Recent advances in the synthesis of analogues of phytohormones strigolactones with ring-closing metathesis as a key step

Article abstract of DOI:10.1039/c7ob01917c

In this paper, we synthesized and evaluated the biological activity of structural analogues of natural strigolactones in which the butenolide D-ring has been replaced with a γ-lactam. The key step to obtain the α,β-unsaturated-γ-lactam was an RCM on suitably substituted amides. Strigolactones (SLs) are plant hormones with various developmental functions. As soil signaling chemicals, they are required for establishing beneficial mycorrhizal plant/fungus symbiosis. Beside these auxinic roles, recently SLs have been successfully investigated as antitumoral agents. Peculiar to the SL perception system is the enzymatic activity of the hormone receptor. SARs data have shown that the presence of the butenolide D-ring is crucial to retain the biological activity. The substitution of the butenolide with a lactam might shed light on the mechanism of perception. In the following, a dedicated in silico study suggested the binding modes of the synthesized compounds to the receptor of SLs in plants.

Full text of DOI:10.1039/c7ob01917c

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Takeharu Haino et al.
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Recent Advances in the Synthesis of Analogues of Phytohormones
Strigolactones with Ring-Closing Metathesis as a Key Step
Chiara Lombardi,a Emma Artuso,a Eleonora Grandi,a Marco Lolli,b Francesca Spirakys,b Emanuele
Priola,a and Cristina Prandia*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
In this paper, we synthesized and evaluated the biological activity of structural analogues of natural Strigolactones in
which the butenolide D-ring has been replaced with a γ-lactam. The key step to obtain the α,β-unsaturated-γ-lactam was a
RCM on suitably substituted amides. Strigolactones (SLs) are plant hormones with various developmental functions. As soil
signaling chemicals, they are required for establishing beneficial mycorrhizal plant/fungus symbiosis. Beside these auxinic
roles, recently SLs have been successfully investigated as antitumoral agents. Peculiar to SL perception system is the
enzymatic activity of the hormone receptor. SARs data have shown that the presence of the butenolide D-ring is crucial to
keep the biological activity. The substitution of the butenolide with a lactam might shed light on the mechanism of
perception. In the following, a dedicate in silico study suggested the binding modes of the synthesized compounds to the
www.rsc.org/
receptor
of
SLs
in
plants.
antitumoral effect was demonstrated.12 All the so far identified
natural SLs are sesquiterpene lactone derivatives that sharing the
same skeleton: a core of three fused rings ABC connected to a
fourth butenolide D-ring by means of an enol ether bridge (Figure
1). Stereochemistry at the BC junction and at the 2’ position has
been shown to be tightly connected to biological effects.13The
mode of action of SLs is still under debate. Classical hormone
receptors reversibly and non-covalently bind active hormone
molecules to trigger signal transduction.14 The SLs receptor in plants
is unusual as it behaves both as a receptor and as an enzyme that
cleaves its own substrate.15 After the hormone binds the receptor,
it is cleaved by a hydrolysis reaction catalyzed by the receptor itself,
consequentially the D-ring (Figure 1) becomes trapped into the
receptor pocket and this event induces conformational changes in
the receptor leading to a downstream cascade of events. It has very
recently been shown that as a consequence of the hydrolysis a
covalent bond between His247 and D-ring forms.16
Introduction
Lactam based molecules are found in a wide range of biologically
active compounds, natural products and synthetic drugs.1 They are
also used as highly versatile intermediates for potential synthetic
transformations.2 Compounds containing γ-lactams have direct
applications in the treatment of HIV,1g,
neurodegenerative
3
diseases, and depression.4 Because of the prevalence of this
valuable heterocycle in pharmaceutical, natural products, and
materials research, methods for the efficient stereoselective
synthesis of highly substituted γ-lactams are important objectives
for the synthetic community.5 Among γ-lactams, α,β-unsaturated γ-
lactams are key features in many biologically active compounds,
and widely used as building blocks for the construction of complex
structures. Not surprisingly a literature survey reveals that many
efforts have been devoted to the construction of this core
heterocyclic framework.6 Selective reduction of succinimmide
derivatives7 and RCM have also been reported.8 In the last decade
our group developed efficient strategies to exploit the reactivity of
triflates or phosphates derived lactams in Pd or Au catalyzed
transformations.1e, 9In this framework, we became interested in a
new class of plant hormones known as Strigolactones (SLs) involved
in various plant developmental functions.10 They are also soil
signaling chemicals that are required for establishing beneficial
mycorrhizal plant/fungus symbiosis.11 More recently their
Figure 1. Contest and aim of the present work a)17; b) 18; c) 19; d) 20; e) 21
.
O
R
N
O
O
O
O
C
O
O
O
CH3
O
O
A
B
O
O
O
2'
O
O
Br
O
D
N
O
OH
O
CH3
O
O
O
CH3
3'
4'
(+)-Strigola
(+)-GR24b
(+)-EGO10c
Strigolactamsd
Debranonese
CH3
CH3
CH3
O
O
H247
N
O
O
N
H
O
O
O
(+)-GR24
O
CH3
S97
O
O
this work
R
O
O
ABC
Strigo-D-lactams
N
O
(+)-GR24
CH3
R'
CH3
The availability of analogues with structural modifications at
the D-ring may therefore represent a valuable tool to elucidate
the molecular events happening at the receptor and at the
same time may lead to the identification of new agonists or
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antagonists of SLs. We were intrigued by the possibility to gain under basic conditions. When primary amine was involved, the
further insight into the mechanism of action of SLs by correspondent amides 4a-g were further treated with Boc2O or
selectively modifying the reactivity of the D-ring and convert with CbzCl to provide N-protected analogues. The two
the butenolide D-ring of natural SLs into a lactam functional different protecting groups have been chosen considering
group.
their orthogonal reactivity and removal conditions. The amides
This should give us the opportunity to effectively apply our 4a-e were then subjected to RCM under different conditions to
O
O
O
O
RN
established expertise inside the lactam derived chemistry to
design and synthesize biological active analogues of SLs.12e, 19,
22
RN
H3C
NHR
NBS, CCl4
K2CO3, DCM
0¡C to rt, 16h
Catalyst, (5-10%)
Br
Cl
N
R1
R
+
CH3
1a-e
CH3
2a-e
R1
CH3
R1
R1
PhMe, 80 °C, 14-32 h
4a-g
R= H, CH3
R1 = H, Me
R = H
Boc, CBz
Analogues of SLs with a lactam C ring were recently
1a: R=Boc, R1= H
1b: R=Boc, R1= CH3
1c: R=Cbz, R1= H
1d: R=Cbz, R1= CH3
1e: R=CH3, R1= H
2a: R=Boc, R1= H
2b: R=Boc, R1= CH3
2c: R=Cbz, R1= H
2d: R=Cbz, R1= CH3
2e: R=CH3, R1= H
R = CH3
R1 = H, Me
described20 and they were found to retain activity.
A
combination of C-, D-lactams SLs-like compounds has recently
23
Herein, we report a general and
been patented.7b,
H3C
H3C
CH3
CH3
N
N
N
N
CH3
CH3
H3C
H3C
H3C
H3C
convenient strategy to obtain SLs D-lactam analogues where
D-ring lactams are generated by efficient RCM.
CH3
CH3
Cl
Cl
Cl
Ru
Ru PCy3
Ph
Cl
Ph
PCy3
Grubbs II
catMETium-RF1
furnish α,β-unsaturated lactams 1a-e.
Results and Discussion
Scheme 2. Synthetic sequence to lactams 1a-e and bromo lactams 2a-e
Synthesis. In scheme 1, the general synthetic strategy for the
obtainment of the final compounds type 3 is shown. Moving
backwards, the final step involves a SN2 reaction between an
In an effort to optimize the reaction conditions, variation in
type and amount of the catalysts, temperature and reaction
time were evaluated. Two different catalysts have been used,
Grubbs II and catMETium-RF1 (Scheme 2). This last one has
been reported to be rather efficient with substrates relatively
unreactive to RCM, more stable than other RCM catalyst and
able to better tolerate higher reaction temperatures.26
enolate, generated from the lactone
C of the ABC core (Figure
1), and the bromo lactams type 2 (Scheme 1). These latter
intermediates were obtained as a result of allylic bromination
of lactams 1.
O
R
N
O
O
O
t-BuO-K+, HCHO
O
O
O
+
Table 1. Optimization of the reaction conditions for the preparation of pyrrolidinones
1a-e by ring closing methatesisa
Br
C
R
CH3
THF, rt
O
N
R1
O-
O
2
3
ABC core
R1
CH3
Grubbs
Catalyst
Catalyst
load
Time,
h
Temp
(C°)
Obtained
lactam
NBS
R= H, Boc, Cbz
R1= H, CH3
Entry
R
R1
Yieldb
R
N
O
1
2
3
4
5
6
7
8
9
Boc
Boc
Cbz
Cbz
Me
Boc
Boc
CBz
Cbz
H
H
G II
8%
1%
8%
1%
1%
8%
1%
8%
1%
18
1.5
16
80
110
80
1a
1a
1c
1c
1e
1b
1b
1d
1d
83
95
76
78
82
11
48
15
58
CH3
R1
catMETium
G II
1
H
H
catMETium
catMETium
G II
1.5
1.5
16
110
110
80
Scheme 1. Synthetic strategy to obtain final compounds 3.
H
Me
Me
Me
Me
This study was then specifically focused on the design of
effective methodologies to obtain the lactams type 1. In
particular, we relied on a Ring Closing Methatesis (RCM)
starting from suitable diene amides using the second
catMETium
G II
1.5
16
110
80
catMETium
1.5
110
a)
All the reactions have been performed under inert atmosphere in anhydrous toluene: G II stays for
Grubbs II, catMETium for catMETium-RF1. b Yield of pure compound.
generation
catalysts
benzyliden[1,3-bis-(2,4,6-
trimethylphenyl)-2-
imizadolidinylidene]dichloro(tricyclohexylphosphine)rutheniu
m (Grubbs II) and catMETium-RF1. The precursors diene
Then, we explored the feasibility of Grubbs II catalyst with N-
Boc (entries 1, 2, 6, 7) diene amides with 8% loading in
toluene. Reaction times were quite long, as it takes 18 h for
the reaction to be complete, yield between 76 - 83%. Besides,
the catalyst was found very sluggish when the reaction was
amides
4 were prepared by condensation of meta acryloyl
chloride with primary amines under basic conditions. The use
of meta acrolyl chloride was mandatory to install the methyl
group in position 4’ of the final compounds. As a matter of
fact, extensive SAR studies on SLs have demonstrated that
methyl group in 4’ is essential to retain biological activity.24
Additionally, a remarkable observation was that an extra
methyl group at C-3’ in GR24 has a boosting effect on the
activity.25 For this reason we decided to use both allyl amine
and 2-methylprop-2-en-1-amine to obtain the appropriate
substituted diene amides precursors 4a-g (Scheme 2 and SI).
Diene amides 4a-g were prepared by the condensation of
meta acryloyl chloride with primary and secondary amines
performed with olefins substituted on both
α and β carbons,
entry 6, where an overall 11% was obtained. The Grubbs II was
found to be completely inactive with N-Me diene amides. This
is in agreement with previous findings according which the
increase of sterical bulk at nitrogen atom of the amide as well
27
as electronic factors facilitates the RCM cyclization.8a, We
then continued the optimization study with catMETium-RF1
(Scheme 2)26. We found that the RCM was very efficient with
2 | J. Name., 2012, 00, 1-3
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all the substrates being the substitution at
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DOI: 10.1039/C7OB01917C
ARTICLE
N
or at
α
and
β
obtaining 3e-g as racemates in yield ranging from 44 to 55%.
positions not affecting the outcome of the reaction. Unfortunately, removal of Boc protection in 3e under usual
Experiments using 1 % loading of catMETium-RF1 at 110 °C
afforded complete conversions after 1.5 h and yields ranging
from 48 – 95 %. Lower yields for entries 6-9 (Table 1) are
expected and are in line with previously reported data on RCM
on substituted amides.26 Based on these optimization results,
we decided to use catMETium-RF1 as a catalyst for the
preparation of all lactams 1a-e. The next step was the allylic
bromination of lactams 1a-e (Scheme 1 and 2). This step was
accomplished under routine procedures (NBS, CCl4, see
experimental) and afforded the correspondent brominated
conditions (TFA, DCM, 10m) led to degradation products only.
lactams 2a-d with good to excellent yields. Unfortunately, the
By contrast, when compounds 3f and 3g were treated under
reaction with lactam 1e led to only a 5 % yield. Any attempt to
H2 with Pd/C the removal of Cbz protecting group was
improve it led to an increased ratio of undesired byproducts.
successfully attained, and compounds 3h and 3i were
We speculated that the lack of an electron-withdrawing group
recovered in almost quantitative yield.
on N hampers the formation of the allylic radical and the
subsequent reaction with bromine.28 We then carried on our
Scheme 4. Synthesis of indolyl D-lactams and mimics D-lactams.
synthetic sequence (Scheme 1) with brominated lactams 2a-d.
The first set of compounds are part of the family of GR24
Eventually, we envisage the synthesis of mimics of SLs as D-
analogues (Figure 1). Racemic (3aR,8bS)-3,3a,4,8b-tetrahydro-
lactams. The so-called ‘SL mimics’ are compounds lacking the
2H-indeno[1,2-b]furan-2-one 518 (Scheme 3) was allowed to
ABC scaffold but retaining the D-ring connected to an
react for 1h in the presence of
with either lactam 2a or 2b. The obtained diasteroisomers
were separated and racemic compounds 3a 3a’ 3b and 3b’
were obtained in yields ranging from 44 to 66 %.
Stereochemistry at the double bond was established to be by
t-BuOK and HCOOEt in DME,
additional group by means of an ether or ester functionality.
The term ‘mimic’ comes from the observation that these
compounds mimic SL activity.21Owing to their simpler
structures with respect to natural and synthetic analogues of
SLs, they can be considered promising candidates for
agricultural applications. One group of mimics show an aryloxy
,
,
E
NMR analysis thus confirming the previously reported results.
Absolute configurations were established by means of X-Ray
analysis on compound (+)-3a (see Supporting Information for
substituent at C-5 (Figure 1), and were named ‘debranones’.21,
31
By treating p-bromophenol
7 under basic conditions with
chiral separation details and XRay data). The removal of the
either 2a or 2c bromo lactam the racemic compounds 3j and
3k were obtained in good yields. In this case, differently from
indolyl derivatives, the conditions for the Cbz removal are
incompatible with the structure of substrates. By contrast, the
Boc removal conditions efficiently gave the final deprotected
compounds 3l in 80 % yield. Intrigued by the challenge of
identifying an effective antagonist of SLs in plants we
synthesized compounds 3m and 3n, whose structures are
strictly related to SLs D-lactams but lack the enol ether bridge
Boc protecting group, accomplished in TFA at 0 °C, led to
compounds 3c, 3c’, 3d, 3d’ even though in unsatisfactory
yields (21 - 25%).29
O
O
O
O
TFA, DCM
H
R
O
O
0 ¡C, 10 min
O
N
N
O
R1
R1
CH3
CH3
3c: R1 = H, 24%
3d: R1 = CH3, 21%
O
O
3a
: R = Boc; R1 = H, 54%
3b: R = Boc; R1 = CH3, 48%
1. t-BuOK, HCOOEt, DME
from 0 ¡C to rt, 1h
accounted to be responsible of bioactivity. Compounds 3m
2a 2b
,
2.
, DME
from 0 ¡C to rt, 16h
and 3n were obtained as a mixture of diasteromers, however
5
O
O
O
O
at this stage we decided to run preliminary biological assays
TFA, DCM
0 ¡C, 10 min
O
before proceeding with the separation of pure isomers
.
H
R
O
O
N
N
O
R1
R1
CH3
CH3
: R = Boc; R1 = H, 44%
3b': R = Boc; R1 = CH3, 42%
3a'
3c': R1 = H, 22%
3d': R1 = CH3, 25%
Scheme 3. Synthesis of GR24-D-lactams
Scheme 5. Synthesis of compounds 3l and 3m.
Indolyl analogues of SLs have been demonstrated to be active
compared to GR24 analogues in most of the biological effects
related to SLs.22a, 30 To check whether the activity is affected by
the change of the butenolide D-ring present in all natural SLs,
we undertook the synthesis of indolyl derivatives D-lactams
Biological assays. The activity of the synthesized D-lactams 3a,
3a’ 3c, 3c’ 3j, 3l and 3n were assayed as germination
,
,
stimulants on seed of the parasitic weed Phelipanche
aegyptiaca using (+) GR24 as comparison. All the compounds
show activity only at 10-5 M whilst at lower concentration their
ability as germination stimulants is comparable to the negative
(
3e-i
dihydrocyclopenta[b]indol-3(2H)-one 6. Indole
in basic conditions with lactams 2a 2c and 2d respectively
,
Scheme
4)
starting
from
4-methyl-1,4-
6
was treated
,
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control acetone. The only exception is for compounds 3a’ and with the rice D14 structure (RMSD equal to 0.8 Å) and a very
3c’, one of the diasteroisomers of GR24-D-lactam.
well conserved binding site. In our studies, we selected the
structure of rice D14 co-crystallized with GR24 given its high
similarity with the ligands here reported, and the high
conservation of the binding site residues. We selected in
particular compound 3c for docking experiments because
coherent in terms of stereochemistry with GR24. The
crystallographic identification of only one enantiomer within
D14 pocket suggests it to be the most probable substrate. The
most favourable binding mode of compound 3c within D14 is
reported in Figure 3.
Figure 2. Biological assays. Percentage of seeds germination. Y-axis: Percentage
of germinated seeds. X-axis: SL-D-lactams at 10-10, 10-9, 10-8, 10-7, 10-6, 10-5
concentration.
M
Remarkably, the two compounds show the same
stereochemistry of the fused ring systems and at the 2’
position, they only differ as for the presence of Boc protecting
group in 3a’. The same activity data were observed for Boc
protected and unprotected mimic derivatives 3j and 3l
.
Compound 3n exhibits a biological activity statistically even
lower than acetone at all the tested concentrations.
Modeling. To investigate the possible binding mode of the
newly synthesized GR24-based lactams within the SL receptor,
and have insight about their mechanism of action, we
performed docking simulations of compound 3c within the
binding pocket of D14 (PDB code 5DJ5). In the last years,
possible SL receptors, as the rice dwarf 14 (D14) and the
petunia deceased apical dominance 2 (DAD2), were identified
and characterized.32 Isolation of the D14 and DAD2 genes
showed that they encode for members of an α/β-barrel super
family of proteins highly similar to esterases, having in the
binding site the typical Ser-His-Asp hydrolytic catalytic triad.
The D14 gene encodes for DWARF14 (D14) and DWARF14-LIKE
(D14L) proteins, respectively involved in the branching
inhibition pathway and in the signaling pathway of karrikins,
found in the smoke of forest fires and capable of stimulate
seed germination.32 The DAD2 gene is an ortholog of the rice
and Arabidopsis D14 genes, and is also involved in
strigolactone perception and signalling.15a All the
aforementioned proteins are able to hydrolyze the D-ring of
GR24, even if with a very low turnover. Recently Zhao and co-
workers succeeded in crystallizing the complex of D14 with
intact GR24.32b This was accomplished by means of a high
GR24 molar ratio of GR24, extensively screened crystallization
conditions, and further soaking with fresh GR24. However,
while the protein is well resolved, the ligand has a poor
resolution, indicating its incomplete occupancy. The electron
density map is most consistent with the presence of a mixture
of intact GR24 and the D-ring hydrolysis product.33 In the same
year, also the structure of the hemiparasitic plant Striga
hermontica34 was crystallized, showing a good superimposition
Figure 3. a) Superimposition of the docking model of compound 3c (blue) and of
the crystallographic pose of (+)-GR24 (green) in the binding site of rice DWARF14
(PDB code 5DJ5;35). The ligand and the residues lining the pocket are shown in
capped sticks. For clarity resides 158-166 have been removed. b) Hydrogen
bonds made by compound 3c within the pocket and Molecular interaction Fields
calculated by FLAP,36 Red, blue and yellow contours identify the hydrogen bond
acceptor, hydrogen bond donor and hydrophobic MIFs, respectively.
Superimposition of the crystallographic pose of (+)-GR24
(Figure 3a, green) with the docking model of compound 3c
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1
(Figure 3a, blue) highlighted that once located and stabilized column chromatography. H-NMR, 13C-NMR and COSY spectra
through hydrophobic and electrostatic interactions in the were recorded on a Bruker Avance-200 spectromer or on a
1
binding site (Figure 3b), the molecule could be easily Jeol JNM-ECZR600 in CDCl3. H NMR spectra were recorded at
hydrolysed by means of Ser97. Preliminary results on 200 MHz or 600 MHz; 13C NMR at 50.2 MHz or 150 MHz with
germination activity of SLs-D-lactams are in line with these complete proton decoupling. Multiplicity is indicated as
findings. However, the proposed binding mode is unable to following: s (singlet), br (broad signal), d (doublet), t (triplet),
explain the observed activity of the Boc protected analogues 3j dd (doublet-doublet), td (triplet-doublet),
m (multiplet).
and 3l, being the presence of such bulky group inconsistence Chemical shifts were reported in ppm from the residual pick
with an optimal binding. Further studies are at the present in solvent as an internal standard. The coupling costants J are
progress to shade light of the peculiar behaviour of these expressed in Hz. HRMS data were recorded on an LTQ Orbitrap
compounds.
Hybrid mass spectrometer. MS data were recorded at an
ionizing voltage of 70 eV. M abbreviation indicates molecular
ion. Enantiomers were separated on either a semipreparative
or an analytical Chiralpak IC column (particle size 5μm, Daicel,
Conclusions.
Osaka, Japan). Dimensions: analytical column 4.6⦶×250 mmL;
semipreparative column 10 ×250 mmL. A Jasco P-2000
In this study we designed a series of SLs analogues based on
the D-lactam system. γ-Lactams were obtained by Ring Closing
Metathesis on suitable substituted amides under optimized
conditions. To investigate the possible binding mode of the
newly synthesized GR24-based lactams within the SL receptor
and have insight about their mechanism of action, we
performed docking simulations within the binding pocket of
D14 (PDB code 5DJ5). These studies demonstrated that given
the pose of GR-24-D-lactam (3c) inside D14, it would be able to
undergo nucleophilic attack by Ser 97 and in principle mimic SL
activity, thus supporting the hypothesis that led to the SL-D-
lactams design. All the D-lactam derivatives were found to
induce seed germination although much less potently then
GR24. A compound lacking the active bioactiphore responsible
for SLs activity and unable to undergo hydrolysis at the
receptor site was synthesized (3n) and found to be completely
inactive. Whether this implies the potential use of this
compound as inhibitor of SLs is currently under study.
⦶
polarimeter was used for the determination of optical
rotations. Synthetic procedures to obtain compounds 4a-g are
described in the Supporting Information.
Typical Metathesis procedure: The reaction was assembled
under an inert atmosphere using oven-dried glassware. A
Schlenk three-neck round-bottom flask, equipped with a N2
inlet and a rubber septum, was evacuated and filled with N2.
Catalyst (Grubbs II 8% or catMETium-RF1 1%) was added under
inert atmosphere, the flask was evacuated and filled again
with N2 (this sequence is carried out three times). Then a
solution of alkyl allyl(methacryloyl)carbamate (1.00 eq) in dry
and degassed toluene (105 mL) was added via syringe. The
reaction mixture was thoroughly degassed by bubbling N2 and
heated at the conditions described in Table 1. Then the
reaction mixture was filtered through a celite pad washing
with CH2Cl2. The solvent was removed in vacuo and
purification by column chromatography.
tert-Butyl 3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxy
late (1a). Following the typical procedure 4a was treated with
catMEtium-RF1 (1%) at 110 °C for 1.5 h. The crude product was
purified by column chromatography on silica gel with
Experimental Section
General details
All solvents were purchased by Sigma-Aldrich and used
without further purification unless specified. Anhydrous THF
and anhydrous toluene were prepared by distillation from Na
and benzophenon. The persistent blue-violet color of the
solution, due to the benzophenone ketyl, confirmed
anhydrous conditions. Anhydrous CH2Cl2, DME and ethyl
formate were obtained by distillation from CaH2. Anhydrous
CCl4 was prepared by drying for 24h over 4Å activated
petroleum ether/ethyl acetate 8:2 (Rf=0.07) to give 1a (95%)
1
as a white solid. H NMR (200 MHz, CDCl3):
δ = 6.74-6.72 (m,
1H, =CH), 4.14-4.12 (m, 2H, CH2), 1,82 (s, 3H, CH3), 1.49 (s, 9H,
Boc). Spectral data correspond to those previously reported in
literature.37
tert-Butyl 3,4-dimethyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carbo
xylate (1b). Following the typical procedure 4b was treated
with catMEtium-RF1 (1%) at 110 °C for 1.5 h. The crude
product was purified by column chromatography on silica gel
molecular sieves. tBuOK was sublimated immediately before
using. NBS was recrystallized from water. All the other
reagents were used as received if not otherwise specified.
Glassware for moisture-sensitive reactions were oven-dried at
150 °C and assembled under nitrogen. Reactions involving air-
sensitive reagents were performed under a dry nitrogen
atmosphere. Reactions were monitored by TLC carried out on
0.25-mm silica gel plates (Merck F254). Chromatographic
purifications were carried out on silica gel (Merck grade 7734,
pore size 60 Å, 70−230 mesh) using flash-column or classical
techniques; Rf values refer to TLC carried out on 0.25 mm silica
gel plates (Merck F254), with the same eluent indicated for the
with petroleum ether/ethyl acetate 9:1 (Rf= 0.66) to give 1b
1
(48%) as a white solid. H NMR (600 MHz, CDCl3):
δ = 4.08 (s,
2H, CH2), 1.98 (s, 3H, CH3), 1.76 (s, 3H, CH3), 1.53 (s, 9H, Boc);
13C NMR (150 MHz, CDCl3):
= 170.42 (CON); 149.91 (CO Boc),
δ
149.10 (Cq), 129.03 (Cq), 82.57 (Cq), 52.94 (CH2), 28.23
(3xCH3), 13.41 (CH3), 8.48 (CH3); HRMS (ESI) for C11H17NO3
Calcd 212.1287 [M + H]+; found 212.2199 [M + H]+.
Benzyl 3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(1c). Following the typical procedure 4c was treated with
catMEtium-RF1 (1%) at 110 °C for 1.5 h. The crude product was
purified by column chromatography on silica gel with
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ARTICLE
Journal Name
petroleum ether/ethyl acetate 8:2 (Rf=0.21) to give 1b (78%) Benzyl
1
as a white solid. H NMR (200 MHz, CDCl3):
5-bromo-3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-
δ = 7.41–7.18 (m, carboxylate (2c). The crude product was purified by column
5H, ArH), 6.78 – 6.77 (m, 1H, =CH), 5.25 (s, 2H, CH2Cbz), 4.20– chromatography on silica gel with petroleum ether/ethyl
4.18 (m, 2H, CH2), 1.83 – 1.82 (m, 3H, CH3); 13C NMR (50.2 acetate 8:2 (Rf=0.41) to give 2c (58%) as a pale yellow oil. H
1
MHz, CDCl3):
δ =169.64 (CON), 151.16 (CO Cbz), 138.52 (CH), NMR (200 MHz, CDCl3): δ = 7.51 – 7.33 (m, 5H, ArH), 6.94 –
135.46 (Cq + ArC), 128.67 (2ArCH), 128.42 (ArCH), 128.16 6.92 (m, 1H, CHBr), 6.50 – 6.48 (m, 1H, CH=CCH3), 5.46 – 5.32
(2ArCH), 67.96 (CH2Cbz), 49.39 (CH2), 11.10 (CH3); HRMS (ESI) (m, 2H, CH2Cbz), 1.97 – 1.96 (m, 3H, CH3); 13C NMR (150 MHz,
for C11H17NO3 Calcd 254.0793 [M + Na]+; found 254.0856 [M + CDCl3):
δ = 166.67 (CON), 149.31 (CO Cbz), 141.31 (CH=CCH3),
Na]+.
134.84 (CH=CCH3), 134.55 (ArC), 128.67 (2ArCH), 128.57
(ArCH), 128.22 (2ArCH), 68.75 (CH2Cbz), 57.30 (CHBr), 10.79
Benzyl 3,4-dimethyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxy
late (1d). Following the typical procedure 4d was treated with (CH3). HRMS (ESI) for C13H12BrNO3 Calcd [M + Na]+ 331.9898
catMEtium-RF1 (1%) at 110 °C for 1.5 h. The crude product was (100.0%), 333.9878 (97.3%); found [M + Na]+ 332.0000
purified by column chromatography on silica gel with (100%), 333.9980 (97.3%).
petroleum ether/ethyl acetate 1:1 (Rf=0.48) to give 1d (58%) Benzyl 2-bromo-3,4-dimethyl-5-oxo-2,5-dihydro-1H-pyrrole-
as a white solid; mp 105.9–107.5 °C. 1H NMR (200 MHz, CDCl3): 1-carboxylate (2d). The crude product was purified by column
δ
= 7.47– 7.30 (m, 5H, ArH), 5.31 (s, 2H, CH2Cbz), 4.16 – 4.15 chromatography on silica gel with petroleum ether/ethyl
(m, 2H, CH2), 1.99 (s, 3H, CH3), 1.80 – 1.78 (m, 3H, CH3); 13C acetate 7:3 (Rf=0.81) to give 2d (54%) as a pale yellow oil. H
NMR (50.2 MHz, CDCl3): = 169.98 (CON), 150.88 (CO Cbz), NMR (600 MHz, CDCl3): = 7.36 – 7.34 (m, 2H, ArH), 7.26 –
149.85 (Cq), 135.53 (Cq), 128.68 (ArC), 128.54 (2ArCH), 128.25 7.18 (m, 3H, ArH), 6.25−6.24 (m, 1H, (CHBr), 5.25 (d, = 12.4
(ArCH) , 128.01 (2ArCH), 67.67 (CH2Cbz), 52.72 (CH2), 13.34 Hz, 1H, CH2Cbz), 5.19 (d, = 12.5 Hz, 1H, CH2Cbz), 1.96 (s, 3H,
(CH3), 8.34 (CH3). HRMS (ESI) for C14H15NO3 Calcd 268.0950 [M CH3), 1.70 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3):
= 166.46
+ Na]+; found 268.1002 [M + Na]+.
(CON), 151.25 (CO Cbz), 148.79 (BrCHC=CCH3), 134.63 (ArC),
1
δ
δ
J
J
δ
1,3-Dimethyl-1,5-dihydro-2H-pyrrol-2-one (1e). Following the 128.96 (ArCH), 128.18 (2ArCH), 128.00 (2ArCH), 127.65
typical procedure 4e was treated with catMEtium-RF1 (1%) at (BrCHC=CCH3), 67.98 (CH2Cbz), 61.83 (CHBr), 12.39 (CH3), 8.33
110 °C for 1.5 h. The crude product was purified by column (CH3). HRMS (ESI) for C14H14BrNO3 Calcd [M + K]+ 361.9794
chromatography on silica gel with petroleum ether/ethyl (100.0%), 363.9774 (97.3%); found [M + K]+ 361.9892(100%),
acetate 8:2 (Rf=0.13) to give 1e (82 %) as a pale yellow liquid. 363. 9872 (97.3%).
1H NMR (200 MHz, CDCl3):
(m, 2H, CH2), 2.89 (s, 3H, NCH3), 1.75−1.72 (m, 3H, CH3). solution of the ABC-framework ±
Spectral data were in agreement with literature values.38
mg) in anhydrous DME (15 mL), cooled to 0 °C and under
Allylic Bromination of lactams 1: general method. In a round nitrogen atmosphere, were added anhydrous ethyl formate
bottom, a solution of lactam (1.00 eq) in anhydrous CCl4 (21 (10.0 eq, 4.70 mmol, 0.40 mL) and BuOK (2.00 eq, 0.94 mmol,
δ
= 6.52−6.50 (m, 1H, CH), 3.69-3.67 General procedure for the Synthesis of 3a/3a′, 3b/3b′. To a
(1.00 eq, 0.470 mmol, 82
5
1
t
mL) was added under N2 atmosphere. Then NBS (1.00 eq) and 105.3 mg). The reaction mixture was stirred at room
AIBN (2%) were added and the mixture was stirred at 90°C temperature until a TLC control (PE/EtOAc 6:4) showed the
overnight. When TLC analyses showed no further reaction, the disappearance of the starting material. After complete
mixture was quenched with water and the aqueous phase was consumption of the substrate (2h), the reaction mixture was
extracted with CH2Cl2 (3x15mL). Drying (Na2SO4) and cooled to 0 °C and a solution of the suitable brominated
concentration under low pressure gave a crude product which lactam
2 (1.70 eq) in anhydrous DME (10 mL) was added
was purified by column chromatography. dropwise. The reaction mixture turned to brown and was
tert-Butyl 5-bromo-3-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1- stirred at room temperature under N2 overnight. Then the
carboxylate (2a). The crude product was purified by column reaction was quenched by addition of water and the aqueous
chromatography on silica gel with petroleum ether/ethyl layer was extracted with CH2Cl2 (3x20 mL). The combined
acetate 7:3 (Rf=0.54) to give 2a (82 %) as a pale yellow solid. organic layers was dried over Na2SO4, filtrated and
1H NMR (200 MHz, CDCl3):
δ = 6.83-6.82 (m, 1H, CHBr), 6.38- concentrated under vacuum. The crude product was purified
6.35 (m, 1H, CH=CH2), 1.88 (s, 3H, CH3), 1.51 (s, 9H, Boc). by flash chromatography (PE/EtOAc 3:2, 0.3% Et3N) to give the
Spectral data were in agreement with literature values.37
two diastereomeric compounds GR24-N-Boc-D-lactams D1 3a
or 3b and GR24- -Boc-D-lactams D2 3a′or 3b′ all as white
tert-Butyl 2-bromo-3,4-dimethyl-5-oxo-2,5-dihydro-1H-pyrro
N
le-1-carboxylate (2b). The crude product was purified by powders.
column chromatography on silica gel with petroleum tert-Butyl-3-methyl-2-oxo-5-((E)-(2-oxo-4,8b-dihydro-2H-
ether/ethyl acetate 7:3 (Rf=0.73) to give 2b (71 %) as a yellow indeno[1,2-b]furan-3(3aH)-ylidene) methoxy)-2,5-dihydro-
solid. 1H NMR (600 MHz, CDCl3):
= 6.26 (s, 1H, CHBr), 2.05 (s, 1H-pyrrole-1-carboxylate (±3a). Yield: 54%; white solid, mp
3H, CH3), 1.77 (s, 3H, CH3), 1.52 (s, 9H, Boc); 13C NMR (150 176.7°C–178.0 °C. TLC Rf=0.62 (PE/EtOAc 1:1 v/v); 1H NMR
MHz, CDCl3): 167.13 (CON), 150.42 (CO Boc), 147.38 (Cq), (200 MHz, CDCl3): = 7.53−7.48 (m, 2H, ArH), 7.37−7.20 (m,
129.47 (Cq), 83.78 (CqBr), 62.30 (CH), 27.78 (3xCH3), 12.51 4H, ArH+H6′), 6.66 − 6.64 (m, 1H, H3′), 6.09−6.08 (m, 1H, H2′),
(CH3), 8.47 (CH3). HRMS (ESI) for C10H14BrNO3 Calcd [M + Na]+ 5.96 (d,
=7.9 Hz, 1H, H8b), 3.97−3.86 (m, 1H, H3a), 3.42 (dd,
δ
δ
δ
J
298.0055 (100.0%), 300.0034 (97.3%); found [M + Na]+ J=16.9 Hz, J=9.2 Hz, 1H, H4), 3.08 (dd,
J = 17.0 Hz, J = 3.0 Hz,
297.9975 (100%), 299.9954 (97.3%).
1H, H4), 1.99−198 (m, 3H, CH3), 1.56 (s, 9H, Boc); 13C NMR (50.2
6 | J. Name., 2012, 00, 1-3
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MHz, CDCl3):
View Article Online
DOI: 10.1039/C7OB01917C
ARTICLE
δ
= 172.47 (CON), 168.33 (COO), 153.3 (6′CH), corresponding GR24-N-Boc-lactam D1 (3a, 3b) or D2 (3a′, 3b′)
148.82 (CO Boc), 143.25 (ArC), 139.76 (ArC), 139.07 (4′Cq), (1.00 eq) in 2.00 ml of CH2Cl2 was prepared. The solution was
136.62 (3′CH), 130.68 (ArCH), 128.18 (ArCH), 127.15 (ArCH), then cooled to 0°C and TFA (19.00 eq) was added. The mixture
125.92 (ArCH), 110.60 (3Cq), 90.15 (2′CH), 86.45 (8bCH), 85.37 was stirred at 0°C with monitoring by TLC (PE/EtOAc 1:1). After
(Cq Boc), 39.61 (3aCH), 38.08 (4CH2), 28.73 (3xCH3), 11.55 15 min, TFA and CH2Cl2 were immediately removed under
(CH3). HRMS (ESI) for C22H23NO6 Calcd 436.1157 [M + K]+; reduced pressure. The crude product was purified by column
found 436.1170 [M + K]+.
tert-Butyl 3-methyl-2-oxo-5-((E)-(2-oxo-4,8b-dihydro-2H- 3-methyl-5-((E)-2-oxo-4,8b-dihydro-2H-indeno[1,2-b]furan-
indeno[1,2-b]furan-3(3aH)-ylidene) methoxy)-2,5-dihydro- 3(3aH)-ylidene)methoxy)-1,5-dihy dro-2H-pyrrol-2-one (±3c).
chromatography on silica gel.
1H-pyrrole-1-carboxylate (±3a′). Yield: 44%; white solid, mp Eluent used for the chromatography: petroleum ether/ethyl
170.6°C–173.2 °C. TLC Rf=0.40 (PE/EtOAc 1:1 v/v); 1H NMR acetate 1:1, Rf=0.30. White solid. Yield: 24%. 1H NMR (600
(200 MHz, CDCl3):
4H, ArH+H6′), 6.61 (br s, 1H, H3′), 6.00 (br s, 1H, H2′), 5.88 (d, 7.33–7.32 (m, 1H, ArH), 7.28–7.27 (m, 1H, ArH), 7.24–7.23 (m,
=7.9 Hz, 1H, H8b), 3.89−3.78 (m, 1H, H3a), 3.32 (dd, J=16.9 Hz, 1H, ArH), 6.62 (br s, 1H, H3′), 5.94 (d, = 7.9 Hz, 1H, H8b), 5.86
J=9.2 Hz, 1H, H4), 2.97 (dd, = 17.0 Hz, = 3.0 Hz, 1H, H4), 1.91 (br s, 1H, H2′), 3.94–3.90 (m, 1H, H3a), 3.43 (dd, = 16.8 Hz,
(s, 3H, CH3), 1.39 (s, 9H, Boc); 13C NMR (50.2 MHz, CDCl3):
9.2 Hz, 1H, H4), 3.10 (dd, = 16.8 Hz, = 2.9 Hz, 1H, H4), 1.96 (s,
171.83 (CON), 167.70 (COO), 154.24 (6′CH), 148.18 (CO Boc), 3H, CH3); 13C NMR (150 MHz, CDCl3):
= 172.87 (CON), 172.14
δ = 7.49−7.42 (m, 2H, ArH), 7.29−7.11 (m, MHz, CDCl3): δ = 7.50–7.49 (m, 1H, ArH), 7.41 (br s, 1H, H6′),
J
J
J
J
J
J =
δ
=
J
J
δ
142.62 (ArC), 139.12 (ArC), 138.44 (4′Cq), 135.98 (3′CH), (COO), 150.79 (6′ CH), 142.81 (ArC), 140.00 (ArC), 139.11
130.04 (ArCH), 127.54 (ArCH), 126.51 (ArCH), 125.29 (ArCH), (4′Cq), 136.90 (3′CH), 130.09 (ArCH), 127.58 (ArCH), 126.56
110.09 (3Cq), 89.52 (2′CH), 85.82 (8bCH), 84.74 (Cq Boc), 38.97 (ArCH), 125.32 (ArCH), 111.60 (3Cq), 85.99 (2′CH), 85.67
(3aCH), 37.45 (4CH2), 28.09 (3xCH3), 10.92 (CH3). HRMS (ESI) (8bCH), 39.04 (3aCH), 37.59 (4CH2), 10.81 (CH3). HRMS (ESI)
for C22H23NO6 Calcd 436.1157 [M + K]+; found 436.1169 [M + for C17H15NO4 Calcd 336.0633 [M + K]+; found 336.0642 [M +
K]+.
K]+.
tert-Butyl 3,4-dimethyl-2-oxo-5-((E)-(2-oxo-4,8b-dihydro-2H- 3-methyl-5-((E)-2-oxo-4,8b-dihydro-2H-indeno[1,2-b]furan-
indeno[1,2-b]furan-3(3aH)-ylidene)methoxy)-2,5-dihydro-1H- 3(3aH)-ylidene)methoxy)-1,5-dihy dro-2H-pyrrol-2-one (±3c′).
pyrrole-1-carboxylate (±3b). Yield: 48%; white solid, mp Eluent used for the chromatography: petroleum ether/ethyl
185.6°C – 187.8°C. TLC Rf 0.62 (PE/EtOAc 1:1 v/v); 1H NMR acetate 1:1, Rf=0.26. White solid. Yield: 22%. 1H NMR (600
(600 MHz, CDCl3):
1H, ArH), 7.31–7.19 (m, 3H, ArH), 5.93 (d,
5.88 ( br s, 1H, H2′), 3.93–3.89 (m, 1H, H3a), 3.42 (dd,
Hz, = 9.2 Hz, 1H, H4), 3.05 (dd, = 16.8 Hz, = 2.9 Hz, 1H, H4), (br s, 1H, H2′), 3.93–3.90 (m, 1H, H3a), 3.41 (dd,
1.95 (s, 3H, CH3), 1.85 (s, 3H, CH3), 1.53 (s, 9H, Boc); 13C NMR 9.0 Hz, 1H, H4), 3.10 (dd,
= 16.8 Hz, = 3.0 Hz, 1H, H4), 1.95 (s,
(150 MHz, CDCl3): δ = 171.82 (CON), 167.88 (COO), 153.65 (6′ 3H, CH3); 13C NMR (150 MHz, CDCl3):
= 172.89 (CON), 172.16
δ
= 7.53– 7.52 (m, 1H, H6′), 7.48–7.47 (m, MHz, CDCl3):
= 7.9 Hz, 1H, H8b), 7.32–7.31 (m, 1H, ArH), 7.27–7.26 (m, 1H, ArH), 7.23–7.22 (m,
= 16.8 1H, ArH), 6.60 (br s, 1H, H3′), 5.93 (d, = 8.0 Hz, 1H, H8b), 5.84
= 16.6 Hz,
δ = 7.49–7.47 (m, 1H, ArH), 7.39 (br s, 1H, H6′),
J
J
J
J
J
J
J
J =
J
J
δ
CH), 148.35 (CO Boc), 146.54 (ArC), 142.63 (ArC), 139.12 (COO), 150.78 (6′ CH), 142.83 (ArC), 139.99 (ArC), 139.13
(3′Cq), 131.78 (4′Cq), 130.01 (ArCH), 127.54 (ArCH), 126.55 (4′Cq), 136.92 (3′CH), 130.11 (ArCH), 127.60 (ArCH), 126.57
(ArCH), 125.15 (ArCH), 110.38 (3Cq), 91.20 (2′CH), 85.79 (ArCH), 125.34 (ArCH), 111.61 (3Cq), 86.00 (2′CH), 85.69
(8bCH), 84.33 (Cq Boc), 38.93 (3aCH), 37.61 (CH2), 28.17 (8bCH), 39.05 (3aCH), 37.61 (4CH2), 10.83 (CH3). HRMS (ESI) for
(3xCH3), 11.72 (CH3), 8.57 (CH3). HRMS (ESI) for C23H25NO6 C17H15NO4 Calcd 336.0633 [M + K]+; found 336.0649 [M + K]+.
Calcd 434.1580 [M+Na]+; found 434.1689 [M+Na]+.
(3,4-dimethyl-5-((E)-2-oxo-4,8b-dihydro-2H-indeno[1,2-
tert-Butyl 3,4-dimethyl-2-oxo-5-((E)-(2-oxo-4,8b-dihydro-2H- b]furan-3(3aH)-ylidene)methoxy)-1,5-dihydro-2H-pyrrol-2-
indeno[1,2-b]furan-3(3aH)-ylidene)methoxy)-2,5-dihydro-1H- one (±3d). Eluent used for the chromatography:
pyrrole-1-carboxylate (±3b′). Yield: 42%; white solid, mp dichloromethane/ethyl acetate 4:1, Rf=0.21. White solid. Yield:
1
170.0°C–172.4°C. TLC Rf=0.55 (PE/EtOAc 1:1 v/v); 1H NMR (600 21%. H NMR (600 MHz, CDCl3):
δ
= 7.50 (d,
= 6.6 Hz, 1H, ArH),
= 7.5 Hz, 1H, ArH), 6.70
= 7.9 Hz, 1H, H8b), 5.65 (s, 1H, H2′), 3.96 –
= 2.9 Hz, 1H, H4), 1.96 (s, 3.93 (m, 1H, H3a), 3.45 (dd, = 16.8 Hz, = 9.2 Hz, 1H, H4), 3.12
3H, CH3), 1.85 (s, 3H, CH3), 1.43 (s, 9H, Boc); 13C NMR (150 (dd, ,
= 16.8 Hz, = 3.0 Hz, 1H, H4), 1.95 (s, 3H, CH3), 1.86 (s,
J = 7.5 Hz , 1H,
MHz, CDCl3):
ArH), 7.31–7.17 (m, 3H, ArH), 5.94 (d,
br s, 1H, H2′), 3.92–3.88 (m, 1H, H3a), 3.37 (dd,
9.2 Hz, 1H, H4), 3.02 (dd, = 16.8 Hz,
δ
= 7.55 – 7.54 (m, 1H, H6′), 7.48–7.47 (m, 1H, ArH), 7.35 (d, J=2.4 Hz, 1H, H6′), 7.33 (d,
= 7.9 Hz, 1H, H8b), 5.83 ( 7.28 (d, = 7.5 Hz, 1H, ArH), 7.24 (d,
= 16.8 Hz, (s, 1H, NH), 5.95 (d,
J
J
J
J
J
J
=
J
J
J
J
J
J
J
MHz, CDCl3): δ = 171.88 (CON), 167.05 (COO), 154.57 (6′ CH), 3H, CH3); 13C NMR (150 MHz, CDCl3): δ 173.42 (CON), 172.01
148.23 (CO Boc), 146.70 (ArC), 142.59 (ArC), 139.09 (3′Cq), (COO), 150.47 (6′ CH), 147.23 (ArC), 142.71 (ArC), 139.08
131.54 (4′Cq), 130.05 (ArCH), 127.55 (ArCH), 126.51 (ArCH), (3′Cq), 132.62 (4′Cq), 130.04 (ArCH), 127.55 (ArCH), 126.53
125.29 (ArCH), 110.04 (3Cq), 91.96 (2′CH), 85.83 (8bCH), 84.45 (ArCH), 125.24 (ArCH), 110.60 (3Cq), 87.89 (2′CH), 85.88
(Cq Boc), 38.96 (3aCH), 37.50 (CH2), 28.11 (3xCH3), 11.73 (CH3), (8bCH), 38.98 (3aCH), 37.51 (CH2), 11.64 (CH3), 8.44 (CH3).
8.56 (CH3). HRMS (ESI) for C23H25NO6 Calcd 434.1580 [M+Na]+; HRMS (ESI) for C18H17NO4 Calcd 334.1055 [M+Na]+; found
found 434.1726 [M+Na]+.
334.1132 [M+Na]+.
General procedure for the Synthesis of 3c/3c′ and 3d/3d′. In a (3,4-dimethyl-5-((E)-2-oxo-4,8b-dihydro-2H-indeno[1,2-
round bottom flask an anhydrous solution of the b]furan-3(3aH)-ylidene)methoxy)-1,5-dihydro-2H-pyrrol-2-
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Journal Name
one (±3d′). Eluent used for the chromatography: mL) was added dropwise. The reaction mixture turned to pale
dichloromethane/ethyl acetate 4:1, Rf=0.17. White solid. Yield: orange and it was stirred at room temperature under N2
25%. 1H NMR (600 MHz, CDCl3):
δ
= 7.48 (d,
ArH), 7.34 (d, J=2.5 Hz, 1H, H6′), 7.31 (d, = 6.4 Hz, 1H, ArH), water and the aqueous layer was extracted with CH2Cl2 (3x20
7.27 (d, = 7.5 Hz, 1H, ArH), 7.22 (d, = 7.5 Hz, 1H, ArH), 6.69 mL). The combined organic layers was dried over Na2SO4,
(s, 1H, NH), 5.93 (d, = 8.0 Hz, 1H, H8b), 5.64 (s, 1H, H2′), 3.95– filtrated and concentrated under vacuum. The crude product
3.91 (m, 1H, H3a), 3.43 (dd, = 16.9 Hz, = 9.2 Hz, 1H, H4), 3.11 was purified by flash chromatography.
(dd, , = 17.0 Hz, = 3.0 Hz, 1H, H4), 1.95 (s, 3H, CH3), 1.84 (s, Benzyl (E)-3-methyl-5-((4-methyl-3-oxo-3,4-dihydrocyclopen-
3H, CH3); 13C NMR (150 MHz, CDCl3): δ 173.48 (CON), 172.06 ta[b]indol-2(1H)-ylidene)
methoxy)-2-oxo-2,5-dihydro-1H-
J = 7.4 Hz, 1H, overnight. Then the reaction was quenched by addition of
J
J
J
J
J
J
J
J
(COO), 150.52 (6′ CH), 147.29 (ArC), 142.77 (ArC), 139.09 pyrrole-1-carboxylate (±3f). Eluent used for flash
(3′Cq), 132.68 (4′Cq), 130.09 (ArCH), 127.60 (ArCH), 126.58 chromatography: petroleum ether/ethyl acetate 1:1, Rf=0.23.
(ArCH), 125.30 (ArCH), 111.65 (3Cq), 87.94 (2′CH), 85.93 Yield: 55%, pale yellow solid. 1H NMR (600 MHz, CDCl3):
δ =
(8bCH), 39.04 (3aCH), 37.56 (CH2), 11.70 (CH3), 8.49 (CH3). 7.67 (d, J = 8.0 Hz, 1H, ArH), 7.46 (s, 1H, H6′), 7.42–7.37 (m, 5H,
HRMS (ESI) for C18H17NO4 Calcd 334.1055 [M+Na]+; found ArH), 7.27–7.25 (m, 2H, ArH), 7.21–7.17 (m, 2H, ArH), 6.72 (s,
334.1148 [M+Na]+.
1H, H3′), 6.17 (s, 1H, H2′), 5.39 (d,
J = 12.2 Hz, 1H, CH2 Cbz), 5.24
tert-Butyl (E)-3-methyl-5-((4-methyl-3-oxo-3,4-dihydrocyclo-
(d, J = 12.2 Hz, 1H, CH2 Cbz), 3.97 (s, 3H, NCH3), 3.50–3.42 (m,
penta[b]indol-2(1H)-ylidene) methoxy)-2-oxo-2,5-dihydro-1H- 2H, CH2), 1.99 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3):
183.60 (CO), 167.38 (CON), 149.99 (CO Cbz), 147.63 (6′CH),
δ =
pyrrole-1-carboxylate (±3e). To a solution of ABC-framework
6
(1.00 eq, 0.498 mmol, 92.0 mg) in anhydrous ethyl formate 144.51 (Cq), 138.23 (ArC), 137.04 (3′CH), 136.81 (Cq), 134.92
(10.0 mL), cooled to 0 °C and under nitrogen atmosphere, (Cq), 128.68 (4′Cq), 128.63 (2xArCH), 128.61 (ArCH), 126.52
were added tBuOK (3.00 eq, 1.49 mmol, 167 mg). The pink (2xArCH), 122.95 (ArC), 122.34 (Cq), 121.74 (ArCH), 120.47
reaction mixture was stirred at room temperature with (ArCH), 110.98 (ArCH), 88.19 (2′CH), 68.58 (CH2 Cbz), 30.37
monitoring by TLC (PE/EtOAc, 3:2). After complete (NCH3), 22.53 (CH2), 10.98 (CH3). HRMS (ESI) for C26H22N2O5
consumption of the substrate (1 h), the solvent was removed Calcd 465.1426 [M + Na]+; found 465.1396 [M + Na]+.
under nitrogen flow giving a solid residue to which were Benzyl (E)-3,4-dimethyl-2-((4-methyl-3-oxo-3,4-dihydrocyclo-
added, after cooling to 0 °C, a solution of the suitable penta[b]indol-2(1H)-ylidene) methoxy)-5-oxo-2,5-dihydro-1H-
brominated lactam 2a (1.70 eq, 0.847 mmol, 234 mg) in pyrrole-1-carboxylate (±3g). Eluent used for flash
anhydrous DME (10.0 mL). The resulting pale brown mixture chromatography: petroleum ether/ethyl acetate 1:1, Rf=0.55.
was stirred at room temperature overnight. Then it was Yield: 55% , pale yellow solid, mp 84.3 °C–85.1 °C. 1H NMR (600
quenched by addition water (10.0 mL) extracted with CH2Cl2 MHz, CDCl3):
(3x10 mL). The combined organic layers were dried over ArH+H6′), 7.27–7.25 (m, 2H, ArH), 7.21–7.17 (m, 2H, ArH), 5.95
Na2SO4, filtrated and concentrated under vacuum. The crude (s, 1H, H2′), 5.38 (d, = 12.2 Hz, 1H, CH2 Cbz), 5.24 (d, = 12.2
product was purified by column chromatography on silica gel Hz, 1H, CH2 Cbz), 3.97 (d, =3.4 Hz, 3H, NCH3), 3.52–3.44 (m,
with petroleum ether/ethyl acetate (1:1) to give 3e as a pale 2H, CH2), 1.98 (s, 3H, CH3), 1.88 (s, 3H, CH3); 13C NMR (150
yellow solid in 44% yield (89 mg). TLC Rf=0.40 (PE/EtOAc 1:1); MHz, CDCl3): = 183.57 (CO), 167.72 (CON), 150.06 (CO Cbz),
1H NMR (200 MHz, CDCl3):
= 7.68 (dt, = 8.11 Hz, 1H, ArH), 148.00 (ArC), 147.84 (6′CH), 144.52 (3′Cq), 141.05 (ArC),
δ = 7.67 (d, J = 8.9 Hz, 1H, ArH), 7.45–7.37 (m, 5H,
J
J
J
δ
δ
J
7.51−7.50 (m, 1H, ArH), 7.41-7.38 (m, 2H, ArH+H6′), 7.22-7.14 136.75 (Cq), 135.03 (Cq), 131.33 (4′Cq), 128.68 (3xArCH),
(m, 1H, ArH), 6.70−6.66 (m, 1H, H3′), 6.11−6.10 (m, 1H, H2′), 128.58 (2xArCH), 126.47 (ArCH), 122.96 (ArC), 122.40 (Cq),
3.97 (s, 3H, NCH3), 3.57 (s, 2H, CH2), 1.99−1.97 (m, 3H, =CCH3), 121.73 (ArCH), 120.48 (ArCH), 111.00 (ArCH), 90.51 (2′CH),
1.54 (s, 9H, Boc); 13C NMR (50.2 MHz, CDCl3):
δ = 183.64 (CO), 68.45 (CH2 Cbz), 30.37 (NCH3), 22.58 (CH2), 11.84 (CH3), 8.61
167.93 (CON), 148.66 (6′CH), 148.27 (CO Boc), 144.53 (ArC), (CH3). HRMS (ESI) for C27H24N2O5 Calcd 479.1583 [M + Na]+;
141.03 (ArC), 138.25 (4′Cq), 136.77 (Cq), 136.42 (3′CH), 126.56 found 479.1594 [M + Na]+.
(ArCH), 122.96 (Cq), 121.75 (ArCH), 121.69 (Cq), 120.51 (ArCH), General procedure for the Synthesis of (±3h) and (±3i). To a
111.00 (ArCH), 88.76 (2′CH), 84.46 (CqBoc), 30.40 (NCH3), solution of compound ±3f or ±3g (0.100 mmol) in anhydrous
28.22 (3xCH3), 22.57 (CH2), 10.96 (CH3). HRMS (ESI) for THF (10.0 mL), was added Pd/C 10% (13.0 mg) under a
C23H24N2O5 Calcd 431.1583 [M + Na]+; found 431.1570 [M + nitrogen atmosphere. The reaction mixture was stirred under a
Na]+.
General procedure for the Synthesis of ±3f and ±3g. To a filtered through celite and the filter was washed with CH2Cl2.
solution of ± (1.00 eq, 0.470 mmol, 82 mg) in anhydrous DME The solvent was evaporated and the crude product did not
satured hydrogen atmosphere for 10 min. The mixture was
6
(10 mL), cooled to 0 °C and under nitrogen atmosphere, were require any further purification.
added anhydrous ethyl formate (10.0 eq, 4.70 mmol, 0.40 mL) (E)-4-methyl-2-(((4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)
and
mixture was stirred at room temperature until a TLC control (±3h). Pale yellow solid (yield: 100%). TLC Rf=0.25 (PE/EtOAc
(PE/EtOAc 6:4) showed the disappearance of the starting 3:7); 1H NMR (600MHz, CDCl3):
= 7.67 (d, = 8.0 Hz, 1H, ArH),
material. After complete consumption of the substrate (2 h), 7.41–7.35 (m, 2H, ArH+H6′), 7.30 (t, = 1.3 Hz, 1H, ArH), 7.17
the reaction mixture was cooled to 0 °C and a solution of the (ddd, = 8.0 Hz, = 6.8 Hz, = 1.1 Hz, 1H, ArH), 6.50 (s, 1H, NH),
t-BuOK (2.00 eq, 0.94 mmol, 105.3 mg). The pink reaction oxy)methylene)-1,4-dihydrocyclopenta[b]indol-3(2H)-one
δ
J
J
J
J
J
suitable brominated lactam
2
(1.70 eq) in anhydrous DME (5 6.42 (s, 1H, H2′), 5.86 (s, 1H, H3′), 3.95 (s, 3H, NCH3), 3.60 (s, 2H,
8 | J. Name., 2012, 00, 1-3
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CH2), 1.98 (s, 3H, CH3); 13C NMR (150 MHz, CDCl3): δ = 183.74 5-(4-Bromophenoxy)-3-methyl-1,5-dihydro-2H-pyrrol-2-one
(CO), 173.51 (CON), 147.84 (ArC), 145.30 (6′CH), 137.15 (3′CH), (±3l). A solution of debranone ±3j (1.00 eq, 0.375 mmol, 138
136.79 (ArC+Cq), 132.27 (4′Cq), 126.55 (ArCH), 123.09 (Cq), mg) in CH2Cl2 (2.00 mL) were cooled at 0°C and after 2 min TFA
122.93 (Cq), 121.72 (ArCH), 120.48 (ArCH), 110.99 (ArCH), (19.0 eq, 1.24 mmol, 0.10 mL) was added. The mixture was
87.01 (2′CH), 30.35 (NCH3), 22.60 (CH2), 10.81 (CH3). HRMS stirred at 0°C with monitoring by TLC (PE/EtOAc 4:1). After
(ESI) for C18H16N2O3 Calcd 331.1059 [M + Na]+; found 331.1127 complete consumption of ±3j (25 min), TFA and CH2Cl2 were
[M + Na]+.
immediately evaporated under vacuum. The crude product
was purified by column chromatography with petroleum
ether/ethyl acetate 7:3 (Rf=0.82) to give ±3l as a white solid
(E)-2-(((3,4-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)oxy)
methylene)-4-methyl-1,4-dihydrocyclopenta[b]indol-3(2H)-
one (±3i)
(PE/EtOAc 1:1); H NMR (600MHz, CDCl3):
Hz, 1H, ArH), 7.42–7.37 (m, 2H, ArH+H6′), 7.31 (t,
ArH), 7.18 (ddd, = 8.1 Hz, = 6.7 Hz,
= 1.1 Hz, 1H, ArH), 6.53 5.92 – 5.91 (m, 1H, H2′), 1.93 (s, 3H, CH3); 13C NMR (150 MHz,
(s, 1H, NH), 5.66 (s, 1H, H2′), 3.96 (s, 3H, NCH3), 3.60 (s, 2H, CDCl3): = 173.02 (C=O), 155.43 (ArCO), 138.45 (3′CH), 137.38
CH2), 1.96 (s, 3H, CH3), 1.88 (s, 3H, CH3); 13C NMR (150 MHz, (4′Cq), 132.93 (2ArCH), 118.96 (2ArCH), 115.53 (ArCBr), 82.97
CDCl3): δ = 183.72 (CO), 173.48 (CON), 147.82 (ArC), 145.27 (2′CH), 10.73 (CH3); HRMS (ESI) for C11H11BrNO2 Calcd
(6′CH), 144.53 (3′Cq), 141.06 (ArC), 136.75 (Cq), 132.28 (4′Cq), 267.9973 [M + H]+; found 267.9960 [M + H]+.
.
Pale yellow solid (yield: 100%). TLC Rf=0.20 (80 mg, 80%). Mp 156 – 157.5 °C; 1H NMR (600 MHz, CDCl3):
δ
1
δ
= 7.68 (d,
J
= 8.1 = 7.42 (dd, J = 2.22 Hz, J = 9.05 Hz, 2ArH), 6.84 (dd, J =2.30 Hz, J
J
= 1.2 Hz, 1H, = 9.05 Hz, 2ArH), 6.72 – 6.70 (m, 1H, H3′), 6.58 (br, 1H, NH),
J
J
J
δ
126.54 (ArCH), 123.10 (Cq), 122.94 (Cq), 121.72 (ArCH), 120.47 Benzyl 3-methyl-5-(4-methyl-3-oxo-1,2,3,4-tetrahydrocyclo-
(ArCH), 111.01 (ArCH), 87.59 (2′CH), 30.38 (NCH3), 22.69 (CH2), penta[b]indol-2-yl)-2-oxo-2,5 dihydro-1H-pyrrole-1-carboxy-
11.71 (CH3), 8.49 (CH3). HRMS (ESI) for C19H18N2O3 Calcd late (3m). To a solution of ±
361.0954 [M + K]+; found 361.0998 [M + K]+.
anhydrous DME (15 mL), cooled to 0 °C and under nitrogen
Synthesis of 3j and 3k. To a solution of a brominated lactam atmosphere, were added BuOK (2.00 eq, 1.20 mmol, 134 mg).
2a or 2c (1.00 eq) in CH2Cl2 (1.50 mL) were added TBABr (1.00 The reaction mixture was stirred at room temperature until a
eq), K2CO3 (1.20 eq), -Bromophenol (1.00 eq) and water (1.00 TLC control (PE/EtOAc 6:4) showed the disappearance of the
6 (1.00 eq, 0.60 mmol, 111 mg) in
t
p
mL). The reaction mixture was stirred at room temperature starting material. After complete consumption of the substrate
overnight. Then it was quenched with a saturated solution of (1.5 h), the reaction mixture was cooled to 0 °C and a solution
Na2CO3 and the aqueous phase was extracted with CH2Cl2 (3x5 of lactam 2c (1.70 eq, 1.02 mmol, 316 mg) in anhydrous DME
mL). The collected organic layers were dried (Na2SO4), filtered (5 mL) was added dropwise. The reaction mixture turned to
and evaporated. The crude product was purified by brown and was stirred at room temperature under N2
chromatography on silica gel.
overnight. Then the reaction was quenched by addition of
tert-Butyl 5-(4-bromophenoxy)-3-methyl-2-oxo-2,5-dihydro- water and the aqueous layer was extracted with CH2Cl2 (3x20
1H-pyrrole-1-carboxylate (±3j). The crude product was mL). The combined organic layers was dried over Na2SO4,
purified by column chromatography with petroleum filtrated and concentrated under vacuum. The crude product
ether/ethyl acetate 4:1 (Rf=0.57) to give 3j as a white solid in was purified by flash chromatography with petroleum
1
80% yield. Mp 105.3
7.42 (dd, = 2.22 Hz,
= 8.96 Hz, 2H, ArH), 6.74−6.71 (m, 1H, H3′), 6.27−6.26 (m, 1H, 7.64 (dt,
H2′), 1.93−1.91 (m, 3H, CH3), 1.44 (s, 9H, Boc); 13C NMR (50.2 7.36–7.33 (m, 1H, ArH), 7.27 – 7.25 (m, 2H, ArH), 7.20 – 7.14
MHz, CDCl3): = 167.91 (CON), 155.62 (CO Boc), 148.28 (m, 4H, ArH), 6.75 – 6.74 (m, 1H, H3′), 5.22–5.14 (m, 3H,
(ArCO), 137.75 (3′CH), 136.80 (4′Cq), 132.62 (2ArCH), 119.55 CH2Cbz and H2′), 3.64 – 3.62 (m, 1H, CH2CHC=O), 3.14 (dd,
(2ArCH), 115.53 (ArCBr), 85.73 (2′ CH), 83.53 (CqBoc), 27.93 16.9 Hz, J = 6.9 Hz, 1H, CH2CHCO), 2.73 (dd, = 16.9 Hz, J = 2.6
(3xCH3), 10.79 (CH3); HRMS (ESI) for C16H18BrNO4 Calcd Hz, 1H, CH2CHC=O), 1.89 (t,
= 1.7 Hz, 3H, CH3). 13C NMR (150
406.0056 [M + K]+; found 406.0082 [M + K]+.
MHz, CDCl3): = 191.80 (C=O) , 169.62 (CON), 151.48 (COO
–
106.3 °C; H NMR (200MHz, CDCl3):
δ
=
ether/ethyl acetate 1:1, 0.1% NEt3 (Rf=0.36) to give 3m as a
= 2.22 Hz, pale yellow solid (112 mg, 45%). 1H NMR (600 MHz, CDCl3):
= 8.1 Hz. J = 0.9 Hz, 1H. ArH), 7.45–7.42 (m, 1H. ArH),
J
J
= 9.05 Hz, 2H, ArH), 6.88 (dd,
J
δ =
J
J
δ
J
=
J
J
δ
Benzyl 5-(4-bromophenoxy)-3-methyl-2-oxo-2,5-dihydro-1H- Cbz), 145.10 (Cq), 141.65 (3′CH), 138.25 (2ArC), 135.78 (ArC),
pyrrole-1-carboxylate (±3k). The crude product was purified 135.44 (4′Cq), 128.48 (2ArCH), 128.14 (ArCH), 127.75 (2ArCH),
by column chromatography with petroleum ether/ethyl 127.15 (ArCH), 122.97 (Cq), 121.94 (ArCH), 120.59 (ArCH),
acetate 4:1 (Rf = 0.42) to give 3j as a white solid in 85% yield. 111.22 (ArCH), 67.93 (CH2Cbz), 60.32 (2′CH), 52.44 (CH2CHCO),
Mp 143.5
= 2.40 Hz, J = 9.00 Hz, 2ArH), 7.32 (s, 5H, ArH Cbz), 6.81 (dd, J = C25H22N2O4 Calcd 437.1477 [M + Na]+; found 437.1594 [M +
2.40 Hz, J = 9.00 Hz, 2ArH), 6.77–6.76 (m, 1H, H3′), 6.31−6.30 Na]+.
− δ = 7.34 (dd, J 30.21 (NCH3), 21.60 (CH2), 11.13 (CH3). HRMS (ESI) for
145.0 °C; 1H NMR (600 MHz, CDCl3):
(m, 1H, H2′), 5.26 (s, 2H, CH2Cbz), 1.94−1.93 (m, 3H, CH3); 13C 4-Methyl-2-(4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)-1,4-
NMR (150 MHz, CDCl3):
150.05 (ArCO), 137.56 (3′CH), 137.42 (4′Cq), 135.00 (ArC), compound 3m (0.050 mmol, 22.0 mg) in anhydrous THF (5.00
132.71 (2ArCH), 128.72 (2ArCH), 128.62 (ArCH), 128.40 mL), was added Pd/C 10% (6.0 mg) under nitrogen
δ = 167.65 (CON), 155.27 (CO Cbz), dihydrocyclopenta[b]indol-3(2H)-one (3n). To a solution of
a
(2ArCH), 120.00 (2ArCH), 116.04 (ArCBr), 85.91 (2′CH), 68.44 atmosphere. The reaction mixture was stirred under a satured
(CH2Cbz), 10.88 (CH3). HRMS (ESI) for C19H16BrNO4 Calcd hydrogen atmosphere for 2 h. The mixture was filtered
424.0160 [M + Na]+; found 424.0296 [M + Na]+.
through celite and the filtrate was evaporated to dryness to
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ARTICLE
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afford 3n (32 mg, 100%) as a pale yellow solid. The product did
Conflicts of interest
not require any further purification. TLC Rf = 0.11 (PE/EtOAc
There are no conflicts to declare.
1:1); 1H NMR (600 MHz, CDCl3):
δ
= 7.63 (d,
= 7.0 Hz, = 1.1 Hz, 1H, ArH), 7.36
= 8.5 Hz, 1H, ArH), 7.18 – 7.16 (m, 1H, ArH), 6.82 – 6.81
(m, 1H, H3′), 5.86 (br, 1H, NH), 4.81 (br, 1H, H2′), 3.91 (s, 3H,
NCH3), 3.30 – 3.28 (m, 1H, CH2CHC=O), 2.93 (dd, = 16.8 Hz,
= 6.6 Hz, 1H, CH2CHCO), 2.47 (dd, = 16.8 Hz, J = 2.6 Hz, 1H,
CH2CHCO), 1.95 (t,
= 1.7 Hz, 3H, CH3). 13C NMR (150 MHz,
CDCl3): = 193.28 (C=O), 174.70 (CON), 145.61 (Cq), 144.98
J = 8.1 Hz, 1H,
ArH), 7.44 (ddd,
(d,
J
= 8.2 Hz,
J
J
J
Acknowledgements
We would like to thank Elisa Acciardo for her support, Prof.
Valter Maurino for HR-MS analysis. We thank the Cost
Association STREAM FA1206 “Strigolactones: biological roles
and applications”, Compagnia di San Paolo Foundation for
their support (project SLEPS and Stritools), the Lagrange
Project – CRT Foundation/ISI for their grant, the Italian
Ministry of Universities and Research and the Regione
Piemonte. We also like to thank Strigolab srl for kindly
providing GR24.
J
J
J
J
δ
(ArC), 141.79 (3′CH), 136.21 (ArC and 4′Cq), 127.77 (ArCH),
123.01 (Cq), 122.15 (ArCH), 120.73 (ArCH), 111.16 (ArCH),
56.87 (2′CH), 53.84 (CH2CHCO), 30.36 (NCH3), 20.29 (CH2),
11.04 (CH3). HRMS (ESI) for C17H16N2O2 Calcd 303.1109 [M +
Na]+; found 303.1210 [M + Na]+.
Materials and Methods (Modeling)
Notes and references
Compound 3c was docked in the protein binding site with the
docking software GOLD, version 5.5 (www.ccd.cam.ac.uk). For
each compound, 25 diverse poses were generated and
analyzed. A radius of 10 Å was used to define the pocket
extension. Automatic default parameters were set for the
Genetic Algorithm. Shape constraints were imposed using as
template the structure of GR34 as co-crystallized within the
target. ChemScore was used as scoring function.
1.
(a) S. Cinar, C. Unaleroglu, A. Ak and B. Garipcan, Design,
synthesis and cytotoxic evaluation of β-aryl-α-
dimethoxyphosphoryl-γ-lactams, Med. Chem. Res., 2017,
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and C. Hertweck, The chemistry and biology of
cytochalasans, Nat Prod Rep, 2010, 27, 869-886; (c) A.
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Okada, K. Isono and H. Osada, Epolactaene, a Novel
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Produced by a Marine Fungus, J Antibiot, 1995, 48, 733-
735; (e) E. G. Occhiato, C. Prandi, A. Ferrali and A. Guarna,
Remote stereocontrol in the Nazarov reaction: A new
approach to the core of roseophilin, J Org Chem, 2005, 70,
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All calculations were performed on
a Dell Precision
workstation, having two Intel Xeon processors, twelve core,
1TB 7.2K 6GBPS SAS Hard Drive, NVidia GTX 980 graphic card,
and a Linux operating system centos 7, kernel version 3.10.0-
514.10.2.el7.x86_64.
Molecular Interaction Fields were calculated by FLAP36 using
the DRY probe to describe potential hydrophobic interactions,
the sp2 carbonyl oxygen O and the amide N1 probes for
hydrogen-bond donor and acceptor regions, respectively.
X-Ray analysis. Colorless crystalline platelets suitable for
analysis of compound (+)-3a have been obtained by slow
evaporation of a methanol solution. X-Ray diffraction analysis
of compound (+)-3a was performed at room temperature
using an Oxford Diffraction Gemini R-Ultra diffractometer
equipped Enhanced Ultra Cu X-ray Source (
λ= 1.54184 Å).
Copper radiation has been chosen to enhance the anomalous
scattering of light atoms for a more significant Bijvoet intensity
difference and more reliable statistic of the absolute
configuration determination.39 The intensities were corrected
for absorption with the numerical correction based on
2.
(a) L. Bartali, D. Scarpi, A. Guarna, C. Prandi and E. G.
Occhiato, Chemistry of Lactam-Derived Vinyl Phosphates:
Stereoselective Synthesis of (+)-Fagomine (pg 913, 2009),
Synlett, 2010, 839-839; (b) L. Sernissi, M. Petrovic, D.
Scarpi, A. Trabocchi, F. Bianchini and E. G. Occhiato,
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Journal Name
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