Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate-thiourea hybrid with mechanistic DFT analysis

Article abstract of DOI:10.1039/c6ob02158a

A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-β-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d₀. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol^?1 of energy towards the product formation.

Full text of DOI:10.1039/c6ob02158a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Organocatalyzed Asymmetric Michael Addition by Efficient
Bifunctional Carbohydrate-Thiourea Hybrid with Mechanistic
DFT Analysis
Received 00th January 20xx,
Accepted 00th January 20xx
Chandra S. Azada, Imran A. Khanb*†, Anudeep K. Narulaa*†
DOI: 10.1039/x0xx00000x
A series of thiourea based bifunctional organocatalysts having DꢀGlucose as core scaffold were synthesized and examined as
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the catalysts for asymmetric Michael addition reaction of aryl/alkyl transꢀβꢀnitrostyrenes over cyclohexanone and other
Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields
(<99%) were attained under solvent free conditions using 10 mol % of 1d0. The obtained results were explained through
DFT calculations using B3LYP/6ꢀ311G(d,p)//B3LYP/6ꢀ31G(d) basic set. The QM/MM calculations revealed the role of
cyclohexanone as solvent as well as reactant at the rate determining step imparting 31.91 Kcal/mol of energy towards the
product formation.
After accessing the importance of chiral scaffolds described by
Takemoto, several research groups used the different chiral
Introduction
templates e.g. 1,2ꢀdiamino cyclohexane1cꢀe
,
binaphtyl2a,b
,
Recently, the process of asymmetric catalysis based on
hydrogen bonding has seen an advancement and the use of
bifunctional organocatalysts that include a thiourea group and a
tertiary amino group has made a substantial impact. This class
of organocatalysts acting as the hydrogen bond donors and
acceptors, respectively, which facilitates the activation of a
nucleophile and an electrophile simultaneously, in a controlled
direction, thus leading to the desired stereochemistry1. The first
example of such type of catalyst has pronounced by Takemoto.
The necessary structural feature of the catalyst was well
cinchona alkaloids2cꢀf, and amino acids2g. Only limited chiral
templates/scaffolds have been used for the synthesis of
bifunctional organocatalysts because of complex synthetic
manipulation in addition to cost effectiveness. Whenever
discussing the need of chiral templates it is hard to ignore the
importance of carbohydrates. The carbohydrate could be
consider as chiral template for chiral catalyst like Takemoto’s
one because of their conformational stability and the presence
of distinct spatial arrangement of substituent and various
hydroxyl groups3.
explained by the Takemoto et al as illustrated in the figure 11cꢀe
.
The first example of urea moiety containing carbohydrate
based bifunctional organocatalysts containing
Dꢀglucosamine
scaffold have been described by Kunz et al4. Whereas later on
Ma et al described the thiourea based bifunctional
organocatalysts consisting of monosaccharide and primary
amine moieties for the enantioselective Michael addition5.
Several monosaccharides containing chiral thiourea/urea–amine
compounds as bifunctional organocatalyst for stereoselective
Michael additions and azaꢀHenry reactions have been reported6.
In most of the findings related to monosaccharides containing
E
Chiral
Scaffold
CF3
S
X
S
N
H
N
H
F3C
N
N
Base
H
H
NMe2
H
R1
R2
Nu
Figure 1. Takemoto catalyst and its prototype.
chiral
thioureaꢀamine
compounds
as
bifunctional
organocatalysts, the chiral 1,2ꢀdiamino cyclohexane or
enantiopure diamine scaffolds were retained for controlling
stereochemistry of the reaction, while saccharide have been
a.“Hygeia” Centre of Excellence in Pharmaceutical Sciences (CEPS), GGS
Indraprastha University, Sec. 16-C, Dwarka, New Delhi, 110078, India. E mail:
aknarula58@gmail.com
b.Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, 143005,
India. E mail: imrankhan090@gmail.com
† These authors contributed equally.
introduced only as
a supplementary scaffold probably
beneficial for a tuning of the organocatalyst. To the best of our
knowledge, only two reports are published, in which
Electronic Supplementary Information (ESI) available: The experiment detail of the
synthesized catalysts, 1H, 13C, 19F and HPLC data of catalyst and Michael product,
values of thermochemical and DFT calculations are added in ESI. See
DOI: 10.1039/x0xx00000x
bifunctional
thioureaꢀamine
organocatalysts
with
monosaccharide as a core scaffold have been used for Michael
and Henry reaction with enantiomeric excesses ranging from
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12.9 to 18.7 % (in 24h)7a and from 7 to 20 % (in 72ꢀ720h)7b
respectively.
carbon. The reaction conditions reported by by the Ochiai et al
were screened, nevertheless the amine in lesser yield was
,
From the literature available and endeavour towards
formed. The multispot reaction observed on TLC plates was
6, 8
10a
exploring carbohydrate chemistry
an attempt was made to
ascribed to the use of HBF4
, however the use of
synthesize a new type of thiourea–amine organocatalysts where
both catalytic residues were linked by an enantiomerically pure
carbohydrate centred scaffold, as a substitute of chiral skeleton
to 1,2ꢀdiamino cyclohexane. The two type of organocatalysts
were designed (i) the ꢀCH2ꢀ (n=1) bearing organocatalysts
based on the results published by Tang et al9a designated as
subscript 1 (ii) and rigid analogue (n=0) based on Takemoto
[bis(trifluoroacetoxy)iodo]benzene [PhI(CF3COO)2] improved
the formation of amine in good yield10b,c. The crude amine was
further treated with aryl isothiocyanate to yield the desired
bifunctional organocatalsyt (10 through condition vi in scheme
1
). After getting trans 1 series we synthesized the cis 2 series
catalysts in which Cꢀ3 hydroxy of the glucose diacetonide was
flipped with oxidation reduction method16.Tthe other step of the
reaction were the same as in the synthesis of catalyst 1 series
design 9b as subscript 0 (Figure 2).
(Scheme 1) (For detailed synthetic procedure see ESI).
Figure 2. Schematic representation of synthesized catalyst.
Scheme 1. The synthesis of Glucose based organocatalysts and reaction conditions. (i)
(a) Tf2O, DCM, 0oC, 5h, 95% (b) NaN3, DMF, 50oC, 8h, 68% (c) LiAlH4, THF, 0oC,
Results and discussion
The synthesis of series 11 (subscript 1 stand for n=1, Figure 5h, 76% (d) RX, NaH, Dry DMF, 0oCꢀrt. 12h, (90 % mono alkylated, 24 % di Bn) (ii)
(a) 60 % AcOH, 50oC, 4h, 99 % (b) NaIO4, THF:Water (1:1), rt, 1h, 90% (c) NaBH4,
2) was carried out by the conversion of
Dꢀglucose into its
MeOH, rt, 10h, 95% (d) MsCl, TEA, DCM , rt, 12h, 99% (e) NaN3, DMF, 80oC, 12h,
93% (iii) ArNCS, PPh3, THF, 0oCꢀrt, N2 balloon, 12h, 72% (iv) (a) PCC, Ac2O, DCM,
rtꢀrelux, 3h, 89% (b) NaBH4, MeOH:Water (1:1), rt, 3h, 80% then same sequence of
reaction as applied for 11 (v) (a) Tf2O, DCM, 0oC, 5h, 95% (b) NaN3, DMF, 50oC, 8h,
diacetonide (
A in scheme 1) with acetone using phosphoric acid
as catalyst. The Cꢀ3 hydroxy of glucose diacetonide was
triflated and subsequently replaced by azide with inverted
stereochemistry. The Cꢀ3 azide was reduced with LAH and 66% (c) LiAlH4, THF, 0oC, 5h, 75% (d) RX, NaH, Dry DMF, 0oCꢀrt. 12h, (92 % mono
alkylated, 44 % di Bn) (ii) (a) 60 %AcOH, 50oC, 4h, 95% (b) NaIO4, THF:Water (1:1),
alkylated with the suitable alkylated reagent (
B through
rt, 1h, 88% (c) aq AgNO3, KOH, rt, 1h, 75% (d) COCl2, DCM, 0oC, 5h, 54% (e)
Methanolic ammonia, 0oCꢀrt, 12 h, 82% (vi) (a) PhI(CF3CO2)2, ACN–H2O (1:1), rt, 4 h,
42% (b) ArNCS, THF, 0oCꢀrt, N2 balloon, 12h, 44%.
condition
i in scheme 1). The Cꢀ5,6 protection is cleaved by
acetic acid and diol so formed upon periodate oxidation gave
aldehyde which was reduced without purification to generate Cꢀ
4
primary alcohol. The Cꢀ4 alcohol is mesylated and
After getting designed carbohydrate based bifunctional
subsequently azidated with NaN3 in DMF (
C through condition organocatalysts in hand, the catalytic activity was studied on
ii in scheme 1). The azide so formed was reacted with aryl conjugate addition reaction. The asymmetric Michael addition
1a,11
isothiocyanate in presence of PPh3, in which azide reduced in
situ and led to the formation of thiourea linkage (11 through
involving α−enolizable ketones to electron deficient
nitroolefins, received attention after first reported by List and
Barbas, independently 11d,e. These reactions led to the formation
condition iii in scheme 1).
In the synthesis of 1o (n=0) series, the authors proposed to
descend the catalyst by one carbon for which same reaction
sequence was repeated (condition i, scheme 1) upto Cꢀ3 amine
of γꢀnitro carbonyl compounds, found to be important building
blocks in organic/medicinal chemistry12. Several examples are
available till date in which aromatic nitroolefines were used
6g,13
alkylation and then Cꢀ5,6 linkage was cleaved with acetic acid
and then diol was oxidative cleaved with sodium periodate, the
aldehyde so formed was oxidized with freshly prepared silver
oxide to get the Nꢀalkylated sugar amino acid. The acid was
converted to the corresponding acid chloride with oxalyl
chloride in DCM. This acid chloride was left over night in
methanolic ammonia in which amide was formed in good yield
nevertheless reaction of alkyl nitroolefins with
cyclohexanone are few,9a,14 this may be due to the less
reactivity of than alkyl nitroolefins then aryl nitroolefins. So
cyclohexanones and alkyl/aryl nitroolifines were chosen as
model substrates. The screening of the reaction was carried
using cyclohexanone (
% of synthesized catalyst in DCM for 24h. As, given in table
D through condition v in scheme 1). The best method to yield and enantioselectivity toward the formation of 5a varied
3), transꢀβꢀnitrostyrene (4a) and 20 mol
1
,
(
descend the carbon in the amide is the Hofmann rearrangement, significantly. The catalyst with one CF3 substitution failed to
in which amide is converted into amine with the loss of one catalyse the reaction as traces of product were noticed over the
2 | J. Name., 2012, 00, 1-3
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TLC plate (Table
1
, Entry
1), revealing the necessity of two hindrance (Table
1
entry
5
), so it was predicted that adding
CF3 groups on aromatic ring. The Cꢀ3,4 trans catalysts (1b1 and external base would increase the yield and selectivity. The
1c1) with methylene at C5 carbon found to be active and screening of some common bases like bicarbonate, carbonate,
increasing the size of alkyl group at C3ꢀamine led to the and pyridine, likewise disappointed (Table
decrease in yield (Table , entries and ), although increased hindered bases like DABCO, DBU and Pr2NH gave the desired
in syn/anti ratio and enantioselectivity was noticed. Inspired product 5a in maximum 72% yield with 62% enantiomeric
form these results benzyl as another substrate was considered as excess (Table , entries ). The use of Pr2NH suggested the
2 entries 1ꢀ2). The
1
2
3
i
2
4
ꢀ
6
i
it may produce facial hindrance with lesser bulky environment use of Et3N and in 20 mol % of the same, the significant
at amine. This resulted in the formation of product 5a in 52 % improvement of the yield and enantioselectivity was noticed
yield with 73 % enantiomeric excess (Table
di alkylated catalyst 1e1 failed to produce the 5a in good compound the impact of reaction medium was also evaluated
yield and enantioselectivity (Table , entry ) may be due to and it was established that reaction medium influenced the
1, entry 4). The N, (Table 2 entry 7). After getting 92% yield of the desired
N
1
5
steric problem. In the next approach it was proposed to cut off process. The most commercial available solvents are attuned
the C5 methylene because it was envisaged that the flexible with optimized asymmetric conditions and afforded excellent
nature of this –CH2ꢀ would be responsible for decrease in yield yields (<92%) with excellent to good diastereoselectivities (up
and enantioselectivity. As expected the rigid catalyst 1d0 served to 96:4) and diverse enantioselectivities (Table
the purpose and 5a was formed in 68 % yield with 88% When the reaction was performed in halogenated solvents, e.g.
enantiomeric excess (Table , entry ). The necessity of Bn DCM, DCE and CHCl3, excellent diastereoselectivities (< 95/5)
over the Cꢀ3 amine was cross checked by putting Me instead of and good enantioselectivities (<86%) were obtained (entries
Bn and that again led to inadequate results (Table , entry ). ). The reaction in polar solvents, such as THF, Et2O, ACN and
2, entries 7−16).
1
6
7ꢀ
1
7
9
This showed the importance of Bn in the synthesized catalyst.
Although trans- symmetry is suggested in between thiourea and
base in prototype of Takemoto catalyst, nevertheless cisꢀ
symmetry catalyst was also screened, which was hypothesized
on the basis of study published by Fugedi et al.7a. The catalyst
Table 2. Screening of base, solvent and catalyst loading on the Reaction
of cyclohexanone to transꢀnitrostyrene by 1d0*
2d0
enantiomeric excess was achieved with 63 % yield (Table
entries 10). Form the above results 1d0 was selected as the
catalyst of choice.
, 2d1 and 2a0 gave poor results as maximun 25%
1,
8ꢀ
Entry
1
Base
NaHCO3
Na2CO3
Pyridine
DABCO
iPr2NH
DBU
Et3N
solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
Yield
ꢀꢀꢀꢀ
23
43
26
72
32
92
86
72
54
48
32
44
18
77
82
92
96
94
68
98
syn/anti
ꢀꢀꢀꢀꢀ
ee
ꢀꢀꢀꢀꢀ
52
48
42
62
56
86
84
86
72
54
62
49
22
69
76
90
88
91
80
94
2
95/5
92/8
60/40
93/7
85/15
90/10
95/5
85/5
93/3
96/4
92/8
86/14
92/8
91/9
94/6
94/6
95/5
96/4
94/6
99/1
Table 1. Screening of catalyst selectivity on the Reaction of
Cyclohexanone to transꢀNitrostyrenea
3
4
5
6
7
8
Et3N
Et3N
Et3N
9
CHCl3
THF
10
11
12
13
14
15
16
17
18
19
20
21
Entry
Catalyst
1a1
Yield
traced
28
Syn/antib
ꢀꢀꢀ
eec
ꢀꢀꢀꢀ
42
52
72
15
88
75
23
25
ꢀꢀꢀ
Et3N
Et2O
1
2
Et3N
ACN
1b1
76/23
80/20
95/5
Et3N
DMSOa
MeOHb
Benzene
Toluene
neatc
3
1c1
23
Et3N
4
1d1
52
Et3N
Et3N
5
6
1e1
1d0
34
68
60/40
95/5
Et3N
7
1b0
52
90/10
55/45
75/25
ꢀꢀe
Et3N
neatd
8
2d1
53
Et3N
neate
9
2d0
63
Et3N
neatf
10
2a0
<10
Et3N
Neatg
a
All reactions were carried out in DCM (5 mL for 1 mmol of cyclohexanone)
*Unless otherwise noted, all reactions were carried out at rt for24h using 10
mol % 1d0 Reaction time was 36 h. b Reaction time was 2 days. c The 25
equiv of cyclohexanone was used. With 30 mol %. With 10 mol %.
With 5 mol%. g Reaction performed at ꢀ10oC for 2.5 days.
using 3 (5 equiv) and 4 (1 equiv) in the presence of 10 mol % of catalysts for 24h.
b Determined by 1H NMR. c Determined by chiral HPLC. d Anlysed by TLC only.
e Not determined.
.
a
d
e
f
From the results obtained by initial screening (Table 1), the
DMSO, yielded the 5a with relatively lower enantioselectivities
(entries 10 13). The adverse effect of the solvent polarity was
clearly verified, when reaction performed in the protic solvent
like MeOH, poorly yielded the 5a (Table , entry 14). When the
improvement in the yields was assumed on the basis of basicity
of C3 sec-amine of sugar counterpart. The secꢀamine in
designed catalyst was not that much sufficient and increasing
electron donating groups may reduce the yield due to steric
ꢀ
2
reaction was carried out in hydrocarbon solvents, product 5a
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was formed good yield with significant loss of complete the reaction (Table
Journal Name
3
, entries 4, 7, 8, 11). The alkyl
enantioselectivity (Table 2, entries 15 and 16). The excellent nitroolefins also gave good results (entries 14 and 15).
result was obtained when reaction was carried out devoid of Additionally, alkenyl substituted nitroolefin also effectively
any solvent with 25 equivalent cyclohexanone (entry 17). employed offering high diastereoꢀ and enantioselectivity as
Additional catalyst loading screening suggested the 10 mol % those found in the aryl substituted ones (entry 16). The absolute
was sufficient to catalyze he reaction (entries 18ꢀ20). The configuration of the major isomer was recognized by
temperature also showed the effect on the reacting and it was comparison of optical rotation in the published literature as
found that lowering the temperature enhanced the yield with described in ESI†.
slightly increase in selectivity at the cost of reaction time. The
The result so obtained, fortified us to explore the scope of
optimized temperature was found ꢀ10oC, which can easily be the reaction on other ketones and aldehydes. The acetone and
achieved by ice salt. The required ratio of Et3N was also methyl ethyl ketone yielded the desired products in 70 and 78
screened and 20% found to be optimum.
% respectively, nevertheless in case of unsymmetrical ketone
), a variety (Scheme , entry ) two products were formed in which the
Under the optimized condition (entry 21 table
2
2
b
of substrates were studied, and the corresponding products were lesser substituted enol based product was formed in excess with
formed in moderate to high yields with high moderate enantiomeric excess (<75%) but poor regioselectivity.
diastereoselectivities
enantioselectivity (up to 95% ee) (Table
phenyl, electron rich and electron deficient aryl groups, heteroꢀ
aromatic and aliphatic substituents were well tolerated under similar reaction condition offered the desired products in 83 %
the optimized reaction condition. The transꢀβꢀnitrostyrene with yield with 58% ee (Scheme , entry ), whereas in the case of
(up
to
99:1)
and
). In addition to the product was formed in 82 %yield with good ee (79%) (Scheme
, entry ). The reaction of cyclopentanone with 4a under
excellent The isobutyraldehyde also showed good results as desired
3
2
c
3
d
electronꢀwithdrawing groups gave slightly higher yields than cycloheptanone multiple products were obtained, in which selfꢀ
those with electronꢀdonating groups and substituents on aryl condensed product predominates as analysed by NMR
groups slightly influenced the diastereoselectivities and spectroscopy.
enantioselectivities. Although sterically demanding substrates
are also well tolerated in this reaction, nevertheless higher
reaction time was required to
Table 3. Substrate scope of 1d0 catalyzed asymmetric Michael addition
of cyclohexanone to transꢀβꢀnitrostyrenea
Entry
R
time Yieldb
(h)
syn/
antic
99/1
95/5
96/4
98/2
94/6
95/5
96/4
eed
1
2
3
4
5
6
7
Ph (4a)
1ꢀNaphthyl (4b)
4ꢀMeC6H4 (4c)
2ꢀCF3C6H4 (4d)
3ꢀCF3C6H4 (4e)
4ꢀClC6H4 (4f)
2ꢀNO2ꢀ5ꢀClC6H3
(4g)
60
60
66
72
60
66
78
98
92
89
94
92
96
95
94
94
87
90
91
94
93
Scheme 2. Reactions of other ketones and Aldehyde.
For extending the substrate scope of the reaction, authors
examined the Michael reaction of βꢀnitrostyrene with other
Michael donors viz. 1,3 dicarbonyl, 1,3 dicyano,
βꢀketo esters
and ꢀcyano esters. The results are summarized in Table
α
4.
Under optimized condition, upto 95 % yield with 96%
enantioselectivity was obtained even without the use of TEA.
The stereochemical outcome of the reaction was found to be
significantly influenced by the structure of the Michael donors.
The sterically more hindered donors readily reacted with
nitrostyrene in presence of 1d0 to give the corresponding adduct
8
9
2ꢀNO2C6H4 (4h)
Benzo[d][1,3]diox
olꢀ5ꢀyl (4i)
72
60
94
91
93/7
94/6
91
95
10
11
4ꢀMeOC6H4 (4j)
2,4ꢀ(MeO)2C6H3
(4k)
66
84
86
88
93/7
92/8
93
88
in higher ee and yield (entries 6, 7 and 9, 11, table 4). The βꢀ
12
13
14
15
16
2ꢀFuryl (4l)
60
60
72
78
60
90
85
62
58
72
94/6
98/2
96/4
80/10
95/5
91
92
92
90
89
keto esters showed the excellent diastereoselectivity as methyl
3ꢀoxobutanoate and ethyl 3ꢀoxobutanoate gave 96:4 and 92:8
diastereoselectivity respectively (entries 9 and 10, table 4),
2ꢀThienyl (4m)
isoꢀpropyl (4n)
isoꢀbutyl (4o)
(E) cinnamyl (4p)
while in case of
αꢀcyano ester less than 5% of
diastereoselectivity was observed (entry 11, table 4). The
Michael adducts so formed noticeably showed the applicability
of the optimised methodology on the wide range of substrates.
The optimized method can be utilized for the synthesis of
a
All reactions were carried out using
3
(25.0 equiv.) and
4
(1.0 equiv.) in
the presence of 10 mol % of 1do and 20 mol % of TEA in neat at ꢀ10oC.
b
Isolated yield. c Determined by 1H NMR of the products. Determined by
d
chiral HPLC analysis.
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To explain the stereochemical outcome of the reaction,
computational studies were performed. All theoretical
calculations were performed using the Gaussian 09 program
package. Density functional theory (DFT), which has been
proved to be a powerful tool for the study of reaction
mechanisms, was chosen in this computational work16.
enatiopure Baclofen, Rolipram, and Femoxitine drug molecules
in good ee using published literature 9b,15 (Figure
3).
Considering the complexity of the theoretical model used
for this study, all the structural optimizations were carried out
at the B3LYPꢀ6ꢀ311g(d,p)/6ꢀ31G(d,p) level in gaseous
condition at 263K, Additionally, the structures (local minima or
firstꢀorder saddle points) were located by performing full
geometry optimization. Then the corresponding vibrational
frequencies were calculated at the same level to take account of
the zeroꢀpoint vibrational energy (ZPVE) and to identify the
transition states. It was confirmed that all the reactants, reaction
precursors, intermediates, and products had no imaginary
frequencies, and each transition state had only one, imaginary
frequency. Intrinsic reaction coordinate (IRC) calculations at
the same level were performed to verify that each saddle point
links two desired minima and the transition states led to the
expected reactants and products. Based on the optimized
structures, the singleꢀpoint energies were further refined using
the 6ꢀ311+G(d,p) basis set in gaseous phase. All discussions in
this manuscript are based on the Gibbs free energies. According
to DFT studies, the possible catalytic mechanism for the title
Figure 3. The drug candidates which can be synthesized by devised methodology.
Table 4. Enantioselective Michael reaction of nitroolefins with Michael
a
donors in the presence of 1d0
Entry Nitroolefins
Michael
donor
Time
(h)
66
Yield
eec
(Config)d
94 (R)
92 (R)
89 (R)
92 (S)
85 (S)
82 (S)
96 (S)
92 (R)
94g
(%)b
1
2
4a
4c
4f
R1=R2=CO2Et
R1=R2=CO2Et
R1=R2=CO2Et
R1=R2=CO2Et
R1=R2=CO2Et
R1=R2=COMe
R1=R2=COEt
R1=R2=CN
R1=COMe;
R2=CO2Me
R1=COMe;
R2=CO2Et
95 (11a)
92 (11b)
85 (11c)
93 (11d)
84 (11e)
91 (11f)
95 (11g)
88 (11h)
92 (11i)
dr 96:4f
95 (11j)
dr 92:8 f
78 (11k)
dr < 5%f
78
3
78
4
4m
4o
4a
4a
4a
4a
60
5
84
reaction is depicted in Scheme
be divided primarily in four parts after the formation of the
adduct; (i) Formation of thioureaꢀnitrostyrene (TU NS adduct)
complex ( ); Activation of the ketone through TEA ( to );
(ii) the Michael addition ( ); (iii) proton abstraction from the
TEAH+ resulting to the formation of
; and (iv) regeneration of
catalyst ( ) (Scheme ).
3. The reaction mechanism can
6
96
60
7e
8e
9
ꢀ
72
B
C
D
87
D
E
10
11
4a
4a
92
90
96g
72g
A
3
The first step of the reaction in mechanism is the
combination of TEA with cyclohexanone and formation of
cyclohexanenolate ion (Scheme 3) and simultaneously the
formation of stabilized octa membered hexagonal adduct
R1=CN;
R2=CO2Me
aThe reaction was carried out with 1 equiv. of
4 and 10 equiv. of Michael
b c
donor in the presence of 10 mol% of catalyst at ꢀ10oC. Isolated yield.
d
between Nitrostyrene and 1ꢀ((3aR,5S,6S,6aR)ꢀ6ꢀ(benzylamino)ꢀ
Enantiomeric excess was determined by HPLC. Absolute configuration
was determined by comparing the optical rotation with published literature. e
2,2ꢀdimethyltetrahydrofuro[2,3ꢀd][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ(3,5ꢀ
bis(trifluoromethyl)phenyl)thiourea (1do) formed by the strong
hydrogen bond interactions. The optimized structure of adducts
f
Reaction was performed in the presence of 4 ml of DCM per 1 mmol of
4.
Determined by 1H NMR of the products. g Not assigned.
(
Fig 4 in ESI) formed with the inversed stereochemistry at the
C3 of the sugar part was found to be more thermodynamically
stable than the naturally occurring stereoisomer. A weak
hydrogen bond was found to be formed between sulfur of TU
and NH of sugar at C3 which was not found favorable in case
of normal isomer based TU catalyst. This showed the greater
favorability of adduct (
B) for the Michael addition in the fate
giving 3 , 17 product which directly proved the formation of
S
R
SR product as the favorable due the decrement of the pꢀ
character of the bond as suggested through the output files. The
NBO studies revealed that shortened C1(α)=C2(β) (NS) in
adduct was assisted with change in NBO charge from 0.08e and
0.06e to 0.015e and 0.06 in Fig 3 (ESI) and 0.017e and 0.09
Fig 4 (ESI), showed a slight decrement of
p characters is
imparted by TU (both normal and inverted forms) to the
Michael acceptor site. Obviously, polarization of NS in this
step, indicated the catalyst to be the Lewis base organocatalyst.
The energy barriers of the first step were 26.0 kcal mol−1
Scheme 3. Mechanistic insight of the reaction Michael addition reaction of aryl/alkyl
transꢀβꢀnitrostyrenes over cyclohexanone
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(associated with normalꢀconfiguration TS1
(
anti), Fig. 7 in that the stage VI could be the key for the stereoselectivity. In
syn), Fig. 21 in addition, the difference of the energy barrier between SR and
ESI) and 9.9 kcal mol−1 (associated with TS1
(
ESI). The second step in mechanism is the formation of three RS configurations in this stage is 5.89 kcal/mol; this value
hydrogen bond governed intermediate with (O•••N Ar; O•••N correspond to an enantiomer excess of 95%, which was s to our
sugar; O enolate•••N terminal). In this step, the reaction experimental outcome (94% ee). The benzene ring of the nitro
precursor (Fig 8 in ESI) undergoes the Michael addition styrene and phenyl group of the catalyst were 3.41 Å apart in
transition state TS2. There were four different kinds of TS2 which signifies the π–π weak interaction be the driving
stereoisomer, i.e. SS
,
SR
,
RS, and RR configurations, in this force for the formation of
P (RS), whereas the same distance is
addition process. As shown in figure
4
the energy barrier via 3.65 Å at TS2 for the formation of the SR product. Therefore, a
TS2 (SS, RR, SR & RS) is ꢀ63.01/ꢀ63.00/ꢀ75.13/ꢀ60.97 weak π–π interaction, leads the reaction to the observed
kcal/mol, indicating the pathway associated with stage 4 (SR) stereochemical preference. The conformational arrangement at
had the lowest energy barrier among the four competing fates, sugar moiety which favors the SR product formation could be
thus, it should be the most favorable pathway and the SR explained through the spontaneous formation of TS2 and TS3
configuration would be the favorable stereoisomer; this was in supported through the free energy (ꢁGSR>ꢁGSS>ꢁGRS >ꢁGRR
)
agreement with the experiment. Accompanied with the and in the case of TS2 the steepness in IRC curve for the SS
formation of bond C3–C4, the single bond C4–O5 was also conformation thus decreases the favourability (IRC3, ESI).
generated subsequently in step involving conversion to TS3
from stage 5 SS, RR, SR RS via TS2 SS, RR, SR RS), so RR, SR
the addition is a concerted process. Where the distances through transition state TS3
between C2–C3, and O5–C2 in TS2 and TS3 SS RR SR the distances NꢀO•••HꢀN reflects the nature of this reaction
RS) decreased, whereas the distances C3–C4 and C4–O5 are process. The distances NꢀO•••HꢀN are increased to
increased in this process. As depicted in scheme , the different 2.043/2.045/2.011/2.090 Å in TS3 SS, RR, SR RS),
stereoselectivities associated with the chiral carbon centers C3 respectively. The energies of product (SS RR, and SR RS) in
In the last step of mechanism, the catalyst and product (SS,
RS) dissociated by breaking the NꢀO•••HꢀN bond
SS RR SR RS), the change of
(
&
)
(
&
&
(
,
,
&
(
,
,
&
3
(
&
,
&
and C4 were generated in the addition process, so envisaged presence catalyst were found to be lower than those of the
Figure 4. Energy (E+ ZPVE) profile of the possible reaction mechanism. Numbers in parentheses are relative Gibbs free energies (unit: kcal mol−1). The Gibbs free energies of
NS+ R2+ thiourea+TEAH+ was set as references (0.0 kcal/mol); the notations SR, SS, RS and RR stands for the stereochemistry at C2 from NO2 and C2 from C=O of NS and
cyclohexanone respectively.
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reactants respectively, indicating the overall reaction is an General reaction condition for the Michael addition of
exothermic process. Furthermore, the energy barrier via TS3 Michael donors to Nitroolefines by using 1d0 as bifunctional
(
SS, RR, SR &
RS) was found to be ꢀ51.492/ꢀ50.712/ꢀ37.813/ꢀ organocatalysts: To the precooled (ꢀ10oC) 10 (20 mmol) the
41.712 kcal/mol, this suggested that the third step should be catalyst 1d0 (5.35 mg, 10 mol%) was added under nitrogen
also a slow process. The larger energy gap at stage IV and VI atmosphere. The reaction allowed to stir for about 1h and then
were seen unfavorable due to the nonꢀconsideration of the transꢀnitrostyrene (1 mmol) was added by maintaining the
cyclohexanone in excess as it was envisaged that nitrogen atmosphere. The reaction was evaporated under
cyclohexanone played role as solvent. Therefore, to justify the reduced pressure after completion. To the reaction crude water
role of solvent molecular dynamic calculation for the system was added and then extracted with EtOAc (10 ml X3) and
resulting were carried out which resulted the formation of combined organic layer dried over Na2SO4 and evaporated by
product with SR configuration using Desmond in rotatory evaporator. The products were purified by column
Schrondinger17. The obtained system after MD equilibriums chromatography using 20% EtOAc and hexane as eluent.
(4ns) was subject under QM/MM calculations using the Qsite
The enantiomeric excess was determined by the HPLC
protocol with B3LYP/6ꢀ311g and RHF/631g basis set for the
analysis in which series 5 and 11 compounds were further
high layer and low layer respectively. The obtained results
purified by flash chromatography after obtaining the NMR and
showed lowering in the relative energy gap from 72 kcal/mol to
other data.
31.2 kcal/mol at stage IV and 37.81 kcal/mol to 28.80 kcal/mol
Acknowledgements
at stage VI depicting three more cyclohexane molecules around
the reactants (Figure 35, 36 in ESI). The execution of similar
studies was avoided due to the high computational cost.
CSA acknowledge Guru Gobind Singh Indraprastha Univeristy,
New Delhi for the financial assistance and TRC lab for
providing analytical data. IAK is thankful to UGC for granting
Dr. D.S. Kothari postdoctoral fellowship.
Conclusions
Notes and references
In conclusion, we developed an efficient carbohydrate core
scaffold having thiourea and secꢀamine group, which worked
excellent as a bifunctional organocatalyst to carry out the
asymmetric Michael reaction of cyclohexanone and Michael
donors to both aryl and alkyl nitrooelfins. In the current finding,
the designed and synthesized catalyst showed a high catalytic
activity, and reaction was completed with excellent diastereo
(up to >99%) and enantioselectivity (up to 95 % ee), which may
be further useful for the synthesis of βꢀnitroketones. The
devised methodology may find a use in the synthesis of some
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