Exploration of synthetic strategies for the stereoselective preparation of novel tetrahydrofuran-containing biaryls: A high-pressure promoted Diels-Alder approach

Article abstract of DOI:10.1016/j.tet.2018.09.032

Three stereoselective synthetic approaches to tetrahydrofuran-containing biaryl scaffolds are described. All approaches involve a high-pressure promoted Diels-Alder reaction of substituted diene with methyl propiolate to give, after aromatization, the cor

Full text of DOI:10.1016/j.tet.2018.09.032

Accepted Manuscript
Exploration of synthetic strategies for the stereoselective preparation of novel
tetrahydrofuran-containing biaryls: A high-pressure promoted Diels-Alder approach
Francesca Piazzolla, Carlo Siciliano, Lucio Minuti, Andrea Temperini
PII:
S0040-4020(18)31111-6
10.1016/j.tet.2018.09.032
TET 29804
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 July 2018
Revised Date: 12 September 2018
Accepted Date: 15 September 2018
Please cite this article as: Piazzolla F, Siciliano C, Minuti L, Temperini A, Exploration of synthetic
strategies for the stereoselective preparation of novel tetrahydrofuran-containing biaryls: A high-pressure
promoted Diels-Alder approach, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.09.032.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Exploration of Synthetic Strategies for the Stereoselective Preparation of Novel
Tetrahydrofuran-containing Biaryls: a High-Pressure Promoted Diels-Alder approach
a
b
c
a,
Francesca Piazzolla , Carlo Siciliano , Lucio Minuti , Andrea Temperini *
Address:
a
Dipartimento di Scienze Farmaceutiche, Università di Perugia, via del Liceo 1, 06123 Perugia, Italy
b
Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Edificio
Polifunzionale, 87030 Arcavacata di Rende, Cosenza, Italy
c
Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, via Elce di Sotto 8, 06123
Perugia, Italy
*
Corresponding author. Tel./fax: +39 075 5855116; e-mail address: andrea.temperini@unipg.it
Abstract
Three stereoselective synthetic approaches to tetrahydrofuran-containing biaryl scaffolds are described.
All approaches involve a high-pressure promoted Diels-Alder reaction of substituted diene with methyl
propiolate to give, after aromatization, the corresponding biaryl. The tetrahydrofuran moiety can be
2
created starting from aryl-Br or aryl-CO Me functional groups through a γ-phenylseleno ketone
intermediate.
Keywords:
biaryls; tetrahydrofuran; high-pressure; Diels-Alder; selenones
1
. Introduction
Tetrahydrofurans represent a structural motif widely present in natural compounds, such as macrolide
1
2
3
4
antibiotics, polyether ionophores, acetogenins, and oxidized lignans with significant and various
1

ACCEPTED MANUSCRIPT
biological activities. Thus, considerable efforts have been devoted to the stereoselective synthesis of
5
,6
7
such structures. Similarly, biaryl templates are privileged structures occurring in pharmaceutical
8
9
10
11
agents, such as anti-infective, hypocholesterolemic, antipsychotic,
anti-inflammatory,
1
2
13
antidiabetic, and antihypertensive drugs. Moreover, biaryls are valuable synthetic building blocks
1
4-16
17,18
19,20
for metal ligands
and novel organic materials,
and transition metal-catalysed cross-coupling
is the preferred method for their synthesis. The development of new chemical entities represents an
important challenge in pharmaceutical science, being the use of privileged scaffolds for library design
and drug discovery a valuable approach. As part of our general interest in high-pressure promoted
2
1-24
Diels-Alder reactions
for the synthesis of 1,1–biaryls and the utility of organochalcogen
2
5-30
intermediates in organic synthesis,
we focused our attention on the tetrahydrofuran-containing
biaryl scaffold due to the ability of each motif to bind multiple targets.
Herein, we report three different and stereoselective syntheses of novel tetrahydrofuran-containing
biaryls (Scheme 1) by combining a high-pressure promoted regiospecific [4+2] Diels-Alder reaction
6
with our previously reported approach to 2-substituted tetrahydrofurans. To the best of our knowledge,
the synthesis of 2-biaryl substituted tetrahydrofurans has not been previously investigated except for
3
1
some C-ribonucleoside and C-2’-deoxyribonucleosides. Only a few examples of 2-aryl- and 2-
3
2-34
heteroaryltetrahydrofurans
non-stereoselective synthesis, based on the activation of THF at the α-
35
position, have been reported.
Br
O
R1
OH
O
Cl
Br
R2
R3
OMe
1
2
R , R = Me, Cl, CO Me or CH OTBDMS
R3= OMe or H
2
2
Scheme 1. Envisaged general approach for the synthesis of tetrahydrofuran-containing biaryls.
2

ACCEPTED MANUSCRIPT
2
. Results and Discussion
A retrosynthetic analysis showed three possible strategies for the assembly of the 2-tetrahydrofuran
moiety on the biaryl system. The first approach (Method 1) was based on the construction of the
tetrahydrofuran ring from a bromo-substituted benzene to give a 2-arylsubstituted tetrahydrofuran
intermediate, which was then employed for the synthesis of the biaryl system (Scheme 2). Our second
strategy (Method 2) featured a late stage installation of the tetrahydrofuran ring on a bromo-
functionalized biaryl (Scheme 3). Finally (Method 3), to overcome the drawbacks of the first and the
second methods, we realised that the tetrahydrofuran could be prepared starting from a carbomethoxy-
functionalized biaryl. This led to a simple and short synthetic pathway (Scheme 5).
2
.1. First strategy
In Method 1, the protected benzyl alcohol 1 was transformed into the corresponding mixed magnesium
6
cuprate intermediate following the procedure reported in the literature and it was then subjected to
couple with 4-(phenylseleno)butanoyl chloride in THF (Scheme 2).
3

ACCEPTED MANUSCRIPT
OTBDMS
OMe
O
OTBDMS
OMe
a) Mg, THF rt
b) ThLi, CuI, -40 °C
Br
PhSe
(S)-Me-CBS, 0 °C
.
PhSe
COCl
BH Me S, THF
3
2
2
73%)
1
(
OH
OTBDMS
OMe
a) m-CPBA, THF
K HPO , rt
O
OTBDMS
PhSe
TBAF, THF, rt
2
4
b) KOH, rt
OMe
3
(75%)
4
(70%)
er= 90.6:9.4
O
a) H IO cat PCC
5 6,
MeCN, rt
O
O
O
CH OH
Ph P=CH
3 2
2
b) Acetone, H2O
NaOH, 40 °C
THF, rt
OMe
5
93%)
6
(62%)
7
(85%)
OMe
OMe
(
CH Cl 50 °C
9
2
kbar
2,
O
O
a) Br CH Cl -70 °C
2, 2 2,
CO Me
b) t-BuOK, THF, rt
2
CO Me
2
CO Me
2
OMe
OMe
8 (46%)
er= 90.6:9.4
Scheme 2. Method 1: Preparation of the tetrahydrofuran-containing biaryl 8 from O-protected-5-
bromo-2-methoxy benzyl alcohol 1.
The resulting γ-phenylseleno ketone 2 was enantioselectively reduced by the oxazaborolidine-catalyzed
3
6
Corey procedure to give the optically active phenylseleno alcohol 3 in excellent yield. The
configuration of the major enantiomer of compound 3 was tentatively assumed according to the
mechanism proposed by Corey and others. Reaction of 3 with an excess of m-chloroperoxybenzoic acid
in the presence of dipotassium hydrogen phosphate afforded the selenone intermediate, which was
further converted into the corresponding 2-substituted tetrahydrofuran 4 by treatment with powdered
6
,29
potassium hydroxide.
The optically active tetrahydrofuran 4 was obtained in good yield and in
9
0.6:9.4 enantiomeric ratio as determined by HPLC analysis on chiral stationary phase. Deprotection of
hydroxyl group in compound 4 with TBAF afforded the free alcohol 5, which was then oxidised with
periodic acid to the corresponding aldehyde intermediate. The aldehyde was immediately reacted with
4

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acetone in the presence of sodium hydroxide to give the benzylideneacetone 6 derivative in satisfactory
2
1
6
2 % global yield. Wittig reaction of this enone with methyltriphenylphosphonium bromide furnished
the expected phenyl-butadiene 7 in excellent yield (Scheme 2). In our approach to tetrahydrofuran-
containing biaryl 8 a high pressure promoted and regiospecific Diels-Alder reaction of 7 with methyl
2
1
propiolate was involved to give a cyclohexadiene intermediate which, after aromatization, gave the
biaryl. Although the expected Diels-Alder product was easily obtained, the reaction of the
cyclohexadiene intermediate with DDQ did not furnish the awaited biaryl 8, whereas treatment with
NBS and subsequent reaction with Et N resulted in a complex mixture and no trace of 8 was observed.
3
To overcome this drawback, a milder and sequential bromination-elimination reaction on the activated
3
7
double bond of cyclohexadienyl benzene intermediate was performed. Thus, bromination of the
isolated double bond with a solution of bromine in dichloromethane at -70°C afforded the brominated
derivative that was readily converted into the new benzene ring of the desired biaryl 8 by simple
treatment with potassium tert-butoxide at r.t. The novel functionalized scaffold 8 was obtained in 46%
global yield from 7 (Scheme 2). To our knowledge, this aromatization protocol has not been reported
before. No loss of enantiomeric purity occurred during these reactions, as demonstrated by the
enantiomeric ratio of 8, measured by HPLC analysis on chiral stationary phase.
2
.2. Second strategy
Method 2 was based on the construction of the tetrahydrofuran ring in the last part of the synthetic
sequence described above. This second approach to obtain a novel tetrahydrofuran-containing biaryl 14
is reported in Scheme 3.
5

ACCEPTED MANUSCRIPT
CH Cl , 50 °C
9
2
kbar
2
a) Br CH Cl -70 °C
2
,
2
2,
b) t-BuOK, THF, rt
CO Me
2
CO Me
CO Me
2
Br
2
Br
Br
9
10
52%)
(
a) Mg, THF rt
b) ThLi, CuI, -40 °C
a) KOH, MeOH, 60 °C
b) BH THF, 0 °C
c) TBDMSCl, Im
SePh
3
,
PhSe COCl
Br
OTBDMS
OTBDMS
11
68%)
O
12
(60%)
(
(
0
S)-Me-CBS
°C
a) m-CPBA, THF
K HPO , rt
2
4
SePh
.
BH Me S
b) KOH, rt
3
THF
2
O
OTBDMS
3 (75%)
er= 87.7:12.3
OTBDMS
14 (73%)
OH
1
Scheme 3. Method 2: Preparation of tetrahydrofuran-containing biaryl scaffold 14 from (E)-3 methyl-
-(4-bromophenyl)buta-1,3-diene 9.
1
2
2
The required substituted butadiene 9 was readily synthesized in high yield by Wittig reaction from the
commercially available (E)-3 methyl-1-(4-bromophenyl)but-3-ene-2-one. Then, diene 9 was used in a
regiospecific Diel-Alder reaction with methyl propiolate promoted by high-pressure (9 Kbar) in
dichloromethane at 50 °C. According to Scheme 3, the cycloadduct intermediate obtained was
aromatised to biaryl 10 through the same procedure followed to prepare 8. Thus, addition of bromine to
cyclohexadiene intermediate resulted in the formation of a brominated derivative, which was
immediately treated with potassium tert-butoxide to yield biaryl 10 in 52 % global yield. Through the
simple synthetic steps described above for compound 1, it appeared useful to synthesise the
tetrahydrofuran ring from bromobiaryl 10. In this case, due to the reactivity of the carboxymethyl
group under Grignard reaction conditions, ester 10 was easily converted in three steps (without
isolation of the intermediates) into the O-silyl protected benzyl alcohol 11. It is interesting to note that
the direct reaction of 10 with LiAlH afforded the benzyl alcohol 11 with the corresponding
4
6

ACCEPTED MANUSCRIPT
debrominated benzyl alcohol derivative as an equimolecular mixture. Therefore, we reasoned that 11
could be more conveniently prepared through the borane reduction of the acid intermediate (Scheme 3).
The preparation of the Grignard reagent from 11 was the key step of the entire procedure because we
needed it to prepare the required mixed magnesium-cuprate reagent. Following the protocol used to
prepare 2, the γ-phenylseleno ketone 12 was obtained in satisfactory 63% yield (Scheme 2). The
3
6
enantioselective reduction of 12 with (S)-Me-CBS gave the expected γ-phenylseleno alcohol 13 in
7
5% yield and in 87.7:12.3 enantiomeric ratio, measured by HPLC analysis on chiral stationary phase.
Finally, oxidation of the selenium atom of alcohol 13 into the corresponding selenone intermediate was
carried out in THF at r.t. with an excess of m-chloroperoxybenzoic acid in the presence of dipotassium
hydrogen phosphate as above. The tetrahydrofuran-containing biaryl scaffold 14 was clearly formed in
6
,29
good global yield after addition of powdered potassium hydroxide as reported before.
No loss of
enantiomeric purity occurred during this conversion, as demonstrated by the enantiomeric ratio of 14,
measured by HPLC analysis on chiral stationary phase.
2
.3. Third strategy
Methods 1 and 2 described above were unsatisfactory because of the incompatibility of some functional
groups, especially the carbonyl, to Grignard reagent. Therefore, we turned our attention to an
alternative approach to successfully prepare the γ-phenylseleno ketone required for the synthesis of the
tetrahydrofuran moiety. Recently, it has been reported a new complementary route to
δ
-phenylseleno
-valerolactone via a β-ketolactone intermediate which undergoes cleavage of
the alkyl carbon-oxygen bond of lactone by phenylselenolate anion (Scheme 4).
3
8
ketone starting from
δ
O
O
O
O
SePh
RCOCl
PhSeNa
CO2
O
R
O
-
R
7

ACCEPTED MANUSCRIPT
Scheme 4: Complementary route to δ-phenylseleno ketone.
Inspired by this procedure, we envisioned the possibility of using the carbomethoxy group of methyl
propiolate, introduced during the biaryl synthesis by Diels-Alder reaction, as a precursor of the acyl
group necessary to prepare the β-ketolactone. Thus, according the method 3, the commercially
available (E)-4-(2-chlorophenyl)but-3-en-2-one 15 was reacted with isopropenyl acetate, methyl
propiolate and catalytic p-toluenesulfonic acid under high-pressure (9 Kbar) at 40 °C (Scheme 5).
Under these conditions a multicomponent reaction occurred where an acetoxy-1,3-diene, generated in
situ by acid catalysed enolacetylation of the enone with isopropenyl acetate, reacted with the dienophile
2
4
methyl propiolate to give a Diels-Alder cycloadduct intermediate as recently reported. After a quick
purification through a short silica gel column, the crude cycloadduct obtained from 15 was submitted to
oxidation with DDQ and the expected biaryl 16 was isolated in 67% global yield.
O
OAc
a) CH Cl , TsOH cat
5
a) MeOH, Na, rt
b) NaH, MeI, DMF, rt
2
0 °C, 9 kbar
2
Cl
OAc
Cl
+
+
CO Me
2
c) KOH, MeOH, 60 °C
b) DDQ, PhMe, 60 °C
CO Me
2
1
67%)
6
15
(
OMe
OMe
Cl
OMe
Cl
Cl
PhSeSePh, Na
DMF, 110 °C
a) (COCl)2
O
O
CO2H
SePh
O
18
(60%)
b)
O in THF, -70 °C
O
O
17
72%)
(
OMe
OMe
Cl
a) m-CPBA, THF
, rt
(
0
S)-Me-CBS
°C
Cl
K
HPO
2
4
.
BH Me S
b) KOH, rt
3
THF
2
SePh
HO
O
20
(77%)
19
76%)
(
Scheme 5. Method 3: Preparation of tetrahydrofuran-containing biaryl 20 from (E)-4-(2-
chlorophenyl)but-3-en-2-one 15.
8

ACCEPTED MANUSCRIPT
Then biaryl 16 was easily converted in three steps (without isolation of the intermediates) into the
methoxy substituted biaryl acid 17 in 72% overall yield (Scheme 4). The synthesis of γ-phenylseleno
ketone 18 was the key step of the entire synthetic strategy. Thus, γ−butyrolactone was deprotonated by
treatment with LDA in THF at -70 °C and the resulting enolate was reacted with the corresponding acyl
chloride derived from 17 to give the β-ketolactone intermediate, which was employed in the successive
reaction without purification. The crude lactone, upon treatment with sodium phenylselenolate,
2
underwent clean nucleophilic lactone scission with concomitant loss of CO to easily afford the γ-
phenylseleno ketone 18 in 60% overall yield. The stereoselective reduction of 18 using Corey
3
6,29
procedure
furnished the expected γ-phenylseleno alcohol 19 in 76% yield. Chromatographic
separation of configurational isomers of 19 was attempted using different conventional chiral columns,
such as Chiracel OD-H, Lux-Cellulose 2, Lux-Amilose 2, and Welk R,R-1. However, none of the
above-mentioned phases was successful in determination of the enantiomeric ratio of alcohol 19.
Finally, oxidation of 19 with an excess amount of m-chloroperoxybenzoic acid in the presence of
dipotassium hydrogen phosphate occurred smoothly at r.t. to give the corresponding phenylselenone
intermediate, which cyclised in the presence of powdered KOH according to a 5-exo-tet ring pattern to
deliver the new desired tetrahydrofuran-containing biaryl 20 in 77% yield. Unfortunately, the
enantiomeric ratio determination of 20 was not achieved on available chiral stationary phase columns.
Moreover, in the chromatographic run carried out on Lux-Cellulose 2 at 10°C a classical peak-plateau-
peak shape, characteristic of simultaneous on-column separation and intercoversion process of
3
9
unresolved atropoisomers, was observed. The presence of four species was visible at 5°C but
unfortunately the four peaks were not resolved. As a matter of fact, the biaryl 20, as well as alcohol 19,
contains two different ortho substituents besides the presence of a chiral centre. These structural
features are characteristic of a molecule with the potential for hindered rotation about the single bond
connecting the aryl rings, which can lead to formation of conformational isomers (atropoisomers) as
9

ACCEPTED MANUSCRIPT
4
0
enantiomeric pairs. In general, NMR spectra recorded at r.t. for congested biaryl compounds show
1
duplications and broadening of signals. In our case the H NMR spectra of 20 in CDCl
3
at 293 K did
1
3
not show any signal splitting, while it was possible to see the peaks duplication on most CNMR
1
signals. However, not even HNMR in DMSO-d allowed a clear signal assignment (see SI) as it
6
4
1
presented complicated patterns, indicating a priori the presence of different conformers. It was not
possible to establish the relative conformer ratio by NMR nor HPLC profile and further studies are
currently ongoing in our laboratory, given the importance of atropoisomerism in drug discovery and
4
2
development.
3
. Conclusions
Three different and stereoselective strategies for the synthesis of new tetrahydrofuran-containing
biaryls were developed. The procedures were based on the construction of functionalised biaryls by
transition metal-free and high-pressure (9 Kbar) promoted Diels-Alder reactions. The use of a
stereospecific intramolecular nucleophilic substitution of the phenylselenone residue by the oxygen
atom of a hydroxy group allowed efficient formation of the tetrahydrofuran ring. Moreover, we also
showed a mild aromatisation of cyclohexadiene by a novel bromination/dehydrohalogenation
procedure and a new preparation of γ-phenylseleno ketones from butyrolactone. Our current efforts are
directed toward the synthesis of tetrahydropyran-substituted biaryls and heterobiaryls.
4
4
. Experimental section
.1. Materials and methods
All reaction of air- and water-sensitive organometallics were carried out in flame-dried glassware under
argon using standard techniques. All the compounds were purified by column chromatography.
Chromatography was performed on silica gel (Merck 60, 70-230 mesh), and analytical TLC was
1
0

ACCEPTED MANUSCRIPT
carried out on pre-coated silica gel plates (Merck 60 F254, 0.25 mm) using UV light and 0.5% w/v
potassium permanganate aqueous solution (followed by gentle heating) for visualisation. Melting
1
points were measured on a hot plate apparatus and are uncorrected. Proton magnetic resonance ( H
1
3
NMR) spectra were recorded at 200 and 400 MHz. Carbon magnetic resonance ( C NMR) spectra
were recorded at 50 and 100 MHz. Unless otherwise specified, CDCl was used as solvent at 293 K and
3
chemical shifts (δ) are reported in parts per million (ppm). The NMR spectra were calibrated using the
1
proton or carbon signals of residual, non-deuterated solvents peak: δ
H
7.27 and δ
C
77.0 for CDCl
3
. H
NMR spectral data are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; and br, broadened), number of protons, coupling constants, assignments (where possible).
Coupling constant (J) are quoted in Hertz (Hz) to the nearest 0.1 Hz. Infrared (IR) spectra were
recorded with a FT-IR instrument, using a diffuse reflectance sampling cell. Only significant
-1
absorption maxima (νmax) are reported in wavenumbers (cm ). GC-MS analysis were obtained with a
gas chromatograph (HP-5MS capillary column 29.0 m, ID 0.25, film 0.25 µm) equipped with a mass
selective detector at an ionizing voltage of 70 eV. Optical rotations were measured in a 50 mm cell
−
1
2
−1
using the D-line of sodium at the specified temperature. [α] values are given in 10 deg cm g ;
D
−
1
concentrations (c) are quoted in g 100mL . HPLC analyses were performed on an HPLC system
equipped with a UV/vis detector with chiral columns and solvents specified. All chromatograms were
run at 25 °C. Combustion analyses were carried out on a elemental analyzer. Hyperbaric experiments
were conducted on a Unipress LV30/16 apparatus. The synthesis of 1 from the commercially available
4
3
alcohol has been previously reported. The Grignard reagents for the preparation of ketones 2 and 12
were synthesized in large preparation by standard method from the corresponding halide and analyzed
4
4
by the method of Knochel prior to use. Freshly opened bottle of cuprous iodide was found to be
4
5
satisfactory. The well-known diene (9) was prepared by Wittig reaction from the commercially
2
2
available enone. The remaining enone 15 is commercially available.
1
1

ACCEPTED MANUSCRIPT
4
.2. Synthesis of tetrahydrofuran-containing biaryl 8 from O-protected-5-bromo-2-methoxy
benzyl alcohol 1
4
.2.1. Preparation of γ-phenylseleno ketone 2
4
-Phenylselenobutanoic acid (1.46 g, 6.00 mmol) was reacted with oxalyl chloride (2.54 mL, 30.00
mmol) at r.t. for 15 h. The solution was evaporated under reduced pressure. The residue was dissolved
in dry dichloromethane (5 mL), the solvent was removed and the crude acyl chloride obtained was
6
immediately used for the next reaction. In a 100 mL three-necked round-bottom flask , a suspension of
cuprous iodide (1.59 g, 8.40 mmol) in dry THF (20 mL) was cooled down to -30 °C. A 1M 2-
thienyllithium solution in THF (7.2 mL) was added by syringe and the resulting suspension was stirred
for 30 min at the same temperature. After cooling the mixture to -40 °C, a solution of the Grignard
reagent from 1 (7.2 mmol) was added with a syringe. The resulting suspension was stirred for 20 min
and then a solution of 4-phenylselenobutanoic chloride (6.00 mmol) in dry THF (6 mL) was slowly
added. The reaction mixture was allowed to slowly warm to r.t. After 4 h the reaction was quenched
with 10 mL of saturated aqueous ammonium chloride solution and 50 mL of ethyl acetate. Stirring for
2
h dissolved the copper salts. The organic phase was then separated and the aqueous portion was
washed with two 20 mL portions of ethyl acetate. The combined organic fractions were washed once
with 10 mL of 0.1M aqueous sodium thiosulfate and brine. The organic phase was dried and
concentrated in vacuo. Purification of the crude product by chromatography (SiO , dietyl
2
ether/petroleum ether 5:95) afforded 2.05 g (73% yield) of 1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-
-
1
4
1
7
-methoxy-phenyl]-4-phenylselanyl-butan-1-one (2); Light yellow oil; FTIR: νmax/cm 2931, 1676,
1
603, 1257, 1087, 839, 777, 736. H NMR (200 MHz, CDCl ) δ/ppm 8.12 (d, 1H, J = 2.3 Hz, H-Ar),
3
.90 (dd, 1H, J = 8.6, 2.3 Hz, H-Ar), 7.57-7.46 (m, 2H, H-Ar), 7.30-7.20 (m, 3H, H-Ar), 6.87 (d, 1H, J
=
2 3 2
8.6 Hz, H-Ar),4.75 (s, 2H, OCH ), 3.89 (s, 3H, OCH ), 3.11 (t, 2H, J = 7.1 Hz, CH ), 3.02 (t, 2H, J =
1
2

ACCEPTED MANUSCRIPT
1
3
7
.1 Hz, CH ), 2.14 (quint, 2H, J = 7.1 Hz, CH ), 0.99 (s, 9H, CH ), 0.13 (s, 6H, Si-CH ). C NMR
2 2 3 3
(
50 MHz, CDCl
3
) δ/ppm 198.2, 159.7, 132.5 (2C), 130.0, 129.8, 129.0 (2C), 128.5, 127.0, 126.7,
+
1
09.1, 59.8, 55.3, 37.7, 27.4, 25.9 (3C), 24.5, 18.4, -5.3, -5.4. EIMS (70 eV) m/z [M − 57] 421 (52),
3
21 (100), 263 (49), 249 (48), 207 (31), 120 (17), 105 (12), 77 (22). Anal. Calc. for C H N O SeSi:
24 34 2 3
C, 60.36; H, 7.18. Found: C, 60.62; H, 7.40.
4
.2.2. Asymmetric reduction of ketone 2
To a solution of (S)-Me-CBS (1.0 M in toluene, 0.25 mL, 0.25 mmol) in dry THF (10 mL) at 0 °C 2.0
M borane-dimethyl sulfide complex (0.50 ml, 1.00 mmol) was added under inert atmosphere. A
solution of ketone 2 (0.48 g, 1.00 mmol) in dry THF (10 mL) was added slowly along the side of the
reaction flask by using a syringe pump over 2 h under vigorous stirring and allowing the solution to
warm to r.t. The mixture was stirred at r.t. until the ketone disappeared on TLC monitoring (4 h). The
mixture was quenched with methanol and saturated ammonium chloride solution (5 mL). The mixture
was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (5 mL),
4
dried (MgSO ), and concentrated in vacuo. The crude product was purified on a silica gel column with
a mixture of petroleum ether and diethyl ether (70:30) as eluent to give (1R)-1-[3-({[tert-
Butyl(dimethyl)silyl]oxy}methyl)-4-methoxyphenyl]-4-(phenylseleno)butan-1-ol 3 (0.36 g, 75% yield)
-1
1
as colorless oil. FTIR: νmax/cm 3403, 2928, 1499, 1251, 1084, 838, 777. H NMR (200 MHz, CDCl )
3
δ/ppm 7.55-7.38 (m, 3H, H-Ar), 7.32-7.10 (m, 4H, H-Ar), 7.15 (d, 1H, J = 8.3 Hz, H-Ar), 4.75 (s, 2H,
OCH ), 4.70-4.56 (m, 1H, OCH), 3.80 (s, 3H, OCH ), 2.89 (t, 2H, J = 7.2Hz, CH ), 2.02-1.53 (m, 5H,
2
3
2
13
OH and CH ), 0.98 (s, 9H, CH ), 0.11 (s, 6H, Si-CH ). C NMR (50 MHz, CDCl ) δ/ppm 155.5,
2
3
3
3
1
36.2, 132.4 (2C), 130.3, 129.8, 128.9 (2C), 126.6, 125.0, 124.5, 109.4, 73.9, 60.1, 55.1, 38.6, 27.7,
+
2
6.4, 25.9 (3C), 18.4, -5.3, -5.4. EIMS (70 eV) m/z [M − 57] 423 (80), 405 (51), 233 (77), 173 (70),
2
5
9
1 (100), 75 (66). [α] D -3,14 (c 1.075, CHCl ); Anal. Calc. for C H O SeSi: C, 60.11; H, 7.57.
3 24 36 3
Found: C, 60.35; H, 7.83.
1
3

ACCEPTED MANUSCRIPT
4
.2.3. Oxidative-cyclisation of phenylseleno alcohol 3
To a solution of phenylseleno alcohol 3 (1.45 g, 3.02 mmol) in THF (60 mL) at r.t. powdered
dipotassium hydrogen phosphate (2.63 g, 15.10 mmol) and m-chloroperoxybenzoic acid (2.08 g, 12.08
6
,29
mmol) were added.
The reaction mixture was stirred until TLC analysis showed that the starting
selenide was completely converted into the corresponding selenone (2 h). Then powdered potassium
hydroxide was added (1.27 g, 22.65 mmol). The consumption of the selenone was monitored by TLC
(
14 h). The mixture was then poured into 10% aqueous sodium carbonate (30 mL) and extracted with
ethyl acetate (3 x 30 mL). The organic layer was washed with 10% aqueous sodium carbonate (20 mL),
brine, dried over sodium sulphate, and concentrated in vacuo. The reaction product was purified by
column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (30:70) as
eluent. tert-Butyl({2-methoxy-5-[(2R)-tetrahydrofuran-2-yl]benzyl}oxy)dimethylsilane (4)
was
-1
obtained as colorless oil (0.68 g, 70 % yield). FTIR: νmax/cm 2954, 1613, 1500, 1462, 1250, 1082,
1
8
2
4
40, 777. H NMR (200 MHz, CDCl
3
) δ/ppm 7.45 (d, 1H, J = 2.3 Hz, H-Ar), 7.22 (dd, 1H, J = 8.4,
.3 Hz, H-Ar), 6.80 (d, 1H, J = 8.4 Hz, H-Ar), 4.88 (t, 1H, J = 7.1 Hz, O-CH), 4.77 (s, 2H, OCH2),
.19-3.85 (m, 2H, OCH ), 3.80 (s, 3H, OCH ), 2.40-2.20 (m, 1H, CH ), 2.12-1.70 (m, 3H, CH ), 0.96
2
3
2
2
1
3
(
s, 9H, CH ), 0.12 (s, 6H, Si-CH ). C NMR (50 MHz, CDCl ) δ/ppm 155.2, 135.1, 129.6, 124.8,
3 3 3
1
5
24.5, 109.3, 80.7, 68.5, 60.2, 55.2, 34.5, 26.1, 26.0 (3C), 18.5, -5.2, -5.4. EIMS (70 eV) m/z [M −
+
22
7] 265 (100), 235 (55), 173 (449, 105 (40), 91 8299, 75 (59). [α] D 12.89 (c 1.530, CHCl ); Anal.
3
Calc. for C H O Sì: C, 67.03; H, 9.38. Found: C, 66.89; H, 9.62. Phenomenex® Lux Cellulose-2, 1
1
8
30
3
mL/min hexane/i-PrOH/EtOH 94/5/1, (obs: 254 nm): retention times: 4.9 min (S-enantiomer), 5.1 min
R-enantiomer, major), er = 90.6:9.4.
.2.4. Preparation of alcohol 5
(
4
TBAF (0.32 g, 1.00 mmol) was added to a stirred solution of protected alcohol 4 (0.32 g, 1.00 mmol)
in THF (10 mL) at r.t. The reaction mixture was stirred for 16 h, poured into saturated aqueous sodium
1
4

ACCEPTED MANUSCRIPT
hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer
was dried over sodium sulfate, filtered, and evaporated. The residue was purified by column
chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (30:70) as eluent to
obtain {2-methoxy-5-[(2R)-tetrahydrofuran-2-yl]phenyl}methanol (5) as colorless oil (0.19 g, 93 %
-1
1
yield). FTIR: νmax/cm 3335, 2930, 1613, 1506, 1249, 1043, 815. H NMR (200 MHz, CDCl ) δ/ppm
3
7
.45-7.20(m, 2H, H-Ar), 6.86 (d, 1H, J = 8.8 Hz, H-Ar), 4.83 (t, 1H, J = 7.3 Hz, O-CH), 4.69 (s, 2H,
OCH
2
), 4.18-4.03 (m, 1H, OCH
2
), 4.01-3.88 (m, 1H, OCH
2
), 3.87 (s, 3H, OCH
3
), 2.65 (br s, 1H, OH),
1
3
2
.40-2.18 (m, 1H, CH
2
), 2.10-1.91 (m, 2H, CH
2
), 1.90-1.80 (m, 1H, CH
2
). C NMR (50 MHz, CDCl )
3
δ/ppm 156.5, 135.2, 129.0, 126.1, 126.0, 109.9, 80.4, 68.4, 61.8, 55.3, 34.4, 26.0. EIMS (70 eV) m/z
+
22
[
M − 1] 207 (61), 177 (100), 165 (50), 135 (33), 99 (22), 77 (26). [α] D 29.01 (c 1.050, CHCl );
3
Anal. Calc. for C12
16 3
H O : C, 69.21; H, 7.74. Found: C, 69.03; H, 7.99.
4.2.5. Synthesis of enone 6
Alcohol 5 (0.42 g, 2.00 mmol) was dissolved in acetonitrile (16 mL) and periodic acid (0.54 g, 2.26
mmol) and pyridinium chlorochromate (8 mg, 0.04 mmol) were added at 0 °C. The reaction mixture
was stirred for 2 h and then diluted with ethyl acetate (100 mL) and washed once with 10 mL of 0.1M
aqueous sodium sulphite and then brine, dried over sodium sulphate, and concentrated in vacuo giving
the crude aldehyde which was employed in the next step. To a stirred solution of the crude aldehyde in
absolute ethanol (12 mL) at 40 °C, acetone (1.3 mL, 20.00 mmol) and NaOH (10% w/v aq., 0.5 mL)
were added. The resulting mixture was stirred for 17 h, ethanol was evaporated under reduced pressure
and HCl (2N, 10 mL) was added. The resulting mixture was extracted with ethyl acetate (2 x 20 mL)
and the combined organic layers were washed with brine, dried over sodium sulphate, and concentrated
in vacuo. (3E)-4-{2-Methoxy-5-[(2R)-tetrahydrofuran-2-yl]phenyl}but-3-en-2-one (6) (0.15 g) was
isolated after column chromatography on SiO (ethyl acetate/petroleum ether 30:70) in a 62% global
2
-1
1
yield from 5. Colorless oil; FTIR: νmax/cm 2958, 1670, 1496, 1250, 1063, 820; H NMR (200 MHz,
1
5

ACCEPTED MANUSCRIPT
CDCl
3
) δ/ppm 7.88 (d, 1H, J = 16.5 Hz, CH), 7.53 (d, 1H, J = 2.1 Hz, H-Ar), 7.34 (dd, 1H, J = 8.6,
2
.1 Hz, H-Ar), 6.90 (d, 1H, J = 8.6 Hz, H-Ar), 6.89 (d, 1H, J = 16.5 Hz, CH), 4.84 (t, 1H, J = 7.1 Hz,
O-CH), 4.20-4.01 (m, 1H, OCH ), 3.99-3.80 (m, 1H, OCH ), 3.90 (s, 3H, OCH ), 2.40 (s, 3H, CH ),
2
2
3
3
1
3
2
.39-2.20 (m, 1H, CH ), 2.15-1.91 (m, 2H, CH ), 1.89-1.69 (m, 1H, CH ). C NMR (50 MHz, CDCl )
2 2 2 3
δ/ppm 199.0, 157.5, 138.7, 135.6, 129.2, 127.8, 125.7, 123.1, 11.0, 80.0, 68.5, 55.6, 34.5, 27.1, 26.0.
+
24
EIMS (70 eV) m/z [M] 246 (14), 215 (100), 203 (23), 173 (24), 145 (13), 115 (11). [α] D 6.33 (c
1
.370, CHCl ); Anal. Calc. for C H O : C, 73.15; H, 7.37. Found: C, 73.33; H, 7.63.
3
15 18
3
4
.2.6. Synthesis of diene 7
To a suspension of methyltriphenylphosphonium bromide (1.78 g, 5.00 mmol) in dry THF (25 mL) at -
6 °C (NaCl-ice bath) was added dropwise n-butyllithium (1.6 M in hexane, 3.2 mL, 5.00 mmol). The
1
reaction mixture was stirred for 30 min and the enone 6 (0.62 g, 2.50 mmol) was added as a solution in
THF (4 mL) at 0 °C. After 1 h the solution was warmed to r.t. and stirred for additional 2 h. A saturated
solution of NH Cl (10 mL) was added and the mixture was extracted with ethyl acetate (2 x 30 mL).
4
The combined organic phases were washed with brine, dried over MgSo4, and the solvent was
removed under reduced pressure. The residue was purified on a silica gel column with a mixture of
petroleum ether and ethyl ether (70:30) as eluent to give the corresponding (2R)-2-{4-Methoxy-3-[(1E)-
3
ν
2
8
-methylbuta-1,3-dien-1-yl]phenyl}tetrahydrofuran (7); (0.52 g, 85% yield). Colorless oil; FTIR:
-1
1
3
max/cm 2970, 1604, 1495, 1246, 1065, 885, 811; H NMR (200 MHz, CDCl ) δ/ppm 7.50 (d, 1H, J =
.1 Hz, H-Ar), 7.19 (dd, 1H, J = 8.5, 2.1 Hz, H-Ar), 6.93-6-80 (m, 3H, H-Ar and CH), 6.84 (d, 1H, J =
.5 Hz, H-Ar), 5.22 (s, 1H, CH ), 5.06 (s, 1H, CH ), 4.84 (t, 1H, J = 7.2 Hz, O-CH), 4.20-4.05 (m, 1H,
2
2
OCH ), 4.00-3.79 (m, 1H, OCH ), 3.85 (s, 3H, OCH ), 2.38-2.20 (m, 1H, CH ), 2.14-1.90 (m, 2H,
2
2
3
2
1
3
CH
2
), 2.01 8s, 3H, CH
3
), 1.89-1.70 (m, 1H, CH
2
). C NMR (50 MHz, CDCl
3
) δ/ppm 156.0, 142.7,
1
35.3, 132.2, 126.2, 125.8, 123.8, 123.3, 116.8, 110.8, 80.5, 66.5, 55.6, 34.5, 26.1, 18.7. EIMS (70 eV)
1
6

ACCEPTED MANUSCRIPT
+
25
m/z [M] 244 (44), 185 (36), 173 (100), 158 (60), 128 (21), 115 (20), 71 (51). [α] D 5.54 (c 1.020,
CHCl ); Anal. Calc. for C16 : C, 78.65; H, 8.25. Found: C, 78.47; H, 8.51.
.2.7. Transformation of 1-arylbuta-1,3-diene 7 into biaryl 8
A solution of arylbutadiene 7 (0.12 g, 0.5 mmol) in 3 ml of CH Cl was placed in a 5 mL Teflon vial.
3
20 2
H O
4
2
2
Methyl propiolate (0.42 mL, 1.5 mmol) and a few crystals of hydroquinone were added, and the vial
was filled with the solvent. The vial was closed and kept at 9 Kbar at 45°C for 60 h. After
depressurizing, the mixture was poured into saturated NaHCO solution (10 mL) and extracted with
3
CH Cl (2 x 10 mL). The combined extracts were washed with brine, dried (Na SO ), and evaporated
2
2
2
4
under vacuum and the residue filtered through a plug of silica and eluted with a mixture of ethyl
acetate/petroleum ether 30:70. After evaporation, the crude cycloadduct intermediate was dissolved in
dichloromethane (10 mL) and a 0.1 M bromine solution in chloroform (5 mL) was slowly added at - 70
°
C. The addition was stopped when a further drop gave a persistent red colour. The mixture was
poured into saturated aqueous NaCl and extracted twice with 10 mL of chloroform. The combined
organic layers were dried over Na SO and concentrated under vacuum. The crude residue was
2
4
dissolved in THF (10 mL) and potassium tert-butoxide (0.45 g, 4.00 mmol) was added at r.t. When the
elimination/aromatization reaction ceased (3 h), the mixture was poured into saturated aqueous NH Cl
4
and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with brine,
2 4
dried over Na SO , and concentrated under vacuum. Purification of the residue by silica gel column
chromatography with a mixture of petroleum ether and diethyl ether 80:20 as eluent gave 75 mg of
Methyl 2'-methoxy-5-methyl-5'-[(2R)-tetrahydrofuran-2-yl]biphenyl-2-carboxylate (8) in 46% global
-1
1
yield. Colorless oil; FTIR: νmax/cm 2951, 1729, 1608, 1501, 1290, 1097, 783; H NMR (200 MHz,
CDCl ) δ/ppm 7.80 (d, 1H, J = 7.8 Hz, H-Ar), 7.47-7.11 (m, 4H, H-Ar), 6.86 (d, 1H, J = 8.4 Hz, H-
3
Ar), 4.89 (t, 1H, J = 7.3 Hz, O-CH), 4.21-4.08 (m, 1H, OCH ), 4.00-3.86 (m, 1H, OCH ), 3.72 (s, 3H,
2
2
1
3
OCH ), 3.64 (s, 3H, OCH ), 2.43 (s, 3H, CH ), 2.41-2.22 (m, 1H, CH ), 2.11-1.87 (m, 3H, CH ). C
3
3
3
2
2
1
7

ACCEPTED MANUSCRIPT
NMR (50 MHz, CDCl
3
) δ/ppm 168.5, 155.3, 141.9, 138.8, 135.2, 132.1, 130.6, 129.5, 128.7, 127.8,
+
1
2
27.4, 126.0, 109.8, 80.4, 68.4, 56.3, 51.5, 34.4, 26.0, 21.4. EIMS (70 eV) m/z [M] 326 (100), 295 (4),
2
6
65 (55), 253 (77), 225 (49), 165 (43), 152 (37). [α] D 23.48 (c 0.800, CHCl ); Anal. Calc. for
3
C H O : C, 73.60; H, 6.79. Found: C, 73.78; H, 7.05. Phenomenex® Lux Cellulose-2, 1 mL/min
20
22
4
hexane/i-PrOH 96/4, (obs: 254 nm): retention times: 17.29 min (R-enantiomer, majour), 27.6 min (S-
enantiomer, minor), er = 90.6:9.4.
4
.3. Synthesis of tetrahydrofuran-containing biaryl scaffold 14 from (E)-3 methyl-1-(4-
bromophenyl)buta-1,3-diene 9
.3.1. Synthesis of biaryl 10
A solution of arylbutadiene 9 (0.11 g, 0.5 mmol) in 3 ml of CH Cl was placed in a 5 mL Teflon vial.
4
2
2
Methyl propiolate (0.42 mL, 1.5 mmol) and a few crystals of hydroquinone were added and the vial
was filled with the solvent. The vial was closed and kept at 9 Kbar and 45°C for 60 h. After
depressurizing, the mixture was poured into saturated NaHCO
3
solution (10 mL) and extracted with
SO ), and evaporated
CH Cl (2 x 10 mL). The combined extracts were washed with brine, dried (Na
2
2
2
4
under vacuum and the residue was filtered through a plug of silica and eluted with a mixture of ethyl
acetate/petroleum ether 30:70. After evaporation, the crude cycloadduct intermediate was dissolved in
dichloromethane (10 mL) and a 0.1 M bromine solution in chloroform (5 mL) was slowly added at -
4
6
7
0 °C. The addition was stopped when a further drop gave a persistent red colour. The mixture was
poured into saturated aqueous NaCl and extracted twice with 10 mL of chloroform. The combined
organic layers were dried over Na SO and concentrated under vacuum. The crude residue was
dissolved in THF (10 mL) and potassium tert-butoxide (0.45 g, 4.00 mmol) was added at r.t. When the
elimination/aromatization reaction ceased (3 h), the mixture was poured into saturated aqueous NH Cl
and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with brine,
2
4
4
1
8

ACCEPTED MANUSCRIPT
dried over Na SO , and concentrated under vacuum. Purification of the residue by silica gel column
2
4
chromatography with a mixture of petroleum ether and diethyl ether 90:10 as eluent gave 79 mg of
Methyl 4'-bromo-5-methylbiphenyl-2-carboxylate (10) as pale yellow oil in 52% global yield. FTIR:
-1
1
νmax/cm 2926, 1734, 1653, 1559, 1457, 1009, 828; H NMR (200 MHz, CDCl ) δ/ppm 7.81 (d, 1H, J
3
=
7.9 Hz, H-Ar), 7.52 (d, 2H, J = 8.4 Hz, H-Ar), 7.28-7.18 (m, 4H, H-Ar), 3.65 (s, 3H, OCH ), 2.43 (s,
3
1
3
3
1
H, CH
3
). C NMR (50 MHz, CDCl
3
) δ/ppm 168.4, 142.0, 141.6, 140.5, 131.4, 130.9 (2C), 130.3,
+
29.9 (2C), 128.2, 127.3, 121.3, 51.8, 21.4. EIMS (70 eV) m/z [M] 304 (52), 273 (40), 194 (100), 165
(
80); Anal. Calc. for C H BrO: C, 59.04; H, 4.29. Found: C, 58.89; H, 4.53.
15 13
4
.3.2. Preparation of protected biaryl alcohol 11
To a solution of 10 (0.46 g, 1.50 mmol) in 1:1 mixture of methanol and water (8 mL), solid potassium
hydroxide (84 mg, 1.5 mmol) was added and the resulting mixture was kept at 60°C until complete
consumption of the starting material (10 h) and then allowed to cool to r.t. After addition of 10%
hydrochloric acid (5 mL) the acidic mixture was extracted with CH Cl (3 x 10 mL). The combined
2
2
extracts were washed with brine (10 mL), dried (MgSO ), filtered, and concentrated in vacuo to give
4
the crude acid, which was dissolved in THF (2 mL). The flask was immersed in an ice bath and cooled
to 0°C. Then 1.95 mL (1.95 mmol) of borane-THF solution was slowly added over a period of 15 min
47
and the solution was vigorously stirred for an additional period of 2 h. Excess hydride was carefully
destroyed with 5 mL of a 1:1 mixture of THF and water and the aqueous phase was saturated with
potassium carbonate. The mixture was extracted three times with 10 mL portions of ethyl acetate. The
combined organic extracts were dried over magnesium sulfate. Removal of the solvent gave the crude
alcohol. The alcohol, tert-butyldimethylsilyl chloride (0.25 g, 1.65 mmol), and imidazole (13.82 g, 3.30
mmol) were stirred in DMF (8 mL) for 18 h. The solution was poured into water (10 mL) and extracted
with ethyl acetate (2 x 10 mL). The organic phase was washed with HCl (1N, 5 mL), water, then brine,
1
9

ACCEPTED MANUSCRIPT
and dried over MgSO to give, after evaporation of solvent, the crude product. Purification on a silica
4
gel column with a mixture of petroleum ether and ethyl ether (80:20) as eluent gave [(4'-Bromo-5-
methylbiphenyl-2-yl)methoxy](tert-butyl)dimethylsilane (11) in 68% yield (0.399 g) as a colorless oil.
-1
1
FTIR: νmax/cm 2955, 1472, 1252, 1074, 836, 776; H NMR (200 MHz, CDCl ) δ/ppm 7.58-7.38 (m,
3
3
H, H-Ar), 7.31-7.11 (m, 3H, H-Ar), 7.04 (s, 1H, H-Ar), 4.54 (s, 2H, OCH ), 2.38 (s, 3H, CH ), 0.88
2 3
1
3
(
3 3 3
s, 9H, CH ), 0.02 (s, 6H, Si-CH ).. C NMR (50 MHz, CDCl ) δ/ppm 140.6, 139.5, 136.5, 135.3,
1
30.9 (2C), 130.4, 128.5 (2C), 128.0, 127.0, 62.9, 26.0, 25.9 (2C), 21.1, 18.3, -5.2, -5.3. EIMS (70 eV)
+
m/z [M-57] 333 (100), 259 (31), 180 (99), 165 (53), 75 (28); Anal. Calc. for C H BrOSi: C, 61.37;
2
0
27
H, 6.95. Found: C, 61.59; H, 7.10
4
.3.3. Preparation of γ-phenylseleno ketone 12
-Phenylselenobutanoic acid (0.49 g, 2.00 mmol) was reacted with oxalyl chloride (0.85 mL, 10.00
4
mmol) at r.t. for 15 h. The solution was evaporated under reduced pressure. The residue was dissolved
in dry dichloromethane (5 mL), the solvent was removed, and the crude phenylselenobutanoic chloride
obtained was immediately used for the next reaction. In a 100 mL three-necked round-bottom flask, a
suspension of cuprous iodide (0.53 g, 2.80 mmol) in dry THF (10 mL) was cooled down to -30 °C. A
1
M 2-thienyllithium solution in THF (2.4 mL) was added by syringe and the resulting suspension was
stirred for 30 min at the same temperature. After cooling the mixture to -40°C, a solution of the
Grignard reagent from 12 (2.4 mmol) was added with a syringe. The resulting suspension was stirred
for 20 min and then a solution of 4-phenylselenobutanoic chloride in dry THF (4 mL) was slowly
added. The reaction mixture was allowed to slowly warm to r.t. After 4 h the reaction was quenched
with 5 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate. Stirring for 2
h dissolved the copper salts. The organic phase was then separated and the aqueous portion was washed
with two 10 mL portion of ethyl acetate. The combined organic fractions were washed once with 5 mL
of 0.1M aqueous sodium thiosulfate and brine. The organic phase was dried and concentrated in vacuo.
2
0

ACCEPTED MANUSCRIPT
Purification of the crude product by chromatography (SiO , diethyl ether/petroleum ether 20:80)
2
afforded 0.64 g (60% yield) of 1-[2'-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5'-methylbiphenyl-4-yl]-
-1
4
-(phenylseleno)butan-1-one (12) as pale yellow oil. FTIR: νmax/cm 2927, 1683, 1604, 1477, 1222,
1
1
073, 839, 738; H NMR (200 MHz, CDCl ) δ/ppm 7.97 (d, 2H, J = 8.6 Hz, H-Ar), 7.59-7.42 (m, 5H,
3
H-Ar), 7.34-7.18 (m, 4H, H-Ar), 7.06 (s, 1H, H-Ar), 4.56 (s, 2H, OCH
2
), 3.19 (t, 2H, J = 7.1 Hz, CH
2
),
3
0
1
.07 (t, 2H, J = 7.1 Hz, CH ), 2.40 (s, 3H, CH ), 2.20 (quint, 2H, J = 7.1 Hz, CH ), 0.89 (s, 9H, CH ),
2
3
2
3
1
3
.10 (s, 6H, Si-CH ). C NMR (50 MHz, CDCl ) δ/ppm 199.1, 146.0, 139.5, 136.9, 135.4, 135.3,
3
3
32.6 (2C), 130.1, 129.4 (3C), 129.1 (2C), 128.8, 128.4, 127.8 (2C), 126.8, 62.8, 38.1, 27.4, 25.9, 25.8
+
(
2C), 24.5, 21.0, 18.3, -5.3 (2C). EIMS (70 eV) m/z [M-157] 380 (6), 249 (64), 231 (19), 216 (15),
1
78 (20), 75 (43). Anal. Calc. for C H O SeSi: C, 67.02; H, 7.12. Found: C, 67.18; H, 7.27
30 38 2
4
.3.4. Asymmetric reduction of ketone 12
To a solution of (S)-Me-CBS (1.0 M in toluene, 0.25 mL, 0.25mmol) in dry THF (10 mL) at 0°C a 2.0
M borane-dimethyl sulfide complex (0.50 ml, 1.00 mmol) was added under inert atmosphere.. A
solution of ketone 2 (0.54 g, 1.00 mmol) in dry THF (10 mL) was added slowly along the side of the
reaction flask by using a syringe pump over 2 h with vigorous stirring and the solution was allowed to
warm to r.t. The mixture was stirred at r.t. until the ketone disappeared on TLC monitoring (6 h). The
mixture was quenched with methanol and saturated ammonium chloride solution (5 mL). The mixture
was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (5 mL),
dried (MgSO ), and concentrated in vacuo. The crude product was purified on a silica gel column with
4
a mixture of petroleum ether and ethyl acetate (70:30) as eluent to give the corresponding (1R)-1-[2'-
(
{[tert-Butyl(dimethyl)silyl]oxy}methyl)-5'-methylbiphenyl-4-yl]-4-(phenylseleno)butan-1-ol (13) in
-1
7
9% yield (0.42 g) as pale yellow oil. FTIR: νmax/cm 3028, 2920, 1611,1457, 1338, 1011, 850, 737;
1
H NMR (200 MHz, CDCl ) δ/ppm 7.57-7.42 (m, 3H, H-Ar), 7.35 (s, 4H, H-Ar), 7.30-7.13 (m, 4H, H-
3
2 2
Ar), 7.08 (s, 1H, H-Ar), 4.82-4.68 (m, 1H, OCH), 4.58 (s, 2H, OCH ), 3.03-2.88 (m, 2H, CH ), 2.40 (s,
2
1

ACCEPTED MANUSCRIPT
1
3
3
H, CH ), 2.09-1.71 (m, 5H, CH ), 0.92 (s, 9H, CH ), 0.30 (s, 6H, Si-CH ). C NMR (50 MHz,
3 2 3 3
3
CDCl ) δ/ppm 143.0, 140.4, 140.2, 136.6, 135.3, 132.6 (2C), 130.4, 129.7, 129.3 (2C), 128.9, 128.2
(
2C), 126.7, 125.5 (2C), 73.8, 62.9, 38.9, 27.7, 26.4, 25.9, 25.8 (2C), 21.0, 18.3, -5.3 (2C). EIMS (70
+
21
eV) m/z [M- 214] 325 (14), 233 (100), 218 (30), 205 (19), 178 (15), 165 (22), 75 (16). [α] D 6.66 (c
.750, CHCl3); Anal. Calc. for C H O SeSi: C, 66.77; H, 7.47. Found: C, 66.89; H, 7.73.
2
30
40
2
Phenomenex® Lux Cellulose-2, 1 mL/min hexane/i-PrOH 97:3, (obs: 254 nm): retention times: 7.1
min (S-enantiomer, minor), 8.0 min (R-enantiomer, major), er= 87.7:12.3.
4
.3.5. Synthesis of biaryl 14 by oxidative-cyclization of phenylseleno alcohol 13
To a solution of phenylseleno alcohol 13 (0.32 g, 0.59 mmol) in THF (20 mL) at r.t. powdered
dipotassium hydrogenphosphate (0.51 g, 2.95 mmol) and m-chloroperoxybenzoic acid (0.41 g, 2.36
mmol) were added. The reaction mixture was stirred until TLC analysis showed that the starting
selenide had been completely converted into the corresponding selenone (2 h). Then powdered
potassium hydroxide was added (0.25 g, 4.42 mmol). The consumption of the selenone was monitored
by TLC (16 h). The mixture was then poured into 10% aqueous sodium carbonate (10 mL) and
extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with 10% aqueous sodium
carbonate (10 mL), then brine, dried over sodium sulphate, and concentrated in vacuo. The reaction
product was purified by column chromatography on silica gel using a mixture of diethyl ether and
petroleum ether (20:80) as eluent. tert-Butyl(dimethyl)({5-methyl-4'-[(2R)-tetrahydrofuran-2-
yl]biphenyl-2-yl}methoxy)silane (14) was isolated in 73% yield (0.17 g) as colourless oil. FTIR:
νmax/cm-1 2856, 1610, 1462, 1254, 1069, 834, 775. 1H NMR (400 MHz, CDCl ) δ/ppm 7.51 (d, 1H,
3
J = 8.0 Hz, H-Ar), 7.42 (d, 2H, J = 8.4 Hz, H-Ar), 7.37 (d, 2H, J = 8.4 Hz, H-Ar), 7.23 (d, 1H, J = 8.0
2
Hz, H-Ar), 7.10 (s, 1H, H-Ar), 4.98 (t, 1H, J = 7.2 Hz, O-CH), 4.62 (s, 2H, OCH ), 4.23-4.14 (m, 1H,
OCH
2
), 4.05-3.97 (m, 1H, OCH
2
), 2.50-2.34 (m, 1H, CH
2
), 2.41 (s, 3H, CH
3
2
), 2.19-2.01 (m, 2H, CH ),
1
.97-1.84 (m, 1H, CH ), 0.97 (s, 9H, CH ), 0.08 (s, 6H, Si-CH ). 13C NMR (100 MHz, CDCl ) δ/ppm
2
3
3
3
2
2

ACCEPTED MANUSCRIPT
1
2
42.0, 140.3, 139.8, 136.5, 135.4, 130.4, 129.1, (2C), 128.0, 127.9, 125.4 (2C), 80.6, 86.7, 62.9, 34.5,
6.1, (3C), 25.9, 21.0, -5.3 (2C); EIMS (70 eV) m/z [M − 57]+ 325 (24), 233 (100), 205 (36), 179
(
3 36 2
25), 165 (39), 75 (30). [α]20 D 8.69 (c 1.150, CHCl ); Anal. Calc. for C24H O Si: C, 75.34; H, 8.96.
Found: C, 75.19; H, 9.19. Phenomenex® Lux Cellulose-2, 1 mL/min hexane/i-PrOH 99:1, obs: (254
nm): retention times: 3.9 min (S-enantiomer), 4.0 min (R-enantiomer), er= 10.95-89.05.
4
1
4
.4. Synthesis of tetrahydrofuran-containing biaryl 20 from (E)-4-(2-chlorophenyl)but-3-en-2-one
5
.4.1. Preparation of biaryl 16
A solution of enone 15 (0.27 g, 1.5 mmol), isopropenyl acetate (0.81 mL, 7.5 mmol), and methyl
propiolate (0.42 mL, 4.5 mmol) in CH Cl was placed in a 5 mL Teflon vial. TsOH (12 mg, 4 mol%)
was added and the vial was filled with the solvent. The vial was closed and kept at 9 Kbar and 45°C for
0 h. After depressurizing, the mixture was poured into saturated NaHCO solution (10 mL) and
2
2
6
3
extracted twice with 20 mL of CH Cl . The combined extracts were washed with brine, dried (Na SO ),
2
2
2
4
and evaporated under vacuum. The crude residue was dissolved in toluene (20 mL) and DDQ (0.34 g,
.5 mmol) was added. The mixture was stirred at 60°C for 24 h and then poured into saturated aqueous
Na CO and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried
over Na SO , and concentrated under vacuum. The crude mixture was purified by silica gel column
chromatography with a mixture of petroleum ether and diethyl ether 60:40 as eluent to give 0.31 g of
1
2
3
2
4
-1
Methyl 5-(acetyloxy)-2'-chlorobiphenyl-2-carboxylate (16) in 67% global yield. Oil; FTIR: νmax/cm
1
2
8
951, 1768, 1730, 1436, 1290, 1202, 1027, 758; H NMR (200 MHz, CDCl
3
) δ/ppm 8.05 (d, 1H, J =
.6 Hz, H-Ar), 7.46-7.36 (m, 1H, H-Ar), 7.34-7.18 (m, 4H, H-Ar), 7.03 (d, 1H, J = 2.4 Hz, H-Ar), 3.68
1
3
(
s, 3H, OCH ), 2.31 (s, 3H, CH ); C NMR (50 MHz, CDCl ) δ/ppm 168.7, 166.4, 153.0, 142.2,
3 3 3
1
39.6, 132.5, 131.7, 130.0, 128.9, 128.8, 127.9, 126.5, 124.2, 121.0, 52.0, 21.1; EIMS (70 eV) m/z [M
2
3

ACCEPTED MANUSCRIPT
+
–
4
4
35.5] 269 (94), 227 (100), 211 (59), 168 (26), 139 (38); Anal. Calcd for C H ClO : C, 63.06; H,
16 13 4
.30. Found: C, 62.92; H, 4.57.
.4.2. Synthesis of acid 17
To a solution of sodium methoxide prepared dissolving 0.46 g (20.0 mmol) of sodium in 100 mL of dry
methanol at r.t., ester 16 ( 3.01 g, 10.0 mmol) was added and the resulting mixture was kept at r.t. until
complete consumption of the starting material (2 h). The mixture was concentrated and after addition of
1
0% hydrochloric acid (10 mL) the acidic mixture was extracted three times with 30 mL of CH Cl .
2 2
The combined extracts were washed with brine, dried (MgSO ), filtered, and concentrated in vacuo.
4
The crude residue was dissolved in 80 mL of dry DMF at 0°C and NaH (0.31 g, 13.0 mmol) was
added under inert atmosphere. After 1 h methyl iodide (0.81 mL, 13.0 mmol) was added to the
resulting mixture, which was then allowed to warm to r.t. (8 h). After addition of 10% hydrochloric
acid (10 mL) the acidic mixture was extracted with diethyl ether (4 x 30 mL). The combined extracts
were washed with brine, dried (MgSO ), filtered, and concentrated in vacuo. The residue was dissolved
4
in a 3:1 mixture of methanol and water (40 ml) and potassium hydroxide (1.12 g, 20.0 mmol) was
added. The mixture was heated to 60°C for 16 h and then allowed to cool to r.t. After addition of 10%
hydrochloric acid (20 mL) the acidic mixture was extracted with CH Cl (3 x 30 mL). The combined
2
2
4
extracts were washed with brine (10 mL), dried (MgSO ), filtered, and concentrated in vacuo to give a
solid, which was triturated with diethyl ether (2x20 ml). The solid was filtered to afford 2'-Chloro-5-
methoxybiphenyl-2-carboxylic acid (17) as white solid (2.10 g, 72% yield). mp 48−50 °C; FTIR:
-1
1
νmax/cm 3085, 2923, 1685, 1594, 1457, 1303, 1033, 755; H NMR (200 MHz, CDCl ) δ/ppm 10.05
3
(
br s, 1H, H-Ar), 8.09 (d, 1H, J = 8.8 Hz, H-Ar), 7.47-7.10 (m, 4H, H-Ar), 6.95 (dd, 1H, J = 2.4 Hz, H-
13
Ar), 6.73 (d, 1H, J = 2.6 Hz, H-Ar), 3.84 (s, 3H, OCH ); C NMR (50 MHz, CDCl ) δ/ppm 171.5,
3
3
1
62.8, 143.6, 140.5, 133.4, 132.6, 129.8, 128.9, 128.5, 126.3, 121.1, 116.8, 113.1, 55.5; Anal. Calcd for
C H ClO : C, 64.01; H, 4.22. Found: C, 63.88; H, 4.50.
14
11
4
2
4

ACCEPTED MANUSCRIPT
4
.4.3. Preparation of ketone 18
Biaryl acid 17 (1.74 g, 6.0 mmol) was reacted with oxalyl chloride (2.54 mL, 30.0 mmol) at r.t. for 15
h. The solution was evaporated under reduced pressure. The residue was dissolved in dry
dichloromethane (5 mL), the solvent was removed, and the crude acyl chloride obtained was
immediately used for the next reaction. A 1M LDA solution (13.2 mL) was added to 30 mL of dry THF
at –70°C. Then 0.46 mL (6 mmol) of γ-butyrolactone was added and the mixture stirred for 40 min
4
8
under inert atmosphere. To this mixture a solution (5 ml of dry THF) of the crude acid chloride
prepared above was slowly added in 5 min. The mixture was allowed to warm to r.t. (5 h) and then
quenched with 10% hydrochloric acid (10 mL). The mixture was extracted with ethyl acetate (3 x 40
mL). The combined extracts were washed with brine (10 mL), dried (MgSO ), filtered, and
4
concentrated in vacuo. The residue was applied to a plug of silica, eluted with CH Cl , and the solvent
2
2
was removed to obtain the crude β-ketolactone intermediate sufficiently pure to be used. Thus,
diphenyl diselenide (0.95 g, 3.0 mmol) and sodium (0.14 g, 6.0 mmol) were placed in an oven-dried
round-bottom flask under argon. Dry THF (30 mL) and dry DMF (20 mL) were added to the contents
of the flask using a syringe and the mixture was heated at 100°C for 30-45 min yielding a red solution
of sodium phenylselenide. To this homogeneous solution was added the crude β-ketoester intermediate,
obtained as described before, dissolved in 5 mL of DMF. The reaction was heated at 110°C for 22 h
and then allowed to cool to r.t. After addition of 10% hydrochloric acid (10 mL) the acidic mixture was
extracted with three 30 mL portions of ethyl acetate. The combined extracts were washed with brine (3
x 10 mL), dried (MgSO
chromatography on silica using dichloromethane-hexane 1:1 mixture as eluent to afford 1.61 g of 1-
2'-Chloro-5-methoxybiphenyl-2-yl)-4-(phenylseleno)butan-1-one (18) in 60% global yield. Light
4
), filtered, and concentrated in vacuo. The residue was purified by column
(
-1
1
yellow oil; FTIR: νmax/cm 2936, 1684, 1600, 1473, 1214, 1022, 760, 736; H NMR (200 MHz,
CDCl ) δ/ppm 7.74 (d, 1H, J = 8.7 Hz, H-Ar), 7.50-7.14 (m, 9H, H-Ar), 6.94 (dd, 1H, J = 8.7, 2.6 Hz,
3
2
5

ACCEPTED MANUSCRIPT
H-Ar), 6.76 (d, 1H, J = 2.6 Hz, H-Ar), 3.85 (s, 3H, OCH ), 2.83 (t, 2H, J = 7.2 Hz, CH ), 2.75 (t, 1H,
3
2
13
J = 7.2 Hz, CH
2
), 2.72 (t, 1H, J = 6.8 Hz, CH
2
2
), 1.94 (dq, 2H, J = 7.2,6.8 Hz, CH ); C NMR (50
MHz, CDCl ) δ/ppm 200.7, 161.5, 140.7, 140.3, 132.4, 132.3, 131.4, 130.6, 130.4, 130.0, 129.3,
3
1
6
4
28.9, 128.8, 126.7, 126.6, 116.7, 112.9, 55.2, 40.0, 27.2, 24.8; Anal. Calcd for C H ClO Se: C,
23 21 2
2.24; H, 4.77. Found: C, 62.31; H, 5.01.
.4.4. Asymmetric reduction of ketone 18 to alcohol 19
To a solution of (S)-Me-CBS 1.0 M in toluene (0.43 mL, 0.85 mmol) in dry THF (10 mL) at 0°C was
added a 2.0 M borane-dimethyl sulfide complex (0.17 ml, 0.17 mmol). A solution of ketone 18 (0.38 g,
0
.85 mmol) in dry THF (10 mL) was added slowly using a syringe pump over 2.5 h with vigorous
stirring and the solution was allowed to warm to r.t. The mixture was stirred at r.t. until the ketone
disappeared on TLC monitoring (20 h). The mixture was quenched with methanol and saturated
ammonium chloride solution (2 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The
combined extracts were washed with brine (10 mL), dried (MgSO ), filtered, and concentrated in
4
vacuo. The crude product was purified on a silica gel column with a mixture of petroleum ether and
diethyl ether 60:40 as eluent to give the corresponding chiral secondary alcohol (1R)-1-(2'-Chloro-5-
-1
methoxybiphenyl-2-yl)-4-(phenylseleno)butan-1-ol (19) in 76% yield. (0.25 g) as oil. FTIR: νmax/cm
1
3
416, 2933, 1608, 1576, 1472, 1437, 1219, 1067, 1035, 761, 735. H NMR (200 MHz, CDCl3):
approx. 3:2 mixture of conformers. δ/ppm 7.57-7.12 (overlapped, m, 10H, H-Ar), 6.98 (overlapped,
ddd, 1H, J = 8.6, 3.8, 2.8 Hz, H-Ar), 6.68 (minor, d, 1H, J = 2.7, H-Ar), 6.62 (major, d, 1H, J = 2.7 Hz,
H-Ar), 4.48-4.35 (overlapped, m, 1H, OCH), 3.81 (overlapped, s, 3H, OCH ), 2.76 (minor, t, 2H, J =
3
13
6
.9 Hz, CH ), 2.68 (major, t, 2H, J = 7.1 Hz, CH ), 1.98-1.45 (overlapped, m, 5H, OH and CH ); C
2 2 2
NMR (50 MHz, CDCl
3
): approx. 3:2 mixture of conformers. δ/ppm 158.3 (major rotamer), 158.0
(
minor rotamer), 139.2, 139.0, 138.9, 134.2, 132.7, 132.4 (2C), 132.3, 131.4, 131.0, 130.3, 130.2,
1
29.5, 129.1, 128.8,(2C); 126.9, 126.8, 126.7, 126.5, 126.4, 126.3, 114.8, 114.3 (2C), 114.2, 69.8
2
6

ACCEPTED MANUSCRIPT
(
major rotamer), 69.5 (minor rotamer9, 55.1, 38.2 (major rotamer), 37.6 8minor rotamer), 27.4 (minor
+
rotamer), 27.3 (major rotamer), 26.2 (minor rotamer), 26.0 (major rotamer); EIMS (70 eV) m/z [M]
4
6
4
46 (1), 271 (25), 229 (100), 207 (16), 190 (18), 165 (16), 91 (16); Anal. Calcd for C23
1.96; H, 5.20. Found: C, 61.81; H, 5.44.
2
H23ClO Se: C,
.4.5. Oxidative-cyclization of phenylseleno alcohol 19
To a solution of phenylseleno alcohol 19 (0.20 g, 0.45 mmol) in THF (20 mL) at r.t. powdered
dipotassium hydrogenphosphate (0.32 g, 1.80 mmol) and m-chloroperoxybenzoic acid (0.24 g, 1.35
mmol) were added. The reaction mixture was stirred until TLC analysis showed that the starting
selenide was completely converted into the corresponding selenone (2 h). Then powdered potassium
hydroxide was added (0.19 g, 3.37 mmol). The consumption of the selenone was monitored by TLC
(
14 h). The mixture was then poured into 10% aqueous sodium carbonate (10 mL) and extracted with
ethyl acetate (2 x 20 mL). The organic layer was washed with 10% aqueous sodium carbonate (10 mL),
then brine, dried over sodium sulphate, and concentrated in vacuo to afford, after column
chromatography on silica gel (diethyl ether-petroleum ether 3:7)
the (2R)-2-(2'-chloro-5-
-1
methoxybiphenyl-2-yl)tetrahydrofuran (20) as oil (0.10 g, 77%). FTIR: νmax/cm 2950, 2865, 1608,
1
1
470, 1219, 1067, 1038, 758. H NMR (200 MHz, CDCl ): mixture of conformers. δ/ppm 7.60-7.41
3
(
overlapped, m, 2H, H-Ar), 7.40-7.20 (overlapped, m, 3H, H-Ar), 7.04-6.92 (overlapped, m, 1H, H-
Ar), 6.72-6.65 (overlapped, m, 1H, H-Ar), 4.57 (t, 1H, J = 7.0 Hz, OCH), 4.15-3.98 (overlapped, m,
1
H, OCH ), 3.90-3.80 [(m, partly overlapped s (3H, OCH ), m (1H, CH )], 2.12-1.50 (overlapped, m,
2 3 2
1
3
4
1
1
H, CH ); C NMR (50 MHz, CDCl ): mixture of conformers. δ/ppm 158.0, 139.5, 138.8, 138.3,
2 3
34.1, 133.6, 132.4, 133.1, 131.5, 131.1, 129.4, 129.3, 128.7, 126.8, 126.5, 126.4, 126.2, 114.6, 114.2,
13.9, 78.0, 77.6, 68.6, 68.4, 55.3, 34.9 (minor rotamer), 33.9 (major rotamer), 26.3, 26.2; EIMS (70
+
eV) m/z [M] 288 (79), 257 (52), 253 (79), 245 (53), 225 (42), 218 (17), 211 (100), 195 (12), 177 (40),
1
68 (28), 152 (33), 139 (29); Anal. Calcd for C H ClO : C, 70.71; H, 5.93. Found: C, 70.65; H, 6.15.
17 17 2
2
7

ACCEPTED MANUSCRIPT
4
9
HPLC analysis at variable temperature on Phenomenex® Lux Cellulose-2 column (250 x 4.60 mm
ID), n-hexane/2-propanol = 99:1, flow rate = 1.0 mL/min, 254 nm UV detector.
Acknowledgements
Financial support from University of Perugia, Fondo per il Sostegno della Ricerca di Base 2017 is
gratefully acknowledged.
Supplementary data
Supplementary data (HPLC traces and Copies of product NMR spectra) related to this article can be
found at http://
References and notes
1
2
3
. Kang, E. J.; Lee, E. Chem. Rev. 2005, 105, 4348.
. Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407.
. Bermejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod.
Rep. 2005, 22, 269.
4
5
. Saleem, M.; Kim, H. J.; Ali, M. S.; Lee. Y. S. Nat. Prod. Rep. 2005, 22, 696.
. De La Torre, A.; Cuyamendous, C.; Bultel-Poncè, V.; Durand, T.; Galano, J.M.; Oger, C.
Tetrahedron 2016, 72, 5003.
. Minuti, L.; Barattucci, A.; Bonaccorsi, P. M.; Di Gioia, M. L.; Leggio, A.; Siciliano, C.; Temperini,
A. Org. Lett. 2013, 15, 3906.
. Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65.
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