Enantioselective Organocatalyzed Consecutive Synthesis of Alkyl 4,5-Dihydrofuran-2-carboxylates from α-Keto Esters and (Z)-β-Chloro-β-nitrostyrenes

Article abstract of DOI:10.1055/s-0035-1562446

Alkyl 4,5-dihydrofuran-2-carboxylates can be efficiently obtained via an enantioselective organocatalyzed consecutive reaction between α-keto esters and (Z)-(2-chloro-2-nitroethenyl)benzenes. The overall sequence combines a (R,R)-TUC-catalyzed Michael addition with a DABCO-promoted intramolecular O-alkylation leading to the title products as single diastereomers with enantiomeric excesses from 86% up to 97%.

Full text of DOI:10.1055/s-0035-1562446

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
D. Becerra et al.
Paper
Synthesis
Enantioselective Organocatalyzed Consecutive Synthesis of
Alkyl 4,5-Dihydrofuran-2-carboxylates from α-Keto Esters and
(Z)-β-Chloro-β-nitrostyrenes
Diana Becerra
CF3
O
O
Wilfried Raimondi
Thierry Constantieux
Damien Bonne*
Jean Rodriguez*
O2N
Cl
O
14 examples
20–79%
> 20:1 dr
S
(R,R)-TUC
NO2
R3O
R3O
+
then, base
F3C
N
N
R1
O
R2
R2
86–97% ee
H
H
R1
N
(R,R)-TUC
Aix Marseille Université, CNRS, Centrale Marseille iSm2,
13397, Marseille, France
damien.bonne@univ-amu.fr
jean.rodriguez@univ-amu.fr
Dedicated to Professor Dieter Enders on the occasion of his
70th birthday
Received: 26.05.2016
Accepted: 06.06.2016
Published online: 07.07.2016
DOI: 10.1055/s-0035-1562446; Art ID: ss-2016-z0383-op
deed, the 2-carbonyl-4,5-dihydrofuran substructure is
present in various families of bioactive natural products
such as cheimonophyllal,7 and jiadifenlactone A8 and no ef-
ficient enantioselective method to construct this moiety
has been reported so far.9
Abstract Alkyl 4,5-dihydrofuran-2-carboxylates can be efficiently ob-
tained via an enantioselective organocatalyzed consecutive reaction
between α-keto esters and (Z)-(2-chloro-2-nitroethenyl)benzenes. The
overall sequence combines a (R,R)-TUC-catalyzed Michael addition with
a DABCO-promoted intramolecular O-alkylation leading to the title
products as single diastereomers with enantiomeric excesses from 86%
up to 97%.
NO2
O
Z
O
chiral
organocatalyst
O2N
Br
Ar
Ar
eq (1)
+
base
Rueping
Xie
Key words dihydrofurans, organocatalysis, domino Michael/alkyla-
tion, Takemoto catalyst, (Z)-β-chloro-β-nitrostyrenes
O
Z
O
Lu
Feng
Z = CH2, O, NR
3-acyl-4,5-dihydrofurans
NO2
OH
O
Dihydrofuran is a structural subunit found in a number
of important natural products and pharmaceutically rele-
vant compounds.1 In consequence, important efforts have
been devoted towards the enantioselective synthesis of di-
hydrofurans derivatives.2 Since the pioneer reports of
Dauzonne and co-workers twenty-five years ago,3 the
Michael–alkylation domino reaction between (Z)-(2-halo-
2-nitroethenyl)benzenes and various bis-nucleophiles has
become an attractive strategy to access dihydrofurans en-
antioselectively (Scheme 1). Hence, the groups of Rueping,
Xie, Lu, and Feng employed 1,3-dicarbonyls as 1,3-bis-nu-
cleophiles activated by an hydrogen-bonding organocata-
lyst to access 3-carbonyl-4,5-dihydrofurans (Scheme 1, eq
1),4,5 while the groups of Alemán and Xie used β-naphthols
as 1,3-bis-nucleophiles to efficiently construct the corre-
chiral
organocatalyst
Ar
O2N
Br
eq (2)
+
base
Alemàn
Xie
Ar
4-aryl-4,5-dihydrofurans
eq (3)
NO2
O
This work
chiral
organocatalyst
O
O2N
Cl
Ar
+
R1
OR2
R2O2C
base
Ar
R1
O
4,5-dihydrofuran-2-carboxylates
α-keto esters
OH
HO
H
O
O
O
O
O
O
H
HO
O
CHO
sponding 2,3-dihydrobenzofurans via
a Friedel–Crafts/
O
alkylation domino reaction (Scheme 1, eq 2).6
cheimonophyllal
jiadifenlactone A
However, none of these approaches allows for the chal-
lenging introduction of a key carbonyl moiety in the 2-posi-
tion of the final optically active dihydrofuran target. In-
Scheme 1 Strategies for the construction of optically active dihydrofu-
rans with β-halo-β-nitrostyrenes
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
D. Becerra et al.
Paper
Synthesis
α-Dicarbonyl compounds are privileged substrates for
the development of new multiple bond-forming transfor-
mations10 due to their high number of adjacent reactive
sites that can participate in the successive creation of sever-
al bonds.11,12 Therefore, to address this synthetic lack, we
propose a sequential enantioselective heterocyclization of
α-keto esters with β-chloro-β-nitrostyrenes combining an
enantioselective Michael addition promoted by a chiral H-
bonding donor bifunctional catalyst13 with a base-promot-
ed intramolecular O-alkylation (Scheme 1, eq 3).
proportion of undesired furan 5a compared to the use of
DABCO (entry 4). Finally, lowering the temperature had a
beneficial impact on the yield (entries 5 and 6), which could
be increased to 79% when conducting the reaction at 25 °C,
while maintaining excellent diastereo- and enantioselectiv-
ities. In this last case, prolonged reaction time was required
(72 h) to consume starting materials while keeping a limit-
ed ratio of 5a.
Having found conditions that gave good yields and high
stereoselectivities in this formal [3+2] heterocyclization, we
explored alternative β-chloro-β-nitrostyrenes 1 and α-keto
esters 2 (Table 2). Concerning the nitroalkene, the reaction
worked well with β-substituted aromatic rings bearing ei-
ther electron-donating (entries 1–5) or electron-withdraw-
ing groups (entries 6–8), including sterically demanding
ortho functionalization (entry 7), or a 2-naphthyl moiety
(entry 9). The introduction of an heteroaromatic moiety (3-
chromenyl, entry 10) was possible, but a poor yield of 4j
was obtained and the reaction was found to be very slow,
both for the formation of the Michael adduct and for the
heterocyclization step. On the other hand, tert-butyl ester
as well as ethyl ester can be employed and the desired
Optimized conditions13 for the enantioselective Michael
addition leading to 3a were used and our initial efforts fo-
cused on the base-promoted heterocyclization from 3a (Ta-
ble 1). An encouraging result was obtained with the use of 1
equivalent of TMEDA at 60 °C leading to the desired dihy-
drofuran 4a in only 27% yield, but with excellent stereose-
lectivities together, with the side product furan 5a (entry
1). Lowering the amount of base to 0.2 equivalents resulted
in lower yield (entry 2). Further improvements in yield
were achieved using other organic bases even if in the case
of DBU (entry 3) a marked erosion of both diastereo- and
enantioselectivity was observed as well as an increased
Table 1 Optimization of the Reaction Conditionsa
OMe
OMe
(R,R)-TUC
(10 mol%)
O
O
Cl
OBn
Cl
OBn
+
EtOAc, 0 °C
NO2
O
NO2
O
1a
2a
3a
base, T (°C)
O
CF3
NO2
S
O
BnO2C
BnO2C
F3C
N
N
H
H
N
(R,R)-TUC
OMe
5a (undesired)
OMe
4a (major)
Entry
Base
TMEDA
T (°C)
Ratiob 3a/4a/5a
Yieldc (%)
drb
12:1
eed (%)
93
1
60
60
60
60
40
25
1:13:3
8:6:1
27
7
2e
3
TMEDA
DBU
>20:1
14:1
–
f
1:16:3
1:20:4
1:18:1
1:21:1
51
47
57
79
78
94
95
95
4
DABCO
DABCO
DABCO
>20:1
>20:1
>20:1
5
6g
a Reaction conditions: 1. 1a (0.1 mmol), 2a (0.2 mmol), catalyst (R,R)-TUC (10 mol%), EtOAc (1.0 mL), stirring, 0 °C, 24 h; 2. base (1 equiv), stirring, T (°C), 24 h;
unless otherwise noted.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield after column chromatography.
d Determined by chiral HPLC analysis.
e 0.2 equiv of base was used.
f Not determined.
g 72 h of reaction time after addition of base.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
D. Becerra et al.
Paper
Synthesis
products were obtained in fairly good yields with excellent
diastereo- and enantioselectivities (entries 11–14). We no-
ticed also that adding steric bulk around pro-nucleophilic
carbon atom of the α-keto ester (use of 2c, 2d, and 2e, en-
tries 12–14) had a negative impact on the kinetics of both
the Michael addition as well as on the heterocyclization
step.
NO2
NH2
activated Zn
AcOH, THF, rt
O
O
BnO2C
BnO2C
OMe
OMe
6, 38%
dr > 20:1
ee = 57%
4a, 93% ee
NaNO2
DMSO/H2O, 65 °C, 12 h
To evaluate the synthetic usefulness of this methodolo-
gy, the nitro group of 4a was reduced to the primary amine
moiety affording the relatively labile aminal 6 in moderate
yield suffering substantial erosion of enantiomeric excess
(Scheme 2). Also, an attempt to convert dihydrofuran 4a
into the corresponding lactone using the Mioskowski pro-
cedure14 resulted in the formation of nitrofuran 7 in 65%
yield.
NO2
O
BnO2C
OMe
7, 65%
Scheme 2 Transformations of dihydrofuran 4a
Table 2 Reaction Scopea
R2
1) (R,R)-TUC (10 mol%)
EtOAc, 0 °C
Cl
NO2
O
R1
OR3
O
R2
OR3
+
R1
1 (1 equiv)
2) DABCO (1 equiv), rt
O
O2N
O
2 (2 equiv)
4
2a, R2 = Et, R3 = Bn
2b, R2 = Et, R3 = t-Bu
2c, R2 = i-Pr, R3 = Bn
2d, R2 = Bn, R3 = Et
2e, R2 = i-Pr, R3 = i-Bu
Entry
R1
1
2
4
Time (h)
Yieldb (%)b
drc
eed (%)
3
4
1
2
4-MeOC6H4
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
4f
24
24
48
72
72
24
24
72
48
96
48
72
96
96
90
48
72
72
72
48
72
58
48
96
48
72
72
72
79
54
48
48
42
20
62
43
61
20
36
38
52
26
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
97
93
95
94
93
97
90
95
97
94
95
86
91
2-MeOC6H4
2-MeC6H4
4-HOC6H4
2-BnOC6H4
4-ClC6H4
1b
1c
1d
1e
1f
3
4
5
6
7
2-FC6H4
1g
1h
1i
4g
4h
4i
8
3-ClC6H4
9
2-naphthyl
3-chromenyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
10e
11f
12f
13f
14f
1j
4j
1a
1a
1a
1a
4k
4l
4m
4n
a Reaction conditions: 1. 1 (0.1 mmol), 2 (0.2 mmol), catalyst (R,R)-TUC (10 mol%), EtOAc (1.0 mL) stirring, 0 °C, for the indicated time; 2. mixture brought to r.t.
followed by addition of DABCO (0.1 mmol).
b Isolated yield after column chromatography.
c Determined by 1H NMR analysis of the crude reaction product.
d Determined by chiral HPLC analysis.
e THF was used as the reaction solvent.
f When DABCO was added, the reaction was heated to 40 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
D. Becerra et al.
Paper
Synthesis
In conclusion we have developed an efficient consecu-
tive reaction to optically active alkyl trans-4,5-dihydrofu-
ran-2-carboxylates by a Michael/O-alkylation sequence be-
tween α-keto esters and β-chloro-β-nitrostyrenes. This
protocol nicely complements the ones existing using this
strategy, making possible the introduction of an ester func-
tion in the 2 position of the dihydrofuran structure, ready
for further functionalizations. The more challenging activa-
tion of α-keto esters in comparison to the well-known 1,3-
dicarbonyls explains usually long reaction times for this
methodology. But this is well counterbalanced by very high
stereoselectivities obtained in all cases.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.34 (m, 5 H, ArH), 7.12 (d, J = 8.7
Hz, 2 H, ArH), 6.91 (d, J = 8.7 Hz, 2 H, ArH), 5.76 (d, J = 1.9 Hz, 1 H,
CHNO2), 5.36 (d, J = 2.1 Hz, 2 H, CH2Ph), 4.37 (d, J = 1.9 Hz, 1 H, CHAr),
3.81 (s, 3 H, OCH3), 2.81 (dq, J = 14.9, 7.5 Hz, 1 H, CH2CH3), 2.04 (dq, J =
14.9, 7.5 Hz, 1 H, CH2CH3), 0.91 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.1, 159.5, 139.9, 135.2, 134.0, 128.8
(2 C), 128.8 (2 C), 128.7, 128.6 (2 C), 127.8, 115.0 (2 C), 109.4, 67.4,
59.1, 55.5, 18.3, 12.8.
Benzyl (4R,5S)-3-Ethyl-4-(2-methoxyphenyl)-5-nitro-4,5-dihydro-
furan-2-carboxylate (4b)
Isolated as a light yellow oil; yield: 21 mg (54%); Rf = 0.50 (EtOAc/PE,
1:6); dr anti/syn >20:1; HPLC (Chiralpak IA, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 8.84 (major), 7.43 min (mi-
nor); 97% ee; [α]D20 +109.76 (c 1.26, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.46–7.30 (m, 6 H, ArH), 7.01 (dd, J =
7.7, 1.8 Hz, 1 H, ArH), 6.91–6.98 (m, 2 H, ArH), 5.82 (d, J = 2.2 Hz, 1 H,
CHNO2), 5.36 (d, J = 3.6 Hz, 2 H, CH2Ph), 4.94 (d, J = 2.2 Hz, 1 H, CHAr),
3.87 (s, 3 H, OCH3), 2.86 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 2.01 (dq, J =
14.8, 7.4 Hz, 1 H, CH2CH3), 0.93 (t, J = 7.4 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 159.5, 157.0, 140.1, 135.3, 133.8, 130.1,
128.8 (2 C), 128.6, 128.5 (2 C), 128.2, 124.0, 121.3, 111.2, 109.4, 67.2,
55.7, 52.7, 18.5, 12.8.
All reagents were weighed and handled in air at room temperature.
1H NMR spectra were measured on a Bruker AC 400 (400 MHz) spec-
trometer. Data were reported as chemical shifts in ppm referenced to
the internal solvent signal. 13C NMR spectra were measured on a
Bruker AC 400 (100 MHz) spectrometer with complete proton decou-
pling. High-performance liquid chromatography (HPLC) was per-
formed on a VWR Hitachi (pump L-2130/Diode Array detector L-
2455) instrument. High-resolution mass spectra (HRMS) were per-
formed on a QStar Elite (Applied Biosystems SCIEX) spectrometer
equipped with atmospheric pressure ionization source (API) pneu-
matically assisted. Samples were ionized by positive electrospray
mode as follows: electrospray tension (ISV): 5500 V; opening tension
(OR): 50 V; nebulization gas pressure (air): 20 psi. Optical rotations
were measured with a Perkin-Elmer 241 micropolarimeter. Melting
points (mp) were determined with a Büchi Melting-Point B-450 appa-
ratus and were not corrected. Thin-layer chromatography (TLC) was
carried out on silica Merck 60F254. Visualization was achieved under
a UVP mineralight UVGL-58 lamp, and by developing the plates with
p-anisaldehyde reagent or phosphomolybdic acid reagent. The prod-
ucts were purified by flash column chromatography on silica gel 60
(Merck, 230–400 mesh). All reagents were obtained from commercial
suppliers unless otherwise stated.
HRMS (ESI+): m/z [M + NH4]+ calcd for C21H25N2O6: 401.1707; found:
401.1708.
Benzyl (4S,5S)-3-Ethyl-5-nitro-4-(o-tolyl)-4,5-dihydrofuran-2-car-
boxylate (4c)
Isolated as a light yellow oil; yield: 18 mg (48%); Rf = 0.35 (EtOAc/PE,
1:12); dr anti/syn >20:1; HPLC (Chiralpak IE, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 7.72 (major), 6.76 min (mi-
nor); 93% ee; [α]D20 +168.77 (c 1.14, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.5 Hz, 2 H, ArH), 7.43–7.35
(m, 3 H, ArH), 7.30–7.17 (m, 3 H, ArH), 6.97 (d, J = 7.3 Hz, 1 H, ArH),
5.72 (d, J = 1.9 Hz, 1 H, CHNO2), 5.38 (d, J = 3.5 Hz, 2 H, CH2Ph), 4.73 (d,
J = 1.9 Hz, 1 H, CHAr), 2.87 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 2.50 (s, 3
H, CH3), 2.02 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 0.91 (t, J = 7.6 Hz, 3 H,
CH2CH3).
trans-4,5-Dihydrofuran-2-carboxylates; General Procedure
13C NMR (100 MHz, CDCl3): δ = 159.4, 140.5, 136.5, 135.2, 134.1,
133.8, 131.4, 128.9 (2 C), 128.8, 128.7, 128.6 (2 C), 127.3, 126.9, 109.2,
67.4, 55.3, 20.0, 18.4, 12.9.
HRMS (ESI+): m/z [M + NH4]+ calcd for C21H25N2O5: 385.1758; found:
385.1759.
To a solution of nitroalkene 1 (0.1 mmol, 1.0 equiv) and α-keto ester 2
(0.2 mmol, 2.0 equiv) in EtOAc (1.0 mL) at 0 °C was added (R,R)-TUC
(10 mol%). The reaction was stirred until complete conversion of the
starting materials (monitored by TLC). Then, DABCO (0.1 mmol, 1.0
equiv) was added at 0 °C with stirring and the mixture was warmed
1
to r.t. After completion of the reaction (monitored by H NMR of the
crude mixture), the reaction was quenched with sat. aq NH4Cl and ex-
tracted with EtOAc (3 × 5.0 mL). The combined organic layers were
then dried (Na2SO4), filtered, and concentrated in vacuo. The resulting
crude product was purified by flash column chromatography (silica
gel, EtOAc/PE) to afford the desired product. The diastereomeric ratio
was determined by H NMR spectroscopy analysis of the crude mix-
ture and the enantiomeric excess (ee) was determined by HPLC anal-
ysis on a chiral phase.
Benzyl (4S,5S)-3-Ethyl-4-(4-hydroxyphenyl)-5-nitro-4,5-dihydro-
furan-2-carboxylate (4d)
Isolated as a light yellow oil; yield: 18 mg (48%); Rf = 0.10 (EtOAc/PE,
1:6); dr anti/syn >20:1; HPLC (Chiralpak IA, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 11.15 (major), 9.95 min (mi-
nor); 95% ee; [α]D20 +282.58 (c 0.37, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.49–7.31 (m, 5 H, ArH), 7.06 (d, J = 8.5
Hz, 2 H, ArH), 6.84 (d, J = 8.5 Hz, 2 H, ArH), 5.75 (d, J = 1.8 Hz, 1 H,
CHNO2), 5.43–5.25 (m, 3 H, CH2Ph, OH), 4.36 (d, J = 1.8 Hz, 1 H, CHAr),
2.81 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 2.03 (dq, J = 15.0, 7.6 Hz, 1 H,
CH2CH3), 0.90 (t, J = 7.6 Hz, 3 H, CH2CH3).
1
Benzyl (4S,5S)-3-Ethyl-4-(4-methoxyphenyl)-5-nitro-4,5-dihydro-
furan-2-carboxylate (4a)
Isolated as a yellow oil; yield: 30 mg (79%); Rf = 0.47 (EtOAc/PE, 1:4);
dr anti/syn >20:1; HPLC (Chiralpak IA, heptane/EtOH, 90:10, flow
rate = 1.0 mL/min, λ = 254 nm): tR = 10.47 (major), 9.51 min (minor);
95% ee.
13C NMR (75 MHz, CDCl3): δ = 159.5, 156.3, 139.9, 135.1, 134.1, 129.1
(2 C), 128.8 (2 C), 128.7, 128.6 (2 C), 127.8, 116.5 (2 C), 109.4, 67.4,
59.1, 18.3, 12.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
D. Becerra et al.
Paper
Synthesis
HRMS (ESI+): m/z [M + NH4]+ calcd for C20H23N2O6: 387.1551; found:
Benzyl (4S,5S)-4-(3-Chlorophenyl)-3-ethyl-5-nitro-4,5-dihydrofu-
387.1551.
ran-2-carboxylate (4h)
Isolated as a light yellow oil; yield: 17 mg (43%); Rf = 0.52 (EtOAc/PE,
1:6); dr anti/syn >20:1; HPLC (Chiralpak IE, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 8.92 (major), 6.64 min (mi-
nor); 90% ee; [α]D20 +136.8 (c 0.90, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.49–7.32 (m, 7 H, ArH), 7.20 (s, 1 H,
ArH), 7.14–7.08 (m, 1 H, ArH), 5.76 (d, J = 2.0 Hz, 1 H, CHNO2), 5.37 (d,
J = 1.7 Hz, 2 H, CH2Ph), 4.40 (d, J = 2.0 Hz, 1 H, CHAr), 2.85 (dq, J = 15.0,
7.5 Hz, 1 H, CH2CH3), 2.01 (dt, J = 15.0, 7.5 Hz, 1 H, CH2CH3), 0.92 (t, J =
7.5 Hz, 3 H, CH2CH3).
Benzyl (4R,5S)-4-[2-(Benzyloxy)phenyl]-3-ethyl-5-nitro-4,5-dihy-
drofuran-2-carboxylate (4e)
Isolated as a light yellow oil; yield: 19 mg (42%); Rf = 0.54 (EtOAc/PE,
1:5); dr anti/syn >20:1; HPLC (Lux-Cellulose-4, heptane/EtOH, 80/20,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.80 (major), 7.74 min (mi-
nor); 94% ee; [α]D20 +117.2 (c 1.05, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.23 (m, 12 H, ArH), 6.99–6.91
(m, 2 H, ArH), 5.78 (d, J = 2.4 Hz, 1 H, CHNO2), 5.25 (s, 2 H, CH2Ph),
5.06 (s, 2 H, CH2Ph), 4.90 (d, J = 2.4 Hz, 1 H, CHAr), 2.73 (dq, J = 14.8,
7.6 Hz, 1 H, CH2CH3), 1.95 (dq, J = 14.8, 7.6 Hz, 1 H, CH2CH3), 0.81 (t, J =
7.6 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 159.3, 140.6, 137.8, 135.7, 135.1, 133.0,
131.0, 129.4, 128.9 (2 C), 128.8, 128.6 (2 C), 127.8, 125.9, 108.7, 67.5,
59.1, 18.3, 12.8.
13C NMR (75 MHz, CDCl3): δ = 159.5, 156.1, 140.1, 136.3, 135.3, 133.9,
130.1 (2 C), 128.8 (2 C), 128.8, 128.7, 128.6, 128.5 (2 C), 128.3, 127.6
(2 C), 124.3, 121.6, 112.6, 109.4, 70.7, 67.2, 53.1, 18.5, 12.9.
HRMS (ESI+): m/z [M + NH4]+ calcd for C20H22ClN2O5: 405.1212;
found: 405.1212.
HRMS (ESI+): m/z [M + NH4]+ calcd for C27H29N2O6: 477.2020; found:
Benzyl (4S,5S)-3-Ethyl-4-(naphthalen-2-yl)-5-nitro-4,5-dihydrofu-
477.2019.
ran-2-carboxylate (4i)
Isolated as a light yellow oil; yield: 25 mg (61%); Rf = 0.43 (EtOAc/PE,
1:12); dr anti/syn >20:1; HPLC (Chiralpak AD-H, heptane/EtOH,
50:50, flow rate = 1.0 mL/min, λ = 254 nm): tR = 7.80 (major), 9.73 min
(minor); 95% ee; [α]D20 +240.08 (c 1.05, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.5 Hz, 1 H, ArH), 7.87–7.82
(m, 2 H, ArH), 7.69 (s, 1 H, ArH), 7.57–7.50 (m, 2 H, ArH), 7.47 (d, J =
6.8 Hz, 2 H, ArH), 7.44–7.35 (m, 3 H, ArH), 7.28 (dd, J = 8.5, 1.6 Hz, 1 H,
ArH), 5.87 (d, J = 2.0 Hz, 1 H, CHNO2), 5.40 (d, J = 3.3 Hz, 2 H, CH2Ph),
4.60 (d, J = 2.0 Hz, 1 H, CHAr), 2.87 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3),
2.07 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 0.93 (t, J = 7.6 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 159.5, 140.3, 135.2, 133.7, 133.6,
133.4, 133.1, 129.9, 128.9 (2 C), 128.7, 128.6 (2 C), 128.1, 127.9, 127.2,
127.1, 126.9, 124.7, 109.2, 67.5, 59.9, 18.4, 12.9.
HRMS (ESI+): m/z [M + NH4]+ calcd for C24H25N2O5: 421.1758; found:
421.1758.
Benzyl (4S,5S)-4-(4-Chlorophenyl)-3-ethyl-5-nitro-4,5-dihydrofu-
ran-2-carboxylate (4f)
Isolated as a light yellow oil; yield: 8 mg (20%); Rf = 0.57 (EtOAc/PE,
1:6); dr anti/syn >20:1; HPLC (Chiralpak IA, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 9.21 (major), 8.43 min (mi-
nor); 93% ee; [α]D20 +292.7 (c 0.36, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.47–7.36 (m, 7 H, ArH), 7.15 (d, J = 8.4
Hz, 2 H, ArH), 5.74 (d, J = 1.9 Hz, 1 H, CHNO2), 5.36 (d, J = 4.0 Hz, 2 H,
CH2Ph), 4.41 (d, J = 1.9 Hz, 1 H, CHAr), 2.83 (dq, J = 15.0, 7.6 Hz, 1 H,
CH2CH3), 2.02 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 0.91 (t, J = 7.6 Hz, 3 H,
CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 159.3, 140.4, 135.1, 135.1, 134.3,
133.2, 129.9 (2 C), 129.1 (2 C), 128.9 (2 C), 128.8, 128.6 (2 C), 108.8,
67.5, 59.0, 18.3, 12.8.
HRMS (ESI+): m/z [M + NH4]+ calcd for C20H22ClN2O5: 405.1212;
found: 405.1212.
Benzyl (4R,5S)-3-Ethyl-5-nitro-4-(4-oxo-4H-chromen-3-yl)-4,5-di-
hydrofuran-2-carboxylate (4j)
Benzyl (4R,5S)-3-Ethyl-4-(2-fluorophenyl)-5-nitro-4,5-dihydrofu-
ran-2-carboxylate (4g)
Isolated as a light yellow oil; yield: 8 mg (20%); Rf = 0.10 (EtOAc/PE,
1:5); dr anti/syn >20:1; HPLC (Chiralpak ID, heptane/EtOH, 50:50,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 8.39 (major), 9.89 min (mi-
nor); 97% ee; [α]D20 +61.5 (c 0.30, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.0 Hz, 1 H, ArH), 7.77–7.71
(m, 2 H, ArH), 7.50–7.37 (m, 7 H, ArH), 5.87 (d, J = 2.4 Hz, 1 H, CHNO2),
5.35 (d, J = 4.7 Hz, 2 H, CH2Ph), 4.76 (d, J = 2.4 Hz, 1 H, CHAr), 2.92 (dq,
J = 14.8, 7.5 Hz, 1 H, CH2CH3), 2.09 (dq, J = 14.8, 7.5 Hz, 1 H, CH2CH3),
1.01 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 176.1, 159.1, 156.5, 154.2, 141.2,
135.1, 134.6, 131.1, 128.9 (2 C), 128.7, 128.6 (2 C), 126.2, 126.1, 123.7,
119.6, 118.4, 107.9, 67.5, 50.0, 18.4, 13.0.
HRMS (ESI+): m/z [M + NH4]+ calcd for C23H23N2O7: 439.1500; found:
439.1500.
Isolated as a yellow oil; yield: 23 mg (62%); Rf = 0.42 (EtOAc/PE, 1:5);
dr anti/syn >20:1; HPLC (Chiralpak IE, heptane/EtOH, 90:10, flow
rate = 1.0 mL/min, λ = 254 nm): tR = 10.28 (major), 7.49 min (minor);
97% ee; [α]D20 +210.0 (c 0.64, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.47–7.32 (m, 6 H, ArH), 7.21–7.06 (m,
3 H, ArH), 5.85 (d, J = 2.1 Hz, 1 H, CHNO2), 5.36 (d, J = 1.8 Hz, 2 H,
CH2Ph), 4.83 (d, J = 2.1 Hz, 1 H, CHAr), 2.84 (dq, J = 15.0, 7.6 Hz, 1 H,
CH2CH3), 2.02 (dq, J = 15.0, 7.6 Hz, 1 H, CH2CH3), 0.93 (t, J = 7.6 Hz, 3 H,
CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.4 (J = 247.2 Hz), 159.3, 140.5, 135.1,
132.8, 130.8 (J = 8.25 Hz), 128.9 (2 C), 128.7, 128.7, 128.6 (2 C), 125.3
(J = 3.9 Hz), 123.0 (J = 14.3 Hz), 116.4 (J = 21.5 Hz), 108.6, 67.4, 52.0
(J = 3.75 Hz), 18.3, 12.8.
HRMS (ESI+): m/z [M + NH4]+ calcd for C20H22FN2O5: 389.1507; found:
tert-Butyl (4S,5S)-3-Ethyl-4-(4-methoxyphenyl)-5-nitro-4,5-dihy-
389.1506.
drofuran-2-carboxylate (4k)
Isolated as a yellow oil; yield: 25 mg (36%); Rf = 0.49 (EtOAc/PE, 1:5);
dr anti/syn >20:1; HPLC (Chiralpak IF, heptane/EtOH, 70:30, flow
rate = 1.0 mL/min, λ = 254 nm): tR = 4.55 (major), 5.20 min (minor);
94% ee; [α]D20 +259.3 (c 1.05, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
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1H NMR (300 MHz, CDCl3): δ = 7.13 (d, J = 8.6 Hz, 2 H, ArH), 6.91 (d, J =
8.6 Hz, 2 H, ArH), 5.74 (d, J = 2.1 Hz, 1 H, CHNO2), 4.34 (d, J = 2.1 Hz, 1
H, CHAr), 3.81 (s, 3 H, OCH3), 2.73 (dq, J = 14.8, 7.6 Hz, 1 H, CH2CH3),
2.00 (dq, J = 14.8, 7.6 Hz, 1 H, CH2CH3), 1.59 (s, 9 H, t-Bu), 0.91 (t, J =
7.6 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.0, 159.8, 140.0, 137.2, 128.9 (2 C),
128.9, 114.9 (2 C), 109.8, 71.8, 57.5, 55.5, 27.9, 25.7, 22.4, 21.5, 19.3 (2
C).
HRMS (ESI+): m/z [M + NH4]+ calcd for C19H29N2O6: 381.2020; found:
381.2024.
13C NMR (75 MHz, CDCl3): δ = 160.0, 158.8, 141.0, 131.7, 128.9 (2 C),
128.1, 114.9 (2 C), 109.3, 83.3, 59.2, 55.5, 28.3, 18.4, 12.9.
HRMS (ESI+): m/z [M + NH4]+ calcd for C18H27N2O6: 367.1864; found:
Benzyl (4S,5S)-5-Amino-3-ethyl-4-(4-methoxyphenyl)-4,5-dihy-
drofuran-2-carboxylate (6)
367.1864.
A solution of 4,5-dihydrofuran-2-carboxylate 4a (0.13 mmol, 1.0
equiv) in dry THF (1.0 mL) was added activated zinc powder (18.2
mmol, 140.0 equiv), followed by the addition dropwise of AcOH (6.0
mL). The mixture was stirred for 2 h at r.t. The mixture was concen-
trated and extracted with sat. NaHCO3 solution (2 × 6.0 mL). The com-
bined aqueous phases were extracted with CH2Cl2 (2 × 10.0 mL) and
the combined organic layers were washed with water (10.0 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The resulting crude
product was purified by flash column chromatography (silica gel,
EtOAc/PE, 40:60). Isolated as a light yellow oil; yield: 17 mg (38%); Rf =
0.37 (EtOAc/PE, 4:6); dr anti/syn >20:1; HPLC (Chiralpak IA, hep-
tane/EtOH, 90:10, flow rate = 1.0 mL/min, λ = 254 nm): tR = 10.83
(major), 11.91 min (minor); 57% ee (from 93% ee in the starting mate-
rial); [α]D20 +65.1 (c 0.28, CHCl3).
Benzyl (4S,5S)-3-Isopropyl-4-(4-methoxyphenyl)-5-nitro-4,5-di-
hydrofuran-2-carboxylate (4l)
Isolated as a light yellow oil; yield: 30 mg (38%); Rf = 0.47 (EtOAc/PE,
1:5); dr anti/syn >20:1; HPLC (Chiralpak IB, heptane/EtOH, 80:20,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.74 (major), 6.13 min (mi-
nor); 95% ee; [α]D20 +151.4 (c 0.80, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.49–7.32 (m, 5 H, ArH), 7.14 (d, J = 8.7
Hz, 2 H, ArH), 6.89 (d, J = 8.7 Hz, 2 H, ArH), 5.66 (d, J = 1.3 Hz, 1 H,
CHNO2), 5.38 (s, 2 H, CH2Ph), 4.42 (d, J = 1.3 Hz, 1 H, CHAr), 3.81 (s, 3
H, OCH3), 3.50 (hept, J = 7.1 Hz, 1 H, CH), 1.03 (d, J = 7.1 Hz, 3 H, CH3),
0.66 (d, J = 7.1 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 160.0, 159.5, 139.6, 138.1, 135.3, 128.9
(2 C), 128.8 (2 C), 128.7, 128.7, 128.5 (2 C), 114.9 (2 C), 109.8, 67.3,
57.5, 55.5, 25.7, 22.3, 21.5.
HRMS (ESI+): m/z [M + NH4]+ calcd for C22H27N2O6: 415.1864; found:
415.1864.
1H NMR (300 MHz, CDCl3): δ = 7.45–7.32 (m, 5 H, Ar-H), 7.11 (d, J =
8.8 Hz, 2 H, Ar-H), 6.86 (d, J = 8.8 Hz, 2 H, Ar-H), 5.31 (d, J = 3.8 Hz, 2
H), 5.11 (d, J = 5.3 Hz, 1 H), 3.79 (s, 3 H), 3.70 (d, J = 5.3 Hz, 1 H), 2.81–
2.70 (m, 1 H, CH2CH3), 2.27 (br s, 2 H, NH2), 2.00–1.90 (m, 1 H,
CH2CH3), 0.89 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.1, 159.1, 138.7, 135.8, 132.0, 129.1
(2 C), 128.7 (2 C), 128.7 (2 C), 128.7, 128.5, 114.4 (2 C), 95.3, 66.8,
59.4, 55.4, 18.8, 12.9.
Ethyl (4S,5S)-3-Benzyl-4-(4-methoxyphenyl)-5-nitro-4,5-dihydro-
furan-2-carboxylate (4m)
Isolated as a yellow solid (40 mg (52%); mp 104–105 °C; Rf = 0.51
(EtOAc/PE, 1:5); dr anti/syn >20:1; HPLC (Chiralpak IC, heptane/EtOH,
95:5, flow rate = 1.0 mL/min, λ = 254 nm): tR = 8.66 (major), 9.35 min
(minor); 86% ee; [α]D20 +256.7 (c 1.53, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.30–7.17 (m, 3 H, ArH), 7.08–6.98 (m,
4 H, ArH), 6.90 (d, J = 8.7 Hz, 2 H, ArH), 5.78 (d, J = 1.8 Hz, 1 H, CHNO2),
4.51–4.39 (m, 3 H, CH2Ph, OCH2CH3), 4.08 (d, J = 1.8 Hz, 1 H, CHAr),
3.83 (s, 3 H, OCH3), 3.03 (d, J = 15.1 Hz, 1 H, CH2Ph), 1.43 (t, J = 7.1 Hz,
3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.1, 159.7, 140.7, 137.1, 130.6, 129.0
(2 C), 128.9 (2 C), 128.6 (2 C), 127.6, 127.1, 115.0 (2 C), 109.3, 62.0,
58.6, 55.5, 30.6, 14.3.
HRMS (ESI+): m/z [M + NH4]+ calcd for C21H25N2O6: 401.1707; found:
401.1708.
HRMS (ESI+): m/z [M + H]+ calcd for C21H24NO4: 354.1700; found:
354.1699.
Benzyl 3-Ethyl-4-(4-methoxyphenyl)-5-nitrofuran-2-carboxylate
(7)
A solution of the 4,5-dihydrofuran-2-carboxylate 4a (0.13 mmol, 1.0
equiv) and NaNO2 (0.26 mmol, 1.0 equiv) in DMSO/water (7:1, 0.4 M)
was stirred at 65 °C for 12 h. The mixture was cooled to r.t. and then
an equal volume of water was then added and the aqueous layer was
extracted several times with Et2O. The combined organic layers were
dried (Na2SO4) and concentrated and the resulting crude was purified
by flash column chromatography (silica gel, EtOAc/PE, 1:15) to afford
the desired product.14 Isolated as a green solid; yield: 32 mg (65%);
mp 91–92 °C; Rf = 0.61 (EtOAc/PE, 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.44–7.50 (m, 2 H, ArH), 7.35–7.44 (m,
3 H, ArH), 7.24 (d, J = 8.8 Hz, 2 H, ArH), 7.00 (d, J = 8.8 Hz, 2 H, ArH),
5.42 (s, 2 H, CH2Ph), 3.87 (s, 3 H, OCH3), 2.71 (q, J = 7.5 Hz, 2 H,
CH2CH3), 1.02 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 160.4, 158.0, 139.3 (2 C), 138.9, 135.1,
130.8 (2 C), 128.9 (2 C), 128.8, 128.7 (2 C), 128.1, 120.1, 114.3 (2 C),
67.5, 55.5, 17.7, 14.4.
Isobutyl (4S,5S)-3-Isopropyl-4-(4-methoxyphenyl)-5-nitro-4,5-di-
hydrofuran-2-carboxylate (4n)
Isolated as a light yellow oil; yield: 19 mg (26%); Rf = 0.43 (EtOAc/PE,
1:4); dr anti/syn >20:1; HPLC (Chiralpak AD-H, heptane/EtOH, 90:10,
flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.17 (major), 5.11 min (mi-
nor); 91% ee; [α]D20 +198.1 (c 0.40, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.15 (d, J = 8.7 Hz, 2 H, ArH), 6.90 (d, J =
8.6 Hz, 2 H, ArH), 5.66 (d, J = 1.3 Hz, 1 H, CHNO2), 4.41 (d, J = 1.3 Hz, 1
H, CHAr), 4.13 (qd, J = 10.7, 6.7 Hz, 2 H, OCH2), 3.81 (s, 3 H, OCH3), 3.50
(sept, J = 7.0 Hz, 1 H, CH), 2.08 (sept, J = 6.7 Hz, 1 H, CH), 1.05 (d, J = 7.0
Hz, 3 H, CH3), 1.02 (d, J = 6.7 Hz, 6 H, 2 CH3), 0.68 (d, J = 7.0 Hz, 3 H,
CH3).
HRMS (ESI+): m/z [M + NH4]+ calcd for C21H23N2O6: 399.1551; found:
399.1551.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
D. Becerra et al.
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Synthesis
Acknowledgment
(7) Stadler, M.; Anke, H.; Sterner, O. J. Antibiot. 1994, 47, 1284.
(8) Liu, J.-F.; Li, Y.-C.; Wang, L.; Wang, Y.-F.; Jia, L.; Bi, Y.-F.; Zhang,
Y.-B. Tetrahedron Lett. 2014, 55, 2942.
Financial support from the Agence Nationale pour la Recherche (ANR-
11-BS07-0014), the Centre National de la Recherche Scientifique
(CNRS), Aix-Marseille Université, is gratefully acknowledged. We also
thank Dr. N. Vanthuyne and M. Jean (ee measurements).
(9) For recent domino synthesis of 2-acyldihydrofurans in the
racemic series, see: (a) Xie, P.; Li, E.; Zheng, J.; Li, X.; Huang, Y.;
Chen, R. Adv. Synth. Catal. 2013, 355, 161. (b) Li, B.-S.; Lu, W.-X.;
Zhang, Q.-W.; Wang, S.-H.; Zhang, F.-M.; Zhang, S.-Y.; Tu, Y.-Q.;
Cao, X.-P. Chem. Eur. J. 2013, 19, 5246.
(10) (a) Stereoselective Multiple Bond-Forming Transformations in
Organic Synthesis; Rodriguez, J.; Bonne, D., Eds.; John Wiley &
Sons: Hoboken, 2015. (b) Bonne, D.; Constantieux, T.; Coquerel,
Y.; Rodriguez, J. Chem. Eur. J. 2013, 19, 2218. (c) Green, N. J.;
Sherburn, M. S. Aust. J. Chem. 2013, 66, 267. (d) Menéndez, J. C.
Curr. Org. Chem. 2013, 18, 1919; and reviews included in this
special issue. (e) Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol,
D.; Rodriguez, J. In Ideas in Chemistry and Molecular Sciences:
Advances in Synthetic Chemistry; Pignataro, B., Ed.; Wiley-VCH:
Weinheim, 2010, Chap. 9, 187–202.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562446.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G