syn-Selective Michael Reaction of α-Branched Aryl Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid Derived Bifunctional Br?nsted Bases

Article abstract of DOI:10.1002/ejoc.202100355

Here we describe a direct access to 2,2,3-trisubstituted syn γ-nitroaldehydes by addition of α-branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid-derived amino acid peptide. Different α-methyl arylacetaldehydes react with β-aromatic and β-alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn-selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E-enolate. The interaction between the substrates and the catalyst follows Pápai's model, wherein an intramolecular H-bond interaction in the catalyst between the NH group of one of the tert-leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.

Full text of DOI:10.1002/ejoc.202100355

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: syn-Selective Michael Reaction of alpha-Branched Aryl
Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid
Derived Bifunctional Brønsted Bases
Authors: Ane García Urricelqui, Abel de Cózar, Teresa Esperanza
Campano, Antonia Mielgo, and Claudio Palomo
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100355
Link to VoR: https://doi.org/10.1002/ejoc.202100355
01/2020

10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
syn-Selective Michael Reaction of -Branched Aryl
Acetaldehydes with Nitroolefins Promoted by Squaric Amino Acid
Derived Bifunctional Brønsted Bases
Ane García-Urricelqui,[a] Abel de Cózar,[a,b] Teresa E. Campano,[a] Antonia Mielgo*[a] and Claudio
Palomo*[a]
[a]
A. García-Urricelqui, Dr. A. de Cózar, Dr. T. E. Campano, Dr. A. Mielgo and Prof. C. Palomo
Departamento de Química Orgánica I, Universidad del País Vasco UPV/EHU
Manuel Lardizábal 3, 20018 San Sebastián (Spain)
E-mail: antonia.mielgo@.ehu.es; claudio.palomo@ehu.es
[b]
Dr. A. de Cózar,
IKERBASQUE, Basque Foundation for Science
48009, Blbao (Spain)
Supporting information for this article is given via a link at the end of the document.
Abstract: Here we describe the direct access to 2,2,3-trisubstituted
syn -nitroaldehydes from the addition reaction of -branched aryl
acetaldehydes to nitroolefins promoted by a cinchona based squaric
acid-derived amino acid peptide. The reaction is quite general for
different -methyl arylacetaldehydes and aromatic and -alkyl
nitroolefins affording the Michael adducts in high enantioselectivity
and syn-selectivity. NMR experiments and DFT calulations predict the
reaction to occur through the E-enolate. The interactions between the
substrates and the catalyst follow Pápai’s model, wherein an
intramolecular H-bonding interaction in the catalyst between the NH
group of one of the tert-leucines and the squaramide oxygen seems
to be key for discrimination of the corresponding reaction transition
states.
selectivity.[8] The first use of -branched aldehydes for this
reaction was reported by Barbas III in 2004.[9] Following this work,
several amine catalysts have also been investigated[10] and, albeit
with few exceptions,[10a,e] most provide the adducts in modest
selectivity (poor dr and/or poor ee). In this context, the question of
whether BB catalysis can work as a complementary alternative for
the stereoselective -functionalization of aldehydes is still open.
Recently we reported the first use of -substituted -amino
aldehydes as pronucleohiles in a BB catalyzed Michael addition
to nitroolefins[11-13] (Scheme 1, a). The reaction is promoted by the
tert-leucine derived catalysts of type I and produces densely
functionalized products bearing up to two, quaternary and tertiary,
vicinal
stereocenters
with
high
diastereo-
and
enantioselectivity.[11] Notably, no side reactions nor homoaldol
products are observed under these conditions and an
intramolecular H-bonding between the NH group and the carbonyl
Introduction
Organocatalysis has experienced a significant growth over the
last years and today a broad range of efficient asymmetric
transformations for different substrates is available.[1] In this
context an extensive number of chiral bifunctional Brønsted base
(BB) mediated reactions has been reported, most of them
triggered by bifunctional tertiary amines.[2] Despite this progress,
the use of these tertiary amine catalysts has been mainly limited
to relatively acidic substrates (pka < 17)[3] and their application
with aldehydes as pronucleophiles has been hardly
investigated.[4] The inherent high reactivity of the carbon atom in
that oxidation state which difficults effective control of side
reactions,[5] may account for this lack of studies, a complication
that has to be added to the usual problems associated with
aldehyde activation and reaction enantiocontrol. Aminocatalysis[6]
has shown to be an excellent option to solve these problems and,
at present, a broad range of efficient reactions to access -
functionalized aldehydes in high stereoselectivity is available. In
particular, the addition reaction of aldehydes to nitroolefins
provides an expedient route to-nitro aldehydes, important
intermediates in synthesis.[7] However, the application of this
reaction to -branched aldehydes has shown problematic, mainly
because of the difficulty for the condensation of the amine catalyst
with the -branched aldehyde due to steric hindrance, the
relatively lower reactivity of the resulting -disubstituted
enamine and the difficulty in controlling the E/Z enamine
Scheme 1. Activation of -branched aldehydes by BB catalysis. a) Previous
work on -branched -amino aldehydes. b) This work by using -branched aryl
acetaldehydes.
1
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10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
oxygen atom in the starting -amino aldehyde appears to be key
for both reactivity and stereocontrol. We wondered whether this
BB activation strategy might be extended to -branched
aldehydes lacking the above noted intramolecular H-bonding,
Table 1. Catalyst screening for the 1,4-addition of (+)-2-propionaldehyde 1A to
nitroolefin 5a to afford 6Aa.[a]
Entry
Cat.
t(h)
T(ºC) Conv.
(%)[b]
Yield
(%)[c]
dr[d]
ee[e]
such as -branched
aryl acetaldehydes (Scheme 1, b),
particularly -methyl aryl acetaldehydes, which might produce
compounds of biological interest having quaternary carbon
stereocenters.[14] In this instance, we expected that the BB
catalyst might control both enolate configuration and face
discrimination during reaction, thus enhancing the utility of the
approach.
1
2
C1
C2
C3
C4
C5
C6
C7
C8
C9
29
13
72
72
35
30
15
20
10
15
15
23
40
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
rt
rt
0
92
74
69
68
90
91
85
89
87
92
82
84
78
74
71
83:17
85:15
81:19
86:14
88:12
90:10
86:14
88:12
91:9
47
-2
3
88
24
84
89
94
85
93
88
94
74
96
96
4
>99
98
5
Results and discussion
6
98
Preliminary experimental observations and catalyst
screening
7
>99
>99
98
Our initial studies were carried out on the reaction between (+)-2-
phenylpropionaldehyde 1A and nitroolefin 5a (Scheme 2). First
attempts using ureidopeptide derived bifunctional Brønsted bases
previously developed by us[15] (C1, C2 and C3) showed that the
reaction indeed proceeded to afford -nitroaldehyde 6Aa with
8
9
10
11
12
13
85
95:5
C10
C11
C12
88
92:8
93
84:16
86:14
98
[a] Reactions conducted on a 0.2 mmol scale in 0.6 mL of CH2Cl2 (mol ratio
nitroolefin/aldehyde/catalyst 3:1:0.1). [b] Determined by the disappearance of
the starting aldehyde. [c] Yield of the isolated two isomers. [d] Determined by
1H NMR (300 MHz) analysis on the crude product. [e] Determined by chiral
HPLC.
moderate syn diastereoselectivity,[16] but the enantioselectivity
was essentially negligible (Table 1, entries 1-3). The reaction
catalyzed by the tert-leucine derived squaric acid C4, which
provided the best results for -branched -amino aldehydes,[11]
afforded the Michael adduct in better enantioselectivity and quite
good syn selectivity (84% ee, 86:14 dr, entry 4), but improvement
was still needed. Variations at the amide terminus in catalyst C4
led to C5 and C6 and the reaction in the presence of these
catalysts (entries 5 and 6) showed significant stereoselectivity
improvement. Whilst the tert-butylamine derived catalyst C5
provided 6Aa in better enantio- and diastereoselectivity, catalyst
C6 led to excellent enantioselectivity and quite good
diastereoselectivity. At this point and, with the aim to further
improve reaction diastereoselectivity, we considered the
incorporation of a second amino acid unit in catalyst C6.
Accordingly, catalysts C7, C8 and C9,[17,18] were synthesized and
tested. Whereas C7 provided adduct 6Aa in lower diastereo- and
enantioselectivity than C6, catalyst C8 produced 6Aa in similar
diastereo- and enantioselectivity. In the presence of C9, which
incorporates two tert-leucine units, product 6Aa was obtained in
higher syn selectivity, although slightly lower enantioselectivity.
Lowering the temperature to 0 ºC, the reaction using this catalyst
led to product 6Aa with better diastereo- and enantioselectivity in
reasonable time (entry 10). The position of the amino acid unit in
these catalysts seems also to be significant as the reaction in the
presence of C10, which incorporates the tert-leucine unit at other
position, provided adduct 6Aa in lower enantioselectivity.[19]
Further proof of the robustness of this subclass of catalysts was
provided from the reaction of 1A with 5a using the commercially
Scheme 2. Catalyst screened in the Michael addition of (±)1A to 5a.
2
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10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
available standard squaramides C11 and C12 which led to 6Aa in
good enantioselectivity but in both cases with lower levels of
diastereoselectivity.[20] Therefore, the scope of the reaction was
studied with the dipeptide derived catalyst C9.
120
100
80
60
40
20
0
Reaction scope
As the results in Table 2 show, the above conditions were equally
efficient for the Michael addition of (+)-2-phenylpropionaldehyde
1A to different nitroolefins (5b-i). The reaction tolerates well
nitrostyrenes carrying both electron-withdrawing and electron-
donating substituents at the aromatic ring of the nitroolefin
independently of the substituent position. In every case the
corresponding adducts 6Aa-6Ah were obtained in excellent
enantioselectivity and very good syn-diastereoselectivity.
Time (min)
C9
C6
Table 2. Scope of the Michael reaction of -methyl aryl/heteroaryl
acetaldehydes 1-4 with nitroolefins 5a-i assisted by C9.[a]
Figure 1. Conversion evolution of the reaction between (+) 1A and nitroolefin
5a in the presence of C6 and C9 catalysts at RT.
The above difference between both catalysts was also observed
in the reaction of the ethyl and benzyl derivatives 1B and 1D with
nitroolefins 5c and 5b respectively (Table 3). In the presence of
C9, the Michael adduct 6Bc was produced after 67 h at 0ºC in
56% conversion, while catalyst C6 necessitates 112 h to reach
the same conversion. Likewise, adduct 6Db was formed in 85%
conversion after 142 h of reaction when C9 was used, but in the
presence of C6 the reaction progresses more slowly.
Table 3. Scope of the Michael reaction of -branched aryl/heteroaryl
acetaldehydes 1-4 with nitroolefins 5a-c assisted by C9/C6.[a]
[a] Reactions conducted at 0 ºC on a 0.2 mmol scale in 0.6 mL of CH2Cl2 (mol
ratio nitroolefin/aldehyde/catalyst 3:1:0.1). Conversion determined by the
disappearance of the starting aldehyde. Yield of the isolated major
diastereoisomer. Diastereomeric ratio determined by 1H NMR (300 MHz)
analysis on the crude product. Enantioselectivity determined by chiral HPLC. [b]
Reaction carried out at RT. [c] Yield of the isolated two isomers.
Significantly, the most recalcintrant -aliphatic nitroolefins such as
5g and 5h also react under these conditions to provide the
Michael adducts 6Ag and 6Ah with excellent enantio- and syn-
diastereocontrol. Similarly, the reaction may be extended to other
aryl and heteroaryl -methyl acetaldehydes leading to Michael
adducts such as 7Aa, 8Aa, 8Ai and 9Ac with excellent diastereo-
and enantioselectivity. In general, the dipeptide derived catalyst
C9, which bears several H-bond donors,[21] is somewhat better
On the other hand, as shown in Table 3, under the usual
conditions and in the presence of C9 catalyst a decrease in both
reactivity and stereoselectivity was observed when changing from
-metyl aryl acetaldehydes to other -susbtituted derivatives.
With -ethyl and -allyl phenyl acetaldehydes 1B and 1C adducts
6Bc and 6Cb were obtained in quite good diastereo- and
enantioselectivity (83:17 dr and 78% ee for 6Bc and 85:15 dr and
77% ee for 6Cb). However, In the case of the -benzyl
acetaldehyde 1D poor diastereomeric ratio and enantiomeric
excess were measured in the synthesis of 6Db (57:43 dr and 40%
ee). The -ethyl 3-thiophenyl acetaldehyde 3B also reacted with
p-chloro nitrostyrene 5a, although the Michael adduct 8Ba was
produced in moderate stereoselectivity. Finally, the more acidic
than C4-C6 catalysts
not only regarding reaction
stereoselectivity,[22]
but also with respect to the reaction
conversion. For instance, the reaction between 1A and 5a at RT
in the presence of C6 and C9, Figure 1, shows that with the former
catalyst the reaction progresses relatively slower than with the
dipeptide derived catalyst C9.
3
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10.1002/ejoc.202100355
European Journal of Organic Chemistry
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-allyl 2-naphthylacetaldehyde 4C proved to be more active as
90% conversion was detected after 64h reaction and adduct 9Ca
was obtained in quite good diastereoselectivity, (85:15 dr) albeit
in relatively poor enantiomeric excess (46% ee). Accordingly,
while this BB approach may be extended to other ,-
disubstituted aryl acetaldehydes,[23] better conditions are still
needed to improve both reaction time and stereocontrol. In this
respect, during the preparation of racemic adducts we observed
that reaction of 1A with nitroolefin 5c carried out in the presence
of triethylamine (30 mol% ) at RT for 16 h led to rac-6Ac in 71:29
dr, ( 90:10 dr with C9). Similarly, reaction of 3A with 5i promoted
by catalyst C13 (10 mol%) at RT provided after 16h rac-8Ai in
76:24 dr while using the chiral catalyst C9 the adduct was formed
in 90:10 dr. Thus, a combination of both, substrate and catalyst
control may be operating for the observed syn selectivity. A single
crystal X-ray analysis of 6Ab (Figure 2)[24] confirmed both its
relative and absolute configuration and that of the remaining
adducts was assumed on the basis of a uniform reaction
mechanism.
Figure 3. Three alternative substrate-catalyst combinations proposed for
bifunctional Brønsted base activation mode.
Our calculations show that the less energetic transition
structures,[25] correspond to a Pápai’s activation mode wherein the
enolate interacts with the squaramide core of the catalyst and the
nitroolefin is activated through H-bonding interaction with the
cinchona moiety of C9, as previously described for the Michael
addition of -amino aldehydes to -nitro styrenes catalyzed by
analogous BB catalysts.[11] Remarkably, transition structures
involving E-enolates are more stabilized than analogues from Z-
enolates, as shown by the energy difference of +4.2 kcal mol–1
Figure 2. ORTEP diagram of compound 6Ab. View of the molecular structure
of 6Ab with 50% probability displacement ellipsoids.
Other interesting point of this protocol is that these
transformations can be scaled up without lost of yield nor
stereoselectivity as shown by the reaction of (+)-2-
phenylpropionaldehyde 1A with nitroolefin 5c on a 4 mmol scale,
which provided adduct 6Ac in 82% yield and with 94:6 dr and 95%
ee for the major syn-isomer. Notably, the catalyst was recovered
after flash column chromatography in 87% yield.[25]
Theoretical probes and mechanistic observations
In order to get insights into the mechanism of the reaction and the
origin of the syn-selectivity in these transformations, we next
performed some DFT calculations[26] on the reaction of (+)-2-
phenyl propanal 1A with nitrostyrene 5c promoted by C9.
Up to (at least) three different non covalent coordination patterns
(model A or Takemoto’s proposal, model B or Pápai’s proposal
and model C or Wang’s proposal, Figure 3) have been
documented for reactions promoted by bifunctional thiourea (or
squaramide)-tertiary amine catalysts.[27] In our reaction we
identified two of the previous H-bonding net activation modes,
Takemoto’s proposal (electrophile dual-activation by the
squaramide core, model A) and Papai’s proposal (nucleophile
dual-activation by the squaramide core, model B). All attempts to
find transition structures following Wang’s model (squaramide-
activation of both reagents) evolved to Takemoto’s model and
therefore were discarded. For this study, we considered that the
system behaves under Curtin–Hammett kinetic scenario, where
the product ratio depends on the free Gibbs activation energy
difference of the corresponding transition structure, and both E–
and Z–enolate configurations were evaluated.
Figure 4. Main geometrical features and relative Gibbs free energies of least
energetic transition structures TS1 associated with the reaction of 1A and 5c
catalyzed by C9 that lead to the formation of syn-S,R-6Ac considering E– and
Z–enolates. Some hydrogen atoms are omitted for clarity. Energy values in kcal
mol–1 computed at B3LYP-D3(PCM)/6-311+G(d,p)//B3LYP-D3/6-31G(d) level
(298 K). The reactive prochiral faces of the aldehyde and nitroalkene are given
in grey and blue respectively.
between TS1-E-syn and TS1-Z-syn (Figure 4), despite reactive
complexes involving Z-enolates being close in energy to their E-
counterparts. This is a consequence of the higher deformation
required to adopt the geometry of the transition structure in Z-
4
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10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
enolates, where oxygen–phenyl repulsion during the C–C bond
formation leads to an additional torsion in the phenyl group.
Noteworthy, the observed facial selection is consequence of the
existence of an intramolecular H-bonding interaction between the
NH of one of the tert-leucines and the carbonyl of squaramide
moiety that fix the catalyst conformation independently of the
activation mode considered. Within this conformational restricted
catalytic system, TS1-E-syn was found to be the least energetic
transition structure due to a lower steric hindrance between the t-
butyl group of tert-leucine and the phenyl group of the enolate,
thus yielding compound syn-S,R-6Ac. Note that in TS1ENT-E-syn
and TS1-E-anti (Figure 5) the enolate has to rotate due to steric
hyndrance, leading to less optimal catalyst-substrate H-bonding
interactions. These calculations predict a theoretical ee of 99%
and dr >99:1, in good agreement with the experimental results.
Scheme 3. Formation of the E/Z enol acetates from (+)-2-phenylpropanal 1A in
the presence of triethylamine (TEA) and acetyl chloride.
Conclusion
In summary, we have demonstrated that the -functionalization of
-methyl aryl acetaldehydes may be accomplished by Brønsted
base activation catalysis, thus providing a complementary
alternative platform to the known enamine strategy. The protocol
seems to work through the formation of the corresponding E
ammonium enolate by the action of a cinchona based squaric
acid-derived amino acid peptide. Further reaction of the transient
ammonium enolate with different nitroolefins provides 2,2,3-
trisubstituted syn -nitroaldehydes in high enantio- and
diastereoselectivity and in the absence of homoaldol reaction.
Experimental Section
Catalytic conjugate additions of -branched aryl/heteroaryl
acetaldehydes to nitroolefins.
General Procedure: The corresponding aldehyde (0.2 mmol, 1 equiv),
nitroolefin (0.6 mmol, 3 equiv) and catalyst C6 or C9 (0.02 mmol, 10 mol%)
were dissolved in CH2Cl2 (0.6 mL) and the resulting mixture was stirred at
0 ºC. Reaction completion was followed by 1H NMR and after the indicated
time the mixture was directly submitted to flash column chromatography
on silica gel. Reaction conversions and diastereomeric ratios were
determined by 1H NMR. Enantiomeric ratios were determined by chiral
HPLC.
The corresponding racemic reactions were ran following the above
procedure but using achiral catalyst C13 (30 mol%).
(2S,3R)-3-(4-Chlorophenyl)-2-methyl-4-nitro-2-phenylbutanal (6Aa).
Prepared according to the General Procedure starting from aldehyde 1A,
nitroolefin 5a and catalyst C9 to afford a 95:5 diastereomer mixture. The
product was isolated as a colorless oil in a 88:12 diastereomeric ratio (53.9
mg, 0.169 mmol, 84% yield) after flash column chromatography on silica
gel (95:5 Hexane:EtOAc). The enantiomeric excess was determined by
chiral HPLC analysis (Daicel Chirapak IC Hexane:iPrOH 95:5, flow rate=1
mL/min). Retention times: 21.6 min (minor) and 23.1 min (major). 1H NMR
(300 MHz, CDCl3) δ 9.54 (s, 1H), 7.49-7.11 (m, 5H), 7.07 (dd, J = 7.7, 2.0
Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.05-4.83 (m, 2H), 4.21 (dd, J = 11.4, 4.0
Hz, 1H), 1.54 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 202.3, 138.6, 135.7,
132.3, 130.9, 130.1, 130.0, 129.0, 78.0, 58.2, 50.7, 18.1. UPLC-DAD-
QTOF: C17H16ClNO3Na [M+Na]+ calcd.: 340.0716, found: 340.0731.
Figure 5. Main geometrical features and relative Gibbs free energies of least
energetic transition structures TS1 associated with the reaction of 1A and 5c
catalyzed by C9 that lead to the formation of syn-S,R-6Ac considering E– and
Z–enolates. Some hydrogen atoms are omitted for clarity. Energy values in kcal
mol–1 computed at B3LYP-D3(PCM)/6-311+G(d,p)//B3LYP-D3/6-31G(d) level
(298 K). The reactive prochiral faces of the aldehyde and nitroalkene are given
in grey and blue respectively.
(2S,3R)-2-Methyl-4-nitro-2-phenyl-3-(p-tolyl)butanal (6Ab). Prepared
according to the General Procedure starting from aldehyde 1A, nitroolefin
5b and catalyst C9 to afford a 97:3 diastereomer mixture. The product was
isolated as a colorless solid in a 91:9 diastereomeric ratio (49.2 mg, 0.165
mmol, 83% yield) after flash column chromatography on silica gel (95:5
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak OD-H Hexane:iPrOH 90:10, flow rate=1 mL/min).
Retention times: 12.5 min (minor) and 18.1 min (major).1H NMR (300 MHz,
CDCl3) δ 9.60 (s, 1H), 7.42-7.24 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 6.97 (d,
Concordant with the above DFT observations, treatment of (+)-2-
phenyl propanal 1A with triethylamine (TEA) (1.5 equiv.) and
acetyl chloride (1.2 equiv.) in Cl2CH2 at RT for 16h provided a
5.5:1 (85:15) mixture of the corresponding 10 E and Z enol
acetates[28,29] (Scheme 3).
5
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10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
J = 7.9 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 5.15-4.75 (m, 2H), 4.18 (dd, J =
11.5, 3.8 Hz, 1H), 2.26 (s, 3H), 1.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
202.6, 138.7, 133.5, 130.9, 130.5, 130.4, 130.3, 129.4, 128.7, 77.7, 58.0,
50.8, 22.3, 18.4. UPLC-DAD-QTOF: C18H19NO3Na [M+Na]+ calcd.:
320.1263, found: 320.1266.
(2S,3R)-2-Methyl-3-(nitromethyl)-2,5-diphenylpent-4-ynal
(6Ag).
Prepared according to the General Procedure, starting from aldehyde 1A,
nitroolefin 5g and catalyst C9 to afford a 90:10 diastereomer mixture. The
major diastereoisomer was isolated as a yellow oil (44.1 mg, 0.143 mmol,
72% yield) after flash column chromatography on silica gel (98:2
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak IC Hexane:iPrOH 98:2, flow rate=1 mL/min).
(2S,3R)-2-Methyl-4-nitro-2,3-diphenylbutanal
(6Ac).
Prepared
23
Retention times: 24.7 min (minor) and 39.1 min (major). [α]D = 74.32º
according to the General Procedure starting from aldehyde 1A, nitroolefin
5c and catalyst C9 to afford a 94:6 diastereomer mixture. The major
diastereoisomer was isolated as a colorless oil (46.8 mg, 0.165 mmol, 83%
yield) after flash column chromatography on silica gel (95:5
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak OD-H Hexane:iPrOH 95:5, flow rate=1 mL/min).
(c=0.5, 96% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.57 (s, 1H), 7.49-
7.37 (m, 3H), 7.37-7.31 (m, 2H), 7.30-7.19 (m, 5H), 4.654.51 (m, 2H), 4.19
(dd, J = 9.6, 4.9 Hz, 1H), 1.73 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 199.42,
136.76, 131.78, 129.36, 128.66, 128.60, 128.32, 127.52, 122.32, 86.40,
84.47, 76.37, 55.84, 38.19, 16.95. UPLC-DAD-QTOF: C19H17NO3Na
[M+Na]+ calcd.: 330.1106, found: 330.1098.
23
Retention times: 21.8 min (minor) and 39.2 min (major). [α]D = 113.99º
(c=1, 96% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.59 (s, 1H), 7.40-
7.26 (m, 4H), 7.21-6.92 (m, 6H), 5.17-4.81 (m, 2H), 4.22 (dd, J = 11.5, 3.8
Hz, 1H), 1.55 (s, 3H). All the spectroscopic data were consistent with those
previously reported.[31]
(2S,3R)-2-Methyl-3-(nitromethyl)-2-phenylhexanal (6Ah). Prepared
according to the General Procedure, but at room temperature, starting
from aldehyde 1A, nitroolefin 5h and catalyst C9 to afford a 96:4
diastereomer mixture. The product was isolated as a yellow oil (28.4 mg,
0.114 mmol, 57% yield) after flash column chromatography on silica gel
(95:5 Hexane:EtOAc). The enantiomeric excess was determined by chiral
(2S,3R)-3-(3-Methoxyphenyl)-2-methyl-4-nitro-2-phenylbutanal (6Ad).
Prepared according to the General Procedure starting from aldehyde 1A,
nitroolefin 5d and catalyst C9 to afford a 94:6 diastereomer mixture. The
major diastereoisomer was isolated as a white foam (30.9 mg, 0.099 mmol,
49% yield) after flash column chromatography on silica gel (95:5
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak OD-H Hexane:iPrOH 90:10, flow rate=1 mL/min).
HPLC analysis (Daicel Chirapak OD-H Hexane:iPrOH 98:2, flow rate=1
20
mL/min). Retention times: 13.7 min (minor) and 18.3 min (major). [α]D
=
30.45º (c=1, 99% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H),
7.46-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.32-7.29 (m, 1H), 7.29-7.27 (m, 1H),
4.48 (dd, J = 13.4, 4.3 Hz, 1H), 4.28 (dd, J = 13.4, 7.3 Hz, 1H), 3.14 (ddt,
J = 8.6, 4.3, 2.7 Hz, 1H), 1.48 (s, 3H), 1.28-0.99 (m, 4H), 0.74 (t, J = 6.9
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 200.91, 137.67, 129.34, 128.17,
127.54, 77.75, 57.01, 41.80, 31.84, 21.01, 15.29, 14.10. UPLC-DAD-
QTOF: C14H19NO3Na [M+Na]+ calcd.: 272.1263, found: 272.1263.
23
Retention times: 18.8 min (minor) and 25.9 min (major). [α]D = 83.10º
(c=1, 92% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.56 (s, 1H), 7.38-
7.21 (m, 3H), 7.15-7.00 (m, 3H), 6.68 (dd, J = 8.3, 2.5 Hz, 1H), 6.57 (d, J
= 7.7 Hz, 1H), 6.45-6.32 (m, 1H), 5.00 (dd, J = 13.2, 11.4 Hz, 1H), 4.84
(dd, J = 13.2, 3.9 Hz, 1H), 4.17 (dd, J = 11.4, 3.8 Hz, 1H), 3.61 (s, 3H),
1.52 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 201.08, 159.30, 137.43, 137.03,
129.21, 129.14, 128.19, 127.47, 121.36, 115.43, 113.36, 76.22, 75.15,
56.72, 55.17, 49.72, 16.79. UPLC-DAD-QTOF: C18H19NO4Na [M+Na]+
calcd.: 336.1212, found: 336.1209.
(2S,3R)-3-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-methyl-4-
nitrobutanal (7Aa). Prepared according to the General Procedure starting
from aldehyde 2A, nitroolefin 5a and catalyst C9 to afford a 93:7
diastereomer mixture. The final product was isolated as a colorless oil in a
93:7 diastereomeric ratio (51.5 mg, 0.148 mmol, 74% yield) after flash
column chromatography on silica gel (90:10 Hexane:EtOAc). The
enantiomeric excess was determined by chiral HPLC analysis (Daicel
Chirapak IC Hexane:iPrOH 95:5, flow rate=1 mL/min). Retention times:
33.4 min (minor) and 37.3 min (major). 1H NMR (300 MHz, CDCl3) δ 9.44
(s, 1H), 7.15-7.07 (m, 2H), 6.98-6.90 (m, 2H), 6.89-6.77 (m, 4H), 4.94 (dd,
J = 13.1, 11.2 Hz, 1H), 4.85 (dd, J = 13.1, 4.3 Hz, 1H), 4.16 (dd, J = 11.2,
4.3 Hz, 1H), 3.78 (s, 3H), 1.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 200.51,
159.47, 134.23, 133.66, 131.14, 130.68, 129.46, 128.67, 128.46, 128.33,
76.12, 55.98, 55.41, 49.03, 16.43. UPLC-DAD-QTOF: C18H18ClNO4Na
[M+Na]+ calcd.: 370.0822, found: 370.0822.
(2S,3R)-2-Methyl-4-nitro-2-phenyl-3-(o-tolyl)butanal (6Ae). Prepared
according to the General Procedure starting from aldehyde 1A, nitroolefin
5e and catalyst C9 to afford a 95:5 diastereomer mixture. The product was
isolated as a colorless oil (49.3 mg, 0.166 mmol, 83% yield) after flash
column chromatography on silica gel (95:5 Hexane:EtOAc). The
enantiomeric excess was determined by chiral HPLC analysis (Daicel
Chirapak IC Hexane:iPrOH 95:5, flow rate=1 mL/min). Retention times:
23
17.3 min (major) and 19.3 min (minor). [α]D = 88.18º (c=1, 94% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 7.31 (dt, J = 6.5, 3.8
Hz, 4H), 7.22-7.14 (m, 1H), 7.12 (dd, J = 7.4, 1.4 Hz, 1H), 7.10-7.04 (m,
2H), 6.99 (d, J = 7.4 Hz, 1H), 5.05 (dd, J = 13.1, 11.5 Hz, 1H), 4.89 (dd, J
= 13.2, 3.7 Hz, 1H), 4.59 (dd, J = 11.4, 3.7 Hz, 1H), 2.07 (s, 3H), 1.57 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 201.99, 138.43, 137.94, 134.64, 131.01,
129.01, 128.15, 127.64, 127.31, 127.23, 126.10, 77.23, 56.92, 43.67,
19.84, 17.73. UPLC-DAD-QTOF: C24H23NO3Na [M+Na]+ calcd.: 320.1263,
found: 320.1256.
(2S,3R)-3-(4-Chlorophenyl)-2-methyl-4-nitro-2-(thiophen-3-yl)butanal
(8Aa). Prepared according to the General Procedure starting from
aldehyde 3A, nitroolefin 5a and catalyst C9 to afford a 91:9 diastereomer
mixture. The major diastereoisomer was isolated as a yellow oil (51.9 mg,
0.16 mmol, 80% yield) after flash column chromatography on silica gel
(90:10 Hexane:EtOAc). The enantiomeric excess was determined by
chiral HPLC analysis (Daicel Chirapak IC Hexane:iPrOH 98:2, flow
rate=0.5 mL/min). Retention times: 82.6 min (minor) and 98.1 min (major).
[α]D24 = 128.59º (c=1, 94% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.54
(s, 1H), 7.37 (dd, J = 5.1, 3.0 Hz, 1H), 7.20-7.13 (m, 2H), 6.94-6.84 (m,
4H), 4.95 (dd, J = 13.2, 11.5 Hz, 1H), 4.78 (dd, J = 13.2, 4.0 Hz, 1H), 4.16
(dd, J = 11.4, 3.9 Hz, 1H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 200.32,
138.30, 134.05, 133.99, 130.53, 128.66, 127.50, 126.10, 123.45, 76.09,
54.74, 49.02, 17.80. UPLC-DAD-QTOF: C15H14NO3SClNa [M+Na]+ calcd.:
346.0281, found: 346.0282.
(2S,3R)-3-(4-Methoxyphenyl)-2-methyl-4-nitro-2-phenylbutanal (6Af).
Prepared according to the General Procedure starting from aldehyde 1A,
nitroolefin 5f and catalyst C9 to afford a 96:4 diastereomer mixture. The
product was isolated as a yellow oil in a 92:8 diastereomeric ratio (57.5 mg,
0.184 mmol, 92% yield) after flash column chromatography on silica gel
(95:5 Hexane:EtOAc). The enantiomeric excess was determined by chiral
HPLC analysis (Daicel Chirapak OD-H Hexane:iPrOH 95:5, flow rate=1
23
mL/min). Retention times: 25.7 min (minor) and 47.9 min (major). [α]D
=
95.45º (c=1, 92:8 dr, 87% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.59
(s, 1H), 7.37-7.29 (m, 3H), 7.10 (dd, J = 8.0, 1.5 Hz, 2H), 6.88 (d, J = 8.7
Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 5.07-4.78 (m, 2H), 4.18 (dd, J = 11.5, 3.8
Hz, 1H), 3.73 (s, 3H), 1.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 202.6,
160.2, 138.7, 131.6, 130.3, 129.7, 129.3, 128.6, 127.3, 114.9, 77.7, 58.0,
56.4, 50.3, 18.2. UPLC-DAD-QTOF: C18H19NO4Na [M+Na]+ calcd.:
336.1212, found: 336.1213.
(2S,3R)-2-Methyl-3-(nitromethyl)-5-phenyl-2-(thiophen-3-yl)pentanal
(8Ai). Prepared according to the General Procedure starting from
aldehyde 3A, nitroolefin 5i and catalyst C9 to afford a 90:10 diastereomer
mixture. The major diastereoisomer was isolated as a yellow oil (28.9 mg,
0.091 mmol, 45% yield) after flash column chromatography on silica gel
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
(95:5 Hexane:EtOAc). The enantiomeric excess was determined by chiral
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak IC Hexane:iPrOH 98:2, flow rate=1 mL/min).
Retention times for the major diastereomer: 34.3 min (minor) and 60.5 min
(major) and for minor diastereomer: 15.1 min (minor) and 16.3 min (major).
1H NMR (300 MHz, CDCl3) δ 9.89 (s, 1H, minor diastereomer), 9.69 (s, 1H,
mayor diastereomer), 7.47-7.40 (m, 3H, mayor diastereomer), 7.36 (d, J =
7.2 Hz, 3H, minor diastereomer), 7.18-7.11 (m, 7H, both diastereomers),
7.11-6.99 (m, 9H, both diastereomers), 6.97 (dd, J = 6.5, 3.1 Hz, 2H, both
diastereomers), 6.77 (d, J = 8.1 Hz, 2H, mayor diastereomer), 6.64 (dd, J
= 8.0, 1.5 Hz, 2H), 4.91 (dd, J = 13.2, 11.8 Hz, 1H, minor diastereomer),
4.79 (dd, J = 12.0, 3.3 Hz, 1H, mayor diastereomer), 4.68 (dd, J = 13.2,
3.2 Hz, 1H, minor diastereomer), 4.38-4.27 (m, 2H, both diastereomers),
4.22 (dd, J = 11.9 Hz, 1H, mayor diastereomer), 3.30-3.18 (m, 2H, minor
diastereomer), 3.19-3.07 (m, 2H, mayor diastereomer), 2.34 (s, 3H, minor
diastereomer), 2.31 (s, 3H, mayor diastereomer). 13C NMR (75 MHz,
CDCl3) δ 204.45, 204.33, 138.28, 138.06, 137.51, 135.58, 134.64, 134.58,
131.97, 131.50, 130.54, 130.50, 130.28, 129.87, 129.63, 129.54, 129.32,
129.17, 128.99, 128.79, 128.69, 128.48, 128.19, 128.12, 127.20, 126.91,
77.45, 77.30, 60.62, 59.55, 51.09, 47.30, 42.23, 41.66, 21.21. UPLC-DAD-
QTOF: C24H23NO3Na [M+Na]+ calcd.: 396.1576, found: 396.1573.
i
HPLC analysis (Daicel Chirapak IB Hexane : PrOH 98:2, flow rate=1
21
mL/min). Retention times: 24.9 min (major) and 26.8 min (minor). [α]D
=
21.39º (c=1, 97% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H),
7.38 (dd, J = 5.1, 2.9 Hz, 1H), 7.25-7.14 (m, 3H), 7.06 (dd, J = 2.9, 1.4 Hz,
1H), 7.02-6.95 (m, 2H), 6.92 (dd, J = 5.1, 1.4 Hz, 1H), 4.50 (dd, J = 13.2,
4.6 Hz, 1H), 4.34 (dd, J = 13.2, 7.2 Hz, 1H), 3.17-3.05 (m, 1H), 2.59 (ddd,
J = 16.7, 8.4, 3.4 Hz, 1H), 2.33 (ddd, J = 13.6, 9.7, 7.2 Hz, 1H), 1.73-1.55
(m, 2H), 1.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 199.74, 140.82, 138.82,
128.65, 128.51, 127.44, 126.37, 126.22, 123.44, 77.48, 55.44, 41.17,
34.26, 31.78, 15.67. UPLC-DAD-QTOF: C17H19NO3SNa [M+Na]+ calcd.:
340.0983, found: 340.0982.
(2S,3R)-2-Methyl-2-(naphthalen-2-yl)-4-nitro-3-phenylbutanal (9Ac).
Prepared according to the General Procedure starting from aldehyde 4A,
nitroolefin 5c and catalyst C9 to afford a 98:2 diastereomer mixture. The
product was isolated as a white foam (47.3 mg, 0.142 mmol, 71% yield)
after flash column chromatography on silica gel (95:5 Hexane:EtOAc). The
enantiomeric excess was determined by chiral HPLC analysis (Daicel
Chirapak IB Hexane:iPrOH 95:5, flow rate=1 mL/min). Retention times:
21
19.1 min (major) and 21.7 min (minor). [α]D = 175.05º (c=1, 91% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 7.88-7.72 (m, 3H),
7.54-7.44 (m, 3H), 7.23 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 5.1, 2.0 Hz, 3H),
6.99 (dd, J = 5.2, 1.6 Hz, 2H), 5.10 (dd, J = 13.1, 11.5 Hz, 1H), 4.87 (dd, J
= 13.1, 3.8 Hz, 1H), 4.31 (dd, J = 11.5, 3.8 Hz, 1H), 1.63 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 201.27, 135.48, 134.82, 133.20, 132.69, 129.46,
129.18, 128.42, 128.21, 127.89, 127.69, 127.03, 126.92, 126.83, 124.45,
76.46, 56.96, 49.87, 17.54. UPLC-DAD-QTOF: C21H19NO3Na [M+Na]+
calcd.: 356.1263, found: 356.1259.
(2S,3R)-3-(4-Chlorophenyl)-2-ethyl-4-nitro-2-(thiophen-3-yl)butanal
(8Ba). Prepared according to the General Procedure starting from
aldehyde 3B, nitroolefin 5a and catalyst C9 to afford a 55:45 diastereomer
mixture. The product was isolated as a yellow oil in a 62:38 diastereomeric
ratio (28.4 mg, 0.084 mmol, 42% yield) after flash column chromatography
on silica gel (98:2 Hexane:EtOAc). The enantiomeric excess was
determined by chiral HPLC analysis (Daicel Chirapak IC Hexane:iPrOH
95:5, flow rate=1 mL/min). Retention times for the major diastereomer:
12.4 min (major) and 13.4 min (minor) and for minor diastereomer: 21.5
min (major) and 31.1 min (minor). 1H NMR (300 MHz, CDCl3) δ 9.73 (s,
1H), 7.44 (dd, J = 5.1, 2.9 Hz, 1H), 7.27-7.18 (m, 2H), 7.06 (dd, J = 2.9,
1.4 Hz, 1H), 7.01-6.90 (m, 3H), 4.86 (dd, J = 13.3, 11.6 Hz, 1H), 4.65 (dd,
J = 13.3, 3.7 Hz, 1H), 4.07 (dd, J = 11.6, 3.7 Hz, 1H), 1.95 (qd, J = 7.4, 1.1
Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 203.11,
130.97, 130.85, 128.84, 128.65, 127.27, 126.26, 123.87, 76.96, 57.92,
50.36, 28.22, 9.09. UPLC-DAD-QTOF: C17H20NO4S [M+ CH3OH-Cl]+
calcd.: 334.1113, found: 334.1113.
(2S,3R)-2-Ethyl-4-nitro-2,3-diphenylbutanal (6Bc). Prepared according
to the General Procedure starting from aldehyde 1B, nitroolefin 5c and
catalyst C9 to afford an 83:17 diastereomer mixture. The product was
isolated as a white oil in a 82:18 diastereomeric ratio (36.3 mg, 0.122 mmol,
61% yield) after flash column chromatography on silica gel (98:2
Hexane:EtOAc). The enantiomeric excess was determined by chiral HPLC
analysis (Daicel Chirapak IF Hexane:iPrOH 98:2, flow rate=1 mL/min).
Retention times: 12.5 min (major) and 15.9 min (minor). 1H NMR (300 MHz,
CDCl3) δ 9.83 (s, 1H), 7.47-7.36 (m, 3H), 7.29-7.21 (m, 3H), 7.18-7.11 (m,
2H), 7.11-7.02 (m, 2H), 4.98 (dd, J = 13.2, 11.7 Hz, 1H), 4.68 (dd, J = 13.3,
3.4 Hz, 1H), 4.16 (dd, J = 11.7, 3.4 Hz, 1H), 1.96 (dq, J = 14.4, 7.1 Hz, 2H),
0.78 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 204.10, 137.03,
135.44, 129.80, 129.26, 128.56, 128.19, 128.07, 127.97, 77.06, 50.96,
27.77, 9.04. UPLC-DAD-QTOF: C18H19NO3Na [M+Na]+ calcd.: 320.1263,
found: 320.125.
(S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)-2-(naphthalen-2-yl)pent-4-
enal (9Ca). Prepared according to the General Procedure starting from
aldehyde 4C, nitroolefin 5a and catalyst C9 to afford an 85:15
diastereomer mixture. The product was isolated as a white foam in a 80:20
diastereomeric ratio (53.6 mg, 0.136 mmol, 68% yield) after flash column
chromatography on silica gel (98:2 Hexane:EtOAc). The enantiomeric
excess was determined by chiral HPLC analysis (Daicel Chirapak IA
Hexane:iPrOH 98:2, flow rate=1 mL/min). Retention times: 17.5 min
(minor) and 29.5 min (major). 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H),
7.92 (d, J = 8.7 Hz, 2H), 7.88-7.77 (m, 2H), 7.60-7.52 (m, 1H), 7.51-7.45
(m, 1H), 7.31-7.13 (m, 3H), 7.05 (d, J = 8.3 Hz, 2H), 5.61-5.43 (m, 1H),
5.16-5.01 (m, 3H), 4.70 (dd, J = 13.4, 3.3 Hz, 1H), 4.21 (dd, J = 11.7, 3.2
Hz, 1H), 2.92 (dd, J = 14.8, 5.5 Hz, 1H), 2.65 (dd, J = 14.7, 8.6 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 203.21, 134.28, 133.98, 133.77, 133.15,
132.76, 131.81, 131.34, 129.64, 128.84, 128.26, 127.76, 127.65, 127.19,
127.12, 124.43, 120.47, 76.67, 59.28, 50.37, 38.66. UPLC-DAD-QTOF:
C23H20ClNO3Na [M+Na]+ calcd.: 416.1029, found: 416.1033.
(S)-2-((R)-2-Nitro-1-(p-tolyl)ethyl)-2-phenylpent-4-enal
(6Cb).
Prepared according to the General Procedure starting from aldehyde 1C,
nitroolefin 5b and catalyst C9 to afford an 85:15 diastereomer mixture. The
product was isolated as a colorless oil in a 79:21 diastereomeric ratio (42.7
mg, 0.132 mmol, 66% yield) after flash column chromatography on silica
gel (99:1 Hexane:EtOAc). The enantiomeric excess was determined by
chiral HPLC analysis (Daicel Chirapak IB Hexane:iPrOH 98:2, flow rate=1
mL/min). Retention times: 10.7 min (minor) and 12.2 min (major). 1H NMR
(300 MHz, CDCl3) δ 9.79 (s, 1H), 7.46-7.31 (m, 3H), 7.15 (dd, J = 6.8, 1.6
Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 5.58-5.37 (m,
1H), 5.10-4.96 (m, 3H), 4.69 (dd, J = 13.2, 3.4 Hz, 1H), 4.11 (dd, J = 11.7,
3.3 Hz, 1H), 2.77 (ddt, J = 14.7, 5.9, 1.4 Hz, 1H), 2.67-2.55 (m, 1H), 2.30
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 203.81, 138.19, 132.44, 130.06,
129.88, 129.52, 129.21, 129.19, 128.40, 128.03, 120.22, 77.78, 59.50,
50.87, 39.16, 21.37. UPLC-DAD-QTOF: C20H21NO3Na [M+Na]+ calcd.:
346.1419, found: 346.1411.
Acknowledgements
Support has been provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(GV grant IT1236-19), and Ministerio de Ciencia e Innovación
(grant PID2019-109633GB-C21), Spain. A. G. and T. E. thank
(2S,3R)-2-Benzyl-4-nitro-2-phenyl-3-(p-tolyl)butanal (6Db). Prepared
according to the General Procedure starting from aldehyde 1D, nitroolefin
5b and catalyst C9 to afford a 57:43 diastereomer mixture. The product
was isolated as a white solid in a 63:37 diastereomeric ratio (33.6mg, 0.09
mmol, 45% yield) after flash column chromatography on silica gel (98:2
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100355
European Journal of Organic Chemistry
FULL PAPER
Pellissier, Asymmetric Domino Reactions, RSC Publishing, Cambridge,
2013.
Basque Government and MINECO respectively for fellowships.
We would like to express our gratitude to the students I. González
and M. Campo for their participation in conducting some
experiments of the reaction scope. We also thank SGIker
(UPV/EHU) for providing NMR, HRMS. X-Ray and computational
resources.
[8]
[9]
For a review on the -functionalization of -disubstituted aldehydes via
enamine activation, see: A. Desmarchelier, V. Coeffard, X. Moreau, C.
Greck, Tetrahedron 2014, 70, 2491–2513.
N. Mase, R, Thayumanavan, F, Tanaka, C. F. Barbas III, Org. Lett. 2004,
6, 2527–2530.
[10] a) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew. Chem. 2006, 118,
6514–6518; Angew. Chem. Int. Ed. 2006, 45, 6366–6370; b) Y.-F. Ting,
Ch. Chang, R. J. Reddy, D. R. Magar, K. Chen, Chem. Eur. J. 2010, 16,
7030–7038; c) J.-R. Chen, Y.-Q. Zou, L. Fu, F, Ren, F. Tan, W.-J. Xiao,
Tetrahedron 2010, 66, 5367–5372; d) T. C. Nugent, M. Shoaib, A. Shoaib,
Org. Biomol. Chem. 2011, 9, 52–56; e) P. Szczśniak, O. Staszewska-
Krajewska, B. Furman, J. Młynarsky, Chemistry Select 2017, 2, 2670–
2676. For other contributions on the addition of aldehydes to nitroolefins
which include some specific examples on ,-disubstitued aldehydes,
see: d) S. H. Mc Cooey, S. J. Connon, Org. Lett. 2007, 9, 599–602; e) M.
Yoshida, A. Sato, S. Hara, Org. Biomol. Chem. 2010, 8, 3031–3036. For
a protocol on solid phase under continuos flow conditions: f) R. Porta, M.
Benaglia, F. Coccia, F. Cozzi, A. Puglisi, Adv. Synth. Catal. 2015, 357,
377–383.
Keywords: -branched arylacetaldehydes • Brønsted bases •
Michael reaction • nitroolefins • organocatalysis
[1]
a) Comprehensive Asymmetric Catalysis, Vol I-III, Suppl. I-II (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin 1999; b)
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8
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9
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European Journal of Organic Chemistry
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Entry for the Table of Contents
Expanding the substrate scope for BB catalysis: -Branched aryl acetaldehydes are efficiently activated by a cinchona based
squaric acid-derived peptide to provide, upon reaction with nitroolefins, 2,2,3-trisubstituted syn -nitroaldehydes with high diastereo-
and enantioselectivity.
10
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