One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of Functionalized Nitrocyclopropanes

Article abstract of DOI:10.1021/acs.joc.5b01607

The asymmetric synthesis of functionalized nitrocyclopropanes has been achieved by a one-pot, four-step method catalyzed by (S)-diphenylprolinol TMS ether, which joins two sequential domino reactions, namely a domino sulfa-Michael/aldol condensation of α,β-unsaturated aldehydes with 1,4-dithiane-2,5-diol, and a domino Michael/α-alkylation reaction of the derived chiral dihydrothiophenes with bromonitromethane. The title compounds were obtained in 27-45% yields, with high levels of diastereoselectivity (93:7 to 100:0 dr) and generally good enantioselectivities (up to 95:5 er).

Full text of DOI:10.1021/acs.joc.5b01607

Article
pubs.acs.org/joc
One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of
Functionalized Nitrocyclopropanes
Anna Zaghi, Tatiana Bernardi, Valerio Bertolasi, Olga Bortolini, Alessandro Massi, and Carmela De Risi*
Dipartimento di Scienze Chimiche e Farmaceutiche, Universita
S Supporting Information
̀
degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
*
ABSTRACT: The asymmetric synthesis of functionalized
nitrocyclopropanes has been achieved by a one-pot, four-step
method catalyzed by (S)-diphenylprolinol TMS ether, which
joins two sequential domino reactions, namely a domino sulfa-
Michael/aldol condensation of α,β-unsaturated aldehydes with
1
,4-dithiane-2,5-diol, and a domino Michael/α-alkylation
reaction of the derived chiral dihydrothiophenes with
bromonitromethane. The title compounds were obtained in
2
1
7−45% yields, with high levels of diastereoselectivity (93:7 to
00:0 dr) and generally good enantioselectivities (up to 95:5
er).
7
INTRODUCTION
as the peptide lactone hormaomycin 5 (Figure 2), and used in
■
8
many synthetic transformations, including the preparation of
the broad-spectrum antibiotic Trovafloxacin.
About 130 years after the first synthesis of a cyclopropane
derivative by William Henry Perkin, the strained three-
membered carbocyclic ring motif still attracts attention from
synthetic organic chemists.
9
Cyclopropane compounds are widely distributed among
1
natural products and biologically active agents, such as the N-
methyl-D-aspartate (NMDA) receptor partial agonist 1-amino-
2
cyclopropane-1-carboxylic acid (ACC, 1), the antibiotic and
3
4
antitumor duocarmycin A 2, the phytotoxin coronatine 3, and
5
the cholesteryl ester transfer protein inhibitor U-106305 4
(Figure 1).
Due to their distinguishing structural features, cyclopropanes
can also serve as convenient synthons in several types of
6
reactions.
Nitrocyclopropanes represent a special family of cyclo-
propane compounds, which are found in natural products, such
Figure 2. Structure of hormaomycin 5.
In the past few decades, there has been a growing interest in
10,11
developing stereoselective approaches to cyclopropanes.
In this context, the Michael-initiated ring-closure (MIRC)
12
reaction strategy has been largely used to obtain nitro-
1
0b
cyclopropane derivatives.
In this approach, the target
compounds are formed through a domino Michael/α-alkylation
reaction, wherein the conjugate addition of a nucleophile to an
electron-poor alkene generates a stabilized carbanion inter-
mediate that then undergoes intramolecular ring-closure.
We have recently demonstrated that racemic 2,5-dihydro-
thiophene-3-carbaldehydes 8, obtained by secondary amine-
catalyzed domino sulfa-Michael/aldol condensations between
Figure 1. Structures of the cyclopropane-based bioactive compounds
Received: July 12, 2015
1−4.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01607
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The Journal of Organic Chemistry
Article
Scheme 1. Diastereoselective Nitrocyclopropanation of Racemic Dihydrothiophenes 8 Derived from Sulfa-Michael/Aldol
Condensation Reaction
1
,4-dithiane-2,5-diol 6 and α,β-unsaturated aldehydes 7, were
organocatalyst, while in the second case we counted on the
stereochemical bias of the preexisting stereogenic center upon
nitrocyclopropanation.
To test the feasibility of our hypotheses, we performed a
series of experiments using the model compound 8a as reaction
partner of bromonitromethane. As shown in Scheme 3,
suitable substrates for cyclopropanations with bromonitro-
13
methane catalyzed by DL-proline (Scheme 1). These reactions
provided unprecedented bicyclic nitrocyclopropanes, namely 6-
nitro-3-thiabicyclo[3.1.0]hexane-1-carbaldehydes 9, in fair to
good yields (55−71%) and good to excellent diastereoselectiv-
ities (up to 100:0 dr).
The compounds obtained are highly interesting bicyclic
systems, due to the fusion of the nitrocyclopropane moiety to a
tetrahydrothiophene nucleus, which is comprised in a number
of pharmacologically important systems too. To date,
structurally related derivatives have been already proved to be
Scheme 3. Investigation of Route A
14
effective as agonists of metabotropic glutamate receptors.
As a logical extension of our previous work, we embarked on
the development of an asymmetric variant using chiral proline
surrogates as catalysts, with a view to join the two catalytic
domino sequences in a challenging four-step reaction, one-pot
tandem process. Herein, we report the details of our studies
which led us to disclose a one-pot, four-step asymmetric
organocatalytic method, promoted by a single proline-based
catalyst, giving the functionalized nitrocyclopropanes 9 with
good to high diastereo- and enantioselectivies.
RESULTS AND DISCUSSION
■
At the outset, we conceived that the asymmetric synthesis of
compounds 9 could be achieved by carrying out the two
catalytic domino reactions separately, as we have done in
racemic series. With this in mind, we explored two different
MIRC strategies to install the nitrocyclopropane moiety onto a
preformed 2,5-dihydrothiophene-3-carbaldehyde scaffold
(
Scheme 2): the reaction of bromonitromethane with a racemic
investigation of route A was undertaken on racemic 8a,
15
13
conveniently prepared as reported. We used catalysts 10,
1
6
17
1
1, and 12, which have been selected among the ones most
efficiently used in asymmetric nitrocyclopropanation reactions
21
Scheme 2. Potential Strategies for the Asymmetric Synthesis
of Functionalized Nitrocyclopropanes
18−20
of α,β-unsaturated carbonyl compounds.
Catalysts 13
22
and 14 were also included in our study.
With particular regards to catalyst 14, we believed that it
could promote the nitrocyclopropanation process through
simultaneous activation of the Michael donor and the
electrophilic aldehyde group by the tertiary amine and thiourea
moieties, respectively.
Successful reactions were observed when (±)-8a was reacted
with bromonitromethane (1.3 equiv) and triethylamine (1.3
equiv) in CH Cl at room temperature, using primary and
secondary amine catalysts 10−13 (20−40 mol %) in the
presence of benzoic acid (10−40 mol %) as an additive. The
expected nitrocyclopropane 9a was obtained in yields ranging
from 43 to 65% (Table S1, Supporting Information). In terms
of enantioselectivity, the results were totally disappointing. In
all cases, compound 9a was obtained as a racemate, albeit
2
2
substrate catalyzed by a chiral amine organocatalyst (route A)
or the reaction between bromonitromethane and an
enantiopure (or enantioenriched) substance (route B).
In the first case, we hoped to obtain enantioenriched
nitrocyclopropane adducts through kinetic resolution of the
racemic dihydrothiophene substrate by means of the chiral
B
DOI: 10.1021/acs.joc.5b01607
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Article
Scheme 4. Re-examined Synthesis of Diidrothiophene (+)-8a
a
Table 1. One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of Nitrocyclopropane (+)-9a
b
c
d
e
entry
additive
solvent
t (°C)
t (h)
yield (%)
er (%)
1
2
3
4
5
6
7
8
PhCO H
CH Cl2
40
rt
2
2
45
95:5
−
−
90:10
92:8
92:8
99:1
89:11
2
2
f
PhCO H
EtOH
MeOH
PhMe
−
−
2
f
PhCO H
rt
2
2
PhCO H
rt
5
26
20
18
18
32
2
PhCO H
CH Cl2
rt
4
2
2
4-NO C H CO H
CH Cl2
rt
4
2
6
4
2
2
4-NO C H CO H
PhMe
PhMe
rt
16
2
2
6
4
2
4-NO C H CO H
40
2
6
4
2
a
Reaction conditions: 6 (0.372 mmol), 7a (0.62 mmol), catalyst 10 (20 mol %), and additive (10 mol %) were stirred in solvent (2.0 mL) at the
given temperature for the indicated time. Upon completion, the reaction mixture was cooled down to 0 °C, bromonitromethane (0.8 mmol) and
b
triethylamine (0.8 mmol) were sequentially added, and the reaction mixture was kept at room temperature overnight. Temperature at which the
c
d
e
dihydrothiophene-forming step took place. Duration of the dihydrothiophene-forming step. Yield of isolated product. Determined by HPLC
f
analysis on a chiral stationary phase. The thiophene product was obtained exclusively.
2
3
diastereomerically pure. On the basis of these results, we turned
our attention to route B. Hence, an enantiopure (or
enantioenriched) 2,5-dihydrothiophene-3-carbaldehyde sub-
stance was needed.
some other chiral dihydrothiophenes among those reported,
but we experienced the same hurdles in any case. On the
strength of this, we reasoned that a “one-pot” process, wherein
the intermediate dihydrothiophene was not isolated but treated
in situ with bromonitromethane anion, could circumvent the
observed problems. In doing so, we envisioned to use the single
organocatalyst 10 to promote both the dihydrothiophene-
forming step and the following Michael/α-alkylation reaction
rather than exploiting different amine organocatalysts for each
domino process.
To prove the feasibility of this tactic, we ran an optimization
study based on the findings obtained thus far. As shown in
Table 1, the one-pot process could be run in CH Cl (Table 1,
entries 1, 5, and 6) or toluene (Table 1, entries 4, 7, and 8),
with yields and enantioselectivities being influenced by both the
acid additive and the temperature at which the dihydrothio-
phene-forming step took place.
The recent work on the enantioselective synthesis of
functionalized dihydrothiophenes through organocatalytic
domino sulfa-Michael/aldol condensation reaction was selected
23
for this purpose. Accordingly, we attempted to prepare the
known chiral dihydrothiophene (+)-8a under the reported
experimental conditions. Thus, cinnamaldehyde 7a and 1,4-
dithiane-2,5-diol 6 (0.6 equiv) were reacted in toluene at room
temperature for 12 h in the presence of (S)-diphenylprolinol
TMS ether 10 (20 mol %) and 4-nitrobenzoic acid (10 mol %)
as additive. Disappointingly, we were unable to reproduce the
authors’ findings. As a matter of fact, compound (+)-8a has
been isolated in only 25% yield, with >99.5:0.5 er. Therefore,
the reaction was re-examined (Table S2, Supporting
Information) and slightly improved conditions were deter-
mined by carrying out the domino sulfa-Michael/aldol
condensation reaction in CH Cl at 40 °C for 2 h using
2
2
Optimal conditions (Table 1, entry 1) were established by
reacting dithiane 6, cinnamaldehyde 7a, amine catalyst 10 (20
mol %), and benzoic acid (10 mol %) in CH Cl at 40 °C for 2
2
2
2
2
benzoic acid (10 mol %) as additive (Scheme 4).
h, under inert atmosphere. Upon completion (TLC analysis),
the reaction mixture was cooled down to 0 °C, treated with a
bromonitromethane/triethylamine (1.3 equiv each) system,
and kept at room temperature overnight. Gratifyingly, nitro-
cyclopropane (+)-9a was obtained as a single diastereomer in
45% isolated yield and 95:5 er (Table 1, entry 1).
Having established the best conditions for the one-pot, four-
step organocatalytic process, we proceeded to investigate its
scope using a variety of α,β-unsaturated aldehydes as partners
of 1,4-dithiane-2,5-diol 6. The results of these studies are
summarized in Table 2.
Although we ran the reaction under very carefully controlled
conditions, we could not completely avoid the formation of
various uncharacterized byproducts together with a certain
amount of the aromatic thiophene derivative arising from
oxidation of (+)-8a. Therefore, a very time-consuming and
wasteful chromatographic purification of the crude reaction
mixture was needed in order to isolate the target compound. At
best, (+)-8a was obtained in 52% yield and 98:2 er.
We doubted that these difficulties might depend on the
selected model compound, so we attempted the synthesis of
C
DOI: 10.1021/acs.joc.5b01607
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Article
a
Table 2. One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of Functionalized Nitrocyclopropanes 9a−p
b
c
d
entry
aldehyde
R
product
t (h)
yield (%)
dr (%)
er (%)
95:5
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
2-MeOC H
9a
9b
9c
9d
9e
9f
2
2
2
1
2
2
1
1
1
1
1
1
1
1
1
1
45
40
28
40
40
35
42
30
31
27
27
30
35
27
27
100:0
94:6
6
4
4
4
e
3-MeOC H
nd
6
4-MeOC H
100:0
100:0
94:6
86:14
93:7
6
2-MeC H
6
4
4
4
f
f
3-MeC H
82:18
85:15
90:10
92:8
6
g
4-MeC H
94:6
6
7g
7h
7i
2-NO C H
4
9g
9h
9i
100:0
100:0
100:0
96:4
2
6
2-Me-5-NO C H
4
2
6
2-BrC H
91:9
6
4
4
4
4
f
10
11
12
13
14
15
16
7j
3-BrC H
9j
87:13
93:7
6
7k
7l
4-BrC H
9k
9l
100:0
100:0
100:0
100:0
94:6
6
4-ClC H
92:8
6
7m
7n
7o
7p
2-CF C H
9m
9n
9o
9p
94:6
3
6
4
3-CF C H
93:7
3
6
4
h
f
2-furanyl
Ph
80:20
i
e
31
93:7
nd
a
Reaction conditions: 6 (0.372 mmol), 7 (0.62 mmol), catalyst 10 (20 mol %), and PhCO H (10 mol %) were stirred in CH Cl (2.0 mL) at 40 °C
2
2
2
for the indicated time. Upon completion, the reaction mixture was cooled down to 0 °C, bromonitromethane (0.8 mmol) and triethylamine (0.8
b
c
1
mmol) were sequentially added, and the reaction mixture was kept at room temperature overnight. Yield of isolated product. Determined by H
d
e
f
g
NMR analysis. Determined by HPLC analysis on a chiral stationary phase. Not determined. The er value of the major isomer. Additional 10 mol
h
%
of catalyst 10 and 5 mol % of PhCO H were used in the cyclopropanation step. 40 mol % of catalyst 10 and 20 mol % of PhCO H were used.
2
2
i
Compound 9p was slightly contaminated by uncharacterized byproducts.
Scheme 5. Derivatization of Nitrocyclopropane 9o to the Mosher Esters 16 and 17
1
β-Phenyl (Table 2, entry 16) and substituted β-phenyl
Table 2, entries 1−14) α,β-unsaturated aldehydes were
firmed by TLC and H NMR monitoring. Every attempt to
improve these outcomes failed, regardless of the reaction
conditions and the α,β-unsaturated aldehyde used. Even so, it is
worth noting that the observed yields are in regard with a
process that takes place through four sequential reaction steps
involving the formation of one C−S and three C−C bonds as
well as one dehydration step, all of them occurring in a single
operation.
(
suitable substrates for the organocatalytic process, providing
the target nitrocyclopropanes in 27−45% yields. The position
and nature of substituents on the β-phenyl ring had slight effect
on stereocontrol. Good to very good enantioselectivities were
observed (85:15 to 95:5 er), except for compound 9e (82:18 er,
Table 2, entry 5). The one-pot, four-step method was also
applicable to the β-heteroaryl α,β-unsaturated aldehyde 7o,
providing compound 9o in 27% yield and 80:20 er (Table 2,
entry 15).
Notably, the organocatalytic process displayed high diaster-
eoselectivity. The nitrocyclopropane derivatives have been
obtained as single diastereomers (100:0 dr, Table 2, entries 1, 3,
4, 7−9, and 11−14) or as mixtures of two diastereomers (93:7
to 96:4 dr, Table 2, entries 2, 5, 6, 10, 15, and 16). The latter
were inseparable except for 9o (94:6 dr, Table 2, entry 15). In
this case, the major diastereomer was partially isolated by flash
chromatography.
The relative and absolute configurations of the major
diastereomers have been unambiguously assigned by X-ray
crystallography. Since we were unable to obtain good quality
single crystals of any diastereomerically pure nitrocyclopropane,
we carried out a series of chemical transformations to prepare
On the contrary, the reactions of 1,4-dithiane-2,5-diol 6 with
alkyl α,β-unsaturated aldehydes were completely unsuccessful,
leading to complex product mixtures.
It should be pointed out that the organocatalytic reactions
gave moderate yields mainly due to the low efficiency of the
dihydrothiophene-forming step. Similarly to what we have
observed in the optimization studies of the sulfa-Michael/aldol
condensation reaction, the chiral dihydrothiophenes were
generally formed together with the corresponding thiophene
derivatives and various uncharacterized byproducts, as con-
D
DOI: 10.1021/acs.joc.5b01607
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The Journal of Organic Chemistry
Article
Scheme 6. Plausible Mechanism for the One-Pot, Four-Step Organocatalytic Process
Scheme 7. Enantiofacial Discrimination of Activated Olefin I
compounds suitable for X-ray structure determination. To our
delight, reduction of the pure diastereomer 9o (80:20 er) to the
corresponding primary alcohol under standard conditions
ester 17 was produced by slow evaporation of an EtOAc
solution at room temperature.
X-ray diffraction analysis of 17 allowed us to determine the
(
1S,2R,5R,6S) absolute configuration of its bicyclic core (Figure
(
NaBH , MeOH, rt), followed by DMAP-catalyzed esterifica-
4
24
S3, Supporting Information). This result revealed a cis-
relationship between the nitro functional group, the hydrox-
ymethyl ester moiety and the substituent at C2. Accordingly,
we assigned the structure to compound 16, and the
configurations of all the major nitrocyclopropanes 9a−p were
tion with (S)-Mosher acid 15, gave diastereomeric esters 16
and 17 (80:20 dr) in 75% combined yield (Scheme 5).
Purification by flash chromatography provided analytical
samples of both products, and a single crystal of the minor
E
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Article
established by analogy. Importantly, NMR analysis further
(TLC) on silica gel 60 F254 precoated plates, and all compounds were
1
visualized by UV light and KMnO (2% aqueous) spray test. Flash
supported this assignment. Indeed, H NMR spectra of 9a−p
4
column chromatography was performed on silica gel 60 (230−400
mesh), using reagent grade solvents. Melting points (mp) were
recorded with a melting point apparatus and are uncorrected.
showed a diagnostic doublet signal for hydrogen H6 with J
H5,H6
=
3.3−3.6 Hz, which reflects its trans configuration with
25
hydrogen H5.
1
13
19
H (300 MHz), C (101 MHz), and F (376 MHz) NMR spectra
On the other hand, the structures of the minor nitro-
cyclopropane isomers have not been definitively identified.
However, we may tentatively assume that the nitro and formyl
groups have a cis-relationship, due to the H5−H6 coupling
were recorded on 300 and 400 MHz spectrometers in CDCl , at room
3
temperature unless otherwise stated. Chemical shifts are reported in δ
(ppm), and coupling constants (J) are given in Hertz (Hz).
Optical rotations (α) were measured on a polarimeter with a
sodium lamp in the given solvent at the indicated concentration (c, g/
100 mL) and temperature (°C).
High resolution mass spectra (HRMS) data were obtained using a
QTOF LC/MS mass spectrometer with a dual-electrospray ionization
1
constants observed in the H NMR spectra of these
compounds.
Based on previous literature results,
2
3,26
a plausible
mechanism for the one-pot, four-step organocatalytic process
has been postulated (Scheme 6). Thus, activation of the α,β-
unsaturated aldehyde by the organocatalyst 10 generates the
iminium-ion I, which is attacked by in situ generated
mercaptoacetaldehyde (sulfa-Michael reaction) to give the
stereodefined enamine II. Next, intramolecular aldol reaction
and dehydration (aldol condensation reaction) form inter-
mediate III that undergoes reaction with bromonitromethane
anion (Michael reaction) providing adduct IV. It is likely that
the Re face of the carbon−carbon double bond in the iminium-
ion III is effectively shielded by the bulky substituent on the
organocatalyst framework, leaving the Si face exposed for
carbon−carbon bond formation. Intramolecular nucleophilic
substitution (α-alkylation reaction) of IV and hydrolysis of the
resulting iminium-ion intermediate V provide the major
nitrocyclopropane isomer 9.
It may be assumed that benzoic acid promotes both the
formation of I and the aldol condensation step as well as the
hydrolysis of intermediate V. Moreover, we cannot exclude that
intermediate III could be hydrolyzed to the corresponding
aldehyde, but a plausible re-equilibration to III might take place
under the reaction conditions.
In terms of enantiocontrol during the dihydrothiophene-
forming step, we anticipated that the sterically demanding
group at the organocatalyst residue efficiently shielded one face
of the olefin in intermediate I. Hence, the incoming S-
nucleophile preferentially attacked at the opposite, less
hindered face (Scheme 7). Thus, shielding of the Si face forced
the nucleophile to attack on the Re face to provide the (R)-
configured enamine II. Notable exceptions would be the 2-
furanyl- and 2-bromophenyl-substituted activated olefins, which
gave the (S)-configured product via conjugate addition of
mercaptoacetaldehyde from the deshielded Si face.
(
ESI) source. Samples were dissolved in 10 mM solution of formic
acid (0.1%) in 60:40 MeCN/H O, and the compounds were detected
2
in positive ion mode by HPLC-Chip Q/TOF-MS (nanospray) analysis
using a quadrupole and a time-of-flight unit to produce spectra.
Enantiomeric ratios (er) were determined by chiral HPLC analysis
using 250 × 4.6 mm Lux 5 μm Cellulose-1 and 250 × 4.6 mm 5 μm
ChiralPak ID columns. The mobile phase was a binary mixture n-
hexane/i-PrOH.
1
5
22
Catalysts 10 and 14 were commercially available and were used
1
6
17
21
without purification. Catalysts 11, 12, and 13 were known
compounds. They were synthesized according to the literature
procedures, starting from quinine, (1S,2S)-diphenylethylenedi-
amine, and (1R,2R)-1,2-diamino cyclohexane, respectively.
Aldehydes 7a, 7g, 7o, and 7p were commercial products and were
used as received. Aldehydes 7b−f, 7j, 7l, 7m, and 7n were
known compounds, and aldehyde 7h was a new compound. All of
them were prepared from the appropriate aryl halide and acrolein
diethyl acetal according to the literature procedure. Aldehydes 7i and
7k were known compounds and were prepared from a suitable
1
6
17
21
27
28
27
29
27
2
7
28
benzaldehyde precursor and triphenylphosphoranilidene acetaldehyde
following known directions.
3
0
General Procedure for the Nitrocyclopropanation of
Dihydrothiophene (± )-8a. The amine catalyst and the additive
were added to a solution of (±)-8a (55 mg, 0.25 mmol) in CH Cl
2
2
(
0.5 mL). After cooling to 0 °C, bromonitromethane (0.023 mL, 0.325
mmol) and the base (0.325 mmol) were sequentially added, and
stirring was continued at room temperature for the indicated time
(Table S1, Supporting Information). Upon completion (TLC
analysis), the reaction mixture was evaporated to dryness, and the
crude residue was purified by flash chromatography (7:1 cyclohexane/
EtOAc) to afford compound (±)-9a. The physical and spectral data
13
obtained are in accordance with those reported in the literature.
(
+)-(R)-2-(2-Methoxyphenyl)-2,5-dihydrothiophene-3-carbalde-
hyde (8a). To a solution of catalyst 10 (40 mg, 0.124 mmol) and
PhCO H (8 mg, 0.062 mmol) in CH Cl (2 mL), cinnamaldehyde 7a
2
2
2
(100 mg, 0.62 mmol) and 1,4-dithiane-2,5-diol 6 (57 mg, 0.372 mmol)
were sequentially added, and the reaction mixture was heated at 40 °C
for 2 h. After cooling down, the reaction mixture was loaded onto a
silica-gel column for purification (7:1 cyclohexane/EtOAc) to afford
CONCLUSION
■
In summary, we have developed the asymmetric synthesis of
functionalized nitrocyclopropanes via a one-pot, four-step
organocatalytic process, catalyzed by (S)-diphenylprolinol
TMS ether, which evolves through domino sulfa-Michael/
aldol condensation of α,β-unsaturated aldehydes and 1,4-
dithiane-2,5-diol followed by domino Michael/α-alkylation
reaction of the derived chiral dihydrothiophene adducts with
bromonitromethane. In spite of quite moderate yields (up to
23
the product (+)-8a (71 mg, 52%) as an amorphous yellow solid.
20
1
[
α]D + 194 (c 0.96, CHCl ); H NMR (300 MHz, CDCl ): δ 9.80
3
3
(
6
s, 1H), 7.24−7.16 (m, 1H), 7.15−7.10 (m, 1H), 7.00−6.94 (m, 1H),
.90−6.82 (m, 2H), 5.88 (dt, J = 5.5, 1.7 Hz, 1H), 4.13 (ddd, J = 18.1,
13 1
5.5, 2.5 Hz, 1H), 4.02−3.91 (m, 1H), 3.87 (s, 3H) ppm; C{ H}
NMR (101 MHz, CDCl ): δ 187.5, 156.5, 150.7, 147.9, 130.6, 128.6,
3
126.9, 120.8, 111.0, 55.8, 47.9, 38.3 ppm; HRMS (ESI-TOF) m/z: [M
+
+
H] Calcd for C H O S 221.0631, Found 221.0637; HPLC
12 13
2
conditions: Chiralpak ID, n-hexane/i-PrOH = 95:5, flow rate = 0.5 mL
4
5%), the products were obtained in good to high
diastereoselectivities (up to 100:0 dr) and enantioselectivities
up to 95:5 er).
−
1
min , λ = 220 nm, 25 °C, t = 31.69 (major), 33.46 (minor), 98:2 er.
R
(
E)-3-(2-Methyl-5-nitrophenyl)acrylaldehyde (7h). Compound 7h
(
was obtained as an amorphous yellow solid (67 mg, 70%) from 2-
methyl-5-nitrobenzaldehyde (96 mg, 0.5 mmol) according to the
EXPERIMENTAL SECTION
General Experimental Methods. All reactions were run under
argon atmosphere, using freshly distilled solvents under anhydrous
conditions. Reactions were monitored by thin-layer chromatography
27
■
literature procedure. The compound was purified by column
1
chromatography (10:1 cyclohexane/EtOAc). H NMR (300 MHz,
CDCl ): δ 9.79 (d, J = 7.4 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.17 (dd,
3
J = 8.4, 2.4 Hz, 1H), 7.73 (d, J = 15.9 Hz, 1H), 7.43 (d, J = 8.4 Hz,
F
DOI: 10.1021/acs.joc.5b01607
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1
H), 6.77 (dd, J = 15.9, 7.4 Hz, 1H), 2.58 (s, 3H) ppm; 13C{ H}
1H), 6.97−6.89 (m, 2H), 5.11 (d, J = 3.6 Hz, 1H), 4.83 (s, 1H), 3.74
(t, J = 3.7 Hz, 1H), 3.58 (dd, J = 12.0, 3.9 Hz, 1H), 3.32 (d, J = 12.0
NMR (101 MHz, CDCl ): δ 192.8, 146.9, 144.7, 134.2, 132.0, 131.8,
24.9, 121.8, 121.7, 20.1 ppm; HRMS (ESI-TOF) m/z: [M + H]
3
+
13
1
1
Hz, 1H), 2.33 (s, 3H) ppm; C{ H} NMR (101 MHz, CDCl ) (as
3
Calcd for C H NO 192.0655, Found 192.0658.
General Procedure for the One-Pot, Four-Step Organo-
catalytic Asymmetric Synthesis of Nitrocyclopropanes 9. To a
major isomer): δ 192.3, 141.2, 139.3, 129.4, 129.1, 127.4, 123.7, 66.6+,
53.5, 52.7, 36.5, 32.6, 21.6 ppm; HRMS (ESI-TOF) m/z: [M + H]
Calcd for C H NO S 264.0689, Found 264.0688; HPLC conditions:
10
10
3
13
14
3
−1
solution of catalyst 10 (0.124 mmol) and PhCO H (0.062 mmol) in
Lux Cellulose-1, n-hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ
2
CH Cl (2 mL), cinnamaldehyde 7 (0.62 mmol) and 1,4-dithiane-2,5-
= 210 nm, 25 °C, t = 20.20 (minor), 17.08 (major), 82:18 er (for
2
2
R
diol 6 (0.372 mmol) were sequentially added, and the reaction mixture
was heated at 40 °C for the indicated time (Table 2). Upon
completion (TLC analysis), the reaction mixture was cooled down to
major isomer).
(1R,2R,5S,6R)-6-Nitro-2-(4-methylphenyl)-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9f). Column chromatography with 11:1
0
°C, bromonitromethane (0.8 mmol) and triethylamine (0.8 mmol)
cyclohexane/EtOAc afforded the orange oil 9f (57 mg, 35%) as a
1
were sequentially added, and stirring was continued at room
temperature overnight. The crude reaction mixture was loaded onto
a silica-gel column for purification (cyclohexane/EtOAc) to afford the
nitrocyclopropanation products 9.
diastereomeric mixture (94:6 dr); H NMR (300 MHz, CDCl ) (as
3
major isomer): δ 9.51 (s, 1H), 7.16−7.09 (m, 2H), 7.06−7.00 (m,
2H), 5.11 (d, J = 3.5 Hz, 1H), 4.84 (s, 1H), 3.75−3.70 (m, 1H), 3.62−
1
3
1
3.54 (m, 1H), 3.32 (d, J = 12.0 Hz, 1H), 2.31 (s, 3H) ppm; C{ H}
(
+)-(1R,2R,5S,6R)-2-(2-Methoxyphenyl)-6-nitro-3-thiabicyclo-
3.1.0]hexane-1-carbaldehyde (9a). Column chromatography with
:1 cyclohexane/EtOAc afforded the title compound 9a (78 mg, 45%)
NMR (101 MHz, CDCl ) (as major isomer): δ 192.1, 138.1, 130.1,
3
[
7
126.5, 66.4, 53.2, 52.7, 36.3, 32.5, 26.9, 21.1 ppm; HRMS (ESI-TOF)
+
m/z: [M + H] Calcd for C H NO S 264.0694, Found 264.0690;
13
14
3
20
1
as an amorphous yellow solid. [α]D + 70.3 (c 1.0, CHCl ); H NMR
HPLC conditions: Lux Cellulose-1, n-hexane/i-PrOH = 70:30, flow
3
−1
(
300 MHz, CDCl ): δ 9.51 (s, 1H), 7.30−7.20 (m, 1H), 7.11−7.03
rate = 1 mL min , λ = 210 nm, 25 °C, t = 19.33 (minor), 16.00
3
R
(
m, 1H), 6.96−6.83 (m, 2H), 5.22 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H),
(major), 85:15 er (for major isomer).
3
3
1
3
.86 (s, 3H), 3.67 (t, J = 3.8 Hz, 1H), 3.56 (dd, J = 11.5, 3.8 Hz, 1H),
(+)-(1R,2R,5S,6R)-6-Nitro-2-(2-nitrophenyl)-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9g). Column chromatography with 3:1
cyclohexane/EtOAc afforded 9g (77 mg, 42%) as an amorphous
.26 (d, J = 11.5 Hz, 1H) ppm; 13C{ H} NMR (101 MHz, CDCl ): δ
1
3
92.2, 155.9, 129.6, 128.5, 128.3, 121.3, 111.2, 77.2, 67.0, 55.6, 52.2,
8.1, 33.0 ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for
+
20
1
orange solid. [α]D + 19 (c 1.0, CHCl ); H NMR (300 MHz, CDCl ,
3
3
C H NO S 280.0638, Found 280.0647; HPLC conditions: Lux
Cellulose-1, n-hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ =
55 °C): δ 9.56 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.5 Hz,
1H), 7.42 (t, J = 7.4 Hz, 1H), 7.26−7.19 (m, 1H), 5.51 (s, 1H), 5.21
(d, J = 3.3 Hz, 1H), 3.82 (t, J = 3.6 Hz, 1H), 3.53 (dd, J = 12.1, 3.8 Hz,
1H), 3.35 (d, J = 12.2 Hz, 1H) ppm; 13C{ H} NMR (101 MHz,
13
14
4
−
1
2
80 nm, 25 °C, t = 36.85 (minor), 21.27 (major), 95:5 er.
R
1
(
1R,2R,5S,6R)-2-(3-Methoxyphenyl)-6-nitro-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9b). Column chromatography with 6:1
CDCl , 55 °C): δ 191.3, 148.1, 136.2, 133.6, 128.7, 128.2, 125.4, 66.2,
3
+
cyclohexane/EtOAc afforded the yellow oil 9b (69 mg, 40%) as a
52.5, 48.4, 37.2, 32.4 ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd
1
diastereomeric mixture (94:6 dr); H NMR (300 MHz, CDCl ) (as
for C H N O S 295.0383, Found 295.0374; HPLC conditions:
3
12 11
2
5
−1
major isomer): δ 9.53 (s, 1H), 7.31−7.19 (m, 1H), 6.83−6.76 (m,
Chiralpak ID, n-hexane/i-PrOH = 40:60, flow rate = 0.5 mL min , λ =
1
1
1
H), 6.76−6.69 (m, 1H), 6.68−6.65 (m, 1H), 5.11 (d, J = 3.5 Hz,
H), 4.82 (s, 1H), 3.79 (s, 3H), 3.73 (t, J = 3.5 Hz, 1H), 3.58 (dd, J =
2.1, 3.9 Hz, 1H), 3.33 (d, J = 12.1 Hz, 1H) ppm; 13C{ H} NMR (101
254 nm, 25 °C, t = 18.20 (minor), 19.20 (major), 90:10 er.
R
(+)-(1R,2R,5S,6R)-2-(2-Methyl-5-nitrophenyl)-6-nitro-3-
thiabicyclo[3.1.0]hexane-1-carbaldehyde (9h). Column chromatog-
raphy with 5:1 cyclohexane/EtOAc afforded 9h (57 mg, 30%) as an
1
MHz, CDCl ) (as major isomer): δ 192.0, 160.2, 142.7, 130.6, 118.7,
3
amorphous yellow solid. [α]D20 + 54.7 (c 1.62, CHCl ); H NMR
1
1
13.0, 112.9, 66.4, 55.2, 53.3, 52.6, 36.3, 32.5 ppm; HRMS (ESI-TOF)
3
+
m/z: [M + H] Calcd for C H NO S 280.0644, Found 280.0650.
(300 MHz, CDCl ): δ 9.62 (s, 1H), 8.00 (dd, J = 8.4, 2.3 Hz, 1H),
13
14
4
3
(
+)-(1R,2R,5S,6R)-2-(4-Methoxyphenyl)-6-nitro-3-thiabicyclo-
3.1.0]hexane-1-carbaldehyde (9c). Column chromatography with
:1 cyclohexane/EtOAc afforded 9c (49 mg, 28%) as a yellow oil.
7.76 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.27 (d, J = 3.3 Hz,
1H), 5.07 (s, 1H), 4.00 (t, J = 3.4 Hz, 1H), 3.64 (dd, J = 12.4, 3.7 Hz,
1H), 3.44 (d, J = 12.4 Hz, 1H), 2.50 (s, 3H) ppm; C{ H} NMR
[
6
1
3
1
α]D20 + 60.3 (c 1.2, CHCl ); H NMR (300 MHz, CDCl ): δ 9.50 (s,
1
[
(101 MHz, CDCl ): δ 192.4, 147.0, 143.0, 141.9, 132.0, 122.6, 119.9,
3
3
3
1
1
1
H), 7.10−7.04 (m, 2H), 6.88−6.81 (m, 2H), 5.09 (d, J = 3.5 Hz,
H), 4.85 (s, 1H), 3.78 (s, 3H), 3.71 (t, J = 3.7 Hz, 1H), 3.58 (dd, J =
2.0, 3.9 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H) ppm; 13C{ H} NMR (101
66.0, 52.7, 48.2, 36.4, 32.5, 20.4 ppm; HRMS (ESI-TOF) m/z: [M +
+
H] Calcd for C H N O S 309.0540, Found 309.0554; HPLC
13
13
2
5
1
conditions: Lux Cellulose-1, n-hexane/i-PrOH = 50:50, flow rate = 1
−1
MHz, CDCl ): δ 192.1, 159.4, 133.1, 127.9, 114.7, 66.5, 55.3, 53.0,
5
C H NNaO S 302.0457, Found 302.0469; HPLC conditions: Lux
mL min , λ = 210 nm, 50 °C, t = 13.52 (minor), 9.91 (major), 92:8
3
R
+
2.8, 36.3, 32.5 ppm; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
er.
13
13
4
(+)-(1R,2S,5S,6R)-2-(2-Bromophenyl)-6-nitro-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9i). Column chromatography with 4.5:1
cyclohexane/EtOAc afforded 9i (63 mg, 31%) as an amorphous yellow
solid. [α]D20 + 82.8 (c 1.98, CHCl ); H NMR (300 MHz, CDCl ): δ
−
1
Cellulose-1, n-hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ =
80 nm, 25 °C, t = 22.38 (minor), 20.40 (major), 86:14 er.
2
R
1
(
+)-(1R,2R,5S,6R)-6-Nitro-2-(2-methylphenyl)-3-thiabicyclo-
3.1.0]hexane-1-carbaldehyde (9d). Column chromatography with
0:1 cyclohexane/EtOAc afforded 9d (65 mg, 40%) as an amorphous
3
3
[
1
9.59 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.32−7.25 (m, 1H), 7.13 (td, J
= 7.8, 1.5 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.44 (s, 1H), 5.22 (d, J =
3.3 Hz, 1H), 3.80 (t, J = 3.5 Hz, 1H), 3.46 (dd, J = 12.2, 3.5 Hz, 1H),
20
1
yellow solid. [α]D + 120 (c 1.0, CHCl ); H NMR (300 MHz,
3
3.32 (d, J = 12.2 Hz, 1H) ppm; 13C{ H} NMR (101 MHz, CDCl ): δ
1
CDCl ): δ 9.57 (s, 1H), 7.20−7.12 (m, 3H), 6.99−6.91 (m, 1H), 5.19
3
3
(
d, J = 3.4 Hz, 1H), 5.12 (s, 1H), 3.78 (t, J = 3.6 Hz, 1H), 3.52 (dd, J =
191.9, 140.1, 133.7, 129.4, 128.5, 126.9, 123.8, 66.1, 52.1, 51.9, 36.3,
31.7 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C H BrNO S 327.9617, Found 327.9622; HPLC conditions: Lux
1
2.1, 3.7 Hz, 1H), 3.33 (d, J = 12.1 Hz, 1H), 2.39 (s, 3H) ppm;
1
3
1
C{ H} NMR (101 MHz, CDCl ): δ 192.4, 139.4, 135.2, 131.3,
3
12 11
3
−1
1
28.0, 127.1, 125.2, 66.4, 52.4, 48.7, 36.5, 32.1, 20.1 ppm; HRMS
Cellulose-1, n-hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ =
+
(
ESI-TOF) m/z: [M + H] Calcd for C H NO S 264.0694, Found
210 nm, 25 °C, t = 33.16 (minor), 40.21 (major), 91:9 er.
13
14
3
R
2
7
1
64.0696; HPLC conditions: Lux Cellulose-1, n-hexane/i-PrOH =
0:30, flow rate = 1 mL min , λ = 210 nm, 25 °C, t = 26.32 (minor),
8.28 (major), 93:7 er.
(1R,2R,5S,6R)-2-(3-Bromophenyl)-6-nitro-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9j). Column chromatography with 5:1
−1
R
cyclohexane/EtOAc afforded the yellow solid 9j (45 mg, 27%) as a
1
(
1R,2R,5S,6R)-6-Nitro-2-(3-methylphenyl)-3-thiabicyclo[3.1.0]-
diastereomeric mixture (96:4 dr); H NMR (300 MHz, CDCl
3
) (as
hexane-1-carbaldehyde (9e). Column chromatography with 8:1
cyclohexane/EtOAc afforded the yellow oil 9e (65 mg, 40%) as a
diastereomeric mixture (94:6 dr); H NMR (300 MHz, CDCl ) (as
major isomer): δ 9.51 (s, 1H), 7.26−7.15 (m, 1H), 7.11−7.02 (m,
major isomer): δ 9.53 (s, 1H), 7.43−7.36 (m, 1H), 7.28 (t, J = 1.8 Hz,
1H), 7.20 (t, J = 7.8 Hz, 1H), 7.09−7.03 (m, 1H), 5.13 (d, J = 3.5 Hz,
1H), 4.79 (s, 1H), 3.78 (t, J = 3.6 Hz, 1H), 3.59 (dd, J = 12.2, 3.9 Hz,
1H), 3.35 (d, J = 12.2 Hz, 1H) ppm; 13C{ H} NMR (101 MHz,
1
3
1
G
DOI: 10.1021/acs.joc.5b01607
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
CDCl ) (as major isomer): δ 192.0, 143.6, 131.4, 131.0, 129.7, 125.4,
(ESI-TOF) m/z: [M + H] Calcd for C H NO S 240.0325, Found
10 10 4
3
1
23.4, 66.4, 52.9, 52.7, 36.4, 32.7 ppm; HRMS (ESI-TOF) m/z: [M +
240.0330; HPLC conditions: Lux Cellulose-1, n-hexane/i-PrOH =
+
−1
H] Calcd for C H BrNO S 327.9643, Found: 327.9650; HPLC
conditions: Chiralpak ID, n-hexane/i-PrOH = 40:60, flow rate = 0.5
mL min , λ = 230 nm, 25 °C, t = 13.53 (minor), 14.78 (major),
70:30, flow rate = 1 mL min , λ = 210 nm, 25 °C, t = 20.36 (minor),
12
11
3
R
22.54 (major), 80:20 er.
−1
(1R,2R,5S,6R)-6-Nitro-2-phenyl-3-thiabicyclo[3.1.0]hexane-1-car-
baldehyde (9p). Column chromatography with 5:1 cyclohexane/
EtOAc afforded the orange oil 9p as a diastereomeric mixture (93:7
R
8
7:13 er (for major isomer).
+)-(1R,2R,5S,6R)-2-(4-Bromophenyl)-6-nitro-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9k). Column chromatography with 7:1
(
dr) slightly contaminated by uncharacterized byproducts (48 mg,
20
1
cyclohexane/EtOAc afforded 9k (45 mg, 27%) as a yellow oil. [α]D
5
7
+
31%); H NMR (300 MHz, CDCl
3
) (as major isomer): δ 9.51 (s, 1H),
1
0.9 (c 0.67, CHCl ); H NMR (300 MHz, CDCl ): δ 9.51 (s, 1H),
7.38−7.21 (m, 3H), 7.18−7.10 (m, 2H), 5.13 (d, J = 3.5 Hz, 1H), 4.86
3
3
.48−7.42 (m, 2H), 7.05−6.98 (m, 2H), 5.13 (d, J = 3.5 Hz, 1H), 4.82
(s, 1H), 3.74 (t, J = 3.4 Hz, 1H), 3.59 (dd, J = 12.1, 3.9 Hz, 1H), 3.34
(d, J = 12.1 Hz, 1H) ppm; 13C{ H} NMR (101 MHz, CDCl
1
) (as
(
(
s, 1H), 3.76 (t, J = 3.6 Hz, 1H), 3.57 (dd, J = 12.2, 3.9 Hz, 1H), 3.36
3
d, J = 12.2 Hz, 1H) ppm; 13C{ H} NMR (101 MHz, CDCl ): δ
1
major isomer): δ 192.1, 141.3, 129.5, 128.3, 126.8, 66.5, 53.5, 52.8,
3
36.5, 32.6 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
1
91.8, 140.3, 132.5, 128.3, 122.1, 66.2, 52.8, 52.6, 36.2, 32.6 ppm;
+
C H NO S 250.0538, Found 250.0544.
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H BrNO S
3
hexane/i-PrOH = 50:50, flow rate = 1 mL min , λ = 210 nm, 40 °C,
tR = 11.11 (minor), 9.15 (major), 93:7 er.
12 12
3
1
2
11
3
Synthetic Procedure for the Preparation of Mosher Esters
27.9637, Found 327.9626; HPLC conditions: Lux Cellulose-1, n-
−1
16 and 17. To a cooled (0 °C) solution of 9o (30 mg, 0.12 mmol) in
MeOH (0.7 mL), NaBH (6 mg, 0.16 mmol) was added, and the
4
reaction mixture was vigorously stirred for 1 h at room temperature.
The solvent was then removed in vacuo, and the crude product
(+)-(1R,2R,5S,6R)-2-(4-Chlorophenyl)-6-nitro-3-thiabicyclo[3.1.0]-
hexane-1-carbaldehyde (9l). Column chromatography with 4:1
cyclohexane/EtOAc afforded 9l (53 mg, 30%) as an orange oil.
dissolved in CH Cl (3 mL). (S)-Mosher acid 15 (35 mg, 0.15 mmol),
2
2
α]D20 + 54.9 (c 2.21, CHCl ); H NMR (300 MHz, CDCl ): δ 9.51
1
DCC (37 mg, 0.18 mmol), and a catalytic amount of DMAP were
sequentially added. The reaction mixture was left to stand at room
temperature for 48 h, then filtered and evaporated. Purification of the
crude residue by flash-chromatography (6:1 petroleum ether/EtOAc)
gave esters 16 and 17 (41 mg, 75% overall yield).
[
3
3
(
1
1
s, 1H), 7.33−7.26 (m, 2H), 7.11−7.04 (m, 2H), 5.13 (d, J = 3.5 Hz,
H), 4.83 (s, 1H), 3.76 (t, J = 3.7 Hz, 1H), 3.58 (dd, J = 12.1, 3.9 Hz,
13
1
H), 3.36 (d, J = 12.1 Hz, 1H) ppm; C{ H} NMR (101 MHz,
CDCl ): δ 192.0, 139.9, 134.1, 129.6, 128.1, 66.4, 52.8, 52.5, 36.3, 32.7
ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for C H ClNO S
2
hexane/i-PrOH = 50:50, flow rate = 1 mL min , λ = 240 nm, 40 °C,
tR = 10.54 (minor), 8.90 (major), 92:8 er.
3
+
(+)-(S)-{(1R,2S,5S,6R)-2-(Furan-2-yl)-6-nitro-3-thiabicyclo[3.1.0]-
12
11
3
hexan-1-yl}methyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
84.0143, Found 284.0149; HPLC conditions: Lux Cellulose-1, n-
20
1
(
16). White amorphous solid; [α]D + 80.5 (c 1.0, CHCl ); H
3
−1
NMR (300 MHz, CDCl ): δ 7.45−7.34 (m, 6H), 6.32 (dd, J = 3.2, 1.9
3
Hz, 1H), 6.13−6.04 (m, 1H), 5.00 (d, J = 3.1 Hz, 1H), 4.70 (d, J =
(
+)-(1R,2R,5S,6R)-6-Nitro-2-[2-(trifluoromethyl)phenyl]-3-
1
2.7 Hz, 1H), 4.61 (s, 1H), 4.19−4.11 (m, 1H), 3.59 (dt, J = 16.6, 8.3
thiabicyclo[3.1.0]hexane-1-carbaldehyde (9m). Column chromatog-
raphy with 4.5:1 cyclohexane/EtOAc afforded 9m (69 mg, 35%) as an
amorphous orange solid. [α]D + 78.8 (c 3.54, CHCl ); H NMR
13 1
Hz, 1H), 3.44 (d, J = 1.1 Hz, 3H), 3.23−3.09 (m, 2H) ppm; C{ H}
NMR (101 MHz, CDCl ): δ 165.7, 152.5, 143.1, 131.8, 129.7, 128.5,
1
6
CDCl ): δ − 71.9 ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for
C H F NO S 458.0879, Found 458.0886.
20
1
3
3
1
2
27.3, 123.6 (q, J = 287 Hz), 110.5, 108.0, 84.7 (q, J = 28 Hz),
C−F C−F
(
300 MHz, CDCl ): δ 9.53 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.53 (t, J
3
19
2.7, 61.4, 55.4, 47.9, 43.6, 35.9, 33.0 ppm; F NMR (376 MHz,
=
7.6 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.26
+
3
(
1
s, 1H), 5.21 (d, J = 3.6 Hz, 1H), 3.85 (t, J = 3.6 Hz, 1H), 3.54 (dd, J =
2.3, 3.8 Hz, 1H), 3.35 (d, J = 12.3 Hz, 1H) ppm; 13C{ H} NMR (101
1
20 19
3
6
(
−)-(S)-{(1S,2R,5R,6S)-2-(Furan-2-yl)-6-nitro-3-thiabicyclo[3.1.0]-
2
MHz, CDCl ): δ 191.6, 140.6, 133.0, 128.0, 127.3 (q, J
1
4
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H F NO S
3
hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ = 210 nm, 25 °C,
tR = 14.21 (minor), 22.14 (major), 94:6 er.
= 30 Hz),
3
C−F
hexan-1-yl}methyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
3
1
27.0, 126.7 (q, J
= 5.6 Hz), 124.2 (q, J
= 274 Hz), 66.2, 52.6,
7.9, 36.7, 32.1 ppm; F NMR (376 MHz, CDCl ): δ − 58.1 ppm;
20
C−F
C−F
(17). White solid, mp 128−129 °C (EtOAc); [α] − 109.8 (c 1.0,
D
19
1
3
CHCl ); H NMR (300 MHz, CDCl ): δ 7.46−7.33 (m, 6H), 6.24
3
3
+
13
11
3
3
(dd, J = 3.2, 1.9 Hz, 1H), 5.78 (d, J = 3.2 Hz, 1H), 5.03 (d, J = 3.0 Hz,
18.0406, Found 318.0403; HPLC conditions: Lux Cellulose-1, n-
1
H), 4.54 (d, J = 2.5 Hz, 2H), 4.12 (d, J = 12.7 Hz, 1H), 3.60 (dd, J =
−1
1
1.6, 3.7 Hz, 1H), 3.44 (d, J = 1.0 Hz, 3H), 3.16 (dd, J = 8.7, 5.7 Hz,
13
1
2H) ppm; C{ H} NMR (101 MHz, CDCl ): δ 165.8, 152.2, 143.0,
3
1
(
+)-(1R,2R,5S,6R)-6-Nitro-2-[3-(trifluoromethyl)phenyl]-3-
1
8
31.9, 129.7, 128.5, 127.1, 123.2 (q, J
4.5 (q, J = 28 Hz), 62.7, 61.6, 55.5, 47.7, 43.5, 35.8, 33.0 ppm;
= 287 Hz), 110.5, 108.1,
C−F
thiabicyclo[3.1.0]hexane-1-carbaldehyde (9n). Column chromatog-
raphy with 4.5:1 cyclohexane/EtOAc afforded 9n (53 mg, 27%) as a
yellow oil. [α]D + 44.1 (c 1.26, CHCl ); H NMR (300 MHz,
2
19
F
C−F
NMR (376 MHz, CDCl ): δ − 71.5 ppm; HRMS (ESI-TOF) m/z:
3
20
1
+
3
[M + H] Calcd for C H F NO S 458.0879, Found 458.0882.
20
19
3
6
CDCl ): δ 9.53 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz,
3
Crystal Structure Determinations. X-ray diffraction suitable
single crystals of 17 were obtained by slow evaporation of an EtOAc
solution at room temperature. The crystal data of compound 17 were
collected at room temperature using a diffractometer with graphite
monochromated Mo−Kα radiation.
1
4
3
1
3
5
H), 7.38 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.18 (d, J = 3.4 Hz, 1H),
.90 (s, 1H), 3.83 (t, J = 3.6 Hz, 1H), 3.61 (dd, J = 12.2, 3.8 Hz, 1H),
.39 (d, J = 12.2 Hz, 1H) ppm; C{ H} NMR (101 MHz, CDCl ): δ
1
3
1
3
2
3
91.8, 142.5, 131.8 (q, J
= 32 Hz), 130.1, 130.0, 125.1 (q, J
= 271 Hz), 123.5 (q, J
=
C−F
C−F
1
3
31
.7 Hz), 123.8 (q, J
= 3.7 Hz), 66.3,
C−F
C−F
The data sets were integrated with the Denzo-SMN package and
1
9
3.0, 52.8, 36.3, 32.8 ppm; F NMR (376 MHz, CDCl ): δ − 63.0;
3
corrected for Lorentz and polarization effects. The structure was
+
32
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H F NO S
13
11
3
3
solved by direct methods using SIR97 system of programs and
3
18.0406, Found 318.0403; HPLC conditions: Lux Cellulose-1, n-
refined using full-matrix least-squares with all non-hydrogen atoms
anisotropically and hydrogens included on calculated positions, riding
on their carrier atoms. All calculations were performed using SHELXL-
−1
hexane/i-PrOH = 70:30, flow rate = 1 mL min , λ = 210 nm, 25 °C,
tR = 18.92 (minor), 14.13 (major), 93:7 er.
3
3
34
(
+)-(1R,2S,5S,6R)-2-(Furan-2-yl)-6-nitro-3-thiabicyclo[3.1.0]-
97 implemented in WINGX system of programs.
hexane-1-carbaldehyde (9o). Column chromatography with 9:1
cyclohexane/EtOAc afforded the pure red brick oil 9o and an
unseparable mixture of 9o and its diastereomer (40 mg, 27%
ASSOCIATED CONTENT
■
combined yield). [α]D20 + 74.4 (c 0.76, CHCl ); H NMR (300
1
*
Supporting Information
S
3
MHz, CDCl ): δ 9.57 (s, 1H), 7.31 (d, J = 1.4 Hz, 1H), 6.31 (dd, J =
3
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01607.
3
1
.3, 1.9 Hz, 1H), 6.22−6.18 (m, 1H), 5.14 (d, J = 3.5 Hz, 1H), 4.93 (s,
H), 3.68 (t, J = 3.7 Hz, 1H), 3.61 (dd, J = 11.7, 3.8 Hz, 1H), 3.26 (d,
13
1
Table S1 (screening of route A), Table S2 (re-
examination and optimization of the organocatalytic
J = 11.7 Hz, 1H) ppm; C{ H} NMR (101 MHz, CDCl ): δ 191.7,
3
152.3, 142.6, 110.8, 107.2, 65.7, 50.4, 45.8, 36.0, 32.2 ppm; HRMS
H
DOI: 10.1021/acs.joc.5b01607
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
domino sulfa-Michael/aldol condensation reaction),
Figure S3 (ORTEP/X-ray view of compound 17), copies
Asymmetric Synthesis; Alexakis, A., Krause, N., Woodward, S., Eds.;
Wiley-VCH: Weinheim, 2014; pp 203−238. (b) Bartoli, G.;
Bencivenni, G.; Dalpozzo, R. Synthesis 2014, 46, 979−1029.
1
13
19
of H, C, F NMR spectra, and HPLC chromatograms
PDF)
X-ray crystallographic data (CIF)
PDF)
(
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(
9
(
̈
1
(
AUTHOR INFORMATION
Corresponding Author
E-mail: drc@unife.it.
■
Angew. Chem., Int. Ed. 2010, 49, 486−488. (b) Doyle, M. P. Angew.
Chem., Int. Ed. 2009, 48, 850−852.
*
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2
612.
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Lett. 2013, 54, 283−286.
14) Monn, J. A.; Massey, S. M.; Valli, M. J.; Henry, S. S.;
Stephenson, G. A.; Bures, M.; Herin, M.; Catlow, J.; Giera, D.; Wright,
Notes
(
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
́
Grateful thanks are due to University of Ferrara (Fondi FAR)
for financial support. Thanks are also given to Mr. P. Formaglio
and Mr. A. Casolari for NMR spectroscopic experiments.
R. A.; Johnson, B. G.; Andis, S. L.; Kingston, A.; Schoepp, D. D. J. Med.
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DOI: 10.1021/acs.joc.5b01607
J. Org. Chem. XXXX, XXX, XXX−XXX