Towards the enantioselective synthesis of axially chiral cyclic bis(bibenzyls) through sulfoxide-controlled diastereoselective Suzuki coupling

Article abstract of DOI:10.1016/j.tet.2015.12.052

Natural macrocyclic bis(bibenzyls) exhibiting configurationally stable axially chiral biaryls are of high interest from a structural as well as from a synthetic point of view. An enantiopure sulfinyl auxiliary controlling an atropo-diastereoselective biar

Full text of DOI:10.1016/j.tet.2015.12.052

Tetrahedron xxx (2016) 1e8
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Towards the enantioselective synthesis of axially chiral cyclic
bis(bibenzyls) through sulfoxide-controlled diastereoselective
Suzuki coupling
a
a
a
a
Petra Schmitz , Marcus Malter , Gregor Lorscheider , Christina Schreiner ,
b
b
b
a,
*
Aude Carboni , Sabine Choppin , Fran c¸ oise Colobert , Andreas Speicher
a
Department of Organic Chemistry, Saarland University, Campus, 66123 Saarbr u€ cken, Germany
Laboratoire de Chimie Mol ꢀe culaire (UMR CNRS 7509), Universit ꢀe de Strasbourg, ECPM, 25 Rue Becquerel, 67087, Strasbourg cedex 2, France
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Natural macrocyclic bis(bibenzyls) exhibiting configurationally stable axially chiral biaryls are of high
interest from a structural as well as from a synthetic point of view. An enantiopure sulfinyl auxiliary
controlling an atropo-diastereoselective biaryl Suzuki coupling reaction has been investigated and
promising results for the preparation of the biaryl moiety of cyclic bis(bibenzyls) like isoplagiochins C or
D have been obtained. Furthermore, models explaining the stereoselectivity during transition state, and
substitution effects including double stereo-differentiation, were discussed.
Received 2 November 2015
Received in revised form 8 December 2015
Accepted 22 December 2015
Available online xxx
Keywords:
Natural product
Ó 2016 Elsevier Ltd. All rights reserved.
Atropisomerism
Suzuki-Miyaura cross-coupling
Sulfoxide
Bis(bibenzyl) macrocycles
1. Introduction
‘
Bis(bibenzyls)’ are phenolic natural products that can be iso-
1
lated with broad diversity from bryophytes. The biosyntheses
originate from bibenzyl units which can be dimerized and cyclized
2
by formation of biaryl (CeC) or biarylether bonds (CeOeC). The
distribution in liverworts, structure elucidation, and numerous bi-
3
,4
ological activities have been reviewed.
In this large family of
bis(bibenzylic) macrocycles, a twofold CeC connection of two
bibenzyl units leads to a subtype represented by isoplagiochin C
5
(
1) and its dihydro analogue isoplagiochin D (2), with two biaryl
axes a/b (Fig. 1). The occurrence of axial and/or planar chirality in
the series of these macrocyclic bis(bibenzyls) has been discussed
earlier6 including for similar representatives containing one biaryl
,7
8
unit and one biaryl ether moiety as in plagiochin G (3) as well as
9
for the unique condensed structure of cavicularin (4).
The existence of configurationally stable atropisomers as a con-
sequence of axial chirality (two biaryl axes, helical elements) to-
10
gether with ring strain for 1 was first discussed in detail by us and
11
also for its dihydro analogue 2.
For both, the absolute
*
Corresponding author. Tel.: þ49 (0) 681 3022749; fax: þ49 (0) 681 3022029;
Fig. 1. Cyclic bis(bibenzyls) with axial and/or planar chirality.
e-mail address: anspeich@mx.uni-saarland.de (A. Speicher).
http://dx.doi.org/10.1016/j.tet.2015.12.052
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
configuration of the natural compound at the stereochemically
stable biaryl axis a (rotational barrierw102 kJ/mol) was determined
by quantum chemical CD calculations combined with HPLC-CD
coupling12 of natural and synthetic (racemic) probes (Scheme 1).
seminal catalytic enantioselective Suzuki conditions developed
2
0
21
concomitantly in 2000 by Buchwald and Cammidge mainly deal
with rather simple substrates. Actually described conditions are not
a generally approved method to insure the required steric crowding
of both coupling partners due to the harsh temperature. To over-
come this difficulty, different classes of both mono- and bidentate
2
2
ligands and Pd-complexes were developed in the past 15 years.
We could successfully reproduce Esumi’s general ‘racemic’
strategy with 10 or a similar new precursor 11 with 41 and 71%
yield, respectively. Deprotection with BBr
3
gave rise to (þ/ꢀ) iso-
plagiochin D (2) in good yield. However, the up to now best pro-
2
0
tocol introduced by Buchwald et al. to perform atroposelective
Suzuki-Miyaura cross-coupling reaction failed in the presence of
the chiral catalyst (P)-KenPhos (no conversion or racemic mixtures,
see Scheme 2). The open-chained precursor 11 was prepared
1
5
starting with a known biaryl unit AeB 5, and a twofold Wittig
Scheme 1. Absolute configuration and chemical correlation of (ꢀ)-(1) extracted from
Plagiochila deflexa and (ꢀ)-(2) extracted from Bazzania trilobata.
18
23
reaction with a D-unit 6 and a new C-unit 9 (obtained from 8 ).
Two additional aspects are important with respect to synthesis,
especially for enantioselective ones: (1) The biaryl axis a with two
ortho-substituents is configurationally stable only because of the
entire cyclic framework. That means, to ensure conformational
stability, an atroposelective formation of this CeC bond must pro-
ceed as ring closing step or additional atropo-stabilising ortho-
substituents are required in open-chained precursors to be re-
moved after cyclization. (2) The biaryl axis b with two smaller or-
tho-hydroxy substituents is conformationally semistable at
ambient temperature (no stable atropo-diastereomers). In case of
two methoxy substituents at this position, however, the rotational
barrier was determined asw66 kJ/mol causing rotamers detectable
13
at room temperature NMR. Nevertheless, this axis together with
more flexible helical elements at the stilbene or ethylene bridge
enhance the stability of axis a.
Many members of the bis(bibenzyl) family have been synthe-
sized; the routes and strategies have been recently reviewed.14 Ring
closure proved to be the main challenge because efficiency depends
on ring strain, substitution pattern, and concomitant dimerization. In
the total syntheses already described for isoplagiochins C (1) and D
1
5
(
(
2) or derivatives, ring closure was realized by (a) Wittig reaction,
b) McMurry reaction,16 both between ring moieties A and D, (c)
Suzuki-Miyaura coupling between C and D, and otherwise (d) Heck
17
18
coupling (including asymmetric) between B and C (Fig. 2).
Fig. 2. Ring closing strategies for the total synthesis of isoplagiochins (1,2).
2
. Results and discussion
Scheme 2. Attempts to synthesize 2 by intramolecular Suzuki-Miyaura coupling. Re-
action conditions: i. K
AIBN, CCl , then Ph
TosNHNH DME, NaOAc,
Pd(PPh
2
CO
3
, 18-crown-6, CH
2
Cl
2
,
D
CO
, 90%; ii. THF, 2 M HCl, 96%; iii. NBS,
4
,
D
3
P, toluene,
D, 81%; iv. K
2
3
, 18-crown-6, CH
2
Cl
2
,
D
, 67%; v. p-
The directed synthesis of enantiopure chiral biaryls has become
17
ꢁ
2
,
D,
84%; vi. Pd(PPh
3
)
4
,
K
3
PO
4
,
DMF, 80 C, 12 h; vii.
19
a challenging tool in organic synthesis. Whereas our previous
effective Wittig and McMurry procedures (Fig. 2, connections (a)
and (b)) in general lack of enantioselective protocols, we realized
ꢁ
3
)
4
, Na
2
CO
3
, toluene/EtOH/H
2
O, 105 C, 16 h; viii. Pd
2
(dba)
3
, (P)-KenPhos, K
3
PO
4
,
ꢁ
toluene, DMF, 80e155 C, 16e48 h (no conversion or racemate only).
An alternative solution to perform stereoselective biaryl cou-
plings is to introduce a chiral auxiliary on one of the coupling
partners. Atropo-diastereoselective Suzuki-Miyaura coupling re-
(Fig. 2, connection (d) the first atroposelective Heck-cyclization and
the first enantioselective approach in the bis(bibenzyl) family,
though with moderate ee.
18
19
actions were initially performed using a planar-chiral chromium
No attempt for an enantioselective approach were mentioned
24
complex as chiral coupling partner (chirality transfer planar /
by Esumi et al. in the total synthesis of 2 by a ring closing Suzuki
coupling (Fig. 2, connection (c)) from a precursor 10. Indeed,
axial). Further, a carbon stereogenic center (benzylic alcohols or the
17
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P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
3
b
-hydroxy p-tolylsulfinyl group next to the coupling position)
The excellent diastereoselectivities that we have observed in
the formation of the biaryl axis prompted us to investigate
whether the method developed would also be applicable to the
enantioselective synthesis of the configurationally stable biaryl
part of bis(bibenzyl) derivatives like isoplagiochins 1/2. It should
be noted that the sulfoxide auxiliary group (R¼p-Tol) was al-
ready used in the synthesis of the bis(bibenzyl) riccardin C to
2
5
proved to be efficient chiral auxiliaries (centro / axial). In 2009,
the t-butylsulfinyl group directly connected in ortho position of ar-
omatic iodides was found to act as an efficient chiral auxiliary
allowing the Suzuki-Miyaura coupling of ortho, ortho’-disubstituted
aryl iodides (e.g., 13a) with ortho-substituted aryl boronic acids
2
6
14aee (Scheme 3) in high yields and atropo-diastereoselectivities.
2
8
A five-membered palladacycle in which the oxygen atom of the
sulfoxide coordinates to palladium is proposed to explain the ster-
eocontrolled transmetallation or a stereodiscriminant reductive
elimination. Minimization of steric hindrance led to the formation of
the M atropisomers 15 aee. The use of the p-tolylsulfinyl group with
opposite configuration at sulfur resulted in formation of the P atro-
pisomers 15fej, though in decreased atropo-diastereoselectivities.
The key advantages of sulfinyl group are to get it in enantiomeri-
cally pure form and to transform it into a myriad of functionalities.
Actually, this chiral auxiliary can be readily removed from the
products under conservation of the chiral information at the biaryl
axis by sulfoxide/lithium exchange followed by electrophilic trap-
ping (various electrophiles are compatible).2
accelerate a S
N
Ar reaction and more recently in the synthesis
symmetrization/asymmetrization
of cavicularin (4) in
a
2
9
approach.
Regarding the foregoing results, we propose the retro-
synthetic approach described in Scheme 4. Final macro-
cyclization could occur by Wittig coupling reaction between
rings A and D (most common in known isoplagiochin synthe-
ses) followed by traceless removal of the sulfinyl group and
demethylation which could give raise to enantiopure iso-
plagiochins 1 or 2. The crucial construction of the CeD biaryl
moiety would be considered using a chiral ortho-sulfinyl group
on the aryl iodide 17 in order (1) to direct the intermolecular
atropo-diastereoselective Suzuki-Miyaura cross coupling re-
action between 17 and a moiety 9 and (2) to ensure the
atropo-stability of this open-chained precursor for iso-
plagiochins. The aryl iodide 17 would be accessible from the
known aryl bromide 18, the AeB biaryl moiety 5 as twofold
7
15
Wittig precursor could be taken from known synthesis (see
also Scheme 2).
Preliminary attempts (see below, Tables 1 and 3) of the atropo-
diastereoselective CeD Suzuki-Miyaura cross-coupling reaction
have been investigated with the enantiopure aryl iodide 17 bearing
in ortho position the p-tolylsulfinyl auxiliary and arylboronic moi-
eties 8 and 22 (bearing in ortho position either a methyl group or
a protected aldehyde, both, in principle, suitable for further CeB
coupling). Our objective was to study the Suzuki-Miyaura cross-
coupling reaction conditions and to evaluate the atropo-
diastereoselectivity.
Firstly, we decided to introduce the enantiopure p-tol-
ylsulfinyl auxiliary (instead of t-butyl-) since it is more easily
obtained on multigrams scale from cheap and natural (ꢀ)
3
0
menthol. The D unit 17 is obtained by condensation of the
3
1
Grignard reagent of methylanisyl bromide 18
with (S
menthyl p-toluenesulfinate 19 giving enantiopure sulfoxide
0, followed by ortholithiation with LDA and addition of diio-
S
)-
3
0
2
dine (Scheme 5).
Scheme 3. Atropo-diastereoselective Suzuki coupling with sulfinyl group as chiral
Next, we studied the Suzuki-Miyaura cross-coupling reaction
between 17 and boronic ester 8 bearing in ortho position the methyl
ꢁ
2
auxiliary. Reaction conditions: i. Pd(OAc) , SPhos, Cs
2
CO
3
, dioxane/H
2
O, 70 C.
Scheme 4. Retrosynthetic scheme for the synthesis of isoplagiochins 1/2.
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4
P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
Table 1
Table 3
Atropo-diastereoselective CeD Suzuki-Miyaura cross-coupling reaction between
enantiopure aryl iodide 17 and methylanisyl boronic ester 8
Atropo-diastereoselective Suzuki-Miyaura cross-coupling between 17 and 22
Entry
Pd(OAc)
equiv]
2
SPhos
[equiv]
Temp
( C)/time (h)
Yield
(%) 21
drb
de (%)
ꢁ
a
[
1
2
3
4
5
6
7
0.1
0.1
0.15
0.1
0.2
0.15
0.15
0.2
0.15
0.30
0.15
0.20
70/4
83
92
98
d
64:36
68:32
71:29
d
28
36
42
d
ꢁ
Entry Ligand [equiv]
Temp ( C)/time (h) Yield (%) 23a drb
de (%)
70/16
70/16
50/48
55/48
60/48
60/48
1
2
3
4
SPhos [0.15]
(M)-BINAP [0.15] 70/16
(P)-BINAP [0.15]
none
70/16
84
68
70
d
99:1 98
99:1 98
99:1 98
72
81
85
73:27
71:29
75:25
45
42
50
70/16
70/16
0.1
0.15
d
d
a
Reaction conditions: Pd(OAc)
2 2 3 2
(0.1 equiv), Cs CO (4 equiv), dioxane/H O,
a
Reaction conditions: Cs
Diastereomeric ratio determined by H NMR spectra or by HPLC analysis.
2
CO
3
(4 equiv), dioxane/H
2
O, 1 mmol of substrate.
1 mmol of substrate.
b
1
b
Diastereomeric ratio determined by 1H NMR spectra or by HPLC analysis.
Table 2
a
Screening for double stereo-differentiation
ꢁ
Entry Ligand [equiv]
Temp ( C)/time (h) Yield (%) 21 dr
de (%)
50
1
2
3
4
5
6
SPhos [0.2]
(P)-BINAP [0.15]
(P)-BINAP [0.2]
(M)-BINAP [0.15] 60/48
(M)-BINAP [0.15] 70/48
(M)-BINAP [0.2]
70/48
60/48
70/48
85
81
91
80
91
91
75:25
65:35 30b
b
65:35 30
c
80:20 60
c
77:23 54
c
70/48
82:18 64
a
Reaction conditions: Pd(OAc)
2
(0.1 equiv), Cs
2
CO
3
2
(4 equiv), dioxane/H O,
1
mmol of substrate.
b
Mismatched pair.
c
Matched pair.
Scheme 5. Synthesis of enantiopure aryl iodide 17.
group (boronic acid gave similar results) (Table 1). As in our pre-
vious work,26 the expected biaryl 21 was obtained with the opti-
mized reaction conditions Pd(OAc)
2
(0.1 equiv), SPhos (0.15 equiv)
configuration Ss of the sulfinyl group in accordance with our
previous results (Fig. 3).
and Cs CO in dioxane/H O (entry 1) with a good 83% yield but
2
3
2
2
5
a low selectivity of 64:36. A detailed screening of reaction condi-
tions (reaction time, temperature and charge of palladium/ligand)
revealed an optimum reaction temperature of 60 C providing 21 in
ꢁ
good yield (85%) and diastereoselectivity (75:25) (entries 2e7).
Furthermore, replacement of S-Phos as achiral Pd coordinating
ligand by (P)- or (M)-BINAP clearly revealed a double stereo-
differentiation with (M)-BINAP as ‘matched pair’ enhancing the
diastereoselectivity up to 82:18 even at slightly higher temperature
and with high yield (Table 2).
The diastereoselectivity observed in Suzuki-Miyaura cross-
coupling reaction using a sulfinyl group as chiral auxiliary was
2
6
discussed in our previous work. Thus, oxidative insertion of the
palladium atom into the CeI bond of the enantiopure aryl iodide
0
1
7 would give rise to the five-membered-ring palladacycle 17
3
2
with PdeO coordination for mainly geometrical reasons. In
0
2 3
presence of Cs CO , approach of the boronate 8 to the complex 17
in the transmetalation step should take place with minimization
of steric hindrance of the p-tolyl group in unit D and the ortho-
substituent R in unit C. Reductive elimination would afford 21 with
P-configuration of the biaryl axis deduced from the absolute
Fig. 3. Model explaining control of atropo-diastereoselectivity during the auxiliary
controlled formation of 21.
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P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
5
We also studied the Suzuki-Miyaura cross-coupling reaction
between 17 and a C unit bearing a dioxolane group 22 (Table 3).
Table 4
a
3
3
Atropo-diastereoselective Suzuki-Miyaura cross-coupling to 25
To our delight, a close to perfect atropo-diastereoselectivity
(
(
>99:1)34 was observed for 23 even with SPhos as achiral ligand
Table 3, entry 1). This e according to Fig. 3 e might be due to the
bulkier dioxanyl-substituent present in ortho-position. Surpris-
ingly, no mismatched effect was observed using (P)-BINAP (entry
3
). To rationalize the observed diastereoselectivity, we propose that
an additional coordination dioxane-O/Pd can replace the external
ligand ensuring a higher stereodiscrimination (Fig. 4). Neverthe-
less, SPhos is necessary at least for the oxidative addition step
(
compare entry 4).
ꢁ
25: E/Z de (%)b
Entry 24: E/Z Ligand
equiv]
SPhos [0.15]
Temp ( C)/ Yield
a
[
time (h)
(%) 25
1
2
3
4
65:35
55:45
55:45
95:5
70/48
61
78
75
80
80:20
80:20
65:35
95:5
98c
c
(M)-BINAP [0.15] 70/48
SPhos [0.2]
(M)-BINAP [0.2]
98
98
c
70/48
70/48
c
98
a
Reaction conditions: Pd(OAc)
2
(0.1 equiv), Cs
2
CO
3
(4 equiv), dioxane/H
2
O,
1
mmol of substrate.
b
Diastereomeric ratio determined by 1H NMR spectra or by HPLC analysis.
c
For E and Z.
Fig. 4. Proposed TS during the sulfinyl-controlled formation of 23.
moiety leading to the impossibility to perform some specific
3
8
transformation (Scheme 6).
. Conclusion
In summary, an enantiopure sulfinyl group in ortho position of
an aryl iodide was enabled to control atropo-diastereoselective
Suzuki coupling reaction with excellent diastereomeric excess (up
to 98%) and this methodology was efficiently applied for the
preparation of the biaryl CeD part of bis(bibenzyls) such as iso-
plagiochin C 1 or D 2. Furthermore, we get deeper insight into
mechanistic aspects of stereocontrol including double stereo-
differentiation. As the final bromination, required for the envi-
sioned macrocyclization by Wittig reaction, was not successful, we
turn now our attention to a ring closing through an atropo-
diastereoselective Suzuki coupling always with the sulfinyl part
as chiral inductor and stabiliser. These investigations will be re-
ported in due course.
In conclusion of these preliminary studies to insure a high
atropo-diastereoselectivity during the Suzuki-Miyaura cross cou-
pling, the best conditions are Pd(OAc) (0.15 equiv), SPhos
0.15 equiv) and Cs CO (4 equiv) in dioxane/H O with or without
an additional chiral ligand such as (M)- or (P)-BINAP depending on
the presence or not of a coordinating substituent in ortho position
of the biaryl axis formed.
Following our principal objective which was the synthesis of
isoplagiochins 1 or 2 in enantiomerically pure form as described in
Scheme 4, we synthesized the boronic ester 24, starting from biaryl
3
2
(
2
3
2
5
and boronic ester 9, to be able to perform the Suzuki-Miyaura
cross coupling reaction with 17.
Using previous optimized conditions, the AeBeCeD unit 25,
a feasible straight forward open chained candidate for cyclic bis(-
bibenzyls) like 1/2, was obtained in fair yields with an excellent
9
9:1 atropo-diastereoselectivity, surprisingly, with or without
adding (M)-BINAP (Table 4). One explanation would be again the
presence of considerable bulky ortho-substituent (see Figs. 3 and 4).
It should be noted that the E/Z-ratio shifted to E, presumably due to
4. Experimental section
4.1. General
3
5
the presence of the Pd-catalyst.
Surprisingly, we were not able to transform 25 into a precursor
for cyclization to obtain 1 or 2. Actually, different hydrogenation
protocols and conditions gave no conversion or resulted in a mix-
ture of the sulfinyl compound 26 and the corresponding thioether
NMR data were recorded on a Bruker Avance 2 Spectrometer
(AVII400, 400 or 100 MHz). Chemical shifts are reported relative to
TMS. High resolution mass analyses were conducted with a Fin-
nigan MAT 95 instrument (CI). Flash chromatography was per-
3
6
2
7, which of course could be used alternatively. Likewise, Wohl-
Ziegler bromination on the verge of a Wittig-cyclization with
15,37
2
8
resulted in concomitant side reactions with the sulfinyl
formed using silica gel (35e70 mm). Analytical HPLC was performed
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6
P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
0
0
4
OCH
OCH
.27H), 6.59 (d, Jcis¼12.3 Hz, 0.27H, (Z)-CH]CH), 6.40 (d, J¼12.1 Hz,
.27H, (Z)-CH]CH), 5.50 (s, 0.73H, OCHO), 5.47 (s, 0.27H, OCHO),
.27e4.24 (m, 2H, OCH ), 4.02e3.94 (m, 2H, OCH ), 3.92 (s, 2.2H,
), 3.77 (s, 2.2H, OCH ), 3.76 (s, 2.2H, OCH ), 3.72 (s, 0.8H,
), 3.71 (s, 0.8H, OCH ), 3.67 (s, 0.8H, OCH ), 2.27e2.18 (m, 1H,
(ppm)¼158.2, 157.6,
57.5, 157.4, 157.3, 156.6, 139.6, 139.4, 139.2, 139.0, 132.0, 131.0,
30.9, 130.9, 129.4, 129.3, 129.2, 129.1, 129.1, 129.0, 128.4, 127.9,
27.8, 127.5, 127.3, 126.5, 126.4, 125.6, 123.4, 120.5, 111.4, 111.0, 110.7,
10.7, 110.7, 108.5, 101.6 (OCHO), 101.5 (OCHO), 83.90 (CAreI), 83.86
AreI), 67.37, 67.35, 56.25 (OCH ), 56.02 (OCH ), 55.89 (OCH ),
5.79 (OCH ), 55.76 (OCH ), 55.68 (OCH ), 25.80, 25.77. HR-MS (Cl):
calcd for C27 558.0903; found 558.0906.
2
2
3
3
3
3
3
3
1
3
2 2 3
CH ), 1.41 (m, 1H, CH ). C NMR (CDCl ): d
1
1
1
1
(C
3
3
3
5
3
3
3
H27IO
5
Part (ii): The acetal from part (i) (10.0 g, 17.9 mmol) was dis-
solved in THF/2 M HCl (1:1; 180 mL) and stirred for 16 h at rt. The
mixture was taken up in EtOAc (270 mL) and satd. NaCl solution
(90 mL) was added. The organic layer was separated and washed
with satd. NaHCO
3
solution (2ꢂ50 mL) and satd. NaCl solution
(2ꢂ50 mL), dried (MgSO
4
) and concentrated; yield 8.60 g (96%) 7,
ꢁ
colourless solid, mp. 164e167 C. The NMR was recorded from an
analytical sample of the E-stilbene, obtained from flash chroma-
1
tography (SiO
9
7
1
2
, n-hexane/EtOAc 3:1). H NMR (CDCl
3
):
d
(ppm)¼
.93 (s, 1H, CHO), 7.91 (dd, J¼8.5, 2.3 Hz, 1H), 7.81 (d, J¼2.0 Hz, 1H),
.71 (d, J¼8.3 Hz, 1H), 7.49 (dd, J¼8.5, 2.3 Hz, 1H), 7.42 (d, J¼2.3 Hz,
H), 7.10 (d, Jtrans¼15.8 Hz, 1H, (E)eCH]CH), 7.08 (d, J¼8.0 Hz, 1H),
6
.98 (d, J¼8.5 Hz, 1H), 6.93 (d, Jtrans¼15.8 Hz, 1H, (E)-CH]CH), 6.92
(
(
(
d, J¼2.0 Hz,1H), 6.86 (dd, J¼8.3, 2.0 Hz,1H), 3.92 (s, 3H, OCH
3
), 3.88
(ppm)¼190.9
CHO), 162.2, 158.3, 157.0, 139.4, 133.1, 131.7, 131.2, 129.6, 129.5,
29.3, 128.9, 127.8, 126.9, 126.1, 120.5, 111.3, 110.9, 108.6, 84.18
AreI), 56.28 (OCH ), 56.03 (OCH ), 55.84 (OCH ). HR-MS (Cl):
calcd for C24 22IO 500.0485 found 500.0416.
13
3 3 3
s, 3H, OCH ), 3.80 (s, 3H, OCH ). C NMR (CDCl ): d
1
(C
3
3
3
H
4
Scheme 6. Further transformation of the AeBeCeD unit 25.
4
.2.2. (5-Methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2yl)
benzyl)triphenyl-phosphonium bromide (9). The methylarene 8
20.0 g, 80.6 mmol), NBS (15.8 g, 88.7 mmol) and a trace of AIBN in
CCl (350 mL) were heated at reflux for 6 h with additional irra-
on a Merck-Hitachi L-6200 Intelligent Pump equipped with a Merck-
Hitachi L-4200 UVevis detector; DataApex Clarity Chromatography
Station. As analytical columns were used: Daicel Chiralcel OD-H
(
4
diation with a 300 W daylight lamp. The resulting suspension was
cooled, filtered and concentrated. The crude benzyl bromide was
taken up in toluene (400 mL) and heated at reflux for 12 h together
with triphenyl phosphane (23.3 g, 88.7 mmol). The phosphonium
salt precipitated and was filtered and washed with petroleum
(
4.6ꢂ250 mm) or Phenomenex Lux Amylose-2 (4.6ꢂ250 mm); el-
uent: 2-propanol/n-hexane; detection: UV 275 nm. Both columns
proved to be suitable for HPLC analyses of enantiomers (e.g.,
compound 17) as well as diastereomers (21, 23, 25). The solvents
used were dried using common laboratory methods. All moisture-
sensitive reactions were carried out in flame-dried glassware under
nitrogen or argon atmosphere. Hydrogenation was conducted in
a Parr 5500 Compact Micro Reactor, 4836 Controller. Melting points
were determined with a B u€ chi melting point apparatus (Dr. Tottoli).
ꢁ
1
ether; yield 38.0 g (81%) 9, colourless solid, mp. 248 C. H NMR
(
6
CDCl
3
):
d
(ppm)¼7.82e7.78 (m, 3H), 7.69 (m, 1H), 7.67e7.61 (m,
H), 7.55e7.49 (m, 6H), 6.88e6.82 (m, 2H), 5.57 (d, JP,H¼14.8 Hz, 2H,
13
Ar-CH
CDCl
35.11/135.08, 134.58/134.49, 130.12/130.00, 118.29, 117.43, 115.95/
15.90, 115.09/115.06, 83.79 (BeOeC), 55.41 (OCH ), 30.65 (d,
P,C¼46.2 Hz, Ar-CH ), 24.81 (CH ).
2
), 3.56 (s, 3H, OCH
3 3 2
), 1.07 (s, 12H, OC(CH ) ). C NMR
(
1
1
J
3
):
d
(ppm)¼162.31/162.27, 138.61/138.51, 135.92/135.83,
Optical rotatory values were determined on a Perkin Elmer 241
polarimeter.
3
2
3 2
)
4
.2. Synthetic procedures
0
0
4
.2.3. 2-(2-(2-(5 -(4-Iodo-3-methoxyphenethyl)-2 ,6-dimethoxy-
0
0
0
0
4
.2.1. 5 -(4-Iodo-3-methoxystyryl)-2 ,6-dimethoxy-[1,1 -biphenyl]-3-
[1,1 -biphenyl]-3-yl)ethyl)-4-methoxyphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (11). Part (iv.): A mixture of the aldehyde 7
(10.5 g, 21.0 mmol), the phosphonium salt 9 (16.1 g, 27.3 mmol),
carbaldehyde (7). Part (i): A mixture of the aldehyde 5 (9.20 g,
8.0 mmol), the phosphonium salt 6 (16.5 g, 28.0 mmol), anhydrous
2
K
2
CO
3
(13.8 g, 0.10 mol) and a catalytic amount of 18-crown-6 in
(200 mL) was heated at reflux for 24 h. After cooling to rt the
anhydrous K
crown-6 in CH
2
CO
3
(29.0 g, 0.21 mol) and a catalytic amount of 18-
2
(400 mL) was heated at reflux for 24 h. After
CH Cl
2
2
2
Cl
mixture was filtered, concentrated and purified by flash chroma-
tography (SiO , n-hexane/EtOAc 3:1); 14.0 g (90%), colourless solid,
E/Z mixture (73:27), mp. 84e85 C. H NMR (CDCl
cooling to rt, the mixture was filtered, concentrated and purified by
2
flash chromatography (SiO
(10.3 g, 67%), mp 84e85 C; complex NMR data because of double
2
, n-hexane/EtOAc 3:1); yellowish solid
ꢁ
1
ꢁ
3
):
d
(ppm)¼7.69
(
7
d, J¼8.0 Hz, 0.73H), 7.61 (d, J¼8.0 Hz, 0.27H), 7.47e7.41 (m, 2H),
6
E/Z mixture. HR-MS (Cl): calcd for C38H40BIO 730.1963 found
730.1942.
Part (v.). The stilbene mixture from iv. (3.65 g, 5.00 mmol) and p-
toluenesulfonic acid hydrazide (13.9 g, 75.0 mmol) in DME (140 mL)
was heated at reflux while adding a solution of NaOAc (10.2 g,
.37 (d, J¼2.3 Hz, 0.73H), 7.20 (d, J¼2.3 Hz, 0.73H), 7.15 (dd,
J¼2.3 Hz, 0.27H), 7.09 (d, Jtrans¼16.3 Hz, 0.73H, (E)-CH]CH), 6.95 (d,
J¼8.5 Hz, 0.73H), 6.93 (d, J¼1.5 Hz, 0.73H), 6.92 (d, J¼2.0 Hz, 1H),
6
.89 (d, J¼3.3 Hz, 0.27H), 6.84 (dd, J¼8.0, 1.8 Hz, 0.73H), 6.80 (d,
J¼8.5 Hz, 0.27H), 6.78 (d, J¼1.8 Hz, 0.27H), 6.67 (dd, J¼8.0, 1.5 Hz,
2
0.125 mol) in H O (210 mL) within 4 h. Heating was continued for
Please cite this article in press as: Schmitz, P.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2015.12.052

P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
7
ꢁ
23
1
2 h. After cooling to rt, H
2
O (250 mL) was added and the mixture
(3ꢂ250 mL). The combined organic
O (2ꢂ200 mL), dried (MgSO ) and
concentrated. Purification by flash chromatography (SiO , n-hex-
colourless solid 17 (2.11 g, 71%), mp. 122 C; [
a
]
D
¼ꢀ143.3 (c¼0.49,
1
was extracted with CH
layers were washed with H
2
Cl
2
acetone), ee>99%. H NMR (CDCl
3
):
d
(ppm)¼7.67 (d, J¼8.2 Hz, 2H),
2
4
7.44 (d, J¼1.0 Hz, 1H), 7.22 (d, J¼8.2 Hz, 2H), 6.72 (d, J¼1.0 Hz, 1H),
13
2
3.87 (s, 3H, OCH
NMR (CDCl ):
(ppm)¼158.0, 148.9, 141.9, 141.6, 141.2, 129.9, 126.9,
119.2, 114.2, 81.66 (CAreI), 56.67 (OCH ), 21.66 (CH ), 21.47 (CH ).
S 385.9837 found 385.9830.
3
), 2.43 (s, 3H, CH
3
), 2.34 (s, 3H, p-C
6
H
4
eCH
3
).
C
1
ane/EtOAc 3:1) gave 11 as a pale yellow oil (2.88 g, 84%). H NMR
3
d
(
(
(
6
3
CDCl
3
):
d
(ppm)¼7.78 (d, J¼8.0 Hz, 1H), 7.64 (d, J¼7.8 Hz, 1H), 7.24
3
3
3
dd, J¼8.3, 2.3 Hz,1H), 7.12 (d, J¼2.3 Hz,1H), 7.08e7.06 (m, 2H), 6.90
d, J¼8.3 Hz, 1H), 6.87 (d, J¼8.3 Hz, 1H), 6.73 (dd, J¼8.3, 2.3 Hz, 1H),
HR-MS (Cl): calcd for C15H15IO
2
0
0
.70 (d, J¼2.3 Hz, 1H), 6.59e6.56 (m, 2H), 3.81 (s, 3H, OCH
3
), 3.78 (s,
4.2.7. (P,M)-2,4 -Dimethoxy-2 ,4-dimethyl-6-((S
S
)-p-tolylsulfinyl)-
0
H, OCH
3
), 3.75 (s, 3H, OCH
), 2.90e2.80 (m, 6H, CH
):
(ppm)¼161.8, 157.9, 155.5, 155.3, 151.6, 144.1, 139.1,
38.3, 134.6, 133.0, 133.5, 131.5, 129.4, 128.4, 128.3, 128.2, 127.7,
22.8, 115.1, 113.7, 111.7, 111.1, 111.1, 110.7, 83.19 (OC(CH ), 82.49
AreI), 56.19 (OCH ), 55.91 (OCH ), 55.87 (OCH ), 55.02 (OCH ),
9.04, 38.94, 37.96, 36.94, 24.89 (OC(CH ). HR-MS (Cl): calcd for
40BIO 734.2276 found 734.2269.
3
), 3.75 (s, 3H, OCH
3
), 3.18e3.14 (m, 2H,
1,1 -biphenyl (21). Suzuki coupling between (S
boronic ester 8:
S
)-iodoarene 17 and
13
CH
NMR (CDCl
1
1
(
3
C
2
eCH
2
2
eCH ), 1.35 (s, 12H, OC(CH
2
3 2
) ). C
3
d
(a) Procedure with Pd(OAc)
the (S )-iodoarene 17 (386 mg, 1.00 mmol) and the boronic
ester 8 (298 mg, 1.20 mmol) in 1,4-dioxane (15 mL) were added
SPhos (0.15e0.30 equiv, M¼410.54), Pd(OAc) (0.1e0.2 equiv,
M¼224.51) and Cs CO (1.30 g, 4.00 mmol, 4.0 equiv). The re-
action was initiated by adding H O (2.5 mL) and heating
(temperature/time see Table 1). After cooling to rt, H O (20 mL)
2
/SPhos (see Table 1): To a solution of
3
)
2
S
C
3
3
3
3
3
)
2
2
38
H
6
2
3
2
4
.2.4. Isoplagiochin D tetramethylether (12) and isoplagiochin D
2). The iodoboronic ester 11 (100 mg, 0.14 mmol) was dissolved in
a mixture of toluene (2 mL), EtOH (1 mL) and 2 M Na CO solution
1 mL). The mixture was degassed with a stream of argon.
2
(
was added and the mixture was filtered and extracted with
EtOAc (2ꢂ20 mL). The combined organic layers were dried
2
3
(
4
(MgSO ) and concentrated. The crude product was purified by
Pd(PPh
3
)
4
(5.00 mg, w4.3 mmol) was added and the mixture was
flash chromatography (SiO
cous liquid 21. H NMR (CDCl ):
2
, n-hexane/EtOAc 1:1), yellow vis-
ꢁ
1
heated at 105 C for 16 h. After cooling to rt, the mixture was fil-
3
d
(ppm)¼7.68 (s, 0.65H), 7.58 (s,
tered through a short pad of SiO
evaporation of the solvents, the residue was purified by flash
chromatography (SiO n-hexane/EtOAc 3:1), colourless solid
47.8 mg, 71%) 12. The spectroscopic data were identical with those
2
with elution with EtOAc. After
0.35H), 7.20 (d, J¼8.3 Hz, 0.65H), 7.14e7.08 (m, 1.3H), 7.01 (d,
J¼7.8 Hz, 1.3H), 6.90 (d, J¼8.0 Hz, 1.3H), 6.86e6.82 (m, 2H), 6.59
(d, J¼2.5 Hz, 0.65H), 6.55 (dd, J¼2.5, 8.0 Hz, 0.35H), 6.33 (d,
2
,
(
J¼8.5 Hz, 0.35H), 3.85 (s, 2H, OCH
3
), 3.83 (s, 1H, OCH
), 2.49 (s, 1H, CH ), 2.32 (s, 1H, CH
), 2.15 (s, 1H, p-C eCH ), 1.20 (s, 2H,
):
(ppm)¼159.7,
159.4, 156.9, 154.8, 145.3, 142.1, 141.5, 141.4, 141.1, 140.3, 139.9,
39.7, 138.3, 132.7, 131.8, 129.5, 129.3, 126.4, 126.2, 125.2, 125.1,
124.8, 116.0, 115.6, 115.5, 115.1, 114.2, 113.5, 111.1, 110.5, 56.98
3
), 3.69 (s,
15
reported in the literature.
For the preparation of 2 from 12 we applied the procedure given
3H, OCH
2.29 (s, 2H, p-C
p-C eCH ); (entry 1). C NMR (CDCl
3
), 2.51 (s, 2H, CH
3
3
3
),
6
H
4
eCH
3
6
H
4
3
in the literature.1
5,17
The spectroscopic data were identical with
H
4
13
d
6
3
3
those reported therein.
1
S
4.2.5. (S )-1-Methoxy-3-methyl-5-(p-tolylsulfinyl) benzene (20). To
magnesium turnings (635 mg, 26.2 mmol) and a trace of diiodine
under inert gas atmosphere was added dropwise 1/10 of a solution
of 1-bromo-3-methoxy-5-methylbenzene (18, 5.27 g, 26.2 mmol)
in anhydrous THF (20 mL). After initiation, the addition was con-
(OCH
21.94 (CH
HR-MS (Cl): calcd for C23
(b) Procedure using BINAP instead of SPhos (see Table 2): In
a Schlenck tube (argon atmosphere), Pd(OAc) and (M)- or (P)-
3
), 55.83 (OCH
3
), 55.21 (OCH
), 21.40 (CH
S 380.1446 found 380.1456
3
), 55.16 (OCH
3
), 21.98 (CH
), 18.96 (CH
3
),
3
), 21.43 (CH
3
3
), 20.40 (CH
3
3
).
24 3
H O
ꢁ
tinued keeping the temperature between 50 and 55 C and stirring
2
was continued for 1 h. This Grignard solution freshly prepared was
BINAP (for equiv see Table 2) were pre-incubated in 1,4-
ꢁ
slowly transferred into a solution of (S
S
)-menthyl-p-tolylsulfinate
dioxane (15 mL) and H
(S
(298 mg, 1.20 mmol) and Cs
2
O (2.5 mL) for 30 min at 50 C. The
S
)-iodoarene 17 (386 mg, 1.00 mmol), the boronic ester 8
ꢁ
2
3 (7.00 g, 23.8 mmol) in toluene (20 mL) at 0 C. Stirring was
ꢁ
continued for 2 h at 0 C, satd. NH
4
Cl solution was added (10 mL)
2
CO
3
(1.30 g, 4.00 mmol, 4.0 equiv)
ꢁ
ant the mixture was extracted with EtOAc (2ꢂ60 mL). The com-
were added and the mixture was stirred for 48 h (60e70 C, see
bined organic layers were washed with satd. NaCl solution
Table 2). After cooling to rt, the reaction mixture was quenched
(
2ꢂ30 mL), dried (MgSO
product was purified by flash chromatography (SiO
EtOAc 1:1), yellowish viscous oil 20 (4.13 g, 67%); [
4
) and concentrated in vacuum. The crude
with
(2ꢂ20 mL). The combined organic layers were dried (MgSO
and concentrated. The crude product was purified by flash
chromatography (SiO , n-hexane/EtOAc 1:1), yellow viscous
liquid 21; analytical data see above.
2
H O (20 mL), filtered and extracted with EtOAc
2
, n-hexane/
4
)
2
3
a]
D
¼þ4.0
(ppm)¼7.53 (d, J¼8.0 Hz, 2H),
.24 (d, J¼8.0 Hz, 2H), 7.01 (s, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 3.78 (s,
1
(
7
c¼0.70, acetone). H NMR (CDCl
3
):
d
2
13
3
(
1
H, OCH
3
), 2.35 (s, 3H, p-C
(ppm)¼160.2, 146.8, 142.5, 141.6, 140.8, 130.0, 124.9, 117.9,
), 21.47 (CH ), 21.38 (CH ). HR-MS (Cl):
S 260.0871 found 260.0875.
6
H
4
eCH
3 3
), 2.32 (s, 3H, CH ). C NMR
CDCl ): d
3
0
0
0
0
S
)-p-tolylsulfinyl)-[1,1 -
17.4, 106.3, 55.46 (OCH
3
3
3
4.2.8. 2-((P)-2 ,4-Dimethoxy-4 -methyl-6 -((S
biphenyl]-2-yl)-1,3-dioxane (23). The Suzuki coupling reactions
with 1.00 mmol of 17 and 1.20 mmol of 22) were performed
16 2
calcd for C15H O
(
4
.2.6. (S
S
)-2-Iodo-1-methoxy-5-methyl-3-(p-tolyl-sulfinyl)benzene
(20) (2.00 g,
according to the procedures described for the preparation of 21, for
details see Table 3, pale-yellow solid 23, mp. 136e138 C;
ꢁ
(17). (S )-3-Methyl-5-(p-tolyl-sulfinyl)anisol
S
ꢁ
23
1
7
.68 mmol) was dissolved in anhydrous THF (10 mL). At ꢀ78
C
[a
]
D
¼ꢀ109.3 (c¼0.19, acetone), measured for entry 1. H NMR
a solution of LDA (4.86 g, 12.0 mmol; 6.00 mL of a 2 M solution in
THF/n-heptane/ethylbenzene) was added dropwise and stirring
was continued for 1 h. Diiodine (2.34 g, 9.23 mmol) in anhydrous
(CDCl
3
):
d
(ppm)¼7.42 (s, 1H), 7.26 (d, J¼8.4 Hz, 1H), 7.22 (d,
J¼2.8 Hz, 1H), 7.16 (d, J¼8.3 Hz, 2H), 7.09 (d, J¼8.3 Hz, 2H), 7.00 (dd,
J¼8.4, 2.8 Hz, 1H), 6.79 (s, 1H), 4.52 (s, 1H, OCHO), 4.14e4.06 (m, 1H,
ꢁ
THF (15 mL) was added at ꢀ78 C with additional stirring for 12 h.
OCH
OCH
2
3 2
), 3.88 (s, 3H, OCH ), 3.85e3.82 (m, 0.6H, OCH ), 3.68 (s, 3H,
The mixture was quenched with satd. Na
2
S
2
O
3
solution (10 mL) and
3
), 3.52 (td, J¼12.3, 2.3 Hz, 1H), 3.23 (td, J¼12.3, 2.3 Hz, 1H),
eCH ), 2.31 (s, 3H, CH ), 2.14e2.05 (m, 1H, HCH),
1.19 (d, J¼13.3 Hz, 1H, HCH). C NMR (CDCl ): (ppm)¼159.9, 157.1,
146.1, 141.4, 140.9, 140.3, 139.5, 132.0, 129.6, 125.3, 124.7, 124.0,
extracted with Et
dried (MgSO ) and concentrated. The crude product was purified by
flash chromatography (SiO n-hexane/EtOAc/CH Cl 2:1:1),
2
O (2ꢂ50 mL). The combined organic layers were
2.45 (s, 3H, p-C
6
H
4
3
3
13
4
3
d
2
,
2
2
Please cite this article in press as: Schmitz, P.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2015.12.052

8
P. Schmitz et al. / Tetrahedron xxx (2016) 1e8
6. Keser
u€ , G. M.; Kolossv aꢀ ry, I.; N oꢀ gr ꢀa di, M. J. Mol. Struct. 1995, 356, 143e148.
1
16.6, 115.2, 113.6, 111.2, 100.0 (OCHO), 67.28 (OCH
2
), 66.82 (OCH
), 21.41 (CH ). HR-MS
S 452.1657 found 452.1652.
2
),
7
8
9
. Hashimoto, T.; Irita, H.; Takaoka, S.; Tanaka, M.; Asakawa, Y. Tetrahedron 2000,
5
6.82 (OCH
3
), 55.35 (OCH
3
), 25.56, 21.91 (CH
3
3
5
6, 3153e3159.
(
Cl): calcd for C26
H
28
O
5
€
. Schaumloffel, A.; Groh, M.; Knauer, M.; Speicher, A.; Bringmann, G. Eur. J. Org.
Chem. 2012, 6878e6887.
. Toyota, M.; Yoshida, T.; Kan, Y.; Takaoka, S.; Asakawa, Y. Tetrahedron Lett. 1996,
4.2.9. Preparation of 24: Wittig reaction between 5 and 9. A mixture
3
7, 4745e4748.
0. Bringmann, G.; M u€ hlbacher, J.; Reichert, M.; Dreyer, M.; Kolz, J.; Speicher, A. J.
Am. Chem. Soc. 2004, 126, 9283e9290.
of the aldehyde 5 (6.56 g, 20.0 mmol), the phosphonium salt 9
15.3 g, 26.0 mmol), anhydrous K CO (13.8 g, 0.10 mol) and a cata-
lytic amount of 18-crown-6 in CH Cl (200 mL) was heated at reflux
for 24 h. After cooling to rt the mixture was filtered, concentrated
and purified by flash chromatography (SiO , n-hexane/EtOAc 3:1);
.72 g (78%), colourless solid 24, E/Z mixture (typical 55:45), mp
1
(
2
3
11. Scher, J. M.; Zapp, J.; Becker, H.; Kather, N.; Kolz, J.; Speicher, A.; Dreyer, M.;
2
2
Maksimenka, K.; Bringmann, G. Tetrahedron 2004, 60, 9877e9881.
12. Bringmann, G.; Gulder, T. A. M.; Reichert, M.; Gulder, T. Chirality 2008, 20,
2
628e642.
13. Speicher, A.; Backes, T.; Hesidens, K.; Kolz, J. Beilstein J. Org. Chem. 2009, 5, 71.
8
ꢁ
1
14. Harrowven, D. C.; Kostiuk, S. L. Nat. Prod. Rep. 2012, 29, 223e242.
1
(
(
45e146 C. H NMR (CDCl
E)-CH]CH), 7.75 (d, J¼8.3 Hz, 0.45H), 7.73 (d, J¼8.3 Hz, 0.55H), 7.49
dd, J¼8.5, 2.3 Hz, 0.55H), 7.45 (dd, J¼8.0, 2.3 Hz, 0.55H), 7.42 (d,
3
):
d
(ppm)¼7.96 (d, Jtrans¼16.3 Hz, 0.45H,
15. Eicher, T.; Fey, S.; Puhl, W.; Buchel, E.; Speicher, A. Eur. J. Org. Chem. 1998,
877e888.
16. Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis 2002, 2503e2512.
17. Esumi, T.; Wada, M.; Mizushima, E.; Sato, N.; Kodama, M.; Asakawa, Y.; Fu-
J¼2.3 Hz, 0.55H), 7.39 (d, J¼2.3 Hz, 0.25H), 7.38 (d, J¼2.3 Hz, 0.5H),
.21 (d, J¼2.3 Hz, 0.55H), 7.19 (d, J¼2.3 Hz, 0.45H), 7.11 (dd, J¼2.3,
.5 Hz, 0.45H), 7.07 (d, J¼2.3 Hz, 0.45H), 7.00 (d, Jcis¼12.3 Hz, 0.55H,
Z)-CH]CH), 6.98 (d, Jtrans¼16.3 Hz, 0.45H, (E)-CH]CH), 6.96 (d,
J¼3.0 Hz, 0.45H), 6.94 (d, J¼3.0 Hz, 0.55H), 6.90e6.88 (m, 1H), 6.78
kuyama, Y. Tetrahedron Lett. 2004, 45, 6941e6945.
18. Groh, M.; Meidlinger, D.; Bringmann, G.; Speicher, A. Org. Lett. 2012, 14,
4548e4551.
7
8
(
19. (a) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384e5427; (b) Wencel-Delord, J.;
Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44, 3418e3430; (c)
Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29, 899e934.
(
dd, J¼2.5, 8.3 Hz, 0.55H), 6.74e6.71 (m, 1H), 6.52 (d, Jcis¼12.3 Hz,
20. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051e12052.
0
4
3
.55H, (Z)-CH]CH), 5.49 (s, 0.55H, OCHO), 5.44 (s, 0.45H, OCHO),
.26e4.22 (m, 2H, CH ), 3.99e3.92 (m, 2H, CH ), 3.86 (s, 1.7H, OCH ),
.77 (s, 1.7H, OCH ), 3.76 (s, 1.7H, OCH ), 3.70 (s, 1.3H, OCH ), 3.67 (s,
), 3.60 (s, 1.3H, OCH ), 2.26e2.14 (m, 1H), 1.44e1.40 (m,
H), 1.33 (s, 6.7H, OC(CH ), 1.29 (s, 5.3H, OC(CH
):
(ppm)¼161.9, 161.2, 157.6, 157.5, 156.9, 156.2, 146.0, 145.9,
38.0, 137.8, 132.6, 131.1, 130.9, 130.5, 130.2, 130.1, 129.7, 129.3, 129.3,
29.2, 129.2, 129.0, 128.1, 127.8, 127.8, 127.7, 127.6, 126.8, 126.3, 126.2,
13.6, 113.1, 112.4, 111.2, 110.8, 110.7, 110.6, 109.2, 101.6 (OCHO), 101.6
OCHO), 83.39 (OC(CH ), 83.27 (OC(CH ), 67.33, 55.92 (OCH ),
), 55.76 (OCH ), 55.71 (OCH ), 55.12 (OCH ), 54.87
), 25.81, 24.94 (OC(CH ), 24.88 (OC(CH ). HR-MS (Cl): calcd
for C33 558.2789 found 558.2804.
21. Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723e1724.
2
2
3
2
2. (a) Wang, S.; Li, J.; Miao, T.; Wu, W.; Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org. Lett.
2012, 14, 1966e1969; (b) Zhou, Y.; Wang, S.; Wu, W.; Li, Q.; He, Y.; Zhuang, Y.; Li,
L.; Pang, J.; Zhou, Z.; Qiu, L. Org. Lett. 2013, 15, 5508e5511; (c) Tang, W.; Patel,
N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.;
Wei, X.; Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.; Sen-
anayake, C. H. Org. Lett. 2012, 14, 2258e2261; (d) Shen, X.; Jones, G. O.; Watson,
D. A.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278e11287; (e)
3
3
3
1
1
(
1
1
1
(
5
.3H, OCH
3
3
13
)
3 2
3 2
) ). C NMR
CDCl
3
d
ꢀ
ꢀ
Ros, A.; Estepa, B.; Bermejo, A.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M. J. Org.
Chem. 2012, 77, 4740e4750; (f) Bermejo, A.; Ros, A.; Fern ꢀa ndez, R.; Lassaletta, J.
M. J. Am. Chem. Soc. 2008, 130, 15798e15799; (g) Zhang, S.-S.; Wang, Z.-Q.; Xu,
M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5546e5549; (h) Genov, M.; Almorín, A.;
Espinet, P. Chem.dEur. J. 2006, 12, 9346e9352; (i) Yamamoto, T.; Akai, Y.; Na-
gata, Y.; Suginome, M. Angew. Chem., Int. Ed. 2011, 50, 8844e8847; (j) Uozumi,
Y.; Matsuura, Y.; Arakawa, T.; Yamada, Y. M. A. Angew. Chem., Int. Ed. 2009, 48,
2708e2710.
)
3 2
)
3 2
3
5.82 (OCH
OCH
3
3
3
3
(
3
)
3 2
3 2
)
39 7
H O
23. Cao, S.; Christiansen, R.; Peng, X. Chem.dEur. J. 2013, 19, 9050e9058.
24. Uemura, M.; Nishimura, H.; Hayashi, T. Tetrahedron Lett. 1993, 34, 107e110.
25. (a) Baudoin, O. Eur. J. Org. Chem. 2005, 4223e4229; (b) Broutin, P.-E.; Colobert,
F. Org. Lett. 2003, 5, 3281e3284; (c) Broutin, P.-E.; Colobert, F. Org. Lett. 2005,
S
4.2.10. Preparation of 25: Suzuki coupling between the (S )-iodoar-
ene 17 and the stilbene 24 (see Table 4). The Suzuki coupling re-
actions (with 1.00 mmol of 17 and 1.20 mmol of 24) were
performed according to the procedures described for the prepara-
tion of 21 (b), for details see Table 4. The crude product was purified
by flash chromatography (SiO
pale-yellow solid 25, mp. 98e100 C. complex NMR data. HR-MS
7, 3737e3740; (d) for the application of a related approach to the synthesis of
the biaryl part of vancomycin, steganacin and dibenzoxepine derivatives see:
Leermann, T.; Broutin, P.-E.; Leroux, F. R.; Colobert, F. Org. Biomol. Chem. 2012,
10, 4095e4102; (e) Yalcouye, B.; Choppin, S.; Panossian, A.; Leroux, F. R.;
Colobert, F. Eur. J. Org. Chem. 2014, 6285e6294 and; (f) Joncour, A.; Decor, A.;
Thoret, S.; Chiaroni, A.; Baudoin, O. Angew. Chem., Int. Ed. 2006, 45,
2
, n-hexane/EtOAc/CH
2
Cl
2
2:1:1),
ꢁ
4149e4152.
(
Cl): calcd for C42
H
42
O
7
S 690.2651 found 690.2704.
26. Colobert, F.; Valdivia, V.; Choppin, S.; Leroux, F. R.; Fernandez, I.; Alvarez, E.;
Khiar, N. Org. Lett. 2009, 11, 5130e5133.
2
7. (a) Leroux, F. R.; Berthelot, A.; Bonnafoux, L.; Panossian, A.; Colobert, F. Chem.
dEur. J. 2012, 18, 14232e14236 and references cited herein; (b) Leroux, F. R.;
Panossian A. Ed. J. Mortier, John Wiley & Sons; 2015; 813e833.
Supplementary data
2
2
3
8. Takiguchi, H.; Ohmori, K.; Suzuki, K. Chem. Lett. 2011, 40, 1069e1071.
9. Takiguchi, H.; Ohmori, K.; Suzuki, K. Angew. Chem. 2013, 125, 10666e10670.
0. (a) Andersen, K. K.; Gaffied, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I. J.
Am. Chem. Soc. 1964, 86, 5637e5646; (b) Solladi eꢀ , G.; Hutt, J.; Girardin, A.
Supplementary data (Experimental procedures and full spec-
troscopic data for all new compounds; details of HPLC.) associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2015.12.052.
Synthesis 1987 173e173.
3
1. (a) Coleman, R.; Guernon, J.; Roland, J. Org. Lett. 2000, 277e280; (b) Chan, J. H.;
Hong, J. S.; Hunter, R. N.; Orr, G. F.; Cowan, J. R.; Sherman, D. B. J. Med. Chem.
001, 44, 1866e1882.
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Please cite this article in press as: Schmitz, P.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2015.12.052