Organocatalytic Michael addition to (D)-mannitol-derived enantiopure nitroalkenes: A valuable strategy for the synthesis of densely functionalized chiral molecules

Article abstract of DOI:10.3390/molecules24244588

Carbohydrates are abundant renewable resources and are a feedstock for green chemistry and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass, mannitol was selected in the present project as a valuable platform, directly available from the chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic Michael addition of dimethyl malonate, β-keto esters, and other nucleophiles on the nitro alkene afforded high stereoselectivity and densely functionalized chiral molecules, which were further synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation of enantiomerically pure organic molecules from the chiral pool.

Full text of DOI:10.3390/molecules24244588

molecules
Article
Organocatalytic Michael Addition to
D)-Mannitol-Derived Enantiopure Nitroalkenes:
(
A Valuable Strategy for the Synthesis of Densely
Functionalized Chiral Molecules
Lucia Caruso, Alessandra Puglisi , Emmerance Gillon and Maurizio Benaglia *
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy;
lucia.caruso@unimi.it (L.C.); alessandra.puglisi@unimi.it (A.P.); emmerance.gillon@student.uclouvain.be (E.G.)
*
Correspondence: Maurizio.benaglia@unimi.it; Tel.: +2-5031-4171
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Alessandro Palmieri
Received: 28 October 2019; Accepted: 12 December 2019; Published: 14 December 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Carbohydrates are abundant renewable resources and are a feedstock for green chemistry
and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass,
mannitol was selected in the present project as a valuable platform, directly available from the
chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene
glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral
nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic
Michael addition of dimethyl malonate, β-keto esters, and other nucleophiles on the nitro alkene
afforded high stereoselectivity and densely functionalized chiral molecules, which were further
synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies
showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under
continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation
of enantiomerically pure organic molecules from the chiral pool.
Keywords: nitro alkenes; stereoselective synthesis; renewable sources; organocatalysis; chiral molecules
1
. Introduction
Efficient use of resources is the key to realizing sustainable growth through the development of
new technologies with low environmental impact [1]. This will also lead to the creation of new jobs [2].
In this framework, one of the challenges is the replacement of nonrenewable carbon sources, such as
oil, by alternative renewable sources, including biomass, which is gaining increasing attention as a
source of energy [3].
New chemistry has to be developed in order to convert natural starting materials into a variety of
chemicals comparable to the oil-derived ones. Such an effort asks for fundamental research covering a
novel series of synthetic transformations from bio-based building blocks. For instance, rather than the
functionalization of hydrocarbon-derived intermediates, the defunctionalization of easily available and
redundantly functionalized natural building blocks will become critical. An innovative series of fine
chemicals, endowed with similar or improved properties (e.g., better biodegradability), will emerge
from these studies [4].
Seventy-five percent of biomass is carbohydrates and only 3–4% is used by industry. Sugars are
the most abundant renewable resources and they are seen as the feedstock for green chemistry of the
future. [5]
In this work, we selected 1,2:5,6-Di-O-cyclohexylidene-protected D-mannitol as a valuable
enantiopure starting material for the preparation of chiral compounds [6]. D-mannitol has found
Molecules 2019, 24, 4588; doi:10.3390/molecules24244588
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extensive use in organic synthesis and it been employed for the synthesis of chiral ligands [
7],
organocatalysts [ ], and in total synthesis [ ]. In our study, we exploited D-mannitol for the synthesis
8
9
of an enantiomerically pure nitro alkene. Such compounds have recently attracted a lot of attention
due to their synthetic versatility: nitroalkanes are direct precursors of amines [10] and may be used
as nucleophiles, while nitro alkenes are excellent electrophilic reagents and reactive dienophiles in
cycloaddition reactions; the role of the nitro group as a hydrogen bond acceptor to guarantee an
efficient mutual reagent/catalyst recognition has been extensively exploited in several organocatalytic
transformations [11].
Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, easily prepared on a large scale from
D-mannitol, enantiopure chiral nitro alkenes may be obtained by reaction with nitroalkanes, and
their reactivity explored to synthesize functionalized molecules featuring tertiary and quaternary
stereocenters, as seen in Scheme 1.
Scheme 1. D-Mannitol-derived chiral nitro alkenes and their reactivity.
2
. Results and Discussion
This article reports the catalytic Michael addition of dimethyl malonate and methyl phenylacetylacetate
to the known sugar nitro olefin
following a known procedure (see experimental section). The reduction of the carbon–carbon double
bond to the corresponding nitroalkane was also accomplished with sodium borohydride and silica in
2, which was obtained from (R)-2,3-O-cyclohexylidene glyceraldehyde 1
3
a nonoptimized 55% yield, as seen in Scheme 2.
We started our investigation on the reactivity of nitro olefin 2 by studying the catalytic Michael
addition of dimethyl malonate
mixture 5a 5b resulted (45/55 ratio, determined by H-NMR), confirming that the malonate addition is
poorly stereocontrolled by the stereocenter of the starting compound 2, as seen in Scheme 2.
4 in the presence of an achiral base (triethylamine, TEA). A diastereomeric
–

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Scheme 2. Stereoselective catalytic Michael malonate addition to nitroalkene 2.
In order to improve the diastereoselectivity, a catalytic version of this Michael addition was
assayed, using Takemoto’s catalyst [12]. The reaction promoted by the (S,S)-catalyst afforded the
expected mixture 5a
the catalyst was used, the Michael adduct mixture 5a
–
5b in high yield (87%) and 86/14 isomeric ratio. When the (R,R) enantiomer of
5b was isolated in 91% yield and 12/88 ratio,
–
with opposite diastereofacial selectivity. The absolute configuration of the two isomers was assigned
based on the stereofacial preference of Takemoto catalyst, as reported in the literature and taking into
account that the configuration of the nitroalkene is (S).
Other thiourea-based catalysts, such as Jacobsen-type catalysts, were less active, highlighting the
need of a basic site in the bifunctional catalyst in order to efficiently promote the Michael addition to
such nitroalkenes.
The reaction between the
either with TEA or the chiral Takemoto catalyst, the reaction afforded the adduct
51% and 70%, respectively) as a mixture of isomers; however, due to the presence of an additional
β-ketoester
6
and nitroalkene
2
was also preliminarily investigated;
7
in good yields
(
stereocenter, it was not possible to unambiguously determine the isomeric ratio, as seen in Scheme 3.
Deprotection of the diol in the presence of water and trifluoroacetic acid [13] led to the formation of
compound
8, which is currently under investigation as a starting material for several transformations
(hydrolysis, decarboxylation, nitro reduction, intramolecular reductive amination).

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Scheme 3. Stereoselective catalytic Michael addition of β-keto ester 6 to nitroalkene 2.
Beyond the
nitroalkene
73% yield), as seen in Scheme 4. We obtained the diastereoisomers 10a
comparable to that reached in the reaction shown in Scheme 2.
β
-ketoester
6
, we also studied the addition of the diketone acetylacetone
9
to the
2
in presence of the same (S,S)-Takemoto catalyst and the reaction worked quite well
in 82/18 ratio, which is
(
,b
Scheme 4. Stereoselective catalytic Michael addition of acetylacetone 9 to nitroalkene 2.
Finally, further reactions were studied for the catalytic Michael addition reaction on the same
substrate
2 by employing nitromethane as the nucleophile, but under the present experimental
conditions, only a very small amount of addition product was detected and the starting material
was almost quantitatively recovered. However, by adding a stoichiometric amount of triethylamine,
the reaction produced a 70% nonoptimized yield, but with only very moderate diastereoselectivity.
Further studies are needed with other catalysts in order to address the issue of the observed lack of
reactivity of nitroalkanes.
Synthetic elaboration of adduct
5 was more successful and led to the formation of valuable,
enantiopure cyclic derivatives, as seen in Scheme 5.
Scheme 5. Synthetic elaboration of adduct 5 to lactone 12 and lactam 13.

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Starting from isomer 5a, the reaction with aqueous trifluoroacetic acid directly afforded enantiopure
lactone 12 in 65% yield. The structural characterization was performed by ESI mass spectrometry,
1
13
1
13
1
1
H NMR, C NMR, H- C HSQC, and H- H COSY.
The reduction of the nitro group of lactone 12 was accomplished by catalytic hydrogenation,
by performing the reaction in methanol and in the presence of acetic acid under continuous flow
conditions [14]. A ThalesNano H-Cube® mini was used in recirculating mode, with a cartridge of
Pd/C (10%) catalyst, operating at hydrogen pressure of 15 bar, a flow rate of 1 mL/min, and a stable
◦
temperature of 35 C. The reaction was monitored by TLC and showed complete conversion after
3
h. It was observed that the reduction was followed by a spontaneous lactamization to afford the
five-membered bicyclic lactam 13. The relative configuration was confirmed by NMR analysis.
Considering the rising interest in the in-flow preparation of APIs [15 17], based on these results
–
and with the aim to further accelerate the reaction, we explored the possibility of developing a
continuous flow method for the organocatalytic Michael addition to nitroalkene 2 [18].
Therefore, the Michael addition of the dimethylmalonate to nitroalkene
2 was studied in flow
®
conditions using a Labtrix Start by Chemtrix provided with a 15
µL glass microreactor, heated at
◦
8
0 C, as seen in Scheme 6. A 1 M nitroalkene solution in toluene in syringe A and the dimethyl
malonate and Takemoto’s catalyst solution of syringe B were pumped into the reactor. A total flow rate
of 1 L/min and a residency time of 15 min in the reactor were obtained. Under the present conditions,
the Michael adduct was isolated in very low yield (<10%). However, better results were observed
in the reaction of the -ketoester ; operating at the same experimental conditions, product was
µ
β
6
7
isolated in 45% yield. Further work is needed to optimize the reaction conditions and to find the correct
parameters to successfully perform the malonate addition to nitroalkene, for example, by introducing
a premixing phase of the catalyst and the reagents. Although very preliminary, the present results
show that the use of microfluidic devices is indeed viable in the synthesis of highly functionalized
chiral molecules.
Scheme 6. Continuous flow organocatalytic β-ketoester 6 addition to nitroalkene 2 in a microreactor.
3
. Materials and Methods
Reactions were monitored by analytical thin-layer chromatography (TLC) using silica gel 60 F254
precoated glass plates (0.25 mm thickness) and visualized using UV light. Most of the products are
UV-visible; KMnO solution was used to stain the TLC plates and detect compounds 4, 9, and 13. Flash
4
chromatography was carried out on silica gel (230–400 mesh). Proton NMR spectra were recorded on
spectrometers operating at 300 MHz (Bruker Fourier 300); proton chemical shifts are reported in ppm
(
δ
) with the solvent reference relative to tetramethylsilane (TMS) employed as the internal standard
(
CDCl3
δ
= 7.26 ppm). 13C-NMR spectra were recorded on 300 MHz spectrometers (Bruker Fourier 300)
operating at 75 MHz, with complete proton decoupling; carbon chemical shifts are reported in ppm (
δ)
relative to TMS with the respective solvent resonance as the internal standard (CDCl3 = 77.0 ppm).
δ

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Mass spectra and accurate mass analysis were carried out on a VG AUTOSPEC-M246 spectrometer
double-focusing magnetic sector instrument with EBE geometry) equipped with EI source or with
(
LCQ Fleet ion trap mass spectrometer, ESI source, with acquisition in positive ionization mode in the
mass range of 50–2000 m/z. For the flow experiments, a Chemtrix Labtrix® Start Standard platform
equipped with a Chemyx Fusion 100 syringe pump and two Hamilton gastight syringes was used.
3
.1. General Procedure for the Synthesis of (R)-Cyclohexylideneglyceraldehyde 1
The 1,2:5,6-Di-O-cyclohexylidene-D-mannitol (2.00 g, 5.85 mmol) and NaIO (1.25 g, 5.86 mmol)
4
◦
were added in 13 mL of H O and 25 mL of EtOAc. The solution was stirred for 3 h at 35 C [19].
2
The reaction mixture was extracted with 3
×
20 mL EtOAc and dried over Na SO . After evaporation
2 4
under reduced pressure, the combined organic filtrates were carefully concentrated in vacuo and the
crude mixture was purified by distillation under reduced pressure (approximately 20 mbar) and at
◦
1
a temperature of 90 C, to yield a colorless oil as product (1.99 g, 99%). H NMR (300 MHz, CDCl )
3
δ
9.73 (d, J = 1.7 Hz, 1H), 4.39 (m, 1H), 4.17 (dd, J = 8.8, 7.3 Hz, 1H), 4.10 (dd, J = 8.8, 4.8 Hz, 1H),
1
.72–1.53 (m, 8H), 1.49–1.37 (m, 2H).
3
.2. General Procedure for the Synthesis of (E)-2-(2-Nitrovinyl)-1,4-Dioxaspiro [4.5] Decane 2
TEA (0.270 mL, 1.936 mmol) was added to an ice cooled solution of nitromethane (2.00 mL,
3
9
7.3 mmol). After 15 min, (R)-Cyclohexylideneglyceraldehyde
.00 mL of nitromethane was added dropwise over a period of 15 min. The reaction mixture was
1 (1.99 g, 11.7 mmol) dissolved in
allowed to reach room temperature (RT) and stirred for 21 h. The excess nitromethane was removed
under reduced pressure. The crude mixture is then purified by column chromatography on silica
gel (hexane/EtOAc = 3/7 as eluent, KMnO stained) [20]. After removing the solvents under reduced
4
pressure, a yellow oil was obtained (2.55 g, 94%). The nitro aldols are afforded as diastereoisomeric
1
ratio 1/10. H NMR (300 MHz, CDCl )
δ 4.78 (dd, J = 7.2, 2.2 Hz, 1H, minor), 4.70 (dd, J = 13.9, 2.3 Hz,
3
1
H, major), 4.66–4.51 (m, 1H, minor), 4.54–4.40 (m, 1H, major), 4.38–4.30 (m, 1H, minor), 4.25–4.17 (m, 1H,
major), 4.17–4.08 (m, 2H, both isomers), 4.05–3.92 (m, 4H, both isomers), 1.66–1.49 (m, 16H, both isomers),
1
1
.45–1.33 (m, 4H, both isomers). To a solution of 2-nitro-1-(1,4-dioxaspiro[4.5]decan-2-yl)ethanol (2.55 g
,
◦
1.0 mmol) in 5.50 mL of dry DCM at
−30 C was added MsCl (1.80 mL, 23.3 mmol), followed by
the addition of TEA (3.40 mL, 24.4 mmol) over a period of 30 min. After 15 min H O was added
2
to the reaction mixture and the organic phase was extracted with 3
×
DCM, washed with brine and
dried over Na SO . The solvents were removed under reduced pressure. The crude mixture was then
2
4
purified by column chromatography on silica gel (hexane/EtOAc = 8/2 as eluent, KMnO stained).
4
After evaporation of the solvents under reduced pressure, a yellow oil was obtained (1.04 g, 44%);
1
H NMR (300 MHz, CDCl3) δ 7.21 (s, 2H), 4.79 (td, J = 6.7, 2.1 Hz, 1H), 4.26 (dd, J = 8.4, 6.8 Hz, 1H),
3
.76 (dd, J = 8.4, 6.6 Hz, 1H), 1.71–1.54 (m, 8H), 1.47–1.36 (m, 2H) [21].
3
.3. General Procedure for the Synthesis of 2-(2-Nitroethyl)-1,4-Dioxaspiro[4.5]decane 3
To a stirred mixture of the nitro alkene (0.215 g, 1.01 mmol), silica gel (2.01 g), 3 mL of i-PrOH,
1
1
6 mL of chloroform was added NaBH (0.173 g, 4.56 mmol) in 40.0 mg portions over a period of
4
5 min at RT. The mixture was stirred for additional 15 min. Excess NaBH was decomposed with
4
dilute aqueous HCl solution and the mixture was filtered. The filter was washed with DCM and the
combined filtrates were washed with brine, dried over Na SO , and then evaporated in vacuo to
2
4
1
dryness to give the nitro alkane as an orange oil (0.0763 g, 35%). H NMR (300 MHz, CDCl )
(
(
δ
4.54
t, J = 7.4 Hz, 2H), 4.23–4.13 (m, 1H), 4.09 (dd, J = 8.1, 6.1 Hz, 1H), 3.60 (dd, J = 8.1, 6.0 Hz, 1H), 2.32
m, 1H), 2.20–2.03 (m, 1H), 1.63–1.51 (m, 8H), 1.44–1.32 (m, 2H).
3

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3
.4. General Procedure for the Synthesis of Dimethyl 2-(2-nitro-1-((S)-1,4-Dioxaspiro[4.5]Decan-2-
yl)Ethyl)Malonate 5a/5b
To a stirred solution of dimethyl malonate (600 µL, 5.24 mmol) and Takemoto catalyst (0.109 g,
10% mol, 0.264 mmol) in 5 mL of dry toluene was added nitro alkene (0.557 g, 2.61 mmol) at RT.
After being stirred for 24 h, the reaction mixture was concentrated in vacuo. The thiourea catalyst
was eliminated through a short silica pad (DCM as eluent) and the excess of dimethyl malonate was
removed by heating the flask under reduced pressure. An orange oil was obtained (KMnO stained,
4
1
0
.901 g, 86%). H NMR (300 Mhz, CDCl )
δ
4.76 (dd, J = 14.8, 5.7 Hz, 1H), 4.67 (dd, J = 14.8, 5.0 Hz,
3
1
6
(
H), 4.28 (q, J = 6.3 Hz, 1H), 4.11 (dd, J = 8.7, 6.5 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.72 (dd, J = 8.7,
.1 Hz,1H), 3.62 (d, J = 5.2 Hz, 1H), 3.18 (J = 5.3 Hz, 1H), 1.62–1.46 (m, 8H), 1.42–1.30 (m, 2H). 13C NMR
300 Mhz, CDCl3) 168.35, 168.04, 110.08, 74.41, 74.15, 66.59, 52.82, 52.48, 49.68, 39.97, 35.71, 34.21,
δ
2
4.91, 23.78, 23.54; HRMS (ESI+) requires 345.1424, found 345.14104.
3.5. General Procedure for the Synthesis of Ethyl 2-benzoyl-4-nitro-3-((S)-1,4-dioxaspiro[4.5]decan-
2-yl)butanoate 7
To a stirred solution of ethyl 3-oxo-3-phenylpropanoate (1.30 mL, 6.52 mmol) and Takemoto
catalyst (0.135 g, 10% mol, 0.326 mmol) in 6.58 mL of dry toluene was added nitro alkene (0.6952 g,
.26 mmol) at RT. After being stirred for 24 h, the reaction mixture was concentrated in vacuo. Then the
3
reaction mixture was purified by flash column chromatography on silica gel (eluent: hexane/AcOEt
1
8
/3) obtaining a yellow oil (1.13 g, 85%). H NMR (300 MHz, CDCl )
δ
8.02 (dd, 1H), 7.76–7.41 (m, 4H)
,
3
5
(
7
.09–4.63 (m, 2H), 4.35–3.98 (m, 4H), 3.74–3.60 (m, 2H), 3.31 (m, 1H), 1.68–1.41 (m, 10H), 1.27–1.13
194.52, 168.20, 136.42, 135.50, 134.03, 133.93, 128.89, 111.29,
5.21, 74.72, 67.04, 62.16, 51.74, 40.89, 34.53, 24.97, 23.83, 13.82. HRMS (ESI+) requires 405.1788,
m, 3H). 13C NMR (300 MHz, CDCl3)
δ
found 405.17742.
3
.6. General Procedure for the Synthesis of (4S)-ethyl 2-benzoyl-4,5-dihydroxy-3-(nitromethyl)pentanoate 8
In a one-necked flask, a mixture of Ethyl 2-benzoyl-4-nitro-3-((S)-1,4-dioxaspiro[4.5]decan-2-
yl)butanoate
Trifluoroacetic acid (600
7
(0.672 g, 1.66 mmol) in equal volumes of water and tetrahydrofuran was stirred.
L, 7.78 mmol) was then added and the reaction mixture was stirred at RT
µ
until the disappearance of the substrate. After the evaporation of the solvents under reduced pressure,
the crude mixture was purified by flash column chromatography on silica gel (eluent: exhane/AcOEt
=
7/3). The product was obtained as colorless liquid (0.175 g, 32%). The product is in the enol form,
1
13
as suggested by the lack of one proton signal in the H NMR and the signal at 100.89 ppm in the
NMR spectra. H NMR (300 MHz, CDCl )
C
1
δ 7.78–7.70 (m, 2H), 7.53–7.35 (m, 3H), 4.98 (dd, J = 11.6,
3
5
(
1
.8 Hz, 1H), 4.80 (dd, J = 9.8, 4.8 Hz, 1H), 4.58 (dd, J = 13.3, 9.8 Hz, 1H), 4.21–4.15 (m, 2H), 4.15–4.10
m, 2H), 3.96 (m, 1H), 1.23 (t, J = 11.5 Hz, 3H). 13C NMR (75 MHz, CDCl3)
167.64, 164.11, 131.13, 129.50,
29.10, 127.71, 100.89, 85.32, 64.02, 60.46, 44.42, 29.68, 14.03. ESI-MS requires 325.1162, found 308.1134.
δ
3
.7. General Procedure for the Synthesis of 3-((R)-2-nitro-1-((S)-1,4-dioxaspiro[4.5]decan-2-
yl)ethyl)pentane-2,4-dione 10
To a stirred solution of acetylacetone 9 (96.81 mL, 0.938 mmol) and Takemoto catalyst (19.39 mg,
◦
1
0% mol, 0.469 mmol) in 1 mL of dry toluene was added nitro alkene
2
(100 mg, 0.469 mmol) at 35 C.
After being stirred for 24 h, the reaction mixture was concentrated in vacuo. Then the reaction crude
was purified by flash column chromatography obtaining a yellow oil (hexane/EtOAc 4:1, 70% yield).
1
H NMR (300 MHz, CDCl3)
δ 4.61 (dd, J = 13.7, 5.8 Hz, 1H), 4.47 (dd, J = 13.7, 3.5 Hz, 1H), 4.09 (td,
J = 13.7, 6.0 Hz, 2H), 3.64 (t, J = 6.9 Hz, 1H), 3.06 (s, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.52 (t, J = 30.8 Hz,
0H); 13C NMR (75 MHz, CDCl3)
203.01, 202.09, 110.52, 74.95, 74.39, 67.54, 66.28, 40.87, 36.04, 34.65,
1.09, 30.08, 29.67, 24.95, 23.89, 23.71. ESI-MS requires 313.1525, found 313.1527.
1
δ
3

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3
5
2
.8. General Procedure for the Synthesis of (5S)-methyl
-(hydroxymethyl)-4-(nitromethyl)-2-oxotetrahydrofuran-3-carboxylate 12 A solution of Dimethyl
-(2-nitro-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)ethyl)malonate 5a/5b
(
0.239 g, 0.692 mmol) in TFA (230 µL, 3.00 mmol), 0.45 mL of H O, and 0.45 mL of THF was stirred
2
at RT for 3 h. Then the reaction mixture was evaporated under reduced pressure. The crude mixture was
purified by column chromatography on silica gel (hexane/EtOAc = 3/7 as eluent). After evaporation
1
of the solvent under reduced pressure, an orange oil is obtained (0.106 g, 65%). H NMR (300 MHz,
CD OD) δ 4.79 (dd, J = 9.2, 3.5 Hz, 2H), 4.40–4.34 (m, 1H), 3.86 (dd, J = 12.7, 3.3 Hz, 1H), 3.79 (s, 3H), 3.71
3
13
(
6
dd, J = 12.7, 4.2 Hz, 1H), 3.65–3.55 (m, 1H); C NMR (75 MHz, CD OD) δ 170.83, 167.75, 80.97, 74.67,
3
0.87, 52.06, 38.37; HRMS (ESI+) requires 233.0536, found 203.19810 [(M -CH OH)]. The compound
2
+
was also fully characterized using CD CN as a solvent; the J values showed a trans-trans configuration
3
1
of the protons on the cycle (see Supplementary Materials). H NMR (500 MHz, CD CN)
δ
4.37 (ddd,
3
J = 7.5, 4.0, 3.0 Hz, 1H), 3.85 (dd, J = 9.2, 3.6 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1 H), 3.78 (s, 3H), 3.73 (dd,
13
J = 8.6, 3.4 Hz, 2H) 3.68 (d, J = 9.9, 3.8 Hz, 1H), 3.6 (dd, J = 8.0, 7.5 Hz, 1H); C NMR (125 MHz,
CD CN) δ 170.30, 167.59, 80.57, 60.83, 52.67, 51.20, 50.17, 38.12
3
3.9. General Procedure for the Synthesis of (5S)-methyl
4-(aminomethyl)-5-(hydroxymethyl)-2-oxotetrahydrofuran-3-carboxylate 13
The 5-(S)-methyl 5-(hydroxymethyl)-4-(nitromethyl)-2-oxotetrahydrofuran-3-carboxylate 12
(0.175 g, 0.749 mmol) was placed into a beaker and dissolved in methanol (15 mL). The reaction
mixture was pumped into ThalesNano H-Cube mini containing a cartridge of Pd/C (10%) with
◦
1
mL/min as flow rate, at the pressure 15 mbar of H and at 35 C. Reaction progress was monitored by
2
TLC. After 3 h, the crude mixture was passed through a short silica pad, concentrated under vacuum,
and then purified by flash column chromatography on silica gel (DCM/MeOH and 2% TEA = 9/1 as
1
eluent) in order to afford the product (0.038 g, 22%). H NMR (300 Mhz, CD OD)
δ
4.48–4.44 (s, 1H),
3
3
6
.86–3.81 (dd, 2H), 3.76–3.56 (dddd, 4H). 13C NMR (125 MHz, CD OD) 172.01, 170.88, 85.77, 65.04,
2.03, 44.90, 38.59. HRMS (ESI+) requires 171.0532, found 140.03456 [(M -CH OH)].
3
+
2
4
. Conclusions
Carbohydrates represent a widely available, chiral, renewable resource. They are a biomass-derived,
highly diversified platform that could be employed to develop new sustainable synthetic pathways.
Among the hexoses and the pentoses present in the biomass, in the present project, mannitol was
selected as a valuable starting material, directly available from the chiral pool, to build highly
functionalized molecules. Starting from (R)-2,3-O-Cyclohexylidene glyceraldehyde, easily prepared
on large scale from D-mannitol, by reaction with nitromethane, an enantiopure chiral nitro alkene
was prepared and its reactivity explored [22]. Organocatalytic Michael addition of dimethyl malonate
or β-ketoesters on the nitro alkene afforded high stereoselectivity and densely functionalized chiral
molecules, which were further synthetically elaborated, leading to five-membered lactones and bicyclic
lactams [23]. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene
can also be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic
systems for the preparation of enantiomerically pure organic molecules from the chiral pool [24].
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/24/4588/s1.
Figures S1–S8: NMR spectra of compounds 5a/5b, 12, 13.
Author Contributions: Methodology and experimental work: E.G. and L.C.; Validation: L.C. and A.P.; Data
Curation: A.P.; conceptualization and supervision: M.B.
Funding: This research was funded by European Union’s Horizon 2020 research and innovation programme
under the Marie Sklodowska Curie grant agreement number 812944 “TECHNOTRAIN”. A.P. would like to thank
Università degli Studi di Milano for a Transition grant 2018-2019.
Conflicts of Interest: The authors declare no conflict of interest

Molecules 2019, 24, 4588
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Sample Availability: Samples of the compounds
1, 2, 3, 4, 5a/5b, 6, 9, 10a/10b, (S,S) and (R, R)-Takemoto catalyst,
Jacobsen type catalyst. are available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(