Synthesis and Resolution of a Chiral Diamine: 2,2′-(Propane-2,2-diyl)dipyrrolidine

Article abstract of DOI:10.1055/s-0036-1589023

A short and practical synthesis of a new chiral dipyrrolidine is presented. The three-step route includes a hydrogenation and a resolution with mandelic acid, which easily affords large quantities of the title compound.

Full text of DOI:10.1055/s-0036-1589023

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
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A. F. Kotthaus et al.
PSP
Synthesis
Synthesis and Resolution of a Chiral Diamine: 2,2′-(Propane-2,2-
diyl)dipyrrolidine
Andreas F. Kotthaus
Frederic Ballaschk
Vjoni Stakaj
Fabian Mohr
Stefan F. Kirsch*
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0-
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3
2-
6
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8
8-
7
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Bergische Universität Wuppertal,
Gaußstr. 20, 42119 Wuppertal,
Germany
sfkirsch@uni-wuppertal.de
Received: 24.03.2017
Accepted after revision: 07.04.2017
Published online: 18.05.2017
bipyrrolidine (5) were found to be excellent for our purpos-
es, the related methylene-bridged 2,2′-dipyrrolidine core 6
was, to our surprise, unknown. We now describe a short
and practical synthesis of this C2-symmetrical dipyrrolidine
unit, as shown in Scheme 1.
DOI: 10.1055/s-0036-1589023; Art ID: ss-2017-z0188-psp
Abstract A short and practical synthesis of a new chiral dipyrrolidine is
presented. The three-step route includes a hydrogenation and a resolu-
tion with mandelic acid, which easily affords large quantities of the title
compound.
H2 (70 bar)
O
TFA
Rh-Al2O3
AcOH, 23 °C
(93%)
+
N
(70%)
NH HN
NH HN
6
rac/meso = 55/45
Key words diamine, chiral, pyrrolidine, hydrogenation, resolution
H
7
OH
OH
Chiral diamines are present in a large number of natu-
rally occurring molecules.1 Recently, chiral diamines be-
came also a leading motif in ligand design for asymmetric
synthesis.2 As summarized in Figure 1, the diamine struc-
tures most widely used as ligands in metal-catalyzed reac-
tions are based on ethylenediamine (1), cyclohexanedi-
amine (2), BINAM (3), sparteine (4), and 2,2′-bipyrrolidine
(5).3 In particular, fields like copper-catalyzed arylations,4
oxidations,5 and asymmetric deprotonations6 have profited
from readily available diamine compounds.
NaOH
(2.5 N)
NH
6
NH
(S)-mandelic acid
Ph
(R,R)-6
2
recrystallization
(80%)
(97%)
O
>99% ee
NH
NH
(R,R)-6
OH
NaOH
(2.5 N)
NH
6
NH
NH
(R)-mandelic acid
OH
Ph
(S,S)-6
2
recrystallization
(75%)
(97%)
O
>99% ee
NH
(S,S)-6
Scheme 1 Synthesis of the chiral dipyrrolidine 6
We started the synthesis of dipyrrolidine 6 using a mod-
ified protocol by Neier and co-workers: Pyrrole and acetone
were condensed in the presence of trifluoroacetic acid,
yielding the dipyrrole 7 in 70% yield.8 As the next step, the
dipyrrole was converted to a mixture of rac- and meso-
dipyrrolidine 6 in a ratio of 55:45 (by 1H NMR). This hydro-
genation was improved greatly over the partial one previ-
ously reported9 by employing rhodium on activated alumi-
na as the hydrogenation catalyst in acetic acid. The crude
mixture of dipyrrolidines was obtained in almost quantita-
tive yield, and the purity was sufficient for the subsequent
resolution step. At this point, precipitation of the diamine
mixture with (S)-mandelic acid and recrystallization from
acetone–ethanol gave an 80% yield of the (R,R)-6 (S)-man-
NH2
NH2
3
NH2
H2N
H2N
2
NH2
1
N
N
4
NH HN
6
N
N
H
5
H
Figure 1 Diamine motifs
During our research aiming at Lewis base catalyzed hy-
drosilylations,7 we became interested in chiral diamines
with C2-symmetry. While derivatives of the standard 2,2′-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

B
A. F. Kotthaus et al.
PSP
Synthesis
delic acid salt. Accordingly, the mother liquor from the res-
olution of the one enantiomer could be treated with (R)-
mandelic acid to obtain the (S,S)-6 salt.
CuI (5 mol%)
rac-6 (10 mol%)
K3PO4
O
H
N
I
NH2
+
O
dioxane, 110 °C
(85%)
The mandelic acid salts were simply treated with aque-
ous NaOH (2.5 N) to obtain the diamines 6 in pure form
(Scheme 1). To determine the enantiomeric access of the di-
amine compounds, derivatization with benzoyl chloride
was required. The corresponding diamides were then easily
analyzed with chiral HPLC: Both diamine enantiomers were
formed with an enantiopurity of >99% ee, and almost free
of any residual meso-diastereomer.
8
9
10
NH
Ph
N
CHO
(S,S)-11 (6 mol%)
+
NO2
Ph
CHO
NO2
hexanes, 23 °C
(92%)
Ph
95% ee
12
13
14
dr 93:7
As shown in Figure 2, the absolute configuration of the
dipyrrolidine (S,S)-6 was determined by an X-ray crystallo-
graphic analysis of the (R)-mandelic acid salt. The structure
unequivocally proves that the (R)-mandelic acid crystal-
lized with the (S,S)-6 (see the Supporting Information for
detailed X-ray crystal data).
Scheme 2 Selected reactions with diamine 6
In summary, a new chiral diamine with C2-symmetry
was introduced. The short multigram synthesis provides
the methylene-bridged dipyrrolidine in excellent enatiopu-
rity through resolution. We encourage researchers to use
this diamine core for all types of future efforts.
All reagents and solvents were purchased from commercial sources
and were used as received. NMR spectra were recorded using a
Bruker Avance 400 or a Bruker Avance III 600 spectrometer. All 1H and
13C NMR chemical shifts are reported in parts per million (ppm) using
1
1
the solvent signal (CDCl3: H 7.26 ppm, 13C 77.16 ppm; DMSO-d6: H
2.50 ppm, 13C 39.52 ppm) as reference. Multiplicities are indicated
with standard abbreviations. All coupling constants (J) are reported in
hertz (Hz). IR spectra were recorded using ATR technique on a Bruker
ALPHA FT-IR spectrometer. High-resolution mass spectra were ob-
tained on a Bruker MicroTOF using ESI or APCI ionization methods.
Low-resolution mass spectra were taken on an Agilent MSD-5975C
using EI ionization. Single crystal X-ray diffraction studies were per-
formed on an Oxford Diffraction Gemini Ultra diffractometer. Flash
chromatography was performed with silica gel 43–60 μm (VWR
Chemicals). TLC was performed on aluminum plates precoated with
silica gel 60 F254 (Merck), and components were visualized by obser-
vation under UV light or by treating the plates with KMnO4 or CAM
(cerium ammonium molybdate in dil H2SO4) or ninhydrin (in EtOH).
Enantiomeric purities were determined using chiral HPLC (Agilent
1200 series, Chiralpak IA or Chiralcel OD-H column with solvent mix-
tures consisting of heptane and i-PrOH).
Figure 2 Crystal structure of the (S,S)-6 salt; ellipsoids are drawn at
30% probability
2,2′-(Propane-2,2-diyl)di(1H-pyrrole) (7)
Trifluoroacetic acid (1.3 mL, 17 mmol) was slowly added to a vigor-
ously stirred solution of pyrrole (95 mL, 1.37 mol) and acetone (12
mL, 0.163 mol) under an argon atmosphere. The temperature of the
reaction mixture was maintained below 80 °C in a water bath. After 5
min, the reaction was quenched with aq NaOH (1.1 g in 1 mL H2O, 28
mmol). Unreacted pyrrole and H2O were removed by distillation at 40
mbar. The residue was then distilled to provide 19.8 g (70%) of the ti-
tle compound as a colorless solid (bp 110–120 °C/~1 × 10–3 mbar); mp
56–59 °C.
We then briefly tested the chiral diamine in arbitrarily
selected reactions: The copper-catalyzed formation of
amide 10 through arylation was, for example, possible in
the presence of racemic diamine 6 in 85% yield (Scheme
2).10 The reaction of trans-β-nitrostyrene (12) with pro-
panal (13) was efficiently catalyzed by amino catalyst 11,
derived from diamine (S,S)-6 through arylation.11,12 The
nitro-containing product 14 was formed in 92% yield with a
dr of 93:7 (syn/anti) and 95% ee.
1H NMR (400 MHz, CDCl3): δ = 7.58 (s, 2 H), 6.58 (td, J = 2.7, 1.6 Hz, 2
H), 6.16 (dt, J = 3.4, 2.6 Hz, 2 H), 6.12 (ddd, J = 3.4, 2.7, 1.6 Hz, 2 H),
1.64 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 139.2, 117.2, 107.8, 103.9, 35.4, 29.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

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A. F. Kotthaus et al.
PSP
Synthesis
MS (EI, 70 eV): m/z (%) = 174 (18, M+), 159 (64), 92 (100), 67 (22), 65
(S,S)-2,2′-(Propane-2,2-diyl)di(pyrrolidin-1-ium) Bis[(R)-hy-
(30).
droxy(phenyl)]acetate
HRMS-APCI: m/z [M + H]+ calcd for C11H15N2: 175.1230; found:
175.1230.
The mother liquors (taken from the resolution of the other enantio-
mer) were concentrated in vacuo and then dissolved in aq 2.5 N NaOH
(pH >12). This solution was extracted with Et2O (3 × 100 mL), dried
(K2CO3), and the solvent was removed under reduced pressure. The
recovered material (14.0 g, max. 77 mmol) was dissolved in acetone
(45 mL) and heated to reflux using an oil bath (90 °C). Then, (R)-man-
delic acid (23.4 g, 154 mmol) was added in one portion and stirred
vigorously for 1 min before the oil bath was removed. The solution
was cooled down to r.t. and then to 0 °C in an ice bath (1 h). The color-
less precipitate was collected by suction and washed with acetone (3
×). The filter residue was suspended in EtOH (60 mL) and refluxed for
2 h. Then, acetone (60 mL) was added slowly and the solution was
cooled down to r.t. and then to 0 °C in an ice bath (1 h). After suction,
the solid was washed with acetone (3 × 30 mL) and purified again, as
detailed above, to provide 10.5 g (75% based on the isomer content,
>99% ee, >99:1 dr) of the title compound as colorless needles; mp
185–186 °C.
The analytical and spectral data were in complete agreement with the
previously published data.8
rac- and meso-2,2′-(Propane-2,2-diyl)dipyrrolidine (6)
2,2′-(Propane-2,2-diyl)di(1H-pyrrole) (7; 19.5 g, 112 mmol) was dis-
solved in AcOH (350 mL). Then, 5% Rh on activated alumina (1.95 g,
0.95 mmol Rh) was added, and the reaction mixture was placed in an
autoclave. After flushing the apparatus with H2 for 5 min, the mixture
was stirred for 18 h under H2 atmosphere (70 bar) at r.t. The catalyst
was removed by filtration over Celite and the filtrate was concentrat-
ed in vacuo. The residue was dissolved in aq 2.5 N NaOH (pH >12),
and the mixture was extracted with Et2O (3 ×). The combined organic
extracts were dried (K2CO3) and the solvent was removed under re-
duced pressure. The crude product (yellow oil) contained a mixture of
rac- and meso-2,2′-(propane-2,2-diyl)dipyrrolidine (6; 19.0 g, max.
93%, ratio 55:45 by 1H NMR) and was pure enough for the subsequent
resolution step.
1H NMR (400 MHz, CDCl3): δ = 2.98–2.87 (m), 2.83–2.72 (m), 1.81 (br
s), 1.70–1.57 (m), 1.48–1.36 (m), 0.84 (s, CH3 meso), 0.82 (s, CH3 rac),
0.77 (s, CH3 meso).
13C NMR (101 MHz, CDCl3): δ = 67.3, 66.1, 47.2, 47.1, 38.5, 38.2, 26.7,
26.5, 25.9, 25.7, 21.0, 20.5, 17.5.
The enantiomeric excess was determined after derivatization with
benzoyl chloride by chiral HPLC [Chiralpak IA, heptane–i-PrOH 7:3,
0.8 mL/min, tR (meso) = 8.3 min, tR (S,S) = 10.4 min, tR (R,R) = 16.6
min].
IR (ATR): 3408, 3381, 2971, 2951, 2894, 2723 (br), 2410 (br), 1636,
1345, 1324, 1058, 739 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.41–7.36 (m, 4 H), 7.30–7.23 (m, 4
H), 7.22–7.16 (m, 2 H), 6.21 (br s, 6 H), 4.71 (s, 2 H), 3.34–3.26 (m, 2
H), 3.00–2.93 (m, 2 H), 2.90–2.82 (m, 2 H), 1.85–1.74 (m, 4 H), 1.68–
1.56 (m, 4 H), 0.86 (s, 6 H).
(R,R)-2,2′-(Propane-2,2-diyl)di(pyrrolidin-1-ium) Bis[(S)-hy-
droxy(phenyl)]acetate
13C NMR (151 MHz, DMSO-d6): δ = 174.9, 142.6, 127.5, 126.5, 126.3,
To a hot (oil bath 90 °C) and vigorously stirred solution of crude rac-
and meso-2,2′-(propane-2,2-diyl)dipyrrolidine (6; 19 g, max. 104
mmol) in acetone (50 mL), was added (S)-mandelic acid (31.7 g, 208
mmol) in one portion. After 1 min, the oil bath was removed, and the
solution was cooled down to r.t. and then to 0 °C in an ice bath (1 h).
The colorless precipitate was collected by suction and was washed
with acetone (3 ×) [the mother liquor was saved for the recovery of
the (S,S)-2,2′-(propane-2,2-diyl)dipyrrolidine, see below]. The filter
residue was suspended in EtOH (60 mL) and refluxed for 2 h. Then,
acetone (60 mL) was added slowly and the solution was cooled down
to r.t. and then to 0 °C in an ice bath (1 h). After suction, the solid was
washed with acetone (3 × 30 mL) and purified twice, as detailed
above, to provide 11.22 g (80% based on the isomer content, >99% ee,
>99:1 dr) of the title compound as colorless needles; mp 185–186 °C.
73.2, 64.9, 45.1, 36.1, 25.4, 24.5, 20.6.
HRMS-ESI: m/z [M – 2 × mandelic acid + H]+ calcd for C11H23N2:
183.1856; found: 183.1855.
(R,R)-2,2′-(Propane-2,2-diyl)dipyrrolidine [(R,R)-6]
(R,R)-2,2′-(Propane-2,2-diyl)di(pyrrolidin-1-ium)
bis[(S)-hy-
droxy(phenyl)]acetate (1.50 g, 3.08 mmol) was dissolved in aq 2.5 N
NaOH (pH >12) and extracted with Et2O (4 × 5 mL). The combined or-
ganic phases were dried (K2CO3) and then concentrated in vacuo to
provide 550 mg (97%) of the title compound as a colorless liquid;
[α]D25 +17.6 (c 1.00, MeOH).
IR (ATR): 3289, 2959, 2869, 1466, 1385, 1080, 1052, 802, 557 cm–1
1H NMR (400 MHz, CDCl3): δ = 3.01–2.88 (m, 4 H), 2.84–2.72 (m, 2 H),
1.86 (br s, 2 H), 1.71–1.59 (m, 6 H), 1.52–1.35 (m, 2 H), 0.83 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 66.1, 47.1, 38.2, 26.5, 25.9, 20.5.
MS (EI, 70 eV): m/z (%) = 182 (4, M+), 113 (17), 96 (56), 81 (19), 70
.
The enantiomeric excess was determined after derivatization with
benzoyl chloride by chiral HPLC [Chiralpak IA, heptane–i-PrOH 7:3,
0.8 mL/min, tR (meso) = 8.3 min, tR (S,S) = 10.4 min, tR (R,R) = 16.6
min].
(100), 56 (12).
IR (ATR): 3408, 3382, 2972, 2950, 2894, 2724 (br), 2407 (br), 1636,
1345, 1324, 1058, 739 cm–1
.
HRMS-ESI: m/z [M + H]+ calcd for C11H23N2: 183.1856; found:
183.1853.
1H NMR (600 MHz, DMSO-d6): δ = 7.41–7.34 (m, 4 H), 7.31–7.23 (m, 4
H), 7.24–7.16 (m, 2 H), 6.10 (br s, 6 H), 4.71 (s, 2 H), 3.34–3.26 (m, 2
H), 3.00–2.93 (m, 2 H), 2.91–2.82 (m, 2 H), 1.85–1.74 (m, 4 H), 1.68–
1.56 (m, 4 H), 0.86 (s, 6 H).
(S,S)-2,2′-(Propane-2,2-diyl)dipyrrolidine [(S,S)-6]
(S,S)-2,2′-(Propane-2,2-diyl)di(pyrrolidin-1-ium)
bis[(R)-hy-
13C NMR (151 MHz, DMSO-d6): δ = 174.9, 142.6, 127.5, 126.5, 126.3,
73.2, 64.9, 45.1, 36.1, 25.4, 24.5, 20.6.
HRMS-ESI: m/z [M – 2 × mandelic acid + H]+ calcd for C11H23N2:
183.1856; found: 183.1856.
droxy(phenyl)]acetate (1.50 g, 3.08 mmol) was dissolved in aq 2.5 N
NaOH (pH >12) and extracted with Et2O (4 × 5 mL). The combined or-
ganic phases were dried (K2CO3) and then concentrated in vacuo to
provide 550 mg (97%) of the title compound as a colorless liquid;
[α]D25 –17.8 (c 1.00, MeOH).
IR (ATR): 3287, 2959, 2869, 1466, 1385, 1080, 1052, 804, 557 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

D
A. F. Kotthaus et al.
PSP
Synthesis
1H NMR (400 MHz, CDCl3): δ = 3.00–2.89 (m, 4 H), 2.83–2.73 (m, 2 H),
1.81 (br s, 2 H), 1.72–1.58 (m, 6 H), 1.52–1.36 (m, 2 H), 0.83 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 66.1, 47.1, 38.2, 26.5, 25.9, 20.5.
MS (EI, 70 eV): m/z (%) = 182 (4, M+), 113 (16), 96 (59), 81 (21), 70
tracted with Et2O (3 × 0.75 mL). The combined organic extracts were
dried (MgSO4) and then concentrated in vacuo. The residue was puri-
fied by flash column chromatography (cyclohexane–EtOAc, 10 to 30%
EtOAc) to yield 64 mg (92%) of the desired aldehyde as a colorless oil;
syn/anti = 93:7 (by 1H NMR of the crude mixture), 95% ee (syn).
(100), 56 (14).
The enantiomeric excess was determined by HPLC [Chiralcel OD-H,
heptane–i-PrOH 9:1, 1.0 mL/min, tR (syn major) = 29.9 min, tR (syn
minor) = 21.0 min].
HRMS-ESI: m/z [M + H]+ calcd for C11H23N2: 183.1856; found:
183.1857.
1H NMR (400 MHz, CDCl3): δ = 9.71 (d, J = 1.7 Hz, 1 H), 7.36–7.26 (m, 3
H), 7.19–7.14 (m, 2 H), 4.79 (dd, J = 12.7, 5.5 Hz, 1 H), 4.68 (dd, J =
12.7, 9.3 Hz, 1 H), 3.81 (td, J = 9.1, 5.5 Hz, 1 H), 2.82–2.72 (m, 1 H),
1.00 (d, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.3, 136.7, 129.2, 128.3, 128.2, 78.2,
48.6, 44.2, 12.3.
N-(4-Methylphenyl)benzamide (10)
A 4 mL vial was charged with benzamide (73 mg, 0.6 mmol, 1.2
equiv), K3PO4 (222 mg 1.05 mmol, 2.1 equiv), and CuI (4.76 mg, 0.025
mmol, 5 mol%). p-Iodotoluene (109 mg, 0.5 mmol, 1 equiv) and rac-6
(9 mg, 0.05 mmol, 10 mol%), dissolved in 1,4-dioxane (0.5 mL), were
added to the mixture and the reaction mixture was stirred at 110 °C
for 24 h under an argon atmosphere. The mixture was diluted with
EtOAc (1–2 mL), filtered through a short pad of silica gel, and washed
with EtOAc (5–10 mL). The filtrate was concentrated under reduced
pressure to provide the crude product, which was purified by column
chromatography (cyclohexane–EtOAc 90:10) to afford 90 mg (85%) of
10 as a white solid; Rf = 0.54 (cyclohexane–EtOAc 1:1 [UV]).
The analytical data were in complete agreement with the previously
published data.14
Supporting Information
Supporting information for this article is available online at
1H NMR (600 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.87–7.83 (m, 2 H), 7.57–
7.50 (m, 3 H), 7.49–7.43 (m, 2 H), 7.16 (d, J = 8.1 Hz, 2 H), 2.34 (s, 3 H).
https://doi.org /10.1055/s-0036-1589023.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
13C NMR (151 MHz, CDCl3): δ = 165.8, 135.5, 135.3, 134.4, 131.8,
129.7, 128.9, 127.1, 120.5, 21.0.
References
MS (EI): m/z (%) = 211.1 (10), 106.1 (9), 105.1 (100), 77.1 (72), 51.1
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The analytical and spectral data were in complete agreement with the
previously published data.13
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(2S)-1-Phenyl-2-{2-[(2S)-pyrrolidin-2-yl]propan-2-yl}pyrrolidine
[(S,S)-11]
(S,S)-2,2′-(Propane-2,2-diyl)dipyrrolidine [(S,S)-6; 150 mg, 0.823
mmol), bromobenzene (95 μL, 0.905 mmol), and KOt-Bu) (146 mg,
95%, 1.23 mmol) were suspended in xylene (5 mL) and heated for 45
min to 210 °C in a microwave reactor. After the mixture was cooled
down to r.t., the solids were filtered off and the solvent was removed
under reduced pressure. The residue was purified by flash column
chromatography (CH2Cl2–MeOH–25% aq NH3 93:5:2) to yield 119 mg
25
(56%) of the title compound as a colorless oil; [α]D +13.6 (c 1.365,
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IR (ATR): 3354, 3057, 2961, 2869, 1595, 1501, 1474, 1361, 1319, 1292,
1156, 1077, 991, 960, 745, 693, 524 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.17 (m, 2 H), 6.90–6.86 (m, 2 H),
6.67 (tt, J = 7.1, 1.1 Hz, 1 H), 4.07 (dd, J = 8.3, 1.7 Hz, 1 H), 3.63–3.57
(m, 1 H), 3.35–3.26 (m, 1 H), 3.01–2.87 (m, 2 H), 2.82–2.76 (m, 1 H),
2.09–1.96 (m, 1 H), 1.96–1.56 (m, 6 H), 1.54–1.43 (m, 1 H), 0.91 (s, 3
H), 0.84 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 151.4, 128.7, 116.2, 114.1, 65.2, 63.7,
52.8, 47.1, 43.0, 26.8, 26.8, 26.2, 24.9, 21.2, 20.6.
(9) Journot, G.; Neier, R.; Stoeckli-Evans, H. Acta Crystallogr., Sect. C
2012, 68, o119.
HRMS-ESI: m/z [M + H]+ calcd for C17H27N2: 259.2169; found:
(10) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
259.2172.
(11) For the arylation protocol, see: Shi, L.; Wang, M.; Fan, C.-A.;
Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515.
(12) (a) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach,
D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719. (b) Seebach, D.;
Sun, X.; Sparr, C.; Ebert, M.-O.; Schweizer, W. B.; Beck, A. K. Helv.
Chim. Acta 2012, 95, 1064.
(2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (14)
Propanal (242 μL, 3.35 mmol, 10 equiv) was added to a suspension of
(S,S)-11 (5 mg, 0.02 mmol, 0.06 equiv) and trans-β-nitrostyrene (12;
50 mg, 0.335 mmol, 1 equiv) in n-hexane (1 M). The reaction mixture
was stirred at r.t. for 5 h. Then aq 1 N HCl (1 mL) was added and ex-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

E
A. F. Kotthaus et al.
PSP
Synthesis
(13) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.; Qi, X.; Lan, Y.; Lei, A. Angew.
Chem. Int. Ed. 2014, 53, 502.
(14) (a) Petruzziello, D.; Gualandi, A.; Grilli, S.; Cozzi, P. G. Eur. J. Org.
Chem. 2012, 6697. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji,
M. Angew. Chem. Int. Ed. 2005, 44, 4212. (c) Betancort, J. M.;
Barbas, C. F. III Org. Lett. 2001, 3, 3737.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E