Synthesis of chiral γ-lactones by one-pot sequential enantioselective organocatalytic michael addition of boronic acids and diastereoselective intramolecular passerini reaction

Article abstract of DOI:10.1021/jo501908z

The synthesis of α,γ-substituted chiral γ-lactones was quickly achieved in a one pot sequential process. The procedure involves an enantioselective organocatalysed transfer of boronic acid to 5-hydroxyfuran-2(5H)-one, followed by an intramolecular diastereoselective Passerini-type reaction. The methodology was developed and optimized with N-Boc-indole-2-boronic acid giving access to α-indole-γ-substituted lactones in high yields and good diastereoisomeric and enantiomeric ratios. By applying the process to other boronic acids, the synthesis of structurally diversified α,γ-substituted chiral lactones was also achieved in good yields albeit with lower enantioselectivities.

Full text of DOI:10.1021/jo501908z

Article
pubs.acs.org/joc
Synthesis of Chiral γ‑Lactones by One-Pot Sequential
Enantioselective Organocatalytic Michael Addition of Boronic Acids
and Diastereoselective Intramolecular Passerini Reaction
Maxence Bos and Emmanuel Riguet*
́ ́
Universite de Reims Champagne-Ardenne, Institut de Chimie Moleculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et
Naturelles, BP 1039, 51687 Reims Cedex 2, France
S
* Supporting Information
ABSTRACT: The synthesis of α,γ-substituted chiral γ-
lactones was quickly achieved in a one pot sequential process.
The procedure involves an enantioselective organocatalysed
transfer of boronic acid to 5-hydroxyfuran-2(5H)-one,
followed by an intramolecular diastereoselective Passerini-
type reaction. The methodology was developed and optimized
with N-Boc-indole-2-boronic acid giving access to α-indole-γ-
substituted lactones in high yields and good diastereoisomeric
and enantiomeric ratios. By applying the process to other
boronic acids, the synthesis of structurally diversified α,γ-substituted chiral lactones was also achieved in good yields albeit with
lower enantioselectivities.
transfers of boronic acids to α,β-unsaturated carbonyl
compounds have been recently reported.21−29 When the α,β-
unsaturated carbonyl compound is activated by the catalyst
(i.e., LUMO-lowering activation), the process usually requires
activation of the boronic acid by the substrate as an “ate
complex”. This substrate activation entails the use of a
restricted class of α,β-unsaturated carbonyl com-
pounds.23,25,26,29 The use of vinyl and heteroaryl trifluoroborate
salts,22 even if the use of an hydrofluoric acid additive is
required, overcame this limitation and found spectacular
application in the total synthesis of natural products.24
However, the use of polyfunctional α,β-unsaturated carbonyl
derivatives able to activate boronic acids is particularly
interesting when its functionality is further exploited in a
consecutive step. On the basis of our working hypothesis, the
carboxylate group on the iminium ion resulting from the
activation of 5-hydroxyfuran-2(5H)-one 1 by secondary amine
catalyst should activate the boronic acid as an “ate complex”
(intermediate I, Scheme 1). The chiral adducts obtained after
boronic acid substituent migration (intermediate II) should
then react with isocyanides to produce the desired variously
substituted chiral lactones (Scheme 1).
INTRODUCTION
■
The development of synthetic methodologies enabling the
increase of molecular diversity starting from simple and readily
available materials is an ongoing challenge in organic synthesis.
The two main fields of organic synthesis, i.e., target-oriented
synthesis (TOS) and diversity-oriented synthesis (DOS),1,2 are
expected to benefit from these new methodologies. The
chemical biology and medicinal chemistry areas are especially
concerned with the development of new methods allowing
efficient functionalization of privileged heterocyclic struc-
tures.3−5 Therein, the exploration of chemical space by
increasing the number of sp3 hybridized carbons is of particular
interest,6 even more so with the stereospecific construction of
an sp3 hybridized asymmetric center.7,8 A promising strategy to
address this task is to combine an enantioselective organo-
catalytic step and a multicomponent reaction (MCR)9 to
increase chemical diversity on the chiral primary adduct
through a tandem one-pot process.10−14 In this context we
recently explored a new synthetic application of γ-hydrox-
ybutenolides.15 We demonstrated that 5-hydroxyfuran-2(5H)-
one 1, a readily available biobased molecule, can be engaged in
an efficient one pot sequential process involving an
enantioselective organocatalytic Friedel−Crafts and a 4-center
3-component Ugi reaction.16 In order to further demonstrate
the usefulness of 1 as reactant in both organocatalytic and
multicomponent reaction processes, we described herein a one
pot sequential procedure involving the organocatalytic
enantioselective transfer of a boronic acid substituent and the
subsequent transformation of the intermediate into an α,γ-
substituted chiral lactone via an intramolecular Passerini type
reaction (Scheme 1).17 Inspired by the mechanism of the
Petasis reaction,18−20 efficient enantioselective organocatalytic
RESULTS AND DISCUSSION
■
In view of the biological relevance of the indole moiety,5,30 the
N-Boc-indole-2-boronic acid 3 was first chosen as a reaction
partner. As we have previously established, the catalysts derived
from diphenyl prolinol are suitable to activate the 5-
Received: August 18, 2014
© XXXX American Chemical Society
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Scheme 1. Approach to Chiral α,γ-Substituted γ-Lactones
hydroxyfuran-2(5H)-one 1.16 Reactions were conducted on 0.5
mmol scale in the presence of 10 mol % of catalysts 2a−f and
1.1 equiv of indole boronic acid 3 in acetonitrile at 0 °C. In a
first instance, the organocatalytic enantioselective transfer of
the boronic acid substituent to 5-hydroxyfuran-2(5H)-one 1
was evaluated by conversion of the addition adduct into the
monosubstituted lactone 4 (Table 1). In the preliminary
reaction was carried out under anhydrous conditions, very low
conversion of the addition adduct was observed even after
prolonged reaction time. The presence of a large excess of
water led to sluggish transfer of the boronic acid substituent. In
the end, we established that the addition of 5 equiv of water
allowed the transformation with reproducible reaction times
and isolated yields. When the reaction was performed under
these reaction conditions, full consumption of compound 1 was
observed after 6 h (entry 1). After in situ reduction by NaBH4
and lactonization of the obtained chiral primary adduct, the
lactone 4 was isolated in very good yield (93%) and good
enantiomeric ratio (92:8). We have previously established that
iminium activation of 1 is efficient in both anhydrous
conditions and in the presence of a large excess of water, as
exemplified in Friedel−Craft reactions.16 In the present
reaction conditions, the boric acid, which accumulates during
the reaction course, can unfavorably interfere with the catalytic
cycle. We think that the addition of an optimized amount of
water might limit this interference. In order to further improve
the process, a broader range of catalysts belonging to the
diphenylprolinol family was evaluated. In all cases the reaction
was efficient and lactone 4 was isolated in good to excellent
yields (from 67 to 98%, entries 2 to 6). Longer reaction time
and lower yields of lactone 4 were observed when catalysts 2b
and 2c containing OCH3 and OTMS groups instead of the
hydroxyl group were used (entries 2 and 3). Lower
enantioselectivities were also noticed using these two catalysts;
however, the same major enantiomer was obtained, which
imply that specific involvement of the hydroxyl group in the
catalyst activation mode could be excluded. This fact was
confirmed by the good catalytic performance of diphenylpro-
linol silyl ether 2d. Indeed when catalyst 2d was used, a
significantly shorter reaction time (2 h) and higher isolated
yield (98%) were observed (entry 4) while maintaining a good
enantioselectivity (er 92:8). Unfortunately neither the use of
catalyst 2e31 and 2f with potentially higher shielding effect
(Table 1, entries 5 and 6) nor the use of different solvents
(Table 2, entries 2−11) improved the enantiomeric ratio of the
lactone 4. In all other tested solvents this ratio decreased until
71:29 (Table 2). The migration of the boronic acid substituent
worked well in a shorter time (from 1.5 h to 6 h) in other
Table 1. Organocatalytic Transfer of Boronic Acid to the 5-
a
Hydroxyfuranone-2(5H)-one 1
b
c
entry
catalyst
time (h)
yield (%)
er
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
6
93
67
86
98
93
80
92:8
10
12
2
70:30
83:17
92:8
3
87:13
91:9
4.5
2
d
d
2d
60
99:1
a
The reactions were carried out at 0 °C with 0.55 mmol of boronic
acid, 0.5 mmol of 5-hydroxyfuran-2(5H)-one 1, 0.05 mmol of catalyst
2 in CH3CN (1.5 mL) and water (45 μL). Reaction time needed for
b
the total consumption of 5-hydroxyfuran-2(5H)-one 1 in the
c
organocatalytic boronic acid transfer. Determined by chiral HPLC
analysis; absolute configuration was assigned by X-ray crystallography.
d
Reaction carried out on 1 mmol scale; yield and er obtained after
recrystallization.
experiments using diphenyl prolinol 2a as catalyst we were
pleased to isolate the expected product 4, nevertheless we
encountered great variation in the reaction time of the boronic
acid substituent transfer as well as inconsistencies in the
isolated yields of the lactone 4. After careful examination of the
experimental conditions, we found that the amount of water in
the reaction medium strongly affected the reaction. When the
B
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Table 2. Solvent Effect on Boronic Acid Transfer to 5-
a
Hydroxyfuranone-2(5H)-one
b
c
entry
solvent
time (h)
yield (%)
er
1
CH3CN
CH3CH2CN
nBuCN
EtOAc
DCM
2
98
85
83
76
67
60
55
60
62
42
20
92:8
2
1.5
2
82:18
85:15
78:22
85:15
82:18
71:29
78:22
84:16
80:20
78:22
Figure 1. Structure of compound 5 from single-crystal X-ray data.
3
4
6
keto acids, is a commonly used strategy to obtain hetero-
cycles.32 Despite the numerous studies involving the Ugi
reaction,32 only a few deal with the intramolecular Passerini
reaction.33−36 Notably, and to the best of our knowledge, a
direct access to chiral lactone using the intramolecular Passerini
reaction as a key step has not been previously reported. In our
prototypical synthesis, 1.5 equiv of isocyanide was added after
the transfer of the boronic acid substituent under the previously
optimized conditions. The reaction mixture was then stirred at
room temperature until full consumption of the chiral primary
adduct (Scheme 3). When the reaction was carried out with N-
5
2
6
MTBE
DME
48
48
48
24
240
240
7
8
MeTHF
EtOH
9
10
11
DMF
DMSO
a
The reactions were carried out at room temperature with 0.55 mmol
of boronic acid, 0.5 mmol of 5-hydroxyfuran-2(5H)-one 1, 0.05 mmol
of catalyst 2d in solvent (1.5 mL) and water (45 μL). Reaction time
needed for the total consumption of 5-hydroxyfuran-2(5H)-one 1 in
the organocatalytic boronic acid transfer. Determined by chiral HPLC
b
c
1
Boc-indole-2-boronic acid 3 and tert-butyl isocyanide, the H
analysis; absolute configuration was assigned by X-ray crystallography.
NMR spectra of the crude reaction mixture showed the
formation of the expected γ-lactones 6a and 6b in a
diastereoisomeric ratio of 72:28. These two diastereoisomeric
γ-lactones 6a and 6b were easily isolated by chromatography in
high yields (56 and 17% respectively). An enantiomeric ratio of
90:10 was obtained for both of them. The X-ray crystallography
structure of the minor diastereoisomer 6b revealed a cis
relationship between the two substituents of the γ-lactone ring.
The compounds 7a and 7b bearing a methoxygroup on the
indole ring were obtained in the same range of yields,
diastereoselectivity (dr 75:25) and enantioselectivity (er 96:4).
The overall process required trivial reaction conditions and
only one purification step to obtain γ-lactones in high yields. It
is noteworthy that a good level of diastereoselectivity was
obtained for this Passerini type reaction.37 The enantiomeric
ratios obtained are in accordance with those observed for the
simple transfer of the boronic acid (Table 1) indicating no
significant depletion of the chirality during the Passerini
reaction. In order to establish the influence of the reaction
conditions on the diastereoselectivity of the intermolecular
Passerini reaction, an acidic aqueous work up (CH2Cl2/HCl 1
N) was done before the addition of the isocyanide to remove
the catalyst and the formed boric acid. After evaporation of the
solvent, the obtained chiral primary adducts were engaged in
the Passerini reaction. In acetonitrile, the same diasteroselec-
tivity was obtained. In dichloromethane, lower diasteroselec-
tivity (dr 60:40) was observed. We also checked to see if the
observed diastereoselectivity could be the result of epimeriza-
tion in the γ position of the final lactone leading to a steady
ratio of diastereoisomers. The two diastereoisomers 6a and 6b
exhibited a configurational stability over a period of 24 h in
acetonitrile both in neutral conditions and in the presence of
one equivalent of boric acid. These results clearly indicate that
diastereoselectivity cannot arise from an epimerization process
leading to a thermodynamic mixture of diastereoisiomers. The
complexity of Passerini reaction mechanism and the difficulty in
establishing a model for such a 1,3-asymmetric induction, make
nitrile solvents (entries 2 and 3), ethyl acetate (entry 4) and
dichloromethane (entry 5) but occurred much more slowly in
ethereal solvents (entries 6−8) and in ethanol (entry 9). In
polar aprotic solvents, DMF and DMSO, the reaction was not
complete after prolonged reaction time entailing low yields in
lactone 4 (entries 10−11). Finally, the practicality of the
process was illustrated by the synthesis of the lactone 4 under
optimized conditions in high enantiomeric purity (er 99:1) and
in 60% yield after recrystallization (Table 1, entry 7).
In order to assign the absolute configuration of lactone 4,
lactone 5 bearing a bromine atom on the aromatic ring was
obtained in 95% yield using N-bromosuccinimide as brominat-
ing agent (Scheme 2). This transformation proceeded without
Scheme 2. Synthesis of the Brominated Lactone 5
loss of enantiomeric purity. According to the X-ray data
obtained for lactone 5, the absolute configuration of the created
stereocenter was assigned as R using anomalous dispersion
(Figure 1). This stereochemistry is in accordance with our
working hypothesis involving the formation of the iminium
intermediate I and the migration of the boronic acid substituent
through the less hindered Si face (Scheme 1).
Having established convenient reaction conditions for the
asymmetric transfer of the boronic acid substituent, we then
explored the one pot synthesis of substituted α,γ-substituted
lactones by transformation of the primary adduct by an
intramolecular Passerini reaction. The reaction of isocyanide
with bifunctional reagents, especially tethered aldehyde and
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Scheme 3. Access to Indole Substituted Chiral γ-Lactones 6−10 by One Pot Sequential Sequence Enantioselective
a b
,
Organocatalytic Michael Addition of Boronic Acid and Diastereoselective Intramolecular Passerini Reaction
a
The reactions were carried out with 1.1 mmol of boronic acid, 1 mmol of 5-hydroxyfuran-2(5H)-one 1, 0.10 mmol of catalyst 2d in CH3CN (1.5
mL) and water (90 μL). The reactions were stirred at 0 °C until full conversion of 1 (TLC analysis). 1.5 mmol of isocyanide and CH3CN (1.5 mL)
1
were then added, and the reactions were stirred at room temperature until full consumption of primary adduct. dr determined by H NMR of the
b
crude mixture and er determined by chiral HPLC analysis. Structure of minor diastereoisomer 6b from single-crystal X-ray data.
it hard to explain the observed diastereoselectivity. The
synthesis of other diversely substituted indole γ-lactones (8−
10) was achieved using various isocyanides. In all cases the
formation of lactone rings through the Passerini reaction
occurred with a diastereoselectivity higher than 70:30. All
diastereoisomers were easily separated by chromatography and
were obtained with good enantiomeric ratios in moderate to
good yields (Scheme 3).
conditions into γ-lactones 14−16 by reaction with tert-
butylisocyanide. The γ-lactone 14 was obtained in a 60%
yield and a 88:12 enantiomeric ratio for both diastereoisomers
(dr 56:44). When 2,4-dimethoxyphenylboronic acid was used
as a reaction partner the reaction sequence proceeded with a
good level of diastereoselectivity (80:20). Diastereoisomeric
lactones 15a and 15b were isolated in good yields (59 and
14%) albeit with a lower enantioselectivity (er 82:18). The
diastereoisomeric lactones 16a and 16b were obtained in low
yields (25 and 15%) under these reaction conditions illustrating
the significant lower reactivity of 4-methoxyphenyl boronic acid
in this process. Moreover, lactones 16a and 16b were obtained
with virtually no enantioselectivity. N-Boc-pyrrol-2-boronic acid
is highly reactive in this process as the addition adduct was
obtained in a shorter reaction time on the 1 mmol scale and the
conversion into lactones 17a and 17b occurred with a good
level of diastereoselectivity in this case (dr 75:25). Diaster-
eoisomers 17a and 17b were isolated in high yield (64 and
20%, respectively). However, the same low enantiomeric ratio
(70:30) was obtained for both diastereoisomers. Finally, the
lactone 18 bearing a benzofuran substituent was obtained as a
mixture of diastereoisomers in 70% yield but with no
enantioselectivity.
We then explored the use of other boronic acids in this one-
pot process (Scheme 4). The lactones 11, 12 and 13 were thus
obtained in good yields as a mixture of two diastereoismers (79,
63 and 72% respectively) using styrene boronic acid derivatives.
However, a lower diastereoselectivity (dr 61:39) was observed
using styrene boronic acid instead of indole derivatives. Albeit
the enantiomeric ratios obtained for the major diastereoisomers
were close to those previously observed (88:12 to 92:8), a
significant lower enantiomeric ratio was obtained for the minor
diastereoisomers (71:29 to 83:17). We then performed several
experiments in acetonitrile to check the configurational stability
of diastereoisomers 11. Neither the enantiomeric nor the
diastereoisomeric ratio changed over a period of 24 h under
neutral conditions or in the presence of one equivalent of boric
acid. These observations indicated that partial racemization of
the chiral center occurred during the course of the Passerini
reaction rather than after the formation of the final lactone.
Despite the lower reactivity of the aryl boronic acid as a
reaction partner in the Petasis like reactions, the electron rich
aryl boronic acids could be transferred to the 5-hydroxyfuran-
2(5H)-one 1 and subsequently transformed under one-pot
CONCLUSION
■
The transformation of easily available starting materials into
chiral γ-lactones exhibiting an original substitution pattern was
achieved in a one-pot sequence based on the use of the 5-
hydroxyfuran-2(5H)-one 1 as a C-4 building block. The process
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ab
,
Scheme 4. Synthesis α,γ-Substituted γ-Lactones 11−18
EXPERIMENTAL SECTION
■
General Information. Thin-layer chromatography (TLC) analyses
were done using aluminum sheets coated with silica gel 60 F254. Flash
column chromatography (FC) was carried out using silica gel 60 Å
(0.04−0.06 mm). Commercially available products were used without
further purification. NMR spectra were recorded with 250 MHz
(BBFO + Z-GRD Probe) (1H: 250 and 13C: 63 MHz), 500 MHz
(BBFO + Z-GRD Probe) (1H: 500 and 13C: 126 MHz) and 600 MHz
(CPTCI Z-GRD CryoProbe) (1H: 600 and 13C: 151 MHz)
spectrometers in CDCl3. Chemical shifts are given in ppm, calibrated
to the residual solvent peak,38 and coupling constants “J” are expressed
in hertz (multiplicity: s = singlet, bs = broad singlet, d = doublet, dd =
double doublet, dt = double triplet, t = triplet, m = multiplet). Optical
rotations were determined at 20 °C in the specified solvents. High-
resolution mass spectra (HRMS) were performed on Q-TOF Micro
micromass positive ESI (EV = 30 V). Enantiomeric ratios were
determined by high-performance liquid chromatography (HPLC) with
a chiral column.
General Procedure for Synthesis of Lactone 4. The catalyst
(0.05 mmol) and 5-hydroxyfuran-2(5H)-one 1 (0.5 mmol) were
dissolved in acetonitrile (1 mL), then H2O (2.5 mmol) was added.
The reaction mixture was cooled to 0 °C and the boronic acid (0.55
mmol) was added. The reaction was stirred until total consumption of
the boronic acid (TLC analysis). The reaction mixture was then
diluted with CH3CN (1 mL), and NaBH4 (1 mmol) was added. When
the reduction was completed (15 min), 1 M HCl (15 mL) solution
was carefully added. The reaction mixture was extracted with CH2Cl2
(3 × 15 mL). The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture was
dissolved in CHCl3 (2 mL), and p-toluenesulfonic acid was added
(0.05 mmol). The reaction mixture was then stirred overnight. The
crude material was purified by silica gel column chromatography to
yield the desired product.
General Procedure for the One-Pot Sequential Enantiose-
lective Organocatalytic Michael Addition of Boronic Acid and
Diastereoselective Intramolecular Passerini Reaction (Com-
pounds 6−18). The catalyst (0.1 mmol) and 5-hydroxyfuran-2(5H)-
one 1 (1 mmol) were dissolved in acetonitrile (1.5 mL), then H2O (5
mmol) was added. The reaction mixture was cooled to 0 °C and the
boronic acid (1.1 mmol) was added. The reaction was stirred until
total consumption of the boronic acid (TLC analysis) (Reaction time
A). The isocyanide (1.5 mmol) and acetonitrile (1.5 mL) were then
added and the reaction mixture was stirred until total consumption of
the primary adduct (TLC analysis) (Reaction time B). After
concentration under reduced pressure, the crude residue was purified
by silica gel column chromatography to yield the desired products.
(R)-tert-Butyl 2-(2-oxotetrahydrofuran-3-yl)-1H-indole-1-car-
boxylate (4). (Table 1, Entry 4) The title compound (150 mg, 0.49
mmol, 98%) was prepared as a white solid by the general procedure
and eluted from silica gel with CH2Cl2/Hexanes (90/10) (Rf = 0.6
CH2Cl2/Hexanes 80/20): mp 108−109 °C; 1H NMR (250 MHz,
CDCl3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.58−7.40 (m, 1H), 7.36−7.10 (m,
2H), 6.59 (s, 1H), 4.61 (t, J = 9.5 Hz, 1H), 4.49 (td, J = 8.5, 4.0 Hz,
1H), 4.38 (td, J = 9.0, 7.0 Hz, 1H), 2.74 (dddd, J = 12.5, 9.0, 7.0, 4.0
Hz, 1H), 2.50 (ddt, J = 12.5, 10.0, 8.5 Hz, 1H), 1.70 (s, 9H); 13C
NMR (63 MHz, CDCl3) δ 175.9, 150.6, 136.6, 135.6, 128.8, 124.5,
123.1, 120.7, 115.9, 109.7, 84.9, 66.6, 41.3, 30.5, 28.3; IR (KBr plate)
νmax 3005, 2976, 2935, 2913, 1914, 1770, 1732, 1570, 1481, 1546,
1379, 1344, 1323, 1307, 1304, 1258, 1225, 1171, 1161, 1127, 1097,
1021, 951, 904, 840, 748 (cm−1); ESI-HRMS m/z calcd for
a
The reactions were carried out with 1.1 mmol of boronic acid, 1
mmol of 5-hydroxyfuran-2(5H)-one 1, 0.10 mmol of catalyst 2d in
CH3CN (1.5 mL) and water (90 μL). The reaction was stirred at 0 °C
until full conversion of 1 (TLC analysis). 1.5 mmol of tert-butyl
isocyanide and CH3CN (1.5 mL) were then added, and the reaction
was stirred at rt until full consumption of primary adduct. dr
determined by 1H NMR of the crude mixture. er determined by chiral
b
HPLC analysis. Absolute configuration was assigned by analogy.
involved an enantioselective organocatalytic transfer of boronic
acid followed by an intramolecular Passerini reaction. When N-
Boc-indole-2-boronic acid was used as the reaction partner, the
transfer of boronic acid was achieved with a good level of
enantioselectivity. Moreover, the intramolecular Passerini
reaction, applied for the first time for the synthesis of α,γ-
substituted chiral lactones, proceeded diastereoselectively to
afford the desired synthons in high yields. The methodology
was further extended to several other boronic acids, including
styrenes, electron rich phenyl rings and heteroaromatics,
leading to structurally diversified γ-lactones in good yield but
with moderate enantiomeric and diastereoisomeric selectivity.
Further development of merging enantioselective organo-
catalysis and isocyanide chemistry affording new chiral
biologically relevant structures for the generation of structural
diversity is currently under investigation in our group.
+
C17H19NNaO4 ([M + Na]+) 324.1212, found 324.1196; er (8:92);
The enantiomeric ratio was determined by HPLC with a
CHIRALCEL OD-H column (hexane/iPrOH = 83:17, 254 nm, 1
mL/min), tR (minor) = 6.7 min, tR (major) = 8.1 min.
Reaction carried out on 1 mmol scale, compound 4 (180 mg, 0.6
mmol, 60%): [α]20 = +52.5 (c 1, CHCl3), er (1:99).
D
(R)-tert-Butyl 3-bromo-2-(2-oxotetrahydrofuran-3-yl)-1H-in-
dole-1-carboxylate (5). The compound 4 (50 mg, 0.17 mmol) was
dissolved in dichloromethane (2 mL) then the NBS (31 mg, 0.174
mmol) was added. The mixture was heated to reflux for 2 h. Water (10
E
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mL) was added, and the reaction mixture was extracted twice with
dichloromethane (15 mL), and then washed with 1 M NaOH (10
mL). The organic layers were dried over MgSO4, filtered, concentrated
under reduced pressure and purified on silica gel chromatography
(CH2Cl2/Hexanes 90/10) to afford compound 5 (61 mg, 0.16 mmol,
95%) as a white solid (90/10) (Rf = 0.5 CH2Cl2/Hexanes 80/20): mp
180 °C dec; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 1H),
7.53 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz,
1H), 4.64 (t, J = 9.0 Hz, 1H), 4.59 (bs, 1H), 4.43 (dt, J = 9.0, 8.5 Hz,
1H), 2.74 (ddd, J = 21.5, 11.5, 10.0 Hz, 1H), 2.57 (s, 1H), 1.69 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 175.1, 150.1, 135.0, 131.8,
128.1, 125.8, 123.5, 119.5, 115.8, 104.0, 85.8, 66.8, 40.1, 28.2, 27.8;
enantiomeric ratio was determined by HPLC with a CHIRALCEL IC
column (hexane/EtOH = 70:30, 254 nm, 1 mL/min), tR (major) = 9.9
min, tR (minor) = 16.4 min.
tert-Butyl 2-((3R,5S)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-5-methoxy-1H-indole-1-carboxylate (7b). The
title compound was prepared (77 mg, 0.18 mmol, 18%) as a white
solid by the general procedure and eluted from silica gel with CH2Cl2/
AcOEt (98/2) (Reaction time A: 7 h; Reaction time B: 12 h) (Rf = 0.2
CH2Cl2/AcOEt 97/3): mp 148 °C dec; 1H NMR (600 MHz, CDCl3)
δ 7.83 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 9.0,
2.5 Hz, 1H), 6.54 (s, 1H), 6.42 (bs, 1H), 4.79 (dd, J = 10.0, 7.5 Hz,
1H), 4.40 (bs, 1H), 3.84 (s, 3H), 2.96 (m, 1H), 2.61 (q, J = 11.5 Hz,
1H), 1.68 (s, 9H), 1.41 (s, 9H); 13C NMR (151 MHz, CDCl3) δ
174.2, 168.6, 156.2, 150.7, 134.4, 131.0, 129.5, 116.8, 113.6, 112.1,
103.0, 84.9, 76.0, 55.8, 51.5, 42.6, 33.3, 28.8, 28.4; IR (KBr plate) νmax
3430, 2974, 2925, 1786, 1684, 1618, 1528, 1480, 1450, 1380, 1317,
1289, 1255, 1216, 1177, 1157, 1128, 1099, 1042, 1008, 968, 852
+
ESI-HRMS m/z calcd for C17H18BrNNaO4 ([M + Na]+) 402.0317,
found 402.0312; [α]20 = +6.1 (c 1, CHCl3), er (99:1). The
D
enantiomeric ratio was determined by HPLC with a CHIRALCEL IC
column (hexane/iPrOH = 60:40, 254 nm, 1 mL/min), tR (major) =
9.5 min, tR (minor) = 27.3 min.
+
(cm−1); ESI-HRMS m/z calcd for C23H30N2NaO6 ([M + Na]+)
tert-Butyl 2-((3R,5R)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-indole-1-carboxylate (6a). The title compound
(225 mg, 0.56 mmol, 56%) was prepared as a white solid by the
general procedure and eluted from silica gel with CH2Cl2/AcOEt (98/
2) (Reaction time A: 4 h; Reaction time B: 12 h) (Rf = 0.4 CH2Cl2/
453.2002, found 453.2004; [α]20 = +1.3 (c 1.2, CHCl3), er (96:4).
D
The enantiomeric ratio was determined by HPLC with a
CHIRALCEL OD-H column (hexane/EtOH = 70:30, 254 nm, 1
mL/min), tR (minor) = 5.6 min, tR (major) = 9.3 min.
1
AcOEt 98/2): mp 116−118 °C; H NMR (250 MHz, CDCl3) δ 8.02
tert-Butyl 2-((3R,5R)-5-(benzylcarbamoyl)-2-oxotetrahydro-
furan-3-yl)-1H-indole-1-carboxylate (8a). The title compound
(266 mg, 0.61 mmol, 61%) was prepared as a white solid by the
general procedure and eluted from silica gel with CH2Cl2/AcOEt (98/
2) (Reaction time A: 4 h; Reaction time B: 72 h) (Rf = 0.5 CH2Cl2/
AcOEt 98/2): mp 75−76 °C; 1H NMR (250 MHz, CDCl3) δ 8.00 (d,
J = 8.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.43−7.15 (m, 7H), 6.85 (t,
J = 5.5 Hz, 2H), 6.56 (s, 1H), 5.06 (dd, J = 8.5, 5.0 Hz, 2H), 4.63−
4.36 (m, 3H), 3.00−2.78 (m, 2H), 1.68 (s, 9H); 13C NMR (63 MHz,
CDCl3) δ 174.5, 169.8, 150.8, 137.4, 136.5, 134.1, 129.0, 128.6, 128.0,
124.8, 123.3, 120.8, 116.0, 111.1, 85.3, 76.0, 43.6, 40.8, 33.0, 28.3; IR
(KBr plate) νmax 3312, 2978, 2932, 1787, 1730, 1670, 1539, 1454,
1377, 1329, 1252, 1225, 1159, 1122, 1089, 1056, 1029, 964, 850, 819,
(d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.38−7.16 (m, 2H), 6.57
(s, 1H), 6.24 (bs, 1H), 4.92 (dd, J = 9.0, 5.0 Hz, 1H), 4.46 (t, J = 9.0
Hz, 1H), 2.96−2.71 (m, 2H), 1.66 (s, 9H), 1.41 (s, 9H); 13C NMR
(63 MHz, CDCl3) δ 174.7, 168.9, 150.7, 136.6, 134.2, 128.6, 124.8,
123.2, 120.7, 116.0, 111.0, 85.2, 76.2, 51.9, 41.0, 32.8, 28.9, 28.3; IR
(KBr plate) νmax 3338, 3078, 2974, 2929, 2855, 1786, 1732, 1685,
1550, 1545, 1455, 1425, 1376, 1330, 1257, 1224, 1159, 1122, 1091,
1056, 965, 851, 820 (cm−1); ESI-HRMS m/z calcd for
+
C22H28N2NaO5 ([M + Na]+) 423.1896, found 423.1894; [α]20
=
D
−4.2 (c 1, CHCl3), er (90:10). The enantiomeric ratio was determined
by HPLC with a CHIRALCEL OD-H column (hexane/EtOH = 92:8,
254 nm, 1 mL/min), tR (major) = 6.6 min, tR (minor) = 7.6 min.
tert-Butyl 2-((3R,5S)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-indole-1-carboxylate (6b). The title compound
(70 mg, 0.17 mmol, 17%) was prepared as a white solid by the general
procedure and eluted from silica gel with CH2Cl2/AcOEt (98/2)
(Reaction time A: 4 h; Reaction time B: 12 h) (Rf = 0.2 CH2Cl2/
AcOEt 98/2): mp 146 °C; 1H NMR (250 MHz, CDCl3) δ 7.96 (d, J =
8.0 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.36−7.16 (m, 2H), 6.62 (s,
1H), 6.42 (bs, 1H), 4.80 (dd, J = 10.0, 7.5 Hz, 1H), 4.56−4.35 (m,
1H), 2.97 (dt, J = 12.0, 9.0 Hz, 1H), 2.62 (dt, J = 12.0, 11.5 Hz, 1H),
1.70 (s, 9H), 1.41 (s, 9H).13C NMR (63 MHz, CDCl3) δ 174.1, 168.5,
150.9, 136.4, 133.9, 128.7, 124.8, 123.3, 120.7, 116.0, 112.0, 85.1, 76.0,
51.6, 42.6, 33.4, 28.9, 28.4; IR (KBr plate) νmax 3402, 2978, 2934,
1791, 1711, 1685, 1529, 1455, 1381, 1321, 1327, 1273, 1223, 1182,
1157, 1130, 1097, 1044, 1005, 968, 925, 845, 814, 762 (cm−1); ESI-
+
747 (cm−1); ESI-HRMS m/z calcd for C25H26N2NaO5 ([M + Na]+)
457.1739, found 457.1757; [α]20 = −9 (c 1, CHCl3), er (93:7). The
D
enantiomeric ratio was determined by HPLC with a CHIRALCEL
OD-H column (hexane/EtOH = 70:30, 254 nm, 1 mL/min), tR
(major) = 10.2 min, tR (minor) = 11.5 min.
tert-Butyl 2-((3R,5S)-5-(benzylcarbamoyl)-2-oxotetrahydro-
furan-3-yl)-1H-indole-1-carboxylate (8b). The title compound
(51 mg, 0.12 mmol, 12%) was prepared as a light brown gum by the
general procedure and eluted from silica gel with CH2Cl2/AcOEt (98/
2) (Reaction time A: 4 h; Reaction time B: 72 h) (Rf = 0.2 CH2Cl2/
1
AcOEt 98/2): H NMR (250 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz,
1H), 7.49 (d, J = 8.0 Hz, 1H), 7.38−7.15 (m, 7H), 7.03 (bs, 1H), 6.61
(s, 1H), 4.97 (t, J = 8.5 Hz, 1H), 4.60 (dd, J = 14.5, 6.0 Hz, 1H), 4.52−
4.35 (m, 2H), 3.03 (dt, J = 12.0, 9.0 Hz, 1H), 2.66 (q, J = 11.5 Hz,
1H), 1.59 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 173.90, 169.4,
150.8, 137.4, 136.2, 133.7, 128.8, 128.6, 127.9, 127.7 124.7, 123.2,
120.7, 115.9, 112.2, 85.2, 75.8, 43.4, 42.3, 33.1, 28.2; IR (KBr plate)
νmax 3420, 2976, 2921, 2856, 1790, 1723, 1680, 1533, 1452, 1379,
1324, 1271, 1221, 1155, 1122, 1092, 1049, 963, 904, 837, 754 (cm−1);
+
HRMS m/z calcd for C22H28N2NaO5 ([M + Na]+) 423.1896, found
423.1896; [α]20 = −9 (c 1, CHCl3), er (90:10). The enantiomeric
D
ratio was determined by HPLC with a CHIRALCEL OD-H column
(hexane/EtOH = 92:8, 254 nm, 1 mL/min), tR (minor) = 8.0 min, tR
(major) = 12.5 min.
+
ESI-HRMS m/z calcd for C25H26N2NaO5 ([M + Na]+) 457.1739,
tert-Butyl 2-((3R,5R)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-5-methoxy-1H-indole-1-carboxylate (7a). The
title compound was prepared (250 mg, 0.58 mmol, 58%) as a white
solid by the general procedure and eluted from silica gel with CH2Cl2/
AcOEt (98/2) (Reaction time A: 7 h; Reaction time B: 12 h) (Rf = 0.4
CH2Cl2/AcOEt 97/3): mp 65−67 °C; 1H NMR (600 MHz, CDCl3) δ
7.89 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 9.0, 2.5
Hz, 1H), 6.49 (s, 1H), 6.23 (bs, 1H), 4.90 (dd, J = 9.5, 4.5 Hz, 1H),
4.43 (bs, 1H), 3.83 (s, 3H), 2.86 (ddd, J = 14.5, 10.0, 4.5 Hz, 1H), 2.78
(dt, J = 13.0, 9.0 Hz, 1H), 1.67 (s, 9H), 1.40 (s, 9H); 13C NMR (151
MHz, CDCl3) δ 174.7, 168.9, 156.2, 150.6, 134.8, 131.2, 129.4, 116.8,
113.6, 110.9, 103.0, 85.0, 76.2, 55.8, 51.8, 41.0, 32.5, 28.8, 28.3; IR
(KBr plate) νmax 3347, 2974, 2935, 1784, 1729, 1684, 1618, 1541,
1479, 1451, 1379, 1323, 1256, 1219, 1160, 1126, 1093, 1035, 965, 901,
found 457.1729; [α]20 = +10 (c 1, CHCl3), er (93:7). The
D
enantiomeric ratio was determined by HPLC with a CHIRALCEL
IC column (hexane/EtOH = 60:40, 254 nm, 1 mL/min), tR (minor) =
7.3 min, tR (major) = 23.0 min.
tert-Butyl 2-((3R,5R)-5-(cyclohexylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-indole-1-carboxylate (9a). The title compound
(254 mg, 0.6 mmol, 60%) was prepared as a white solid by the general
procedure and eluted from silica gel with CH2Cl2/AcOEt (98/2)
(Reaction time A: 4 h; Reaction time B: 12 h) (Rf = 0.5 CH2Cl2/
AcOEt 98/2): mp 78−80 °C; 1H NMR (250 MHz, CDCl3) δ 8.01 (d,
J = 8.0 Hz, 1H), 7.50 (d, J = 6.5 Hz, 1H), 7.38−7.15 (m, 2H), 6.57 (s,
1H), 6.35 (d, J = 8.5 Hz, 1H), 5.00 (dd, J = 8.0, 6.0 Hz, 1H), 4.44 (t, J
= 9.5 Hz, 1H), 3.94−3.69 (m, 1H), 3.03−2.68 (m, 2H), 1.93 (bs, 2H),
1.69 (s, 9H), 1,68 (m, 2H), 1.50−1.04 (m, 6H); 13C NMR (63 MHz,
CDCl3) δ 174.7, 168.8, 150.7, 136.5, 134.2, 128.6, 124.8, 123.3, 120.7,
+
850 (cm−1); ESI-HRMS m/z calcd for C23H30N2NaO6 ([M + Na]+)
453.2002, found 453.2005; [α]20D = +9.9 (c 1, CHCl3), er (96:4). The
F
dx.doi.org/10.1021/jo501908z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
116.0, 111.2, 85.3, 76.0, 48.6, 40.9, 33.2, 33.0, 28.3, 25.5, 25.0; IR (KBr
plate) νmax 3222, 2975, 2933, 2856, 1786, 1731, 1665, 1542, 1454,
1377, 1330, 1254, 1224, 1159, 1123, 1092, 1056, 1033, 965, 851, 748
the general procedure and eluted from silica gel with CH2Cl2/AcOEt
(98/2) (Reaction time A: 6 h; Reaction time B: 12 h) (Rf = 0.4 and 0.6
1
CH2Cl2/AcOEt 97/3): H NMR (250 MHz, CDCl3) δ 7.47−7.16
+
(cm−1); ESI-HRMS m/z calcd for C24H30N2NaO5 ([M + Na]+)
(m), 6.61 (dd, J = 6.5, 1.5 Hz, 1H, minor), 6.55 (dd, J = 6.5, 1.5 Hz,
1H, major), 6.31−6.09 (m), 4.81 (dd, J = 8.5, 4.5 Hz, 1H, major), 4.73
(dd, J = 9.5, 7.0 Hz, 1H, minor), 3.63−3.37 (m), 2.95 (ddd, J = 13.0,
8.0, 7.0 Hz, 1H, minor), 2.79 (ddd, J = 13.0, 9.0, 4.5 Hz, 1H, major),
2.56 (dt, J = 13.0, 8.5 Hz, 1H, major), 2.27 (ddd, J = 13.0, 11.0, 9.5 Hz,
1H, minor), 1.38 (s, 9H, major), 1.37 (s, 9H, minor); 13C NMR (63
MHz, CDCl3) δ 176.0 (major), 175.5 (minor), 168.3 (major), 168.1
(minor), 136.1, 134.1 (major), 134.0 (minor), 128.8, 128.3 (major),
128.2 (minor), 126.6, 123.0 (minor), 122.8 (major), 76.2 (major),
76.1 (minor), 51.9 (major), 51.8 (minor), 43.5 (minor), 42.0 (major),
32.8 (minor), 32.2 (major), 28.8; IR (KBr plate) νmax 3276, 3091,
3029, 2970, 2932, 1785, 1683, 1658, 1565, 1490, 1454, 1391, 1365,
1327, 1266, 1220, 1154, 1120, 1052, 1008, 966, 924, 864, 835, 792
449.2052, found 449.2050; [α]20D = +1,4 (c 1, CHCl3), er (91:9). The
enantiomeric ratio was determined by HPLC with a CHIRALCEL IC
column (hexane/EtOH = 70:30, 254 nm, 1 mL/min), tR (major) =
10.0 min, tR (minor) = 18.1 min.
tert-Butyl 2-((3R,5S)-5-(cyclohexylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-indole-1-carboxylate (9b). The title compound
(51 mg, 0.12 mmol, 12%) was prepared as a white solid by the general
procedure and eluted from silica gel with CH2Cl2/AcOEt (98/2)
(Reaction time A: 4 h; Reaction time B: 12 h) (Rf = 0.2 CH2Cl2/
AcOEt 98/2): mp 176 °C; 1H NMR (250 MHz, CDCl3) δ 7.96 (d, J =
8.0 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.37−7.11 (m, 2H), 6.62 (s,
1H), 6.51 (d, J = 8.0 Hz, 1H), 4.89 (dd, J = 10.0, 8.0 Hz, 1H), 4.53−
4.35 (m, 1H), 3.93−3.63 (m, 1H), 3.12−2.81 (m, 1H), 2.63 (dt, J =
12.0, 11.5 Hz, 1H), 1.94 (s, 2H), 1.70 (m, 2H), 1.69 (s, 9H), 1.48−
1.05 (m, 6H); 13C NMR (63 MHz, CDCl3) δ 174.1, 168.4, 150.9,
136.4, 133.9, 128.7, 124.8, 123.3, 120.7, 116.0, 112.0, 85.1, 75.9, 48.3,
42.5, 33.2, 33.1, 28.4, 25.6, 25.0; IR (KBr plate) νmax 3391, 2929, 2855,
1790, 1723, 1673, 1532, 1479, 1452, 1379, 1325, 1271, 1222, 1157,
1123, 1095, 1049, 967, 925, 895, 868, 841, 810, 754 (cm−1); ESI-
+
(cm−1); ESI-HRMS m/z calcd for C17H21NNaO3 ([M + Na]+)
310.1419, found 310.1427; er (12:88 major ; 29:71 minor). The
enantiomeric ratio was determined by HPLC with a CHIRALCEL
OD-H column (hexane/EtOH = 80:20, 254 nm, 1 mL/min), tR
(major, major) = 12.6 min, tR (minor, major) = 16.2 min, tR (minor,
minor) = 14.3 min, tR (major, minor) = 23.6 min.
(4R)-N-(tert-Butyl)-4-((E)-4-methoxystyryl)-5-oxotetrahydro-
furan-2-carboxamide (12). The title compound (mixture of
diastereoisomers 62:38) was prepared (200 mg, 0.6 mmol, 60%) as
a pale yellow solid by the general procedure and eluted from silica gel
with CH2Cl2/AcOEt (98/2) (Reaction time A: 3 h; Reaction time B:
+
HRMS m/z calcd for C24H30N2NaO5 ([M + Na]+) 449.2052, found
449.2060; [α]20 = +15 (c 1, CHCl3), er (9:91). The enantiomeric
D
ratio was determined by HPLC with a CHIRALCEL OD-H column
(hexane/iPrOH = 77:23, 254 nm, 1 mL/min), tR (minor) = 5.2 min, tR
(major) = 7.5 min.
1
12 h) (Rf = 0.4 and 0.5 CH2Cl2/AcOEt 97/3): H NMR (600 MHz,
CDCl3) δ 7.32−7.28 (m), 6.87−6.83 (m), 6.56−6.47 (m), 6.16 (s, 1H,
minor), 6.15 (s, 1H, major), 6.07 (dd, J = 16.0, 6.5 Hz, 1H, minor),
6.02 (dd, J = 16.0, 6.5 Hz, 1H, major), 4.80 (dd, J = 8.5, 4.5 Hz, 1H,
major), 4.72 (dd, J = 9.5, 7.0 Hz, 1H, minor), 3.80 (s, 3H, major), 3.80
(s, 3H, minor), 3.50 (dddd, J = 10.5, 8.5, 6.5, 1.5 Hz, 1H, minor), 3.43
(tdd, J = 8.5, 6.5, 1.5 Hz, 1H, major), 2.94 (ddd, J = 13.0, 9.0, 7.0 Hz,
1H, minor), 2.77 (ddd, J = 13.5, 9.0, 5.0 Hz, 1H, major), 2.54 (dt, J =
13.0, 8.5 Hz, 1H, major), 2.26 (ddd, J = 13.0, 10.5, 9.5 Hz, 1H, minor),
1.38 (s, 9H, major), 1.36 (s, 9H, minor); 13C NMR (151 MHz,
CDCl3) δ 176.2 (major), 175.8 (minor), 168.4 (major), 168.1
(minor), 159.74 (major), 159.70 (minor), 133.50 (major), 133.47
(minor), 128.90 (minor), 128.88 (major), 127.8, 120.6 (minor), 120.4
(major), 114.18 (major), 114.16 (minor), 76.2 (major), 76.0 (minor),
55.43 (major), 55.41 (minor), 51.9 (major), 51.8 (minor), 43.6
(minor), 42.0 (major), 32.9 (minor), 32.3 (major), 28.80 (major),
28.78 (minor); IR (KBr plate) νmax 3277, 3093, 3036, 2968, 2933,
2841, 1782, 1659, 1608, 1564, 1513, 1457, 1393, 1365, 1294, 1252,
1225, 1172, 1155, 1035, 965, 928, 821 (cm−1); ESI-HRMS m/z calcd
tert-Butyl 2-((3R,5R)-5-((4-methoxyphenyl)carbamoyl)-2-ox-
otetrahydrofuran-3-yl)-1H-indole-1-carboxylate (10a). The title
compound (270 mg, 0.6 mmol, 60%) was prepared as a pale yellow
solid by the general procedure and eluted from silica gel with CH2Cl2/
AcOEt (98/2) (Reaction time A: 4 h; Reaction time B: 144 h) (Rf =
0.5 CH2Cl2/AcOEt (98/2): mp 86−88 °C; 1H NMR (250 MHz,
CDCl3) δ 8.19 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.56−7.42 (m, 3H),
7.37−7.10 (m, 2H), 6.86 (m, 2H), 6.59 (s, 1H), 5.16 (dd, J = 9.0, 5.0
Hz, 1H), 4.50 (t, J = 9.5 Hz, 1H), 3.80 (s, 3H), 3.07−2.81 (m, 2H),
1.69 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 174.5, 167.7, 157.0,
150.7, 136.4, 133.8, 129.8, 128.5, 124.7, 123.2, 121.9, 120.7, 115.9,
114.3, 111.4, 85.2, 75.9, 55.5, 40.8, 32.7, 28.2; IR (KBr plate) νmax
3327, 3139, 3072, 2977, 2935, 2837, 1785, 1729, 1687, 1605, 1543,
1513, 1454, 1416, 1377, 1330, 1245, 1158, 1122, 1092, 1034, 964, 830,
+
748 (cm−1); ESI-HRMS m/z calcd for C25H26N2NaO6 ([M + Na]+)
473.1689, found 473.1679; [α]20 = −1.1 (c 1, CHCl3), er (90:10).
D
The enantiomeric ratio was determined by HPLC with a
CHIRALCEL OD-H column (hexane/EtOH = 85:15, 254 nm, 1
mL/min), tR (major) = 14.6 min, tR (minor) = 18.4 min.
+
for C18H23NNaO4 ([M + Na]+) 340.1525, found 340.1521; er (93:7
major ; 17:83 minor). The enantiomeric ratio was determined by
HPLC with a CHIRALCEL OD-H column (hexane/EtOH = 70:30,
254 nm, 1 mL/min), tR (major, major) = 9.2 min, tR (minor, major) =
11.7 min, tR (major, minor) = 9.8 min, tR (minor, minor) = 16.0 min.
(4R)-N-(tert-Butyl)-4-((E)-4-fluorostyryl)-5-oxotetrahydrofur-
an-2-carboxamide (13). The title compound (mixture of diaster-
eoisomers 61:39) was prepared (220 mg, 0.72 mmol, 72%) as a white
solid by the general procedure and eluted from silica gel with CH2Cl2/
AcOEt (98/2) (Reaction time A: 5 h; Reaction time B: 12 h) (Rf = 0.4
and 0.6 CH2Cl2/AcOEt 97/3): 1H NMR (600 MHz, CDCl3) δ 7.38−
7.31 (m), 7.05−6.98 (m), 6.60−6.50 (m), 6.17−6.12 (m), 6.09 (dd, J
= 16.0, 6.5 Hz, 1H, major), 4.81 (dd, J = 8.5, 4.5 Hz, 1H, major), 4.74
(dd, J = 9.5, 7.0 Hz, 1H, minor), 3.52 (dddd, J = 10.5, 8.5, 6.0, 1.5 Hz,
1H, minor), 3.44 (tdd, J = 8.5, 6.5, 1.5 Hz, 1H, major), 2.95 (ddd, J =
13.0, 8.5, 7.0 Hz, 1H, minor), 2.81 (ddd, J = 13.5, 9.0, 4.5 Hz, 1H,
major), 2.55 (dt, J = 13.0, 8.5 Hz, 1H, major), 2.27 (dt, J = 13.0, 10.0
Hz, 1H, minor), 1.39 (s, 9H, major), 1.37 (s, 9H, minor); 13C NMR
(151 MHz, CDCl3) δ 176.0 (major), 175.5 (minor), 168.3 (major),
tert-Butyl 2-((3R,5S)-5-((4-methoxyphenyl)carbamoyl)-2-ox-
otetrahydrofuran-3-yl)-1H-indole-1-carboxylate (10b). The title
compound (60 mg, 0.13 mmol, 13%) was prepared as a brown gum by
the general procedure and eluted from silica gel with CH2Cl2/AcOEt
(98/2) (Reaction time A: 4 h; Reaction time B: 144 h) (Rf = 0.2
CH2Cl2/AcOEt 98/2): 1H NMR (500 MHz, CDCl3) δ 8.30 (bs, 1H),
7.92 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.0 Hz,
1H), 7.29 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 9.0
Hz, 2H), 6.65 (s, 1H), 5.03 (t, J = 9.0 Hz, 1H), 4.42 (s, 1H), 3.81 (s,
3H), 3.07 (dt, J = 10.5, 9.5 Hz, 1H), 2.70 (q, J = 11.0 Hz, 1H), 1.57 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 174.1, 167.6, 156.8, 151.1,
136.2, 133.6, 130.3, 128.7, 124.9, 123.4, 121.7, 120.8, 116.0, 114.3,
112.9, 85.5, 75.6, 55.6, 42.4, 32.9, 28.2; IR (KBr plate) νmax 3405, 3339,
3045, 2974, 2931, 2837, 1789, 1725, 1683, 1601, 1539, 1513, 1453,
1414, 1381, 1329, 1246, 1159, 1125, 1036, 964, 916, 831, 744 (cm−1);
+
ESI-HRMS m/z calcd for C25H26N2NaO6 ([M + Na]+) 473.1689,
found 473.1683; [α]20 = +21.4 (c 0.2, CHCl3), er (90:10). The
D
enantiomeric ratio was determined by HPLC with a CHIRALCEL
OD-H column (hexane/EtOH = 85:15, 254 nm, 1 mL/min), tR
(minor) = 12.2 min, tR (major) = 21.4 min.
(4R)-N-(tert-Butyl)-5-oxo-4-((E)-styryl)tetrahydrofuran-2-car-
boxamide (11). The title compound (mixture of diastereoisomers
61:39)) was prepared (228 mg, 0.79 mmol, 79%) as a white solid by
168.0 (minor), 162.9 (d, JC−F = 248.5 Hz, major), 162.8 (d, JC−F
=
248.5 Hz, minor), 133.0 (major), 132.9 (minor), 132.30 (d, JC−F = 4.0
Hz, minor), 132.27 (d, JC−F = 4.0 Hz, major) 128.21 (d, JC−F = 2.0 Hz,
major), 128.20 (d, JC−F = 2.0 Hz, minor), 122.7 (d, JC−F = 2.0 Hz,
minor), 122.6 (d, JC−F = 2.0 Hz, major), 115.8 (major), 115.7 (minor),
G
dx.doi.org/10.1021/jo501908z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
76.2 (major), 76.1 (minor), 52.0 (major), 51.8 (minor), 43.5 (minor),
41.9 (major), 32.8 (minor), 32.2 (major), 28.81 (major), 28.78
(minor); 19F NMR (235 MHz, CDCl3) δ −113.79 − −114.04 (m). IR
(KBr plate) νmax 3341, 3277, 3089, 2973, 2931, 1891, 1765, 1683,
1662, 1602, 1558, 1510, 1456, 1393, 1366, 1329, 1266, 1232, 1172,
1095, 1045, 967, 924, 820 (cm−1); ESI-HRMS m/z calcd for
(c 0.6, CHCl3), er (84:16). The enantiomeric ratio was determined by
HPLC with a CHIRALCEL IC column (hexane/EtOH = 60:40, 254
nm, 1 mL/min), tR (minor) = 7.7 min, tR (minor) = 25.0 min.
(2R,4R)-N-(tert-Butyl)-4-(4-methoxyphenyl)-5-oxotetrahy-
drofuran-2-carboxamide (16a). The title compound was prepared
(73 mg, 0.25 mmol, 25%) as a white solid by the general procedure
and eluted from silica gel with Hexanes/AcOEt (85/15) (Reaction
time A: 48 h; Reaction time B: 12 h) (Rf = 0.7 CH2Cl2/AcOEt 97/3):
mp 109−111 °C ; 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz,
2H), 6.90 (d, J = 8.5 Hz, 2H), 6.19 (bs, 1H), 4.84 (dd, J = 8.5, 4.5 Hz,
1H), 3.82−3.75 (m, 4H), 2.93 (ddd, J = 13.5, 9.5, 4.5 Hz, 1H), 2.66
(dt, J = 13.5, 8.5 Hz, 1H), 1.39 (s, 9H); 13C NMR (151 MHz, CDCl3)
δ 176.6, 168.4, 159.4, 128.9, 127.7, 114.6, 76.0, 55.5, 52.0, 43.9, 34.4,
28.8; IR (KBr plate) νmax 3529, 3280, 3096, 2967, 2929, 2848, 2794,
1775, 1661, 1616, 1565, 1517, 1458, 1393, 1366, 1307, 1255, 1225,
1177, 1149, 1040, 1013, 983, 900, 831, 800, 773 (cm−1); ESI-HRMS
m/z calcd for C16H21NNaO4+ ([M + Na]+) 314.1368, found 314.1367;
er (58:42). The enantiomeric ratio was determined by HPLC with a
CHIRALCEL IC column (hexane/EtOH = 60:40, 280 nm, 1 mL/
min), tR (major) = 6.0 min, tR (minor) = 7.5 min.
(2R,4S)-N-(tert-Butyl)-4-(4-methoxyphenyl)-5-oxotetrahy-
drofuran-2-carboxamide (16b). The title compound was prepared
(42 mg, 0.15 mmol, 15%) as a colorless gum by the general procedure
and eluted from silica gel with Hexanes/AcOEt (85/15) (Reaction
time A: 48 h; Reaction time B: 12 h) (Rf = 0.55 CH2Cl2/AcOEt 97/
3): 1H NMR (500 MHz, CDCl3) δ 7.21 (d, J = 8.5 Hz, 2H), 6.90 (d, J
= 8.5 Hz, 2H), 6.20 (bs, 1H), 4.76 (dd, J = 9.5, 7.0 Hz, 1H), 3.87 (dd,
J = 11.5, 9.0 Hz, 1H), 3.80 (s, 3H), 3.07 (ddd, J = 13.5, 9.0, 7.0 Hz,
1H), 2.40 (ddd, J = 13.5, 11.5, 9.5 Hz, 1H), 1.38 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 175.9, 168.1, 159.4, 129.0, 127.2, 114.5, 75.6,
55.5, 51.8, 45.4, 34.7, 28.8; IR (KBr plate) νmax 3420, 3273, 3095,
2964, 2927, 2856, 1776, 1729, 1664, 1615, 1569, 1514, 1456, 1383,
1327, 1303, 1253, 1179, 1153, 1036, 936, 833, 805 (cm−1); ESI-HRMS
m/z calcd for C16H21NNaO4+ ([M + Na]+) 314.1368, found 314.1357;
er (58:42). The enantiomeric ratio was determined by HPLC with a
CHIRALCEL IC column (hexane/EtOH = 60:40, 280 nm, 1 mL/
min), tR (minor) = 6.5 min, tR (minor) = 11.5 min.
+
C17H20FNNaO3 ([M + Na]+) 328.1325, found 328.1328; er (89:11
major ; 73:27 minor). The enantiomeric ratio was determined by
HPLC with a CHIRALCEL IC column (Hexane/EtOH = 88:12, 254
nm, 1 mL/min), tR (major, major) = 16.4 min, tR (minor, major) =
21.5 min, tR (major, minor) = 18.2 min, tR (minor, minor) = 25.8 min.
(4R)-N-(tert-Butyl)-4-(4-(dimethylamino)phenyl)-5-oxotetra-
hydrofuran-2-carboxamide (14). The title compound (mixture of
diastereoisomers 56:44) was prepared (183 mg, 0.59 mmol, 60%) as a
white solid by the general procedure and eluted from silica gel with
CH2Cl2/AcOEt (98/2) (Reaction time A: 3 h; Reaction time B: 12 h)
(Rf = 0.4 and 0.45 CH2Cl2/AcOEt 97/3): 1H NMR (600 MHz,
CDCl3) δ 7.17−7.08 (m), 6.75−6.66 (m), 6.23 (bs), 4.83 (dd, J = 8.5,
5.0 Hz, 1H, major), 4.73 (dd, J = 9.5, 7.0 Hz, 1H, minor), 3.81 (dd, J =
11.5, 9.0 Hz, 1H, minor), 3.74 (t, J = 9.0 Hz, 1H, major), 3.03 (ddd, J
= 13.0, 9.0, 7.0 Hz, 1H, minor), 2.93 (s, 6H, minor), 2.93 (s, 6H,
major), 2.87 (ddd, J = 13.5, 9.0, 5.0 Hz, 1H, major), 2.65 (dt, J = 13.5,
8.5 Hz, 1H, major), 2.37 (ddd, J = 13.0, 11.5, 9.5 Hz, 1H, minor), 1.38
(s, 9H, major), 1.37 (s, 9H, minor); 13C NMR (151 MHz, CDCl3) δ
176.9 (major), 176.3 (minor), 168.6 (major), 168.2 (minor), 150.22
(minor), 150.17 (major), 128.5 (minor), 128.3 (major), 123.1
(major), 122.6 (minor), 112.9 (major), 112.8 (minor), 76.0 (major),
75.6 (minor), 51.8 (major), 51.6 (minor), 45.3 (minor), 43.7 (major),
40.58 (minor), 40.55 (major), 34.7 (minor), 34.4 (major), 28.73
(major), 28.71 (minor); IR (KBr plate) νmax 3338, 3280, 3091, 2967,
2928, 2886, 2800, 1782, 1659, 1618, 1561, 1525, 1454, 1393, 1361,
1271, 1225, 1194, 1149, 1056, 1015, 935, 899, 820, 799 (cm−1); ESI-
+
HRMS m/z calcd for C17H25N2O3 ([M + H]+) 305.1865, found
305.1863; er (12:88). The enantiomeric ratio was determined by
HPLC with a CHIRALCEL IC column (hexane/EtOH = 60:40, 254
nm, 1 mL/min), tR (major, major) = 9.3 min, tR (minor, minor) = 11.6
min, tR (minor, minor) = 10.2 min, tR (major, minor) = 21.7 min.
(2R,4R)-N-(tert-Butyl)-4-(2,4-dimethoxyphenyl)-5-oxotetra-
hydrofuran-2-carboxamide (15a). The title compound was
prepared (190 mg, 0.59 mmol, 59%) as a pale yellow gum by the
general procedure and eluted from silica gel with Hexanes/AcOEt
(85/15) (Reaction time A: 6 h; Reaction time B: 12 h) (Rf = 0.6
CH2Cl2/AcOEt 95/5): 1H NMR (500 MHz, CDCl3) δ 7.03 (d, J = 8.0
Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 8.5, 2.5 Hz, 1H), 6.22
(bs, 1H), 4.85 (dd, J = 9.5, 4.5 Hz, 1H), 3.92−3.67 (m, 7H), 2.78
(ddd, J = 13.0, 10.5, 4.5 Hz, 1H), 2.62 (dt, J = 13.0, 9.0 Hz, 1H), 1.39
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 177.3, 169.2, 161.0, 157.8,
130.8, 117.8, 104.6, 99.4, 76.1, 55.6, 55.5, 51.8, 41.4, 33.0, 28.8; IR
(KBr plate) νmax 3420, 3355, 3079, 2967, 2933, 2842, 1778, 1672,
1615, 1588, 1547, 1510, 1459, 1388, 1365, 1296, 1265, 1210, 1157,
1033, 933, 899, 834, 796, 754 (cm−1); ESI-HRMS m/z calcd for
C17H24NO5+ ([M + H]+) 322.1654, found 322.1653; [α]20D = −6.8 (c
1, CHCl3), er (82:18). The enantiomeric ratio was determined by
HPLC with a CHIRALCEL IC column (hexane/EtOH = 60:40, 254
nm, 1 mL/min), tR (major) = 6.6 min, tR (minor) = 8.9 min.
tert-Butyl 2-((3R,5R)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-pyrrole-1-carboxylate (17a). The title com-
pound was prepared (224 mg, 0.64 mmol, 64%) as a colorless gum by
the general procedure and eluted from silica gel with CH2Cl2/AcOEt
(98/2) (Reaction time A: 1 h; Reaction time B: 12 h) (Rf = 0.4
1
CH2Cl2/AcOEt 97:3): H NMR (600 MHz, CDCl3) δ 7.23 (dd, J =
3.5, 2.0 Hz, 1H), 6.22 (bs, 1H), 6.15 (dd, J = 3.5, 2.0 Hz, 1H), 6.12 (t,
J = 3.5 Hz, 1H), 4.86 (dd, J = 9.0, 4.5 Hz, 1H), 4.30 (bs, 1H), 2.80
(ddd, J = 13.0, 10.0, 4.5 Hz, 1H), 2.70 (dt, J = 13.0, 9.0 Hz, 1H), 1.58
(s, 9H), 1.39 (s, 9H); 13C NMR (151 MHz, CDCl3) δ 175.0, 168.9,
149.2, 128.0, 122.6, 114.6, 110.3, 84.5, 76.0, 51.7, 39.6, 32.6, 28.7, 27.9;
IR (KBr plate) νmax 3421, 3358, 2975, 2933, 1787, 1741, 1683, 1547,
1486, 1457, 1413, 1372, 1336, 1257, 1227, 1141, 1064, 977, 900, 846,
769, 728, 686 (cm−1); ESI-HRMS m/z calcd for C18H26N2NaO5+ ([M
+ Na]+) 373.1739, found 373.1733; [α]20 = +8 (c 1, CHCl3), er
D
(70:30). The enantiomeric ratio was determined by HPLC with a
CHIRALCEL IC column (hexane/iPrOH = 70:30, 254 nm, 1 mL/
min), tR (major) = 6.9 min, tR (minor) = 8.8 min.
tert-Butyl 2-((3R,5S)-5-(tert-butylcarbamoyl)-2-oxotetrahy-
drofuran-3-yl)-1H-pyrrole-1-carboxylate (17b). The title com-
pound was prepared (70 mg, 0.2 mmol, 20%) as a white solid by the
general procedure and eluted from silica gel with CH2Cl2/AcOEt (98/
2) (Reaction time A: 1 h; Reaction time B: 12 h) (Rf = 0.25 CH2Cl2/
AcOEt 97/3): mp 106−108 °C; 1H NMR (600 MHz, CDCl3) δ 7.21
(dd, J = 3.5, 2.0 Hz, 1H), 6.40 (bs, 1H), 6.20 (dd, J = 3.5, 2.0 Hz, 1H),
6.12 (t, J = 3.5 Hz, 1H), 4.74 (dd, J = 10.0, 7.5 Hz, 1H), 4.28 (m, 1H),
2.90 (dt, J = 12.0, 9.0 Hz, 1H), 2.49 (q, J = 12.0 Hz, 1H), 1.58 (s, 9H),
1.40 (s, 9H); 13C NMR (151 MHz, CDCl3) δ 174.7, 168.6, 149.4,
127.9, 122.7, 115.7, 110.5, 84.5, 75.9, 51.5, 41.4, 33.3, 28.8, 28.1; IR
(KBr plate) νmax 3426, 3117, 2973, 2934, 2878, 1793, 1734, 1678,
1529, 1495, 1478, 1453, 1413, 1365, 1342, 1256, 1227, 1143, 1072,
(2R,4S)-N-(tert-Butyl)-4-(2,4-dimethoxyphenyl)-5-oxotetra-
hydrofuran-2-carboxamide (15b). The title compound was
prepared (46 mg, 0.14 mmol, 14%) as a pale yellow solid by the
general procedure and eluted from silica gel with Hexanes/AcOEt
(85/15) (Reaction time A: 6 h; Reaction time B: 12 h) (Rf = 0.4
CH2Cl2/AcOEt 95/5): mp 127−129 °C; 1H NMR (500 MHz,
CDCl3) δ 7.06 (d, J = 8.0 Hz, 1H), 6.54−6.39 (m, 2H), 6.28 (bs, 1H),
4.72 (dd, J = 10.0, 7.5 Hz, 1H), 3.86 (dd, J = 11.5, 9.5 Hz, 1H), 3.81−
3.74 (m, 6H), 2.92 (ddd, J = 13.0, 9.5, 7.5 Hz, 1H), 2.37 (ddd, J =
13.0, 11.5, 10.0 Hz, 1H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3)
δ 176.6, 168.8, 161.1, 157.9, 130.9, 117.2, 104.7, 99.5, 75.8, 55.59,
55.57, 51.56, 43.1, 33.7, 28.9; IR (NaCl film) νmax 3422, 3353, 2964,
2929, 1781, 1679, 1614, 1587, 1530, 1511, 1458, 1393, 1363, 1291,
1266, 1209, 1152, 1036, 936, 834 (cm−1); ESI-HRMS m/z calcd for
C17H23NNaO5+ ([M + Na]+) 344.1474, found 344.1484; [α]20D = −6
1052, 987, 929, 881, 846, 829, 728 (cm−1); ESI-HRMS m/z calcd for
+
C18H26N2NaO5 ([M + Na]+) 373.1739, found 373.1733; [α]20
=
D
H
dx.doi.org/10.1021/jo501908z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−5.5 (c 0.9, CHCl3), er (70:30). The enantiomeric ratio was
determined by HPLC with a CHIRALCEL OD-H column (hexane/
iPrOH = 70:30, 254 nm, 1 mL/min), tR (minor) = 6.7 min, tR (major)
= 8.1 min.
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem.
1988, 31, 2235.
(4) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
4-(Benzofuran-2-yl)-N-(tert-butyl)-5-oxotetrahydrofuran-2-
carboxamide (18). The title compound (mixture of diastereoisomers
(dr 60:40)) was prepared (210 mg, 0.7 mmol, 70%) as a white solid by
the general procedure and eluted from silica gel with CH2Cl2/AcOEt
(98/2) (Reaction time A: 5 h; Reaction time B: 12 h) (Rf = 0.15 and
(5) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem.
Biol. 2010, 14, 347.
(6) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752.
(7) Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163.
(8) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41,
3969.
1
0.25 CH2Cl2/AcOEt 95/5): H NMR (600 MHz, CDCl3) δ 7.56−
7.51 (m), 7.48−7.40 (m), 7.32−7.25 (m), 7.25−7.20 (m), 6.74 (s, 1H,
minor), 6.71 (s, 1H, major), 6.25−6.13 (m), 5.00 (dd, J = 8.0, 5.5 Hz,
1H, major), 4.83 (dd, J = 9.0, 7.5 Hz, 1H, minor), 4.15 (t, J = 9.5 Hz,
1H, minor), 4.10 (dd, J = 9.5, 7.5 Hz, 1H, major), 3.11 (ddd, J = 13.5,
9.5, 7.5 Hz, 1H, minor), 2.99−2.85 (m, 2H, major), 2.69 (ddd, J =
13.5, 10.5, 9.5 Hz, 1H, minor), 1.40 (s, 9H, major), 1.38 (s, 9H,
minor); 13C NMR (151 MHz, CDCl3) δ 173.3 (major), 172.8
(minor), 168.0 (major), 167.6 (minor), 155.15 (minor), 155.12
(major), 151.0 (major), 150.7 (minor), 128.01 (minor), 127.96
(major), 124.8 (major), 124.7 (minor), 123.3 (major), 123.2 (minor),
121.20 (major), 121.17 (minor), 111.3, 105.6 (minor), 105.4 (major),
76.6 (major), 76.0 (minor), 52.0 (major), 51.9 (minor), 40.8 (minor),
39.8 (major), 32.0 (minor), 31.6 (major), 28.8 (major), 28.7 (minor);
IR (KBr plate) νmax 3289, 3089, 2968, 2930, 2785, 1779, 1664, 1609,
1561, 1455, 1395, 1369, 1323, 1271, 1255, 1225, 1185, 1043, 1013,
954, 924, 874, 816, 799, 744 (cm−1); ESI-HRMS m/z calcd for
(9) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
̈
(10) Umbreen, S.; Brockhaus, M.; Ehrenberg, H.; Schmidt, B. Eur. J.
Org. Chem. 2006, 4585.
(11) Deobald, A. M.; Correa, A. G.; Rivera, D. G.; Paixao, M. W. Org.
Biomol. Chem. 2012, 10, 7681.
(12) Morana, F.; Basso, A.; Bella, M.; Riva, R.; Banfi, L. Adv. Synth.
Catal. 2012, 354, 2199.
(13) Morana, F.; Basso, A.; Riva, R.; Rocca, V.; Banfi, L. Chem.Eur.
J. 2013, 19, 4563.
(14) Banfi, L.; Basso, A.; Moni, L.; Riva, R. Eur. J. Org. Chem. 2014,
2005.
(15) Miles, W. H. Curr. Org. Synth. 2014, 11, 244.
(16) Riguet, E. J. Org. Chem. 2011, 76, 8143.
(17) Banfi, L.; Riva, R. In Organic Reactions; John Wiley & Sons, Inc.:
New York, 2005; Vol. 65, p 1.
(18) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
(19) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(20) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P.
Chem. Rev. 2010, 110, 6169.
+
C17H19NNaO4 ([M + Na]+) 324.1212, found 324.1220; er (50:50).
The enantiomeric ratio was determined by HPLC with a
CHIRALCEL IC column (hexane/EtOH = 70:30, 254 nm, 1 mL/
min), tR (major, major) = 5.2 min, tR (minor, major) = 6.6 min, tR
(major, minor) = 6.1 min, tR (minor, minor) = 8.9 min.
(21) Roscales, S.; Csaky, A. G. Chem. Soc. Rev. 2014, DOI: 10.1039/
C4CS00195H.
ASSOCIATED CONTENT
(22) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129,
15438.
(23) Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148.
(24) Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D. W. C. Chem. Sci.
2010, 1, 37.
■
S
* Supporting Information
Copies of NMR spectra and HPLC chromatograms of all new
compounds. X-ray structural data (CIF) of compounds 4, 5 and
6b. This material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Inokuma, T.; Takasu, K.; Sakaeda, T.; Takemoto, Y. Org. Lett.
2009, 11, 2425.
(26) Choi, K.-S.; Kim, S.-G. Tetrahedron Lett. 2010, 51, 5203.
(27) Choi, K.-S.; Kim, S.-G. Synthesis 2010, 3999.
(28) Le, P. Q.; Nguyen, T. S.; May, J. A. Org. Lett. 2012, 14, 6104.
(29) Akagawa, K.; Sugiyama, M.; Kudo, K. Org. Biomol. Chem. 2012,
10, 4839.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: emmanuel.riguet@univ-reims.fr.
(30) Shiri, M. Chem. Rev. 2012, 112, 3508.
(31) Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed.
2011, 50, 11860.
Notes
The authors declare no competing financial interest.
(32) Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. In Isocyanide
Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2012;
p 335.
(33) Passerini, M. Gazz. Chim. Ital. 1923, 53, 331.
(34) Passerini, M.; Ragni, G.; Simone, L. Gazz. Chim. Ital. 1931, 61,
964.
(35) Falck, J. R.; Manna, S. Tetrahedron Lett. 1981, 22, 619.
(36) Marcaccini, S.; Miguel, D.; Torroba, T.; García-Valverde, M. J.
Org. Chem. 2003, 68, 3315.
ACKNOWLEDGMENTS
■
We gratefully thank the Agence Nationale de la Recherche for
financial support (HFOrgCat Project ANR JCJC: ANR-12-
JS07-0009). We thank CNRS and Conseil Regional Cham-
pagne-Ardenne, the Conseil General de la Marne, and the EU-
program FEDER for the facilities of the Analytical Platform
(PlAneT CPER project). We thank Sylvie Lanthony and
Dominique Harakat for their technical assistance with HPLC
and HRMS; Dr. Christian Philouze (UMR CNRS 5250, ICMG
FR-2607) for X-ray crystallographic structure determination of
(37) Van Berkel, S. S.; Bogels, B. G. M.; Wijdeven, M. A.;
̈
Westermann, B.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2012, 3543.
(38) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997,
62, 7512.
́
compounds 4, 5 and 6b. We thank Dr. Karen Ple for linguistic
advice.
REFERENCES
■
(1) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(2) Spandl, R. J.; Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008,
6, 1149.
(3) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
I
dx.doi.org/10.1021/jo501908z | J. Org. Chem. XXXX, XXX, XXX−XXX