Synthetic Studies toward Bazzanin K: Regioselective and Chemoselective Three-Component Suzuki Coupling

Article abstract of DOI:10.1021/acs.joc.9b02043

The terphenyl substructure of the chiral cyclophane natural product bazzanin K was constructed. The key step involved sequential Suzuki couplings of a nonsymmetric dibromobenzene, which can be performed as a two-step process or as a one-pot three-componen

Full text of DOI:10.1021/acs.joc.9b02043

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Note
Synthetic Studies Toward Bazzanin K: Regioselective
and Chemoselective Three-Component Suzuki Coupling
Xuan Ju, Marshall J Allen, Peng Zhao, Patrick Salvo, Frank B Dyer, and Christopher M. Beaudry
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 26, 2019
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Synthetic Studies Toward Bazzanin K:
Regioselective and Chemoselective Three-
Component Suzuki Coupling
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Xuan Ju, Marshall Allen, Peng Zhao, Patrick Salvo,
Frank B. Dyer and Christopher M. Beaudry*
Department of Chemistry, Oregon State University,
1
53 Gilbert Hall, Corvallis, OR 97331, United States
Email: christopher.beaudry@oregonstate.edu
Abstract: The terphenyl substructure of the chiral cyclophane natural product
bazzanin K was constructed. The key step involved sequential Suzuki couplings of a
non-symmetric dibromobenzene, which can be performed as a two-step process or as
a one-pot three-component coupling. The key step represented a regioselective
coupling of a dibromobenzene, as well as a chemoselective coupling of phenyl
bromides in the presence of phenyl chlorides. Terphenyl intermediates displayed
atropdiastereoisomerism, and they were converted to a single phenanthrene target by
way of ring-closing metathesis.
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The macrocyclic bis(bibenzyl) (MBB) natural products are a family of several dozen
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dimeric molecules produced by liverworts (Figure 1). Various members of the family
have interesting biological activities including anti-tumor, antimicrobial, and antiviral
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activities.
Figure 1. MBB Natural Products.
The MBB natural products are biosynthesized from two equivalents of
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lunularin by oxidative phenolic couplings. The two lunularin substructures can be
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joined by either C–C bonds (e.g., isoplagiochin D), by C–O bonds (e.g., marchantin
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C), or by one of each linkage type. MBB family members display a wide range of
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linkage regiochemistry resulting from the phenolic radical couplings. Additional
oxidation of the MBB scaffold is very common, usually in the form of additional
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benzene hydroxylation or unsaturation of the ethylene tethers. Particularly interesting
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MBB structures arise from additional ring-forming oxidations, such as cavicularin
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and bazzanin K (Figure 1, bottom). These molecules are quite strained; the crystal
structure of cavicularin reveals that the A-ring exists in a non-planar boat-like
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conformation.
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Our interest in MBB natural products arises from the structural and
conformational properties of these more highly oxidized congeners. Specifically, the
strained molecular architectures lead to conformations with restricted bond rotations,
and they can display molecular chirality. Cavicularin exists as a non-racemic chiral
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molecule that is conformationally stable up to approximately 180 C. Bazzanin K was
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isolated as an optically active sample. Assuming the sample was pure, this indicates
that it is both chiral and conformationally stable as a non-racemic sample at room
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temperature. However, its conformational stability has not been confirmed or
investigated at elevated temperatures. Strained macrocyclic molecules are not trivial
to prepare, especially as non-racemic compounds, and these structures represent
formidable challenges for synthetic chemists.
We previously synthesized cavicularin using a key Suzuki reaction (or
Suzuki–Miyaura reaction) cascade to build the dihydrophenanthrene portion of the
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molecule (Scheme 1). It was discovered that a regioselective Suzuki coupling of 1
and 2 occurs at the C12’ bromide (cavicularin numbering) to give 3. The C10’
bromide, which is proximal to the vinyl group, is kinetically deactivated, and the
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regioselectivity for the bromide distal to the alkene is high (>10:1). A subsequent
second Suzuki reaction occurs at the C10’ bromide of 3 with boronic ester 4 to give 5.
It was also found that this sequence could be performed as a three-component Suzuki
coupling of 1, 2, and 4 to give terphenyl 5 by sequential addition of the boronic esters
(as shown in Scheme 1). Terphenyl 5 was advanced by ring-closing metathesis to give
a phenanthrene, which was then hydrogenated to give dihydrophenanthrene 6.
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Scheme 1. Suzuki Cascade for Cavicularin.
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Investigations into the regioselective Suzuki coupling of dibromobenzenes
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suggest that the kinetic selectivity occurs during oxidative addition (Scheme 2).
Complexes involving Pd(0) and a C–Br bond (7) undergo oxidative addition with
relatively fast rates to give Pd(II) intermediates (8), which proceed via the familiar
Suzuki mechanism to give coupled products 9. However, when the σ-bond complex
is flanked by an adjacent alkene (10), further coordination can occur to render the
Pd(0) coordinatively saturated (11), prohibiting oxidative addition. This coordinative
saturation lowers the concentration of the available starting material for the oxidative
addition step (10), and in turn, lowers the rate of oxidative addition to give 12.
Scheme 2. Alkenes as Regiocontrol Elements in Oxidative Addition.
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It was anticipated that the regiochemical directing effect of alkenes could be
used to access the structurally more complicated target bazzanin K (Scheme 3).
Application in a bazzanin K synthesis would demonstrate that this control element
could be used in structurally complicated systems. Retrosynthetic simplification of the
natural product leads to intermediate phenanthrene 13. The terphenyl substructure of
13 would be prepared using Suzuki couplings of 1, 14, and 15 subject to the
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regiochemical control model discussed above.
Scheme 3. Retrosynthetic Analysis of Bazzanin K.
The key Suzuki strategy envisioned for bazzanin K represented a process with
more potential complications than our previous work. First, both boronic esters (14
and 15) are α,α-disubstituted, which would lead to more sterically congested products
than we prepared in our cavicularin synthesis. Second, both boronic esters contain
resident chlorides, and the desired couplings require chemoselectivity with respect to
the different halogens. It is well known that bromides undergo Suzuki reactions in the
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presence of chlorides; however, it should be noted that the presence of chloride also
complicates the synthesis of the boronic esters themselves, as they are commonly
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prepared from halide starting materials.
At first glance, boronic ester coupling partners 14 and 15 appear to be simple
building block molecules; however, they are deceptively challenging to construct.
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Regioselective syntheses of tetra- and penta-substituted benzenes are far from trivial.
Moreover, 14 and 15 have multiple carbon, oxygen, and halogen substituents, and
synthetic approaches to these coupling partners must balance the reactivity of the
resident substituents, but also introduce new substituents with control of
regiochemistry.
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We planned on installing the boronic ester from the corresponding bromide.
Since we would perform halogenation reactions that would likely not be compatible
with alkenes, we also decided to introduce the styrenes late in the synthesis through
olefinations of the corresponding aldehydes. The aldehyde functional group would
also provide a key regiochemical control element in the substitution reactions, and
many benzaldehydes are readily available. With the above considerations in mind, we
began our synthesis of bazzanin K.
Our studies commenced with 3-hydroxybenzaldehyde, which underwent
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regioselective bromination to give 16 following literature precedent (Scheme 4). The
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phenol was protected as the isopropyl ether (17) using standard conditions.
Regioselective chlorination was directed by the isopropyl ether to give intermediate
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8. Wittig olefination produced styrene 19. Intermediate 19 underwent
chemoselective halogen-boron exchange with the bromide at low temperature to give
coupling partner 14. Chemical yields on this final step were substantially lower if the
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reaction was performed at –78 C.
Scheme 4. Preparation of Boronic Ester Coupling Partners.
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Boronic ester 15 was prepared using a similar strategy. Following literature
precedent, vanillin was regioselectively chlorinated and dealkylated to give
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benzaldehyde 20. Bromination yielded 21 with the desired regiochemistry.
Protection of the catechol produced intermediate 22. Olefination of benzaldehyde 22
gave styrene 23. Chemoselective bromine-boron exchange at low temperature
completed the preparation of coupling partner 15.
With the key coupling partners in hand, the sequential Suzuki couplings were
investigated. We began with dibromide 1 and boronic ester 14 using conditions
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identified in our cavicularin synthesis (Table 1, entry 1). Gratifyingly, neither the
steric hindrance of the boronic ester, the spectator chloride, nor the vinyl group
adjacent to the boronic ester prevented a successful and selective coupling reaction.
Although the regio- and chemoselectivity of the coupling were high (only one
observable coupling product), the chemical yield of 24 was modest. It was found that
NaOH was superior to phosphate bases (entry 2). We also found that yields were
higher when 1,2-dimethoxyethane (DME) was used as the solvent, rather than 1,4-
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dioxane (entry 3). After a brief screen of bases in DME (entries 4–6), we settled on
NaOH over phosphate or carbonate bases. Finally, we found that adding 1.4
equivalents of boronic ester 14 in portions gave acceptable yields of 24 (entry 7).
Table 1. Regioselective Chemoselective Suzuki Reaction.
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With biphenyl 24 in hand, we investigated the second Suzuki coupling with
boronic ester 15 (Table 2). We started with conditions from the previous Suzuki
coupling, and we were pleased to observe a successful coupling to give terphenyl 25
in 36% yield (entry 1). The balance of the material was unreacted starting material
and products of dehalogenation or protodeboronation. Increasing the temperature to
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0 C led to full consumption of the starting material and an increase in chemical
yield of 25 to 53% (entry 2). Further increases to the reaction temperature had a
deleterious effect on the yield (entry 3). The amount of 15 was increased to 1.5
equivalents and the yield increased to 69% (entry 4). No undesired reactivity of the
chloride substituents was observed. We also briefly evaluated different solvents and
bases, but the chemical yields of the coupling did not increase (entries 5–6).
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Table 2. Chemoselective Suzuki Reaction.
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Interestingly, we discovered that 25 exists as two diastereomeric atropisomers
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(Figure 2).
The atropisomers were separated using standard column
chromatography. Figure 2 shows two conformations of the terphenyl; key NOE
correlations are indicated, which allowed us to tentatively assign each
atropdiastereomer. Conformer 25a showed NOE cross peaks between the isopropyl
ether and one of three nearly chemical-shift identical vinyl groups, whereas 25b
showed correlation of the isopropyl group and the benzodioxole methylene protons.
The atropisomers appeared conformationally stable at room temperature during the
NMR experiments; however, over the course of a few days we observed small
amounts of equilibration of the terphenyls. We dissolved purified samples of 25a and
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5b in C D and heated them to 80 C. Both diastereomers converged on a 1.15:1 ratio
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of atropisomers within a few hours at 80 C. The modest thermodynamic preference
for 25a is perhaps unsurprising, since there are no obvious steric effects that would
destabilize either of the diastereomers.
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Figure 2. Atropisomerism in 25.
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With the successful sequential Suzuki couplings of 1, 14, and 15, a one-pot
three-component coupling was investigated (Scheme 5). Subjection of 14 and 1 to
our standard conditions led to formation of 24 as evidenced by TLC. Boronic ester 15
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an additional 48 hours. Terphenyls 25a-b were isolated as single regioisomers in
modest yield.
Scheme 5. Three-Component Suzuki Coupling and Phenanthrene Synthesis.
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We subjected purified atropisomers 25a and 25b independently to ring-closing
metathesis conditions, and each diastereomer cyclized to the identical phenanthrene
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(
13) in nearly quantitative yield. This result further confirms our assignment of 25a-
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b as conformational isomers. More conveniently, chemical mixtures of 25a and 25b
also react to give phenanthrene product 13. This completed the full BCD-ring
substructure of bazzanin K.
In summary, we have developed a chemoselective (Cl vs Br) and
regioselective (Br vs Br) Suzuki reaction of two chloride-substituted boronic esters
(
14 and 15) and a non-symmetric dibromobenzene (1). The reaction may be
performed sequentially, or as a one-pot three-component coupling. The product
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terphenyl (25) exists as two atropdiastereomers that undergo equilibration at 80 C.
These intermediates are converted into the C12’-phenyl-substituted phenanthrene
substructure of the MBB natural product bazzanin K in nearly quantitative yield.
Efforts to advance this material to bazzanin K are underway, and synthetic material
will be used to study the conformational properties of the natural product.
Experimental Section
General Experimental Details:
All reactions were carried out under an inert Ar atmosphere in oven-dried
glassware. External (heated oil or cryogenic solvent) bath temperatures were used to
record all reaction temperatures. Flash column chromatography (FCC) was carried out
with SiliaFlash P60, 60 Å silica gel. Reactions and column chromatography were
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monitored with EMD silica gel 60 F254 plates and visualized with potassium
permanganate stain. Tetrahydrofuran (THF), methylene chloride (CH Cl ), and
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methanol (MeOH) were dried by passage through activated columns. 1,4-Dioxane,
,2-dimethoxyethane (DME) were dried and distilled over sodium. All other reagents
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
and solvents were used without further purification from commercial sources. Unless
otherwise noted, melting points were obtained from material that solidified after
chromatography.
Instrumentation: FT-IR spectra were obtained on NaCl plates with a PerkinElmer
1
13
Spectrum Vision spectrometer. Proton and carbon NMR spectra ( H NMR and C
NMR) were recorded in deuterated chloroform (CDCl ) unless otherwise noted on a
3
Bruker 700 MHz Avance III Spectrometer with carbon-optimized cryoprobe or
Bruker 400 MHz DPX-400 spectrometer. Multiplicities are abbreviated as follows: s
=
singlet, d = doublet, t = triplet, q = quartet, sept = septet, br = broad, m = multiplet.
Melting points were determined with a Cole-Parmer instrument and are uncorrected.
ꢀ
2
-Bromo-3-isopropoxybenzaldehyde
(17).
A
solution
of
2-bromo-3-
hydroxybenzaldehyde (4.15 g, 20.6 mmol, 1.0 eq) and K CO (5.70 g, 41.3 mmol, 2.0
2
3
eq) in DMF (41.2 mL, 0.5 M) was stirred for five minutes upon which time iPrBr
3.80 g, 30.9 mmol, 1.5 eq) was added, and the reaction mixture was heated to 55 °C.
After 6 h, the reaction mixture was cooled to rt, quenched with aqueous LiCl solution,
and extracted with Et O (90 mL×3). The combined organic layers were washed with
(
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aqueous LiCl (40 mL), H O (40 mL), and brine (40 mL). The organic phase was dried
2
over Na SO , filtered, and concentrated to yield 17 (4.98 g, 99%) as a yellow oil.
2
4
Data for 17: R 0.76 (3:1 hexanes:EtOAc); IR (thin film) 3070, 2978, 2933, 2871,
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1 1
1
690, 1567, 1267, 1237, 828 cm ; H NMR (400 MHz, CDCl ) δ 10.42 (s, 1 H), 7.50
3
(d, J =8.0 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.60 (sept, J =
1
3
1
6.0 Hz, 1 H), 1.41 (d, J = 6.0 Hz, 6 H); C{ H} NMR (176 MHz, CDCl ) δ 192.6,
3
1
55.0, 135.0, 128.1, 121.6, 120.5, 119.0, 72.7, 21.9; HRMS (TOF MS ES+) calcd for
C H O Br [M+H]: 241.9942, found 241.9941.
1
0
11
2
2
-Bromo-6-chloro-3-isopropoxybenzaldehyde (18). A solution of 17 (3.06 g, 12.6
mmol, 1.0 eq) and pTsOH·H O (4.79 g, 25.2 mmol, 2.0 eq) in CH CN (50.3 mL, 0.25
2
3
M) was stirred for 5 min. N-Chlorosuccinimide (0.850 g, 13.2 mmol, 1.05 eq) was
added and the reaction mixture was heated to 70 °C. After 7 h, the reaction mixture
was cooled to rt and quenched with aqueous Na S O solution (100 mL) and extracted
2
2
3
with Et O (200 mL×3). The combined organic layers were washed with H O (200
2
2
mL) and brine (200 mL). The organic phase was then dried over Na SO , filtered, and
2
4
concentrated. Purification by FCC (12:1 hexanes:EtOAc) yielded 18 (2.75 g, 79%) as
a white solid.
Data for 18: mp 48–50 °C; R 0.38 (12:1 hexanes:EtOAc); IR (thin film) 3075, 2978,
f
-1
1
2
932, 2872, 1704, 1557, 1445, 1285, 1108, 804 cm ; H NMR (400 MHz, CDCl ) δ
3
10.33 (s, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 7.00 (d, J = 8.8 Hz, 1 H), 4.56 (sept, J = 6.0
1
3
1
Hz, 1 H), 1.40 (d, J = 6.0 Hz, 6 H); C{ H} NMR (176 MHz, CDCl ) δ 190.7, 154.0,
3
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
133.4, 130.3, 126.6, 119.0, 116.7, 73.1, 21.9; HRMS (TOF MS ES+) calcd for
C H O ClBr [M+H]: 276.9631, found 276.9630.
1
0
11
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-Bromo-4-chloro-1-isopropoxy-3-vinylbenzene (19). To a slurry of NaH (4.03 g,
3
6.0 mmol, 2.0 eq) in THF (180 mL, 0.1 M) was added methyltriphenylphosphonium
bromide (14.1 g, 39.6 mmol, 2.2 eq) portionwise at 0 °C. The reaction mixture was
stirred for 10 min. A solution of aldehyde 18 (5.00 g, 18.0 mmol, 1.0 eq) in THF (20
mL, 0.9 M) was added dropwise, and the mixture was warmed to rt and stirred for 30
min. Water (50 mL) was added, and the mixture was extracted with EtOAc (50
mL×3). The combined organic layers were dried over Na SO , filtered and
2
4
concentrated. Purification by FCC (40:1 hexanes:EtOAc) yielded 19 as a colorless oil
4.74 g, 96%).
Data for 19: R 0.68 (30:1 hexanes:EtOAc); IR (thin film) 2979, 1557, 1446, 1384,
(
f
-
1
1
1
281 cm ; H NMR (700 MHz, CDCl ) δ 7.29 (d, J = 8.8 Hz, 1 H), 6.76 (d, J = 8.8
3
Hz, 1 H), 6.65 (dd, J = 17.8, 11.6 Hz, 1 H), 5.67 (dd, J= 11.6, 1.2 Hz, 1 H), 5.65 (dd,
1
3
1
J = 17.8, 1.2 Hz, 1 H), 4.52 (sept, J = 6.0 Hz, 1 H), 1.38 (d, J = 6.1 Hz, 6 H); C{ H}
NMR (176 MHz, CDCl ) δ 153.6, 138.2, 133.7, 128.8, 125.0, 122.4, 116.0, 114.6,
3
7
2.7, 22.0; HRMS (TOF MS ES+) calcd for C H OClBr [M+H]: 274.9838, found
11 13
2
74.9823.
2-(3-Chloro-6-isopropoxy-2-vinylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
14). To a solution of bromide 19 (100 mg, 0.36 mmol, 1.0 eq) in THF (3.63 mL,
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0.1 M) at –98 °C was added tBuLi (0.43 mL, 1.86 M in pentane, 0.80 mmol, 2.2 eq)
dropwise. The solution was stirred for 10 min. iPrOBPin (0.30 mL, 1.45 mmol, 4.0
eq) was added dropwise, and mixture was stirred for an additional 30 min. The
reaction was quenched with water (3 mL) and extracted with EtOAc (5 mL×3). The
combined organic layers were washed with brine (3 mL), dried over Na SO , filtered,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
and concentrated. Purification by FCC (30:1 hexanes:EtOAc) afforded 14 (71.4 mg,
0%) as a white solid.
Data for 14: mp 94–96 °C; R 0.50 (30:1 hexanes: EtOAc); IR (thin film) 2978, 1578,
6
f
-
1 1
1
443, 1326, 1143 cm ; H NMR (700 MHz, CDCl ) δ 7.22 (d, J = 9.1 Hz, 1 H), 6.95
3
(dd, J = 17.5, 11.2 Hz, 1 H), 6.69 (d, J = 9.1 Hz, 1 H), 5.59 (d, J = 17.5 Hz, 1 H), 5.40
(d, J = 11.2 Hz, 1 H), 4.51 (sept, J = 6.3 Hz, 1 H), 1.35 (s, 12 H), 1.32 (d, J = 6.3 Hz,
1
3
1
6
1
H); C{ H} NMR (176 MHz, CDCl ) δ 159.7, 141.4, 135.9, 130.4, 124.4, 119.7,
3
12.5, 83.9, 70.5, 24.9, 22.1 (the carbon directly attached to the B atom was not
detected, likely due to quadrupolar broadening); HRMS (TOF MS ES+) calcd for
C H O ClB [M+H]: 323.1585, found 323.1601.
1
7
25
3
4
-Bromo-7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (22). To a solution of
aldehyde 20 (7.50 g, 43.5 mmol, 1.0 eq) in MeOH (150 mL, 0.30 M) at 0 °C was
added pyridinium tribromide (18.6 g, 116 mmol, 2.7 eq). The reaction mixture was
warmed to rt and stirred for 1 h. The solvent was evaporated and the residue was
diluted with 1% aqueous H SO (150 mL) and EtOAc (150 mL). The aqueous layer
2
4
was extracted with EtOAc (150 mL×2). The combined organic phases were washed
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with saturated Na S O solution (150 mL), dried over MgSO , filtered, and
2
2
3
4
concentrated. The crude 21 was used directly without further purification.
To a solution of crude 21 from above (1.00 g, 3.97 mmol, 1.0 eq) in DMF (9.92 mL,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.4 M) was added Cs CO (3.22 g, 9.92 mmol, 2.5 eq), and the mixture was stirred at
2 3
rt for 15 min. CH Br (0.31 mL, 4.4 mmol, 1.1 eq) was added dropwise. The reaction
2
2
mixture was warmed to 65 °C and stirred for 4 h. The mixture was cooled to rt,
quenched with H O (8 mL), and extracted with EtOAc (10 mL×3). The combined
2
organic layers were washed with brine (10 mL), dried over Na SO , filtered and
2
4
concentrated. Purification by FCC (6:1 hexanes:EtOAc) delivered 22 (530 mg, 65% 2
steps) as a white solid.
Data for 22: mp 164–165 °C; R 0.55 (6:1 hexanes:EtOAc); IR (thin film) 1680, 1592,
f
-
1 1
1
453, 1435, 1337, 1260 cm ; H NMR (700 MHz, CDCl ) δ 10.12 (s, 1H), 7.56 (s, 1
3
1
3
1
H), 6.24 (s, 2H); C{ H} NMR (176 MHz, CDCl ) δ 188.5, 148.8, 147.5, 128.2,
3
1
26.2, 114.4, 103.21,103.19; HRMS (TOF MS ES+) calcd for C H O ClBr [M+H]:
8 5 3
2
62.9111, found 262.9110.
4
-Bromo-7-chloro-5-vinylbenzo[d][1,3]dioxole (23). To a slurry of NaH (168 mg,
6
0 % dispersion in mineral oil, 4.19 mmol, 1.2 eq) in THF (23.3 mL, 0.15 M) at 0 °C
was added methyltriphenylphosphonium bromide (1.50 g, 4.19 mmol, 1.2 eq). The
mixture was stirred for 20 min. A solution of aldehyde 22 (920 mg, 3.49 mmol, 1.0
eq) in THF (11.6 mL, 0.3 M) was added dropwise, and the reaction mixture was
stirred for 4 h. The reaction was quenched by addition of H O (20 mL) and extracted
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with EtOAc (20 mL×3). The combined organic layers were washed with brine (20
mL), dried over Na SO , filtered, and concentrated. Purification by FCC (6:1
2
4
hexanes:EtOAc) yielded 23 (901.8 mg, 99%) as white solid.
Data for 23: mp 78–80 °C; R 0.74 (6:1 hexanes: EtOAc); IR (thin film) 2922, 2851,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
-1
1
1
457, 1435, 1247, 1060, 1039, 933 cm ; H NMR (700 MHz, CDCl ) δ 7.09 (s, 1 H),
3
6.88 (dd, J = 17.5, 11.2 Hz, 1 H), 6.13 (s, 2 H), 5.62 (d, J = 17.5 Hz, 1 H), 5.32 (d, J =
1
3
1
1
1
2
1.2 Hz, 1H); C{ H} NMR (176 MHz, CDCl ) δ 147.0, 143.6, 133.6, 132.5, 120.2,
3
16.5, 113.5, 102.3, 100.8; HRMS (TOF MS ES+) calcd for C H O ClBr [M+H]:
9
7
2
60.9318, found 260.9324.
2-(7-Chloro-5-vinylbenzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (15). To a solution of bromide 23 (300 mg, 1.15 mmol, 1.0 eq) in
THF (5.7 mL, 0.2 M) at –98 °C was added nBuLi (0.570 mL, 2.21 M in hexane, 1.26
mmol, 1.1 eq) dropwise, and the solution was stirred for 10 min. iPrOBpin (0.702 mL,
3
.44 mmol, 3.0 eq) was added dropwise, and mixture was stirred for an additional 2.5
h. The reaction was quenched with saturated NH Cl solution (3 mL) and extracted
4
with EtOAc (6 mL×3). The combined organic layers were washed with brine (3 mL),
dried over Na SO , filtered and concentrated. Purification by FCC (10:1
2
4
hexanes:EtOAc) gave 15 (251 mg, 71%) as white solid.
Data for 15: mp 95–97 °C; R 0.30 (30:1 hexanes: EtOAc); IR (thin film) 2980, 1608,
f
-
1
1
1
1415, 1329, 1131cm ; H NMR (700 MHz, CDCl ) δ H NMR (700 MHz, CDCl ) δ
3
3
7
.15 (dd, J = 17.2, 10.8 Hz, 1 H), 7.08 (s, 1 H), 6.06 (s, 1 H), 5.54 (dd, J = 17.2, 0.8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
Hz, 1 H), 5.18 (dd, J = 10.8, 0.8 Hz, 1 H), 1.37 (s, 12 H); C{ H} NMR (176 MHz,
CDCl ) δ 153.8, 142.8, 138.2, 136.3, 119.5, 116.2, 114.6, 101.7, 84.1, 24.8 (the
3
carbon directly attached to the B atom was not detected, likely due to quadrupolar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
broadening); HRMS (TOF MS ES+) calcd for C H O ClB: 309.1065, found
15 19
4
3
09.1071.
5
'-Bromo-3-chloro-6-isopropoxy-2'-methoxy-2,4'-divinyl-1,1'-biphenyl (24). A
flask containing bromide 1 (18.7 mg, 0.0642 mmol, 1.0 eq), boronic ester 14 (20.7
mg, 0.0642 mmol, 1.0 eq), Pd(PPh ) (7.4 mg, 6.4 µmol, 10 mol%), KBr (30.5 mg,
3
4
0
.257 mmol, 4.0 eq) and NaOH (10.3 mg, 0.257 mmol, 4.0 eq) was degassed 3 times
(evacuation followed by backfill with Ar), then dimethoxyethane (0.64 mL, 0.1 M)
and H O (0.032 mL, 5% v/v) were added under argon. The mixture was heated to 60
2
°
C for 16 h. Additional boronic ester 14 (4.1 mg, 0.0128 mmol, 0.2 eq) was added to
o
the mixture, and it was stirred at 60 C for another 8 h. Additional boronic ester 14
(
4.1 mg, 0.0128 mmol, 0.2 eq) was again added to the mixture, and it was stirred at 60
o
C for another 12 h, upon which time TLC indicated consumption of 1. The reaction
mixture was cooled to rt, filtered, and concentrated. Purification by FCC (100:1
hexanes:EtOAc) yielded 24 (16.9 mg, 0.0417 mmol, 65%) as a colorless oil.
Data for 24: R 0.62 (30:1 hexanes:EtOAc); IR (thin film) 2979, 2934, 1447, 1372,
f
-1
1
1
274, 1115 cm ; H NMR (700 MHz, CDCl ) δ 7.31 (d, J = 8.8 Hz, 1 H), 7.22 (s, 1
3
H), 7.08 (dd, J = 17.4, 11.0 Hz, 1H), 7.06 (s, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 6.47 (dd,
J = 17.9, 11.6 Hz, 1H), 5.75 (dd, J = 17.4, 0.84 Hz, 1H), 5.39 (dd, J = 11.0, 0.91 Hz, 1
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H), 5.24 (dd, J = 11.6, 1.5 Hz, 1 H), 5.12 (dd, J = 17.9, 1.5 Hz, 1 H), 4.33 (sept, J =
1
3
1
6
.0 Hz, 1H), 3.75 (s, 3H), 1.15 (d, J = 6.0 Hz, 3 H), 1.12 (d, J = 6.0 Hz, 3 H); C{ H}
NMR (176 MHz, CDCl ) δ 156.5, 154.4, 137.2, 136.8, 136.1, 135.5, 132.9, 129.5,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
28.2, 128.1, 124.8, 120.8, 116.1, 114.6, 113.8, 108.4, 71.5, 55.6, 22.0, 21.9; HRMS
(
TOF MS ES+) calcd for C H O ClBr [M+H]: 406.0335, found 406.0345.
2
0
20
2
7
5
0
-chloro-4-(3'-chloro-6'-isopropoxy-6-methoxy-2',4-divinyl-[1,1'-biphenyl]-3-yl)-
-vinylbenzo[d][1,3]dioxole (25a & 25b). A flask containing bromide 24 (6.0 mg,
.015 mmol, 1.0 eq), boronic ester 15 (6.8 mg, 0.022 mmol, 1.5 eq), Pd(PPh ) (1.7
3 4
mg, 1.5 µmol, 10 mol%), KBr (7.0 mg, 0.059 mmol, 4.0 eq) and NaOH (2.4 mg,
0.059 mmol, 4.0 eq) was degassed 3 times (evacuation followed by backfill with Ar).
Dimethoxyethane (0.15 mL, 0.1 M) and H O (0.0075 mL, 5% v/v) were added under
2
argon, and the mixture was heated to 80 °C for 14 h upon which time TLC indicated
consumption of the bromide. The reaction mixture was cooled to rt, filtered, and
concentrated. Purification by FCC (70:1 to 30:1 hexanes:EtOAc) yielded 25a (2.8 mg,
37%) as a colorless oil and 25b (2.5 mg, 32%) as a colorless oil.
Data for 25a: R 0.44 (30:1 hexanes: EtOAc); IR (thin film) 2924, 2853, 1454, 1378,
f
-
1
1
1
261, 1115 cm ; H NMR (700 MHz, CDCl ) δ 7.30 (d, J = 8.8 Hz, 1 H), 7.21 (s, 1
3
H), 7.16 (s, 1 H), 6.87 (s, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 6.50 (dd, J = 17.5, 11.2 Hz,
H), 6.47 (dd, J = 17.5, 11.1 Hz, 1 H), 6.37 (dd, J = 17.5, 11.0 Hz, 1H), 6.00 (d, J =
1.3 Hz, 1 H), 5.98 (d, J = 1.3 Hz, 1H), 5.74 (d, J = 17.5 Hz, 1 H), 5.51 (d, J = 17.5 Hz,
H), 5.23 (dd, J = 11.7, 1.5 Hz, 1 H), 5.19 (dd, J = 11.0, 0.77 Hz, 1 H), 5.18 (dd, J =
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17.9, 1.5 Hz, 1 H), 5.03 (dd, J = 11.1, 0.84 Hz, 1 H), 4.32 (sept, J = 6.1 Hz, 1H), 3.79
1
3
1
(
s, 3H), 1.11 (m, 6 H); C{ H} NMR (176 MHz, CDCl ) δ 156.8, 154.4, 146.8,
3
1
43.0, 137.1, 136.5, 134.6, 134.5, 133.5, 132.9, 132.5, 129.24, 129.21, 126.3, 124.9,
24.1, 120.6, 119.9, 119.1, 114.9, 114.7, 114.3, 113.2, 106.7, 101.9, 71.4, 55.6, 22.0,
1.9; HRMS (TOF MS ES+) calcd for C H O Cl [M+H]: 509.1286, found
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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9
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9
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8
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1
2
2
9
27
4
2
509.1274.
Data for 25b: R 0.33 (30:1 hexanes: EtOAc); IR (thin film) 2926, 1451, 1382, 1241,
f
-
1 1
1
115 cm ; H NMR (700 MHz, CDCl ) δ 7.29 (d, J = 8.8 Hz, 1 H), 7.20 (s, 1 H), 7.14
3
(
s, 1 H), 6.84 (s, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 6.53 (dd, J = 17.8, 11.6 Hz, 1H), 6.48
dd, J = 17.5, 11.1 Hz, 1 H), 6.29 (dd, J = 17.5, 11.1 Hz, 1H), 6.01 (d, J = 1.3 Hz, 1
(
H), 5.95 (d, J = 1.3 Hz, 1 H), 5.74 (d, J = 17.5 Hz, 1 H), 5.49 (dd, J = 17.4, 0.91 Hz, 1
H), 5.24 (dd, J = 11.6, 1.7 Hz, 1 H), 5.20 (dd, J = 11.0, 0.8 Hz, 1 H), 5.08 (dd, J =
1
7.9, 1.6 Hz, 1 H), 5.04 (dd, J = 11.0, 0.9 Hz, 1 H), 4.29 (sept, J = 6.1 Hz, 1H), 3.81
1
3
1
(
s, 3H), 1.10 (d, J = 6.0 Hz, 3 H), 1.09 (d, J = 6.0 Hz, 3 H); C{ H} NMR (176 MHz,
CDCl ) δ 157.0, 154.6, 146.7, 143.0, 137.4, 136.5, 134.7, 134.6, 133.7, 133.3, 132.7,
3
129.2, 129.1, 126.4, 125.1, 124.1, 120.4, 119.9, 119.2, 115.3, 114.7, 114.5, 113.2,
1
06.5, 101.8, 71.7, 55.5, 22.0, 21.9; HRMS (TOF MS ES+) calcd for C H O Cl
29 27 4 2
[M+H]: 509.1286, found 509.1262.
One-pot three-component coupling to give 7-chloro-4-(3'-chloro-6'-isopropoxy-6-
methoxy-2',4-divinyl-[1,1'-biphenyl]-3-yl)-5-vinylbenzo[d][1,3]dioxole (25).
flask containing bromide 1 (76.9 mg, 0.263 mmol, 1.0 eq), boronic ester 14 (85.0 mg,
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0.263 mmol, 1.0 eq), Pd(PPh ) (30.4 mg, 0.0263 mmol, 10 mol%), KBr (125 mg,
3
4
1
.05 mmol, 4.0 eq) and NaOH (42.1 mg, 1.05 mmol, 4.0 eq) was degassed 3 times
(evacuation followed by backfill with Ar). Dimethoxyethane (2.63 mL, 0.1 M) and
1
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H O (0.132 mL, 5% v/v) were added under argon and the mixture was heated to 60 °C
2
for 16 h. Additional boronic ester 14 (42.4 mg, 0.132 mmol, 0.5 eq) was added
o
portionwise and the reaction was maintained at 60 C for another 48 h, upon which
time TLC indicated consumption of the bromide. Boronic ester 15 (114 mg, 0.368
o
mmol, 1.4 eq) was added to the mixture, and it was heated to 80 C for an additional
4
8 h upon which time TLC indicated completion of the reaction. The reaction mixture
was cooled to rt, filtered, and concentrated. Purification by FCC (60:1 to 30:1
hexanes:EtOAc) yielded 25a (12.8 mg, 9.5%) as a colorless oil and 25b (14.0 mg,
1
0.5%) as a colorless oil.
4
-Chloro-10-(3-chloro-6-isopropoxy-2-vinylphenyl)-9-methoxyphenanthro[3,4-
d][1,3]dioxole (13). To a solution of terphenyl 25a (2.0 mg, 3.9 µmol, 1.0 eq) in
nd
CH Cl (0.39 mL, 0.01 M) was added Grubbs 2 generation catalyst (0.1 mg, 0.16
2
2
µmol, 4 mol%). The reaction mixture was heated to 45 °C and stirred for 16 h. The
mixture was cooled to rt, filtered, and concentrated. Purification by FCC (60:1
hexanes:EtOAc) yielded 13 (1.9 mg, 99%) as a colorless oil.
Data for 13: R 0.28 (30:1 Hexanes: EtOAc); IR (thin film) 2924, 2853, 1509, 1465,
f
-
1 1
1424, 1284, 1100, 1059 cm ; H NMR (700 MHz, CDCl ) δ 8.64 (s, 1 H), 7.55 (dd, J
3
=
12.2, 9.0 Hz, 2 H), 7.44 (s, 1 H), 7.37 (d, J = 8.9 Hz, 1 H), 7.22 (s, 1 H), 6.89 (d, J =
2
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8.4 Hz, 1 H), 6.52 (dd, J = 17.9, 11.7 Hz, 1 H), 6.250 (d, J = 11.2 Hz, 1 H), 6.248 (d,
J = 11.2 Hz, 1 H), 5.13 (dd, J = 11.6, 1.7 Hz, 1 H), 5.08 (dd, J = 17.8, 1.6 Hz, 1 H),
4.35 (sept, J = 6.1 Hz, 1 H), 3.87 (s, 3 H), 1.09 (d, J = 6.1 Hz, 3 H), 1.07 (d, J = 6.1
0
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1
Hz, 3 H); C{ H} NMR (176 MHz, CDCl ) δ 156.4, 154.8, 143.7, 142.0, 137.5,
3
1
33.2, 133.1, 130.4, 130.0, 129.2, 128.2, 127.0, 126.3, 125.7, 124.9, 121.6, 121.5,
120.6, 115.5, 114.8, 113.4, 107.1, 102.0, 71.5, 55.5, 22.0, 21.9; HRMS (TOF MS
ES+) calcd for C H O Cl [M+H]: 481.0973, found 481.0998.
2
7
23
4
2
4
-Chloro-10-(3-chloro-6-isopropoxy-2-vinylphenyl)-9-methoxyphenanthro[3,4-
d][1,3]dioxole (13). To a solution of terphenyl 25b (2.0 mg, 3.9 µmol, 1.0 eq) in
nd
CH Cl (0.39 mL, 0.01 M) was added Grubbs 2 generation catalyst (0.1 mg, 0.16
2
2
µmol, 4 mol%). The reaction mixture was warmed to 45 °C and stirred for 10 h. The
mixture was cooled to rt, filtered, and evaporated. Purification by FCC (60:1
hexanes:EtOAc) yielded 13 (1.7 mg, 90%) as a colorless oil.
Equilibration of 25a. A solution of 25a (2.0 mg, 3.9 µmol, 1.0 eq) in C D (0.50
6
6
o
mL, 0.008 M) in an NMR tube was heated to 80 C. The NMR tube was cooled and
1
the ratio of 25a:25b was measured by integration of the H NMR spectrum at 6 h
(25a:25b = 1.15:1.0), and 16 h (25a:25b = 1.15:1.0).
Equilibration of 25b. A solution of 25b (2.0 mg, 3.9 µmol, 1.0 eq) in C D (0.50
6
6
o
mL, 0.008 M) in an NMR tube was heated to 80 C. The NMR tube was cooled and
1
the ratio of 25a:25b was measured by integration of the H NMR spectrum at 20 min
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(25a:25b = 0.9:1.0), 60 min (25a:25b = 1.12:1.0), 120 min (25a:25b = 1.15:1.0), 6 h
(25a:25b = 1.15:1.0), and 16 h (25a:25b = 1.15:1.0).
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13
Supporting Information: Depiction of H and C NMR spectra of all new
compounds. This material is available free of charge via the Internet at
http://pubs.acs.org/.
(b)ꢀ
Acknowledgment: The authors acknowledge financial support from the National
Science Foundation (CHE-1465287) and Oregon State University.
(a)ꢀ
*
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1
For reviews, see: (a) Keserű, G. M.; Nógrádi, M. The Chemistry of Macrocyclic
Bis(bibenzyls). Nat. Prod. Rep. 1995, 12, 69–75. (b) Asakawa, Y.; Toyota, M.; Tori,
M.; Hashimoto, T. Chemical Structures of Macrocyclic Bis(bibenzyls) Isolated from
Liverworts (Hepaticae). Spectroscopy 2000, 14, 149–175.
2
For reviews of MBB biological activities, see: (a) Keserű, G. M.; Nógrádi, M. The
Biological Activity of Cyclic Bis(bibenzyls): A Rational Approach. Bioorg. Med.
Chem. 1995, 3, 1511–1517. (b) Asakawa, Y.; Ludwiczuk, A.; Nagashima, F.
Phytochemical and Biological Study of Bryophytes. Phytochemistry 2013, 91, 52–80.
3
(a) Asakawa, Y. Progress in the Chemistry of Organic Natural Products, Springer-
Verlag, New York, 1995, 65, 335–351. (b) Harrowven, D. C.; Kostiuk, S. L.
Macrocylic Bisbibenzyl Natural Products and their Chemical Synthesis. Nat. Prod.
Rep. 2012, 29, 223–242.
4
Hashimoto, T; Kanayama, S.; Kan, Y.; Tori, M.; Asakawa, Y. Isoplagiochins C and
D, New Type of Macrocyclic Bis(bibenzyls), Having Two Biphenyl Linkages from
the Liverwort Plagiochila fruticosa. Chem. Lett. 1996, 25, 741–742.
5
Asakawa, Y.; Toyota, M.; Matsuda, R.; Takikawa, K.; Takemoto, T. Distribution of
Novel Cyclic Bisbibenzyls in Marchantia and Riccardia Species. Phytochemistry
1
983, 22, 1413–1415.
6
Toyota, M.; Yoshida, T.; Kan, Y.; Takaoka, S.; Asakawa, Y. (+)-Cavicularin: A
Novel Optically Active Cyclic Bibenzyl-Dihydrophenanthrene Derivative from the
Liverwort Cavicularia densa Steph. Tetrahedron Lett. 1996, 37, 4745–4748.
7
Martini, U.; Zapp, J.; Becker, H. Chlorinated Macrocyclic Bisbibenzyls from the
Liverwort Bazzania trilobata. Phytochemistry 1998, 47, 89–96.
8
Zhao, P. Racemic and Enantioselective Synthesis of Cavicularin. Ph.D. Thesis,
Oregon State University, December, 2015.
9
We have discovered several natural products that were isolated as optically active
samples, which turned out to be achiral molecules. Presumably, impurities in the
natural sample led to false positive optical rotations. See: (a) Salih, M. Q.; Beaudry,
C. M. Total Synthesis of Russuphelol: A Case of Mistaken Chirality. Org. Lett. 2014,
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6, 4964–4966. (b) Zhu, Z.-Q.; Beaudry, C. M. Structural Revision of Garuganin IV
and 1,9’-Didesmethylgaruganin III through Total Synthesis. J. Org. Chem. 2013, 78,
336–3341.
3
1
0
(
a) Zhao, P.; Beaudry, C. M. Total Synthesis of (±)-Cavicularin: Control of Pyrone
Diels–Alder Regiochemistry Using Isomeric Vinyl Sulfones. Org. Lett. 2013, 15,
02–405. (b) Zhao, P.; Beaudry, C. M. Enantioselective and Regioselective Pyrone
1
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Diels–Alder Reactions of Vinyl Sulfones: Total Synthesis of (+)-Cavicularin. Angew.
Chem. Int. Ed. 2014, 53, 10500–10503. (c) Zhao, P.; Beaudry, C. M. Total Synthesis
of (+)-Cavicularin: The Pyrone Diels–Alder Reaction in Enantioselective Cyclophane
Synthesis. Synlett 2015, 26, 1923–1929.
1
1
Zhao, P.; Young, M. D.; Beaudry, C. M. Regioselective Suzuki Couplings of Non-
Symmetric Dibromobenzenes: Alkenes as Regiochemical Control Elements. Org.
Biomol. Chem. 2015, 13, 6162–6165.
1
2
For other examples of constructing terphenyls with Suzuki reactions, see: (a)
Beekman, A. M.; Barrow, R. A. Syntheses of the Fungal Metabolites Boletopsins 7,
1, and 12 from the Papua New Guinea Medicinal Mushroom Boletopsis sp. J. Org.
1
Chem. 2014, 79, 1017–1024. (b) Takahashi, S.; Suda, Y.; Nakamura, T.; Matsuoka,
K.; Koshino, H. Total Synthesis of Kehokorins A–E, Cytotoxic p-Terphenyls. J. Org.
Chem. 2017, 82, 3159–3166. (c) Fujiwara, K.; Motousu, R.; Sato, D.; Kondo, Y.;
Akiba, U.; Suzuki, T.; Tokiwano, T. Total Synthesis of Kehokorins A and B.
Tetrahedron Lett. 2019, 60, 1299–1301.ꢀ
1
3
(a) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of
Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. (b) Stanforth, S. P.
Catalytic Cross-coupling Reactions in Biaryl Synthesis. Tetrahedron 1998, 54, 263–
3
03. (c) Littke, A. F.; Dai, C.; Fu, G. C. Versatile Catalysts for the Suzuki Cross-
Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild
Conditions. J. Am. Chem. Soc. 2000, 122, 4020–4028.
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(a) Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis
and Medicine. Wiley-VCH, Weinheim, 2005. b) Lennox, A. J. J.; Lloyd-Jones, G. C.
Selection of Boron Reagents for Suzuki–Miyaura Coupling. Chem. Soc. Rev. 2014,
43, 412–443.
1
5
Matoušová, E.; Koukal, P.; Formánek, B.; Kotora, M. Enantioselective Synthesis of
the Unsaturated Fragment of Callyspongiolide. Org. Lett. 2016, 18, 5656–5659.
16
(a) Sala, T.; Sargent, M. V. Depsidone Synthesis. Part 14. The Total Synthesis of
Psoromic Acid: Isopropyl Ethers as Useful Phenolic Protecting Groups. (b) Zhu, Z.-
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Q.; Salih, M. Q.; Fynn, E.; Bain, A. D.; Beaudry, C. M. The Garuganin and
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