Intermolecular domino Michael/aldol reactions of α,β-unsaturated esters, aromatic aldehydes, and various nucleophiles promoted with a catalytic amount of a guanidine base in DMSO

Article abstract of DOI:10.1016/j.tet.2021.132329

In DMSO, a catalytic amount of Barton's base (2-t-butyl-1,1,3,3-tetramethylguanidine, BTMG) effectively catalyzed intermolecular three-component reactions of α,β-unsaturated esters, aldehydes, and carbon-, sulfur-, or nitrogen-pronucleophiles to give three-component addition products with the formation of two new σ-bonds: pronucleophiles and aldehydes reacted with α,β-unsaturated esters at their β-positions and α-positions, respectively. Mechanism studies suggested that these reactions proceeded by the first intermolecular Michael addition of anionic nucleophiles that were formed from pronucleophiles with a catalytic amount of BTMG, followed by intermolecular aldol reactions of transient ester enolates even in the presence of more than stoichiometric amounts of acidic pronucleophiles. High nucleophilicity over Br?nsted basicity of transient enolates in polar solvents was observed for transient ester enolates rather than ketone enolates.

Full text of DOI:10.1016/j.tet.2021.132329

Tetrahedron 94 (2021) 132329
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Intermolecular domino Michael/aldol reactions of a,b-unsaturated
esters, aromatic aldehydes, and various nucleophiles promoted with a
catalytic amount of a guanidine base in DMSO
Shunya Morita, Tomoyuki Yoshimura, Jun-ichi Matsuo*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In DMSO, a catalytic amount of Barton's base (2-t-butyl-1,1,3,3-tetramethylguanidine, BTMG) effectively
Received 18 May 2021
Received in revised form
29 June 2021
Accepted 29 June 2021
Available online 15 July 2021
catalyzed intermolecular three-component reactions of
a,b-unsaturated esters, aldehydes, and carbon-,
sulfur-, or nitrogen-pronucleophiles to give three-component addition products with the formation of
two new
tions and
s
a
-bonds: pronucleophiles and aldehydes reacted with
-positions, respectively. Mechanism studies suggested that these reactions proceeded by the
a,b-unsaturated esters at their b-posi-
first intermolecular Michael addition of anionic nucleophiles that were formed from pronucleophiles
with a catalytic amount of BTMG, followed by intermolecular aldol reactions of transient ester enolates
even in the presence of more than stoichiometric amounts of acidic pronucleophiles. High nucleophi-
licity over Brønsted basicity of transient enolates in polar solvents was observed for transient ester
enolates rather than ketone enolates.
Keywords:
Domino reaction
Aldol reaction
Michael reaction
Catalytic reaction
Transient enolate
Multi-component reaction
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
with a catalytic amount of a base [6]. A more facile intramolecular
aldol reaction rather than intermolecular protonation to Michael
Multicomponent reactions (MCRs) are valuable synthetic tools
for the preparation of structurally diverse compounds and for
efficient synthesis of target molecules [1]. They are especially useful
for building chemical libraries in drug discovery [2]. We have been
adducts enabled the catalytic use of a base for domino Michael/
intramolecular aldol reactions. Organocatalytic asymmetric
Michael/aldol reactions involving intramolecular aldol reactions
have also been reported recently [7]. However, only a few examples
of catalytic intermolecular three-component reactions of 1e3 to 4
have been reported.
interested in MCRs for the synthesis of a variety of -hydroxy car-
b
boxylates 4 composed of three reactants including a,b-unsaturated
carbonyl compounds 1, acidic pronucleophiles 2, and aldehydes 3
since -hydroxy carbonyl compounds 4 are important synthetic
intermediates in the synthesis of pharmaceuticals and bioactive
compounds [3] (Scheme 1a).
To achieve the intermolecular three-component synthesis of 4,
sequential Michael/aldol reactions have been developed by stoi-
chiometric pretreatment of pronucleophiles HX into anionic nu-
cleophiles MX (M including Li [4], SiR3 [5], etc.). Thus, a proton
source from HX has been deprotonated in advance by using a
stoichiometric amount of a base to avoid termination of the
sequential reaction at the first Michael addition. Exceptions are
domino Michael/intramolecular aldol reactions that were promoted
A catalytic MCR to 4 without stoichiometric pretreatment of HX
was achieved by tandem Baylis-Hillman/Michael reactions using a
catalytic amount of a phosphine, ethyl acrylate 1, sulfonamides as a
pronucleophile 2, and aldehydes 3 (Scheme 1b) [8]. However,
Baylis-Hillman reactions to 6 have a limitation for substrates: it was
pointed out that Baylis-Hillman reaction of b-substituted acrylates
including alkyl crotonate, cinnamate, and 3,3-dimethylacrylate
occurred sluggishly [9]. Also, Baylis-Hillman reaction inherently
b
does not proceed with
methacrylates.
a-substituted acrylates such as
We focused on a catalytic domino Michael/intermolecular aldol
reaction to 4 expecting broader substrate scope (Scheme 1c). The
difficulty of this method had been pointed out by Wang's group [9].
They reported that mixing methyl acrylate and 2-nitropropane first
with a stoichiometric amount of DBU followed by addition of
* Corresponding author.
E-mail address: jimatsuo@p.kanazawa-u.ac.jp (J.-i. Matsuo).
https://doi.org/10.1016/j.tet.2021.132329
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
(8a), 2-nitropropane (9a), and 2-nitrobenzaldehyde (10a) by add-
ing a solution of 9a (2.0 equiv) and 10 mol% of a base in DMSO to a
solution of acrylate 8a (2.0 equiv) and aldehyde 10a (1.0 equiv) in
DMSO (Table 1, entries 1e8). It was found that strongly basic cat-
alysts (pKBHþ >23 (CH3CN) [12]) promoted the MCR smoothly, and
2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) catalyzed the
reaction most efficiently to afford the desired three-component
adduct 11a in 94% isolated yield as a mixture of syn- and anti-iso-
mers (syn/anti ¼ 55:45) (entry 3). In this case, the Michael adduct
13a was also isolated in a mol ratio of 13a/11a ¼ 0.67, but the Henry
adduct 12a was not detected. Less basic catalysts including Et3N
and 2-phenyl-1,1,3,3-tetramethylguanidine (PhTMG) afforded the
Henry adduct 12a as the major product (entries 1 and 2). DBU and
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) worked effectively as
BTMG (entries 4 and 5). Potassium tert-butoxide and potassium
hydroxide promoted the three-component reaction smoothly, but
the use of LHMDS gave the three-component adduct 11a in only
14% yield along with the Michael adduct 13a as the major product
(entries 6e8). Thus, potassium ion was superior to lithium ion for
the counter cation of a strong base, and this result implied naked
anionic species would be suitable for the present intermolecular
MCR. It was found that the diastereomeric ratios of 11a were not
drastically changed by the choice of bases. The stereochemistry of
11a was determined by similarity of 1H NMR spectra of syn-13a and
anti-13a11e of which stereochemistries were determined by
reductive removal of the nitro group of the minor diastereomer of
11e into a stereochemically defined compound [13c]. The solvent
Scheme 1. Three-component reaction of acrylates 1, acidic pronucleophiles 2, and
aldehydes 3 with a catalytic amount of a base.
benzaldehyde gave a Michael/aldol product 4 in less than 5% yield
but afforded a Michael adduct 5 as the major product. Thus, three-
component adduct 4 was not formed efficiently even with the use
of a stoichiometric amount of DBU. The challenging point of our
strategy was reaction selectivity between the intermolecular aldol
reaction to 4 of catalytically formed transient ester enolates 7 and
protonation with more than a stoichiometric amount of HX 2 to a
Michael adduct 5. Since the ester enolate 7 was sufficiently basic,
protonation from an acidic nucleophile HX 2 or/and from a counter
cation R3NHþ in 7 was suspected, especially in the reaction with a
catalytic amount of a base. There have been only two reports of
domino Michael/intermolecular aldol reactions using a catalytic
amount of a base. Shibasaki reported catalytic asymmetric Michael/
aldol reaction of enone, malonate, and aldehyde by using an AlLi-
BINOL catalyst, and they reported that the formation of Michael
adducts was inhibited as much as possible [10]. They proposed a
slow protonation of an in-situ formed aluminum ketone enolate on
the basis of the electronegativity of aluminium. Recently, we re-
ported KOH-catalyzed intermolecular three-component reactions
Table 1
Optimization of the reaction conditions.
of acrylamides, nitroalkanes, and aldehydes to afford b g-
0-hydroxy-
nitro amides [11]. Catalytic Michael/aldol reactions of acrylamides
took place only with nitroalkanes due to the low electrophilicity of
acrylamides. It was thus expected that the higher electrophilicity of
alkyl acrylates would enable three-component reactions with
various pronucleophiles other than nitroalkanes. However, it was
also thought that the lower reactivity of transient ester enolates
than that of amide enolates might influence the reaction selectivity
between aldolization and protonation. Thus, we were interested in
whether the difference of parent carbonyl compounds would affect
Brønsted basicity and nucleophilicity of transient enolates. In this
paper, we report details of domino intermolecular Michael/aldol
reactions of various nucleophiles including nitroalkanes, malo-
nates, sulfonamides, and thiols using a catalytic amount of a base in
DMSO. We also report here the differences in nucleophilicity and
Brønsted basicity of some kinds of catalytically formed transient
enolates including esters, nitriles, and ketones.
entry basea
Solvent
11ab syn/anti of 11ac 12ad 13a/11ae
1
Et3N (18.83)
DMSO
7
9
56:44
57:43
55:45
56:44
56:44
50:50
53:47
56:44
54:46
58:42
57:43
57:43
50
53
0
0
0.22
0.67
2
PhTMG (20.85) DMSO
3
4
5
6
BTMG (23.56)
DBU (24.31)
TBD (26.02)
LHMDS
KOtBu
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
THF
94
91
88
14
67
76
58
23
23
trace 1.11
0
0
0
7
0
4
0
4
0.74
7.36
1.33
0.66
2.34
5.30
6.17
6.31
7
8
KOH
9
BTMG
10
11
12
BTMG
BTMG
BTMG
CH2Cl2
Toluene 13
a
Numbers in parentheses are pKBH values in acetonitrile. PhTMG: 2-phenyl-
þ
1,1,3,3-tetramethylguanidine. BTMG: 2-tert-butyl-1,1,3,3-tetramehylguanidine.
TBD: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene.
b
Isolated yield (%).
2. Results and discussion
c
Syn/anti ratio that was determined by 1H NMR analysis.
d
Yield (%) that was determined by 1H NMR analysis of a mixture of 10a and 12a.
Mol ratio.
e
First, a suitable base was explored in an MCR of ethyl acrylate
2

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
Table 3
effects of DMSO were critical for the MCR since the use of less polar
aprotic solvents including acetonitrile, THF, dichloromethane, and
toluene gave lower yields of the desired product 11a (entries 9e12).
Judging from the ratio of 13a/11a in various solvents, Michael
adduct 13a was found to form preferentially in less polar aprotic
solvents.
Substrate scope of the various a,b-unsaturated carbonyl compounds.
The MCRs of benzaldehyde derivatives having electron-
withdrawing groups including 4-nitro, 4-cyano, 4-bromo groups
gave the corresponding desired products 11b-d in good to high
yields (Table 2, entries 1e3), while those of non-substituted and
electron-releasing group-substituted benzaldehydes proceeded to
afford the three-component adducts 11e-g in moderate to low
yields (entries 4e6). The ratios of 13a/11 suggested that the re-
actions of lower electrophilic aldehydes [14] tended to provide the
Michael adduct 13. Lower electrophilic aldehydes caused proton-
ation of in-situ formed enolates to 13a rather than aldol reactions to
11. The reaction of pivalaldehyde, acrylate 8a, and nitroalkane 9a
did not give the desired three-component adduct probably due to
the low electrophilicity of aliphatic aldehydes.
entry 11
1
11 (%)a
92
syn/antib
12 (%)c
0
13/11d
1.05
55:45
Reactions of secondary nitroalkanes including nitro-
cyclopentane and nitrocyclohexane proceeded smoothly (Table 3,
entries 1 and 2). However, the reaction with nitromethane gave the
desired MCR adduct 11j in 23% yield along with a Henry adduct 12j
in 60% yield (entry 3).
MCRs with some electrophilic alkenes were investigated. It
should be noted that ethyl methacrylate reacted with 2-
nitrobenzaldehyde and 2-nitropropane to give the MCR adduct
11k in 67% yield as a mixture of diastereomers (syn/anti ¼ 57:43)
(entry 4). The stereochemistry of the minor diastereomer of 11k
was determined by X-ray crystallography of the similar compound.
This result suggested that the present MCR did not proceed by the
tandem Baylis-Hillman/Michael reaction [8] since the Baylis-
Hillman reaction of methacrylates did not take place inherently. It
was also found that BTMG was superior to DBU in the reaction with
ethyl methacrylate by comparing the use of these two bases in
11h
2
89
23
56:44
69:31
trace
0.96
11i
3
60
1.52e
11j
4f
67 (40)g 57:43 (56:44)g 16 (37)g 0.87 (1.30)g
Table 2
Substrate scope of the various aromatic aldehydes.
11k
5
72
24
50:50
54:46
0
0
1.22
5.83
11l
6f
11m
a
Isolated yield (%).
b
Syn/anti ratio of 11 that was determined by 1H NMR analysis.
c
Yield (%) that was determined by H NMR analysis of a mixture of 10 and 12. .
Mol ratio.
d
entry
X
11a
syn/antib
12c
13a/11d
1
2
3
4
5
6
4-NO2 (10b)
4-CN (10c)
4-Br (10d)
H (10e)
4-Me (10f)
4-MeO (10g)
92
85
74
55
32
26
57:43
57:43
56:44
58:42
50:50
53:47
3
4
0
5
0
0
0.99
1.06
1.70
2.16
3.63
5.62
e
Compound 14 was formed (14/11jd ¼ 1.87).
f
Reaction time: 2 h.
DBU was used in place of BTMG.
g
a
Isolated yield (%).
b
c
Syn/anti ratio of 11 that was determined by 1H NMR analysis.
Yield (%) that was determined by 1H NMR analysis of a mixture of 10 and 12.
Mol ratio.
d
3

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
Table 4
DMSO (entry 4). The reaction with ethyl crotonate by the use of a
catalytic amount of BTMG in DMSO did not give the desired three-
component adduct, and the Henry adduct 12 was obtained as the
Reactions of various nucleophiles.
major product. Thus, substitution on the b-position of an unsatu-
rated ester substantially influenced the reaction efficiency. The
three-component reaction with acrylonitrile also proceeded
smoothly to afford the corresponding product 11l in 72% yield
(entry 5), whereas the reaction with methyl vinyl ketone gave the
desired product 11m in only 24% yield (entry 6). In the case of
methyl vinyl ketone, a Michael adduct 13m was obtained as the
major product.
Reactions of various nucleophiles other than nitroalkanes were
investigated using o-nitrobenzaldehyde (10a) and ethyl acrylate
(8a) (Table 4). As a carbon nucleophile, we used diethyl malonate
and diethyl methylmalonate (entries 1 and 2). The use of diethyl
malonate afforded the desired compound 11n in 41% yield, whereas
the use of diethyl methylmalonate gave 11o in a good yield (75%). In
the case of diethyl malonate, base-catalyzed aldol condensation of
diethyl malonate with 10a might cause a decrease in the efficiency.
Next, we studied the reactions of nitrogen nucleophiles using
phthalimide and N-methyl-p-toluenesulfonamide (entries 3 and 4).
Both nitrogen nucleophiles afforded the corresponding three-
component adducts 11p,q in moderate yields. In the case of N-
methyl-p-toluenesulfonamide, elimination products 15q and 16
were also obtained in 2% and 23% yields, respectively (entry 4).
Finally, various thiols were used as pronucleophiles (entries
5e9). Optimization of the reaction conditions revealed that the use
of aldehyde (5.0 equiv), thiol (1.0 equiv), and acylate (1.2 equiv)
effectively promoted the three-component reactions. The results
suggested that sterically hindered alkanethiols tended to give the
desired products more efficiently (entries 5e8). Steric hindrance of
alkanethiols might suppress the addition of alkanethiols to alde-
hydes to form the corresponding hemithioacetals [15]. When tri-
phenylmethanethiol and 1-methyl-1-phenylethanethiol were
used, low yields of dehydrated products 15t,u accompanied by the
desired products 11t,u were obtained (entries 7 and 8). The reaction
of benzenethiol gave the desired product 11v in a low yield (entry
9). The higher acidity of benzenethiol might result in preferential
formation of the Michael adduct.
entry
1c
11
11 (%)a
41
syn/antib
15 (%)a
0
64:36
11n
11o
2c
75
55
50:50
56:44
0
0
3d
11p
11q
4
59e
59:41
71:29
2
0
In order to study the reaction mechanism, ethyl
(8a-D, 92% D) was used for the MCR (Scheme 2a). 1H NMR analysis
of the product 11a revealed that the D content of the carbonyl
a-D-acrylate
a
-
5f
46
position of 11a-D remained at 92%, indicating that the reaction did
not proceed by Bailys-Hillman/Michael reaction [8] but proceeded
by the domino Michael/Aldol reaction. Attempted aldol reaction of
2-nitrobenzaldehyde (10a) and an equimolar amount of Michael
adduct 13a with a catalytic amount (10 mol%) of BTMG in DMSO
under identical conditions to those of the three-component reac-
tion (Table 1, entry 3) gave the aldol product 11a in only 4% yield
(Scheme 2b). Therefore, the three-component reaction of acrylate,
aldehyde, and nitroalkane took place mainly by the aldol reaction of
transient ester enolates 7 that were formed by Michael addition of
nitronates to acrylates (Scheme 1c). A reaction of Henry adduct 12a
with ethyl acrylate 8a in the presence of 10 mol% of BTMG gave the
three-component adduct 11a in 47% yield along with the Michael
adduct 13a in 48% yield (Scheme 2c). This result suggested that
retro-Henry reaction of 12a followed by the three-component re-
action took place. It was also suggested that the use of Et3N and
PhTMG as a catalyst for the three-component reaction did not
promote the retro-Henry reaction (Table 1, entries 1 and 2). As
described in the results for solvent effects (Table 1, entries 3 and
9e12), protonation of the transient ester enolate to the Michael
adduct 13a tended to proceed feasibly in less polar solvents. It was
also assumed that retro-Henry reaction took place slowly in the
case of the Henry adduct 12j that was formed from nitromethane
11r: R ¼ nHex
11s: R ¼ Bn
6f
7f
8f
9f
69
69
79
37
55:45
68:32
56:44
54:46
0
11
5
11t: R ¼ Ph3C
11u: R ¼ PhMe2C
11v: R ¼ Ph
0
a
Isolated yield based on the aldehyde.
The ratio was determined by 1H NMR.
Reaction time: 0.5 h.
b
c
d
Reaction time: 60 h.
e
f
Compound 16 (27%) was obtained.
Aldehyde (5.0 equiv), thiol (1.0 equiv), and acrylate (1.2 equiv) were used.
because of the less steric hindrance of 12j (Table 3, entry 3).
In 1H NMR reaction monitoring of the BTMG-catalyzed reaction
of acrylate 8a, nitroalkane 9a, and aldehyde 10a in DMSO-d6 at
room temperature, the Henry adduct 12a was not detected even in
the early stage (7 min). This result was different from the three-
4

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
whereas transient ketone enolates showed less nucleophilicity
compared with their Brønsted basicity. In addition, higher nucle-
ophilicity of transient enolates was observed in more polar aprotic
solvents. The utilization of high nucleophilicity of transient eno-
lates would enable other types of MCRs by using catalytic amounts
of bases.
4. Experimental
4.1. General
All melting points were determined on Yanagimoto micro
melting point apparatus and were not corrected. Infrared spectra
(IR) were recorded on Horiba IR-710. 1H NMR spectra were recor-
ded on a JEOL JNM ECA600 (600 MHz) or a JEOL JNM ECS400
(400 MHz) spectrometer at room temperature; chemical shifts (d)
are reported in parts per million relative to tetramethylsilane.
Splitting patterns are designated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. 13C NMR spectra were recorded
on a JEOL JNM ECA600 (150 MHz) or a JEOL JNM ECS400 (100 MHz)
spectrometer with complete proton decoupling. Chemical shifts are
reported in parts per million relative to tetramethylsilane with the
solvent resonance as the internal standard CDCl3. HRMS data were
recorded on JEOL JMS-T100TD. Analytical TLC was performed on
Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm). Silica gel
column chromatography was carried out on silica gel 60 N (Kanto
Kagaku Co., Ltd., spherical, neutral, 63e210 mm). All reactions were
carried out under nitrogen atmosphere in a dried glassware with
magnetic stirring. DMSO was distilled from CaH2. DMSO-d6 was
dried with MS4A. Ph Me2CSH [16], nitrocyclopentane [17], and
nitrocyclohexane [17] were prepared by the reported procedures.
Scheme 2. Mechanism study.
component reactions using acrylamide that showed a rapid gen-
eration of the corresponding Henry adduct followed by the
appearance of the three-component adduct with the gradual
disappearance of the Henry adduct [11]. Almost equimolar amounts
of the three-component adduct 11a and Michael adduct 13a were
detected in the early stage (7 min), and prolonged reaction times
(2 h) did not change the yields of 11a and 13a. Also, the diaste-
reomeric (syn/anti) ratios of the three-component adduct 11a did
not change from the beginning to the last stage of the reaction. The
Henry adduct 12a was not detected by the NMR monitoring
because of the higher electrophilicity of ethyl acrylate than that of
acrylamide, but 12a might have formed just after addition of the
catalyst.
4.2. Synthesis of ethyl a-D-acrylate (8a-D)
A mixture of ethyl acrylate (1.06 mL, 9.2 mmol) and DABCO
(500 mg, 4.6 mmol) in D2O (2.2 ml) was stirred at room tempera-
ture for 11 h. The reaction mixture was extracted, and the combined
organic extracts were dried over anhydrous Na2SO4, filtrated to
afford ethyl a-D-acrylate (8a-D) (90 mg, 10%). Its D-content (92%D)
was determined by 1H NMR.
4.3. General procedure of domino Michael/aldol reaction of
nitroalkanes, acrylates, and aldehydes
As described for the three-component reaction with methyl
vinyl ketone (Table 3, entry 6), Brønsted basicity of a transient ke-
tone enolate was superior to its nucleophilicity to an aldehyde even
in DMSO.
To a mixture of ethyl acrylate (0.60 mmol) and aldehyde
(0.30 mmol) in DMSO (0.50 mL),
a solution of nitroalkane
(0.60 mmol) and BTMG (0.03 mmol) in DMSO (0.50 mL) was added.
The reaction mixture was stirred at room temperature until alde-
hyde was not detected by TLC analysis. The reaction mixture was
quenched by adding saturated aqueous solution of NH4Cl, and the
aqueous layer was extracted with ethyl acetate. The combined
organic extracts were washed with brine and dried over Na2SO4.
The filtrate was concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel
3. Conclusions
In conclusion, we have established intermolecular three-
component reactions of acrylates, aromatic aldehydes, and
various carbon-, nitrogen-, and sulfur-nucleophiles to b-hydroxy
carbonyl compounds in the presence of a catalytic amount of BTMG
in DMSO. Mechanistic studies revealed that the MCRs proceeded by
domino Michael/aldol reactions. The present method provided the
desired three-component adducts in shorter reaction times with
broader substrate scopes than catalytic Baylis-Hillman/Michael
(hexanes/ethyl acetate) to afford b g-nitro carbonyl
0-hydroxy-
compounds 11.
4.4. Three-component adducts
reactions [8], and a variety of linear
b
-hydroxy esters were pre-
Ethyl
methyl-4-nitropentanoate (syn-11a). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
7.69 (1H, dd, J ¼ 7.4, 8.0 Hz), 7.50 (1H, dd, J ¼ 7.4, 7.8 Hz), 5.53 (1H,
dd, J ¼ 3.6, 4.4 Hz), 4.07 (2H, q, J ¼ 7.2 Hz), 3.40 (1H, brs), 2.92 (1H,
ddd, J ¼ 1.8, 4.4, 9.8 Hz), 2.55 (1H, dd, J ¼ 9.8, 15.2 Hz), 2.25 (1H, dd,
(R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-4-
pared directly from three components. It should be noted that
catalytic intermolecular aldol reactions proceeded in the presence
of protic pronucleophiles. We clarified that nucleophilicity for
aldolization over Brønsted basicity of transient enolates was
obvious in the reactions of transient ester enolates in DMSO,
d
8.02 (1H, d, J ¼ 7.8 Hz), 7.83 (1H, d, J ¼ 8.0 Hz),
5

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
J ¼ 1.8, 15.2 Hz), 1.46 (3H, s), 1.45 (3H, s), 1.16 (3H, t, J ¼ 7.2 Hz); 13
C
13C NMR (CDCl3, 100 MHz):
d
173.9, 139.5, 131.6, 127.9, 122.0, 87.1,
NMR (CDCl3, 100 MHz):
d
174.2, 147.7, 135.5, 133.6, 129.5, 129.0,
73.6, 61.3, 48.8, 37.1, 26.1, 25.8, 13.8; IR (CHCl3, cmꢀ1): 3600, 2987,
1726, 1541, 1188; HRMS (DARTþ) (m/z) calcd for C15H21NO851Br
[(M þ H)þ]: 376.05826, found 376.05722.
125.1, 87.1, 70.2, 61.5, 46.3, 36.7, 26.0, 25.8, 13.7; IR (CHCl3, cmꢀ1):
3597, 3030, 2987,1728,1539,1527,1348,1190; HRMS (DARTþ) (m/z)
calcd for C15H21N2O7 [(M þ H)þ]: 341.13488, found 341.13473.
Ethyl
(R*)-2-[(S*)-(4-bromophenyl)hydroxymethyl]-4-
Ethyl
(R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-4-
methyl-4-nitropentanoate (anti-11d). Colorless crystal; mp:
methyl-4-nitropentanoate (anti-11a). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
87.0e88.0 ꢁC (recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
d
8.04 (1H, d, J ¼ 8.4 Hz), 7.66e7.62 (2H, m),
d
7.49 (2H, d, J ¼ 8.2 Hz), 7.18 (2H, d, J ¼ 8.2 Hz), 4.75 (1H, dd, J ¼ 6.4,
7.51e7.46 (1H, m), 5.43 (1H, dd, J ¼ 4.3, 8.3 Hz), 4.02e3.94 (2H, m),
3.87 (1H, d, J ¼ 8.3 Hz), 3.05 (1H, ddd, J ¼ 1.9, 4.3, 10.4 Hz), 2.78 (1H,
dd, J ¼ 10.4, 15.1 Hz), 2.24 (1H, dd, J ¼ 1.9, 15.1 Hz), 1.62 (3H, s), 1.60
6.6 Hz), 4.07 (2H, q, J ¼ 7.3 Hz), 2.89 (1H, d, J ¼ 6.4 Hz), 2.75 (1H,
ddd, J ¼ 1.6, 6.6, 10.1 Hz), 2.45 (1H, dd, J ¼ 10.1, 15.3 Hz), 2.06 (1H, d,
J ¼ 15.3 Hz), 1.54 (3H, s), 1.49 (3H, s), 1.15 (3H, t, J ¼ 7.3 Hz); 13C NMR
(3H, s), 1.05 (3H, t, J ¼ 7.4 Hz); 13C NMR (CDCl3, 100 MHz):
d
174.1,
(CDCl3, 100 MHz): d 174.0, 139.9, 131.7, 127.9, 122.2, 87.2, 75.4, 61.3,
137.2, 133.6, 128.9, 128.1, 125.0, 87.1, 71.9, 61.3, 46.7, 41.0, 26.5, 25.7,
13.7; IR (CHCl3, cmꢀ1): 3597, 2987, 2929, 1730, 1707, 1541, 1527,
1346, 1265, 1188; HRMS (DARTþ) (m/z) calcd for C15H21N2O7
[(M þ H)þ]: 341.13488, found 341.13473.
48.6, 39.6, 26.6, 25.5, 13.8; IR (CHCl3, cmꢀ1): 3599, 2987, 1728, 1541,
1265, 1186; HRMS (DARTþ) (m/z) calcd for
C
15H21NO851Br
[(M þ H)þ]: 376.05826, found 376.05722.
Ethyl
(R*)-2-[(R*)-hydroxy(phenyl)methyl]-4-methyl-4-
Ethyl
(R*)-2-[(R*)-hydroxy-(4-nitrophenyl)methyl]-4-
nitropentanoate (syn-11e). Yellow sticky oil; 1H NMR (CDCl3,
400 MHz):
methyl-4-nitropentanoate (syn-11b). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
7.38e7.27 (5H, m), 4.90 (1H, dd, J ¼ 2.9, 5.4 Hz), 4.00
d
8.24 (2H, d, J ¼ 8.6 Hz), 7.55 (2H, d, J ¼ 8.6 Hz),
(2H, q, J ¼ 7.0 Hz), 2.70 (1H, ddd, J ¼ 1.7, 5.4, 10.2 Hz), 2.63 (1H, d,
J ¼ 2.9 Hz), 2.53 (1H, dd, J ¼ 10.2, 14.9 Hz), 2.23 (1H, dd, J ¼ 1.7,
14.9 Hz), 1.48 (3H, s), 1.45 (3H, s), 1.09 (3H, t, J ¼ 7.0 Hz); 13C NMR
5.07 (1H, brs), 4.13e4.06 (2H, m), 2.99 (1H, d, J ¼ 2.4 Hz), 2.72 (1H,
dd, J ¼ 4.8, 10.1 Hz), 2.53 (1H, dd, J ¼ 10.1, 15.3 Hz), 2.12 (1H, d,
J ¼ 15.3 Hz), 1.48 (3H, s), 1.46 (3H, s), 1.09 (3H, t, J ¼ 7.0 Hz); 13C NMR
(CDCl3, 100 MHz):
d 174.0, 140.5, 128.4, 128.1, 126.1, 87.3, 74.3, 61.1,
(CDCl3, 100 MHz):
d
173.9, 147.6, 127.0, 123.6, 87.0, 73.3, 61.6, 61.5,
49.1, 37.3, 26.1, 25.7, 13.8; IR (CHCl3, cmꢀ1): 3599, 3030, 2987, 1722,
1541, 1188; HRMS (DARTþ) (m/z) calcd for C15H22NO5 [(M þ H)þ]:
296.14980, found 296.15219.
48.3, 36.7, 26.1, 25.9, 21.4, 13.8; IR (CHCl3, cmꢀ1): 3599, 3030, 2987,
1726, 1541, 1523, 1348, 1188; HRMS (DARTþ) (m/z) calcd for
C
15H21N2O7 [(M þ H)þ]: 341.13488, found 341.13504.
Ethyl
nitropentanoate (anti-11e). Colorless crystal; mp: 48.0e49.0 ꢁC
(recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
7.39e7.29 (5H,
(R*)-2-[(S*)-hydroxy(phenyl)methyl]-4-methyl-4-
Ethyl
(R*)-2-[(S*)-hydroxy-(4-nitrophenyl)methyl]-4-
methyl-4-nitropentanoate (anti-11b). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
d
8.23 (2H, d, J ¼ 8.8 Hz), 7.49 (2H, d, J ¼ 8.8 Hz),
m), 4.77 (1H, dd, J ¼ 6.4, 6.4 Hz), 4.09 (2H, q, J ¼ 7.2 Hz), 2.81e2.75
(2H, m), 2.46 (1H, dd, J ¼ 10.4, 15.1 Hz), 2.02 (1H, d, J ¼ 15.1 Hz), 1.51
(3H, s), 1.47 (3H, s), 1.15 (3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3,
4.92 (1H, dd, J ¼ 6.0, 6.8 Hz), 4.03 (2H, q, J ¼ 7.1 Hz), 3.22 (1H, d,
J ¼ 6.8 Hz), 2.82 (1H, ddd, J ¼ 1.8, 6.0, 9.8 Hz), 2.50 (1H, dd, J ¼ 9.8,
15.1 Hz), 2.25 (1H, dd, J ¼ 1.8, 15.1 Hz), 1.60 (3H, s), 1.53 (3H, s), 1.09
100 MHz):
d 174.2, 140.8, 128.6, 128.4, 126.3, 87.3, 76.1, 61.2, 48.9,
(3H, t, J ¼ 7.1 Hz); 13C NMR (CDCl3, 100 MHz):
d
173.7, 148.2, 127.0,
39.6, 26.4, 25.5,13.8; IR (CHCl3, cmꢀ1): 3599, 3032, 2989,1728,1541,
1184; HRMS (DARTþ) (m/z) calcd for C15H22NO5 [(M þ H)þ]:
296.14980, found 296.14958.
127.0, 123.7, 87.2, 75.1, 61.5, 48.3, 39.7, 27.0, 25.2, 13.8; IR (CHCl3,
cmꢀ1): 3597, 3028, 2989. 1728, 1541, 1523, 1348, 1188; HRMS
(DARTþ) (m/z) calcd for C15H21N2O7 [(M þ H)þ]: 341.13488, found
341.13627.
Ethyl
methyl-4-nitropentanoate (syn-11f). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
(R*)-2-[(R*)-hydroxy-(4-methylphenyl)methyl]-4-
Ethyl
(R*)-2-[(R*)-(4-cyanophenyl)hydroxymethyl]-4-
d
7.21 (2H, d, J ¼ 8.2 Hz), 7.15 (2H, d, J ¼ 8.2 Hz),
methyl-4-nitropentanoate (syn-11c). Colorless crystal; mp:
4.86 (1H, d, J ¼ 5.6 Hz), 4.00 (2H, q, J ¼ 7.0 Hz), 2.69 (1H, ddd, J ¼ 1.9,
5.6, 10.1 Hz), 2.52 (1H, dd, J ¼ 10.1, 15.1 Hz), 2.34 (4H, s), 2.30 (1H,
dd, J ¼ 1.9, 15.1 Hz), 1.48 (3H, s), 1.46 (3H, s), 1.10 (3H, t, J ¼ 7.0 Hz);
92.0e92.5 ꢁC (recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.67 (2H, d, J ¼ 8.3 Hz), 7.48 (2H, d, J ¼ 8.3 Hz), 5.00 (1H, dd, J ¼ 2.4,
4.3 Hz), 4.07 (2H, dq, J ¼ 2.0, 7.0 Hz), 2.90 (1H, d, J ¼ 2.4 Hz), 2.69
(1H, dd, J ¼ 4.3, 10.3 Hz), 2.51 (1H, dd, J ¼ 10.3, 15.2 Hz), 2.14 (1H, d,
J ¼ 15.2 Hz), 1.48 (3H, s), 1.46 (3H, s), 1.16 (3H, t, J ¼ 7.0 Hz); 13C NMR
13C NMR (CDCl3, 100 MHz):
d 174.0, 137.8, 137.5, 129.1, 126.0, 87.3,
74.2, 61.1, 49.1, 37.3, 26.1, 25.7, 21.1, 13.8; IR (CHCl3, cmꢀ1): 3521,
3030, 2987, 1726, 1541, 1376, 1348, 1188; HRMS (DARTþ) (m/z) calcd
for C16H22NO4 [(M ꢀ OH)þ]: 292.15488, found 292.15505.
(CDCl3, 100 MHz):
d 173.9, 145.6, 132.3, 126.9, 111.9, 87.0, 73.4, 61.6,
48.4, 36.8, 26.0, 25.9, 13.8; IR (CHCl3, cmꢀ1): 3599, 3028, 2231, 1726,
1541, 1188; HRMS (DARTþ) (m/z) calcd for C16H21N2O5 [(M þ H)þ]:
321.14505, found 321.14619.
Ethyl
(R*)-2-[(S*)-hydroxy-(4-methylphenyl)methyl]-4-
methyl-4-nitropentanoate (anti-11f). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz): 7.20e7.15 (4H, m), 4.72 (1H, brs), 4.11 (2H, q,
d
Ethyl
(R*)-2-[(S*)-(4-cyanophenyl)hydroxymethyl]-4-
J ¼ 7.1 Hz), 2.78 (1H, ddd, J ¼ 1.9, 8.0, 10.5 Hz), 2.61 (1H, brs), 2.44
(1H, dd, J ¼ 10.5, 14.9 Hz), 2.35 (3H, s), 1.96 (1H, dd, J ¼ 1.9, 14.9 Hz),
1.50 (3H, s), 1.47 (3H, s), 1.19 (3H, t, J ¼ 7.1 Hz); 13C NMR (CDCl3,
methyl-4-nitropentanoate (anti-11c). Colorless crystal; mp:
97.0e98.0 ꢁC (recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.67 (2H, d, J ¼ 8.6 Hz), 7.43 (2H, d, J ¼ 8.6 Hz), 4.86 (1H, dd, J ¼ 6.0,
100 MHz): d 174.3, 138.2, 137.8, 129.3, 126.3, 92.4, 87.2, 76.1, 61.1,
6.8 Hz), 4.02 (2H, q, J ¼ 7.2 Hz), 3.15 (1H, d, J ¼ 6.8 Hz), 2.78 (1H, ddd,
48.9, 39.6, 26.3, 25.6, 21.1, 13.9; IR (CHCl3, cmꢀ1): 3512, 3030, 2987,
1728, 1541, 1377, 1186; HRMS (DARTþ) (m/z) calcd for C16H24NO5
[(M þ H)þ]: 310.16545, found 310.16468.
J ¼ 1.9, 6.0, 9.9 Hz), 2.49 (1H, dd, J ¼ 9.9, 15.2 Hz), 2.23 (1H, dd,
J ¼ 1.9, 15.2 Hz), 1.59 (3H, s), 1.52 (3H, s), 1.09 (3H, t, J ¼ 7.2 Hz); 13
C
NMR (CDCl3, 100 MHz):
d
173.7, 146.3, 132.3, 126.8, 118.5, 87.2, 75.3,
Ethyl
(R*)-2-[(R*)-hydroxy-(4-methoxyphenyl)methyl]-4-
61.4, 48.2, 39.8, 27.0, 25.2, 13.8; IR (CHCl3, cmꢀ1): 3597, 3030, 2989,
2231, 1728, 1541; HRMS (DARTþ) (m/z) calcd for C16H21N2O5
[(M þ H)þ]: 321.14505, found 321.14438.
methyl-4-nitropentanoate (syn-11g). Colorless sticky oil; 1H
NMR (CDCl3, 400 MHz):
d
7.25 (2H, d, J ¼ 8.8 Hz), 6.88 (2H, d,
J ¼ 8.8 Hz), 4.82 (1H, d, J ¼ 6.0 Hz), 3.99 (2H, q, J ¼ 7.6 Hz), 3.80 (3H,
s), 2.68 (1H, ddd, J ¼ 1.9, 6.0, 9.9 Hz), 2.52 (1H, brs), 2.51 (1H, dd,
J ¼ 9.9, 15.0 Hz), 2.33 (1H, dd, J ¼ 1.9, 15.0 Hz), 1.49 (3H, s), 1.47 (3H,
Ethyl
(R*)-2-[(R*)-(4-bromophenyl)hydroxymethyl]-4-
methyl-4-nitropentanoate (syn-11d). Slight yellow sticky oil; 1H
NMR (CDCl3, 400 MHz):
d
7.49 (2H, d, J ¼ 8.0 Hz), 7.22 (2H, d,
s), 1.09 (3H, t, J ¼ 7.6 Hz); 13C NMR (CDCl3, 100 MHz):
d 173.9, 159.4,
J ¼ 8.0 Hz), 4.87 (1H, brs), 4.02 (2H, q, J ¼ 7.1 Hz), 2.78 (1H, brs), 2.66
(1H, ddd, J ¼ 1.4, 5.4, 10.2 Hz), 2.50 (1H, dd, J ¼ 10.2, 15.1 Hz), 2.22
(1H, d, J ¼ 15.1 Hz), 1.49 (3H, s), 1.46 (3H, s), 1.13 (3H, t, J ¼ 7.1 Hz);
132.6, 127.4, 113.8, 87.3, 74.1, 61.0, 55.3, 49.3, 37.6, 26.1, 25.8, 13.8; IR
(CHCl3, cmꢀ1): 3600, 3024, 2987, 1724, 1539, 1265, 1178; HRMS
(DARTþ) (m/z) calcd for C16H22NO5 [(M ꢀ OH)þ]: 308.14980, found
6

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
308.15054.
syn), 5.01 (1H, dt, J ¼ 3.2, 10.4 Hz), 4.13 (2H, q, J ¼ 7.5 Hz, syn), 4.06
(2H, q, J ¼ 7.4 Hz, anti), 3.48 (1H, d, J ¼ 6.0 Hz, syn), 3.42 (1H, d,
J ¼ 4.0 Hz, anti), 2.51e2.09 (5H, m, syn), 2.51e2.09 (5H, m, anti),1.25
(3H, t, J ¼ 7.5 Hz, syn), 1.19 (3H, t, J ¼ 7.4 Hz, anti); 13C NMR (CDCl3,
Ethyl
(R*)-2-[(S*)-hydroxy-(4-methoxyphenyl)methyl]-4-
methyl-4-nitropentanoate (anti-11g). Colorless crystal; mp:
78.0e78.5 ꢁC (recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.23 (2H. d. J ¼ 8.8 Hz), 6.89 (2H, d, J ¼ 8.8 Hz), 4.71 (1H, dd, J ¼ 5.4,
100 MHz): d 171.9, 147.8, 147.3, 134.2, 134.0, 133.7, 129.7, 129.6,
7.6 Hz), 4.12 (2H, q, J ¼ 7.2 Hz), 3.81 (3H, s), 2.76 (1H, ddd, J ¼ 1.8, 7.6,
10.6 Hz), 2.53 (1H, d, J ¼ 5.4 Hz), 2.43 (1H, dd, J ¼ 10.6, 15.1 Hz), 1.94
(1H, dd, J ¼ 1.8, 15.1 Hz), 1.50 (3H, s), 1.47 (3H, s), 1.21 (3H, t,
129.2, 128.8, 125.4, 125.1, 125.4, 125.1, 91.2, 89.0, 69.9, 69.5, 61.1,
60.9, 30.1, 29.8, 25.3, 22.2, 14.1, 14.0; IR (CHCl3, cmꢀ1): 3597, 3030,
2985, 1730, 1554, 1529, 1348, 1265; HRMS (DARTþ) (m/z) calcd for
J ¼ 7.2 Hz); 13C NMR (CDCl3, 100 MHz):
d
174.3, 159.7, 132.9, 127.7,
C
13H17N2O7 [(M þ H)þ]: 313.10358, found 313.10310.
114.1, 87.3, 75.9, 61.2, 55.3, 49.1, 39.6, 26.3, 25.6, 13.9; IR (CHCl3,
Ethyl
(R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-2,4-
cmꢀ1): 3599, 2987, 1726, 1541, 1265; HRMS (DARTþ) (m/z) calcd for
dimethyl-4-nitropentanoate (syn-11k). Yellow sticky oil; 1H
NMR (CDCl3, 400 MHz):
C
16H22NO5 [(M ꢀ OH)þ]: 308.14980, found 308.15054.
d
7.82 (1H, d, J ¼ 8.0 Hz), 7.78 (1H, d,
Ethyl
(R*)-2-[(R*)-hydroxy-(2-nirophenyl)methyl]-3-
J ¼ 8.2 Hz), 7.64 (1H, dd, J ¼ 7.6, 8.2 Hz), 7.46 (1H, dd, J ¼ 7.6, 8.0 Hz),
5.68 (1H, d, J ¼ 3.2 Hz), 4.05e3.97 (2H, m), 3.02 (1H, d, J ¼ 3.2 Hz),
2.79 (1H, d, J ¼ 15.4 Hz), 2.57 (1H, d, J ¼ 15.4 Hz), 1.57 (3H, s), 1.49
(3H, s), 1.15 (3H, t, J ¼ 7.4 Hz), 1.01 (3H, s); 13C NMR (CDCl3,
cyclohexylnitromethylpropanoate (syn-11h). Orange sticky oil;
1H NMR (CDCl3, 600 MHz):
d
8.03 (1H, d, J ¼ 8.1 Hz), 8.02 (1H, d,
J ¼ 7.5 Hz), 7.69 (1H, ddd, J ¼ 1.2, 7.5, 7.8 Hz), 7.50 (1H, ddd, J ¼ 1.2,
7.8, 8.1 Hz), 5.51 (1H, dd, J ¼ 4.2, 4.8 Hz), 4.07 (2H, q, J ¼ 7.1 Hz), 3.23
(1H, dd, J ¼ 4.2, 4.2 Hz), 4.07 (2H, q, J ¼ 7.1 Hz), 2.95 (1H, ddd, J ¼ 1.8,
4.5, 9.8 Hz), 2.44 (1H, dd, J ¼ 9.8, 15.5 Hz), 2.28e2.22 (2H, m), 2.20
(1H, dd, J ¼ 1.8, 15.5 Hz), 1.57e1.22 (8H, m), 1.17 (3H, t, J ¼ 7.1 Hz);
100 MHz):
d 175.1, 133.1, 132.3, 130.1, 129.0, 124.4, 86.7, 71.8, 61.8,
50.7, 43.3, 30.6, 23.6, 13.8, 13.7; IR (CHCl3, cmꢀ1): 3599, 3030, 2931,
1720, 1541, 1352; HRMS (DARTþ) (m/z) calcd for C16H23N2O7
[(M þ H)þ]: 355.15053, found 355.15057.
13C NMR (CDCl3, 100 MHz):
d
174.1, 174.7, 135.5, 133.6, 129.5, 129.1,
Ethyl
(R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-2,4-
125.2, 90.4, 70.4, 61.5, 45.4, 36.3, 34.1, 33.8, 24.5, 22.2, 22.1, 13.8; IR
(CHCl3, cmꢀ1): 3597, 2943, 1728, 1535, 1346, 1186; HRMS (DARTþ)
(m/z) calcd for C18H25N2O7 [(M þ H)þ]: 381.16618, found 381.16601.
dimethyl-4-nitropentanoate (anti-11k). Slight yellow sticky oil;
1H NMR (CDCl3, 400 MHz):
d
7.86 (1H, d, J ¼ 8.0 Hz), 7.62e7.61 (2H,
m), 7.50e7.46 (1H, m), 5.66 (1H, d, J ¼ 6.6 Hz), 4.14 (2H, q,
J ¼ 7.1 Hz), 3.17 (1H, d, J ¼ 6.6 Hz), 2.56 (1H, d, J ¼ 15.2 Hz), 2.47 (1H,
d, J ¼ 15.2 Hz), 1.53 (3H, s), 1.48 (3H, s), 1.24 (3H, t, J ¼ 7.1 Hz), 0.97
Ethyl
(R*)-2-[(S*)-hydroxy-(2-nirophenyl)methyl]-3-
cyclohexylnitromethylpropanoate (anti-11h). Yellow sticky oil;
1H NMR (CDCl3, 400 MHz):
d
8.04 (1H, dd, J ¼ 1.3, 7.9 Hz), 7.65 (1H,
(3H, s); 13C NMR (CDCl3, 100 MHz):
d 175.4, 149.5, 134.1, 132.5, 129.1,
ddd, J ¼ 1.3, 7.8, 7.9 Hz), 7.59 (1H, dd, J ¼ 1.6, 7.8 Hz), 7.48 (1H, ddd,
J ¼ 1.6, 7.6, 7.9 Hz), 5.40 (1H, dd, J ¼ 4.6, 8.1 Hz), 3.99 (2H, q,
J ¼ 6.9 Hz), 3.66 (1H, d, J ¼ 8.1 Hz), 3.05 (1H, ddd, J ¼ 1.9, 4.6,
10.6 Hz), 2.68 (1H, dd, J ¼ 10.6,15.2 Hz), 2.41e2.32 (2H, m), 2.17 (1H,
dd, J ¼ 1.9, 15.2 Hz), 1.71e1.32 (8H, m), 1.06 (3H, t, J ¼ 6.9 Hz); 13C
129.0, 124.3, 86.6, 73.2, 61.7, 50.8, 44.5, 30.9, 22.9, 13.9, 13.8; IR
(CHCl3, cmꢀ1): 3604, 3030, 2993, 1718, 1543, 1350; HRMS (DARTþ)
(m/z) calcd for
355.14933.
C16H23N2O7 [(M
þ
H)þ]: 355.15053, found
(R*)-2-[(R*)-Hydroxy-(2-nitrophenyl)methyl]-4-methyl-4-
NMR (CDCl3, 100 MHz):
d 173.9, 147.6, 137.1, 133.6, 128.9, 128.0,
nitropentanenitrile (syn-11l). Yellow sticky oil; 1H NMR (CDCl3,
125.0, 90.3, 71.8, 61.3, 46.0, 34.3, 33.8, 29.7, 24.6, 22.2, 22.1, 13.7; IR
(CHCl3, cmꢀ1): 2941, 1716, 1537, 1346; HRMS (DARTþ) (m/z) calcd
for C18H25N2O7 [(M þ H)þ]: 381.16618, found 381.16605.
400 MHz):
d
8.10e8.07 (2H, m), 7.79 (1H, dd, J ¼ 7.4, 8.0 Hz), 7.57
(1H, dd, J ¼ 7.4, 8.0 Hz), 5.40 (1H, brs), 3.28 (1H, d, J ¼ 9.6 Hz), 2.71
(1H, dd, J ¼ 10.2, 15.1 Hz), 2.63 (1H, brs), 2.59 (1H, dd, J ¼ 2.8,
15.1 Hz), 1.77 (3H, s), 1.74 (3H, s); 13C NMR (CDCl3, 100 MHz):
Ethyl
(R*)-2-[(R*)-hydroxy-(2-nirophenyl)methyl]-3-
cyclopentylnitromethylpropanoate (syn-11i). Slight orange
d 135.8, 134.4, 129.8, 129.0, 125.0, 118.3, 86.9, 70.0, 41.0, 35.9, 27.1,
sticky oil; 1H NMR (CDCl3, 400 MHz):
d
8.02 (1H, d, J ¼ 8.0 Hz), 7.82
25.2; IR (CHCl3, cmꢀ1): 3602, 3357, 3028, 2247, 1543, 1527, 1346,
1265; HRMS (DARTþ) (m/z) calcd for C13H16N3O5 [(M þ H)þ]:
294.10900, found 294.10887.
(1H, d, J ¼ 7.8 Hz), 7.69 (1H, dd, J ¼ 7.6, 7.8 Hz), 7.50 (1H, dd, J ¼ 7.6,
8.0 Hz), 5.51 (1H, brs), 4.11e4.01 (2H, m), 3.45 (1H, brs), 2.90 (1H,
dd, J ¼ 4.8, 10.1 Hz), 2.61 (1H, dd, J ¼ 10.1, 15.2 Hz), 2.48e2.38 (2H,
m), 2.32 (1H, d, J ¼ 15.2 Hz), 1.73e1.51 (6H, m), 1.17 (3H, t,
(R*)-2-[(S*)-Hydroxy-(2-nitrophenyl)methyl]-4-methyl-4-
nitropentanenitrile (anti-11l). Yellow sticky oil; 1H NMR (CDCl3,
J ¼ 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
d
174.3, 147.7, 135.5, 133.5,
400 MHz):
d
8.12 (1H, d, J ¼ 8.0 Hz), 7.92 (1H, d, J ¼ 7.8 Hz), 7.76 (1H,
129.4, 129.0, 125.2, 98.4, 70.1, 61.5, 46.8, 37.4, 37.4, 35.5, 24.1, 23.7,
13.7; IR (CHCl3, cmꢀ1): 3591, 2983, 1728, 1535, 1348, 1265, 1190;
HRMS (DARTþ) (m/z) calcd for C17H23N2O7 [(M þ H)þ]: 367.15053,
found 367.14863.
dd, J ¼ 7.4, 7.8 Hz), 7.57 (1H, dd, J ¼ 7.4, 8.0 Hz), 5.71 (1H, brs),
3.14e3.10 (1H, m), 3.07 (1H, brs), 2.45 (1H, dd, J ¼ 14.7 Hz), 2.33
(1H, dd, J ¼ 10.6, 14.7 Hz), 1.67 (3H, s), 1.62 (3H, s); 13C NMR (CDCl3,
100 MHz):
d 134.8, 134.1, 129.8, 129.0, 125.5, 119.9, 86.9, 69.7, 37.0,
Ethyl
cyclopentylnitromethylpropanoate (anti-11i). Yellow sticky oil;
1H NMR (CDCl3, 400 MHz):
(R*)-2-[(S*)-hydroxy-(2-nirophenyl)methyl]-3-
34.2, 27.3, 24.8; IR (CHCl3, cmꢀ1): 3608, 3350, 3028, 2247, 1543,
1529, 1346; HRMS (DARTþ) (m/z) calcd for C13H16N3O5 [(M þ H)þ]:
294.10900, found 294.10975.
d
8.04 (1H, d, J ¼ 8.4 Hz), 7.68e7.61 (2H,
m), 7.48 (1H, dd, J ¼ 6.8, 8.4 Hz), 5.42 (1H, dd, J ¼ 4.2, 7.6 Hz),
4.01e3.95 (1H, m), 3.98 (2H, q, J ¼ 7.2 Hz), 3.01 (1H, ddd, J ¼ 1.8, 4.2,
10.2 Hz), 2.85 (1H, dd, J ¼ 10.2, 15.2 Hz), 2.62e2.48 (2H, m), 2.33
(1H, dd, J ¼ 1.8, 15.2 Hz), 1.88e1.77 (6H, m), 1.06 (3H, t, J ¼ 7.2 Hz);
(R*)-3-[(R*)-Hydroxy-(2-nitrophenyl)methyl]-5-methyl-5-
nitrohexan-2-one (syn-11m). Orange oil; 1H NMR (CDCl3,
400 MHz):
d
8.01 (1H, dd, J ¼ 1.2, 7.9 Hz), 7.69 (1H, ddd, J ¼ 1.2, 7.5,
8.0 Hz), 7.57 (1H, dd, J ¼ 1.3, 8.0 Hz), 7.51 (1H, ddd, J ¼ 1.3, 7.5,
7.9 Hz), 5.30 (1H, dd, J ¼ 5.7, 6.8 Hz), 3.43 (1H, d, J ¼ 6.8 Hz), 3.31
(1H, ddd, J ¼ 2.0, 5.7, 9.4 Hz), 2.61 (1H, dd, J ¼ 9.4, 15.3 Hz), 2.05 (1H,
dd, J ¼ 2.0, 15.3 Hz), 1.99 (3H, s), 1.60 (3H, s), 1.53 (3H, s); 13C NMR
13C NMR (CDCl3, 100 MHz):
d 174.2, 147.6, 137.2, 133.6, 128.9, 128.1,
125.0, 98.4, 71.8, 61.3, 47.4, 39.8, 38.0, 37.4, 24.2, 24.0, 13.7; IR
(CHCl3, cmꢀ1): 3597, 2985, 1705, 1537, 1346, 1265; HRMS (DARTþ)
(m/z) calcd for C17H23N2O7 [(M þ H)þ]: 367.15053, found 367.15160.
Ethyl 2-[hydroxy(2-nitrophenyl)methyl]-4-nitrobutanoate
(CDCl3,100 MHz): d 212.2,136.5,133.9,129.2,128.5,125.0, 87.2, 72.1,
52.1, 40.8, 32.3, 26.5, 26.3; IR (CHCl3, cmꢀ1): 3030, 1714, 1537, 1348;
HRMS (DARTþ) (m/z) calcd for C14H19N2O6 [(M þ H)þ]: 311.12431
found 311.12467.
(11j). Yellow sticky oil; 1H NMR (CDCl3, 400 MHz):
d 8.11 (1H, dd,
J ¼ 0.8, 8.4 Hz, anti), 8.05 (1H, d, J ¼ 8.4 Hz, syn), 7.93 (1H, d,
J ¼ 8.0 Hz, anti), 7.76e7.73 (1H, m, anti), 7.75e7.72 (2H, m, syn),
7.58e7.53 (1H, m, syn), 7.58e7.53 (1H, m, anti), 5.98 (1H, dd, J ¼ 3.2,
4.0 Hz, anti), 5.73 (1H, dd, J ¼ 5.6, 6.0 Hz, syn), 5.10e5.05 (1H, m,
(R*)-3-[(S*)-Hydroxy-(2-nitrophenyl)methyl]-5-methyl-5-
nitrohexan-2-one (anti-11m). Orange oil; 1H NMR (CDCl3,
400 MHz):
d
8.15 (1H, dd, J ¼ 0.8, 8.1 Hz), 7.92 (1H, d, J ¼ 7.9 Hz), 7.75
7

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
(1H, ddd, J ¼ 1.7, 7.8, 7.9 Hz), 7.53 (1H, ddd, J ¼ 1.7, 7.8, 8.1 Hz), 5.70
(1H, brs), 3.12 (1H, ddd, J ¼ 1.6, 1.9, 9.0 Hz), 2.71 (1H, d, J ¼ 1.6 Hz),
2.52 (1H, dd, J ¼ 9.0, 15.7 Hz), 2.45 (3H, s), 1.97 (1H, dd, J ¼ 1.9,
15.7 Hz), 1.35 (3H, s), 1.27 (3H, s); 13C NMR (CDCl3, 100 MHz):
100 MHz):
d
172.7, 168.2, 135.6, 134.2, 133.4, 131.8, 128.8, 128.7,
125.0, 123.4, 67.6, 61.7, 48.9, 35.5, 29.7, 13.6; IR (CHCl3, cmꢀ1): 2927,
1774, 1718, 1527, 1396, 1265; HRMS (DARTþ) (m/z) calcd for
C
20H19N2O7 [(M þ H)þ]: 399.11923, found 399.11943.
d
210.9, 136.1, 133.9, 131.9, 129.0, 125.6, 123.7, 87.2, 68.7, 51.8, 34.7,
Ethyl (R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]- 3-(1,3-
30.0, 26.4, 25.6; IR (CHCl3, cmꢀ1): 3030, 1714, 1539, 1348; HRMS
(DARTþ) (m/z) calcd for C14H19N2O6 [(M þ H)þ]: 311.12431 found
311.12526.
dioxoisoindolin-2-yl)propanoate (anti-11p). Yellow sticky oil;
1H NMR (CDCl3, 400 MHz):
d
8.04 (1H, d, J ¼ 8.0 Hz), 7.89 (2H, dd,
J ¼ 3.0, 5.0 Hz), 7.85 (1H, d, J ¼ 8.0 Hz), 7.75 (2H, dd, J ¼ 3.0, 5.0 Hz),
7.66 (1H, dd, J ¼ 7.2, 8.0 Hz), 7.44 (1H, dd, J ¼ 7.2, 8.0 Hz), 5.57 (1H,
dd, J ¼ 3.4, 6.6 Hz), 4.25e4.20 (2H, m), 4.14 (1H, dd, J ¼ 6.0, 14.4 Hz),
Triethyl (R*)-1-[(R*)-hydroxy-(2-nitrophenyl)methyl]-1,3,3-
propanetricarboxylate (syn-11n). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
8.01 (1H, dd, J ¼ 1.0, 8.1 Hz), 7.89 (1H, dd,
3.97 (2H, q, J ¼ 7.1 Hz), 3.37e3.32 (1H, m), 0.97 (3H, t, J ¼ 7.1 Hz); 13
C
J ¼ 0.9, 7.9 Hz), 7.68 (1H, ddd, J ¼ 0.9, 7.6, 7.9 Hz), 7.47 (1H, ddd,
J ¼ 1.0, 7.6, 8.1 Hz), 5.70 (1H, d, J ¼ 4.4 Hz), 4.18e4.12 (4H, m), 4.09
(2H, q, J ¼ 7.2 Hz), 3.53 (1H, brs), 3.38 (1H, dd, J ¼ 4.4, 4.7 Hz), 2.97
(1H, dt, J ¼ 4.0, 10.1 Hz), 2.33 (1H, ddd, J ¼ 4.7, 10.1, 14.5 Hz), 2.14
(1H, ddd, J ¼ 4.4, 10.1, 14.5 Hz), 1.24 (3H, t, J ¼ 6.8 Hz), 1.22 (3H, t,
J ¼ 6.6 Hz), 1.16 (3H, t, J ¼ 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
NMR (CDCl3, 100 MHz): d 171.2, 168.5, 146.9, 137.4, 134.3, 133.5,
131.8, 128.7, 128.4, 124.9, 123.6, 67.6, 61.0, 49.3, 36.9, 29.7, 13.7; IR
(CHCl3, cmꢀ1): 3479, 2927, 1774, 1716, 1527, 1396, 1265, 1192; HRMS
(DARTþ) (m/z) calcd for C20H19N2O7 [(M þ H)þ]: 399.11923, found
399.11943.
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-[(N,4-
dimethylphenylsulfonamido)methyl]propanoate (syn-11q). Yel-
d
174.2, 169.0,168.6,147.5,136.1,133.5,129.3,128.6,124.9, 69.3, 61.6,
61.4, 61.3, 49.8, 47.5, 25.2, 13.9, 13.9; IR (CHCl3, cmꢀ1): 1730, 1527,
1348, 1221; HRMS (DARTþ) (m/z) calcd for C19H26NO9 [(M þ H)þ]:
412.16076, found 412.16027.
low sticky oil; 1H NMR (CDCl3, 400 MHz):
d
8.09 (1H, d, J ¼ 8.4 Hz),
7.86 (1H, d, J ¼ 7.8 Hz), 7.73 (2H, d, J ¼ 8.0 Hz), 7.67 (1H, dd, J ¼ 7.4,
7.8 Hz), 7.47 (1H, dd, J ¼ 7.4, 8.4 Hz), 7.35 (2H, d, J ¼ 8.0 Hz), 5.81
(1H, dd, J ¼ 1.8, 6.3 Hz), 4.00e3.84 (2H, m), 3.76 (1H, dd, J ¼ 9.0,
14.1 Hz), 3.32e3.27 (1H, m), 3.12 (1H, dd, J ¼ 6.8, 14.1 Hz), 2.91 (3H,
s), 2.45 (3H, s), 0.95 (3H, t, J ¼ 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
Triethyl (R*)-1-[(S*)-hydroxy-(2-nitrophenyl)methyl]-1,3,3-
propanetricarboxylate (anti-11n). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
8.01 (1H, dd, J ¼ 1.0, 8.0 Hz), 7.71 (1H, dd,
J ¼ 1.6, 7.8 Hz), 7.65 (1H, ddd, J ¼ 1.0, 7.4, 7.8 Hz), 7.46 (1H, ddd,
J ¼ 1.6, 7.4, 8.0 Hz), 5.48 (1H, dd, J ¼ 4.2, 8.0 Hz), 4.25e4.17 (4H, m),
4.10e4.01 (2H, m), 3.92 (1H, d, J ¼ 8.0 Hz), 3.46 (1H, dd, J ¼ 6.0,
6.4 Hz), 3.05 (1H, ddd, J ¼ 4.2, 5.2, 5.4 Hz), 2.45e2.38 (1H, m),
2.33e2.26 (1H, m), 1.30e1.25 (6H, m), 1.10 (3H, t, J ¼ 7.2 Hz); 13C
d 171.4, 146.8, 143.8, 137.8, 134.0, 133.6, 129.9, 128.7, 128.3, 127.4,
124.9, 67.2, 60.8, 49.5, 48.4, 35.8, 21.5, 13.8; IR (CHCl3, cmꢀ1): 3525,
3032, 1728, 1527, 1346, 1161; HRMS (DARTþ) (m/z) calcd for
C
20H25N2O7S [(M þ H)þ]: 437.13825, found 437.13900.
Ethyl (R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-3-[(N,4-
NMR (CDCl3, 100 MHz):
d
173.9, 168.7, 147.8, 137.3, 133.5, 128.7,
dimethylphenylsulfonamido)methyl]propanoate
(anti-11q).
128.4, 124.9, 70.0, 61.7, 61.7, 61.1, 49.6, 48.4, 28.7, 14.0, 14.0, 13.9; IR
(CHCl3, cmꢀ1): 3020, 1730, 1527, 1373, 1216; HRMS (DARTþ) (m/z)
calcd for C19H26NO9 [(M þ H)þ]: 412.16076, found 412.16027.
Triethyl (R*)-1-[(R*)-hydroxy-(2-nitrophenyl)methyl]-1,3,3-
butanetricarboxylate (syn-11o). Yellow sticky oil; 1H NMR
Yellow sticky oil; 1H NMR (CDCl3, 400 MHz):
d
8.00 (1H, d,
J ¼ 8.0 Hz), 7.83 (1H, d, J ¼ 7.8 Hz), 7.67 (1H, dd, J ¼ 7.4, 7.8 Hz), 7.55
(2H, d, J ¼ 7.8 Hz), 7.49 (1H, dd, J ¼ 7.4, 8.0 Hz), 7.29 (2H, d,
J ¼ 7.8 Hz), 5.64 (1H, dd, J ¼ 4.4, 4.8 Hz), 4.12 (2H, q, J ¼ 7.1 Hz),
3.60e3.55 (1H, m), 3.59 (1H, d, J ¼ 4.8 Hz), 3.31e3.27 (1H, m), 3.19
(1H, dd, J ¼ 4.2, 13.4 Hz), 2.66 (3H, s), 2.43 (3H, s), 1.18 (3H, t,
(CDCl3, 400 MHz):
d
7.97 (1H, d, J ¼ 8.2 Hz), 7.82 (1H, d, J ¼ 7.8 Hz),
7.66 (1H, dd, J ¼ 7.2, 7.8 Hz), 7.46 (1H, dd, J ¼ 7.2, 8.2 Hz), 5.44 (1H,
dd, J ¼ 4.2, 5.2 Hz), 4.14e3.97 (6H, m), 3.60 (1H, d, J ¼ 4.2 Hz), 2.98
(1H, ddd, J ¼ 1.3, 5.2, 9.6 Hz), 2.48 (1H, dd, J ¼ 9.6,14.7 Hz), 2.26 (1H,
dd, J ¼ 1.3, 14.7 Hz), 1.29 (3H, s), 1.21 (3H, t, J ¼ 7.0 Hz), 1.16 (3H, t,
J ¼ 7.2 Hz), 1.12 (3H, t, J ¼ 7.4 Hz); 13C NMR (CDCl3, 100 MHz):
J ¼ 7.1 Hz); 13C NMR (CDCl3, 100 MHz):
d 172.9, 147.9, 143.6, 135.8,
133.9, 133.4, 129.7, 129.2, 128.9, 127.5, 125.0, 68.7, 61.5, 49.8, 48.6,
36.2, 21.5, 13.9; IR (CHCl3, cmꢀ1): 3032, 1730, 1527, 1346, 1217, 1161;
HRMS (DARTþ) (m/z) calcd for C20H25N2O7S [(M þ H)þ]: 437.13825,
found 437.13874.
d
174.5, 171.8, 171.6, 147.9, 136.1, 133.3, 129.8, 128.7, 124.9, 71.0, 61.4,
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-(hex-
61.1, 52.9, 47.0, 32.4, 19.8, 13.9, 13.8, 13.8; IR (CHCl3, cmꢀ1): 2987,
2931, 1728, 1527, 1265; HRMS (DARTþ) (m/z) calcd for C20H28NO9
[(M þ H)þ]: 426.17641, found 426.17542.
ylthio)propanoate (syn-11r). Yellow sticky oil; 1H NMR (CDCl3,
400 MHz):
d
8.00 (1H, dd, J ¼ 1.2, 8.1 Hz), 7.86 (1H, dd, J ¼ 1.3,
7.8 Hz), 7.67 (1H, ddd, J ¼ 1.2, 7.6, 7.8 Hz), 7.48 (1H, ddd, J ¼ 1.3, 7.6,
8.1 Hz), 5.63 (1H, dd, J ¼ 3.2, 4.4 Hz), 4.16 (2H, dq, J ¼ 2.7, 7.2 Hz),
3.61 (1H, dd, J ¼ 3.2 Hz), 3.21e3.16 (1H, m), 2.90 (1H, dd, J ¼ 9.2,
13.5 Hz), 2.77 (1H, dd, J ¼ 4.6, 13.5 Hz), 2.42 (2H, dt, J ¼ 3.0, 7.2 Hz),
1.47e1.42 (2H, m), 1.32e1.20 (6H, m), 1.22 (3H, t, J ¼ 7.2 Hz), 0.87
Triethyl (R*)-1-[(S*)-hydroxy-(2-nitrophenyl)methyl]-1,3,3-
butanetricarboxylate (anti-11o). Yellow sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
8.03 (1H, d, J ¼ 8.4 Hz), 7.66e7.62 (2H, m),
7.48e7.43 (1H, m), 5.48 (1H, dd, J ¼ 3.9, 8.2 Hz), 4.26e4.14 (4H, m),
3.92 (2H, q, J ¼ 7.2 Hz), 3.87 (1H, d, J ¼ 8.2 Hz), 3.03 (1H, ddd, J ¼ 2.4,
3.9, 10.1 Hz), 2.64 (1H, dd, J ¼ 10.1, 14.7 Hz), 2.36 (1H, dd, J ¼ 2.4,
14.7 Hz), 1.42 (3H, s), 1.26 (3H, t, J ¼ 7.2 Hz), 1.24 (3H, t, J ¼ 6.8 Hz),
(3H, t, J ¼ 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
d 173.8, 147.8, 135.9,
133.5, 129.4, 128.8, 124.9, 69.6, 61.3, 50.4, 32.5, 31.3, 29.2, 29.0, 28.4,
22.5, 14.0, 14.0; IR (CHCl3, cmꢀ1): 2929, 1726, 1527, 1348, 1200;
HRMS (DARTþ) (m/z) calcd for C18H28NO5S [(M þ H)þ]: 370.16882,
found 370.16815.
0.99 (3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3, 100 MHz):
d 174.4, 171.7,
171.6,137.6,133.4,128.6,128.2,125.0, 72.0, 61.7, 61.5, 60.9, 53.1, 46.8,
36.0, 29.7, 19.6, 13.9, 13.7; IR (CHCl3, cmꢀ1): 2985, 2929, 1728, 1527,
1265; HRMS (DARTþ) (m/z) calcd for C20H28NO9 [(M þ H)þ]:
426.17641, found 426.17586.
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-(hex-
ylthio)propanoate (anti-11r). Slight orange sticky oil; 1H NMR
(CDCl3, 400 MHz):
d
8.02 (1H, dd, J ¼ 1.3, 7.7 Hz), 7.70 (1H, dd,
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]- 3-(1,3-
dioxoisoindolin-2-yl)propanoate (syn-11p). Yellow crystal; mp:
146.0e147.0 ꢁC (recryst. from CHCl3); 1H NMR (CDCl3, 400 MHz):
J ¼ 1.7, 7.9 Hz), 7.64 (1H, ddd, J ¼ 1.3, 7.0, 7.9 Hz), 7.46 (1H, ddd,
J ¼ 1.7, 7.0, 7.7 Hz), 5.62 (1H, dd, J ¼ 3.4, 8.0 Hz), 4.10e4.01 (2H, m),
3.98 (1H, d, J ¼ 8.0 Hz), 3.19 (1H, ddd, J ¼ 3.4, 6.1, 9.3 Hz), 3.00 (1H,
dd, J ¼ 9.3, 13.5 Hz), 2.92 (1H, dd, J ¼ 6.1, 13.5 Hz), 2.60e2.50 (2H,
m),1.60e1.54 (2H, m),1.39e1.26 (6H, m),1.08 (3H, t, J ¼ 7.2 Hz), 0.89
d
7.99 (1H, d, J ¼ 8.2 Hz), 7.88 (1H, d, J ¼ 8.0 Hz), 7.82 (2H, dd, J ¼ 3.1,
5.1 Hz), 7.72 (2H, dd, J ¼ 3.1, 5.1 Hz), 7.64 (1H, dd, J ¼ 7.6, 8.0 Hz),
7.44 (1H, dd, J ¼ 7.6, 8.2 Hz). 5.75 (1H, dd, J ¼ 4.3, 4.4 Hz), 4.25 (1H,
dd, J ¼ 8.6, 14.2 Hz), 4.05e3.99 (3H, m), 3.92 (1H, dd, J ¼ 4.3,
14.2 Hz), 3.38e3.33 (1H, m), 1.01 (3H, t, J ¼ 7.2 Hz); 13C NMR (CDCl3,
(3H, t, J ¼ 7.0 Hz); 13C NMR (CDCl3, 100 MHz):
d 173.7, 147.5, 137.8,
133.5, 128.6, 128.1, 124.9, 69.8, 61.1, 50.6, 32.2, 32.0, 31.4, 29.2, 28.5,
22.5, 14.0, 14.0; IR (CHCl3, cmꢀ1): 2929, 1728, 1705, 1527, 1346, 1196;
8

S. Morita, T. Yoshimura and J.-i. Matsuo
Tetrahedron 94 (2021) 132329
HRMS (DARTþ) (m/z) calcd for C18H28NO5S [(M þ H)þ]: 370.16882,
found 370.16815.
2.93e2.90 (1H, m), 2.68 (1H, dd, J ¼ 9.3, 12.6 Hz), 2.52 (1H, dd,
J ¼ 5.7, 12.6 Hz), 1.70 (3H, s), 1.69 (3H, s), 1.06 (3H, t, J ¼ 7.2 Hz); 13
C
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-(ben-
NMR (CDCl3, 150 MHz): d 173.2, 147.6, 145.9, 137.3, 133.3, 128.5,
zylthio)propanoate (syn-11s). Yellow oil; 1H NMR (CDCl3,
128.2, 128.1, 126.6, 126.5, 124.8, 69.8, 61.0, 50.8, 48.2, 30.2, 29.9,
29.4, 14.0; IR (CHCl3, cmꢀ1): 2985, 1728, 1705, 1527, 1346, 1217;
HRMS (DARTþ) (m/z) calcd for C21H26NO5S [(M þ H)þ]: 404.15317,
found 404.15287.
400 MHz):
d
8.01 (1H, d, J ¼ 7.8 Hz), 7.76 (1H, d, J ¼ 7.6 Hz), 7.60 (1H,
dd, J ¼ 7.6, 7.6 Hz), 7.46 (1H, dd, J ¼ 7.6, 7.8 Hz), 7.19e7.16 (3H, m),
7.13e7.11 (2H, m), 5.61 (1H, dd, J ¼ 3.2, 3.6 Hz), 4.18 (2H, dq, J ¼ 2.4,
6.9 Hz), 3.60 (2H, s), 3.53 (1H, d, J ¼ 3.2 Hz), 3.17e3.12 (1H, m), 2.81
(1H, dd, J ¼ 9.8, 13.5 Hz), 2.54 (1H, dd, J ¼ 4.4, 13.5 Hz), 1.25 (3H, t,
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-(phe-
nylthio)propanoate (syn-11v). Yellow sticky oil; 1H NMR (CDCl3,
J ¼ 6.9 Hz); 13C NMR (CDCl3, 100 MHz):
d
173.9, 137.6, 135.8, 133.5,
400 MHz):
d
8.00 (1H, dd, J ¼ 1.3, 8.2 Hz), 7.87 (1H, d, J ¼ 7.9 Hz),
129.3, 128.7, 128.7, 128.4, 127.0, 124.9, 69.6, 69.3, 61.4, 49.7, 36.1,
27.4, 14.1; IR (CHCl3, cmꢀ1): 3030, 1716, 1527, 1348, 1198; HRMS
(DARTþ) (m/z) calcd for C19H22NO5S [(M þ H)þ]: 376.12187, found
376.12029.
7.68 (1H, ddd, J ¼ 1.3, 7.5, 7.9 Hz), 7.49 (1H, ddd, J ¼ 1.2, 7.5, 8.2 Hz),
7.21e7.16 (5H, m), 5.68 (1H, dd, J ¼ 3.6, 4.4 Hz), 4.09 (2H, q,
J ¼ 7.1 Hz), 3.47 (1H, d, J ¼ 3.6 Hz), 3.29 (1H, dd, J ¼ 9.8, 13.4 Hz),
3.22e3.15 (2H, m), 1.18 (3H, t, J ¼ 7.1 Hz); 13C NMR (CDCl3,
Ethyl (R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-3-(ben-
150 MHz): d 173.3, 147.5, 135.9, 135.3, 133.5, 129.7, 129.2, 128.9,
zylthio)propanoate (anti-11s). Yellow oil; 1H NMR (CDCl3,
128.8, 126.5, 125.0, 69.4, 61.4, 50.2, 31.1, 13.9; IR (CHCl3, cmꢀ1):
400 MHz):
d
8.02 (1H, d, J ¼ 8.0 Hz), 7.66e7.60 (2H, m), 7.48e7.44
2933, 1726, 1527, 1348, 1201; HRMS (DARTþ) (m/z) calcd for
(1H, m), 7.32e7.11 (5H, m), 5.61e5.59 (1H, m), 4.05 (2H, q,
J ¼ 6.9 Hz), 3.90 (1H, d, J ¼ 8.4 Hz), 3.76 (2H, s), 3.22e3.19 (1H, m),
2.87 (1H, dd, J ¼ 8.8,14.0 Hz), 2.70 (1H, dd, J ¼ 6.8,14.0 Hz),1.08 (3H,
C
18H20NO5S [(M þ H)þ]: 362.10622, found 362.10719.
Ethyl (R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-3-(phe-
nylthio)propanoate (anti-11v). Yellow sticky oil; 1H NMR (CDCl3,
t, J ¼ 7.1 Hz); 13C NMR (CDCl3, 100 MHz):
d
173.6, 137.7, 137.6, 133.5,
400 MHz):
d
7.99 (1H, d, J ¼ 7.6 Hz), 7.62 (2H, d, J ¼ 8.0 Hz),
129.0, 128.6, 128.5, 128.4, 128.2, 127.1, 124.9, 69.6, 61.1, 50.2, 35.9,
30.6, 14.0; IR (CHCl3, cmꢀ1): 3032, 1703, 1527, 1346, 1213, 1196;
HRMS (DARTþ) (m/z) calcd for C19H22NO5S [(M þ H)þ]: 376.12187,
found 376.12261.
7.47e7.43 (1H, m), 7.39e7.37 (2H, m), 7.30 (2H, dd, J ¼ 7.2, 8.0 Hz),
7.23e7.18 (1H, m), 5.60 (1H, dd, J ¼ 4.3, 7.9 Hz), 4.10e3.97 (2H, m),
3.92 (1H, d, J ¼ 7.9 Hz), 3.39 (1H, dd, J ¼ 9.6, 13.7 Hz), 3.32 (1H, dd,
J ¼ 5.3, 13.7 Hz), 3.20 (1H, ddd, J ¼ 4.3, 5.3, 9.6 Hz), 1.07 (3H, t,
Ethyl (R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-[(tri-
phenylmethyl)thio]propanoate (syn-11t). Yellow crystal; mp:
J ¼ 7.2 Hz); 13C NMR (CDCl3, 150 MHz):
d 173.3, 147.5, 137.4, 134.8,
133.4, 130.0, 129.0, 128.6, 128.0, 126.7, 124.9, 69.8, 61.2, 50.7, 34.0,
13.9; IR (CHCl3, cmꢀ1): 2929, 1730, 1703, 1527, 1346, 1215; HRMS
(DARTþ) (m/z) calcd for C18H20NO5S [(M þ H)þ]: 362.10622, found
362.10719.
60.0e61.0 ꢁC; 1H NMR (CDCl3, 400 MHz):
d
7.96 (1H, d, J ¼ 8.0 Hz),
7.58 (1H, d, J ¼ 7.6 Hz), 7.53 (1H, dd, J ¼ 7.2, 7.6 Hz), 7.40 (1H, dd,
J ¼ 7.2, 8.0 Hz), 7.30 (6H, d, J ¼ 7.6 Hz), 7,21e7.15 (9H, m), 5.49 (1H,
dd, J ¼ 3.2, 3.6 Hz), 4.17 (2H, q, J ¼ 6.9 Hz), 3.15 (1H, d, J ¼ 3.2 Hz),
2.83e2.78 (1H, m), 2.72 (1H, dd, J ¼ 9.6, 12.2 Hz), 2.22 (1H, dd,
J ¼ 3.6, 12.2 Hz), 1.24 (3H, t, J ¼ 6.9 Hz); 13C NMR (CDCl3, 100 MHz):
4.5. Reduction of the minor diastereomer of 11e for determi-
nation of the stereochemistry.
To a solution of minor-11e (23.9 mg, 0.08 mmol) in benzene
(2.0 mL), AIBN (13.3 mg, 0.08 mmol) and Bu3SnH (0.11 mL,
0.40 mmol) were added. The reaction mixture was refluxed for 17 h.
After cooling to room temperature, benzene was removed under
reduced pressure, and the residue was purified by column chro-
matography on silica gel (hexanes/ethyl acetate ¼ 2:1) to afford
11e’ (16.1 mg, 0.06 mmol, 80% yield). It's spectroscopic data
accorded with the reported value of (2R*,3S*)-ethyl 3-hydroxy-2-
(2-methylpropyl)benzenepropanoate [18].
d
173.5, 147.3, 144.4, 135.9, 133.3, 129.5, 129.2, 128.5, 127.8, 126.6,
124.9, 69.3, 61.3, 49.7, 29.7, 28.4, 14.1; IR (CHCl3, cmꢀ1): 3589, 3010,
1728, 1527, 1346; HRMS (DARTþ) (m/z) calcd for C31H30NO5S
[(M þ H)þ]: 528.18447, found 528.18263.
Ethyl
(R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-3-[(tri-
phenylmethyl)thio]propanoate (anti-11t). Yellow sticky oil; 1H
NMR (CDCl3, 400 MHz):
d
7.94 (1H, d, J ¼ 8.0 Hz), 7.56e7.51 (2H, m),
7.45e7.20 (16H, m), 5.37 (1H, dd, J ¼ 4.4, 7.8 Hz), 4.03 (2H, q,
J ¼ 7.3 Hz), 3.54 (1H, d, J ¼ 7.8 Hz), 2.89e2.84 (1H, m), 2.65 (1H, dd,
J ¼ 9.6, 11.7 Hz), 2.41 (1H, dd, J ¼ 5.4, 11.7 Hz), 1.08 (3H, t, J ¼ 7.3 Hz);
Declaration of competing interest
13C NMR (CDCl3, 100 MHz):
d 173.1, 147.6, 144.3, 136.9, 133.2, 129.5,
128.5, 128.3, 127.9, 126.7, 124.8, 69.8, 67.0, 61.1, 50.3, 31.4, 14.0; IR
(CHCl3, cmꢀ1): 3589, 3008, 1728, 1527, 1348, 1192; HRMS (DARTþ)
(m/z) calcd for C31H30NO5S [(M þ H)þ]: 528.18447, found 528.17922.
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests:
Ethyl
(R*)-2-[(R*)-hydroxy-(2-nitrophenyl)methyl]-3-[(1-
methyl-1-phenylethyl)thio]propanoate (syn-11u). Yellow sticky
Acknowledgements
oil; 1H NMR (CDCl3, 400 MHz):
d
7.96 (1H, d, J ¼ 8.0 Hz), 7.67 (1H, d,
J ¼ 8.0 Hz), 7.58 (1H, dd, J ¼ 7.4, 8.0 Hz), 7.43 (1H, dd, J ¼ 7.4, 8.0 Hz),
7.37 (1H, d, J ¼ 7.8 Hz), 7.22 (1H, dd, J ¼ 7.2, 7.8 Hz), 7.14 (1H, dd,
J ¼ 7.2, 7.2 Hz), 5.49 (1H, brs), 4.10 (2H, q, J ¼ 7.2 Hz), 3.28 (1H, brs),
2.88e2.83 (1H, m), 2.63 (1H, dd, J ¼ 9.4, 12.9 Hz), 2.37 (1H, dd,
We are grateful for the finantial support from JSPS (KAKENHI
Grant Number JP19K05473).
Appendix A. Supplementary data
J ¼ 4.0, 12.9 Hz), 1.61 (3H, s), 1.60 (3H, s), 1.19 (3H, t, J ¼ 7.2 Hz); 13
C
NMR (CDCl3, 150 MHz):
d 173.5, 147.5, 145.8, 136.0, 133.3, 129.2,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132329.
128.5,128.0,126.5,126.4,124.8, 69.1, 61.2, 50.2, 48.0, 30.1, 29.9, 26.3,
14.0; IR (CHCl3, cmꢀ1): 2985,1726, 1527, 1346,1199; HRMS (DARTþ)
(m/z) calcd for C21H26NO5S [(M þ H)þ]: 404.15317, found 404.15522.
References
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(R*)-2-[(S*)-hydroxy-(2-nitrophenyl)methyl]-3-[(1-
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10