Solid supported Hayashi–J?rgensen catalyst as an efficient and recyclable organocatalyst for asymmetric Michael addition reactions

Article abstract of DOI:10.1016/j.tetasy.2017.10.016

A comparison of three different catalytic systems for the efficient, asymmetric synthesis of N-({(3R,4R)-4-[(benzyloxy)methyl]pyrrolidin-3-yl}methyl)-N-(2-methylpropyl)benzenesulfonamide 1 (BZN) is described. The presented strategy is based on the organocatalytic Michael addition of aldehyde 2 to trans-nitroalkene 3, and subsequent reductive cyclization. High yields, enantio-, and diastereoselectivities were achieved in the Michael addition by application of a POSS- or Wang resin-supported Hayashi–J?rgensen catalyst.

Full text of DOI:10.1016/j.tetasy.2017.10.016

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Solid supported Hayashi–Jørgensen catalyst as an efficient and
recyclable organocatalyst for asymmetric Michael addition reactions
a,
b
b
a,b
⇑
´
Piotr Szczesniak , Olga Staszewska-Krajewska , Bartłomiej Furman , Jacek Mlynarski
a Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A comparison of three different catalytic systems for the efficient, asymmetric synthesis of N-({(3R,4R)-
4-[(benzyloxy)methyl]pyrrolidin-3-yl}methyl)-N-(2-methylpropyl)benzenesulfonamide (BZN) is
described. The presented strategy is based on the organocatalytic Michael addition of aldehyde 2 to
trans-nitroalkene 3, and subsequent reductive cyclization. High yields, enantio-, and diastereoselectivi-
ties were achieved in the Michael addition by application of a POSS- or Wang resin-supported
Hayashi–Jørgensen catalyst.
Received 16 September 2017
Accepted 23 October 2017
Available online xxxx
1
Dedicated to Prof. Marek Chmielewski on
his 75th birthday
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
Jørgensen-type catalysts, and reductive cyclization of the obtained
c-nitroaldehyde 4 (Scheme 1).
Pyrrolidine-derived compound 1, known as N-({(3R,4R)-4-
[(benzyloxy)methyl]pyrrolidin-3-yl}methyl)-N-(2-methylpropyl)
benzenesulfonamide (BZN), exhibits interesting binding to HIV-1
protease.1 The pharmacological activity of BZN is still unknown,
while no synthetic pathway has been reported so far, either. Sub-
stituted pyrrolidines are an important framework by virtue of their
frequent appearance in a large number of biologically active natu-
ral products and pharmaceuticals.2 Common methods for the syn-
thesis of optically active pyrrolidines typically involve relatively
long synthetic sequences starting from different natural chiral pool
compounds.3 The main drawback of these approaches lies in the
presence of only oxygen functionalities in the pyrrolidine scaffold.
However, many bioactive pyrrolidine derivatives, such as BZN, pos-
sess substituents of a different nature. For these reasons, appropri-
High efficiency, selectivity, and robustness in asymmetric reac-
tions make the Hayashi–Jørgensen catalyst one of the most impor-
tant organocatalysts.6 However, its practical application suffers
from some limitations, such as high catalyst loading and
difficulties in separating the catalyst from the product. It is also
noteworthy that
a-substituted c-nitroaldehydes can undergo
epimerization in the presence of the catalyst. This situation occurs
when the products remain in contact with the catalyst for an
extended period of time, after turnover is completed. When the
c
-nitroaldehydes with a high syn:anti ratio react with the catalyst,
a low steady-state concentration of the enamine is rapidly estab-
lished, and the equilibration between syn and anti continues until
thermodynamic ratio is reached (Scheme 2).
This effect, intensively studied and explained by Blackmond
et al.7 has been confirmed by our group.8 Bearing in mind that in
order to maintain the high diastereomeric ratio, the catalyst has
to be removed from the reaction mixture immediately after
complete conversion of substrates, we proposed three various
ately substituted
c-nitroaldehydes, which can be easily obtained
via organocatalytic Michael reactions, seem to be interesting pre-
cursors in the synthesis of functionalized pyrrolidines. Although
the organocatalytic asymmetric Michael addition of aldehydes to
nitroolefins leading to
c-nitroaldehydes is a key transformation
in organic synthesis,4 only a few strategies based on organocataly-
sis en route to pyrrolidines have been developed.5 Herein, we pro-
pose a simple and efficient approach to the asymmetric synthesis
of compound 1 (BZN). The synthetic strategy involves sequential
organocatalytic Michael addition of aldehyde 2 to nitroolefin 3 in
the presence of homogenous or heterogenous Hayashi–
Ph
O
O
S
N
O
O
H
N
S
N
O
Ph
reductive
Ph
O
O
cyclization
organocatalysis
S
2
O
N
BnO
1 (BZN)
+
NO2
OBn
4
BnO
NO2
3
⇑
Corresponding author.
E-mail address: alchemik_84@tlen.pl (P. Szczes´niak).
Scheme 1. Retrosynthetic approach to BZN via organocatalytic Michael addition
and subsequent reductive cyclization.
https://doi.org/10.1016/j.tetasy.2017.10.016
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
´
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´
P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
2
been used for Michael addition so far. We also found that the POSS-
or Wang resin-supported Hayashi–Jørgensen catalysts do not
cause epimerization of -substituted -nitroaldehydes, which bol-
Ph
Ph
OTMS
Ph
Ph
OTMS
N
H
N
H
O
O
a
c
S
N
Ph
cat. I
cat. I
sters the practicality of this approach.
+
+
N
O
S
O
NO2
OBn
O
S
O
2. Results and discussion
Ph
Ph
Ph
N
OTMS
N
Ph
We began our investigations by exploring the isomerization
process in the aforementioned Michael addition. Towards this pur-
pose, we conducted a 1H NMR experiment in which we expected to
observe the diastereomeric ratio decreasing in time during the
Michael addition of aldehyde 2 to b-nitrostyrene 3 catalyzed by
the Hayashi–Jørgensen catalyst cat. I (Scheme 3). The reaction
was performed in deuterated chloroform in the presence of 10
mol% of the Hayashi–Jørgensen catalyst cat. I and benzoic acid
(0.5 equiv) as an additive, at ambient temperature. After 35 min,
we observed 87% conversion to the desired product 4 with a syn/
anti ratio of 94:6. After an additional 35 min, the conversion
increased to 97%, without changes in the syn/anti ratio. However,
after complete conversion of the starting aldehyde 2 (110 min),
we began to observe a slight decrease in the syn/anti ratio to
92:8, and the equilibration between syn and anti continued until
the syn/anti ratio reached equilibrium at 50:50, and did not change
with additional time.
Having confirmed that the isomerization process shown in
Scheme 2 occurs in the discussed Michael addition, we decided
that all subsequent reactions would be monitored by 1H NMR
and after complete conversion, the catalyst would be removed by
simple column chromatography, as it was done in our previous
report.8 For this purpose, the Michael addition of aldehyde 2 to
b-nitrostyrene 3 was performed under the same conditions as
described above. After complete conversion (90 min, determined
by 1H NMR, 4 syn/anti ratio 92:8), and further purification by col-
enamine
O
NO2
OBn
4 (syn)
Scheme 2. Reversible enamine formation between cat. 1, 4 (syn), and 4 (anti).
NO2
OBn
(anti)
after 90 min syn:anti 92:8
after 24 h syn:anti 50:50
4
Ph
Ph
Ph
OTMS
Ph
N
N
N
H
OTMS
O
N
O
NH
Hayashi-Jorgensen
catalyst (cat. I)
Wang resin-supported
Hayashi-Jorgensen catalyst (cat. III)
Ph
O
Ph
i
S
O
i
S
O
O
O
Si
O
O
Si
O
N
N
Ph
Ph
Ph
OTMS
Ph
Si
Si
Ph
N
O
O
O
NH
Si
Ph
O
Si
O
POSS-supported
Hayashi-Jorgensen catalyst (cat. II)
Ph
Figure 1. Hayashi–Jørgensen-type catalysts examined in this work.
homogenous and heterogenous catalytic systems based on a Haya-
shi–Jørgensen-type catalyst, which can be easily removed from the
reaction mixture, thus overcoming the mentioned drawback
(Fig. 1).
The first approach is based on complexing the pyrrolidine moi-
ety with copper salts. We observed that the Hayashi–Jørgensen
catalyst cat. I could be easily removed after turnover was com-
pleted by simple extraction with saturated aqueous CuSO4. The
other two approaches involve homogenous and heterogenous
catalysis based on immobilized Hayashi–Jørgensen-type catalysts
cat. II and cat. III.
Several research groups have immobilized the Hayashi–
Jørgensen catalyst on a variety of solid supports including poly-
mers,9 ionic liquids,10 magnetic nanoparticles,11 porous materi-
als,12 dendrimers,13 and fluorous phases14 to exploit the inherent
advantages derived from simple purification of the product, the
possibility of straightforward recycling, reuse of the catalyst, and
the potential for its use in flow chemistry.
Herein, we propose an efficient and easily recoverable homoge-
nous catalyst based on POSS (polyhedral oligomeric silsesquiox-
ane)-supported Hayashi–Jørgensen-type catalyst cat. II. POSS are
a new class of organic–inorganic hybrid materials consisting of a
silicon-oxygen framework. Due to marked differences in solubili-
ties in various solvents, making it possible to separate these com-
pounds by simple precipitation, POSS are ideal soluble supports for
homogenous catalysis.15 Despite that, only one literature prece-
dent for the application of a POSS-supported Hayashi–Jørgensen
catalyst in organocatalytic Michael addition has appeared.16
Beside homogenous catalysis, we propose heterogenous cataly-
sis as an alternative approach, based on the application of insoluble
Wang resin as a solid support for the Hayashi–Jørgensen catalyst
cat. III. Despite insoluble polymers being common support for var-
ious types of heterogenous catalysts,17 to the best of our knowl-
edge, Wang resin-supported Hayashi–Jørgensen catalyst has not
umn chromatography, the corresponding
c-nitroaldehyde 4 was
obtained in 93% yield, and with high enantioselectivity (98% e.e.).
However, the syn/anti ratio was only 67:33. The observed changes
in the diastereomeric ratio (4 syn/anti 92:8 vs 67:33) indicate that
the isomerization progresses not only after turnover is completed,
but also during purification by column chromatography. Bearing in
mind these drawbacks, in the next step we decided to perform the
reaction as a one-pot procedure without isolation of the product,
but with immediate isolation of the catalyst. To achieve this goal,
we first utilized the propensity of copper salts to complex the
pyrrolidine moiety. Proceeding as in the previous example, after
turnover completed (90 min, determined by 1H NMR, 4 syn/anti
ratio 92:8), the reaction mixture was washed with saturated aque-
ous CuSO4 to remove the catalyst and left for 24 h. After that time,
the 1H NMR analysis showed only small changes in the syn/anti
ratio (4 syn/anti 92:8 vs 94:6). After determining suitable condi-
tions, we were ready to exploit the discussed Michael reaction in
the synthesis of compound 1 (BZN). Another purpose of the study
was to confirm the configuration of the major diastereomer 4 (syn)
by converting it into a cyclic nitrone. Following the example
Ph
Ph
OTMS
N
H
BnO
NO2
O
O
O
O
S
N
S
N
Ph
3
(0.37 mmol)
Ph
cat. I
(10 mol%)
PhCO2H
Ph
S
O
+
O
O
+
O
NO2
OBn
CDCl3, rt
NO2
OBn
O
N
4
(anti)
4 (syn)
2 (0.37 mmol)
Scheme 3. 1H NMR analysis of syn/anti equilibration in the Michael addition of
aldehyde 2 to (E)-b-nitrostyrene 3 catalyzed by 10 mol% of the Hayashi–Jørgensen
catalyst cat. I; selected signals corresponding to the carbonyl groups are presented.
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P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
described above, after complete conversion of starting materials
(90 min), and washing with saturated aqueous CuSO4, the solvent
was evaporated, and the crude product 4 with a syn/anti ratio of
92:8 was used in the next step. The subsequent reductive cycliza-
tion was performed with Zn powder (2.0 equiv) and acetic acid in
methanol (1:1). The reaction mixture was stirred for 3 days at 0 °C.
After work-up and further purification by column chromatography,
nitrone 5 (trans) and 5 (cis) was obtained in moderate yield (46%),
in a 87:13 ratio (Scheme 4). The relative configuration of 5 (trans)
and 5 (cis) nitrone was confirmed on the basis of the analysis of
NOE experiments. As described previously, cyclic nitrones are valu-
able building blocks in the synthesis of many biologically active
nitrogen heterocycles, due to their various possibilities of function-
alization.8 In order to obtain compound 1 (BZN), a simple reduction
in standard conditions (H2, Pd/C in methanol at ambient tempera-
ture) proved efficient for nitrone 5 (trans) reduction. The corre-
sponding amine 1 (BZN) was obtained in 43% yield (Scheme 4).
The relative configuration of 1 (BZN) was also confirmed through
the analysis of NOE experiments. Further investigations revealed
that amine 1 (BZN) could be obtained in a more efficient manner
allows for simple recovery of the catalyst by precipitation. To eval-
uate the catalytic efficiency of the POSS-supported catalyst cat. II,
we carried out the Michael addition of aldehyde 2 with b-nitrostyr-
ene 3. The reaction was performed in chloroform in the presence of
10 mol% of the POSS-supported catalyst cat. II, at ambient temper-
ature. However, the reaction catalyzed by cat. II was found to be
significantly slower than the reaction catalyzed by cat. I under
the same conditions (8 days vs 90 min). After 8 days, 1H NMR anal-
ysis indicated that the conversion to the corresponding
c-
nitroaldehyde 4 was only 81%, with a syn/anti ratio 85:15 (Table 1,
Entry 1). Despite incomplete conversion, we decided to ascertain if
cat. II could be easily isolated from the reaction mixture. After
evaporation of the solvent and precipitation with an excess of
MTBE, cat. II was recovered in 76% yield. The crude c-nitroalde-
hyde 4 was subjected to reductive cyclization by employing the
same reducing system (Zn/AcOH in MeOH), leading to amine 1
(BZN) in 39% yield (Table 1, Entry 1). Next, we examined the influ-
ence of catalyst amount on the discussed Michael addition. The
best result was obtained when the reaction was carried out with
20 mol% of cat. II. After 3 days, we observed complete conversion
via direct reduction of
c
-nitroaldehyde 4. When the crude product
to c-nitroaldehyde 4 with a high syn/anti ratio (91:9) and stereos-
4 with syn/anti ratio 92:8, washed with saturated aqueous CuSO4,
was treated with a large excess of Zn powder (25 equiv vs 2.0 eq
uiv) in a mixture of acetic acid and methanol for 3 days at 0 °C,
after work-up and further purification by column chromatography,
only the desired amine 1 (BZN) (trans) diastereomer was isolated
in 66% yield (Scheme 4).
Despite these promising results, we realized that for a more
attractive and efficient synthesis of compound 1 (BZN), the catalyst
used in the Michael reaction should be easily separated and reused
in the next catalytic cycle. To achieve the intended purpose, in the
next step, we decided to examine the POSS-supported Hayashi–
Jørgensen catalyst cat. II developed by Nie et al.16 POSS-supported
cat. II was employed by Nie et al. in the asymmetric Michael addi-
tion reaction of various aldehydes and arylnitroalkenes, providing
electivity (95% e.e.). The catalyst was recovered in 81% yield. After
subsequent reductive cyclization reaction and purification, amine
1 (BZN) was isolated in good yield (62%; Table 1, Entry 2). Increas-
ing the amount of catalyst loading to 50 mol% led to decrease in
reaction time to 1 day, but the diastereoselectivity was slightly
lower (syn/anti ratio 87:13 vs 91:9), and cat. II was recovered in
79% yield. In the next step, amine 1 (BZN) was obtained in a simi-
lar, 61% yield (Table 1, Entry 3). Having optimized the reaction con-
ditions, we continued our studies by exploring the recyclability of
cat. II. As shown in Table 1 (Entry 4), no significant decrease in cat-
alytic activity was observed when 20 mol% of the recovered cat. II
was used in the second catalytic cycle. The reaction proceeded
with similar diastereo- and enantioselectivities (syn/anti ratio
92:8, e.e. 92% vs syn/anti ratio 91:9, e.e. 95%). The recovery of the
catalyst was the same (78%), and amine 1 (BZN) was obtained in
a similar yield (59%; Table 1, Entry 2 vs 4). However, in the third
catalytic cycle, we observed a significant deterioration of the cata-
lyst activity, which proved partial decomposition of cat. II. After
the corresponding c-nitroaldehydes in good yields, and with excel-
lent enantioselectivities and good diastereoselectivities. Moreover,
the catalyst was readily recovered and reused for further transfor-
mations.16 A characteristic feature of the POSS-supported catalyst
cat. II is that it dissolves in typical organic solvents, such as CH2Cl2,
CHCl3, toluene, AcOEt, and is insoluble in Et2O and MTBE, which
13 days, the conversion to the corresponding
c-nitroaldehyde 4
was only 55%. The diastereo- and enantioselectivity was still on
O
N
O
N
Ph
O
O
Ph
O
Zn (2.0 eq.)
O
Ph
1)
S
S
+
Ph
S
Ph
CH3CO2H:MeOH (1:1)
N
N
H
O
O
BnO
N
BnO
5 (cis) 6%
in situ
3 days, 0 o
C
OTMS
O
N
5 (trans) 40%
O
O
cat. I
(10 mol%)
S
N
Ph
PhCO2H
2
CHCl3, rt, 90 min
2) CuSO4 sat. aq.
+
H2, Pd/C
MeOH
O
NO2
OBn
yield 43%
BnO
NO2
3
conversion 100%
H
N
4
(syn/anti) 92:8
e.e. 98.0%
Ph
O
Zn (25.0 eq.)
O
S
CH3CO2H:MeOH (1:1)
N
BnO
3 days, 0 o
C
yield 66%
1
(BZN)
Scheme 4. Optimization of the sequential Michael addition of aldehyde 2 to (E)-b-nitrostyrene 3 catalyzed by the Hayashi–Jørgensen catalyst cat. I and reductive cyclization
to the corresponding pyrrolidine 1 (BZN).
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4
Table 1
The homogenous Michael addition reaction of aldehyde 2 to b-nitrostyrene 3 catalyzed by POSS-supported catalyst cat. II, and subsequent reductive cyclization to amine 1 (BZN)a
Ph
i
S
O
Ph
O
Ph
O
O
O
O
O
S
N
i
S
S
N
H
N
Ph
O
O
O
Ph
Si
O
O
O
Zn (25.0 eq.)
Si
O
N
N
cat. II
O
Ph
Ph
O
S
Ph
Ph
Si
2
O
AcOH, MeOH, rt
+
CHCl3, rt
N
BnO
Si
NO2
OTMS
Ph
N
O
O
NH
1
(BZN)
Si
Ph
BnO
NO2
OBn
4 syn/anti
O
Si
Ph
O
cat. II
3
Entry
Catalyst [%mol]
Catalytic cycle
Catalyst recovery
Conversionb [%]
Time [days]
4 (syn/anti)b
4 (e.e.)c [%]
Yield 1d [%]
1
2
3
4
5
10
20
50
20
20
1
1
1
2
3
76
81
79
78
85
81
100
100
100
55
8
3
1
3
13
85:15
91:9
87:13
92:8
95.9
95.0
94.8
92.0
96.5
39
62
61
59
22
93:7
a
Reaction conditions for the Michael addition: aldehyde 2 (0.37 mmol), nitroalkene 3 (0.37 mmol), CHCl3, rt; the reaction was monitored by TLC and 1H NMR, cat. II was
removed from the reaction mixture by precipitation with an excess of MTBE; Reaction conditions for reductive cyclization: Zn powder (25.0 equiv), AcOH:MeOH (1:1), 0 °C, 3
days.
b
Determined by 1H NMR of the crude reaction mixture.
c
Determined by HPLC of the crude reaction mixture.
d
Yield of isolated product, configuration established by NOE experiments.
Table 2
The heterogenous Michael addition of aldehyde 2 to b-nitrostyrene 3 catalyzed by Wang resin-supported catalyst cat. III, and subsequential reductive cyclization to amine 1
(BZN)a
Ph
O
O
O
O
S
N
S
N
H
N
Ph
Ph
Ph
O
N
N
Ph
O
Zn (25.0 eq.)
cat. III
O
S
O
OTMS
N
O
2
O
NH
AcOH, MeOH, rt
+
N
CHCl3, rt
BnO
NO2
cat. III
1
(BZN)
BnO
NO2
OBn
4 syn/anti
3
Entry
Catalyst [%mol]
Catalytic cycle
Catalyst recovery
Conversionb [%]
Time [h]
4 (syn/anti)b
4 (e.e.)c [%]
Yield 1d [%]
1
2
3
4
5
10
20
50
20
20
1
1
1
2
3
100
100
100
99
100
100
100
100
87
21
15
5
92:8
93:7
94:6
92:8
92:8
94.2
93.2
92.8
93.6
93.8
64
65
64
55
43
20
97
7 days
a
Reaction conditions for the Michael addition: aldehyde 2 (0.37 mmol), nitroalkene 3 (0.37 mmol), CHCl3, rt; the reaction was monitored by TLC and 1H NMR, cat. III was
removed from the reaction mixture by filtration; Reaction conditions for reductive cyclization: Zn powder (25.0 equiv), AcOH:MeOH (1:1), 0 °C, 3 days.
b
Determined by 1H NMR of the crude reaction mixture.
Determined by HPLC of the crude reaction mixture.
Yield of isolated product, configuration established by NOE experiments.
c
d
the same level (syn/anti ratio 93:7, e.e. 96%), but amine 1 (BZN) was
obtained in lower yield (22%; Table 1, Entry 5).
and the crude product 4 was subjected to reductive cyclization to
obtain amine 1 (BZN) in 64% yield (Table 2, Entry 1). Next, we
investigated the influence of catalyst amount on the discussed
Michael addition. Increasing the catalyst loading to 20 mol% or
50 mol% resulted only in a decrease in the reaction time, without
changing the enantio- and diastereoselectivity (Table 2, Entries
1–3). Encouraged by the results, we endeavored to apply cat. III
in the next catalytic cycle. To our satisfaction, no significant
decrease in catalytic activity was observed, when 20 mol% of the
recovered catalyst cat. III was used in the second cycle of the
Michael addition (Table 2, Entry 4). However, the catalytic activity
dropped markedly in the third cycle. After 7 days, 1H NMR analysis
Although the Michael addition catalyzed by cat. II provided the
corresponding
c-nitroaldehyde 4 in high yield and with high
enantioselectivity, without a significant deterioration of diastere-
oselectivity, the catalyst recovery was in the range of 80%. To
achieve higher catalyst recovery, in the next step, we investigated
a heterogenous catalytic system based on insoluble Wang resin-
supported Hayashi–Jørgensen catalyst cat. III, which, to the best
of our knowledge, has not been used for Michael addition so far.
We examined the catalytic efficiency of cat. III in the Michael addi-
tion of aldehyde 2 to b-nitrostyrene 3. The reaction was performed
under the same conditions as in the previous example, in chloro-
form in the presence of 10 mol% of cat. III, at ambient temperature.
In comparition to the POSS-supported cat. II, 10 mol% of cat. III
turned out to be sufficient to achieve complete conversion after
indicated that the conversion to the corresponding
c-nitroalde-
hyde 4 was 87%. However, the stereoselectivity was unaffected
throughout all catalytic cycles (Table 2, Entry 5). These results
demonstrate that cat. III is the best recyclable organocatalyst for
the discussed Michael addition among the ones examined here,
exhibiting high activity as well as a very simple procedure for cat-
alyst recovery.
21 h. c-Nitroaldehyde 4 was obtained with high enantioselectivity
(94%) as an inseparable mixture of diastereomers in syn/anti ratio
92:8. After simple filtration, cat. III was recovered in 100% yield,
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P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.1.3. N-(3-Hydroxypropyl)-N-isobutylbenzenesulfonamide 8
3. Conclusion
To a solution of 7 (5.4 g, 14.0 mmol) in dry THF (150 mL), a 1 M
solution of tetrabutylammonium fluoride in THF (18.2 mL, 18,2
mmol, 1.3 equiv) was added under argon at 0 °C. The resulting
solution was warmed gradually to room temperature and stirred
overnight. The solvent was then evaporated under reduced pres-
sure and the crude product was purified by silica gel column chro-
matography (1:1 AcOEt/hexanes) to afford 3.04 g (80%) of alcohol 8
as a colorless oil. Rf = 0.18 (1:1 AcOEt/hexanes); 1H NMR (300 MHz,
CDCl3) d 7.86–7.79 (m, 2H), 7.63–7.48 (m, 3H), 3.74 (dd, J 10.4, 5.1
Hz, 2H), 3.24 (t, J 6.8 Hz, 2H), 2.92 (d, J 7.6 Hz, 2H), 2.36–2.23 (m,
1H), 1.98–1.82 (m, 1H), 1.81–1.71 (m, 2H), 0.90 (d, J 6.6 Hz, 6H);
13C NMR (75 MHz, CDCl3) d 139.9, 133.1, 129.7, 127.8, 59.7, 57.9,
46.6, 32.3, 27.9, 20.7; IR (film) v: 3533, 2961, 1666, 1446, 1331,
1156, 1091, 994, 781, 743, 691, 583 cmÀ1; HRMS (ESI-TOF) m/z
calcd for C13H21NNaO3S [M+Na+] 294.1140. Found 294.1136.
In conclusion, an attractive method for the formation of opti-
cally active pyrrolidine 1 (BZN) has been developed. The presented
strategy is based on organocatalytic Michael addition of aldehyde 2
to trans-nitroalkene 3, and subsequent Zn-promoted reductive
cyclization process. As it was demonstrated, three catalytic sys-
tems based on a Hayashi–Jørgensen-type catalyst were applied to
the efficient and highly stereoselective Michael addition reaction.
The presented homogenous and heterogenous catalytic systems
could be easily recovered and reused (POSS- or Wang resin-sup-
ported catalyst) in the next catalytic cycle without a significant loss
of catalytic activities and stereoselectivities. One great advantage
for the presented immobilized catalysts are that they do not cause
epimerization of
a-substituted c-nitroaldehydes. Further studies,
focusing on the preparation of more stable solid phase-supported
Hayashi–Jørgensen catalysts, and their application to different bio-
logically active pyrrolidine synthesis are currently under investiga-
tion and will be reported in due course.
4.1.4. N-Isobutyl-N-(3-oxopropyl)benzenesulfonamide 2
To a cooled (À78 °C) mixture of dry DMSO (3.09 mL, 43.52
mmol, 4.0 equiv) and dry CH2Cl2 (30 mL), oxalyl chloride (1.84
mL, 21.76 mmol, 2.0 equiv) was added dropwise under argon.
The reaction mixture was stirred for 90 min at the same tempera-
ture, and then a solution of alcohol 8 (2.952 g, 10.88 mmol) in dry
CH2Cl2 (50 ml) was added dropwise. The reaction was stirred for an
additional 2 h, at À78 °C, and then dry Et3N (12 mL, 87.04 mmol,
8.0 equiv) was added. The resulting solution was warmed
gradually to room temperature and stirred overnight. The reaction
was quenched with satd aq NH4Cl (30 ml), and H2O (30 mL). After
phase separation, the aqueous layer was washed with CH2Cl2 (3 Â
20 mL). The combined organic layers were washed with satd aq
NH4Cl (30 ml), H2O (30 mL), brine (30 ml), and then dried over
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure to give the crude product, which was purified by silica
gel column chromatography (1:4 AcOEt/hexanes); to afford
2.392 g (82%) of aldehyde 2 as a yellow oil. Rf = 0.63 (1:1 AcOEt/
hexanes); 1H NMR (300 MHz, CDCl3) d 9.77 (t, J 0.9 Hz, 1H), 7.84–
7.79 (m, 2H), 7.64–7.50 (m, 3H), 3.44–3.36 (m, 2H), 2.90 (d, J 7.5
Hz, 2H), 2.88–2.82 (m, 2H), 1.92–1.77 (m, 1H), 0.92 (d, J 6.6 Hz,
6H); 13C NMR (75 MHz, CDCl3) d 200.8, 139.6, 133.3, 129.8,
127.8, 57.7, 44.5, 43.0, 27.8, 20.54; IR (film) v: 2963, 1723, 1447,
1336, 1158, 1092, 997, 753, 692, 582 cmÀ1; HRMS (ESI-TOF) m/z
calcd for C13H19NNaO3S [M+Na+] 292.0983. Found 292.0977.
4. Experimental
4.1. Synthesis of aldehyde 2
4.1.1. N-Isobutylbenzenesulfonamide 6
To a solution of 2-methylpropan-1-amine (4 mL, 40.25 mmol)
in dry CH2Cl2 (40 mL), N,N-diisopropylethylamine (7.0 mL, 40.25
mmol, 1.0 equiv) was added under argon at À25 °C, the mixture
was stirred for 15 min, then benzenosulfonylchloride (5.12 mL,
40.25 mmol, 1.0 equiv) was added. The resulting solution was
warmed gradually to room temperature and stirred overnight.
The reaction was quenched with 1 M aq HCl (10 mL). After phase
separation, the organic layer was washed with H2O (20 mL), dried
over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure. Further evaporation under high vacuum gave
8.568 g (quant yield) of sulfonoamide 6 as a white solid. Rf = 0.51
(1:2 AcOEt/hexanes); 1H NMR (300 MHz, CDCl3) d 7.86–7.80 (m,
2H), 7.56–7.43 (m, 3H), 4.75 (t, J 6.2 Hz, 1H), 2.71 (t, J 6.6 Hz,
2H), 1.66 (dp, J 13.4, 6.7 Hz, 1H), 0.82 (d, J 6.7 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 140.7, 133.2, 129.7, 127.6, 51.2, 29.1, 20.5; IR
(film) v: 3286, 2960, 1447, 1323, 1182, 1093, 754, 718, 689, 585
cmÀ1; HRMS (ESI-TOF) m/z calcd for C10H15NNaO2S [M+Na+]
236.0721. Found 236.0725.
4.1.5. 3-((tert-Butyldimethylsilyl)oxy)propan-1-ol 9
To a solution of sodium hydride (2.1 g, 60% disp. in mineral oil,
52.6 mmol) in dry THF (60 mL), a solution of propane-1,3-diol (3.9
mL, 52.6 mmol) in dry THF (20 mL) was added under argon at 0 °C.
The reaction mixture was stirred for 120 min at the same temper-
ature, and then a solution of tert-butyldimethylsilyl chloride (7.9 g,
52.6 mmol) in dry THF (20 ml) was added dropwise. After stirring
overnight, the reaction was quenched with satd aq NaHCO3 (50
ml). The aqueous layer was washed with Et2O (3 Â 20 mL). The
combined organic layers were washed with brine (30 ml), dried
over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to give 9.81 g (98%) of alcohol 9 as a yellow oil,
which was pure enough to be used for Mitsunobu reaction. 1H
NMR (300 MHz, CDCl3) d 3.84–3.76 (m, 4H), 2.60 (s, 1H), 1.82–
1.73 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 63.4, 62.8, 34.9, 26.5, 18.8, À4.9.
4.1.2. N-(3-((tert-Butyldimethylsilyl)oxy)propyl)-N-isobutylben-
zenesulfonamide 7
To a solution of sulfonoamide 6 (4.505 g, 21.1 mmol) in dry THF
(300 mL), triphenylfosfine (16.6 g, 63.4 mmol, 3.0 equiv), a solu-
tion of 3-((tert-butyldimethylsilyl)oxy)propan-1-ol
9 (12.06 g,
63.4 mmol, 3.0 equiv) in dry THF (50 mL), and diisopropyl azodi-
carboxylate (12.48 mL, 63.4 mmol, 3.0 equiv) were added under
argon at 0 °C. The resulting solution was warmed gradually to
room temperature and stirred overnight. Then solvent was then
evaporated under reduced pressure and the crude product was
purified by silica gel column chromatography (1:15 AcOEt/hex-
anes) to afford 5.45 g (67%) of product 7 as a yellow oil. Rf = 0.32
(1:9 AcOEt/hexanes); 1H NMR (300 MHz, CDCl3) d 7.84–7.79 (m,
2H), 7.59–7.46 (m, 3H), 3.57 (t, J 5.9 Hz, 2H), 3.24–3.16 (m, 2H),
2.92 (d, J 7.5 Hz, 2H), 1.99–1.86 (m, 1H), 1.77–1.67 (m, 2H), 0.92
(d, J 6.6 Hz, 6H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 140.5, 132.9, 129.5, 127.8, 61.0, 57.0, 46.7, 32.4, 27.6, 26.5, 20.6,
18.8, À4.8; IR (film) v: 2956, 2928, 2856, 1720, 1470, 1345, 1256,
1158, 1091, 1005, 964, 836, 776, 748, 691, 583 cmÀ1; HRMS (ESI-
TOF) m/z calcd for C19H35NNaO3SSi [M+Na+] 408.2005. Found
408.2000.
4.2. Synthesis of trans-nitroalkene 3
4.2.1. (Z)-1,4-Bis(benzyloxy)but-2-ene 10
To a solution of sodium hydride (2.4 g, 60% disp. in mineral oil,
59.0 mmol, 2.6 equiv) in dry DMF (50 mL), a solution of (Z)-but-2-
´
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P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
6
ene-1,4-diol (1.87 mL, 22.7 mmol) in dry DMF (10 mL) was added
under argon at 0 °C. The resulting solution was warmed gradually
to room temperature and stirred for 1 h. Then benzyl bromide (9.4
mL, 79.5 mmol, 3.5 equiv) was added dropwise. After stirring over-
night, the reaction was quenched with satd aq NH4Cl (30 ml). The
aqueous layer was washed with Et2O (3 Â 20 mL). The combined
organic layers were washed with H2O (30 mL), brine (30 ml), dried
over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to give the crude product, which was purified
by silica gel column chromatography (1:15 AcOEt/hexanes); to
afford 5.97 g (98%) of 10 as a yellow oil. Rf = 0.52 (1:6 AcOEt/hex-
anes); 1H NMR (300 MHz, CDCl3) d 7.44–7.31 (m, 10H), 5.88–5.83
(m, 2H), 4.55 (s, 4H), 4.14–4.11 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 138.9, 130.2, 129.1, 128.5, 128.3, 72.9, 66.5.
4.5. Synthesis of Wang resin-supported Hayashi–Jørgensen
catalyst (cat. III)
4.5.1. 1-Ethyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicar-
boxylate 12
To a suspension of trans-4-hydroxy-L-proline (2.38 g, 18.1
mmol) in 30 mL of methanol, anhydrous K2CO3 (2.5 g, 18.1 mmol,
1.0 equiv) was added followed by the addition of ethyl chlorofor-
mate (3.8 mL, 39.8 mmol, 2.2 equiv) in 7 mL of methanol. After
being stirred at ambient temperature for 18 h methanol was
removed in vacuo. The remaining residue was dissolved in CH2Cl2,
washed with water and dried over Na2SO4 and filtered. The filtrate
was concentrated under reduced pressure to give 3.047 g (78%) of
product 12 as a colorless oil, which was used for the next step
without further purification. Spectroscopic data was complemen-
4.2.2. 2-(Benzyloxy)acetaldehyde 11
tary with literature data.19
[a
]
D
24 = À70 (c 2.5, CHCl3); mixture of
Ozone was passed through a stirred solution of 10 (5.9 g, 22.0
mmol) in dry CH2Cl2 (10 mL) at À78 °C. The progress of the reac-
tion was followed by TLC (1:6 AcOEt/hexanes). After 45 min,
slightly green solution occurred. At this point, oxygen was bubbled
through reaction mixture for 20 min, and the same procedure was
repeated with argone. Than Me2S (3.5 mL, 2.0 equiv) was added.
Resulting mixture was warmed slowly to room temperature and
stirred overnight. The reaction mixture was concentrated under
reduced pressure to give the crude product, which was purified
by silica gel column chromatography (1:6 AcOEt/hexanes); to
afford 3.24 g (98%) of 11 as a colorless oil; Rf = 0.26 (1:4 AcOEt/hex-
anes); 1H NMR (300 MHz, CDCl3) d 9.75–9.73 (m, 1H), 7.40–7.30
(m, 5H), 4.64 (s, 2H), 4.11 (d, J 0.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 201.1, 137.5, 129.2, 128.8, 128.7, 75.9, 74.3.
rotamers 1:1; 1H NMR (300 MHz, CDCl3) d 4.58–4.44 (m, 2H),
4.14 (q, J 7.1 Hz, 2H), 3.74 (d, J 5.7 Hz, 3H), 3.66 (dd, J 11.6, 4.2
Hz, 1H), 3.52 (d, J 11.5 Hz, 1H), 2.46–2.21 (m, 2H), 2.11 and 2.06
(dd, J 8.0, 5.0 Hz, 1H), 1.26 and 1.20 (t, J 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 174.0 and 173.8, 155.9 and 155.5, 70.8 and
70.0, 62.2, 58.4 and 58.3, 55.7 and 55.2, 52.9 and 52.8, 39.8 and
39.1; 15.2 and 15.1; IR (film) v: 3443, 2984, 2954, 1749, 1685,
1435, 1384, 1351, 1205, 1174, 1127, 1087, 1025, 783 cmÀ1; HRMS
(ESI-TOF) m/z calcd for C9H15NNaO5 [M+Na+] 240.0848. Found
240.0843.
4.5.2. Ethyl (2S,4R)-4-hydroxy-2-(hydroxydiphenylmethyl)
pyrrolidine-1-carboxylate 13
To a solution of 12 (3.02 g, 13.9 mmol) in 10 mL of dry THF, phe-
nyl magnesium bromide solution (1M in THF) (41.7 mL, 41.7
mmol, 3.0 equiv) was added dropwise at 0 °C under argon. The
resulting solution was warmed gradually to room temperature
and stirred overnight. The reaction was quenched with satd aq
NH4Cl (5 ml), and H2O (5 mL). After phase separation, the aqueous
layer was washed with Et2O (4 Â 10 mL). The combined organic
layers were washed with brine (30 ml), and then dried over Na2-
SO4, and filtered. The filtrate was concentrated under reduced pres-
sure to give the crude product, which was recrystallized from Et2O.
Further evaporation under high vacuum gave 1.879 g (40%) of 13 as
a white solid. Spectroscopic data was complementary with litera-
4.2.3. (E)-(((3-Nitroallyl)oxy)methyl)benzene 3
To a solution of aldehyde 11 (3.0 g, 20 mmol) in 70 mL of dry
toluene, nitromethane (10.8 ml, 200 mmol, 10.0 equiv) and N,N,N,
N-tetramethylguanidine (253 mL, 2.0 mmol, 10 mol%) were added
at 0 °C under argon. The resulting solution was stirred at the same
temperature for 90 min, until complete conversion of the starting
aldehyde 11 (TLC control, 1:1 AcOEt/hexanes). Next MsCl (2.32
mL, 30 mmol, 1.5 equiv) and Et3N (4.18 mL, 30 mmol, 1.5 equiv)
were added at 0 °C and the reaction mixture was stirred for an
additional 40 min at the same temperature (TLC control, 1:1
AcOEt/hexanes). The reaction mixture was quenched with sat d
aq NaHCO3 (20 mL) and diluted with Et2O (20 mL). After phase sep-
aration, the aqueous layer was washed with Et2O (3 Â 10 mL). The
combined organic layers were dried over anhydr. Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure to give
the crude product, which was purified by silica gel column chro-
matography (1:6 AcOEt/hexanes) to give 2.86 g (74%) nitroalkene
3 as a yellow oil. Rf = 0.77 (1:1 AcOEt/hexanes); 1H NMR (300
MHz, CDCl3) d 7.44–7.31 (m, 6H), 7.29–7.26 (m, 2H), 4.62 (s, 2H),
4.29–4.27 (m, 2H); 13C NMR (75 MHz, CDCl3) d 140.4, 139.1,
137.7, 129.3, 128.8, 128.4, 73.9, 66.2; IR (film) v: 3032, 2864,
ture data.19 Mp 175–176 °C; [
a]
24 = À46.1 (c 2.5, CHCl3); 1H NMR
D
(300 MHz, CDCl3) d 7.46–7.21 (m, 10H), 5.10 (dd, J 8.5, 6.6 Hz,
1H), 4.15–4.01 (m, 1H), 4.01–3.86 (m, 2H), 3.55 (d, J 12.0 Hz, 1H),
3.01 (dd, J 12.0, 4.1 Hz, 1H), 2.15 (dt, J 14.0, 6.0 Hz, 1H), 2.10–
1.99 (m, 1H), 1.77 (s, 1H), 1.16 (t, J 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) d 158.7, 146.0, 143.9, 128.6, 128.4, 128.3, 128.0,
127.9, 127.8, 82.1, 70.4, 66.1, 62.6, 56.7, 39.8, 15.1; IR (film) v:
3410, 2984, 1668, 1428, 1382, 1345, 1199, 768, 702 cmÀ1; HRMS
(ESI-TOF) m/z calcd for C20H23NNaO4 [M+Na+] 364.1525. Found
364.1519.
1658, 1525, 1435, 1356, 1121, 1025, 932, 825, 740, 699 cmÀ1
;
4.5.3. (6R,7aS)-1,1-Diphenyl-6-(prop-2-yn-1-yloxy)tetrahydro-
1H,3H-pyrrolo[1,2-c]oxazol-3-one 14
HRMS (ESI-TOF) m/z calcd for C10H11NNaO3 [M+Na+] 216.0637.
Found 216.0631.
To a solution of sodium hydride (440 mg, 60% disp. in mineral
oil, 11 mmol, 2.0 equiv) in dry DMF (10 mL), a solution of 13
(1.879 g, 5.5 mmol) in dry DMF (10 mL) was added under argon
at 0 °C. The reaction mixture was stirred for 15 min at the same
temperature, and then a solution of propargyl bromide (80% in
toluene) (1.2 mL, 5.5 mmol, 2.0 equiv) was added dropwise. The
resulting solution was warmed to room temperature and stirred
for 90 min, until complete conversion of the starting 13 (TLC con-
trol, 1:2 AcOEt/hexanes). Then the reaction was quenched with sat
d aq NH4Cl (10 ml). After phase separation, the aqueous layer was
washed with CH2Cl2 (3 Â 10 mL). The combined organic layers
were washed with H2O (30 ml), and then dried over Na2SO4, and
4.3. Synthesis of Hayashi–Jørgensen catalyst (cat. I)
The Hayashi–Jorgensen catalyst cat. II was obtained according
to the literature procedure.8
4.4. Synthesis of POSS-supported Hayashi–Jørgensen catalyst
(cat. II)
The POSS-supported Hayashi–Jorgensen catalyst cat. II was
obtained according to the literature procedure.16,18
´
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´
7
P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
filtered. The filtrate was concentrated under reduced pressure to
give 1.804 g (98%) of product 14 as an orange oil, which was used
for the next step without further purification. Spectroscopic data
was complementary with literature data.19 Rf = 0.41 (1:2 AcOEt/
74.6, 64.2, 56.7, 53.3, 34.7, 2.8; IR (film) v: 3303, 2952, 1492,
1446, 1250, 1071, 876, 838, 757, 701 cmÀ1; HRMS (ESI-TOF) m/z
calcd for C23H30NO2Si [M+H+] 380.2046. Found 380.2049.
hexanes); [
a]
D
22 = À200.1 (c 2.8, CHCl3); 1H NMR (300 MHz, CDCl3)
4.5.6. p-Alkoxybenzyl chloride resin 17
d 7.56–7.51 (m, 2H), 7.42–7.28 (m, 8H), 4.85 (dd, J 11.2, 5.0 Hz, 1H),
4.30 (t, J 5.6 Hz, 1H), 4.13 (d, J 2.4 Hz, 2H), 4.05 (dd, J 12.9, 5.9 Hz,
1H), 3.30 (dd, J 12.9, 1.0 Hz, 1H), 2.44 (t, J 2.4 Hz, 1H), 1.90 (dd, J
13.5, 5.0 Hz, 1H), 1.21 (ddd, J 13.6, 11.3, 5.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 161.0, 143.5, 140.7, 129.24, 129.10, 129.05,
128.5, 126.7, 126.0, 86.4, 78.8, 75.5, 67.9, 57.3, 54.2, 36.6; IR (film)
v: 3286, 2954, 1758, 1494, 1449, 1374, 1246, 1226, 1093, 1003,
783, 704 cmÀ1; HRMS (ESI-TOF) m/z calcd for C21H19NNaO3 [M
+Na+] 356.1263. Found 356.1257.
p-Alkoxybenzyl alcohol resin (2.0 g, 2.0 mmol, 1.0 mmol/g load-
ing, 75–100 mesh) was chlorinated with thionyl chloride (1.46 mL,
20 mmol; 10 equiv) in toluene (40 mL) at 70 °C for 2 h. The resin
was filtered and washed with toluene (3 Â 10 mL), DMF (3 Â 10
mL), THF (3 Â 10 mL), and CH2Cl2 (3 Â 10 mL) and dried in a high
vacuum to afford (2.141 g) (99%) of resin 17.
4.5.7. p-Alkoxybenzyl azide resin 18
Resin 17 (2.141 g) was treated with sodium azide (696 mg,
10.71 mmol; 5.0 equiv) under argon in dry DMF (10 mL) at 70 °C
for 24 h. Thereafter, the resin was filtered; washed with DMF (3
 10 mL), water (3  10 mL),(3  10 mL), MeOH (3  10 mL), THF
(3 Â 10 mL), CH2Cl2 (3 Â 10 mL); and dried in a high vacuum to
afford (2.145 g) (97%) of resin 18. IR (KBr) v: 3025, 2922, 2097
4.5.4. Diphenyl((2S,4R)-4-(prop-2-yn-1-yloxy)pyrrolidin-2-yl)
methanol 15
To a solution of 14 (1.8 g, 5.4 mmol) in 15 mL of EtOH, potas-
sium hydroxide (1.5 g, 27.0 mmol, 5.0 equiv) in H2O (3 mL) was
added, and the reaction mixture was refluxing for overnight, until
complete conversion of the starting 14 (TLC control, 1:2 AcOEt/
hexanes). Then the reaction was cooled to room temperature,
and diluted with AcOEt (10 mL) and H2O (15 mL). After phase sep-
aration, the aqueous layer was washed with AcOEt (3 Â 10 mL).
The combined organic layers were washed with brine (30 ml),
and then dried over Na2SO4, and filtered. The filtrate was concen-
trated under reduced pressure to give 1.611 g (97%) of product
15 as a brown waxy solid, which was used for the next step with-
(azide), 1602, 1511, 1493, 1452, 1243, 1029, 759, 698, 538 cmÀ1
.
4.5.8. Wang resin-supported Hayashi–Jørgensen catalyst (cat. III)
To a solution of acetylenic proline 16 (100 mg, 0.263 mmol, 1.0
equiv) in dry CH2Cl2 (2 mL), azide resin 18 (263 mg), copper iodide
(2.5 mg, 0.013 mmol, 5 mol%) and N,N-diisopropylethylamine (46
lL, 0.263 mmol, 1.0 equiv) were added under argon, and the mix-
ture was left at room temperature for overnight. Thereafter, the
resin was filtered; washed with: water (3 Â 10 mL), MeOH (3 Â
10 mL), CH2Cl2 (3 Â 10 mL); and dried in a high vacuum to afford
(357 mg) (54%) of cat. III. IR (KBr) v: 3025, 2922, 1601, 1513,
out further purification. Spectroscopic data was complementary
with literature data.19 Rf = 0.15 (1:2 AcOEt/hexanes);
[a]
=
24
D
À111.1 (c 3.6, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.63–7.56 (m,
2H), 7.52–7.46 (m, 2H), 7.36–7.24 (m, 4H), 7.24–7.13 (m, 2H),
4.57 (dd, J 9.8, 6.6 Hz, 1H), 4.16 (ddt, J 3.5, 2.8, 1.7 Hz, 1H), 4.10
(d, J 1.8 Hz, 1H), 4.09 (d, J 1.8 Hz, 1H), 3.17 (dd, J 11.5, 4.3 Hz,
1H), 3.11 (ddd, J 4.0, 3.0, 1.6 Hz, 1H), 1.80 (ddd, J 13.8, 9.8, 5.3
Hz, 1H), 1.70–1.60 (m, 1H); 13C NMR (75 MHz, CDCl3) d 148.3,
145.5, 128.9, 128.7, 127.3, 127.1, 126.6, 126.0, 80.5, 80.1, 77.5,
74.8, 64.0, 56.7, 52.9, 33.4; IR (film) v: 3362, 3286, 2939, 1598,
1491, 1448, 1356, 1174, 1080, 986, 750, 701, 664, 636 cmÀ1; HRMS
1493, 1452, 1250, 1069, 838, 758, 698, 537 cmÀ1
.
4.5.9. Synthesis of nitrone 7 via organocatalytic Michael
addition catalyzed by Hayashi–Jørgensen catalyst (cat. I) and
subsequent reductive cyclization (Strategy I)
To a solution of nitroalkene 3 (72 mg, 0.37 mmol, 1.0 equiv) in
1 mL of CHCl3, Hayashi–Jørgensen catalyst cat. I (12 mg, 0.037
mmol, 10 mol%) and benzoic acid (22 mg, 0.185 mmol, 0.5 equiv)
were added, and the mixture was stirred at room temperature
for 10 min, then solution of aldehyde 2 (2.0 mmol, 2.0 equiv.) in
1 mL of CHCl3 was added. The resulting mixture was stirred for
90 min, at the same temperature until complete conversion of
the starting substrate (reaction progress was monitored by TLC
and 1H NMR). At the moment of complete conversion, the reaction
was quenched with satd aq CuSO4 (2 ml), and stirred for 15 min.
After phase separation, the aqueous layer was washed with CHCl3
(3 Â 1 mL). The combined organic layers were dried over Na2SO4,
and filtered. The filtrate was concentrated under reduced pressure
(ESI-TOF) m/z calcd for
C
20H22NO2 [M+H+] 308.1651. Found
308.1653.
4.5.5. (2S,4R)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-(prop-
2-yn-1-yloxy)pyrrolidine 16
To a solution of 15 (1.504 g, 4.89 mmol) in dry CH2Cl2 (20 mL),
Et3N (887 mL, 6.36 mmol, 1.3 equiv) was added under argon. The
resulting solution was stirred for 15 min, and then cooled to 0 °C.
Trimethylsilyltriflate (974 mL, 5.38 mmol, 1.1 equiv) was added
dropwise, and the resulting mixture was warmed gradually to
room temperature and stirred for overnight, until complete con-
version of the starting 15 (TLC control, 1:2 AcOEt/hexanes). Then
the reaction was quenched with H2O (10 ml). After phase separa-
tion, the aqueous layer was washed with CH2Cl2 (3 Â 10 mL). The
combined organic layers were washed with brine (30 ml), and then
dried over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to give the crude product, which was purified by
silica gel column chromatography (1:2 AcOEt/hexanes); to afford
1.628 g (88%) of 16 as a yellow oil. Spectroscopic data was comple-
mentary with literature data.19 Rf = 0.64 (1:2 AcOEt/hexanes);
at 20 °C (without bath hitting) to give 161 mg of crude c-nitroalde-
hydes 4 as a yellow oil, which was used for the next step without
further purification.
4.5.10. N-((2S,3R)-4-(Benzyloxy)-2-formyl-3-(nitromethyl)
butyl)-N-isobutylbenzenesulfonamide 4 (syn) and 4 (anti)
Inseparable mixture of diastereomers; [
a
]
24 = À4.9 (c 15.9,
D
CHCl3); syn/anti 92:8 (determined by 1H NMR of crude reaction
mixture); e.e. 97.2% (determined by HPLC of crude reaction mix-
ture); Rf = 0.33 (1:4 AcOEt/hexanes); major isomer 4 (syn) selected
signals: 1H NMR (300 MHz, CDCl3) d 9.81 (d, J 1.3 Hz, 1H), 4.60–
4.55 (m, 2H), 4.48 (d, J 1.3 Hz, 2H), 3.57 (d, J 4.5 Hz, 2H), 3.46
(dd, J 14.8, 8.0 Hz, 1H), 3.25 (dd, J 14.8, 5.4 Hz, 1H), 3.14–3.02 (m,
2H), 2.84 (d, J 7.6 Hz, 2H), 1.91–1.76 (m, 1H), 0.84 (d, J 4.5 Hz,
3H), 0.82 (d, J 4.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 202.3,
138.8, 137.8, 133.6, 129.9, 129.2, 128.7, 128.4, 128.0, 74.6, 74.2,
68.8, 58.7, 51.8, 47.5, 37.9, 27.6, 2Â20.7; minor isomer 4 (anti)
selected signals: 1H NMR (300 MHz, CDCl3) d 9.77 (d, J = 1.5 Hz,
[
a
]
24 = À42.4 (c 3.8, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.52–
D
7.45 (m, 2H), 7.38–7.32 (m, 2H), 7.32–7.19 (m, 6H), 4.33 (t, J 7.9
Hz, 1H), 4.07 (d, J 0.7 Hz, 1H), 4.06 (d, J 0.7 Hz, 1H), 3.98–3.91
(m, 1H), 2.97 (dd, J 11.8, 2.4 Hz, 1H), 2.81 (dd, J 11.8, 4.8 Hz, 1H),
2.37 (td, J 2.4, 0.7 Hz, 1H), 1.83 (s, 1H), 1.72 (d, J 4.0 Hz, 1H), 1.69
(d, J 3.9 Hz, 1H), À0.09 (s, 9H); 13C NMR (75 MHz, CDCl3) d 147.3,
146.0, 129.1, 128.3, 128.2, 128.1, 127.53, 127.45, 83.5, 80.7, 79.9,
´
Please cite this article in press as: Szczesniak, P.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.016

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P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
8
1H), 3.65 (dd, J = 10.1, 4.1 Hz, 1H), 3.55–3.49 (m, 2H), 3.34–3.28 (m,
1H), 3.00–2.92 (m, 1H); 13C NMR (75 MHz, CDCl3) d 201.3, 139.0,
137.7, 128.6, 76.1, 67.2, 58.4, 50.8, 47.9, 38.7; IR (film) v: 2963,
2871, 1720, 1554, 1338, 1160, 1091, 751, 692, 582 cmÀ1; HRMS
(ESI-TOF) m/z calcd for C23H30N2NaO6S [M+Na+] 485.1722. Found
485.1713; HPLC (Chiralcel OZ-H, 40% i-PrOH 60% n–hexane, flow
rate: 1.0 mL minÀ1, k = 210 nm, Tem. 21 °C); major isomer 4 (syn)
29.6 min, 36.4 min; minor isomer 4 (anti) 16.3 min, 96.0 min.
was removed by filtration and the reaction mixture was concen-
trated under reduced pressure to give the crude product, which
was purified by silica gel column chromatography (108:8:1
AcOEt/MeOH/30–33% NH3 aq) to give 21 mg (43%) of amine 1
(BZN) as a waxy solid. [a]
20 = +31.7 (c = 5.8; CHCl3); Rf = 0.15
D
(100% MeOH); 1H NMR (600 MHz, CDCl3) d 7.75 (d, J 7.4 Hz, 2H,
Ph), 7.52 (t, J 7.4 Hz, 1H, Ph), 7.45 (t, J 7.7 Hz, 2H, Ph), 7.32–7.22
(m, 4H, Ph), 4.46 (s, 2H, PhCH2O), 3.41–3.35 (m, 2H, CH2OBn),
3.13 (dd, J 14.0, 10.1 Hz, 1H), 3.07 (dd, J 11.0, 8.2 Hz, 1H,
NHCHHCHCH2OBn), 3.04–2.97 (m, 2H), 2.91 (dd, J 13.7, 7.5 Hz,
1H), 2.77 (dd, J 13.5, 7.4 Hz, 1H), 2.73 (dd, J 11.3, 5.8 Hz, 1H),
2.66 (dd, J 11.2, 5.7 Hz, 1H, NHCHHCHCH2OBn), 2.38–2.23 (m,
1H, NH), 2.20–2.13 (m, 1H, CHCH2NSO2Ph), 1.95 (dq, J 12.8, 6.5
Hz, 1H, CHCH2OBn), 1.87 (tt, J 13.9, 6.9 Hz, 1H, CH(CH3)2), 0.85
(d, J 6.6 Hz, 2H, CH3), 0.80 (d, J 6.6 Hz, 3H, CH3); 13C NMR (75
MHz, CDCl3) d 140.06, 138.96, 132.99, 129.58, 129.00, 128.20,
127.87, 73.82, 73.59, 57.60, 53.32, 52.16, 51.02, 44.37, 43.28,
27.71, 20.71; IR (film) v: 2960, 2926, 2869, 1448, 1336, 1158,
1092, 750, 693, 582 cmÀ1; HRMS (ESI-TOF) m/z calcd for C23H33N2-
O4S [M+H+] 417.2212. Found 417.2221.
To a solution of crude c-nitroaldehyde 4 (syn/anti 92:8) (161
mg, 1.0 mmol, 1.0 equiv.) in 2 mL of MeOH, Zn powder (48 mg,
0.74 mmol, 2.0 equiv) was added, the mixture was cooled to 0 °C,
and acetic acid (2.0 mL) was added. The reaction was stirred at 0
°C for 3 days. Then the reaction was quenched with 4 M aq NaOH
to pH = 7, and diluted with CH2Cl2 (5 mL). After phase separation,
the aqueous layer was washed with CHCl3 (3 Â 3 mL). The com-
bined organic layers were dried over Na2SO4, and filtered. The fil-
trate was concentrated under reduced pressure to give the crude
mixture of nitrones which was purified by silica gel column chro-
matography (1:4 MeOH/AcOEt); to afford 63 mg (40%) of nitrone 5
(trans), and 10 mg (6%) of nitrone 5 (cis).
4.5.11. (3R,4S)-3-((Benzyloxy)methyl)-4-((N-isobutylphenylsul-
fonamido)methyl)-3,4-dihydro-2H-pyrrole 1-oxide (5 trans)
4.5.14. Synthesis of amine 1 (BZN) via organocatalytic Michael
addition catalyzed by Hayashi–Jørgensen catalyst (cat. I) and
subsequent reductive cyclization (Strategy I)
Colorless oil; [a]
20 = +57.7 (c 5.0, CHCl3); 1H NMR (600 MHz,
D
CDCl3) d 7.78–7.76 (m, 2H, Ph), 7.60–7.57 (m, 1H, Ph), 7.50 (t, J
7.8 Hz, 2H, Ph), 7.38–7.34 (m, 2H, Ph), 7.33–7.29 (m, 3H, Ph),
7.00–6.99 (m, 1H, CH@NO), 4.54 (d, J 12.0 Hz, 1H, PhCHHO), 4.52
(d, J 11.9 Hz, 1H, PhCHHO), 4.21–4.16 (m, 1H, CHHNO), 3.88 (dd,
J 14.3, 6.2 Hz, 1H, CHHNO), 3.54 (d, J 9.6 Hz, 1H, CHHOBn), 3.52
(d, J 9.7 Hz, 1H, CHHOBn), 3.38–3.28 (m, 1H, CHCH2NSO2Ph), 3.26
(dd, J 14.2, 6.6 Hz, 1H, CHHNSO2Ph), 3.10 (dd, J 14.2, 8.0 Hz, 1H,
CHHNSO2Ph), 2.87 (dd, J 13.7, 8.0 Hz, 1H, CHH-i-Pr), 2.84 (dd, J
13.8, 7.3 Hz, 1H, CHH-i-Pr), 2.66 (qd, J 11.8, 5.9 Hz, 1H, CHCH2OBn),
1.79 (tt, J 13.8, 6.8 Hz, 1H, CH(CH3)2), 0.85 (d, J 6.6 Hz, 3H, CH3),
0.84 (d, J 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 139.17,
138.18, 136.22, 133.48, 129.82, 129.16, 128.57, 128.41, 127.92,
74.04, 71.26, 64.96, 58.62, 52.51, 45.97, 38.28, 27.74, 20.62,
20.56; IR (film) v: 3403, 2959, 2925, 2870, 1583, 1446, 1336,
1246, 1158, 1091, 996, 776, 751, 693, 582 cmÀ1; HRMS (ESI-TOF)
m/z calcd for C23H30N2NaO4S [M+Na+] 453.1824. Found 453.1819.
To a solution of nitroalkene 3 (72 mg, 0.37 mmol, 1.0 equiv) in
1 mL of CHCl3, Hayashi–Jørgensen catalyst cat. I (12 mg, 0.037
mmol, 10 mol%) and benzoic acid (22 mg, 0.185 mmol, 0.5 equiv)
were added, and the mixture was stirred at room temperature
for 10 min, then a solution of aldehyde 2 (100 mg, 0,37 mmol,
1.0 equiv) in 1 mL of CHCl3 was added. The resulting mixture
was stirred for ꢀ90 min, at the same temperature until complete
conversion of the starting substrate (reaction progress was moni-
tored by TLC and 1H NMR). At the moment of complete conversion,
the reaction was quenched with satd aq CuSO4 (2 ml), and stirred
for 15 min. After phase separation, the aqueous layer was washed
with CHCl3 (3 Â 1 mL). The combined organic layers were dried
over Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure at 20 °C (without bath hitting) to give 161 mg
of crude
the next step without further purification.
To a solution of crude -nitroaldehyde 4 in 2 mL of MeOH, Zn
c-nitroaldehydes 4 as a yellow oil, which was used for
c
4.5.12. (3R,4R)-3-((Benzyloxy)methyl)-4-((N-isobutylphenylsul-
fonamido)methyl)-3,4-dihydro-2H-pyrrole 1-oxide (5 cis)
powder (605 mg, 9.25 mmol, 25.0 equiv) was added, the mixture
was cooled to 0 °C, and acetic acid (2.0 mL) was added. The reac-
tion was stirred at 0 °C for 3 days. Then the reaction was quenched
with 4 M aq NaOH to pH = 7, and diluted with CH2Cl2 (5 mL). After
phase separation, the aqueous layer was washed with CHCl3 (3 Â 3
mL). The combined organic layers were dried over Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure to give
the crude product, which was purified by silica gel column chro-
matography (108:8:1 AcOEt/MeOH/30–33% NH3 aq); to afford
102 mg (66%) of amine 1 (BZN).
Colorless oil; [
a]
D
20 = À30.5 (c 2.5, CHCl3); 1H NMR (600 MHz,
CDCl3) d 7.75 (dd, J 8.4, 1.2 Hz, 2H, Ph), 7.61–7.57 (m, 1H, Ph),
7.51–7.47 (m, 2H, Ph), 7.34–7.29 (m, 3H, Ph), 7.26–7.24 (m, 2H,
Ph), 6.91–6.88 (m, 1H, CH@NO), 4.50–4.45 (m, 2H, PhCH2O), 4.06
(dd, J 14.0, 8.7 Hz, 1H, CHHNO), 3.89 (dd, J 13.9, 5.9 Hz, 1H,
CHHNO), 3.60–3.54 (m, 1H, CHCH2NSO2Ph), 3.55–3.50 (m, 2H, CH2-
OBn), 3.31 (dd, J 14.3, 4.7 Hz, 1H, CHHNSO2Ph), 3.19 (dd, J 14.3,
11.0 Hz, 1H, CHHNSO2Ph), 2.97–2.90 (m, 1H, CHCH2OBn), 2.84
(dd, J 13.7, 8.2 Hz, 1H, CHH-i-Pr), 2.80 (dd, J 13.7, 6.9 Hz, 1H,
CHH-i-Pr), 1.78 (tt, J 13.5, 6.7 Hz, 1H, CH(CH3)2), 0.89 (d, J 6.6 Hz,
3H, CH3), 0.87 (d, J 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d
138.99, 137.89, 136.97, 133.47, 129.82, 129.17, 128.63, 128.36,
127.96, 74.05, 68.38, 65.23, 58.67, 48.96, 44.07, 36.81, 30.30,
27.89, 20.65, 20.59; IR (film) v: 3386, 2960, 2925, 2870, 1585, 48,
337, 45, 1159, 1091, 751, 694, 582 cmÀ1; HRMS (ESI-TOF) m/z calcd
for C23H30N2NaO4S [M+Na+] 453.1824. Found 453.1805.
4.5.15. Synthesis of amine 1 (BZN) via organocatalytic Michael
addition catalyzed by POSS-supported Hayashi–Jørgensen
catalyst (cat. II) and subsequent reductive cyclization (Strategy
II)
To a solution of nitroalkene 3 (72 mg, 0.37 mmol, 1.0 equiv) in
2 mL of CHCl3, POSS-supported Hayashi–Jorgensen catalyst cat. II
(105 mg, 0.074 mmol, 20 mol%) was added, and the mixture was
stirred at room temperature for 10 min, then a solution of aldehyde
2 (100 mg, 0,37 mmol, 1.0 equiv) in 2 mL of CHCl3 was added. The
resulting mixture was stirred for 3 days, at the same temperature
until complete conversion of starting substrate (reaction progress
was monitored by TLC and 1H NMR). Then, solvent was removed
on rotary evaporation (at 20 °C without bath hitting), and the crude
4.5.13. Synthesis of amine 1 (BZN) via reduction of nitrone (5
trans)
To a methanolic solution (2 mL) of nitrone 5 (trans) catalytic
amount of Pd/C (10 wt.%) was added. The mixture was saturated
with hydrogen at ambient temperature for 24 h. Then the catalyst
´
Please cite this article in press as: Szczesniak, P.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.016

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9
P. Szczesniak et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
reaction mixture was treated with MTBE (10 mL) to precipitate the
References
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The combined MTBE filtrates were concentrated under reduced
pressure at 20 °C (without bath hitting) to give crude c-nitroalde-
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hyde 4, which was used for the next step without further
purification.
To a solution of crude c-nitroaldehyde 4 in 2 mL of MeOH, Zn
powder (605 mg, 9.25 mmol, 25.0 equiv) was added, the mixture
was cooled to 0 °C, and acetic acid (2.0 mL) was added. The reac-
tion was stirred at 0 °C for 3 days. Then the reaction was quenched
with 4 M aq NaOH to pH = 7, and diluted with CH2Cl2 (5 mL). After
phase separation, the aqueous layer was washed with CHCl3 (3 Â 3
mL). The combined organic layers were dried over Na2SO4, and fil-
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the crude product, which was purified by silica gel column chro-
matography (108:8:1 AcOEt/MeOH/30–33% NH3 aq); to afford 96
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Acknowledgements
The author is grateful to Polish National Science Center for
financial support of the research (Fuga 4 Grant No. DEC-2015/16/
S/ST5/00440).
The author is grateful to Artur Ulikowski for help in manuscript
preparation.
A. Supplementary data
Supplementary data (the copies of 1H, 13C NMR, NOE, HPLC
spectra) associated with this article can be found, in the online ver-
sion, at https://doi.org/10.1016/j.tetasy.2017.10.016.
´
Please cite this article in press as: Szczesniak, P.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.016