C2-symmetric sulfonamides as homogeneous and heterogeneous organocatalysts that mimic enzymes in enantioselective Michael additions

Article abstract of DOI:10.1002/chir.22984

Herein, we report the synthesis of C₂-symmetric sulfonamides as homogeneous and heterogeneous organocatalysts and their application in the enantioselective conjugate 1,4-Michael addition of carbonylic nucleophiles to β-nitrostyrene. Organocatal

Full text of DOI:10.1002/chir.22984

Received: 29 March 2018
DOI: 10.1002/chir.22984
Revised: 4 May 2018
Accepted: 7 May 2018
R E G U L A R A R T I C L E
C ‐symmetric sulfonamides as homogeneous and
2
heterogeneous organocatalysts that mimic enzymes in
enantioselective Michael additions
1
1
1
1
Harold Cruz | Felipe A. Servín | Domingo Madrigal | Daniel Chávez |
1
1
2
1
Sergio Perez‐Sicairos | Gerardo Aguirre | Andrew L. Cooksy | Ratnasamy Somanathan
1
Centro de Graduados e Investigación en
Abstract
Química del Instituto Tecnológico de
Tijuana, Tijuana, B.C., Mexico
Herein, we report the synthesis of C ‐symmetric sulfonamides as homogeneous
2
2
Department of Chemistry and
and heterogeneous organocatalysts and their application in the
enantioselective conjugate 1,4‐Michael addition of carbonylic nucleophiles to
β‐nitrostyrene. Organocatalysts hydrogen bond to β‐nitrostyrene and enamine
in the transition state, mimicking an enzyme leading to final products in high
yields (up to 98%) and good enantioselectivities (up to 96%). In addition, these
results were supported by density functional calculations.
Biochemistry, San Diego State University,
San Diego, CA, USA
Correspondence
Ratnasamy Somanathan, Centro de
Graduados e Investigación en Química del
Instituto Tecnológico de Tijuana,
Apartado Postal 1166, Tijuana, B.C. 22510,
Mexico.
KEYWORDS
Email: rsomanathan@mail.sdsu.edu
conjugate addition, density functional calculations, immobilized organocatalyst, transition state,
β‐nitrostyrene
Funding information
Consejo Nacional de Ciencia y Tecnología,
Grant/Award Numbers: INFR‐2011‐3‐
173395 and 224405
2
8
1
| INTRODUCTION
addition of acetone to nitroolefins. The organocatalyst
with sulfonamide group (NHSO ) acts as a weak hydro-
2
Enantioselective conjugate 1,4‐Michael addition reactions
using organocatalysts is an important carbon‐carbon bond
forming reaction that has received much attention in recent
gen bond donor and also contains a basic primary amino
group (NH ) that can activate the nucleophilic reaction
2
partner (in this case, acetone) by generation of an
1,2
years. Of the various conjugated 1,4‐Michael addition
reactions, addition of nitroalkanes and carbonylic com-
pounds to α,β‐unsaturated systems, such as nitroalkenes,
enamine (Figure 1A). The acidic ―NH―SO ― hydrogen
2
atom bonds to one of the oxygens of the nitroolefin. In
addition, the organocatalyst also offers an O···Cl interac-
tion with the oxygens of the nitroolefin, thus preventing
the free rotation of the nitroolefin in the transition state
and offering a more rigid alkene face for a syn addition
of the enamine (Figure 1B). This was supported by den-
sity functional calculations, which showed the O···Cl
bond interaction in the transition state with an energy
comparable to that of hydrogen bonding. Thus, the
organocatalyst in this case is proposed to be multifunc-
tional in the transition state of the reaction as shown in
Figure 1B, mimicking an enzyme with multiple non‐
3-27
is of great synthetic interest (Scheme 1).
In particular,
the final products of such additions can be converted
directly into important chiral building blocks, such as
26
γ‐aminocarbonyls, 2‐pyrrolidones, and 2‐piperidones.
Various classes of enantiopure bifunctional organocatalysts
have been used for this conjugate 1,4‐Michael addition,
including cinchona alkaloids, sulphonamides, proline
derivatives, and thioureas; they all gave the final products
28
in good yields and enantioselectivities.
Recently, we reported the use of enantiopure
monosulfonamides as organocatalysts in the conjugate
2
9
covalent interactions stabilizing the transition state.
Chirality. 2018;1–9.
wileyonlinelibrary.com/journal/chir
© 2018 Wiley Periodicals, Inc.
1

2
CRUZ ET AL.
enzyme‐like transition state consistent with our hypothe-
30
sis (Figure 2).
Having excellent results with the organocatalysts 1a
30
and 2a (Table 1, entries 11 and 14), we decided to
increase the steric crowding in the groove by introduc-
ing a bulkier 1,1′‐binaphthyl‐2,2′‐diamine unit, which
may bring the enamine and β‐nitrostyrene closer in
the transition state, making the reaction more
enantioselectively efficient. In order to test our
hypothesis, we herein report the synthesis of five
organocatalysts by coupling (R)‐1,1′‐binaphthyl‐2,2′‐
SCHEME
1
1,4‐Michael addition of nucleophiles to α,β‐
unsaturated systems with an electron‐withdrawing group
diamine,
(1R,2R)‐1,2‐diphenylethane‐1,2‐diamine,
(
1R,2R)‐1,2‐cyclohexane diamine with aromatic sulfonyl
chlorides to give sulfonamides 1c, 2c, 3c, 4a, and 4b,
as shown in Scheme 2.
(
A)
(B)
2
| MATERIALS AND METHODS
FIGURE
monosulfonamide transition states
1
A,
Bifunctional
and
B,
multifunctional
2
8
2.1 | General
Commercially available chemicals as (1R,2R)‐1,2‐
diphenylethane‐1,2‐diamine,
(1R,2R)‐1,2‐cyclohexane
Continuing on the same line, to make the transition
state more stable and enzyme‐like, we recently reported
diamine, (R)‐1,1′‐binaphthyl‐2,2′‐diamine, 1,3‐benzene
disulfonyl chloride, biphenyl‐4,4′‐disulfonyl chloride and
4‐(ethylbenzene)sulfonyl‐silica gel were purchased from
Sigma Aldrich, and (R)‐1,1′‐binaphthyl‐2,2′‐disulfonyl
chloride from TCI America. Melting points were obtained
on an Electrothermal 88629 apparatus and are uncor-
rected. Infrared spectra (IR) were determined on a Perkin
Elmer FT‐IR 1600 spectrophotometer. NMR spectra were
recorded on a Bruker Avance III spectrometer 400 MHz,
in CDCl or DMSO‐d with TMS as internal standard.
the synthesis of C ‐symmetric bis‐sulfonamide
2
30
organocatalysts (1a, 1b, 2a, and 2b, Scheme 2)
and
tested them in the conjugate carbonylic 1,4‐Michael
addition to β‐nitrostyrene. We hypothesized that the
C ‐symmetric organocatalysts could accommodate the
β‐nitrostyrene and the enamine within the groove and
increase the hydrogen bonding with the substrate,
mimicking an enzyme. This strategy allowed us to find
bis‐sulfonamide organocatalyst 1a that led to the 1,4‐
Michael addition of isobutyraldehyde with high yield
and enantioselectivity (yield >99%, ee > 99%, Entry 11,
Table 1). Density functional calculations predict an
2
3
6
Mass spectra were acquired on an Agilent Technologies
5975C MS Spectrometer at 70 eV by direct insertion. High
resolution mass spectra (HRMS DART/TOF) were
obtained on positive mode. Elemental analyses were con-
ducted by NuMega San Diego.
General methodology for the synthesis of mono‐ and
bis‐(R)‐1,1′‐binaphthylsulfonamide organocatalysts 1c,
2c, 3c, 4a, and 4b.
To a solution of quiral diamine (2.5 eq) in dichloro-
methane (35 mL) was added triethylamine (0.3 eq) at
°C; to this stirred mixture, a solution of sulfonyl chloride
1.0 eq) in dichloromethane (20 mL) was added dropwise.
0
(
The reaction mixture was stirred for 24 hours at room
temperature in a sealed flask. The reaction was quenched
with water, extracted into dichloromethane (3 × 25 mL),
and dried over anhydrous MgSO . The solvent was
4
removed under reduced pressure, and the residue was
purified by a silica gel flash column chromatography (elu-
ent petroleum ether/dichloromethane 6:1) to give solid
compound (See Supporting information).
SCHEME
organocatalysts
2
Mono‐sulfonamide
and
bis‐sulfonamide

CRUZ ET AL.
3
a
TABLE 1 Homogeneous 1,4‐Michael addition of aliphatic ketones and isobutyraldehyde to β‐nitrostyrene using organocatalysts 1‐5
b
c
c
Entry
Organocatalyst
Nucleophile
Yield, %
ee, %
dr (syn: anti)
Product and Configuration
1
2
3
4
5
6
1a [6]
1b [6]
1c
2c
4a
91
66
48
98
33
4
88
55
46
57
94
18
‐
‐
‐
‐
‐
‐
4b
7
8
9
1c
2a
2b
2c
72
50
28
21
>99
97
>99
>99
40:60
0–100
0–100
21:79
1
0
11
12
13
14
15
16
17
18
19
1a [6]
1b [6]
1c
2a [6]
2b [6]
2c
3c
4a
4b
>99
78
78
95
84
98
10
12
3
>99
56
93
82
88
96
35
25
23
‐
‐
‐
‐
‐
‐
‐
‐
‐
a
All entries are for 10 mol % in dichloromethane over 5 days.
b
Yields were determined by HPLC Agilent Technologies 1220 Infinity LC column CHIRALPAK AS‐H 0.46 cm φ × 25 cm, flow 1 mL/min. For Entries 1–10,
k = 210 nm and mobile phase 65:35 (Hex/iPrOH) were used. For Entries 11‐19, λ = 220 nm and mobile phase 10:1 (Hex/iPrOH) were used.
c
31-33
R
Enantiomeric excesses were determined by HPLC and the absolute configuration was assigned by comparing t with literature values.
2
.2.2 | Procedure for the addition of ace-
tone, cyclohexanone, and isobutyraldehyde
to β‐nitrostyrene
A mixture of organocatalyst (homogeneous catalysis
10 mol % or heterogeneous catalysis 20 mol %) and
Michael donor (6.0 eq) (acetone, cyclohexanone and
isobutyraldehyde) in dichloromethane (4 mL) was mixed
and stirred at room temperature for 2 hours in a screw‐
capped vial. β‐Nitrostyrene (25 mg, 1 eq) was added to
the above solution. Homogeneous catalysis: After
FIGURE 2 Proposed transition state of acetone addition to β‐
nitrostyrene
3
0
120 hours, the volatile material was removed under
2
2
.2 | Synthesis of organocatalysts 1a,b and
a,b was reported previously
reduced pressure to afford the crude product, which was
purified by column chromatography (petroleum ether/
dichloromethane 4:1). Heterogeneous catalysis: After
30
2
.2.1 | General methodology for
120 hours, the immobilized organocatalyst is separated
immobilized organocatalysts 1a,b,c and
a,b,c
by filtration; the filtrate was evaporated under reduced
pressure to afford the products. The enantiomeric
excesses were determined by HPLC, and the absolute
configuration was assigned by comparing the retention
2
Silica gel functionalized with 2‐ethylbenzenesulfonyl
chloride (1 g, 1 mmol/g) in dichloromethane (30 mL) at
31-33
0
2
°C was stirred, while the organocatalysts (1a,b,c and
a,b,c) 4 eq in 40 mL of dichloromethane were slowly
time (t ) with literature values.
For the products of
R
addition of acetone to β‐nitrostyrene, t for enantiomers
R
added into a 250‐mL flask. The reaction mixture was
maintained under stirring for 24 hours at room tempera-
ture in a sealed flask. Then, the reaction crude was
filtrated and washed with dichloromethane (5 × 30 mL),
then dried overnight in an oven under vacuum at 60°C.
S and R are: tR(minor) = 29.5, tR(mayor) = 42.7 minutes,
respectively; for cyclohexanone to β‐nitrostyrene, t for
R
enantiomers SS, RR, RS, and SR are: tR(minor) = 12.1,
tR(mayor) = 18.0, tR(minor) = 17.9, tR(mayor) = 18.1 minutes,
respectively; for isobutyraldehyde to β‐nitrostyrene, tR

4
CRUZ ET AL.
for enantiomers
tR(mayor) = 13.9 minutes, respectively.
S
and
R
are: tR(minor)
=
11.9,
assisting in bringing the reactant together in the transition
state, thereby improving the enantioselectivity. Interest-
ingly, the monosulfonamide organocatalyst 3c derived
from 1,1′‐binaphthyl‐2,2′‐diamine gave low yield and
enantioselectivity (10% and 35%) (Entry 17). This strongly
2
.2.3 | Characterization of the
immobilized organocatalysts by SEM
supports our hypothesis that the two arms of the C ‐sym-
2
The scanning electron microscope (SEM) analyses of ethyl
metric organocatalysts (1c and 2c) must be participating
in the transition state, mimicking an enzyme. This is
further reinforced by density functional calculations of
the transition state involving organocatalyst 2c,
isobutyraldehyde and β‐nitrostyrene (Figure 3), carried
benzenesulfonyl chloride functionalized SiO reagent and
2
SiO ‐supported organocatalysts 6a,b were performed on a
2
VEGA3 scanning electron microscope (Tescan) equipped
with a Bruker 125 eV EDX detector for elemental analysis.
Micrographs were acquired at 15 and 20 KV.
34
out using Gaussian 09, with the B3LYP density functional
35,36
37
theory
and cc‐pVDZ basis set. Our molecular model-
ing shows catalyst 2c forming the enamine with the car-
bonyl reactant, with both arms hydrogen‐bonding to the
oxygens of the β‐nitrostyrene and stabilizing the transition
state, thus resembling an enzyme‐substrate complex.
Success with catalysts 1c and 2c, derived from (R)‐
1,1′‐binaphthyl‐2,2′‐diamine, led us to hypothesize that
surrounding the transition state with more chiral centers,
using structurally analogous catalysts 4a and 4b (derived
from (R)‐1,1′‐naphthyl‐2,2′‐disulfonyl chloride and the
corresponding (R,R)‐diamine) would lead to higher yields
and enantioselectivities in the conjugate 1,4‐Michael
addition. To our surprise, organocatalysts 4a and 4b gave
very low yields and enantioselectivities (Entries 18 and
19). However, when acetone was used as the nucleophile,
moderate yield and good enantioselectivity were observed
(Entry 5, 33% yield and 94% ee).
3
3
| RESULTS AND DISCUSSION
.1 | Homogeneous catalysis
The synthesized organocatalysts (1c, 2c, 3c, 4a, and 4b,
Scheme 2) were evaluated in the conjugate 1,4‐Michael
addition
isobutyraldehyde to β‐nitrostyrene; the results are
displayed in Table 1. Using organocatalysts 1c and 2c,
derived from (R)‐1,1′‐binaphthyl‐2,2′‐diamine, in the
of
acetone,
cyclohexanone,
and
1
,4‐Michael addition of acetone (Entries 3 and 4), gave
the addition product in yields of 48% and 98% with mod-
erate enantioselectivities (46% and 57%, respectively). In
addition, organocatalysts 1c and 2c gave moderate
diastereoselectivities in the 1,4‐Michael addition of cyclo-
hexanone
enantioselectivities for the anti addition products (Entries
and 10). The organocatalysts 2a and 2b gave moderate
to
β‐nitrostyrene
and
excellent
Density functional calculations on the geometry of the
transition state for organocatalyst 4a, isobutyraldehyde,
7
34-39
yields but excellent anti diastereoselectivity with
enantioselectivity greater than 97% (Entries 8 and 9).
However, with isobutyraldehyde as nucleophile, the
reaction carried out under identical conditions gave prod-
ucts in good to excellent yields (78% and 98%) and
enantioselectivities (93% and 96%) for 1c and 2c, respec-
tively (Entries 13 and 16). Furthermore, the results indicate
a progressive increase in the enantioselectivities for
organocatalysts 2a, 2b, and 2c (derived from (1R,2R)‐1,2‐
and β‐nitrostyrene
indicated that one arm
(NH―SO ―) of the catalyst strongly hydrogen‐bonded
2
to one oxygen of the second arm (―SO ―) of the catalyst
2
(Figure 4). This interaction restricts the groove space
available for the nitroolefin to hydrogen bond to the sul-
fonamide, and this probably leads to lower yields and
enantiomeric excess.
3.2 | Heterogeneous catalysis
diphenylethane‐1,2‐diamine,
(1R,2R)‐1,2‐cyclohexane
diamine and (R)‐1,1′‐binaphthyl‐2,2′‐diamine, respec-
Having shown the usefulness of C ‐symmetric ligands (1a,
2
tively), when isobutyraldehyde is used as nucleophile
b,c and 2a,b,c) as excellent homogeneous organocatalysts
in the conjugate 1,4‐Michael addition of carbonylic type of
compounds to nitrolefin, we turned our attention to
(Entries 14, 15, and 16). Results suggest that steric bulki-
ness of the nucleophile and the organocatalysts must be
FIGURE 3 Geometry of PRO‐R
transition state of isobutyraldehyde
addition to β‐nitrostyrene involving an
interaction between both hydrogens of the
two arms on organocatalyst 2c

CRUZ ET AL.
5
FIGURE 4 Geometry of transition state of isobutyraldehyde addition to β‐nitrostyrene on organocatalyst 4a
SCHEME 3 Immobilized organocatalysts 5a,b,c and 6a,b,c
a
TABLE 2 Heterogeneous 1,4‐Michael addition of aliphatic ketones and isobutyraldehyde to β‐nitrostyrene using organocatalysts 6a‐b
b
c
c
Entry
Organocatalyst
Nucleophile
Yield, %
ee, %
dr (syn: anti)
Product and Configuration
1
2
6a
6b
45
41
35
26
‐
‐
3
4
6a
6b
86
82
70
66
100:0
100:0
5
6
6a
6b
74
69
75
74
‐
‐
a
All entries are for 20 mol % in dichloromethane over 5 days.
b
Yields were determined by HPLC Agilent Technologies 1220 Infinity LC column CHIRALPAK AS‐H 0.46 cm φ × 25 cm, flow 1 mL/min. For Entries 1–4,
k = 210 nm and mobile phase 65:35 (Hex/iPrOH) were used. For Entries 5‐6, λ = 220 nm and mobile phase 10:1 (Hex/iPrOH) were used.
c
31-33
R
Enantiomeric excesses were determined by HPLC, and the absolute configuration was assigned by comparing t with literature values.

6
CRUZ ET AL.
immobilizing these organocatalysts onto silica and explor-
Enantiopure organocatalysts (1a,b,c and 2a,b,c) were
immobilized onto silica using 4‐(ethylbenzene)sulfonyl‐
silica gel to afford immobilized organocatalyst (5a,b,c
and 6a,b,c) (Scheme 3) and tested for their catalytic prop-
erties in the conjugate carbonylic addition to β‐
nitrostyrene. Surprisingly, the organocatalysts 1c and 2c,
which behaved as excellent homogeneous catalysts
ing
their
catalytic
properties.
Heterogenized
organocatalysts offer many advantages, such as, easy sepa-
ration, recyclability, and pores on the silica surface which
may mimic natural enzymes; for these reasons,
immobilized chiral organocatalysts for asymmetric cataly-
40-44
sis have attracted a great deal of attention.
FIGURE 5 SEM and EDX analysis: A, silica gel immobilized organocatalyst 6a (2‐μm magnification) SEM micrograph and B, EDX
spectrum
FIGURE 6 EDX mapping of silica gel immobilized organocatalyst 6a showing: A, N‐S, and B, N‐C
TABLE 3 Results of EDX elemental analysis and relative percentages of immobilized organocatalyst 6a
Element
Series
Norm. C, wt.%
Norm. C, at.%
Error (3 sigma), wt.%
Oxygen
Carbon
Silicon
Sulfur
K‐series
K‐series
K‐series
K‐series
K‐series
45.77
21.48
26.00
4.15
48.57
30.36
15.72
2.20
25.67
18.32
3.92
0.79
Nitrogen
2.60
3.15
4.98

CRUZ ET AL.
7
(
Entries 13 and 16), on immobilization (5c and 6c) led to
in the transition state, mimicking an enzyme, and those
steric factors of the nucleophile and catalyst play a role
in improving yields and enantiomeric excess. Immobiliza-
tion of homogeneous organocatalysts 2a and 2b to obtain
the immobilized organocatalysts 6a and 6b with a biphe-
nyl linker group also gave good yields (69%‐86%) and
enantioselectivities (66%‐75%) when cyclohexanone and
isobutyraldehyde were used in the heterogeneous 1,4‐
Michael addition to β‐nitrostyrene. Furthermore, in the
enantioselective conjugate 1,4‐Michael addition of cyclo-
hexanone to β‐nitrostyrene, the silica gel‐immobilized
ligands reverse the diastereoselectivity of the final prod-
ucts compared with the homogeneous conditions. This
provides a methodology for making both diastereomers
with the same catalyst by changing from homogenous
to heterogeneous conditions.
low yields and racemic mixtures of the final product.
Likewise, immobilized organocatalysts 5a,b also gave
low yields (~25%) and enantioselectivities (<15%). This
low activity of these immobilized catalysts may be attrib-
uted to conformation, intermolecular and intramolecular
hydrogen bonding to the ligand itself and to silica gel,
hindering the transition state formation, similar to
Figure 4. However, immobilized organocatalysts 6a,b
with a biphenyl linker catalyzed and gave moderately
good yields and enantioselectivities with various carbon-
ylic compounds in the addition to β‐nitrostyrene
(Table 2). These results suggest that linker groups play a
role in distancing the active sites from the silica gel sur-
face. Interestingly, in the enantioselective conjugate 1,4‐
Michael addition of cyclohexanone to β‐nitrostyrene, the
silica gel immobilized organocatalysts 6a and 6b, under
heterogeneous conditions gave the syn diastereomer with
a moderate enantiomeric excess. Thus, reversing the
diastereoselectivity of the final product, compared with
the homogeneous reaction (Table 2, entries 3 and 4 vs
Table 1, entries 8 and 9). This provided an easy access
to making the two diastereomers of the final products.
Reactions with the heterogeneous catalysts were carried
out with 20 mmol % loading, and organocatalyst 6a was
recycled three times in the isobutyraldehyde reaction with
only slight loss in the yield and enantioselectivity (~2%).
ACKNOWLEDGMENTS
We gratefully acknowledge support for this project by
Consejo Nacional de Ciencia y Tecnología (CONACyT
Grant 224405) and for Instituto Tecnológico de Tijuana
(ITT) NMR facilities (Grant INFR‐2011‐3‐173395). H.
Cruz acknowledge support from CONACyT in the form
of graduate scholarships.
ORCID
Ratnasamy Somanathan
220-082X
http://orcid.org/0000-0003-
3
.3 | Characterization of the immobilized
1
organocatalyst
SEM micrograph and EDX spectra of organocatalyst 6a
are shown in Figure 5. The nitrogen atom of the sulfon-
amide group in the silica gel immobilized organocatalyst
was determined by EDX (Figure 5B). Figure 6 shows
EDX results by mapping the surface for N―S and N―C,
confirming the lower relative signals of N with respect
to S and C. This agrees with the chemical composition
of the catalyst. Relative percentages of C, N, S, O, and Si
determined on the surface of the silica gel are shown in
Table 3. The occurrence of N and absence of chlorine
confirm the presence of the immobilized organocatalyst
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