further understand the direction of hypothetical pre-TS supramolecular assembly, the Michael reaction was performed with opposite catalysts combination of l-proline 3b and quinidine-NH-thiourea. The structure and absolute stereochemistry of the Michael products, reductive etherification products, and chromenes were confirmed by NMR spectroscopy analysis.

Full text of DOI:10.1002/chem.201200962

DOI: 10.1002/chem.201200962
Asymmetric Supramolecular Catalysis: A Bio-Inspired Tool for the High
Asymmetric Induction in the Enamine-Based Michael Reactions
Dhevalapally B. Ramachary,* Rajasekar Sakthidevi, and Kodambahalli S. Shruthi[a]
The early discovery of l-proline as a small asymmetric
catalyst initiated a new era in asymmetric synthesis.[1] There
are a considerable range of asymmetric reactions effectively
catalyzed by l-proline from last decade, however, it has
some limitations. Although the design and synthesis of pro-
linelike molecules has emerged as alternate catalysts to ach-
ieve high enantioselectivity, these catalysts also have some
limitations. Because when the well-defined catalytic condi-
tions are applied to substrates with additional functionality
in known reactions, they fail to give the product with desired
selectivity.[1b]
Recently, the Barbas and other research groups developed
the amine-catalyzed asymmetric Michael reaction of ketone/
aldehyde with simple nitrostyrene to give the Michael ad-
ducts with high enantioselectivities through enamine activa-
tion.[2] As we were interested in the synthesis of the highly
functionalized chiral Michael adducts for synthetic applica-
tions, when we performed the enamine-based Michael reac-
tion of functionalized 2-(2-nitrovinyl)phenols with cyclohex-
anone under known conditions, we unfortunately obtained
rather low yields. To overcome this problem, we envisioned
that the reaction has to go through a rigid pre-transition-
state (pre-TS) assembly, in which all the active functional
groups of substrates and catalysts should get involved. Thus,
by assembling the suitable chiral catalysts with substrates
through combination of covalent and weak interactions, one
can possibly build up asymmetric supramolecular environ-
ment for high asymmetric induction through the stable pre-
TS assembly (Figure 1). This new paradigm of catalysis
seems to be beyond organocatalysis, predicted to be a bio-
mimetic supramolecular catalysis.[3]
Figure 1. Proposal for asymmetric supramolecular catalysis.
reaction yielded 1:1 ratio of lactol products (+)-5aa in quan-
titative yield with 97% enantiomeric excess (ee) and 92–
95% diastereoisomeric excess (de) at the Michael-reaction
stage (Table 1, entry 1). For the clear understanding of selec-
tivity, we then subjected the crude 5aa to reductive etherifi-
cation conditions with triethylsilane and BF3·OEt2 at À108C
to 258C for 2 h.[4] To our delight, the reductive-etherification
product (À)-6aa was isolated in 90% yield with 94% de and
>99% ee (Table 1, entry 1). This result may give inspiration
to start believing that there is a highly organized supramo-
lecular assembly in the Michael reaction pre-TS, which is re-
sponsible for the highest enantioselectivity. Interestingly, the
lactols 5aa were isolated in 92–95% de at the Michael-reac-
tion stage, but were found to get enriched to >99% de after
the reductive etherification reaction may be due to the de-
composition or hydrolysis of minor isomer of lactols 5aa.
To further understand the direction of hypothetical pre-
TS supramolecular assembly, we performed the Michael re-
action with opposite catalysts combination of l-proline 3b
and quinidine-NH-thiourea 4b. The reaction yielded the an-
ticipated opposite enantiomer of (+)-6aa in 86% yield after
two steps with a little compromise in enantioselectivity of
96% ee and 98% de (Table 1, entry 2). When the catalyst
combination is shuffled to be l-proline 3b and quinine-NH-
thiourea 4a, there was a strong mismatching of catalysts ob-
served to deliver the product 6aa in moderate ee (80%) and
de (88%) for longer reaction time (Table 1, entry 3). Re-
placing the quinine-NH-thiourea 4a with hydroquinine-NH-
thiourea 4c in catalyst combination of 3a/4a for sequential
Michael reaction followed by reductive etherification reac-
tion was not found to give superior results (Table 1, entry 4).
To verify this hypothesis of pre-TS supramolecular assem-
bly, based on the our previous experience,[3f] we examined
the Michael reaction of 2-(2-nitrovinyl)phenol 1a with seven
equivalents of cyclohexanone 2a in the presence of each
5 mol% of d-proline 3a and quinine-NH-thiourea 4a in di-
chloromethane (DCM) at 258C. Surprisingly, within 5 h, the
[a] Prof. Dr. D. B. Ramachary, R. Sakthidevi, K. S. Shruthi
Catalysis Laboratory, School of Chemistry
University of Hyderabad
Hyderabad-500 046 (India)
Fax : (+91)40-23012460
E-mail: ramchary.db@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200962.
8008
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Chem. Eur. J. 2012, 18, 8008 – 8012

COMMUNICATION
Table 1. Reaction optimization.[a]
Scheme 1. Controlled experiments to prove the involvement of supramo-
lecular assembly for high-asymmetric induction. FG=functional group.
Obtaining very poor ee values of Michael-reaction products
8a–c from the reaction of 7a–c with 2a under the 3a/4a cat-
alysis proves that hydrogen-bonding activation between
ortho-phenolic OH group of 2-(2-nitrovinyl)phenol (1a) and
carbonyl group of d-proline (3a) is crucial in determining
the ee of the Michael reaction.
Finally, we have got strong support to our hypothesis of
involving stable pre-TS supramolecular assembly through
careful investigation of the Michael reaction of 1a and 2a
under the 3a/4a catalysis by using electrospray ionization
with high-resolution mass spectrometry (ESI-HRMS) tech-
nique, which allowed us to identify all critical proposed cata-
lytic intermediates (Figure 2). The ESI-HRMS spectrum of
Entry
Catalyst 3/4
[5 mol%]
t [h]
Yield [%][b]
6aa
de [%][c]
ee [%][d,e]
G
1[f]
2[f]
3[f]
4[f]
5
3a/4a
3b/4b
3b/4a
3a/4c
3a/4a
4a
5
8
24
5
5
48
48
72
72
90
86
74
89
90
–
–
–
–
94
98
88
93
94
–
–
–
–
>99
À96
80
97
>99
–
–
–
–
6
7
3a
8[g]
9[h]
3c/TFA
3d/PhCO2H
[a] Unless stated otherwise, all reactions were carried out with 1a
(0.5 mmol), 2a (2.5 mmol), 3 and 4 (5 mol% each) in DCM at 258C.
[b] Yield refers to the column-purified product after two steps. [c] de was
1
determined by H NMR or HPLC analysis. [d] ee was determined by CSP
HPLC analysis. [e] In all entries, except entry 3, the minor diastereomer
was obtained in >99% ee; ee of the minor diastereomer in entry 3 is
57%. [f] Compound 2a (7.0 equiv) was used. [g] Saturated brine solution
as solvent. [h] 3d/PhCO2H (20 mol%) was used.
Employing five equivalents of cyclohexanone 2a under 3a/
4a catalysis followed by reductive etherification gave the
product (À)-6aa in 90% yield with 94% de and >99% ee,
same as entry 1, in which seven equivalents of cyclohexa-
none 2a were used (Table 1, entry 5). The use of 1.5 equiva-
lents of cyclohexanone 2a took longer reaction time (72 h),
resulted in reduced yield (26%), yet maintained the de
(98%) and ee (>99.9%). Interestingly, the precatalyst as-
sembly components 3a or 4a were not effective in promot-
ing the Michael reaction separately (Table 1, entries 6 and
7). Instead of d-proline 3a, when acyclic amino acid (d-phe-
nylglycine) was used, the reaction was found to be not pro-
ceeding at all. As a further support to the hypothetical pre-
TS supramolecular assembly, when the same Michael reac-
tion was carried out under known Michael-reaction condi-
tions, we did not see the product formation even after 72 h
(Table 1, entries 8 and 9).
The possible pre-TS supramolecular assembly (generated
by multiple interactions) described here stands different
from the dual or cooperative activation[5] and is cross exam-
ined by the controlled experiments as shown in Scheme 1. It
is proven from the fact that a modification in the pre-TS as-
sembly by decreasing possible hydrogen-bonding interac-
tions between carbonyl group of d-proline and ortho-phe-
nolic OH group disturbs the hypothetical cyclic supramolec-
ular assembly and diminishes ee of the reactions (Scheme 1).
Figure 2. ESI-HRMS (positive mode) spectrum of the reaction after
120 min of 1a and 2a catalyzed by 3a/4a in DCM at 258C.
an on-going reaction of 1a and 2a (5 equiv) in the presence
of 3a/4a (each 10 mol%) in the DCM at 258C revealed the
presence of [5aa·Na+] (m/z 286.1043) and [9aa·H+] (m/z
246.1135), and the formation of the key catalytic intermedi-
ates [A·H+] (m/z 361.1777) and [B·H+] (m/z 955.3651). In-
terestingly, catalytic pre-TS assembly ions [A·H+] and
[B·H+] were observed from the first moments of reaction
(see the Supporting Information for full details and Fig-
ure S1 therein).[6]
With controlled experimental results in hand, herein, we
firmly elucidate the mechanism of asymmetric Michael reac-
tion through cyclic 19-membered pre-TS assembly by 3a/4a
catalysis—the reaction most likely proceeds through TS-1
mechanism (Figure 3). Herein, we observed four important
interactions among the substrates and the catalysts to favor
a cyclic 19-membered pre-TS assembly (TS-1) to give the
highly enantioselective Michael-reaction product over the
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D. B. Ramachary et al.
as shown in Figures S2 and S3 in the Supporting Informa-
tion.[8]
To explore the utility of the chiral lactols 5, we subjected
them to simple reduction followed by spiro-etherification
protocol to give the analogues of antifungal drug griseoful-
vin [Eq. (1)].[9] Fascinatingly, Lewis-acid-induced dehydra-
tion on chiral diol (+)-10aa (75% de and 99% ee) obtained
from (+)-5aa resulted in spiroetherification of major
Figure 3. Proposed reaction mechanism through pre-TS supramolecular
assembly.
AHCTUNGTRENNUNG
simple acyclic pre-TS (TS-2). According to our observations,
1) carboxylic group of d-proline undergoes proton exchange
with quinoline moiety of quinine-NH-thiourea, thus bringing
the electronic and steric environment closer to the reaction
center; 2) two NH groups of quinine-NH-thiourea engage
themselves in hydrogen bonding with NO2 group of 2-(2-ni-
trovinyl)phenol to activate the electrophilic nature; 3) sec-
ondary amine group of d-proline forms syn-enamine[7] with
cyclohexanone to activate the nucleophilic nature; 4) phe-
nolic OH group of 2-(2-nitrovinyl)phenol protonates car-
bonyl group of d-proline, thus closing the rigid 19-mem-
bered supramolecular cyclic pre-TS to control the facial se-
lectivity (see Figure 3).
The generality of the asymmetric supramolecular catalysis
was further supported by reacting a series of substituted 2-
(2-nitrovinyl)phenols 1a–j with five equivalents of function-
alized cyclohexanones 2a–e and acetone 2c catalyzed by
5 mol% of 3a/4a at 258C in DCM for 5 h followed by re-
ductive etherification on crude products 5 with triethylsilane
and BF3·OEt2 at À108C to 258C for 2 h (Table 2). The chiral
products 6ba–ad were isolated in excellent yields, de and ee
values, tolerating the electronic and steric influence of the
substrates. Interestingly, treatment of 2-(2-nitrovinyl)phenol
1a with simple acetone 2c also gave the expected chiral
product 6ac in 93% yield with >99% de and 94% ee from
two sequential reactions as shown in Table 2, entry 10. Due
to the structural importance of chromene moiety in medici-
nal chemistry, the crude products 5 were treated only with
the BF3·OEt2 to influence the dehydration reaction and a
series of chromenes 9aa–ae were isolated in excellent yields
and ee values. When tetrahydro-4H-pyran-4-one (2d) was
used in the sequential Michael reaction and reductive-ether-
ification reaction, the dehydration reaction of 5ad was
found to influence over the reductive-etherification reaction
(Table 2, entry 11). The structure and absolute stereochemis-
try of the Michael products 5, reductive etherification prod-
ucts 6, and chromenes 9 were confirmed by NMR spectro-
scopy analysis and also finally confirmed by correlation of
specific rotation with Michael-reaction derived product
(À)-8a and X-ray diffraction structural analysis on (À)-6da
AHCTUNGTRENNUNG
tion of hydrogen (hydride) a to the leaving secondary OH
group during water elimination, leading to the formation of
the spiro compound 11aa in 73% yield without racemiza-
tion. The selective reduction–spiroetherification strategy
was demonstrated with one more substrate, 5da to (+)-11da
in 65% yield with 97% ee [Eq. (1)]. Interestingly, Brønsted
acid para-toluenesulfonic acid (p-TSA)-catalyzed dehydra-
tion reaction of (+)-10aa at reflux in benzene for 48 h gave
the inseparable mixture of 11aa and 6aa in the ratio of 5:1
with an overall yield of 64% without racemization (see the
Supporting Information). The spiro compounds 11 are struc-
tural analogues of orally used antifungal drug griseofulvin,[9]
which is highlighting the importance of sequential reduc-
tion–spiroetherification approach to synthesize these medici-
nally important analogues compounds. To further demon-
strate the synthetic application of the chiral hexahydroxan-
thenes 6 in the heterocyclic compounds, (À)-6aa was suc-
cessfully transformed into the azide (À)-12aa through the
intermediacy of amine and finally to the triazole (À)-13aa
under the click-reaction conditions without loss of selectivity
[Eq. (2)].[10]
In conclusion, we have designed a new and efficient su-
pramolecular catalysis for the asymmetric Michael reaction
of cyclohexanone with 2-(2-nitrovinyl)phenols to give the
desired hexahydroxanthenols 5 with high yield, ee and de
values, which have showed further applications in the chiral
synthesis of medicinally important compounds. With ESI-
HRMS technique, we have given strong evidence to the ex-
istence of proposed 19-membered cyclic pre-TS supramolec-
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High Asymmetric Induction in the Enamine-Based Michael Reactions
Table 2. Scope of the asymmetric supramolecular catalysis.[a–d]
COMMUNICATION
ability of these catalysts would also reveal certain mechanis-
tic insights into enzyme-catalyzed reactions.
Experimental Section
Experimental procedures, compound-characterization data (1H NMR,
13C NMR, HRMS, and HPLC) and X-ray crystallographic data (CIF) for
(À)-6da are described in the Supporting Information.
Entry
1
Entry
9[e]
Acknowledgements
This work was made possible by a grant from the Department of Science
and Technology (DST), New Delhi (Grant No.: DST/SR/S1/OC-65/2008).
R.S. and K.S.S. thank Council of Scientific and Industrial Research
(CSIR), New Delhi for their research fellowship. We thank Dr. P. Ragha-
vaiah and Mr. S. Jayavelu for their help in obtaining the X-ray and
HRMS spectral data, respectively.
2
3
4
10
11[f]
Keywords: asymmetric catalysis
·
Michael addition
·
organocatalysis
methods
·
supramolecular chemistry
·
synthetic
12
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Received: March 21, 2012
Published online: May 31, 2012
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