Synthesis of a New N-Diaminophosphoryl-N'-[(2S)-2-pyrrolidinylmethyl]thiourea as a Chiral Organocatalyst for the Stereoselective Michael Addition of Cyclohexanone to Nitrostyrenes and Chalcones – Application in Cascade Processes for the Synthesis of Polyc

Article abstract of DOI:10.1002/ejoc.201801339

A highly diastereoselective and enantioselective Michael addition of enolizable ketones such as cyclohexanone and acetophenone to a variety of substituted trans-?-nitrostyrenes and chalcones was catalyzed by a novel chiral and unsymmetrical thiourea as or

Full text of DOI:10.1002/ejoc.201801339

A Journal of
Accepted Article
Title: Synthesis of a New N-Diaminophosphoryl-N´-[(2S)-2-
pyrrolidinylmethyl]thiourea as a Chiral Organocatalyst for
the Stereoselective Michael Addition of Cyclohexanone to
Nitrostyrenes
Authors: Carlos Cruz-Hernandez, Eduardo Martinez-Martinez, Perla E.
Hernandez-Gonzalez, and Eusebio Juaristi
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801339
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801339
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10.1002/ejoc.201801339
European Journal of Organic Chemistry
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Synthesis of a New N-Diaminophosphoryl-N´-[(2S)-2-
pyrrolidinylmethyl]thiourea as a Chiral Organocatalyst for the
Stereoselective Michael Addition of Cyclohexanone to
Nitrostyrenes and Chalcones - Application in Cascade Processes
for the Synthesis of Polycyclic Systems
Carlos Cruz-Hernández,[a] Eduardo Martínez-Martínez,[a] Perla E. Hernández-González,[a] and Prof. Dr.
Eusebio Juaristi.*[a,b]
Dedication ((optional))
Abstract: A highly diastereoselective and enantioselective Michael
addition of enolizable ketones such as cyclohexanone and
acetophenone to a variety of substituted trans-β-nitrostyrenes and
chalcones was catalyzed by a novel chiral and unsymmetrical
thiourea as organocatalyst in the presence of water or under neat
reaction conditions. The anticipated Michael adducts, γ-nitrocarbonyl
adducts and 1,5-dicarbonyl derivatives, were obtained in up to 98:2
diastereomeric ratio and up to 96% enantiomeric excess. The
application of this new chiral organocatalyst was extended to an
asymmetric Michael addition-proton transfer-aldol reaction cascade
process, a formal [3+3] cyclization reaction of cyclohexanone with
arylidenepyruvates, with high stereoselectivity. The organocatalyst
reported here is one of the very few able to promote the above
cascade process, providing the important bicyclic framework that is
found in many natural products.
organocatalysis has proved to be very useful since both activation
strategies can be applied simultaneously to activate and bring in
close proximity the reactants. In this context, many bifunctional
organocatalysts have been developed to promote aldol, Michael
and Mannich reactions, among other relevant reactions.[5]
Conjugate addition to α,β-unsaturated carbonyl compounds,
known as Michael addition reaction, is an important synthetic
procedure to create C-C bonds. Michael products normally
present functional groups that can be used for subsequent
transformations and most importantly, the reaction generates one
or two new stereogenic centers in a single operation. These
characteristics render the Michael addition reaction a central
strategy for gaining access to useful bioactive compounds.[6] The
enantioselective organocatalytic version has been extensively
and successfully performed in a variety of systems,[7] usually by
means of chiral bifunctional catalysts incorporating a hydrogen
bond donor such as sulphonamide, amide, squaramide, urea, or
thiourea to activate the Michael acceptors, in combination with an
amine (Brønsted base) to promote nucleophile activation. In this
regard, prolinamine derivatives, for example compounds with the
(2S)-2-pyrrolidinylmetanamine fragment, are among the most
widely used as result of the privileged pyrrolidine segment that
readily participates in iminium-enamine activation.
Introduction
Asymmetric organocatalysis has turned into an important and
practical strategy for the preparation of chiral compounds in high
enantiopurity and good yields, under mild reaction conditions.[1]
Since its rediscovery[2] by List, et al.[3a] and McMillan and co-
workers,[3b] the main activation modes for organocatalytic
processes have been established.[4] In particular, covalent
interactions are involved in iminium-enamine chemistry,[4a-d]
whereas non-covalent interactions such as hydrogen bonding or
electrostatic attraction take place in, for example, Brønsted acid-
In connection with the present work, an important additional
characteristic of Michael reactions is that they give rise to a
nucleophilic adduct that in the presence of suitable electrophiles
can further participate in both inter- or intramolecular cascade
processes, giving rise to a more complex system and with
formation of additional centres of chirality.[8]
catalysed
reactions.[4e-h] In this context,
bifunctional
Inspired by the fact that the thiourea functionality has proved to
be an excellent promoter of the Michael addition reaction, we
contemplated the synthesis of a new chiral N-phosphoryl-N´-
pyrrolidinylmethyl thiourea. Important structural features of the
proposed catalyst should include (a) the presence of a chiral
hydrophobic bicyclic phosphorodiamide moiety, which on one
hand increases the thiourea N-H bond acidity, and on the other
allows to exploit potential hydrophobic interactions in reactions
performed in the presence of water.[9] This kind of structure has
[a]
[b]
Departamento de Química,
Centro de Investigación y de Estudios Avanzados,
Avenida IPN 2508, 07360 Ciudad de México, Mexico
E-mail: juaristi@relaq.mx, ejuarist@cinvestav.mx
http://www.relaq.mx/RLQ/EusebioJuaristi.html
El Colegio Nacional
Luis González Obregón 23, Centro Histórico, 06020 Ciudad de
México, Mexico.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801339
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been employed by G. Li et al.[10] to perform the so-called Group
Assisted Purification (GAP) procedure, an important methodology
used to reduce the amount of solvents employed during product
purification by avoiding the use of column chromatography. (b)
The organocatalyst’s structure should include the pyrrolidine ring,
a most important segment present in emblematic activators used
for enamine activation.[1-6] (c) Finally, the presence of a thiourea
functionality as an efficient bidentate hydrogen bond donor is
essential[5d,11c] (Figure 1).
The enantiopure catalyst was evaluated in the asymmetric
Michael addition of ketones (cyclohexanone and acetophenone)
to trans-β-nitrostyrenes[11,15] as well as chalcones.[16] Additionally,
the new catalyst was examined in an enantioselective cascade
process, namely an asymmetric Michael addition-proton transfer-
stereoselective aldol addition sequence between cyclohexanone
and methyl esters of arylidenepyruvates to provide highly
valuable bicyclic adducts.[8d]
The presence of more than one stereogenic carbon atoms in the
proposed catalyst could give rise to a match/mismatch effects.[12]
Nevertheless, previous work with related structures that are able
to catalyse the asymmetric aldol reaction between cyclohexanone
Results and Discussion
2.1 Synthesis of organocatalyst (1R,2R,1’R,2’R,2’’S)-6
and
isatins[13a]
as
well
as
cyclohexanone
and
The synthesis of the proposed organocatalyst envisioned the
arylcarbaldehydes[13b] have shown that the stereochemical
outcome is directly related to the stereochemistry of the proline
segment, whereas the configuration at the phosphoramide moiety
does not influence the observed asymmetric induction. These
observations are in line with previous reports of Ellman’s,[14a]
Hao[14b] and our own group.[11y] Based on this precedent it was
decided to examine exclusively the chiral catalyst with the
configurations shown in Figure 1 and Scheme 1, that is
(1R,2R,1’R,2’R,2’’S)-6.
condensation of two advanced molecular fragments in
convergent approach. In particular, the previously described
triphosphoramide (1R,2R,1’R,2’R)-2[13] and isothiocyanate 4,[17]
a
synthesized from (S)-prolinamine
3 according to literature
protocol[18] were coupled in a one-pot two-reactions process via
formation of the lithium salt of phosphoramide 2 with n-BuLi, to
give
the
desired
N-Boc
protected
pre-catalyst
(1R,2R,1’R,2’R,2’’S)-5. Finally, the protecting group in 5 was
removed with TFA followed by neutralization with ammonium
hydroxide to gain access to the active catalyst
(1R,2R,1’R,2’R,2’’S)-6 (Scheme 1).
Figure 1. Structural characteristics of the bifunctional organocatalyst developed in the present work.
Scheme 1. Synthesis of bifunctional organocatalyst (1R,2R,1’R,2’R,2’’S)-6.
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In addition to the preparation of catalyst (1R,2R,1’R,2’R,2’’S)-6
we also carried out the synthesis of N-phosphorodiamidic
thiourea (1R,2R,1’R,2’R)-7, which lacks the chiral pyrrolidine
moiety. Thiourea (1R,2R,1’R,2’R)-7 was deemed important to
establish the importance of the chiral pyrrolidinic segment on the
stereoinducing efficiency of organocatalyst (1R,2R,1’R,2’R,2’’S)-
6. The synthesis of (1R,2R,1’R,2’R)-7 followed the same reaction
sequence developed for the preparation of (1R,2R,1’R,2’R,2’’S)-
6, but employing phenyl isothiocyanate instead of isothiocyanate
(S)-4 (Scheme 2).
cyclohexanone to trans-β-nitrostyrene. The reaction was
performed with 10% mol of catalyst and with benzoic acid as
additive, both under neat conditions and in water solvent at room
temperature (Table 1, entries 1 and 2). To our surprise both
reaction conditions afforded good results in terms of reaction rate
and selectivity; nevertheless, the reaction in water showed slightly
better diastereomeric ratio in the isolated product, possibly as
consequence of hydrophobic effects provoked by augmented
steric and electronic interactions in the transition state.[9,13] The
essential role played by benzoic acid as additive was examined
finding that in the absence of this Brønsted acid no reaction takes
place, even after 120 hours (entry 3 in Table 1). This observation
is in line with a lack of formation of the required enamine
intermediate, for which the acid additive plays an important
role.[19] On the other hand, catalyst (1R,2R,1’R,2’R)-7 was
evaluated using, in addition to benzoic acid, 10 mol% of
pyrrolidine to facilitate the formation of the required enamine
(Table 1, entry 4). As it can be observed, the reaction proceeded
with very high diastereoselectivity although with very low
enantioselectivity, affording essentially racemic product.
Evaluation of catalyst load (Table 1, entries 2, 5, 6 and 7) revealed
that 7 mol% of catalyst and additive are appropriate
Scheme 2. Synthesis of catalyst (1R,2R,1’R,2’R)-7.
to provide satisfactory results in terms of reaction yield and
stereoselectivity. Finally, it was established that 7 equivalents of
substrate cyclohexanone are necessary to carry out the process
with good yield and high stereoselectivity (Table 1, entries 5, 8
and9).
2.2 Michael addition of cyclohexanone to trans-β-
nitrostyrenes
Preliminary evaluation of the new organocatalysts was
undertaken in the asymmetric Michael addition reaction of
Table 1. Optimization of the asymmetric Michael addition of cyclohexanone to trans-β-nitrostyrene catalysed by thiourea (1R,2R,1’R,2’R,2’’S)-6.
Entry
Cat.* (mol%)
6 (10)
6 (10)
6 (10)
7 (10)
6 (7)
BzOH (mol%)
8 (equiv.)
Solvent
Neat
H2O
t (h)
14
Yield (%)[a]
dr (syn/anti)[b]
er[c]
92:8
92:8
-
1
2
3
4
5
6
7
8
9
10
10
-
10
10
10
10
10
10
10
7
98
98
-
88:12
96:4
-
14
H2O
120
14
10[d]
7
H2O
85
93
87
-
94:6
97:3
85:15
-
49:51
94:6
89:11
-
H2O
14
6 (5)
5
H2O
32
6 (2)
2
H2O
96
6 (7)
7
H2O
16
90
88
98:2
97:3
93:7
92:8
6 (7)
7
5
H2O
16
Reactions performed with 0.2 mmol of β-nitrostyrene and 1.0 mL of water at room temperature. [a] Yield of pure, isolated product containing both diastereomers.
[b] Determined by 1H NMR analysis of crude product. [c] Determined by chiral HPLC of the isolated product. [d] Pyrrolidine (10 mol%) was also added.
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The scope of the reaction was then examined with several
substituted trans-β-nitrostyrenes as substrate, under the best
reaction conditions (cf. Table 1, entry 8). It can be appreciated
(Table 2) that in most cases both the diastereo- and
enantioselectivity are quite good.
of canonical reactive forms I or II, which activate the benzylic
position for the nucleophilic attack giving the desired Michael
adduct (Figure 2). By contrast, derivatives 9b and 9f cannot
generate this activated form and therefore the reactions yields are
lower. Methoxy and benzyloxy groups in 9l and 9m induce the
favourable activation mode and hence high reaction yields.
Table 2. Scope of catalyst (1R,2R,1’R,2’R,2’’S)-6 in the Michael addition of
cyclohexanone to substituted trans-β-nitrostyrenes.[a]
Figure 2. Michael acceptor activation by conjugation with lone electron pairs in
substituent X.
We then turned our attention to other nucleophiles such as
acetone and iso-butyraldehyde. The reaction with acetone was
unsuccessful in water but gave the corresponding product under
neat conditions at room temperature; nevertheless, the
enantioselectivity was poor (Scheme 3). On the other hand, iso-
butyraldehyde substrate did not afford the Michael addition
product regardless of the reaction medium.
Scheme 3. Evaluation of acetone as nucleophile in the organocatalytic Michael
addition to nitrostyrene.
2.3 Michael addition of cyclohexanone to chalcones
To increase the electrophile scope we turned our attention to the
Michael addition of cyclohexanone to chalcones, a reaction that
commonly requires high catalyst loadings as well as long reaction
times.[16] This transformation was performed with catalyst
[(1R,2R,1’R,2’R,2’’S)-6, 7% mol] (Table 3). The reaction in water
turned out to be too slow (entry 1); nevertheless, under neat
conditions it gave very good stereoselectivity but poor yield even
after eight days of reaction (entry 2). To improve the reaction yield,
both the amount of catalyst and additive loading were increased
to 15 % (entry 3). Under these conditions both reaction yield and
stereoselectivity were improved. On the other hand, an increase
of the reaction temperature to 65 °C, resulted in a decrease in
diastereoselectivity (entry 4). Finally, the addition of Lewis
acids[20] (entries 5 and 6) afforded only traces of the desired
product.
Reactions performed with 0.2 mmol of the corresponding β-nitrostyrene, 1.4
mmol of cyclohexanone and 0.014 mmol of Cat.* 6 and BzOH in 1.0 mL of
water at rt [a] Yield of pure, isolated product containing both diastereomers.
dr Determined by 1H NMR analysis of crude. Enantiomeric ratio er
determined by chiral HPLC of the isolated product.
Although the stereoselectivity achieved in this process was
generally quite good (Table 2), the reaction yield was not always
satisfactory. This is particularly true with the 3-halo substituted
derivatives (products, 10b and 10f). On the other hand, the
reaction rate enhancement observed with derivatives presenting
groups with free pairs of electrons could be due to the formation
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Table 3. Optimization of asymmetric Michael addition of cyclohexanone to chalcone catalysed by thiourea (1R,2R,1’R,2’R,2’’S)-6.
Entry
6 / BzOH (mol%)
Solvent
H2O
Lewis acid
T (°C)
25
t (days)
Yield (%)[a]
dr (syn/anti)[b]
er[c]
-
1
2
3
4
5
6
7
-
8
8
7
3
4
4
Trace
12
-
96:4
98:2
85:15
-
7
Neat
Neat
Neat
Neat
Neat
-
25
95:5
98:2
92:8
-
15
15
15
15
-
-
25
48
65
34
CuI
25
Trace
-
Yb(OTf)3
25
-
-
Reactions performed with 0.2 mmol of chalcone and 1.0 mL of water or 1.4 mmol of cyclohexanone. [a] Yield of pure, isolated product containing both
diastereomers. [b] Determined by 1H NMR analysis of crude product. [c] Determined by chiral HPLC of the isolated product.
Best reaction conditions consisted of 15 %mol of catalyst and
Table 4. Scope of catalyst (1R,2R,1’R,2’R,2’’S)-6 in the Michael addition of
cyclohexanone to substituted chalcones.[a]
15 %mol of benzoic acid as additive under neat conditions (ten
equivalents of cyclohexanone) at room temperature (Table 4). As
it can be appreciated, most reactions proceeded with good
stereoselectivity, although in the case of nitro substituted
derivatives the Michael addition products were obtained with poor
diastereoselectivity, which may be due to a competing interaction
between the nitro substituent and the carbonyl group in the
chalcone with the thiourea segment in catalyst 6
Reactions performed with 0.2 mmol of the corresponding chalcone, 2.0 mmol of
cyclohexanone, 0.028 mmol of cat.* 6 and BzOH at rt. [a] Yield of pure, isolated
product containing both diastereomers. dr Determined by 1H NMR analysis of
crude. er Determined by chiral HPLC of the pure product.
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2.4 Michael addition reaction of acetophenone to trans-β-
nitrostyrenes
2.5 Plausible catalytic cycle as evidenced by the
stereochemical outcome of the Michael addition reactions
To further explore the scope of catalyst (1R,2R,1’R,2’R,2’’S)-6, it
was decided to examine the addition of acetophenone to β-
nitrostyrenes, a transformation usually reserved for primary amine
catalysts.[15] To overcome the lower reactivity of the secondary
amine present in catalyst (1R,2R,1’R,2’R,2’’S)-6, it was decided
to increase the concentration of catalyst to 15 % mol both in water
and under neat reaction conditions. As it turned out, water solvent
gave only trace amounts of product, whereas neat reaction
conditions afforded modest yields but with very good
stereoselectivity (cf. product 16a in Table 5). Table 5 summarizes
the results of six illustrative examples where the substituents in
the Michael acceptor were varied. Electron withdrawing
substituents at position two afforded better yields (products 16c
and 16d) relative to the same kind of substituents at position 4
(16e and 16f). Furthermore, the enantioselectivity was rather
good in all cases.
Tables 2 and 4 reveal similar trends in the stereochemical
outcome of the reaction. In particular, syn diastereomers are
favoured in both processes giving rise to the (1S,1’R) enantiomer
as the major product. Furthermore, the addition of acetophenone
to nitrostyrenes afforded the (R) enantiomeric products (Table 5).
It is apparent that both processes follow a similar catalytic
pathway. Figure 3 depicts the proposed catalytic cycle based on
literature precedent,[21] and that is in agreement with the
stereochemical outcome of the experiments. In the presence of
benzoic acid, catalyst (1R,2R,1’R,2’R,2’’S)-6 condenses with the
pro-nucleophilic ketone (cyclohexanone or acetophenone) giving
rise to the s-trans-enamine
A and a
water molecule.[21]
Subsequently, chalcone or nitrostyrene (Michael acceptor) is
hydrogen bonded to the thiourea moiety to afford intermediate B,
where both reaction partners are activated and are positioned
closely enough to react. Bond formation proceeds with like topicity
via Re/Re attack of the enamine to the electrophile. Finally, the
product separates and the catalyst is regenerated by means of
acid-catalysed hydrolysis.
Table 5. Scope of catalyst (1R,2R,1’R,2’R,2’’S)-6 in the Michael addition of
acetophenone to substituted trans-β-nitrostyrenes.[a]
Figure 3. Plausible catalytic cycle of the Michael addition reaction with chiral
urea (1R,2R,1’R,2’R,2’’S)-6.
2.6 Formal [3+3] cyclization reaction through a Michael
addition-proton transfer-aldol cascade sequence
Reactions performed with 0.1 mmol of the corresponding β-nitrostyrene, 0.7
mmol of acetophenone, 0.015 mmol of cat.* 6 and 0.015 mmol of benzoic
acid at room temperature. [a] Yield of pure, isolated product containing both
diastereomers. er Determined by chiral HPLC of the isolated product.
It is well known that Michael adducts can take part in subsequent
transformations via cascade processes that afford more complex
and valuable products.[8] In this regard, our group recently
reported the application of
organocatalyst[11z] in Tang’s formal (3+3) annulation,[8d] a cascade
process that provides chiral 2-hydroxy-9-oxo-
a chiral ionic liquid (CIL) as
bycliclo[3.3.1]nonane derivatives via the Michael addition of
cyclohexanone´s nucleophilic enamine to phenylidenepyruvate
methyl ester, followed by proton transfer and final intramolecular
aldol addition (Figure 4).
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fourth step in the reaction involves intramolecular proton transfer
forming an enamine that attacks the carbonyl group already
activated by the thiourea segment (cf. D’) in a stereoselective
aldol reaction that gives rise to the final stereocenters. In this
regard the enamine is restricted to add on its Si face, but the
carbonyl could be attacked on both prochiral faces. Nevertheless,
the highly selective Si attack is a consequence of the tight
conformational arrangement induced by the hydrogen bonding
interaction between the thiourea and the ketone’s oxygen atom.
In the final step the product and the catalyst are released by acid
catalysed hydrolysis.
Figure 4. Formal (3+3) cyclization reaction of cyclohexanone with benzylidene
pyruvate methyl ester.
Thus, it was decided to examine the efficiency of catalyst
(1R,2R,1’R,2’R,2’’S)-6 in this cascade process, employing three
different arylidenepyruvate methyl esters, with benzoic acid as
additive in water solvent at ambient temperature (Table 6). In the
event, all three Michael acceptors reacted with excellent
enantioselectivity to afford the desired product 18a-c in moderate
yields.
Table 6. Organocatalytic formal (3+3) cyclization reaction through Michael
addition–proton
transfer–aldol
reaction
of
cyclohexanone
with
arylidenepyruvate methyl esters.[a,b]
Figure 5. Proposed catalytic cycle for the formal [3+3] cascade cyclization.
Conclusions
Novel chiral organocatalyst (1R,2R,1’R,2’R,2’’S)-6 proved
efficient in asymmetric Michael addition reactions in aqueous
media. Importantly, this organocatalyst was able to facilitate the
addition of enolizable ketones such as cyclohexanone or
acetophenone to a variety of Michael acceptors. For example,
addition to trans-β-nitrostyrenes gave rise to γ-nitrocarbonyl
compounds, valuable starting material for the synthesis of chiral
pyrrolidine derivatives, among others. Furthermore, the
enantioselective addition to chalcones afforded highly valuable
1,4-dicarbonyl compounds, that are very useful for the
preparation of heterocyclic derivatives. Finally, organocatalyst
(1R,2R,1’R,2’R,2’’S)-6 was evaluated on the addition to
arylidenepyruvate methyl esters providing important bicyclic
cores which are found in many natural products, this by a Michael
addition–proton transfer–aldol reaction cascade process, which
constitutes a formal [3+3] cyclization reaction.
Reactions performed with 0.2 mmol of the corresponding arylidenepyruvate
methyl ester, 1.4 mmol of cyclohexanone, 0.014 mmol of cat.* 6 and 0.014
mmol of benzoic acid in 1.0 mL of water at room temperature. [a] Yield of
isolated product. [b] Enantiomeric ratio determined by chiral HPLC of the
isolated product.
The above cascade process is quite interesting as it provides
highly substituted bicyclic frameworks with up to four well defined
newly created stereocenters. Figure 5 shows a proposed catalytic
cycle based on the stereochemistry of the products as well as
literature precedent.[21] The first three steps involve the Michael
addition process according to the pathway described in Figure 5
(cf. intermediates A’, B’ and C’). This stereochemical pathway is
in accord with the observed formation of the (1S,1’R)
stereoisomeric product via Re/Re prochiral face approach. The
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10.1002/ejoc.201801339
European Journal of Organic Chemistry
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compete consumption of the starting material. The reaction mixture was
poured into a flask with crushed ice, and the product was extracted with
ethyl acetate. The organic layer was dried with sodium sulphate and the
crude product was purified by column chromatography (Hex-EtOAc 100:0
to 90:10 to 80:20) to obtain 0.82 g (1.3 mmol, 71% yield) of pure product
as a white foam. [α]D –25.8, c = 1.44 (CHCl3).
Experimental Section
General
Commercially available reagents were used as received. Anhydrous
solvents were obtained by distillation under the described conditions.[22]
Column chromatography was carried out with Merck Silica Gel (0.040-
0.063 mm). TLC was performed with Merck DC-F254 plates employing UV
light or iodine vapor for visualization. Melting points were measured with a
Büchi B-540 apparatus and are uncorrected. Optical rotations were
measured in an Anton Paar MCP-100 Polarimeter with reagent grade
solvents. IR spectra were recorded on a Varian-640 apparatus. NMR
spectra were obtained with JEOL GSX-270 (270 MHz), Bruker Advance
300 (300 MHz), JEOL Eclipse 400 (400 MHz) and JEOL ECA-500 (500
MHz) spectrometers. High resolution mass spectra (HRMS) were obtained
with a HPLC 1100 coupled to a MSD-TOF Agilent Technologies HR-
MSTOF 1069A. Crystallographic data were collected with Enraf-Nonius
CAD-4 X-ray diffractometer. Diastereoselectivity and enantioselectivity
were measured by chiral HPLC in a Dionex HPLC Ultimate 3000
equipment with UV/Visible detector, diode array, at 210 and 254 nm.
1H-NMR (400 MHz, CDCl3, 20° C): δ = 9.51 (br, 1H); 7.50 (d, J = 7.5 Hz,
2
3
2H); 7.40-7.20 (m, 8H); 6.90 (d, JP-H = 7.7 Hz, 1H); 4.55 (dq, JH-H = 7.1
3
3
3
Hz, JP-H = 15.9 Hz, 1H); 4.28 (dq, JH-H = 7.0 Hz, JP-H = 12.0 Hz, 1H);
4.00-3.73 (m, 2H); 3.55-3.20 (m, 3H); 3.01-2.87 (m, 1H); 2.79-2.67 (m,
1H); 1.97-1.83 (m, 2H); 1.82-1.70 (m, 4H); 1.69-1.67 (m, 1H); 1.66 (d, 3JH-
H = 7.0, 3H); 1.60 (d, 3JH-H = 7.0, 3H); 1.58-1.53 (m, 1H); 1.45 (s, 9H); 1.18-
1.05 (m, 2H); 1.04-0.89 (m, 1H); 0.86-0.72 (m, 1H). 13C-NMR (100.5 MHz,
CDCl3, 20° C): δ = 182.4, 154.6, 144.2, 139.5, 128.5 (3C), 128.1, 127.6,
127.2, 126.9 (2C); 100.0, 79.8, 63.0, 60.8 (d), 56.3 (d), 54.4, 51.6, 47.7,
46.8 (d), 29.8 (d), 29.2, 28.7, 24.1 (d), 22.9, 21.2, 19.4, 14.3, doublets are
due to dynamic effect. 31P-NMR (161.8 MHz, CDCl3, 20° C): δ = 16.6 (d).
2
1H-NMR (400 MHz, DMSO-d6, 20° C): δ = 9.65 (br, 1H); 8.91 (d, JP-H
=
6.7 Hz, 1H); 7.50 (d, J = 6.4 Hz, 2H); 7.43 (d, J = 7.6 Hz, 2H); 7.35-7.25
(m, 4H); 7.23-7.15 (m, 2H); 4.44 (br, 1H); 4.25 (dq, 3JH-H = 6.9 Hz, 3JP-H
=
11.5 Hz, 1H); 3.74 (br, 1H); 3.32-3.15 (m, 4H); 2.60-2.50 (m, 1H); 2.49
Phosphorotriamide (1R,2R,1’R,2’R)-2 and prolinamine (S)-3 were
synthesized as it was previously described.[13,18]
3
(quint, J = 1.6 Hz, 1H); 1.79 (br, 2H); 1.66 (br, 2H); 1.56 (d, JH-H = 7.0,
3
3H); 1.52-1.48 (m, 1H); 1.45 (d, JH-H = 7.0, 3H); 1.42-1.37 (m, 1H); 1.35
(s, 9H); 1.10-0.90 (m, 2H); 0.86-0.75 (m, 1H); 0.63-0.45 (m, 1H). 13C-NMR
(100.5 MHz, DMSO-d6, 20° C): δ = 183.3, 146.6, 141.6, 128.6, 128.0,
127.5, 127.1, 126.9, 79.7, 79.0, 62.0, 61.4, 56.7, 54.2, 51.7, 47.1, 46.8,
29.8, 28.3, 28.7, 24.4, 24.1, 23.0, 21.5, 20.5. 31P-NMR (161.8 MHz,
Synthesis of (2S)-2-(isothiocyanatomethyl)-1-pyrrolidinecarboxylic
acid-1,1-dimethylethyl ester, (S)-4. In a round bottom flask equipped
with magnetic stirrer and under argon atmosphere 1.24 g (6.2 mmol) of
diamine (S)-3 was dissolved in 20 mL of dry THF. The resulting mixture
was cooled to 4° C in an ice bath before the addition of 0.61 g (8.0 mmol,
0.5 mL) of carbon disulphide followed by 3.8 g ((37.1 mml, 5.2 mL of
triethylamine. The reaction mixture was stirred for 10 minutes at room
temperature, then it was cooled at 4° C before treatment with 1.3 g (6.8
mmol) of p-toluenesulphonyl chloride and the resulting mixture was stirred
at this temperature for an additional 30 minutes. The work up was as
follows, 40 mL of dichloromethane was added, the organic layer was
washed with a 10% citric acid solution (2X30 mL) then with water and brine.
The organic layer was dried with sodium sulphate and the crude product
was purified by column chromatography (Hex-EtOAc; 100:0 to 95:5 to
90:10 to 85:15) to obtain 0.79 g (3.3 mmol, 53% yield) of pure product as
a light-yellow oil. [α]D –134.4, c = 1.07 (CHCl3).
1
DMSO-d6, 20° C): δ = 17.6. H-NMR (400 MHz, DMSO-d6, 100° C): δ =
9.54 (t, J = 5.2 Hz, 1H); 8.33 (br, 1H); 7.51 (d, J = 7.5 Hz, 2H); 7.44 (d, J =
7.2 Hz, 2H); 7.34-7.26 (m, 4H); 7.24-7.16 (m, 2H); 4.48 (dq, 3JH-H = 7.0 Hz,
3
3JP-H = 14.0 Hz, 1H); 4.29 (dq, JH-H = 7.1 Hz, 3JP-H = 12.2 Hz, 1H); 3.85-
3.70 (m, 2H); 3.58-3.48 (m, 1H); 3.34-3.20 (m, 3H); 2.67-2.58 (m, 1H); 2.49
(quint, J = 1.9 Hz, 1H); 1.90-1.78 (m, 2H); 1.74-1.63 (m, 3H); 1.60 (d, 3JH-
H = 7.0, 3H); 1.58-1.53 (m,1H); 1.51 (d, 3JH-H = 7.0, 3H); 1.47-1.45 (m, 1H);
1.39 (s, 9H); 1.13 (cq, J = 3.5, 12.0 Hz, 1H); 1.05 (ct, J = 3.6, 13.1 Hz, 1H);
0.89 (ct, J = 3.7, 13.1 Hz, 1H); 0.68 (cd, J = 3.1, 12.2 Hz, 1H). 13C-NMR
(100.5 MHz, DMSO-d6, 100° C): δ = 183.7, 154.2, 146.1, 141.6, 128.5,
128.1, 127.4, 127.1, 79.6, 79.1, 62.0 (d, JP-C = 9.8 Hz), 61.6 (d, JP-C = 4.6
Hz), 56.7, 54.2, 52.0, 47.5, 47.0, 29.9 (d, JP-C = 9.2 Hz), 29.1, 28.8, 24.4,
24.2, 23.4, 21.4, 20.2. 31P-NMR (161.8 MHz, DMSO-d6, 100° C): δ = 17.5.
HR ESI-TOF: m/z [M + H]+ calcd for [C33H48N5O3PS + H]+ : 626.328827;
found: 626.328917 (error = 0.142832 ppm).
1H-NMR (500 MHz, CDCl3): δ = 3.87 (br, 1H); 3.77 (dd, J = 5.0, 13.2 Hz,
1H); 3.55 (br, 1H); 3.36 (br, 1H); 3.30 (br, 1H); 2.00 (br, 1H); 1.88-1.73 (m,
3H), 1.38 (s, 9H). 13C-NMR (125.8 MHz, CDCl3): δ = 154.5, 131.5, 80.0 (d),
56.5, 47.7 (d), 47.0 (d), 29.1 (d), 28.5, 23.4 (d), doublets are due to
dynamic effect. 1H-NMR (400 MHz, DMSO-d6, 20° C): δ = 3.95-3.78 (m,
2H); 3.72-3.61 (m, 1H); 3.34-3.16 (m, 2H); 2.07-1.65 (m, 1H); 1.91-1.80
(m, 1H); 1.79-1.69 (m, 2H): 1.40 (s, 9H). 13C-NMR (100.5 MHz, DMSO-d6,
20° C): δ = 154.0 (d), 100.0, 79.5 (d), 56.5, 48.5 (d), 47.2 (d), 29.1 (d), 28.6
(d), 23.34 (d), doublets are due to dynamic effect. 1H-NMR (400 MHz,
DMSO-d6, 100° C): δ = 3.95-3,82 (m, 2H); 3.68 (dd, J = 3.0, 14.0 Hz, 1H)
3.41-3.33 (m, 1H); 3.29-3.22 (m, 1H); 2.12-1.99 (m, 1H); 1.94-1.84 (m,
1H); 1.82-1.72 (m, 2H); 1.43 (s, 9H). 13C-NMR (100.5 MHz, DMSO-d6,
100° C): δ = 154.2, 100.0, 79.6, 56.7, 48.3, 47.2, 29.3, 28.7, 23.4.
Hydrolysis of N-Boc protecting group to obtain free catalyst N-
{(3aR,7aR)-octahydro-1,3-bis[(1R)-1-phenyl-ethyl]-1H-1,3,2-
benzodiazaphosphyl-2-oxide}-N´-[(2S)-2-pyrrolidinylmethyl]thiourea
(1R,2R,1’R,2’R,2’’S)-6. In a round bottom flask equipped with magnetic
stirrer 0.8 g (1.28 mmol) of (1R,2R,1’R,2’R,2’’S)-5 was dissolved in 20 mL
of CH2Cl2 and cooled to 4° C before the dropwise addition of 1.46 g (12.8
mmol, 0.98 mL) of trifluoroacetic acid in 5 mL of CH2Cl2. The reaction
mixture was stirred at room temperature for 24 hours until the total
deprotection, which was verified by TLC. Solvent was removed by
distillation and the crude product was dissolved in 20 mL of EtOAc to
subsequently add an excess of ammonium hydroxide. The resulting
mixture was stirred for 30 minutes, then the organic layer was washed with
NaOH 1M (2x10mL), brine and distilled water. The organic layer was dried
with anhydrous sodium sulphate and the solvent removed by distillation.
Crude product was purified by column chromatography (CH2Cl2-MeOH
98:2-95:5-90:10) to obtain 0.66 g (1.26 mmol, 98% yield) of pure product
as a white foam.
Synthesis of protected catalysts (1R,2R,1’R,2’R,2’’S)-5. In a round
bottom flask equipped with magnetic stirrer and under argon atmosphere
0.7 g (1.8 mmol) of phosphorotriamide (1R,2R,1’R,2’R)-2 was dissolved in
dry THF, then the mixture was cooled at 4° C for the dropwise addition of
0.14 g (2.2 mmol, 0.81 mL) of n-BuLi 2.7 M. The resulting mixture was
stirred at 4° C for 20 minutes before the addition of 0.53 g (2.2 mmol) of
isothiocyanate (S)- 4 dissolved in dry THF. The reaction mixture was
stirred at room temperature for 24 hours, until the TLC revealed the
Spectroscopic data of TFA salt of catalyst (1R,2R,1’R,2’R,2’’S)-6. [α]D
–
39.3, c = 0.44 (CHCl3). 1H-NMR (400 MHz, CDCl3, 20° C): δ = 11.32 (br,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801339
European Journal of Organic Chemistry
FULL PAPER
1H); 9.51 (br, 1H); 8.67 (br, 1H); 7.45 (d, J = 7.2 Hz, 2H); 7.38-7.29 (m,
7H); 7.26-7.21 (m, 1H); 6.69 (br, 1H); 4.51 (dq, 3JH-H = 6.8 Hz, 3JP-H = 21.0
Hz, 1H); 4.31 (dq, 3JH-H = 6.9 Hz, 3JP-H = 13.7 Hz, 1H); 3.97 (br, 1H); 3.76-
3.60 (m, 2H); 3.56 (br, 1H); 3.42 (br, 1H); 3.15 (br, 1H); 3.06-2.93 (m, 1H);
2.92-2.83 (m, 1H); 2.17-2.09 (m, 1H); 2.06-1.90 (m, 3H); 1.81-1.74 (m,
1H); 1.70-1.67 (m, 1H); 1.65 (d, 3JH-H = 6.9, 3H); 1.64-1.60 (m, 1H); 1.52
(d, 3JH-H = 7.0, 3H); 1.25-1.08 (m, 3H); 0.99-0.87 (m, 1H). 13C-NMR (100.5
MHz, CDCl3, 20° C): δ = 184.2, 162.3, 143.3, 138.7, 128.6, 128.5, 128.1,
127.4, 127.0, 62.7 (d, JP-C = 11.4 Hz), 60.6 (d, JP-C = 10.0 Hz), 60.3, 53.9,
51.6, 45.9, 44.9, 29.5 (d, JP-C = 8.1 Hz), 29.2 (d, JP-C = 9.6 Hz), 27.9, 24.3,
24.0, 23.9, 20.2, 17.9. 31P-NMR (161.8 MHz, CDCl3, 20° C): δ = 16.5. HR
ESI-TOF: m/z [M + H]+ calcd for [C28H40N5OPS + H]+ : 526.276398; found:
526.276181 (error = -0.412216 ppm).
of cyclohexanone. Finally, 0.01 mmol of morpholine were added and the
mixture was stirred at room temperature for 48 h. The solvent was
removed in a rotary evaporator and the crude product purified by column
chromatography with Hex-EtOAc (100:0 to 80:20).
General procedure for the asymmetric organocatalytic Michael
addition of cyclohexanone to β-nitrostyrenes. In a vial equipped with
magnetic stirrer 7.4 mg (0.014 mmol) of catalyst (1R,2R,1’R,2’R,2’’S)-6,
and 1.7 mg (0.014 mmol) of benzoic acid were suspended in 1 mL of
distilled water, before the addition of 0.14 g (1.4 mmol, 0.14 mL) of
cyclohexanone, and finally 0.2 mmol of the corresponding β-nitrostyrene
was added. The resulting mixture was stirred at room temperature for 16
hours. The product was extracted with EtOAc, the organic layer was dried
with sodium sulphate and the crude product was purified by column
chromatography (Hexane-EtOAc 100:0-95:5-90:10-85:15) to obtain the
corresponding Michael adduct. All products except for 10d have been
previously reported. See Supp Info for NMR spectroscopic determination
of dr, and HPLC chromatograms for determinations of er.
Spectroscopic data of free catalyst (1R,2R,1’R,2’R,2’’S)-6. [α]D –44.2, c =
0.31 (CHCl3). 1H-NMR (400 MHz, CDCl3, 20° C): δ = 9.58 (br, 1H); 7.50 (d,
J = 7.2 Hz, 2H); 7.45-7.30 (m, 7H); 7.27-7.21 (m, 1H); 4.59 (dq, 3JH-H = 7.0
3
3
3
Hz, JP-H = 18.0 Hz, 1H); 4.32 (dq, JH-H = 6.9 Hz, JP-H = 13.2 Hz, 1H);
3.61-3.41 (m, 4H); 3.16-3.06 (m, 1H); 3.04-2.89 (m, 2H); 2.84-2.75 (m,
1H); 2.01-1.93 (m, 1H); 1.92-1.79 (m, 3H); 1.78-1.72 (m, 1H); 1.68 (d, 3JH-
H = 7.0, 3H); 1.66-1.62 (m, 1H); 1.60 (d, 3JH-H = 7.1, 3H); 1.53-1.42 (m, 1H);
1.18-1.01 (m, 3H); 0.90 (cd, J = 2.9, 12.1 Hz, 1H). 13C-NMR (100.5 MHz,
CDCl3, 20° C): δ = 182.6 (d, JP-C = 3.8 Hz), 143.8, 138.9, 128.5, 128.4,
128.2, 127.8, 127.2, 126.9, 62.8 (d, JP-C = 11.2 Hz), 60.5 (d, JP-C = 10.1
Hz), 58.3, 54.0 (d, JP-C = 3.5 Hz), 51.5 (d, JP-C = 3.5 Hz), 49.1, 45.8, 29.7
(d, JP-C = 9.4 Hz), 29.5 (d, JP-C = 8.7 Hz), 28.8, 25.0, 24.2, 23.9, 20.4, 18.8.
31P-NMR (161.8 MHz, CDCl3, 20° C): δ = 15.1. HR ESI-TOF: m/z [M + H]+
calcd for [C28H40N5OPS + H]+ : 526.276398; found: 526.276181 (error = -
0.412216 ppm).
General procedure for Michael addition of cyclohexanone to
chalcones. In a test tube was placed 0.1 mmol of the corresponding
chalcone, 0.01 mmol of benzoic acid, 0.01 of thiourea, 1.0 mmol of
cyclohexanone, and 1.0 mL of ethanol. Finally, 0.01 mmol of Et2NH was
added and the resulting mixture was stirred at 70° C in a Büchi syncore®
equipment for 24 h. The solvent was evaporated, and the crude product
purified by column chromatography with Hex-EtOAc (100:0 to 80:20).
General procedure for the asymmetric organocatalytic Michael
addition of cyclohexanone to chalcones. In a vial equipped with
magnetic stirrer 14.8 mg (0.028 mmol) of catalyst (1R,2R,1’R,2’R,2’’S)-6
and 3.4 mg (0.028 mmol) of benzoic acid were placed, before the addition
of 0.2 g (2.0 mmol, 0.21 mL) of cyclohexanone was added. Finally, 0.2
mmol of the corresponding chalcone was added. The reaction mixture was
stirred at room temperature for 7 days. The product was extracted with
EtOAc, the organic layer was dried with sodium sulphate and the crude
product purified by column chromatography (Hexane-EtOAc 100:0-95:5-
90:10-85:15) to obtain the corresponding Michael adduct. All products
were previously reported. See Supp Info for NMR spectra used for the
determination of dr, and HPLC chromatograms for determinations of er.
Synthesis of catalyst (1R,2R,1’R,2’R)-7. In
a round bottom flask
equipped with magnetic stirrer and under argon atmosphere 0.37 g (0.97
mmol) of phosphorotriamide (1R,2R,1’R,2’R)-2 was dissolved in dry THF,
then the mixture was cooled at 4° C before the dropwise addition of 0.08
g (1.27 mmol, 0.51 mL) of 2.5 M n-BuLi. The resulting mixture was stirred
at 4°
C for 20 minutes to finally add 0.17 g (1.27 mmol) of
phenylisothiocyanate. The reaction mixture was stirred at room
temperature for 14 hours, until the TLC revealed the consumption of the
starting material. The reaction mixture was poured into a flask with crushed
ice, and the product was extracted with ethyl acetate. The organic layer
was dried with sodium sulphate and the crude product was purified by
column chromatography (Hex-EtOAc 100:0 to 90:10 to 80:20) to obtain
0.27 g (0.6 mmol, 62% yield) of pure product as a pale-yellow foam. [α]D –
4.6, c = 0.35 (CHCl3).
General procedure for the Michael addition of acetophenone to β-
nitrostyrenes. Method A: In a test tube was placed 0.1 mmol of the
corresponding chalcone, 0.02 mmol of potassium carbonate, 1.0 mmol of
nitromethane and 1.0 mL of ethanol. The resulting mixture was stirred at
80° C in a Büchi syncore® equipment for 24 h. The solvent was evaporated,
and the crude product was purified by column chromatography with Hex-
1H-NMR (500 MHz, CDCl3, 20° C): δ = 11.20 (s, 1H); 7.53 (t, J = 8.1 Hz,
4H); 7.43 (d, J = 7.4, 2H); 7.13-7.37 (m, 9H); 6.72 (d, 2JP-H = 8.0 Hz, 1H);
4.60 (dq, 3JH-H = 7.0 Hz, 3JP-H = 18.3 Hz, 1H); 4.35 (dq, 3JH-H = 7.0 Hz, 3JP-
H = 13.6 Hz, 1H); 2.94-3.04 (m, 1H); 2.79-2.88 (m, 1H); 1.87-1.93 (m, 1H);
1.75-1.81 (m, 1H); 1.70 (d, 3JH-H = 7.0, 3H); 1.66 (d, 3JH-H = 7.0, 3H); 1.59-
1.65 (m, 3H); 1.11-1.22 (m, 2H); 1.06 (ct, J = 3.5, 13.0 Hz, 1H); 0.92 (cd,
EtOAc (100:0 to 80:20). Method B: In
a test tube 0.1 mmol of
corresponding trans-β-nitrostyrene, 0.01 mmol of benzoic acid, 1.0 mmol
of benzophenone and 0.01 mmol of piperidine were placed. The reaction
mixture was stirred at 50° C in a Büchi syncore® equipment for 72 h. The
crude product was purified by column chromatography with Hex-EtOAc
(100:0 to 80:20).
1
J = 3.3, 12.1 Hz, 1H). H{31P}-NMR (500 MHz, CDCl3, 20° C): δ = Same
spectra except for: 6.71 (s, 1H); 4.60 (q, 3JH-H = 76.8 Hz, 1H); 4.35 3JH-H
=
7.0, 1H). 13C-NMR (125.8 MHz, CDCl3, 20° C): δ = 180.5 (d, JP-C = 4.6 Hz),
143.8 (d, JP-C = 3.3 Hz); 139.1 (d, JP-C = 2.2 Hz); 138.8, 128.7 (2C), 128.6
(2C), 128.5 (2C), 128.4 (2C), 127.9, 127.4, 127.1 (2C), 125.8, 123.9, 62.9
(d, JP-C = 11.2 Hz), 60.7 (d, JP-C = 10.3 Hz), 54.3 (d, JP-C = 3.9 Hz), 51.8 (d,
JP-C = 3.6 Hz), 29.8 (d, JP-C = 9.7 Hz), 29.6 (d, JP-C = 8.7 Hz), 24.4 (d, JP-C
= 1.1 Hz), 24.1 (d, JP-C = 1.2 Hz), 20.5 (d, JP-C = 3.7 Hz), 18.9 (d, JP-C = 3.3
Hz). 31P-NMR (202.5 MHz, CDCl3, 20° C): δ = 16.2.
General procedure for the asymmetric organocatalytic Michael
addition of acetophenone to β-nitrostyrenes. In a vial equipped with
magnetic stirrer 7.9 mg (0.015 mmol) of catalyst (1R,2R,1’R,2’R,2’’S)-6
and 1.8 mg (0.015 mmol) of benzoic acid was placed before the addition
of 0.084 g (0.7 mmol, 0.08 mL) of acetophenone. Finally, 0.1 mmol of the
corresponding β-nitrostyrene was added. The reaction mixture was stirred
at room temperature for 7 days. The product was extracted with EtOAc,
the organic layer was dried with sodium sulphate and the crude product
purified by column chromatography (Hexane-EtOAc 100:0-95:5-90:10-
85:15) to obtain the corresponding Michael adduct. All products were
General procedure for the Michael addition of cyclohexanone to β-
nitrostyrenes. In a test tube was placed 0.1 mmol of the corresponding
trans-β-nitrostyrene, 0.01 mmol of benzoic acid, 0.01 of thiourea, 1.0 mmol
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801339
European Journal of Organic Chemistry
FULL PAPER
previously reported. See Supp Info for NMR spectroscopic determination
of dr, and HPLC chromatograms for determinations of er.
[3]
[4]
a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122,
2395-2396. b) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243-4244.
a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138-5175;
Angew. Chem. 2004, 116, 5248-5286. b) A. Erkkilä, I. Majander, P. M.
Pihko, Chem. Rev. 2007, 107, 5416-5470. c) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471-5569. d) T. Akiyama,
Chem. Rev. 2007, 107, 5744-5758. e) P. Melchiorre, M. Marigo, A.
Carlone, G. Bartoli, Angew. Chem. Int. Ed. 2008, 47, 6138-6171; Angew.
Chem. 2008, 120, 6232-6265. f) S. Bertelsen, K. A. Jørgensen, Chem.
Soc. Rev. 2009, 38, 2178-2189. g) M. Terada, Synthesis 2010, 12, 1929-
1982. h) M. Rueping, A. Kuenkel. I. Atodiresei, Chem. Soc. Rev. 2011,
40, 4539-4549. i) T. Akiyama, K. Mori, Chem. Rev. 2015, 115, 9277-9306.
j) R. Mitra, J. Niemeyer, ChemCatChem 2018, 10, 1221-1234.
a) B. List Tetrahedron 2002, 58, 5573-5590. b) H. Kotsuki, H. Ihishima,
A. Okuyama, Heterocycles 2008, 75, 493-528. c) H. Kotsuki, H. Ihishima,
A. Okuyama, Heterocycles 2008, 75, 747-797.
General procedure to racemic formal (3+3) cyclization reaction of
cyclohexanone and arylidenepyruvate methyl esters. In a test tube
was placed 0.1 mmol of the corresponding arylidenepyruvate methyl ester,
0.01 mmol of benzoic acid, 10.0 mmol of cyclohexanone and 0.01 mmol
of piperidine. The reaction mixture was stirred at 50° C in a Büchi syncore®
equipment for 24 h. The solvent was evaporated, and the crude product
purified by column chromatography with Hex-EtOAc (100:0 to 80:20).
General procedure for the asymmetric organocatalytic formal (3+3)
cyclization reaction of cyclohexanone and arylidenepyruvate methyl
esters. In a vial equipped with magnetic stirrer 7.4 mg (0.014 mmol) of
catalyst (1R,2R,1’R,2’R,2’’S)-6, and 1.7 mg (0.014 mmol) of benzoic acid
were suspended in 1 mL of distilled water, before the addition of 0.14 g
(1.4 mmol, 0.14 mL) of cyclohexanone. Finally, 0.2 mmol of the
corresponding arylidenepyruvate methyl ester was added and the resulting
mixture was stirred at room temperature for 48 hours. The product was
extracted with EtOAc, the organic layer was dried with sodium sulphate
and the crude product was purified by column chromatography (Hexane-
EtOAc 100:0-95:5-90:10-85:15) to obtain the corresponding cyclized
adduct. All products were previously reported. See Supp Info for NMR
spectroscopic determination of dr, and HPLC chromatograms for
determinations of er.
[5]
[6]
[7]
See, for example: a) J. L. Vicario, D. Badía, L. Carrillo, Synthesis 2007,
14, 2065-2092. b) Y. Zhang, W. Wang, Catal. Sci. Technol. 2012, 2, 42-
53.
a) X. Han, H.-B. Zhou, C. Dong, Chem. Rec. 2016, 16, 897-906. b) B. L.
Zhao, J.-H. Li, D.-M. Du, Chem. Rec. 2017, 17, 994-1018. c) H. Mayabe,
Y. Takemoto, Bull. Chem. Soc. Jpn. 2008, 81, 785-795. d) S. J. Connon
Synlett 2009, 354-376. e) W. Y. Siau, J. Wang, Catal. Sci. Technol. 2011,
1, 1298-1310. f) G. Koutoulogenis, N. Kaplaneris, C. G. Kokotos,
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J. C.-G. Zhao, Adv. Synth. Catal. 2018, 360, 2-79.
Acknowledgments ((optional))
We are grateful to CONACYT (Consejo Nacional de Ciencia y
Tecnología) Mexico for the financial support (grants 220945 and
324029). We gratefully acknowledge Ma. Teresa Cortes Picasso,
Luisa Rodríguez Pérez, and Víctor González Díaz for their
assistance in the recording of NMR spectra, to Géiser Cúellar
Rivera for obtaining the high-resolution mass spectra, and to
Gabina Dionisio Cadena and Antonio Gómez Pérez for technical
support.
Keywords: Asymmetric organocatalysis • Cascade reaction •
Enamine • Michael addition • Chiral thiourea
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The synthesis of a novel chiral thiourea
containing a segment of privileged
(2S)-2-pyrrolidinylmetan-amine as well
Asymmetric organocatalysis *
Carlos Cruz-Hernández, Eduardo Martínez-
Martínez, Perla E. Hernández-González and
Eusebio Juaristi.*
as
framework is described. The new
organocatalyst exhibited good
performance in asymmetric Michael
additions, in variety of systems
including the formal [3+3] cyclization of
cyclohexanone with
arylidenepyruvates through a cascade
process, which involves the
asymmetric Michael addition/proton
a
hydrophobic phosphoramide
Page No. – Page No.
a
Synthesis of a New N-Diaminophosphoryl-N´-[(2S)-2-
pyrrolidinylmethyl]thiourea as a Chiral
Organocatalyst for the Stereoselective Michael
Addition of Cyclohexanone to Nitrostyrenes and
Chalcones - Application in Cascade Processes for
the Synthesis of Polycyclic Systems
transfer/diastereoselective
reaction.
aldol
*Asymmetric organocatalysis
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Key Topic*
Author(s), Corresponding Author(s)*
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*one or two words that highlight the emphasis of the paper or the field of the study
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