Divergent and Diastereoselective Synthesis of α-Monosubstituted and trans -α,β-Disubstituted γ-Lactams from (S)- N, N -Dibenzyl-α-amino Aldehydes via Henry and Michael Reactions

Article abstract of DOI:10.1055/s-0040-1706423

γ-Monosubstituted and trans -α,β-disubstituted γ-lactams were diastereoselectively synthesized from common intermediates (S)- N, N -dibenzylated aldehydes derived from natural l -(α)-amino acids, employing a divergent approach. The key features of the rou

Full text of DOI:10.1055/s-0040-1706423

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
F. P. Meirelis et al.
Paper
Synthesis
Divergent and Diastereoselective Synthesis of -Monosubstituted
and trans-,-Disubstituted -Lactams from (S)-N,N-Dibenzyl--
amino Aldehydes via Henry and Michael Reactions
O
O
OH
Francine P. Meirelis
Bruna G. N. Vieira
Vera L. P. Pereira*
OH
O
H
O
Reduction/
Lactamization
S
S
R
R
5
R
O
N
H
S
N
NBn2
NBn2 NO2
H
NBn2
O
R/S 4:1 at C5
anti/syn 99:1
Instituto de Pesquisas de Produtos Naturais, Centro de Ciências
da Saúde, Universidade Federal do Rio de Janeiro, Bloco H,
Cidade Universitária, 21941-902, Rio de Janeiro, Brazil
patrocinio.ufrj@gmail.com
- Highly diastereoselective synthesis
- Versatile methodology
- Mild reaction conditions
- Low-cost substrates and reagents
- Reproducible reactions
1) Henry reaction (MeNO2)
2) Michael addition
O
reduction/
lactamization
reduction/
lactamization
O
O
O
OH
O
O
MeO
OMe
NO2
Henry reaction
O
1) Henry reaction (MeNO2)
S
R
R
O
H
2) Elimination
3) Michael addition
NBn2
NBn
2 NO2
O2N
NBn2
anti/syn 99:1
R = Bn, i-Bu,
Me
O
Received: 07.07.2020
Accepted after revision: 20.07.2020
Published online: 24.08.2020
lated from endophytic fungus Cryptosporiopsis cf. quercina
showed high activity against numerous plant pathogenic
fungi.5 Levetiracetam (4, KeppraTM) is a racetam derivative
utilized as an antiepileptic drug6 and Chlortalidone 5 (Hy-
grotonTM) is a diuretic used in the hypertension and heart
failure.7
DOI: 10.1055/s-0040-1706423; Art ID: ss-2020-m0368-op
Abstract -Monosubstituted and trans-,-disubstituted -lactams
were diastereoselectively synthesized from common intermediates (S)-
N,N-dibenzylated aldehydes derived from natural L-()-amino acids,
employing a divergent approach. The key features of the routes include
diastereoselective Henry and Michael reactions that produced chiral -
nitroester derivatives, which were subsequently submitted to a tandem
reduction-lactamization sequence providing the title compounds. The
versatility of routes can allow the preparation of several other mono-,
di-, or tri-substituted -lactams.
O
O
O
OH
O
N
O
O
N
H
N
HO
OH
O
lajollamycin (1)
HO
H
Key words divergent synthesis, Michael addition, Henry reaction, -
lactams, domino reaction, diastereoselective synthesis, 1,3-dicarbonyl
compounds
HO
Cl
O
OH
O
N
O
H
H2N
O
NH2
H
S
O
N
HN
O
O
O
N
H
O
O
The -lactam core is widely distributed in biologically
active naturally occurring products and pharmaceutical
products of diversified structures.1a–i Furthermore, the -
lactamic ring integrates the molecular structure of solvents,
such as N-methyl-2-pyrrolidone and derivatives2a–c and
polymers.2d The pattern of substitution in the -lactam ring
as well as the biological activities of these compounds are
extraordinarily varied (Figure 1). Some selected examples
include Lajollamycin (1) an interesting bacterial secondary
metabolite, isolated from the marine Streptomyces nodosus
that presents a nitroalkene as a rare functional group and a
spiro--lactone--lactam ring.3a,b The alkaloid Stemoamide
(2) and various analogues, isolated from Stemonaceae
plants, present diverse biological activities including anti-
tussive, insecticidal, and anthelmintic.4a–c Cryptocin (3) iso-
H
H
chlortalidone (5)
(HigrotonTM
levetiracetam (4)
(KeppraTM
)
stemoamide (2)
)
cryptocin (3)
Figure 1 Representative natural products and pharmaceutical com-
pounds containing -lactam moiety
Due to the great diversity of biological activities and
structural complexity, there is an expressive number of dif-
ferent synthetic approaches in the literature for obtaining
natural and synthetic -lactams. Some selected approaches
include four-component reaction (4CR) between amines,
maleic anhydride, aldehydes, and thiols,8 intramolecular
cyclization of N-allylpropiolamides,9 expansion or contrac-
tion of a previously formed ring,10,11 sp3 and sp2 C–H amida-
tion12 routes mediated by transition-metal catalysis,1c,13
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. P. Meirelis et al.
Paper
Synthesis
ring-closing metathesis,14 and radical cyclization,15 among
many others. Despite the large number of varied and direct
methods for the substituted -lactam ring, many of them
employ expensive, toxic and complex reagents, besides dif-
ficult experimental execution. Thus, concise and versatile
chiral diastereoselective routes that employ raw materials
and reagents readily available and reactions of easy execu-
tion are still necessary to obtain the target compounds. Chi-
ral N,N-dibenzylated -aminated nitroalkenes and chiral
N,N-dibenzylated -aminated aldehydes are obtained from
natural L-amino acids and have been utilized as versatile
electrophilic chirons that induct high grade of 1,2-diastereo-
selection in diverse diastereoselective syntheses of versatile
synthetic intermediates. Asymmetric or racemic Henry re-
action16–23 and Michael addition24–30 are two of the most
important reactions used to form C–C bonds. They are gen-
erally very easy to perform, are catalyzed by a large number
of different basic homogeneous or heterogeneous systems
and occur at room temperature in the presence of different
organic solvents, water or without solvent. Based on our
continued studies on the synthesis and use of new chiral
nonracemic aliphatic nitro compounds in obtaining useful
synthetic intermediates and natural products,31–39 herein
we describe a divergent and diastereoselective approach to
obtain the -substituted -lactam 15 and trans-,-disub-
stituted -lactam 11 and several possible analogues, using
the easily synthesized (S)-N,N-dibenzylated aldehydes 6a,b,
as common precursors. Highly diastereoselective Michael
additions, Henry reactions, and domino reduction--lact-
amization steps were successfully employed in these syn-
theses. The retrosynthesis proposed for obtaining 15 and 11
from 6a and 6b, respectively, is shown in Scheme 1.
We hypothesized that the -substituted -lactam 15
could be synthesized from chiral 1,3-nitroamine derivative
14, via a tandem reduction-cyclization sequence. On the
other hand, 14 could be diastereoselectively synthesized via
a nitroaldol reaction between the aldehyde 6a and methyl
4-nitrobutanoate (13), under the action of different basic
catalysts (Scheme 1, Route 1). Already 6a–c have been syn-
thesized from corresponding natural L-()-amino acids L-
phenylalanine L-leucine and L-alanine, respectively.40,41 Al-
ternatively, 15 could be also produced via a diastereoselec-
tive Michael addition of the anti-nitroalcohol 7a to methyl
acrylate (12). Already 7a could be diastereoselectively
formed via a Henry reaction between nitromethane and 6a
using TBAF·3H2O, as catalyst31,42 (Scheme 1, Route 2). In
turn, the trans-,-disubstituted -lactam 11, could be syn-
thesized from nitroester derivative 10b, via a domino re-
duction–cyclization process.43 Already 10b,c could be
formed via a diastereoselective anti-Michael addition of di-
methyl malonate (9) to chiral nitroalkenes 8b,c, under the
action of different basic catalysts. The Michael acceptors
8b,c have been synthesized from N,N-dibenzylated alde-
hydes 6b,c by a concise and efficient route developed by
us31 (Scheme 1, Route 3).
We initiated this work preparing the -amino aldehydes
6a–c in multi-grams from the corresponding natural L-()-
amino acids in 75–93% global yield, performing a slight and
useful modification of the original Reetz’s procedure.31 The
required -nitrooester 13 (Scheme 1, Route 1) is commer-
cially available, although at high cost. It is known that 13
can be synthesized, via a 1,4-addition of nitromethane to
methyl acrylate (12), using aqueous NaOH/CH2Cl2, aqueous
KOH/ether, or KF/Al2O3/THF as catalytic systems.44–47 How-
ever, in our hands polymerization products of 12, together
with the dimer and the trimer of 13 were always formed in
appreciable amounts. We also experimented other bases
such as Amberlyst A-2148 and DBU49,50 that are efficiently
used in Michael and Henry reactions but were unsuccessful.
After several trials, we discovered that the use of 0.2 equiv-
alent KF in i-PrOH, at room temperature, is a suitable basic
system to minimize the complex mixture of products
formed in this reaction. Indeed, 13 could be easily produced
in multi-grams in 60% yield, after purification by fractional
distillation. Next, 6a and 13 were reacted using a stoichio-
metric ratio of 1.0:1.5, respectively. Basic catalytic systems
based on fluoride anion were tested aiming to reach the
best stereoselectivity and yield of the key intermediate 14
(Table 1).
OH
O
OH
reduction/
lactamization
OH
NO2
NBn2
14
NBn2
N
O
H
O
O
O
O2N
O
γ-substituted γ-lactam 15
(Route 1)
13
12
Henry reaction
Michael
addition
OH
O
OH
R
NO2
R
Henry reaction
R
Henry reaction
S
NO2
H
R
NBn2
NBn2
NBn2
(Route 2)
(Route 3)
7a, R = Bn
7b, R = i-Bu
7c, R = Me
6a, R = Bn
6b, R = i-Bu
6c, R = Me
2 steps1
NBn2
R
O
O
N
O
O
O2N
R
O
8b, R = i-Bu
8c, R = Me
Michael
addition
MeO
R
OMe
NO2
Thus, TBAF·3H2O in excess and THF as solvent was first
tested as basic catalytic system. The nitroalcohol 14 was
produced in 48% yield as a mixture of four possible diaste-
reomers (Table 1, entry 1). The use of KF/i-PrOH in sub-stoi-
chiometric amounts or in excess, in varied reaction times,
did not lead to significant changes in yield or diastereo-
selectivity (entries 2–5). On the other hand, the use of
H
S
+
NBn2
O
O
NBn2
α,β-disubstituted γ-lactam 11
MeO
OMe
10b, R = i-Bu
10c, R = Me
9
Scheme 1 Retrosynthesis of 15 and 11 from 6a,6b, respectively
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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F. P. Meirelis et al.
Paper
Synthesis
Table 1 Synthesis of 14 via Henry Reaction Between 6a and 13
(Scheme 1, Route 1)
Next, to initiate the synthesis of the ,-disubstituted -
lactam 11 (Route 3 in Scheme 1) the chiral nitroalkenes
8b,c were prepared from N,N-dibenzylated aldehydes 6b,c
in 94% and 86% global yield, respectively, via the route de-
veloped by us31,32 (Table 2). It is worth mentioning that the
nitroalkenes 8b,c are obtained in high chemical and enan-
tiomeric purity and can be stored in a freezer or even at
room temperature for several months without decomposi-
tion. These versatile chiral electron-deficient nitroalkenes
have exhibited excellent stereochemical stability, diastereo-
selectivity, and reactivity in conjugate additions with di-
verse nucleophiles and in sequential hetero-Diels–Al-
der/[3+2] cycloaddition. Next, 8b,c were transformed to
10b,c via a diastereoselective Michael addition of dimethyl
malonate (9) using various basic catalytic systems (Table 2).
Analyzing the contents of Table 2, we can observe that
triethylamine (TEA) promoted the Michael reaction in mod-
erate yields when aprotic polar solvents were used. In vir-
tually all experiments, a high anti-selectivity (anti/syn,
99:1) was obtained (Table 2, entries 1–3). It is known that
aprotic polar solvents favor the Michael reaction when
charged nucleophiles are employed.51 The use of THF, a sol-
vent of lower polarity led to poor yield of 10b along with a
complex mixture of products (entry 4). On the other hand,
the use tetrabutylammonium fluoride trihydrate, as basic
catalyst, produced 10b and 10c in similar yields to the pre-
viously obtained results (entries 5, 6). Aiming to improve
the yield as well as to assay a most benign environmental
condition, the weakly basic resin Amberlyst-A21 was em-
ployed as the catalyst. Thus, the use of 1 or 2 equivalents of
9, in the presence of 2 equivalents of resin in THF as solvent
led to dicarbonyl nitroester 10b and 10c in 47 and 54%
yield, respectively (entries 7,8). Gratifyingly, anti-10b and
anti-10c could be synthesized in 75 and 70% yield, respec-
tively, when the reaction was processed in Amberlyst-A21
in the absence of solvent (entries 9, 10). Other 1,3-dicarbo-
nylated compounds such as pentane-2,4-dione, Meldrum’s
acid, and cyclohexane-1,3-dione were also added to 8b in
the same reaction conditions of entry 9 producing the cor-
responding adducts in 50–56% yield, however, they suffered
degradation when subjected to purification by silica gel
chromatography or even when kept under refrigeration in a
glass flask. The high stability of these nucleophiles (weak
conjugate bases) favors the reaction reversibility.
O
OH
O
O
4
O2N
+
O
5
O
NBn2
NO2
Bn2N
6a
13
14
Entry Base (equiv) Solvent
Temp Time Yield
drb
(°C)
(h)
(%)a
1
2
3
4
5
6
TBAF (1.5)
KF (1.0)
THF
25
29
29
26
26
29
19
48
53
60
55
50
40
1.0:3.6:2.5:3.3
1.4:1.3:2.8:1.0
1.6:1.0:1.1:4.7
1.7:1.0:3.0:2.2
2.1:1.0:2.0:1.7
4.2:1.0:1.2:3.4
i-PrOH
i-PrOH
i-PrOH
i-PrOH
THF
24
20
48
24
6
KF (2.0)
KF (4.5)
KF (0.6)
TBAF (0.5)
a After purification by silica gel column chromatography.
b Obtained by 13C NMR analysis.
catalytic amount of TBAF·3H2O in short reaction times
caused a slight modification in the diastereoselectivity with
concomitant loss in the yield (entry 6). The variation in the
diastereomeric ratio shows that the thermodynamic equi-
librium inherent to nitroaldol reactions34 has not yet been
reached. Next, the mixture of nitroalcohols 14 (entry 3) was
treated with NaBH4 in MeOH in the presence of
NiCl2·6H2O43 leading to the reduction of the nitro group
with concomitant cyclization to the -lactam 15 in 85%
yield in a 2.0:1.0:2.1:1.9 diastereoisomer ratio (Scheme 2).
OH
4
OH
O
5
NaBH4, NiCl2•6H2O
O
MeOH, reflux, 2 h
(85%)
NBn2 N
Bn2N
NO2
H
15
dr = 1.0:2.1:2.3:4.3
O
14 (Table 1, entry 3)
Scheme 2 Synthesis of 15 from 14 via domino reduction–lactamiza-
tion process
Aiming to improve the diastereoselectivity and global
yield of 15, Route 2 in Scheme 1 was investigated. Thus, the
Michael addition between nitromethane and 6a in
TBAF·3H2O in THF31,42 at room temperature for 2 hours, led
to the anti-nitroalcohol 7a, in a diastereoisomeric ratio
13:1 (anti/syn). Here again, the short reaction time was
paramount in the inhibition of equilibrium, since the use of
24 hours, as the reaction time at room temperature or at
0 °C, produced 7a in a 2.7:1 anti/syn ratio. Next, anti-7a was
added to methyl acrylate (12) in KF (2.0 equiv)/i-PrOH/rt/19
h, furnishing 14 in 60% yield as an epimeric mixture in C4
(R/S: 3.0:1). Next, the -nitroalcohol 14 was treated with
NaBH4 in the presence of NiCl2·6H2O leading to 15 (R/S:
4.0:1.0 in C5) in 85% yield and 46% global yield from 6a
(Scheme 2).
As the reaction progressed, the diastereoisomeric ratio
remained unchanged, demonstrating that a kinetic control
is acting. In this manner, we could rationalize the total for-
mation of the anti-diastereoisomer 10b,c invoking the
modified Felkin–Ahn transition state model52 (Figure 2). In
this model, the largest N,N-dibenzylamine group is orthog-
onal to the electron-deficient C=C bond. Thus, the approach
of the nucleophile malonate anion to the -nitro carbon
was preferred by the less hindered Re-C face on the oppo-
site side to the largest group following the Burgi–Dunitz
trajectory.53
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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F. P. Meirelis et al.
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Synthesis
Table 2 Synthesis of 10b,c via 1,4-Addition of 9 to 8b,c
O
O
O
R1
NO2
O
O
1) nitroaldol31
conditions
MeO
R1
OMe
NO2
R1
10b,c
(anti/syn 99:1)
H
S
+
2) elimination31
MeO
OMe
NBn2
R
NBn2
9
NBn2
8b (92% overall yield)
8c (88% overall yield)
6b, R1 = i-Bu
6c, R1 = Me
Entry
E+
8b
Equiv 9
Base (equiv)
Solvent
Time (h)
Yield (%)a
1
2
3
3
3
3
1
1
2
1
1
1
TEA (0.5)
DMSO
DMF
MeCN
THF
48
48
48
48
24
24
24
24
12
12
10b (51)
10b (32)
10b (42)
8b
8b
8b
8b
8c
8b
8b
8b
8c
TEA (0.5)
3
TEA (0.5)
b
4
TEA (0.5 or 2.0)
–
5
TBAF·3H2O (0.2)
THF
10b (49)
10c (51)
10b (47)
10b (54)
10b (75)
10c (70)
6
TBAF·3H2O (0.2)
THF
7
Amberlyst-A21 (2)
Amberlyst-A21 (2)
Amberlyst-A21 (1.5)
Amberlyst-A21 (1.5)
THF
8
THF
9
solventless
solventless
10
a After purification by silica gel column chromatography.
b A complex mixture of products were formed along with 10% of 11.
O
O
Nu
H
O
O
H
R
O
Face Re-Cβ
MeO
NBn2
anti-10b
OMe
NO2
NaBH4, NiCl2•6H2O
R
N
H
S
MeOH, reflux, 2 h
(85%)
NBn2
11 (anti/syn 99:1)
NO2
NBn2
10b (anti/syn 99:1)
Figure 2 Felkin–Ahn transition-state model proposed to rationalize
the anti-stereoselectivity obtained for 10b,c
Scheme 3 Synthesis of 11 from 10b via domino reduction–lactamiza-
tion process
In addition, the X ray diffraction analysis unequivocally
established that the N,N-dibenzylated nitroalkenes 8a–c re-
acts in [4+2] cycloaddition32 and Michael addition with ex-
clusive anti-diastereoselectivity.31 Thus, we could infer that
the anti-diastereoisomers 10b,c were the unique diastereo-
isomers formed in the Michael addition between 8b,c and 9
(Table 2). Next, 10b was submitted to a domino reduction–
cyclization process mediated by NaBH4 and NiCl2·6H2O. The
trans-,-disubstituted -aminolactam 11 was obtained in
85% yield and a diastereoisomeric ratio of 99:1. As expect-
ed, the lactamization led the formation of a new stereogen-
ic center in the -position of 11b with total trans-diastereo-
selectivity, via an equilibrium control (Scheme 3). The abso-
lute stereochemistry of the new stereocenter formed could
In conclusion, three versatile, concise, reproductive, and
diastereoselective synthetic routes for -monosubstituted
and trans-,-disubstituted -lactams N,N-dibenzylated
from common intermediates N,N-dibenzylated S-aldehydes
6a,c derived from natural L-()-amino acids have been de-
veloped via Henry and Michael reactions. The diastereose-
lectivity of the Henry reaction employing the chiral N,N-
dibenzylated aldehydes 6a–c exhibited strong influence of
the reaction time and few influence of the type or concen-
tration of base utilized. Thus, very good diastereoselectivity
(anti/syn, 93:7) was obtained for 7a when short reaction
times were used. Contrarily, in long reaction times, which
are necessary to a best chemical yield, the chemical equilib-
rium is reached and low diastereomeric ratio was observed.
A similar behavior has been observed for production of 14.
On the other hand, in Michael additions between methyl
malonate and S-nitroalkenes 8b,c derived from 6a–c, the
bulky N,N-dibenzyl group induced high anti-1,2-diastereo-
selectivity producing the Michael adducts 10b,c (anti/syn,
99:1) via a kinetic control. Compounds 10b and 14 could be
1
be confirmed by analysis of H NMR spectrum. Thus, the
coupling constant J2,3 presented a magnitude of zero Hz,
which is in perfect concordance with a trans-relationship
observed in -lactam-disubstituted systems described in
literature.54
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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F. P. Meirelis et al.
Paper
Synthesis
efficiently transformed to the N,N-dibenzylated -mono-
substituted and trans-,-disubstituted -lactams, respec-
tively, via a domino reduction–lactamization process.
These new synthetic strategies can enable the access to
various other mono-, di-, or trisubstituted N,N-dibenzylat-
ed -lactams via the use of different -substituted N,N-
dibenzylated nitroalkenes, L-N,N-dibenzylated aldehydes,
nitroalkanes, and 1,3-dicarbonyl compounds. Considering
the important bactericidal activity presented by com-
pounds containing the -lactam core, the assessment of a
possible biological activity of these new -lactam deriva-
tives is under investigation and will be published in due
course.
time, the solvent was evaporated and CH2Cl2 (20 mL) was added to the
residue. The organic phase was washed with H2O (3 × 20 mL), dried
(Na2SO4), and the solvent evaporated at reduced pressure. The re-
maining viscous yellow liquid was purified by column chromatogra-
phy on silica gel using hexane/EtOAc (85:15) as eluent to afford 0.27 g
of 14 (57%) in an anti/syn ratio of 3.0:1.0 in C4–C5.
Via Henry Reaction (Scheme 1, Route 1): To a round-bottomed flask, at
rt, were added 6a (0.2 g, 1.06 mmol), 13 (0.4 g, 2.0 mmol), KF (0.20 g,
0.6 mmol), and i-PrOH (10 mL). The reaction mixture was stirred for
20 hours at rt. Next, the solvent was evaporated and the residue was
purified by a rapid silica gel column chromatography eluting with
hexane/EtOAc (85:15). Product 14 (0.14 mg, 50%; yellow liquid ) was
obtained as a mixture of four diastereoisomers (2.1:1.0:2.0:1.7, deter-
mined by 13C NMR analysis) contaminated with an excess of 13.
Major Diastereoisomer
IR (film): 3446, 2954, 2362, 2343, 1730, 1560, 1436, 1373, 1172, 702
Anhydrous EtOH, MeNO2, KF, MeOH, i-PrOH, TBAF·3H2O, Amberlyst-
A21, methyl acrylate, and dimethyl malonate were purchased from
Aldrich or Merck and were used as received. MeCN and triethylamine
were distillated from CaH2. DMF and DMSO after predrying in BaSO4
were dried in CaH2 and subsequently distillated under reduced pres-
sure. THF was dried according to a literature procedure.55 Optical ro-
tations were recorded at 25 °C using a Jasco P-2000 (PTC-203) po-
larimeter. IR spectra were recorded on a Shimadzu FT-IR spectropho-
tometer as a film between NaCl plates. 1H NMR and 13C NMR spectra
were recorded on a Varian or Bruker spectrometer operating at (400
or 500 MHz) and (100 or 125 MHz), at 25 °C by using CDCl3 0.5% TMS
(v/v) as solvent. Chemical shifts () are reported in ppm. HRMS (ESI)
experiments were performed in positive mode on a Bruker Daltonics
ultrOTOFQ-ESI-TOF mass spectrometer or Synapt HDMS (Waters, Mil-
ford, MA) mass spectrometer.
cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.41–7.02 (15 Harom), 4.43 (t, J = 4 Hz, 1
H, CHOH), 3.66 (s, 3 H), 3.64–3.56 (2 d, J = 12 Hz, 4 H, 2 × NCH2Bn),
2.43 (m, 1 H), 2.26 (m, 1 H), 2.16–1.85 (m, 4 H, -carbonyl hydrogens),
3.47 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 171.98, 139.06, 138.89, 139.14,
126.20–129.55 (CHarom), 88.84, 72.07, 59.24, 55.15, 51.71 (NCH2Bn),
51.71 (CH3O), 30.06, 24.85.
HRMS-ESI+: m/z [M + 1]+ calcd for C28H33N2O5: 477.2311; found:
477.2208.
5-((2S)-2-(Dibenzylamino)-1-hydroxy-3- phenylpropyl)pyrroli-
din-2-one (15) (Scheme 2)
To a round-bottomed flask, containing a solution of 14 (0.072 g, 0.15
mmol, 1.0 equiv) in anhyd MeOH (3.00 mL) under magnetic stirring
and argon atmosphere was added NiCl2·6H2O (37.06 mg, 0.16 mmol,
1.01 equiv) in MeOH (1.0 mL) at rt. Next, NaBH4 (64.60 mg, 1.71
mmol, 11.1 equiv) was slowly added and the reaction mixture was
stirred for 2 h at rt. Then, the mixture was treated with sat. aq NH4Cl
(10 mL) for 10 min. Next, successive extraction with CH2Cl2 (3 × 10
mL) was performed and the combined organic phases were dried
(Na2SO4) and evaporated under reduced pressure. The remaining resi-
due was filtered on a Celite column and purified by silica gel column
chromatography to afford 0.053 g of the -lactam 15 (85%) as a C4 en-
riched isomeric mixture (anti/syn: 4.0:1.0 in C4–C5); pale yellow oil.
(2R,3S)-3-(Dibenzylamino)-1-nitro-4-phenylbutan-2-ol (anti-7a)
To a round-bottomed flask under N2 atmosphere and magnetic stir-
ring were added TBAF·3H2O (0.19 g, 0.61 mmol, 0.20 equiv), MeNO2
(198 L, 0.22 g, 3.7 mmol), and anhyd THF (10.00 mL). Next, 6a (1.00
g, 3.04 mmol) dissolved in THF (3 mL) was added and the reaction
mixture was stirred for 60 min at rt. Then, the solvent was evaporated
at reduced pressure and the resultant residue purified by silica gel
column chromatography, eluting with hexane/EtOAc (80:20) to fur-
nish 1.06 g of 7a (90%) as a diastereoisomeric mixture (anti/syn 93:7);
yellow viscous liquid. If necessary, the anti-isomer can be easily sepa-
rated by flash column chromatography on silica gel 60 (0.040–0.063
mm; eluent: 10% hexane/EtOAc.
Major Diastereoisomer
IR (KBr): 3354, 3085–3004, 2928–2806, 1553, 1350, 1121, 1028, 745,
IR (film): 3412, 2955, 2364, 2360, 1734, 1452, 1261, 1207, 746, 700
699 cm–1
.
cm–1
.
1H NMR (200 MHz, CDCl3):  = 7.4–7.2 (m, 15 H), 4.8 (dd, J = 2.2, 13.15
Hz, 1 H), 4.46 (m, J = 2.2 Hz, 1 H), 4.0 (m, 1 H), 3.8 (d, J = 13.6 Hz, 1 H),
3.5 (d, J = 13.6 Hz, 1 H), 3.2 (m, 1 H), 3.0 (m, 1 H), 2.0 (s, 1 H).
13C NMR (50.4 MHz, CDCl3):  = 140.1–138.7 (C), 129.2–126.1 (CHarom),
79.8 (CH2), 70.6 (CH), 61.5 (CH), 54.6 (CH2), 32.3 (CH2).
1H NMR (400 MHz, CDCl3):  = 7.48–7.09 (15 Harom), 6.61 (br s, 1 H),
4.12–4.07 (dd, J = 12, 8 Hz, 1 H), 3.70–3.65 (m, 1 H), 3.64 (s, 4 H),
3.54–3.42 (m, 1 H), 3.38 (t, J = 4 Hz, 1 H), 3.04 (t, J = 4 Hz, 1 H), 2.47–
2.45 (m, 1 H), 2.30–2.26 (m, 1 H), 2.13–2.02 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 173.40, 139.25, 139.16, 130.00–
126.31(CHarom), 60.96, 60.47 (NCH2Bn), 51.96, 31.02, 29.77, 22.71.
(5R,6S)-6-(Dibenzylamino)-5-hydroxy-4-nitro-7-phenylheptano-
ic Acid (14)
Note: The CHOH and CHNBn2 signals could not be detected, probably
due to incomplete relaxation of all the spins in the sample. These par-
ticular spins might have a longer T1 (spin lattice relaxation time) than
the other spins.
HRMS-ESI+: m/z [M + 1]+ calcd for C27H31N2O2: 415.2307; found:
415.2382.
Via Michael Reaction (Scheme 1, Route 2): To a round-bottomed flask
were added a solution of the anti-nitroalcohol 7a (0.39 g, 1.0 mmol)
in THF (3 mL) and a solution KF (0.12 g, 2.0 mmol) dissolved in i-PrOH
(5 mL) at rt and under stirring. Next, methyl crotonate (12; 0.13 g, 1.0
mmol) was slowly added and the mixture stirred for 12 h. After this
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
F. P. Meirelis et al.
Paper
Synthesis
Dimethyl 2-[(2R,3S)-3-(Dibenzylamino)-5-methyl-1-nitrohexan-
2-yl]malonate (10b); Typical Procedures
IR (KBr): 3028–3331, 2666–2953, 2362, 1739, 1703, 1273, 1163, 748,
700 cm–1
.
1H NMR (400 MHz, CDCl3):  = 0.72 (d, J = 4 Hz, 3 H), 0.89 (d, J = 4 Hz,
3 H), 1.01 (m, 1 H), 1.69 (m, 2 H), 2.62 (m, 1 H), 3.00 (m, 1 H), 3.28 (s,
1 H), 3.36 (m, 2 H), 3.51 (d, J = 12 Hz, 2 H), 3.62 (d, J = 12 Hz, 2 H), 3.72
(s, 3 H).
13C NMR (100 MHz, CDCl3):  = 22.75, 23.36, 25.59, 37.49, 41.04,
44.37, 52.69, 52.74, 53.86, 57.18, 139.52, 128.83, 128.34, 127.03,
170.40, 173.54.
Using Amberlyst A-21 as Base in the Absence of Solvent: Nitroalkene 8b
(357 mg, 1.06 mmol) and dimethyl malonate (9; 120 L, 1.06 mmol)
were added to a round-bottomed flask and stirred for 10 min at rt.
Next, Amberlyst A-21 resin (1.5 mL, 1.0 mmol) was added and the
system maintained for 18 h at rt. After this time, the reaction product
was extracted from the medium with CH2Cl2 (2 × 20 mL). The com-
bined organic phases were evaporated at reduced pressure and the re-
maining viscous yellow liquid was purified by column chromatogra-
phy on silica gel using hexane/EtOAc (85:15) as eluent; yield: 0.37 g
(75%); 98% de; pale yellow oil.
HRMS-ESI+: m/z [M + H]+ calcd for C25H32N2O3: 408.2413; found:
409.2480.
Using TBAF·3H2O as Base: Nitroalkene 8b (0.357 g, 1.06 mmol), di-
methyl malonate (9; 120 L, 1.06 mmol), and THF (10 mL) were add-
ed to a round-bottomed flask and stirred for 10 min at rt. Next,
TBAF·3H2O (0.063 g, 0.2 mmol) dissolved in anhyd THF (4 mL) was
added and the system maintained under stirring for 12 h at rt. After
this time, the THF was evaporated under reduced pressure, CH2Cl2 (20
mL) was added and the organic phase washed with H2O (3 × 30 mL).
The CH2Cl2 was evaporated at reduced pressure and the remaining
viscous yellow liquid was purified by silica gel column chromatogra-
phy, eluting with hexane/EtOAc (85:15); yield: 0.24 g (49%); anti/syn:
99:1; yellow oil; []D25 –19.4 (c 1.6, CHCl3).
Acknowledgment
We thank CAPES for the fellowship for some authors and Unidade de
Espectrometria de Massas e Proteômica (UEMP)-UFRJ-Brazil for
HRMS (ESI) experiments.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706432.
IR (film): 2954, 2868, 1730, 1552, 1163, 747, 698 cm–1
.
S
u
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n
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o
n
1H NMR (400 MHz, CDCl3):  = 0.95 (d, J = 8 Hz, 3 H), 0.99 (d, J = 8 Hz,
3 H), 1.19 (m, 1 H), 1.62 (m, 1 H), 1.74 (m, 1 H), 2.80 (m, 1 H), 3.06 (m,
1H), 3.36 (s, 3 H), 3.39 (d, J = 12 Hz, 2 H), 3.73 (s, 3 H), 3.76 (d, J = 12
Hz, 2 H), 4.45 (s, 1 H), 4.71 (dd, J = 12, 8 Hz, 1 H), 4.74 (dd, J = 12, 4 Hz,
1 H), 7.27 (m, 10 H).
13C NMR (100 MHz, CDCl3):  = 22.93, 23.21, 26.74, 36.28, 40.47,
50.25, 52.19, 52.88, 53.83, 56.55, 127.12, 129.35, 138.39, 139.38.
References
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Dimethyl 2-[(2R,3S)-3-(Dibenzylamino)-1-nitrobutan-2-
yl]malonate (10c) (Table 2, entry 10)
25
Yield: 0.29 g (70%); anti/syn: 99:1; yellow oil; []D +5.5 (c 1.7,
CHCl3).
1H NMR (400 MHz, CDCl3):  = 1.09 (d, J = 8 Hz, 3 H), 2.88 (m, 1 H, NH),
3.05 (m, 1 H), 3.27 (d, J = 12 Hz, 2 H), 3.38 (s, 3 H), 3.76 (s, 3H), 3.78 (d,
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yl), 75.31 (CH2NO2), 127.13 (2 × CH), 128.41 (4 × CH2), 129.27 (4 ×
CH2), 139.03 (2 × Cipso), 168.06 (C=O), 170.13 (C=O).
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451.1849.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G