Nitroprolinates as Nucleophiles in Michael-type Additions and Acylations. Synthesis of Enantiomerically Enriched Fused Amino-pyrrolidino-[1,2-a]pyrazinones and -diketopiperazines

Article abstract of DOI:10.1002/cctc.201902382

The enantioselective formation of nitroprolinates followed by diastereoselective Michael-type addition onto a second unit of the nitro alkene is studied. The reaction occurred in a one pot-sequential process controlled by the chiral phosphoramidite?silver benzoate complex. The origin of the high diastereoselectivity is studied by DFT computational analysis where the crucial effect of the benzoic acid is justified. The employment of this strategy to the preparation of pyrazine-2-ones is also surveyed, as well as the preparation of diketopiperazines from enantiomerically enriched exo-prolinates using conventional N-acylation-amination-cyclization steps.

Full text of DOI:10.1002/cctc.201902382

Accepted Article
Title: Nitroprolinates as nucleophiles in Michael-type additions and ac-
ylations. Synthesis of enantiomerically enriched fused amino-
pyrrolidino-[1,2-a]pyrazinones and -diketopiperazines
Authors: Jose Miguel Sansano, Eduardo García-Mingüens, Verónica
Selva, Olatz Larrañaga, Carmen Nájera, and Abel de Cózar
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To be cited as: ChemCatChem 10.1002/cctc.201902382
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10.1002/cctc.201902382
ChemCatChem
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Nitroprolinates as nucleophiles in Michael-type additions and ac-
ylations. Synthesis of enantiomerically enriched fused amino-
pyrrolidino-[1,2-a]pyrazinones and -diketopiperazines
Eduardo García-Mingüens,[a][b][c] Verónica Selva,[a][b][c] Olatz Larrañaga,[b][d] Carmen Nájera,[a][b] José M.
Sansano,*[a][b][c] and Abel de Cózar,*[b][d][e]
Dedicated to Prof. H. Ila on the occasion of her 75th birthday.
[a]
Mr. E. García-Mingüens, Dr. V. Selva, Prof. C. Nájera, Prof. J. M. Sansano
Departamento de Química Orgánica. Facultad de Ciencias.
Universidad de Alicante, 03080-Alicante, Spain.
E-mail: jmsansano@ua.es
[b]
[c]
Centro de Innovación en Química Avanzada (ORFEO-CINQA)
Instituto de Síntesis Orgánica (ISO).
Universidad de Alicante, 03080-Alicante, Spain.
[d]
Dr. O. Larrañaga, Dr A. de Cózar
Departamento de Química Orgánica I, Facultad de Química
Universidad del País Vasco/Euskal Herriko Unibertsitatea UPV/EHU, and Donostia International Physics Center (DIPC), P. K. 1072, E-20018 San
Sebastián, Spain.
E-mail: abel.decozar@ehu.eus
[e]
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
Supporting information for this article is given via a link at the end of the document.
Abstract: The enantioselective formation of nitroprolinates followed
by diastereoselective Michael-type addition onto a second unit of the
nitro alkene is studied. The reaction occurred in a one pot-sequential
process controlled by the chiral phosphoramidite·silver benzoate
complex. The origin of the high diastereoselectivity is studied by DFT
computational analysis where the crucial effect of the benzoic acid is
justified. The employment of this strategy to the preparation of
pyrazine-2-ones is also surveyed, as well as the preparation of
diketopiperazines from enantiomerically enriched exo-prolinates
using conventional N-acylation-amination-cyclization steps.
mixture.[10] Michael-type addition of ketones to nitroalkenes[11] and
three component ketone-carboxylic acid-nitroalkene
a
cyclization[12] were successfully organocatalyzed by chiral exo-6b
(X = H), providing good to excellent diastereoselections and high
enantiomeric ratios. A series of enantiopure tetrasubstituted
nitroprolinate surrogates has been designed as scaffolds for
proteasome inhibitors with high medicinal prospects.[ 13 ] In
addition, the NH-D-EhuPhos ligand 7 has been efficiently
employed in the 1,3-dipolar cycloadditions (1,3-DC) to yield
nitroprolinates and structurally rigid spirocompounds from chiral
γ-lactams.[9, 14 , 15 ] exo-6a Series were employed as amino
component in the multicomponent amino-aldehyde-dienophile
(AAD)[8] reaction affording chiral cyclohex-2-enyl amines and in
two different multicomponent 1,3-cycloadditions furnishing
pyrrolizidines.[8,16]
Introduction
Nitroprolinates constitute a small series of compounds whose
importance in many scientific areas has recently been
demonstrated.[ 1 ] For example, optically active polysubstituted
nitroprolinates 1 (Figure 1) are important inhibitors of α4,β1-
integrin-mediated hepatic melanoma and in a murine model of
colon carcinoma metastasis, as well as potent antiadhesive
properties in several cancer cell lines.[2,3] Bicyclic heterocycles 2,
have been found as inhibitors of skin cancer.[4] Spiroxindoles 3
increased the mortality of zebrafish embryos,[5] and molecules 4
were tested as antimycobacterials against M. tuberculosis H37Rv
strain.[6] A family of enantiomerically enriched spironitroprolinates
5 were obtained by our group from imino lactones and
nitroalkenes which are currently tested as anticancer agents.[7]
The presence of the nitro group in this skeleton induced special
conformations of the five membered ring causing spectacular
effects in its biological activity and its chemical reactivity.[8]
Figure 1. Nitroprolinates with biological properties and utility in organic
synthesis.
According to the experience of our group in the synthesis[7]
of the enantiomerically enriched nitroprolinates 6,[17,18] and the
reactivity exhibited by the amino moiety of these structures 6-7,
we focused our interest in the Michael type addition of the chiral
Diastereomeric exo-6 and endo-6 4-nitroprolinates have
been used as chiral organocatalysts in aldol reactions.[9] endo-6
Preferentially promoted the polymerization of D-lactide, whereas
exo-6 preferentially polymerized L-lactide from
a racemic
1
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10.1002/cctc.201902382
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pyrrolidines 6. So, in this work we studied the scope and the
stereochemical course of the one pot process starting from imino
ester 9a and 8a to yield compound 10a (Scheme 1), avoiding the
isolation of intermediate exo-6a. That means, performing a
domino enantioselective pyrrolidine formation-diastereoselective
Michael addition onto the nitroalkene to provide the
corresponding adducts, which can be further transformed into
fused nitropyrrolidine-heterocycles. The support of DFT
calculations to the mechanistic outcomes, as well as additions of
other Michael-type acceptors will be surveyed. In addition, N-
acylations of 6 with -chloroacetyl chlorides to provide fused
nitropyrrolidine-diketopiperazines will be discussed.
2
3
4
BzOH (0.5)
BzOH (1)
AcOH (1)
50:50
<2:98
35:65
nd
>98:2
>98:2
>98:2
84%
nd
a Determined by 1H NMR of the crude reaction mixture. b Isolated yield after flash
chromatography. Mixture of 4 diastereomers. Determined by 1H NMR of the
c
crude reaction mixture and in the final purified sample.
The absolute configuration of the new stereogenic center
was unambiguously determined by both X-ray diffraction analysis
and also by vibrational circular dichroism (VCD). In both cases the
structure of compound 10a matched with a (S)-configuration[20]
(see SI).
In the presence of benzoic acid (1 equiv) at rt during 17 h
products 10 were satisfactorily obtained with a very high
diastereoselectivity (Figure 2). For compounds 10a,c and 10e the
same nitroalkene was employed for both enantioselective
cycloaddition and Michael-type addition. However, it was also
possible to introduce
a
different nitroalkene once the
enantioselective cycloaddition took place (Figure 2, products
10b,d). In these examples only one equivalent of nitroalkene was
needed in the first step, meanwhile the other different nitroalkene
(8a, 1 equiv) was added together with the benzoic acid after 17 h.
Despite many attempts and combinations of structural
parameters in all components of the reaction, the scope was
reduced to those examples shown in Figure 2.
The high influence of the chiral silver catalyst in both the
1,3–DC and the Michael addition was analyzed by means of DFT
calculations. Within the accepted 1,3–DC reaction mechanism
(Scheme 2), the last step consists in the reaction of the silver–
pirrolidine INT3 with fresh imine 9a to recover the initial
azomethine ylide INT1[ 21 ] and generate final product exo–6a
(Scheme 2, see SI for further details about 1,3–DC analysis). We
hypothesize that exo–6a formation is an irreversible step, and
therefore, it is not possible to form INT3 (and consequently 10a)
by using exo–6a as starting reagent. In fact, the reaction of
isolated exo–6a, chiral silver(I) complex, β-nitrostyrene 8a, and
benzoic acid did not occur. So, the experimental evidences
support that presence of small amounts of INT3 in this sequential-
one pot process is crucial to promote the Michael-type addition.
Scheme 1. Design of the synthesis of Michael-type adducts 10 in one pot
process from imino ester 9a for the preparation of fused nitropyrrolidino-
pyrazinones and of its acylation for the synthesis of nitropyrrolidino-
diketopiperazines.
Results and Discussion
Initially, we employed the conditions for the synthesis of
enantiomerically enriched exo-6 compounds, described by our
group, but using two equivalents of nitrostyrene. The optimization
is briefly summarized in Table 1. Despite the reaction was
observed in the presence of the reagents involved in the synthesis
of exo-cycloadduct 6, we first tried to perform the reaction of pure
exo-6a with β-nitrostyrene (8a) but no reaction product was
detected. So, the chiral silver complex has a crucial effect not only
in the synthesis of the chiral prolinate but in the Michael-type
addition.[ 19 ] Basic conditions promoted the retro-Michael type
addition obtaining pure exo-6a cycloadduct (Table 1, entry 1). The
addition of several amounts of benzoic acid resulted to be
beneficial, the highest amount of acid the highest yield of 10a was
isolated (Table 1, entries 2 and 3). The replacement of benzoic
acid by acetic acid was not productive lowering the percentage of
10a (Table 1, entry 4). The addition of 1.5 or 2.0 equiv of benzoic
acid instead of 1 equiv did not improve the results of the reaction.
Table 1. Optimization of the reaction parameters of the synthesis of
compound 10a.
Figure 2. Compounds 10 isolated and characterized.
We postulate that INT3 can further react with the excess of
β-nitrostyrene in the absence of benzoic acid to ultimately form
compound 10a (Scheme 2, route a). Within this route, our
calculations shown that formation of RC2 is only slightly favoured
entry
1
additive (equiv)
---
6a:10a[a]
yield of 10a (%)[b]
10a dr [c]
>98:2
---
nd
2
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10.1002/cctc.201902382
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(0.3 kcal·mol-1) and the Gibbs’ barrier activation is of 9.6 kcal·mol-
1 (see SI for further details). These results indicate that formation
of 10a by merely adding a second equivalent of β-nitrostyrene to
the reaction mixture is not a kinetically favored reaction.
In addition, we also analyzed computationally the effect of
adding benzoic acid (Scheme 2, route b). In this case, the additive
effect is twofold: firstly, the phenyl ring of benzoic acid interacts
with the aromatic rings of the ligand. This -stacking interaction
strongly stabilizes RC2’ (see SI).[22] Moreover, it enhances β-
nitrostyrene electrophilicity (as reflected with the lower activation
barrier of TS3’ compared to TS3). Remarkably, both factors
prompt 10a formation.[23]
Exploration of all the possible transition structures
associated with the Michael addition step showed the preferential
reactivity of the S–prochiral face of β-nitrostyrene. The high
selectivity can be attributed to the favourable NO2–Ag interaction
(associated with an inward approach of the former) and a
stabilizing -stacking interaction in TS3’PRO–S (similar to those
found in RC2’) that are not present neither in TS3’PRO–R (Figure 3)
nor in the reaction performed with acetic acid. Note that the
relevance of the counteranion in the coordination sphere of the
silver atom on the 1,3–DC selectivity was previously assessed.[16a]
Therefore, the calculations predict the preferential formation
of compound 10a with a theoretical dr of >99% when using
benzoic acid as additive, in excellent agreement with the
experimental results.
Scheme 2. Proposed catalytic cycles associated with the 1,3–DC and Michael
reaction. Relative and activations Gibbs free energies computed at
M06(PCM)/6-311+G**&LANL2DZ//
level are in kcal·mol-1.
ONIOM(B3LYP/6-31G*&LANL2DZ:UFF)
Another Michael-type addition was successfully tested
following the same sequential strategy (Scheme 3). Methyl vinyl
ketone afforded product 11 in 78% yield, but acrylates did not
work. To overcome this problem a stabilizing group was attached
to the electron-withdrawing entity in order to avoid the retro-
addition. Thus, compounds 12 and 13 could be isolated in 62%
and 71% yields, respectively. An identical situation was observed
when 1,1-bis(phenylsulfonyl)ethylene was allowed to react under
these optimized conditions furnishing product 14 in 72% yield.
Electron-deficient alkynes were also suitable Michael acceptors
such as it was demonstrated in the reactions with dimethyl
acetylenedicarboxylate and but-3-in-2-one. All these products 11-
16 were very sensitive to silica-gel purification, so they were
isolated from recrystallization from the crude reaction mixtures.
Relative configuration of compounds 15 and 16 was determined
by nOe experiments (see SI). Again, the reactions between
starting nitroprolinate exo-6a with all these Michael-type
acceptors were unsuccessful.
As useful application of the structure 10a we envisaged the
possibility to prepare hexahydropyrrolo[1,2-a]pyrazin-1(2H)-ones.
For the preparation of bicyclic δ-lactam 18, compound 10a was
treated with Zn (dust) in the presence of concentrated aqueous
HCl (37%) in ethanol at 60 ºC for 15 min[24] (Scheme 4) affording
the diamine 17 in 87% yield. The cyclization in methanolic KOH
was achieved to generate 18 in 89% yield. In both transformations
any epimerization of the five stereocenters was detected.
Figure 3. Main geometrical features and relative Gibbs Free energies of
transition structures associated with the Michael addition step in presence of
benzoic acid as additive computed at M06(PCM)/6-311+G**&LANL2DZ//
ONIOM(B3LYP/6-31G*&LANL2DZ:UFF) level. Second molecule of -
nitrostyrene and the additive are highlighted in green. Relative Gibbs free
energies and distances are in kcal·mol-1 and Å respectively.
3
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In conclusion, the enantioselective cycloaddition
→diastereoselective Michael-type domino process was
satisfactorily controlled. It was demonstrated the crucial effect
shown by the chiral phosphoramidite/silver benzoate complex in
the almost total diastereoselective control in the Michael-type
addition of the intermediate chiral silver prolinamide onto a
second unit of β-nitrostyrene. The retro-Michael step can be
controlled despite of the lower energetic barrier to yield starting
cycloadduct. The presence and position of the benzoic acid is
crucial for the activation of the nitroalkene. Its extra π-interaction
with the aromatic part of the chiral ligand, together with the
repulsive Pauling interaction between the nitro group of β-
nitrostyerne and the carboxy moiety of the pyrrolidine ring favour
the matching TS arrangement. The scope of this reaction is
limited due to the scarce energy gap between the both associated
cycles operating simultaneously, which can be more similar
depending on the nature of the substituents in both the dipole and
the dipolarophile. This methodology allows the diastereoselective
synthesis of pyrazin-2-ones in very good yields.
Scheme 3. Sequential enantioselective synthesis of nitroprolinates-Michael
type addition.
Experimental Section
General: All commercially available reagents and solvents were
used without further purification, only aldehydes were also
distilled prior to use. Analytical TLC was performed on Schleicher
& Schuell F1400/LS 254 silica gel plates, and the spots were
visualized under UV light (λ = 254 nm). Melting points were
determined with a Reichert Thermovar hot plate apparatus and
are uncorrected. Optical rotations were measured on a JASCO P-
1030 polarimeter with a thermally jacketed 5 cm cell at
approximately 25 ˚C and concentrations (c) are given in g/100 mL.
The structurally most important peaks of the IR spectra (recorded
using a Nicolet 510 P-FT) are listed and wavenumbers are given
in cm-1. NMR spectra were obtained using a Bruker AC-300 or
Scheme 4. Synthesis of enantiomerically enriched pyrazine-2-one 18.
Besides, 2,5-diketopiperazines, a family of very interesting
compounds,[25] were readily prepared from exo-6a and α-chloro
acyl chlorides in very good yields[26] (Scheme 5). The mixture of
diastereoisomers 20 and 21 could be separated and
independently cyclized employing aqueous methylamine. Their
absolute configuration was unambiguously determined according
to nOe experiments (see SI).
1
AC-400 and were recorded at 300 or 400 MHz for H NMR and
75 or 100 MHz for 13C NMR, using CDCl3 as solvent and TMS as
internal standard (0.00 ppm) unless otherwise stated. The
following abbreviations are used to describe peak patterns where
appropriate: s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, m = multiplet or unresolved and br s = broad
signal. All coupling constants (J) are given in Hertz (Hz) and
chemical shifts in ppm. 13C NMR spectra were referenced to
CDCl3 at 77.16 ppm. Low-resolution electron impact (EI) mass
spectra were obtained at 70 eV using a Shimadzu QP-5000 by
injection or DIP; fragment ions in m/z are given with relative
intensities (%) in parentheses. High-resolution mass spectra
(HRMS) were measured on an instrument using a quadrupole
time-of-flight mass spectrometer (QTOF) and also through the
electron impact mode (EI) at 70 eV using a Finnigan VG Platform
or a Finnigan MAT 95S. Vibrational Circular Dichroism (VCD)
studies were accomplished in a Jasco FVS-6000 and X-ray
crystal structure was determined using a Bruker CCD-Apex.
Scheme 5. Synthesis of diketopiperazines 19, 22 and 23.
General procedure A: Synthesis of Michael adducts (10-16):
Silver benzoate (5 mol%, 0.026 mmol, 5.9 mg) and (Sa,R,R)-L (6
mol%, 0.03 mmol, 17.1 mg) were dissolved in toluene (5 mL).
After 1 hour stirring the α-imino ester (136 mg, 0.53 mmol) and
triethylamine (5 mol%, 0.026 mmol, 3.6 µL) were added. Then,
Conclusion
4
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10.1002/cctc.201902382
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nitrostyrene (1 equiv, 80 mg) was introduced and the reaction
mixture was left to stir for 17 hours. Next, benzoic acid (1 equiv,
64.7 mg) and the corresponding Michael acceptor (1.1 equiv)
were added to the solution. The mixture was stirred 17 hours. The
crude was filtered through a pad of celite and the filter was
washed with EtOAc (15 mL). The corresponding solution was
concentrated under reduced pressure and the purification step
depended on the compound (see characterization data).
60:40). Each diastereoisomer (50 mg, 0.12 mmol) was dissolved
in dichloromethane (3 mL) follow by the addition of methylamine
(40% aq., 1.5 mL). The mixture was stirred overnight. The
resulting yellow solution was quenched with water (3 mL) and
extracted three times with dichloromethane. The combined
organic layers were dried over MgSO4 and concentrated under
reduce pressure. The desired products were obtained by
purification by column chromatography (Hx:EtOAc; 7:3).
General procedure B: Nitro group reduction (17): A round bottom
flask was charged with the Michael adduct 10a (47.5 mg, 0.1
mmol), zinc powder (261.52 mg, 4 mmol) and ethanol (3 mL). The
corresponding suspension was heated to 60 ᵒC and the
hydrochloric acid (37% aq., 0.5 mL) was added drop wise
observing formation of hydrogen. The mixture was checked by
TLC until completion of the reaction (15 minutes). The solvent was
removed under reduced pressure and the grey solid was washed
with saturated aqueous potassium carbonate until pH 10 and
extracted with dichloromethane (8 mL) three times. The combined
organic layers were dried over MgSO4 and concentrated under
(2S,3S,4R,5S)-Methyl
4-nitro-1-[(S)-2-nitro-1-phenylethyl]-
3,5-diphenylpyrrolidine-2-carboxylate (10a). White solid (211
mg, 84% yield, de: 95%); precipitation with EtOAc:Et2O; mp: 154-
[ ]26
158 °C; 훼
= 51.2 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δH:
퐷
3.41 (s, 3H, CO2CH3), 3.84 (dd, J = 11.5, 9.8 Hz, 1H, NCHCHPh),
4.29 (d, J = 9.8 Hz, 1H, CHCO2Me), 4.62-4.44 (m, 3H, CH2,
NCHCHNO2), 4.85 (dd, J = 12.1, 9.1 Hz, 1H, NCHCH2NO2), 5.54
(dd, J = 11.5, 8.8 Hz, 1H,CHNO2), 7.08-7.14 (m, 2H, ArH), 7.22-
7.28 (m, 5H, ArH), 7.44-7.60 (m, 8H, ArH) ppm; 13C NMR (CDCl3)
δC: 51.2 (NCHCHPh), 52.2 (OCH3), 60.6 (NCHPh), 63.4 (NCHPh),
70.3 (CCO2Me), 77.4 (CH2NO2), 91.8 (CHNO2), 127.9, 128.0,
128.3, 128.9, 129.5, 129.6, 129.7, 129.9, 132.4, 136.7 (ArC),
172.1 (CO2Me) ppm; IR (ATR) 휐푚푎푥 : 1743, 1552, 1376, 1195,
1140 cm-1; MS (EI): m/z 429 (M+-NO2, <2%), 417 (16), 416 (63),
370 (21), 369 (80), 279 (12), 221 (18), 220 (100), 219 (36), 194
(14), 193 (80), 191 (13), 178 (19), 117 (22), 116 (16), 115 (58),
105 (13), 104 (79), 103 (17), 102 (11), 91 (27), 77 (20); HRMS
calcd. for C26H25N3O6(–CH4N2O4) 367.1561; found: 367.1576.
reduced
pressure
obtaining
a
white
solid
after
precipitation/recrystallization (CH2Cl2/n-Hexane).
General procedure C: Formation of δ-lactam 18: A round bottom
flask was charged with 17 (41.5 mg, 0.1 mmol) in a 4 M solution
of KOH/MeOH (2 mL). The mixture was stirred at room
temperature for 20 hours and the crude mixture was concentrated
under reduced pressure, washed with water and extracted with
dichloromethane three times. The combined organic layers were
dried over MgSO4 and the solvent was removed under vacuum
obtaining a single diastereoisomer, as a white solid, that was
purify by precipitation with CH2Cl2/n-hexane.
(2S,3S,4R,5S)-Methyl 3-(4-methoxyphenyl)-4-nitro-1-[(S)-2-
nitro-1-phenylethyl]-5-phenylpyrrolidine-2-carboxylate (10b).
White solid (174 mg, 65% yield, de: 95%); precipitation with
[ ]28
EtOAc:Et2O; mp: 162-167 °C; 훼
= 83.2 (c 1, CHCl3); 1H NMR
퐷
(300 MHz, CDCl3) δH: 3.45 (s, 3H, CO2CH3), 3.74 (s, 3H, COCH3),
4.24 (d, J = 9.8 Hz, 1H, CHCO2Me), 4.44-4.59 (m, 3H, CH2,
NCHCHNO2), 4.80 (dd, J = 12.2, 9.3 Hz, 1H, NCHCH2NO2), 5.49
(dd, J = 11.6, 8.8 Hz, 1H,CHNO2), 6.77-7.02 (m, 2H, ArH), 7.02-
7.22 (m, 2H, ArH), 7.22-7.24 (m, 2 H, ArH), 7.46-7.56 (m, 8H, ArH)
ppm; 13C NMR (CDCl3) δC: 50.81 (NCHCHPh), 52.2 (OCH3), 55.4
(PhOCH3), 60.6 (NCHPh), 63.5 (NCHPh), 70.2 (CCO2Me), 77.2
(CH2NO2), 92.2 (CHNO2), 114.4, 124.2, 128.0, 128.4, 129.2,
129.6, 129.7, 129.9, 132.6, 136.9, 159.8, (ArC), 172.3 (CO2Me)
ppm; IR (ATR) 휐푚푎푥: 1739, 1612, 1552, 1517, 1494, 1455, 1436,
1373, 1305, 1253, 1139, 1091, 1029, 981, 921, 701 cm-1; MS (EI):
m/z 459 (M+-NO2, <2%), 446 (19), 399 (25), 250 (30), 249 (13),
223 (100), 145 (14), 116 (19), 113 (22), 91 (15), 77 (15); HRMS
calcd. for: C27H27N3O7(–NO2) 459.1920; found: 459.1906.
General procedure D: Formation of diketopiperazine 19 (Method
D.1): To a solution of exo-6a[17] (0.5 mmol, 163 mg) and
triethylamine (1.5 equiv, 0.75 mmol, 105 µL) in dichloromethane
(10 mL) at 0 ºC was added chloroacetyl chloride (1.5 equiv, 0.75
mmol, 60 µL). The reaction was stirred for 30 min. at 0 ºC and
warmed to room temperature. After being stirred for another 1
hour, the reaction mixture was quenched with water (10 mL) and
extracted three times with dichloromethane. The combined
organic layers were dried over MgSO4 and concentrated under
reduce pressure. The crude mixture obtained was dissolved in
dichloromethane (10 mL) follow by the addition of methylamine
(40% aq., 4 mL). The mixture was stirred overnight. The resulting
yellow solution was quenched with water (10 mL) and extracted
three times with dichloromethane. The combined organic layers
were dried over MgSO4 and concentrated under reduce pressure.
The desired product was obtained without purification.
(2S,3S,4R,5S)-Methyl
3-(4-chlorophenyl)-1-[(S)-1-(4-
chlorophenyl)-2-nitroethyl]-4-nitro-5-phenylpyrrolidine-2-
carboxylate (10c). White solid (167 mg, 58% yield, de: 95%);
[ ]28
General procedure D: Formation of diketopiperazines 22 and 23
(Method D.2): To a solution of exo-6a (0.18 mmol, 60 mg)[17] and
triethylamine (1.5 equiv, 38 µL) in dichloromethane (4 mL) at 0 ºC
was added 2-chloropropionylchloride (1.5 equiv, 27 µL) The
reaction was stirred for 30 min. at 0 ºC and warmed to room
temperature. After being stirred for another 2 hours, the reaction
mixture was quenched with water (4 mL) and extracted three
times with dichloromethane. The combined organic layers were
dried over MgSO4 and concentrated under reduce pressure. The
crude mixture was purified by column chromatography
(Hx:EtOAc; 9:1 to 7:3) obtaining both diastereoisomers (dr =
precipitation with EtOAc:Et2O; mp: 184-189 °C; 훼
= 68.4 (c 1,
퐷
1
CHCl3); H NMR (300 MHz, CDCl3) δH: 3.44 (s, 3H, CO2CH3), ),
3.84 (dd, J = 11.5, 9.8 Hz, 1H, NCHCHPh), 4.18 (d, J = 9.8 Hz,
1H, CHCO2Me), 4.44-4.59 (m, 3H, CH2, NCHCHNO2), 4.80 (dd, J
= 12.2, 9.3 Hz, 1H, NCHCH2NO2), 5.49 (dd, J = 11.6, 8.8 Hz,
1H,CHNO2), 7.06-7.52 (13 H, ArH) ppm; 13C NMR (CDCl3) δC:
50.7 (NCHCHPh), 52.5 (OCH3), 60.1 (NCHPh), 63.6 (NCHPh),
70.3 (CCO2Me), 77.0 (CH2NO2), 91.9 (CHNO2), 128.0, 128.3,
128.7, 129.3, 129.4, 129.7, 129.7, 130.0, 130.2, 130.4, 130.9,
131.1, 134.9, 136.0, 136.4 (ArC), 171.9 (CO2Me) ppm; IR (ATR)
휐푚푎푥: 1740, 1687, 1553, 1492, 1365, 1324, 1290, 1202, 1091,
5
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10.1002/cctc.201902382
ChemCatChem
FULL PAPER
1014, 819, 704 cm-1; MS (EI): m/z 429 (M+-NO2, <2%), 417 (16),
416 (63), 370 (21), 369 (80), 279 (12), 221 (18), 220 (100), 219
(36), 194 (14), 193 (80), 191 (13), 178 (19), 117 (22), 116 (16),
115 (58), 105 (13), 104 (79), 103 (17), 102 (11), 91 (27), 77 (20);
HRMS calcd. for: C26H23Cl2N3O6 543.0964; found: 543.1017.
(2S,3S,4R,5S)-Methyl 4-nitro-1-[3-oxo-3-(2-oxooxazolidin-3-
yl)propyl]-3,5-diphenylpyrrolidine-2-carboxylate (12): White
solid (153 mg, 62% yield); mp: 150-152 ⁰C; precipitation with
[ ]17
1
EtOAc:Et2O; 훼 = 15.6 (c 1, CHCl3); H NMR (300 MHz, CDCl3)
퐷
δH: 2.98-3.02 (m, 2H), 3.05-3.16 (m, 2H), 3.30 (s, 3H, CO2CH3),
3.87-3.93 (m, 2H), 4.24 (d, J = 9.9 Hz, 1H), 4.30-4.34 (m, 2H),
4.39-4.49 (m, 2H), 5.38 (dd, J = 9.9, 8.7 Hz, 1H), 7.25-7.31 (m,
5H, ArH), 7.39-7.41 (m, 3H), 7.55-7.57 (m, 2H) ppm; 13C NMR
(CDCl3) δC: 33.2 (NCH2CH2), 42.5 (OCNCH2), 47.5 (NCH2CH2),
51.2 (NCHCHPh), 51.8 (CO2CH3), 62.2 (CO2CH2), 69.1 (NCHPh),
72.4 (NCHCO2CH3), 93.4 (CHNO2), 128.1, 128.2, 128.4, 128.6,
128.8, 129.1, 129.3, 129.4, 130.2, 134.2, 137.3 (ArC), 153.5
(NCOO), 171.3 (CO), 171.6 (CO) ppm; IR (ATR) 휐푚푎푥: 1794, 1743,
1697, 1541, 1383, 1196 cm-1; MS (EI): 421 (M+ -NO2, 26%), 420
(47), 408 (23), 361 (59), 274 (100), 232 (55), 220 (29), 193 (32),
(2S,3S,4R,5S)-Methyl
nitro-1-phenylethyl]-5-phenylpyrrolidine-2-carboxylate (10d).
White solid (193 mg, 60% yield, de: 90%); precipitation with
EtOAc:Et2O; mp: 170-172 °C; 훼
(300 MHz, CDCl3) δH: 3.46 (s, 3H, CO2CH3), 3.78 (dd, J = 11.3,
10.0 Hz, 1H, NCHCHPh) 4.27 (d, J = 9.8 Hz, 1H, CHCO2Me),
4.38-4.60 (m, 3H, CH2, NCHCHNO2), 4.85 (dd, J = 12.2, 9.4 Hz,
1H, NCHCH2NO2), 5.49 (dd, J = 11.5, 8.8 Hz, 1H,CHNO2), 7.04-
7.56 (m, 14H, ArH) ppm; 13C NMR (CDCl3) δC: 50.6 (NCHCHPh),
52.4 (OCH3), 60.6 (NCHPh), 63.3 (NCHPh), 70.3 (CCO2Me),
3-(4-chlorophenyl)-4-nitro-1-[(S)-2-
[ ]28
= 74.7 (c 1, CHCl3); 1H NMR
퐷
77.18 (CH2NO2), 91.8 (CHNO2), 128.1, 128.3, 128.4, 129.2, 129.3, 142 (30), 115 (44), 91 (22), 55 (25); HRMS calcd. for C24H25N3O7:
129.4, 129.5, 129.6, 129.7, 129.9, 130.0, 131.0, 132.4, 134.7,
136.6 (ArC), 172.0 (CO2Me) ppm; IR (ATR) 휐푚푎푥 : 1731, 1547,
1494, 1376, 1204, 1146, 1093, 1031, 1015, 839, 808, 767 cm-1;
MS (EI): m/z 449 (M+-CH2NO2, <2%), 439 (18), 437 (25), 151 (11),
149 (23), 139 (23), 137 (71), 135 (15), 117 (17), 116 (12), 115
(35), 102 (20), 101 (18), 256 (25), 253 (72), 229 (32.5), 227 (100),
219 (15), 192 (24), 191 (21), 189 (13)151 (11), 149 (23), 136 (15),
125 (17), 116 (26), 115 (35), 102 (20), 91 (13), 77 (10); HRMS
calcd. for: C26H25N3O6(–CO2CH3) 450.1221; found: 450.1252.
467.1693; found: 467.1672.
(2S,3S,4R,5S)-Methyl 4-nitro-1-[3-oxo-3-(2-oxopyrrolidin-1-
yl)propyl]-3,5-diphenylpyrrolidine-2-carboxylate (13): white
solid (172 mg, 71% yield); precipitation with EtOAc:Et2O; mp: 134-
[ ]17
136 ⁰C; 훼 = 18.4 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δH:
퐷
1.95-1.98 (m, 2H), 2.47-2.52 (m, 2H), 2.90-2.97 (m, 1H), 3.00-
3.13 (m, 3H), 3.30 (s, 3H), 3.70 (td, J = 7.4, 1.6 Hz, 2H), 4.25 (d,
J = 10.0 Hz, 1H), 4.38-4.46 (m, 2H), 5.37 (dd, J = 10.0, 8.5 Hz,
1H), 7.25-7.30 (m, 5H), 7.36-7.41 (m, 3H), 7.53-7.56 (m, 2H) ppm;
13C NMR (CDCl3) δC: 17.2 (OCNCH2CH2), 33.6 (OCNCOCH2),
34.8 (NCH2CH2CO), 45.5 (OCNCH2CH2), 47.3 (NCH2CH2CO),
51.2 (NCHCHPh), 51.7 (CO2CH3), 68.9 (NCHPh), 72.2
(NCHCO2CH3), 94.0 (CHNO2), 128.0, 128.2, 128.3, 128.6, 128.8,
129.1, 129.2, 130.2, 134.3, 137.6 (ArC), 171.7 (CO), 172.2 (CO),
175.4 (CO) ppm; IR (ATR) 휐푚푎푥: 1742, 1685, 1545, 1353 cm-1;
MS (EI): 419 (M+ -NO2, 31%), 275 (20), 274 (100), 232 (25), 220
(25), 193 (19), 140 (23), 115 (25); HRMS calcd. for C25H27N3O6:
(2S,3S,4R,5S)-Methyl 4-nitro-1-[(S)-2-nitro-1-phenylethyl]-3-
phenyl-5-(p-tolyl)pyrrolidine-2-carboxylate (10e): White solid
(144 mg, 55% yield, de: 95%); precipitation with EtOAc:Et2O; mp:
[ ]26
171-172 °C; 훼
= 50.8 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
퐷
δH: 2.42 (s, 3H, PhCH3), 3.39 (s, 3H, CO2CH3), 3.78-3.88 (m, 1H,
NCHCHPh) 4.27 (d, J = 9.9 Hz, 1H, CHCO2Me), 4.44-4.53 (m, 2H,
CH2), 4.59 (dd, J = 9.1, 6.2 Hz, NCHCHNO2) , 4.84 (dd, J = 12.2,
9.2 Hz, 1H, NCHCH2NO2), 5.51 (dd, J = 11.5, 8.8 Hz, 1H,CHNO2),
7.09-7.52 (m, 14H, ArH) ppm; 13C NMR (CDCl3) δC: 21.6 (PhCH3), 465.1900; found: 465.1894.
51.2 (NCHCHPh), 52.2 (OCH3), 60.5 (NCHPh), 63.5 (NCHPh),
70.2 (CCO2Me), 77.2 (CH2NO2), 91.9 (CHNO2), 128.0, 128.4,
128.6, 129.0, 129.7, 129.7, 130.3, 130.4, 132.6, 132.6, 134.0,
139.8 (ArC), 172.3 (CO2Me) ppm; IR (ATR) 휐푚푎푥 : 1741, 1552,
1453, 1434, 1369, 1199, 1141, 1025, 816 cm-1; MS (EI): m/z 443
(M+-NO2, 2%), 431 (20), 430 (72), 384 (28), 383 (100), 235 (15),
234 (82), 233 (44), 207 (43), 191 (13), 131 (12), 130 (11), 129
(14), 115 (34), 104 (66), 103 (15), 91 (18); HRMS calcd. for:
C26H25N3O6(–CO2CH3) 430.1767; found: 430.1769.
(2S,3S,4R,5S)-Methyl
nitro-3,5-diphenylpyrrolidine-2-carboxylate (14): white solid
1-[3,3-bis(phenylsulfonyl)propyl]-4-
(242.2, 72% yield); precipitation with EtOAc:Et2O; mp: 164-166
[ ]17
⁰C; 훼
= 22.8 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δH: 3.30
퐷
(s, 3H, CO2CH3), 3.61 (dd, J = 16.0, 4.6 Hz, 1H, NCH2), 3.76 (dd,
J = 16.5, 3.2 Hz, 1H, NCH2), 4.40-4.46 (m, 2H, NCHCHPh,
NCHCO2Me), 4.51 (d, J = 8.1 Hz, 1H, NCHPh), 4.84 (t, J = 4.1 Hz,
1H, CH(SO2Ph)2), 5.35 (dd, J = 12.4, 4.4 Hz, 1H, CHNO2), 7.24-
7.72 (m, 20H, ArH) ppm; 13C NMR (CDCl3) δC: 48.3 (NCH2), 51.5
(NCHCHPh), 51.9 (CH3), 69.7 (NCHPh), 72.4 (NCHCO2CH3),
80.9 (CS), 94.5 (CHNO2), 128.2, 128.3, 128.5, 128.9, 129.1,
129.2, 129.4, 129.8, 130.3, 133.7, 134.3, 134.6, 134.7, 137.1,
137.3, 138.0 (ArC), 171.9 (CO) ppm; IR (ATR) 휐푚푎푥: 1739, 1694,
1313, 1143, 1078, 736 cm-1; MS(EI): 437 (20), 423 (14), 422 (77),
421 (60), 363 (26), 362 (100), 330 (31), 303 (11), 302 (40), 298
(15), 277 (31), 271 (17), 270 (68), 244 (21), 243 (25), 193 (41),
178 (26), 115 (94), 91 (42), 77 (29); HRMS calcd. for C18H16NO2:
278.1165; found: 278.1181.
(2S,3S,4R,5S)-Methyl
4-nitro-1-(3-oxobutyl)-3,5-
diphenylpyrrolidine-2-carboxylate (11): White solid (172 mg,
78% yield); mp: 132 ºC; precipitation with EtOAc:Et2O; mp: 142-
[ ]17
1
144 ⁰C;
훼
= 72.0 (c 1, CHCl3); H NMR (300 MHz, CDCl3) δH:
퐷
1.99 (s, 3H, COCH3), 2.61-2.41 (m, 2H, ), 3.00 (t, J = 7 Hz, 1H, ),
3.29 (s, 3H, CO2CH3), 4.17 (d, J = 9.9 Hz, 1H, ), 4.46-4.40 (m,
2H, ), 5.39 (dd, J = 9.9, 8.7 Hz, ), 7.27-7.56 (m, 10H, ArH) ppm;
13C NMR (CDCl3) δC: 30.1 (COCH3), 41.6 (CH2), 47.4 (CH2), 51.2
(NCHCHPh), 51.9 (CO2CH3), 69.5 (NCHPh), 72.8 (NCHCO2CH3),
93.8 (CHNO2), 128.0, 128.1, 128.5, 128.9, 129.2, 129.5, 130.3,
133.7, 134.1, 137.2 (ArC), 171.6 (CO2CH3), 206.9 (COCH3) ppm;
IR (ATR) 휐푚푎푥: 1742, 1714, 1366, 1147 cm-1; MS (EI): m/z 350
(M+ -NO2, 32%), 337 (27), 291 (26), 290 (99), 233 (20), 232 (100),
115 (35); HRMS calcd. for: C22H24N2O5 396.1685; found:
396.1678.
Dimethyl 2-[(2S,3S,4R,5S)-2-(methoxycarbonyl)-4-nitro-3,5-
diphenylpyrrolidin-1-yl]but-2-enedioate (15): White solid
(185.8 mg, 73% yield); mp: 110-112 ⁰C; 훼
1H NMR (300 MHz, CDCl3) δH: 3.40 (s, 3H, CO2CH3), 3.47 (s, 3H,
CO2CH3), 3.56 (s, 3H, CO2CH3), 4.50-4.55 (m, 2H, NCHCHPh,
[ ]25
= 34.6 (c 1, CHCl3);
퐷
6
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10.1002/cctc.201902382
ChemCatChem
FULL PAPER
CCHCO2Me), 4.64 (d, J = 9.2 Hz, 1H, NCHCO2Me), 5.31 (d, J =
8.7 Hz, 1H, NCHPh), 5.71 (dd, J = 11.9, 8.7 Hz, 1H, CHNO2),
7.23-7.25 (m, 2H, ArH), 7.34-7.36 (m, 3H, ArH), 7.39-7.45 (m, 3H,
ArH), 7.58-7.59 (m, 2H, ArH) ppm; 13C NMR (CDCl3) δC: 50.6
(NCHCHPh), 51.3 (CH3), 52.6 (CH3), 52.9 (CH3), 66.9 (NCHPh),
68.3 (NCHCO2CH3), 92.0 (C=C), 92.4 (CHNO2), 127.5, 127.9,
129.2, 129.3, 129.4, 129.6, 130.3, 136.1, 149.6, 164.7 (CO2CH3),
166.8 (CO2CH3), 170.2 (CO2CH3) ppm; IR (ATR) 휐푚푎푥 : 1694,
1668, 1314, 1124 cm-1; MS (EI): 279 (14), 220 (68), 194 (17), 193
(100), 178 (13), 125 (19), 19 (62), 117 (28), 115 (45), 103 (47), 91
(31), 77 (86); HRMS calcd. for C18H17NO2: 279.1269; found:
279.1232.
휐
푚푎푥: 1670, 1491, 1453, 1348, 1313, 1183, 1110, 1071, 1029, 907,
749, 730 cm-1 ;MS (EI): m/z 383 (M+ 8%), 265 (34), 264 (100),
,
248 (13), 247 (64), 208 (11), 206 (13), 161 (52), 160 (28), 130
(16), 119 (23), 118 (17), 117 (15), 104 (20), 103 (13), 91 (19), 90
(11); HRMS calcd. for: C25H25N3O 383.1998; found: 383.1996.
(6S,7R,8S,8aS)-2-Methyl-7-nitro-6,8-
diphenylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
Yellow solid (163.7 mg, 90% yield); Without purification; mp: 188
[ ]25
(19):
ºC; 훼
= 417 (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3) δH: 3.03
퐷
(s, 3H, NCH3), 3.97 (d, J = 17.2, Hz, 1H, CH2), 4.33 (d, J = 17.2
Hz, 1H, CH2), 4.42 (dd, J = 9.6, 6.9 Hz, 1H, NCHCHPh), 4.72 (d,
J = 9.6 Hz, 1H, NCHCO), 5.20 (dd, J = 6.9, 4.3 Hz, 1H, CHNO2),
(2S,3S,4R,5S)-Methyl 4-nitro-1-[(E)-3-oxobut-1-en-1-yl]-3,5-
diphenylpyrrolidine-2-carboxylate (16): Orange foam (145 mg,
5.92 (d, J = 4.3 Hz, 1H, NCHPh), 7.09-7.46 (10H, ArH) ppm; 13
C
NMR (CDCl3) δC: 33.9 (NCH3), 53.1 (NCHCHPh), 54.2 (NCHPh),
64.2 (CH2), 64.9 (CHCO), 96.8 (CHNO2), 125.5, 127.9, 128.4,
129.0, 129.3, 129.7, 136.7, 136.8 (ArC), 161.8 (CO), 164.6 (CO)
ppm; IR (ATR) 휐푚푎푥: 2925, 1666, 1554, 1451, 1329, 90 cm-1 ;MS
(EI): m/z 320 (25), 319 (100), 318 (25), 220 (33), 193 (28), 115
(41), 91 (12); HRMS calcd. for: C20H19N3O4 365.1376; found:
365.1395
[ ]25
= 54.0 (c 1, CHCl3) 1H NMR (300 MHz, CDCl3)
퐷
70% yield);
훼
δH: 1.99 (s, 3H, CHCOCH3), 3.39 (s, 3H, CO2CH3), 4.51-4.65 (m,
2H, NCHCO2, NCHCHPh), 5.02 (d, J = 13.4 Hz, 1H NCHCHCO),
5.20 (d, J = 8.9 Hz, 1H, NCHPh), 5.70 (dd, J = 8.9, 11.4 Hz, 1H,
CHNO2), 7.19 (d, J = 13.4 Hz, 1H, NCHCHCO), 7.25-7.58, (m,
10H, ArH) ppm; 13C NMR (CDCl3) δC: 28.0 (COCH3), 50.8
(CO2CH3), 52.6 (NCHCHPh), 69.9 (CHCO2CH3), 76.8 (NCHPh),
91.6 (CHNO2), 102.7 (C=C), 127.2, 127.8, 128.0, 129.2, 129.8,
130.1, 130.7, 135.7, 145.5 (ArC, C=C) 170.1 (CO2CH3), 195.7
(COCH3) ppm; MS (EI): m/z 349 (25), 348 (100), 306 (12), 288
(33), 244 (16), 193 (11), 115 (29), 91 (13); HRMS calcd. for:
C22H22N2O5 394.1529; found: 394.1547.
(2S,3S,4R,5S)-Methyl 1-[(R)-2-chloropropanoyl]-4-nitro-3,5-
diphenylpyrrolidine-2-carboxylate (21): White foam (126 mg,
38% yield); 훼
[ ]26
= 65.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
퐷
δH: 1.35 (d, J = 6.6 Hz, 3H, CCH3), 3.36 (s, 3H, OCH3), 3.76 (q, J
= 6.6 Hz, 1H, CHCl), 4.44 (dd, J = 11.9, 9.5 Hz, 1H, NCHCHPh),
5.10 (d, J = 9.5 Hz, 1H, NCHCO2CH3), 5.62 (d, J = 8.7 Hz, 1H,
NCHPh), 5.71 (dd, J = 11.9, 8.7 Hz, 1H, CHNO2), 7.25-7.79 (10H,
ArH) ppm; 13C NMR (CDCl3) δC: 19.8, 49.4, 50.3, 52.3, 65.0, 66.3,
93.3, 127.1, 127.8, 129.2, 130.0, 130.1, 130.8, 137.4, 169.1,
171.0 ppm; IR (ATR) 휐푚푎푥: 1745, 1662, 1560, 1364, 1210, 701
cm-1 ;MS (EI): m/z 370 (M+-NO2, 27%), 312 (12), 310 (37), 281
(12), 280 (62), 278 (18), 221 (18), 220 (100), 219 (15), 191 (10),
117 (10), 116 (10), 115 (42), 90 (19); HRMS calcd. for:
C21H21N2O3 370.121; found: 370.1201.
(2S,3R,4R,5S)-Methyl 4-amino-1-[(S)-2-amino-1-phenylethyl]-
3,5-diphenylpyrrolidine-2-carboxylate (17): white foam (87%
[ ]23
yield); precipitation with EtOAc:Et2O; mp.: 50-53 °C; 훼
= 55.6
퐷
(c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δH: 1.66 (s, 4H, 2x NH2),
2.73 (dd, J = 13.5, 5.1 Hz, 1H, NCHCH2NH2), 2.85-2.98 (m, 2H,
NCHCH2NH2, NCHCHNH2), 3.21 (s, 3H, CO2CH3), 3.59 (dd, J =
9.7, 5.1 Hz, 1H, NCHCH2NH2), 3.67 (d, J = 8.4 Hz, 1H,
NCHCO2Me), 3.78 (dd, J = 11.2, 8.4 Hz, 1H, NCHCHPh), 4.12 (d,
J = 10.3 Hz, 1H, NCHCHNH2), 7.10-7.51 (m, 13H, ArH), 7.74-7.82
(m, 2H, ArH) ppm; 13C NMR (CDCl3) δC: 43.9 (NCHCH2NH2), 51.6
(NCHCHPh), 55.1 (OCH3), 60.9 (NCHPh), 63.3 (NCHPh), 64.9
(NCHCHNH2), 73.4 (CCO2Me), 127.6, 128.0, 128.3, 128.4, 128.5,
128.6, 128.7, 128.7, 129.1, 136.1, 136.8, 141.5 (ArC), 174.6
(CO2Me) ppm; IR (ATR) 휐푚푎푥 : 3296, 3216, 1739, 1455, 1265,
(2S,3S,4R,5S)-Methyl 1-[(S)-2-chloropropanoyl]-4-nitro-3,5-
diphenylpyrrolidine-2-carboxylate (20): White foam (190 mg,
57% yield); 훼
[ ]26
= 6.2 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
퐷
δH: (1:1 mixture of rotamers) 1.57 (d, J = 6.6 Hz, 3H, CCH3), 3.37
(s, 1.5 H, OCH3), 3.43 (s, 1.5 H, OCH3), 4.12 (bs, 0.5 H), 4.25 (bs,
0.5H), 4.39 (bs, 0.5 H), 4.54 (bs, 0.5 H), 5.09 (d, 0.5H), 5.32 (d,
0.5H), 5.38 (d, 0.5H), 5.51 (d, 0.5H), 5.51 (d, 0.5H), 5.74 (m, 1H,
CHNO2), 7.23-7.74 (10H, ArH) ppm; 13C NMR (CDCl3) δC:
(Mixture of rotamers) 20.8, 22.0, 49.6, 50.8, 51.0, 51.5, 52.4, 52.8,
64.3, 64.7, 66.7, 67.3, 91.5, 93.4, 126.5, 127.1, 127.8, 128.9,
129.1, 129.3, 130.0, 136.5, 137.6, 167.5, 170.3 ppm; IR (ATR)
1207, 1181, 1144, 1121 cm-1; MS (EI): m/z 415 (M+ <1%), 411
,
(20), 386 (28), 285 (100), 208 (27), 206 (12), 118 (11), 117 (12),
116 (11), 91 (16); HRMS calcd. for: C26H29N3O2(–CH2NH2)
385.1922; found: 385.1916.
(4S,6S,7R,8R,8aS)-7-Amino-4,6,8-
triphenylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one
yellow solid (33 mg, 89% yield); precipitation with EtOAc:Et2O;
[ ]26
(18):
휐
푚푎푥: 1742, 1669, 1556, 1368, 1214, 700 cm-1 ;MS (EI): m/z 370
(M+-NO2, 27%), 312 (12), 310 (37), 281 (12), 280 (62), 278 (18),
221 (18), 220 (100), 219 (15), 191 (10), 117 (10), 116 (10), 115
(42), 90 (19); HRMS calcd. for: C21H21N2O3 370.121; found:
370.1201.
mp: 211-215 °C; 훼
= 102.5 (c 0.7, CHCl3); 1H NMR (300 MHz,
퐷
CDCl3) δH: 1.60 (s, 2H, NH2), 2.90 (d, J = 7.2 Hz, 1H, NCHCO),
3.08 (dd, J = 8.2, 3.8 Hz, 1H, NCHCHNH2), 3.17 (dd, J = 7.2, 3.8
Hz, 1H, NCHCHPh), 3.51 (dd, J = 11.6, 4.0 Hz, 1H, NCHCH2),
3.55 (d, J = 8.2 Hz, 1H, NCHCHNH2), 4.02 (dd, J = 11.6, 5.7 Hz,
1H, NCHCH2), 4.08 (d, J = 5.7 Hz, 1H, NCHCH2), 6.40 (d, J = 4.0
Hz, 1H, OCNH), 7.08-7.25 (m, 3H, ArH), 7.28-7.41 (m, 6H, ArH),
7.43-7.57 (m, 6H, ArH) ppm; 13C NMR (CDCl3) δC: 46.9
(OCNHCH2), 53.5, 62.2 (3x CHPh), 69.9 (NCHCHNH2), 73.4
(CCO), 126.4, 127.3, 128.0, 128.2, 128.2, 128.5, 128.5, 128.9,
129.3, 133.7, 139.4, 144.1 (ArC), 169.9 (OCNH) ppm; IR (ATR)
(3S,6S,7R,8S,8aS)-2,3-Dimethyl-7-nitro-6,8-
diphenylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
Colorless oil (40 mg, 90% yield); 훼
NMR (300 MHz, CDCl3) δH: 1.69 (d, J = 6.9 Hz, 3H, CHCH3), 3.03
(s, 3H, NCH3), 4.26 (q, J = 6.9 Hz, 1H, CHCH3), 4.39 (dd, J = 9.8,
7.0 Hz, 1 H, NCHCHPh), 4.70 (d, J = 9.8 Hz, 1H, NCHCHPh),
5.25 (dd, J = 7.0, 4.3 Hz, 1H, CHNO2), 5.94 (d, J = 4.3 Hz, 1H,
(23):
[ ]25
1
= 14.4 (c 1, CHCl3); H
퐷
7
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10.1002/cctc.201902382
ChemCatChem
FULL PAPER
NCHPh), 7.09-7.47 (10H, ArH) ppm; 13C NMR (CDCl3) δC: 16.8
(CHCH3), 31.2 (NCH3), 54.6 (NCHCHPh), 56.8 (NCHPh), 64.1
(NCHCO), 65.1 (CHCH3), 96.9 (CHNO2), 125.7, 128.0, 128.5,
129.0, 129.4, 129.7, 136.6, 136.8 (ArC), 165.0 (CO), 165.1 (CO)
ppm; IR (ATR) 휐푚푎푥: 1666, 1555, 1453, 1364, 1079 cm-1 ;MS (EI):
m/z 370 (M+-NO2, 27%),; HRMS calcd. for: C21H21N2O3 370.121;
found: 370.1201.
(3R,6S,7R,8S,8aS)-2,3-Dimethyl-7-nitro-6,8-
diphenylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
(22):
[ ]25
1
Colorless oil (22 mg, 50% yield); 훼
= 33.2 (c 1, CHCl3); H
퐷
NMR (300 MHz, CDCl3) δH: 1.59 (d, J = 7.1 Hz, 3H, CHCH3), 3.03
(s, 3H, NCH3), 4.03 (q, J = 7.1 Hz, 1H, CHCH3), 4.46 (dd, J = 9.4,
7.0 Hz, 1 H, NCHCHPh), 4.68 (d, J = 9.4 Hz, 1H, NCHCHPh),
5.17 (dd, J = 7.0, 4.4 Hz, 1H, CHNO2), 5.92 (d, J = 4.4 Hz, 1H,
NCHPh), 7.09-7.48 (10H, ArH) ppm; 13C NMR (CDCl3) δC: 17.4
(CHCH3), 32.2 (NCH3), 53.9 (NCHCHPh), 60.0 (NCHPh), 63.9
(NCHCO), 64.6 (CHCH3), 96.7 (CHNO2), 125.1, 127.9, 128.3,
128.9, 129.2, 129.7, (ArC), 164.7 (CO), 165.5 (CO) ppm; IR (ATR)
휐
푚푎푥: 1666, 1555, 1453, 1364, 1079 cm-1; MS (EI): m/z 370 (M+-
NO2, 27%); HRMS calcd. for: C21H21N2O3 370.121; found:
370.1201.
Associated content
The Supporting Information is available free of charge on the ACS
Publications website at DOI: Computational methods, details on
computational calculations including energies, optimized
geometries, NCI topological calculations and cartesian
coordinates. Experimental details, characterization data, and
NMR spectra for new compounds (PDF), computational data and
X-RD analysis.
Acknowledgements
We gratefully acknowledge financial support from the Spanish
Ministerio de Economía y Competitividad (MINECO) Agencia
Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo
Regional (FEDER, EU) (pro-jects CTQ2013-43446-P, CTQ2014-
51912-REDC, CTQ2016-76782-P, CTQ2016-81797-REDC and
CTQ2016-76155-R), the Generalitat Valenciana (PROMETEOII/
2014/017), the University of Alicante. We also thank Dr. T. Soler
her help in the X-ray diffraction analysis (SSTTI, University of
Alicante). SGI-Iker and DICP are gratefully acknowledged by
generous allocation of computational resources.
Keywords: Michel • diastereoselective • silver • pyrazin-2-one •
diketopiperazine
8
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10.1002/cctc.201902382
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FULL PAPER
Entry for the Table of Contents
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