Lewis Acid-Promoted Regio- and Diastereoselective Cross-Coupling of Aryl-Substituted 1,2-Diols and Boronic Acids

Article abstract of DOI:10.1021/acs.joc.9b00209

A Lewis acid-promoted highly regio- and diastereoselective C(sp³)-C(sp²) cross-coupling reaction between unprotected aryl-substituted 1,2-diols and styryl-, aryl-, heteroaryl-, and polyarylboronic acids has been developed in a one-pot procedure. The regioselective opening of aryl-substituted cyclic boronic esters promoted by a Lewis acid followed by subsequent intramolecular 1,4-transfer of the carbon ligand from boron to a resonance-stabilized benzylic carbenium ion minimizing the allylic 1,3-strain in a stereoselective fashion led to the corresponding α-substituted syn-phenylethyl alcohols. The synthetic utility of the method was illustrated by a short and efficient enantioselective synthesis of cherylline diethyl ether (-)-16.

Full text of DOI:10.1021/acs.joc.9b00209

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Article
Lewis Acid-Promoted Regio- and Diastereoselective Cross-
Coupling of Aryl-Substituted 1,2-Diols and Boronic Acids
Heesun Yu, Ryangha Lee, Hyoungsu Kim, and Dongjoo Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00209 • Publication Date (Web): 20 Feb 2019
Downloaded from http://pubs.acs.org on February 21, 2019
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Lewis Acid-Promoted Regio- and Diastereoselective Cross-Coupling of Aryl-
Substituted 1,2-Diols and Boronic Acids
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Heesun Yu, Ryangha Lee, Hyoungsu Kim and Dongjoo Lee*
College of Pharmacy and Research Institute of Pharmaceutical Science and Technology
(RIPST), Ajou University, 206 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea.
ABSTRACT
3
2
A Lewis acid-promoted highly regio- and diastereoselective C(sp )-C(sp ) cross-coupling
reaction between unprotected aryl-substituted 1,2-diols and styryl-, aryl-, heteroaryl-, and
polyarylboronic acids has been developed in a one-pot procedure. The regioselective opening
of aryl-substituted cyclic boronic esters promoted by a Lewis acid, followed by subsequent
intramolecular 1,4-transfer of the carbon ligand from boron to a resonance-stabilized benzylic
carbenium ion minimizing the allylic 1,3-strain in a stereoselective fashion led to the
corresponding -substituted syn-phenylethyl alcohols. The synthetic utility of the method was
illustrated by a short and efficient enantioselective synthesis of cherylline diethyl ether (–)-16.
R2
Lewis Acid
then OH-
R2
OH
2
R -B(OH)
O B
R1
2
R1
O
X
X
DCM ,rt
"B to C"
1,4-Transfer
OH
X
OH
5 examples
40-90% yield
up to 95:5 ds
R1
2
X = OMe, OTBDPS
1
Aryl-Substituted
Boronic Ester
R = Me, CO Et
2
2
R = Aryl, Heteroaryl,

Highly Regio- & Diastereoselective
 One-Pot/Operationally Simple/Gram-Scale
Polyaryl, Styryl
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INTRODUCTION
The discovery of efficient and elegant methods to create stereogenic centers governed by
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acyclic stereocontrol elements is a continuing challenge to synthetic organic chemists. The
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nucleophilic substitution reaction with chiral -branched benzylic carbenium ions has emerged
as a powerful tool for the highly diastereoselective construction of two contiguous stereogenic
centers adjacent to an substituted benzene moiety.2 The outcome of the highly
diastereoselective substitution developed here can be predicted from conformational analysis
on the basis of the allylic 1,3-strain concept (vide infra).3
Figure 1. Selected Natural Products Containing Phenylethyl Alcohol Moiety
OH
HO
H
MeN
H
O
OH
H
O
MeO
O
O
OH
H
H
O
N
Me
OH
HO
O
Clividine (1)
Galantamine (2)
Brazilin (3)
OH
Me
OH
Me
HO
R3
O
O
O
HO
OH
Liliflol B (4)
3
Agatharesinol (5); R = H
3
Sequirin B (6); R = OH
The phenylethyl alcohol moiety occurs in a myriad of biologically important natural products
such as clividine (1), galantamine (2), brazilin (3), liliflol B (4), agatharesinol (5), sequirin B
(6) and others (Figure 1). Consequently, highly diastereoselective carbon-carbon bond
formation governed by the directing ability of an acyclic stereocontrol element (i.e., substrate-
controlled stereochemistry), especially at the benzylic carbon center, is an important strategy
and a challenging current research topic.
Not surprisingly, extensive synthetic endeavors have been devoted to this approach. One of the
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most notable methods involves the generation of resonance-stabilized benzylic carbenium ions
derived from benzylic alcohols catalyzed by Brønsted or Lewis acids (eq 1, Scheme 1)2,4,5,6
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and aryl-substituted cyclic orthoesters in the presence of BF •OEt (eq 2, Scheme 1), followed
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by introduction of an arene nucleophile in an S 1-type process. However, the scope reported
N
for each method is notably limited to electron-rich arenes as nucleophiles, and their facial
selectivity at the benzylic carbon center depends on the electron demand of the aromatic
substituents. Nucleophilic opening of aryl-substituted epoxides by organometallics is the most
common strategy. However, the requirement for strong nucleophiles such as
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organomagnesium, organoaluminum, and organocuprate reagents restricts the scope of
these reactions due to the functional group incompatibility. A recent approach to circumvent
this limitation involved the use of a combination of potassium trifluoroborates11 as mild
nucleophiles and trifluoroacetic anhydride (TFAA) as the promoter (eq 3, Scheme 1). However,
the substituents of the aryl-substituted epoxides were limited to electron-withdrawing groups
such as carbonyls, presumably due to an increase in the stability of the epoxides through the
inductive effect. While we were investigating Brønsted or Lewis acid-promoted regio- and
diastereoselective cross-coupling reaction of aryl-substituted 1,2-diol and a diverse range of
boronic acids and mechanism of the reaction, in late 2017 Csákÿ and co-workers12
independently reported a cross-coupling reaction of aryl-substituted chiral 1,2-diol and boronic
acids promoted by trifluoroacetic anhydride (TFAA) (eq 4, Scheme 1). However, the reported
method suffers from low diastereoselectivity in some cases, which depends on aryl groups of
substrates or boronic acid nucleophiles used. Despite substantial progress in this research field,
there is still a need for general and mild methods for highly diastereoselective carbon-carbon
bond formation at a benzylic carbon center. On the basis of the ready availability and stability
of aryl-substituted 1,2-diols along with the advantages of using mild and functional group-
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tolerant organoboronic acids as coupling partners, we sought to develop a diastereoselective
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cross-coupling reaction at the benzylic carbon center employing these reagents (eq 5, Scheme
1
).
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Scheme 1. Diastereoselective Carbon-Carbon Bond Formation at the Benzylic Carbon Center
Previous Work
Het/Ar-H,
OH
Het/Ar
TFA, HBF or Au(III), Bi(III)
4
R
R
(eq 1)
Ar
Ar
FG = OH, NO , N etc.
Bach (2005, 2006, 2008),
Hanessian (2014)
2
3
FG
FG
Me OMe
Ar-OH
EWG (eq 2)
H-Ar-OH, BF •OEt2
3
O
O
Ar
EWG = ester
Ar = electron-rich
Bozell (2001)
OAc
Ar
EWG
R
O EWG
R-BF3K, TFAA
EWG
(eq 3)
(eq 4)
Ar
Ar
EWG = ester, ketone
R = alkenyl, styryl, aryl
Csákÿ (2014)
OH
OH
R
R-B(OH) , TFAA
2
CO Me
CO Me
2
2
Ar
Ar
Ar = indole, thiophen, benzene
R = styryl, aryl, het
OH
OH
Csákÿ (2017)
Present Work
OH
R
R-B(OH) , then Lewis Acid
2
FG
FG
OH
(eq 5)
Ar
Ar
FG = alkyl, ester
R = styryl, het, poly, aryl
OH
Highly Regio- and Diastereoselective/One-Pot/Gram-Scale
1
4
Boronic esters have played a pivotal role in rearrangement processes wherein boron accepts
an electron lone pair to form an anionic tetracoordinate organoborate complex. When a carbon
electrophile is appropriately positioned, the resulting anionic organoborate complex undergoes
an intramolecular ligand transfer from boron to carbon, leading to new carbon-carbon bond
formation.
As depicted in Scheme 2, We postulated that a resonance-stabilized benzylic carbenium ion
bearing a boronate ester substituent on the adjacent stereocenter, in which bond rotation is
3
minimized due to the allylic 1,3-strain, could be generated via cleavage of an aryl-substituted
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cyclic boronic ester promoted by a Brønsted or Lewis acid. Then, subsequent stereoselective
intramolecular 1,4-transfer of the carbon ligand from boron to the same face of the resonance-
stabilized planar benzylic carbenium ion would lead to a highly stereocontrolled carbon-carbon
bond formation at the benzylic carbon center.
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Scheme 2. Concept: Bronsted or Lewis Acid Promoted Stereoselective Intramolecular 1,4-
Ligand Transfer from Organoborate to the Resonance-Stabilized Benzylic Carbenium Ion
R1
B
B to C
1,4-Transfer
(M)HO X
B
X OH(M)
B
OH-
R1
H(M)X
OH
R
R1
O
R1
O
H
2
O
O
R2
H
R2
H
R2
H
Ar
H
Ar
H
Ar
H
Ar
H
"
Ar-H Eclipsed"
Borate
Intermediate
syn-Alcohol
Aryl-Substituted
Cyclic Boronic Ester (Minimized A Strain)
syn/anti)
H(M)X = Brønsted (HX) or Lewis Acid (MX)
1,3
1
R = Alkenyl or Aryl
(
2
R = Alkyl or Ester
Herein is reported a highly regio- and diastereoselective boronic ester-mediated intramolecular
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ligand transfer strategy that involves the Lewis acid-promoted C(sp )-C(sp ) cross-coupling
reaction of unprotected aryl-substituted 1,2-diols with structurally diverse boronic acids at the
benzylic carbon center.
RESULTS AND DISCUSSION
Optimization of the Reaction Conditions. To test the viability of the envisioned regio-
and diastereoselective cross-coupling reaction at the outset of our studies, 3,4-
dimethoxyphenyl substituted cyclic boronic ester trans-(±)-9a was employed as a model
1
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substrate, which was derived from known syn-1,2-diol (±)-7a and commercially available
(E)-styrylboronic acid 8a. A variety of Brønsted acids as well as Lewis acids as promoters were
examined in the model reaction in DCM (0.1 M) at room temperature, and the representative
results are summarized in Table 1.
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Table 1. Evaluation of Acid-Promoted Diastereoselective 1,4-Ligand Transfer of trans-(±)-9aa
Ph
Ph
Ph
O B
+
O
MeO
MeO
Me MeO
OH
syn-(±)-10a
Me
OH
anti-(±)-10a
MeO
MeO
conditions
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Me
MeO
trans-(±)-9a
entry promoter solvent time b yield c syn/antid
(h)
(%)
1e
AcOH
PTSA
(+)-CSA
TFA
DCM
DCM
DCM
DCM
DCM
12
12
0
N.A.
2f
N.A.k
0
3g
4h
5i
6j
7
12
0
N.A.
95:5
95:5
95:5
92:8
95:5
95:5
95:5
95:5
95:5
95:5
95:5
95:5
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60
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66
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89
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<5
TfOH
FeCl
BF
Sc(OTf)
Bi(OTf)
Yb(OTf)
InCl
InBr
3
DCM
DCM
3
·OEt
2
DCM
8
3
9
3
MeNO
MeNO
DCM
2
2
1
1
0
1
3
3
1.5
1.5
1.5
12
DCM
12
3
DCM
1
1
3
4
In(OTf)
In(OTf)
In(OTf)
3
3
3
MeCN
THF
15
12
aGeneral conditions: trans-(±)-9a (0.3 mmol, 1.0 eq), promoter (0.36 mmol, 1.2 eq), solvent (3.0 mL, 0.1 M) at
b
c)
room temperature. Time required for a complete conversion. Based on isolated product after purification by
d
1
chromatography. Diastereomeric ratio (syn/anti) of the crude product was determined by H NMR spectroscopy.
e
f
g
h
AcOH (3.0 mmol, 10 eq). PTSA (3.0 mmol, 10 eq). (+)-CSA (1.5 mmol, 5.0 eq). TFA (1.5 mmol, 5.0 eq).
i
j
k
Reaction performed at -78 °C. Reaction performed at 0 °C. Not Available.
Initially, treatment of trans-(±)-9a with AcOH, PTSA or (+)-CSA failed to give the desired
product, despite long exposure to such organic acids, and only unreacted starting trans-(±)-9a
was recovered (entries 1-3, Table 1). Encouragingly, when a stronger Brønsted acid was
employed such as TFA at room temperature or TfOH at –78 °C, syn-(±)-10a was formed as the
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major product in good yield, exhibiting excellent diastereoselectivity (dr = 95:5) at the benzylic
carbon center in a highly efficient manner (entries 4 and 5, Table 1). Also, a diverse range of
Lewis acids were surveyed, and FeCl , BF •OEt , Sc(OTf) , Bi(OTf) , or Yb(OTf) proved to
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be effective for the desired cross-coupling reaction (entries 6-10, Table 1). Among the Lewis
acids tested, In(III) salts most efficiently induced the cleavage and subsequent intramolecular
ligand transfer in trans-(±)-9a. The reactions with InCl , InBr and In(OTf) resulted in rapid,
3
3
3
efficient (1.5 hours at room temperature), and extremely regio- and diastereoselective
transformations that resulted in syn-(±)-10a in high yields (entries 11-13, respectively, Table
1
). However, upon changing the solvent to THF or MeCN, the chemical yield of the cross-
coupling reaction was substantially diminished, however, with no effect on the
diastereoselectivity (entries 14 and 15, Table 1).
Confirmation of the Configuration at the Newly Generated Benzylic Stereocenter.
As depicted in Scheme 3, the relative configuration of the newly generated benzylic
stereocenter was unambiguously established by transformation16 of the major and minor
products syn- and anti-(±)-10a into respectively known cyclic derivatives reported by
1
7
Kawahara and co-workers. The coupling constants of hydrogen atoms between C(2) and C(3)
were compared in the 2,3-substituted tetrahydropyrans trans- and cis-(±)-13, which were
derived from the major and minor diastereomers syn- and anti-(±)-10a in a parallel route
through O-allylation [syn- and anti-(±)-11], ring-closing metathesis of the resultant olefins
1
7
[
trans- and cis-(±)-12] utilizing Grubbs’ second-generation catalyst (Grubbs II), and Pd-
mediated catalytic hydrogenation. The large coupling constant value (J2H-3H = 9.9 Hz) between
C(2) and C(3) in trans-(±)-13 indicates that the relative configuration of the major diastereomer
must be syn, whereas the small constant value (J2H-3H = 3.6 Hz) between C(2) and C(3) in cis-
(±)-13 indicates that the relative configuration of the minor diastereomer must be anti. In
addition, by comparison of the spectral data of syn-(±)-10r (Scheme 6) with those reported by
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Bozell and co-workers, we confirmed the relative configuration of the major and minor
products syn- and anti-(±)-10a, demonstrating that this reaction occurs with overall retention
of configuration at the benzylic stereocenter. The relative configurations of the other major
products were assigned by analogy.
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Scheme 3. Confirmation of the Relative Configuration of Major and Minor Diastereomers
Ph
Ph
MeO
MeO
Me
OH
MeO
MeO
Me
OH
anti-(±)-10a
syn-(±)-10a
Major Product)
(
(Minor Product)
NaH, Allyl Bromide,
o
THF/DMF, 0 C, 30 min
Ph
Ph
MeO
MeO
Me
MeO
MeO
Me
O
O
syn-(±)-11
87%)
anti-(±)-11
(92%)
(
Grubbs 2nd Catalyst,
DCM, rt, 3 h
2
2
MeO
MeO
O
MeO
MeO
O
3
3
Me
Me
syn-(±)-12
92%)
cis-(±)-12
(98%)
(
H (1 atm), Pd/C,
2
MeOH, rt, 3 h
2
MeO
MeO
O
2
MeO
MeO
O
3
3
Me
Me
trans-(±)-13
98%)
J2H-3H = 9.9 Hz)
cis-(±)-13
(90%)
(J2H-3H = 3.6 Hz)
(
(
One-Pot and Gram-Scale Approach. To increase the synthetic utility of this method, we
next focused on a sequential one-pot process involving in situ formation of the transient aryl-
substituted cyclic boronic ester trans-(±)-9a, followed by intramolecular transfer of the styryl
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group promoted by In(OTf) (Scheme 4). We were pleased to find that the sequential treatment
3
of syn-(±)-7a with (E)-styrylboronic acid 8a (1.5 eq) in DCM for 1 hour and In(OTf) (2.0 eq)
3
for 1.5 hour at room temperature led to the desired syn-(±)-10a in 88% overall yield while
retaining excellent diastereoselectivity (dr = 95:5) at the benzylic stereocenter from syn-(±)-7a
without purifying the cyclic boronic ester trans-(±)-9a. This process was also found to be
amenable to gram-scale synthesis without notable erosion of yield and diastereoselectivity.
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
Scheme 4. One-Pot and Gram-Scale Approach for the Lewis Acid-Promoted Cross-Coupling
Reaction of Aryl-Substituted 1,2-Diol syn-(±)-7a and Styrylboronic Acid 8a
Ph
1) (E)-PhCH=CHB(OH) 8a
(1.5 eq), DCM, rt, 1 h
2
OH
MeO
MeO
Me
MeO
MeO
Me
OH
syn-(±)-10a
2
) In(OTf) (2.0 eq), rt, 1.5 h
OH
3
(
88%)
syn/anti = 95:5)
Amenable to Gram-Scale
(
syn-(±)-7a
Scope and Limitations of Substrates. Having optimized reaction conditions in hand, the
scope of this Lewis acid-promoted regio- and diastereoselective cross-coupling reaction was
examined by investigating a diverse range of aryl-substituted 1,2-diols and (E)-styrylboronic
acids as coupling partners. As shown in Scheme 5, the scope was limited to electron-rich aryl-
substituted 1,2-diols, which provided the desired products in high yield with excellent
diastereoselectivities (Scheme 5, syn-(±)-10a-m). Unfortunately, the application of phenyl-
substituted 1,2-diol did not provide the desired product. These results are consistent with the
postulated resonance-stabilized carbenium ion intermediate (vide infra). An ester group was
highly compatible with the present reaction conditions, which enhance the synthetic utility of
the current protocol (Scheme 5, syn-(±)-10b, syn-(±)-10d, syn-(±)-10f). We also explored a
series of (E)-styrylboronic acids with para-substituents having various degrees of electron
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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
demand. Notably, substituents with an electron-withdrawing effect led to the desired products
with high yields (Scheme 5, syn-(±)-10h-j), whereas electron-donating substituents provided
the products in moderate yields (Scheme 5, syn-(±)-10k-m).
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
Scheme 5. Scope of Aryl-Substituted 1,2-Diols and (E)-Styrylboronic Acidsa, b, c
Y
1)
B(OH)2
Y
8
OH
DCM, rt, 1 h
2) Lewis acid, rt, 1.5 h
R
R
X
X
OH
OH
syn-(±)-10
syn-(±)-7
MeO
MeO
R1
MeO
TBDPSO
R2
OH
R3
OH
OH
MeO
(±)-10e; R = Me
1
2
3
(±)-10a; R = Me
(±)-10c; R = Me
(
(
(
88%, dr = 95:5, In(OTf) )
(65%, dr = 95:5, In(OTf) )
(66%, dr = 95:5, InBr )
3
3
3
1
2
3
±)-10b; R = CO Et
(±)-10d; R = CO Et
(±)-10f; R = CO Et
2
2
2
67%, dr = 95:5, In(OTf)3)
(78%, dr = 95:5, InBr3)
(60%, dr = 95:5, InBr3)
(
(
(
(
(
(
(
(
±)-10h; X = CF3
86%, dr = 95:5, InBr3)
±)-10i; X = F
X
79%, dr = 95:5, InBr3)
±)-10j; X = Cl
OMe
Me
82%, dr = 95:5, InBr3)
±)-10k; X = Ph
MeO
MeO
Me
OH
OH
69%, dr = 95:5, InBr3)
MeO
(±)-10l; X = Me
50%, dr = 95:5, InBr3)
OMe
(
(
±)-10g
(±)-10m; X = OMe
(88%, dr = 95:5, In(OTf)3)
(40%, dr = 95:5, BF3•OEt2)
aGeneral conditions: syn-(±)-7a-g (0.3 mmol, 1.0 eq), boronic acid 8a-g (1.5 eq), DCM (3.0 mL, 0.1 M) at room
b
temperature, 1 h, then promoter (in parentheses) (2.0 eq), at room temperature, 1.5 h. Based on isolated product
c
1
after purification by chromatography. Diastereomeric ratio (syn/anti) of the crude product was determined by H
NMR spectroscopy.
Subsequently, we further investigated the substrate scope with respect to a variety of aromatic,
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heteroaromatic, and polyaromatic boronic acid nucleophiles as coupling partners. As depicted
in Scheme 6, the scope was limited to electron-rich aromatic and heteroaromatic boronic acids,
which yielded the desired products in moderate to high yield with excellent
diastereoselectivities (Scheme 6, syn-(±)-10n-v). In contrast to (E)-styrylboronic acids with an
electron-withdrawing substituents, however, the reaction did not perform well with phenyl
boronic acid or electron-poor aromatic boronic acids. There are still more research which needs
to be done to understand the electronic effect of substituents of styryl and aryl ligands upon the
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
,4-ligand transfer process from boron to benzylic carbenium ion. However, based on the
results we observed, we postulated that styryl and aryl ligand on boronic ester would undergo
an intramolecular nucleophilic addition to the benzylic carbenium ion, leading to the resulting
electron-deficient benzylic carbenium and arenium ion, respectively. Subsequent elimination
of the borate group would then reveal 1,4-ligand transfer from boron to benzylic carbon center.
Compared with the stability of the benzylic carbenium ion, that of the high energy-transition
state and dearomatized arenium ion is more susceptible to the electronic effect of substituents.
Therefore, the ability of the electron-donating substituents to stabilize an electron-deficient
arenium ion should promote the desired 1,4-ligand transfer process. Unlike (E)-styrylboronic
acids, aromatic and heteroaromatic nucleophiles required BF •OEt or InBr as a promoter for
3
2
3
the best results rather than In(OTf) . Notably, both high yields and excellent
3
diastereoselectivity were also observed with polyaromatic boronic acids, including 1-naphthyl
(Scheme 6, syn-(±)-10w), 9-phenanthrenyl (Scheme 6, syn-(±)-10x), 1-pyrenyl (Scheme 6,
syn-(±)-10y) groups. However, the more sterically hindered 8-anthracenyl boronic acid was
not compatible with the reaction conditions thus far developed.
Scheme 6. Scope of Aryl-Substituted 1,2-Diols and Aromatic, Heteroaromatic and
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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
Polyaromatic Boronic Acidsa, b, c
1
) Ar-B(OH) 8, DCM, rt, 2h
2) Lewis acid, rt, 1h
2
OH
Ar
R
R
X
X
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
OH
OH
syn-(±)-7
syn-(±)-10
OMe
OMe
OMe
MeO
MeO
MeO
Me
OH
MeO
MeO
Me
OH
MeO
MeO
Me
OH
MeO
(±)-10n
(73%, dr = 92:8, BF •OEt )
(±)-10o
(±)-10p
(66%, dr = 92:8, BF •OEt )
(71%, BF •OEt )
3
2
3
2
3
2
OH
OH
OMe
MeO
MeO
Me
OH
CO Et
MeO
MeO
CO Et
2
2
OH
OH
MeO
(
±)-10s
(
±)-10q
(±)-10r
(
85%, dr = 92:8, BF •OEt )
(
70%, dr = 92:8, BF •OEt )
(72%, dr = 92:8, BF •OEt )
3
2
3
2
3
2
O
S
NBoc
Me
MeO
MeO
Me
OH
MeO
MeO
Me
OH
MeO
MeO
OH
(±)-10t
(±)-10u
(63%, dr = 92:8, InBr3)
(±)-10v
(60%, dr = 92:8, BF •OEt )
(
85%, dr = 92:8, InBr3)
3
2
MeO
MeO
Me
OH
MeO
MeO
Me
OH
MeO
MeO
Me
OH
(
±)-10w
(±)-10x
(76%, dr = 95:5, BF •OEt )
(±)-10y
(68%, dr = 95:5, BF •OEt )
(
90%, dr = 95:5, BF •OEt )
3
2
3
2
3
2
aGeneral conditions: syn-(±)-7a-b, 7f (0.3 mmol, 1.0 eq), boronic acid 8h-q (1.5 eq), DCM (3.0 mL, 0.1 M) at
b
room temperature, 1 h, then promoter (in parentheses) (2.0 eq), at room temperature, 1.5 h. Based on isolated
c
product after purification by chromatography. Diastereomeric ratio (syn/anti) of the crude product was
1
determined by H NMR spectroscopy.
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Stereoconvergent Reaction of Diastereomeric 1,2-Diols and Proposed Reaction
Mechanism. To demonstrate the stereoselective nature of this reaction and gain some insight
into the reaction mechanism, each of the diastereomeric aryl-substituted 1,2-diols syn- and anti-
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
(
±)-7a was treated separately with (E)-styrylboronic acid 8a (1.5 eq) and In(OTf) (2.0 eq) in
3
DCM under one-pot conditions (Scheme 7). In both cases, syn-(±)-10a was formed
preferentially.
Scheme 7. Stereoconvergent Reaction of Each of syn- and anti-(±)-7a with 8a under the One-
Pot Condition
OH
OH
MeO
MeO
Me
MeO
MeO
Me
OH
OH
syn-(±)-7a
anti-(±)-7a
Ph
8a (1.5 eq.)
8a (1.5 eq.)
then
then
In(OTf) (2 eq.)
In(OTf) (2 eq.)
3
3
MeO
Me
(
88%)
(85%)
(dr = 95:5)
(
dr = 95:5)
OH
syn-(±)-10a
MeO
1
2
Csákÿ and co-workers proposed the 1,4-transfer of the carbon ligand (R) from boron to the
benzylic carbon center via a borderline S i-type mechanism when a cyclic boronic ester was
N
treated with trifluoroacetic anhydride (TFAA) as the promoter, which would lead to the
coupling product with retention of the original configuration at the benzylic carbon center.
However, based on the results from our stereoconvergent reactions, we demonstrated a reaction
mechanism that involves an S 1-type process (Scheme 8). The favorable stereochemical
N
outcome observed in this transformation can be rationalized on the basis that the most stable
“
Ar-H eclipsed” geometry predominates over the “Ar-Me or Ar-CO Et eclipsed” geometry, in
2
which the aryl substituent eclipses the hydrogen in the transition state to minimize the allylic
3
1
,3-strain in the resonance-stabilized benzylic carbenium ion. Then, the intramolecular 1,4-
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1
1
1
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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
2
transfer of the sp -hybridized carbon ligand from boron to the same face of the resonance-
stabilized planar benzylic carbenium ion and subsequent basic hydrolysis would generate syn-
alcohol as the major diastereomer.
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
Scheme 8. Proposed Reaction Mechanisma
C-C Bond
Rotation
R
B
X MO
X
X MO
X
R
B
2
2
MX3
MX3
B
B
O
O
R
H
O
R
O
O
O
H
Y
Y
Ar
Y
Ar
Y
Ar
H
Ar
H
H
H
H
H
trans-Cyclic
Boronic Ester
"Ar-H Eclipsed"
"Ar-Y Eclipsed"
cis-Cyclic
(favored)
(disfavored)
Boronic Ester
ligand (R) transfer,
then Hydrolysis
ligand (R) transfer,
then Hydrolysis
R
R
Y
Y
Ar
Ar
OH
OH
syn-alcohol
anti-Alcohol
(Major Product)
(Minor Product)
aM =metal, X = ligand (OTf, Br, F), R = aryl, heteroaryl, or polyaryl, Y = Me or CO
Et
2
A Short and Efficient Enantioselective Synthesis of Cherylline Dimethyl Ether
(–)-16. We next turned our attention to a short and efficient enantioselective synthesis of
cherylline dimethyl ether (–)-16 to prove the synthetic utility of this method (Scheme 9).
1
8
Sequential treatment of chiral diol syn-(+)-7b with 4-methoxyphenyl boronic acid 8h in DCM
for 1 hour and BF •OEt for 1.5 hours at room temperature afforded syn-(+)-10s in 85% yield,
3
2
19
exhibiting excellent diastereoselectivity (dr = 92:8). Reduction of α-hydroxy ester syn-(+)-
1
0s with an excess amount of NaBH afforded the resulting diol (–)-14, which was transformed
4
into the corresponding methyl amine (–)-15 through oxidative cleavage, followed by
subsequent reductive amination20 in 56% yield over 2 steps. Finally, Pictet-Spengler
2
1
cyclization according to Soundararajan and co-workers generated cherylline dimethyl ether
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(
–)-16. The spectral characteristics and optical rotation of our synthetic material (–)-16 were
in good agreement with those reported for cherylline dimethyl ether synthesized by an
2
3
alternative route: [α] = –12.44 (c = 0.50, MeOH) [synthetic: lit. [α] = –21.65 (c = 0.965,
D
D
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
MeOH)].
Scheme 9. A Short and Efficient Enantioselective Synthesis of Cherylline Dimethyl Ether (–)-
1
6
OMe
4
-MeOPhB(OH) 8h,
2
OH
CH Cl , rt, 1 h
2
2
MeO
MeO
CO Et
2
then,
OH
MeO
MeO
CO Et
2
BF •OEt , rt, 1.5 h
3
2
syn-(+)-7b
]25 = +4.17
OH
syn-(+)-10s
(85%)
[
(dr = 92:8)
D
(
lit. []25 = +3.53)
D
1) NaIO ,acetone/H O
4
2
NaBH4,
MeOH,
rt, 3.5 h
OMe
(2:1), rt, 1 h
OMe
2) MeNH Cl, NaCNBH ,
3
3
MeOH, rt
OH
(100%)
(56%)
2 steps)
MeO
MeO
MeO
MeO
(
OH
NHMe
(
-)-14
(-)-15
OMe
HCHO, CH CO H,
3
2
reflux, 2 h
(94%)
MeO
MeO
NMe
Cherylline Dimethyl Ether (-)-16
CONCLUSIONS
3
2
In conclusion, we have developed a highly regio- and diastereoselective C(sp )-C(sp ) cross-
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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6
coupling reaction of unprotected aryl-substituted 1,2-diols with styryl, aryl, heteroaryl, and
polyaryl boronic acids as nucleophiles in a one-pot procedure under mild reaction conditions.
The Lewis acid-promoted regioselective cleavage of an aryl-substituted cyclic boronic ester,
followed by the stereoselective intramolecular 1,4-transfer of the carbon ligand from boron to
the same face of the resulting resonance-stabilized planar benzylic carbenium ion resulted in
the highly diastereoselective carbon-carbon bond formation at the benzylic carbon center. The
synthetic utility of the method was illustrated by a short asymmetric synthesis of cherylline
dimethyl ether (–)-16 in 5 steps from known chiral diol.
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
EXPERIMENTAL SECTION
General Information
Except as otherwise indicated, reactions were carried out under a nitrogen (N ) atmosphere in
2
flame- or oven-dried glassware. In aqueous work-up, all organic solutions were dried over
sodium sulfate or magnesium sulfate, and filtered prior to rotary evaporation at water aspirator
pressure. Reactions were monitored by thin layer chromatography (TLC) with 0.25-mm E.
Merck pre-coated silica gel plates (Kieselgel 60F , Merck). Spots were detected by viewing
2
54
under a UV light, colorizing with charring after dipping in p-anisaldehyde solution with acetic
acid and sulfuric acid and MeOH or ceric ammonium molybdate solution with sulfuric acid
and ethanol. Silica gel for flash chromatography (particle size 0.040-0.063 mm) was supplied
by E. Merck. Yields refer to chromatographically and spectroscopically pure compounds unless
otherwise noted. Commercial reagents and solvents were used as received with the following
exceptions. All solvents were freshly purified and dried by standard techniques just before use.
Tetrahydrofuran (THF) was distilled from sodium/benzophenone. Dichloromethane (DCM)
and acetonitrile (MeCN) were distilled from calcium hydride (CaH ). Methanol (MeOH) was
2
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distilled from magnesium sulfate (MgSO ). H and C spectra were recorded on a 400 MHz
4
or 600 MHz spectrometer. Chemical shifts are reported as  value relative to internal
1
13
chloroform ( 7.26 for H and  77.0 for C). Data are represented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),
integration, coupling constant in Hz, and assignment. Infrared (IR) spectra were measured on
a FT-IR spectrometer referenced to a polystyrene standard. Data are represented as follows:
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
frequency of the absorption (cm ), intensity of absorption (s = strong, m = medium, w = weak,
br = broad), and assignment (where appropriate). High resolution mass spectra (HRMS) were
recorded with FAB (fast atom bombardment) or EI (electron impact) method. High resolution
values are calculated to four decimal places from the molecular formula, all found values being
within a tolerance of 5 ppm.
General Procedure for the Synthesis of (E)-Styrenes
To a stirred solution of phenol (1.0 equiv.) in DCM (10.0 mL/mmol) was added imidazole (3.0
o
equiv.), DMAP (0.1 equiv.), and TBDPSCl (1.2 equiv.) at 0 C. The reaction mixture was
stirred at room temperature for 2 hours under N atmosphere and then poured onto water (10.0
2
mL/mmol) and the layers were separated. The aqueous layer was extracted with DCM (2×10.0
mL/mmol), and the combined organic layer was washed with brine (5.0 mL/mmol), dried over
Na SO , filtered, and concentrated in vacuo. Purification of the crude residue by flash
2
4
chromatography on silica gel, using the appropriate mixture of eluents, provided the
corresponding (E)-styrenes.
(
E)-tert-Butyl-(2-methoxy-4-(prop-1-en-1-yl)phenoxy)diphenylsilane [(E)-SI-1c]. From
isoeugenol (206.0 mg, 1.26 mmol), imidazole (236.0 mg, 3.77 mmol), DMAP (15.0 mg, 0.126
mmol), and TBDPSCl (0.40 ml, 1.51 mmol) in DCM, following the general procedure, (E)-SI-
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2
2
2
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5
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5
6
1
c was obtained. Chromatographic purification (hexanes/EtOAc 100:1 to 70:1) provided (E)-
1
SI-1c (458.7 mg, 90.8%) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.69-7.71 (m, 4H),
3
7.31-7.41 (m, 6H), 6.76 (s, 1H), 6.60 (s, 2H), 6.25 (dd, J = 15.6, 1.6 Hz, 1H), 6.02 (dq, J =
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
13
1
1
5.6, 6.4 Hz, 1H), 3.57 (s, 3H), 1.82 (dd, J = 6.4, 1.6 Hz, 3H), 1.10 (s, 9H); C{ H} NMR (100
MHz, CDCl ): δ 150.3, 144.1, 135.3, 133.6, 131.6, 130.7, 129.6, 127.5, 123.5, 120.1, 118.5,
3
-1
109.6, 55.4, 26.9, 20.0, 18.6; IR (Film) 2931, 1577, 1509, 1427, 1278, 1112, 1037 (cm );
+
HRMS (FAB-magnetic sector) m/z: [M + H] Calcd for C H O Si 403.2093; Found 403.2087.
2
6
31
2
(E)-Ethyl 3-(4-((tert-Butyldiphenylsilyl)oxy)-3-methoxyphenyl)acrylate [(E)-SI-1d].
From ethyl 4-hydroxy-3-methoxycinnamate (267.0 mg, 1.20 mmol), imidazole (245.1 mg, 3.60
mmol), DMAP (14.7 mg, 0.12 mmol), and TBDPSCl (0.37 ml, 1.44 mmol) in DCM, following
the general procedure, (E)-SI-1d was obtained. Chromatographic purification (hexanes/EtOAc
1
20:1) provided (E)-SI-1d (553.4 mg, 100%) as a colorless oil. H NMR (400 MHz, CDCl ) δ
3
7
.68-7.70 (m, 4H), 7.54 (d, J = 16.0 Hz ,1H), 7.32-7.43 (m, 6H), 6.93 (d, J = 1.6 Hz, 1H), 6.84
(dd, J = 8.0, 1.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 16.0 Hz, 1H), 4.24 (q, J = 7.2
1
3
1
Hz, 2H), 3.59 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.12 (s, 9H); C{ H} NMR (100 MHz, CDCl ):
3
δ 167.1, 150.7, 147.3, 144.6, 135.3, 133.1, 129.7, 128.1, 127.6, 122.0, 120.3, 115.9, 111.0,
-1
6
0.5, 55.5, 26.8, 20.1, 14.6; IR (Film) 2931, 1705, 1595, 1509, 1428, 1262, 1155, 1035 (cm );
+
HRMS (FAB-magnetic sector) m/z: [M + H] Calcd for C H O Si 461.2148; Found 461.2152.
28 33
4
General Procedure for the Synthesis of Aryl-Substituted 1,2-syn-Diols
To a stirred solution of (E)-styrene or (E)-ethyl cinnamate (1.0 equiv.) in acetone/H O (2:1,
2
v/v, 10.0 mL) at room temperature was added 4-methylmorpholine N-oxide (1.2 equiv.) and
OsO (0.02 M in H O, 0.025 equiv.). The reaction mixture was stirred at room temperature for
4
2
1
2 hours under N atmosphere, then quenched by the addition of saturated Na S O solution
2 2 2 3
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(
10 mL) and diluted with EtOAc (10 mL) and the layers were separated. The aqueous layer
was extracted with EtOAc (2 × 30 mL), and the combined organic layer was washed with brine
(5 mL), dried over Na SO , filtered, and concentrated in vacuo. Purification of the crude
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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3
3
3
3
3
3
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4
4
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5
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5
5
5
5
5
6
0
1
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8
9
0
1
2
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8
9
0
residue by flash chromatography on silica gel, using the appropriate mixture of eluents,
provided the corresponding 1,2-diols.
(±)-(2S,3R)-Ethyl 3-(3,4-Dimethoxyphenyl)-2,3-dihydroxypropanoate [syn-(±)-7b].
2
4
From (E)-Ethyl 3-(3,4-Dimethoxyphenyl)acrylate (316.0 mg, 1.338 mmol), OsO (0.02 M,
4
1
.67 mL, 0.033 mmol), 4-methylmorpholine N-oxide (203.7 mg, 1.739 mmol) in acetone/H O,
2
following the general procedure, syn-(±)-7b was obtained. Chromatographic purification
1
(hexanes/EtOAc 1:1 to 1:2) provided syn-(±)-7b (317.0 mg, 1.173 mmol) as a colorless oil. H
NMR (400 MHz, CDCl ) δ 6.97 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 6.85 (d, J
3
= 8.0 Hz, 1H), 4.94 (d, J = 2.8 Hz, 1H), 4.33 (d, J = 2.8 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.89
13
1
(s, 3H), 3.87 (s, 3H), 3.14 (brs, 1H), 2.74 (brs, 1H), 1.28 (t, J = 7.2 Hz, 3H); C{ H} NMR
(100 MHz, CDCl ) δ 172.3, 148.4, 148.2, 132.3, 118.4, 110.5, 109.4, 75.1, 74.3, 61.6, 55.7,
3
-1
55.6, 13.9; IR (Film) 3472, 2938, 1732, 1594, 1515, 1464, 1258, 1139, 1023 (cm ); HRMS
+
(FAB-magnetic sector) m/z: [M] Calcd for C H O 270.1103; Found 270.1106.
1
3
18
6
(±)-(1R,2R)-1-(4-((tert-Butyldiphenylsilyl)oxy)-3-methoxyphenyl)propane-1,2-diol
[
syn-(±)-7c]. From (E)-SI-1c (243.0 mg, 0.604 mmol), OsO (0.02 M, 0.75mL, 0.015 mmol),
4
4
-methylmorpholine N-oxide (91.9 mg, 0.785 mmol) in acetone/H O, following the general
2
procedure, syn-(±)-7c was obtained. Chromatographic purification (hexanes/EtOAc 4:1 to 2:1)
1
provided syn-(±)-7c (263.5 mg, 0.604 mmol) as a colorless oil. H NMR (400 MHz, CDCl ) δ
3
7
.67-7.69 (m, 4H), 7.29-7.40 (m, 6H), 6.73 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.58
(dd, J = 8.0, 2.4 Hz, 1H), 4.20 (d, J = 7.2 Hz, 1H), 3.75 (dq, J = 7.2, 6.4 Hz, 1H), 3.55 (s, 3H),
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3
3
3
3
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6
1
3
1
2
.55 (brs, 1H), 2.47 (brs, 1H), 1.11 (s, 9H), 0.97 (d, J = 6.4 Hz, 3H); C{ H} NMR (100 MHz,
CDCl ) δ 150.6, 144.9, 135.4, 134.2, 133.4, 129.6, 127.5, 120.1, 119.1, 110.6, 80.0, 72.4, 55.5,
3
-1
26.9, 20.0, 18.9; IR (Film) 3378, 2931, 1589, 1513, 1428, 1266, 1139, 1113 (cm ); HRMS
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
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
FAB-magnetic sector) m/z: [M] Calcd for C H O Si 436.2070; Found 436.2067.
2
6
32
4
(±)-(2S,3R)-Ethyl
3-(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)-2,3-
dihydroxypropanoate [syn-(±)-7d]. From (E)-SI-1d (724.0 mg, 1.572 mmol), OsO (0.02
4
M, 1.96 mL, 0.040 mmol), 4-methylmorpholine N-oxide (239.4 mg, 2.043 mmol) in
acetone/H O, following the general procedure, syn-(±)-7d was obtained. Chromatographic
2
purification (hexanes/EtOAc 1:1 to 1:2) provided syn-(±)-7d (476.2 mg, 0.963 mmol) as a
1
colorless oil. H NMR (400 MHz, CDCl ) δ 7.68-7.70 (m, 4H), 7.31-7.41 (m, 6H), 6.85 (s,
3
1
H), 6.63-6.67 (m, 2H), 4.83 (dd, J = 6.0, 3.2 Hz, 1H), 4.27 (dd, J = 5.6, 3.6 Hz, 1H), 4.21 (q,
J = 7.2 Hz, 2H), 3.58 (s, 3H), 3.02 (d, J = 6.0 Hz, 1H), 2.61 (d, J = 6.8 Hz, 1H), 1.23 (t, J = 7.2
13
1
Hz, 3H), 1.10 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ 172.6, 150.3, 144.7, 135.2, 133.4,
3
1
33.0, 129.5, 127.5, 119.7, 118.5, 110.6, 75.0, 74.6, 62.1, 55.5, 26.8, 20.0, 14.3; IR (Film) 3456,
-1
2932, 1732, 1589, 1514, 1428, 1265, 1155, 1106 (cm ); HRMS (FAB-magnetic sector) m/z:
+
[M] Calcd for C H O Si 494.2125; Found 494.2128.
2
8
34
6
Procedure for the Synthesis of Cyclic Boronic Ester
±)-(4R,5R)-4-(3,4-Dimethoxyphenyl)-5-methyl-2-((E)-styryl)-1,3,2-dioxaborolane
(
1
5
[
trans-(±)-9a]. To a stirred solution of syn-(±)-7a (713.0 mg, 3.359 mmol) in anhydrous
DCM (22.4 mL) at room temperature was added trans-2-phenylvinylboronic acid 8a (994.2
mg, 6.719 mmol). The reaction mixture was stirred for 1 hour under N atmosphere and
2
concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, using
(
hexanes/EtOAc 2:1 to 1:1) as elutant, provided trans-(±)-9a (1.089 g, 3.359 mmol) as a
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colorless oil. H NMR (400 MHz, CDCl ) δ 7.49-7.53 (m, 3H), 7.29-7.38 (m, 3H), 6.85-6.91
3
(
m, 3H), 6.26 (d, J = 18.0 Hz, 1H), 4.87 (d, J = 7.6 Hz, 1H), 4.37 (dq, J = 7.6, 6.4 Hz, 1H),
1
3
1
3.90 (s, 3H), 3.88 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 150.1,
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
2
49.0, 148.8, 137.0, 132.5, 128.8, 128.4, 126.9, 118.2, 115.2, 110.9, 108.5, 85.6, 80.9, 55.8,
-1
0.8; IR (Film) 2930, 1623, 1577, 1516, 1450, 1348, 1233, 1139 (cm ); HRMS (FAB-magnetic
+
sector) m/z: [M] Calcd for C H BO 324.1533; Found 324.1535.
1
9
21
4
General Procedure for the Synthesis of syn-Alcohol (±)-10 from Aryl-Substituted
syn-1,2-Diol (±)-7 with Aryl-, Heteroaryl, Polyaryl Boronic Acids Promoted by a
Lewis acid (One-Pot Protocol).
To a stirred solution of syn-(±)-1,2-diol (1.0 equiv.) in anhydrous DCM (1.0 mL/mmol) at room
temperature was added the corresponding boronic acid (1.5 equiv.). The reaction mixture was
stirred for 1 hour under N atmosphere, and the appropriate Lewis acid (2.0 equiv.) was added
2
o
to the resulting mixture at 0 C. The reaction mixture was stirred at room temperature for 1.5
hours under N atmosphere, then quenched by the addition of saturated NaHCO solution (1.0
2
3
mL/mmol) and diluted with DCM (1.0 mL/mmol) and the layers were separated. The aqueous
layer was extracted with DCM (2 × 10 mL), and the combined organic layer was washed with
brine (5 mL), dried over Na SO , filtered, and concentrated in vacuo. Purification of the crude
2
4
residue by flash chromatography on silica gel, using the appropriate mixture of eluents,
provided the corresponding syn-alcohol.
(
±)-(2R,3R,E)-3-(3,4-Dimethoxyphenyl)-5-phenylpent-4-en-2-ol [syn-(±)-10a]. From
1
5
syn-(±)-7a (68.5 mg, 0.323 mmol, (E)-styrylboronic acid 8a (71.6 mg, 0.484 mmol) and
In(OTf) (362.8 mg, 0.646 mmol) in DCM, following the general procedure, syn-(±)-10a was
3
obtained. Chromatographic purification (hexanes/EtOAc 10:1 to 2:1) provided syn-(±)-10a
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2
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5
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5
5
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6
1
5
(
84.7 mg, 0.316 mmol, dr = 95:5) as a colorless oil. From anti-(±)-7a (93.6 mg, 0.441 mmol),
(
E)-styrylboronic acid 8a (97.9 mg, 0.661 mmol) and In(OTf) (495.3 mg, 0.882 mmol) in
3
DCM, following the general procedure, syn-(±)-10a was obtained. Chromatographic
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
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7
8
9
0
1
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
purification (hexanes/EtOAc 10:1 to 2:1) provided syn-(±)-10a (111.8 mg, 0.375 mmol, dr =
1
9
5:5) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.37-7.38 (m, 2H), 7.28-7.32 (m, 2H),
3
7.22-7.24 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.77 (d, J = 1.6
Hz, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.46 (dd, J = 15.6, 8.4 Hz, 1H), 4.01-4.08 (m, 1H), 3.89 (s,
3
3
1
1
2
H), 3.87 (s, 3H), 3.29 (dd, J = 8.4, 7.2 Hz, 1H), 1.86 (d, J = 2.8 Hz, 1H), 1.14 (d, J = 6.4 Hz,
1
3
1
H); C{ H} NMR (100 MHz, CDCl ) δ 148.9, 147.6, 136.8, 134.2, 132.6, 129.7, 128.4, 127.3,
3
26.2, 119.8, 111.4, 111.3, 70.8, 57.6, 56.0, 55.9, 21.0; IR (Film) 3440, 2931, 1709, 1590, 1513,
-1
+
449, 1259, 1141, 1025 (cm ); HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O
3
1
9
22
98.1569; Found 298.1570.
(
±)-(2S,3R,E)-Ethyl 3-(3,4-Dimethoxyphenyl)-2-hydroxy-5-phenylpent-4-enoate [syn-
1
8
(
±)-10b]. From a solution of syn-(±)-7b (78.0 mg, 0.289 mmol) in DCM, (E)-styrylboronic
acid 8a (64.0 mg, 0.433 mmol) and In(OTf) (324.4 mg, 0.577 mmol), following the general
3
procedure, benzylic substituted alcohol syn-(±)-10b was obtained. Chromatographic
purification (hexanes/EtOAc 6:1 to 3:1) provided syn-(±)-10b (68.4 mg, 0.192 mmol, dr = 95:5)
1
as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.34-7.36 (m, 2H), 7.20-7.31 (m, 3H), 6.93-
3
6
1
1
.96 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 6.52 (dd, J = 16.0, 7.2 Hz, 1H), 6.46 (d, J = 16.0 Hz,
H), 4.53 (dd, J = 5.6, 3.2 Hz, 1H), 4.16-4.30 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.87-3.89 (m,
1
3
1
H), 2.94 (d, J = 5.6 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ
3
173.4, 148.8, 148.0, 136.9, 133.0, 132.9, 128.5, 127.5, 126.8, 126.4, 120.3, 111.2, 111.1, 74.6,
2.1, 56.1, 52.4, 14.6; IR (Film) 3479, 2936, 1727, 1590, 1513, 1464, 1261, 1142 (cm-1);
6
+
HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O 356.1624; Found 356.1624.
2
1
24
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(
±)-(2R,3R,E)-3-(4-((tert-Butyldiphenylsilyl)oxy)-3-methoxyphenyl)-5-phenylpent-4-
en-2-ol [syn-(±)-10c]. From a solution of syn-(±)-7c (132.0 mg, 0.302 mmol) in DCM, (E)-
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
styrylboronic acid 8a (67.1 mg, 0.454 mmol) and In(OTf) (339.8 mg, 0.605 mmol), following
3
the general procedure, syn-(±)-10c was obtained. Chromatographic purification
(hexanes/EtOAc 15:1 to 6:1) provided syn-(±)-10c (103.4 mg, 0.198 mmol) as a colorless oil.
1
H NMR (400 MHz, CDCl ) δ 7.68-7.70 (m, 4H), 7.19-7.40 (m, 11H), 6.66 (d, J = 8.0 Hz, 1H),
3
6
3
6
1
2
.61 (d, J = 2.0 Hz, 1H), 6.48-6.54 (m, 2H), 6.40 (dd, J = 15.6, 8.8 Hz, 1H), 3.91-3.95 (m, 1H),
.56 (s, 3H), 3.18 (dd, J = 8.8, 7.6 Hz, 1H), 1.82 (d, J = 2.8 Hz, 1H), 1.11 (s, 9H), 1.05 (d, J =
1
3
1
.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 150.7, 144.0, 137.1, 135.6, 135.0, 133.7,
3
32.9, 130.0, 129.8, 128.7, 127.69, 127.65, 126.5, 120.5, 120.0, 112.4, 71.1, 58.1, 55.8, 27.1,
-1
1.1, 20.2; IR (Film) 3439, 2936, 1588, 1512, 1463, 1266, 1113 (cm ); HRMS (FAB-magnetic
+
sector) m/z: [M] Calcd for C H O Si 522.2590; Found 522.2598.
3
4
38
3
(±)-(2S,3R,E)-Ethyl 3-(4-((tert-Butyldiphenylsilyl)oxy)-3-methoxyphenyl)-2-hydroxy-5-
phenylpent-4-enoate [syn-(±)-10d]. From a solution of syn-(±)-7d (159.0 mg, 0.321 mmol)
in DCM, (E)-styrylboronic acid 8a (71.3 mg, 0.482 mmol) and In(OTf) (227.9 mg, 0.643
3
mmol), following the general procedure, syn-(±)-10d was obtained. Chromatographic
purification (hexanes/EtOAc 10:1 to 5:1) provided syn-(±)- 10d (145.6 mg, 0.251 mmol, dr =
1
9
6
5:5) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.68-7.71 (m, 4H), 7.18-7.40 (m, 11H),
3
.80 (s, 1H), 6.64-6.65 (m, 2H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 4.45
(dd, J =6.0, 4.0 Hz, 1H), 4.13-4.21 (m, 2H), 3.79 (dd, J = 8.0, 4.0 Hz, 1H), 3.58 (s, 3H), 2.83
1
3
1
(d, J = 6.0 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.10 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ
3
1
1
73.4, 150.3, 144.1, 137.0, 135.3, 133.62, 133.60, 133.3, 132.8, 129.6, 128.5, 127.5, 127.1,
26.4, 120.3, 120.0, 112.7, 74.6, 61.9, 55.7, 52.5, 26.9, 20.0, 14.6; IR (Film) 3478, 2931, 1730,
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9
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2
2
2
2
2
2
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2
2
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3
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5
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5
5
5
5
5
5
5
6
-
1
+
1
587, 1513, 1464, 1278, 1251 (cm ); HRMS (FAB-magnetic sector) m/z: [M + H] Calcd for
C H O Si 581.2723; Found 581.2721.
36 41
5
0
1
2
3
4
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6
7
8
9
0
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0
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9
0
(
±)-(2R,3R,E)-3-(4-Methoxyphenyl)-5-phenylpent-4-en-2-ol [syn-(±)-10e]. From a
2
5
solution of syn-(±)-7e (41.0 mg, 0.225 mmol) in DCM, (E)-styrylboronic acid 8a (49.9 mg,
0.338 mmol) and InBr (159.5 mg, 0.450 mmol), following the general procedure, syn-(±)-10e
3
was obtained. Chromatographic purification (hexanes/EtOAc 10:1 to 8:1) provided syn-(±)-
1
1
0e (40.0 mg, 0.149 mmol, dr = 95:5) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.37-
3
7
.39 (m, 2H), 7.27-7.31 (m, 2H), 7.19-7.23 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4
Hz, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.4 Hz, 1H), 3.99-4.07 (m, 1H), 3.80 (s,
1
3
1
3
H), 3.30 (dd, J = 8.4, 7.6 Hz, 1H), 1.87 (d, J = 2.8 Hz, 1H), 1.12 (d, J = 6.0 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 158.3, 136.9, 133.7, 132.8, 129.9, 128.9, 128.5, 127.5, 126.3, 114.2,
3
-1
70.9, 57.4, 55.4, 21.0; IR (Film) 3440, 2929, 1609, 1582, 1509, 1449, 1244, 1177 (cm );
+
HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O 268.1463; Found 268.1461.
1
8
20
2
(±)-(2S,3R,E)-Ethyl 2-Hydroxy-3-(4-methoxyphenyl)-5-phenylpent-4-enoate [syn-(±)-
26
1
0f]. From a solution of syn-(±)-7f (82.0 mg, 0.341 mmol) in DCM, (E)-styrylboronic acid
8
a (75.7 mg, 0.512 mmol) and InBr (242.0 mg, 0.683 mmol), following the general procedure,
3
syn-(±)-10f was obtained. Chromatographic purification (hexanes/EtOAc 10:1 to 8:1) provided
1
syn-(±)-10f (66.5 mg, 0.204 mmol, dr = 95:5) as a colorless oil. H NMR (400 MHz, CDCl ) δ
3
7
6
.26-7.35 (m, 6H), 7.19-7.23 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.52 (dd, J = 15.6, 8.0 Hz, 1H),
.45 (d, J = 15.6 Hz, 1H), 4.51 (dd, J = 5.6, 3.6 Hz, 1H), 4.15-4.29 (m, 2H), 3.90 (dd, J = 8.0,
1
3
1
4.0 Hz, 1H), 3.80 (s, 3H), 2.93 (d, J = 5.6 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H); C{ H} NMR
100 MHz, CDCl ) δ 173.5, 158.5, 136.9, 132.9, 132.4, 129.3, 128.5, 127.5, 127.0, 126.4, 114.0,
(
3
7
4.6, 62.0, 55.4, 52.1, 14.6; IR (Film) 3478, 2982, 1726, 1610, 1583, 1511, 1447, 1245, 1177
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8
9
-
1
+
(
cm ); HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O 326.1518; Found 326.1521.
2
0
22
4
(±)-(2R,3R,E)-5-Phenyl-3-(2,4,5-trimethoxyphenyl)pent-4-en-2-ol [syn-(±)-10g]. From
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
4
4
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4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
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4
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8
9
0
1
2
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7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
27
a solution of syn-(±)-7g (70.4 mg, 0.291 mmol) in DCM, (E)-styrylboronic acid 8a (64.5 mg,
0
.436 mmol) and In(OTf) (326.6 mg, 0.581 mmol), following the general procedure, syn-(±)-
3
10g was obtained. Chromatographic purification (hexanes/EtOAc 10:1 to 1:1) provided syn-
1
(
±)-10g (84.1 mg, 0.256 mmol, dr = 95:5) as a colorless oil. H NMR (400 MHz, CDCl ) δ
3
7
.37-7.39 (m, 2H), 7.27-7.31 (m, 2H), 7.19-7.22 (m, 1H), 6.76 (s, 1H), 6.54-6.56 (m, 3H), 4.12
(
(
m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.72 (m, 1H), 2.05 (d, J = 3.2 Hz, 1H), 1.13
1
3
1
d, J = 6.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 151.0, 148.1, 143.0, 137.1, 132.7,
3
1
2
29.3, 128.4, 127.3, 126.2, 121.6, 113.1, 98.1, 70.0, 56.9, 56.7, 56.2, 51.5, 20.9; IR (Film) 3439,
-1
+
931, 1598, 1507, 1451, 1201, 1177 (cm ); HRMS (EI-magnetic sector) m/z: [M] Calcd for
C H O 328.1675; Found 328.1674.
2
0
24
4
(
±)-(2R,3R,E)-3-(3,4-Dimethoxyphenyl)-5-(4-(trifluoromethyl)phenyl)pent-4-en-2-ol
1
5
[syn-(±)-10h]. From a solution of syn-(±)-7a (65.1 mg, 0.307 mmol) in DCM, trans-2-[4-
trifluoromethyl)phenyl]vinylboronic acid 8b (104.6 mg, 0.460 mmol) and InBr (217.5 mg,
(
3
0
.613 mmol), following the general procedure, syn-(±)-10h was obtained. Chromatographic
purification (hexanes/EtOAc 10:1 to 5:1) provided syn-(±)- 10h (97.0 mg, 0.265 mmol, dr =
1
9
5:5) as a white soild. mp 111 °C; H NMR (400 MHz, CDCl ) δ 7.55 (d, J = 8.4 Hz, 2H), 7.47
3
(
d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 6.76 (d, J = 2.0
Hz, 1H), 6.62 (dd, J = 16.0, 8.0 Hz, 1H), 6.55 (d, J = 16.0 Hz, 1H), 4.04-4.12 (m, 1H), 3.90 (s,
3H), 3.87 (s, 3H), 3.33 (dd, J = 8.0, 7.2 Hz, 1H), 1.76 (d, J = 4.0 Hz, 1H), 1.16 (d, J = 6.4 Hz,
13
1
3
1
H); C{ H} NMR (100 MHz, CDCl ) δ 149.1, 147.9, 140.4 (d, J = 1.5 Hz), 133.8, 132.6,
3 C-F
31.4, 129.2 (q, JC-F = 31.9 Hz) 126.4, 125.5 (q, JC-F = 3.8 Hz), 119.9, 111.4, 111.2, 70.9, 57.6,
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6
-
1
5
6.1, 56.0, 21.3; IR (Film) 3477, 2963, 1614, 1591, 1514, 1464, 1321, 1259 (cm ); HRMS (EI-
+
magnetic sector) m/z: [M] Calcd for C H F O 366.1443; Found 366.1443.
20 21
3
3
0
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0
(
±)-(2R,3R,E)-3-(3,4-Dimethoxyphenyl)-5-(4-fluorophenyl)pent-4-en-2-ol [syn-(±)-10i].
From a solution of syn-(±)-7a15 (66.4 mg, 0.313 mmol) in DCM, trans-2-[4-
fluorophenyl]vinylboronic acid 8c (82.0 mg, 0.469 mmol) and InBr (221.8 mg, 0.626 mmol),
3
following the general procedure, syn-(±)-10i was obtained. Chromatographic purification
(
hexanes/EtOAc 8:1 to 4:1) provided syn-(±)-10i (77.8 mg, 0.246 mmol, dr = 95:5) as a
1
colorless oil. H NMR (400 MHz, CDCl ) δ 7.34 (dd, J = 8.8, 5.6 Hz, 2H), 6.99 (t, J = 8.8 Hz,
3
2
H), 6.84 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.50 (d,
J = 16.4 Hz, 1H), 6.38 (dd, J = 16.4, 8.8 Hz, 1H), 4.02-4.06 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
1
3
1
3
.27 (dd, J = 8.8, 7.6 Hz, 1H), 1.82 (d, J = 3.2 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H); C{ H} NMR
(100 MHz, CDCl ) δ 162.1 (d, J = 244.3 Hz), 149.0, 147.8, 134.2, 133.1 (d, JC-F = 3.8 Hz),
3
C-F
1
31.6, 129.4 (d, JC-F = 2.3 Hz), 127.8 (d, JC-F = 7.6 Hz), 119.8, 115.4 (d, JC-F = 21.2 Hz), 111.4,
1
11.2, 70.9, 57.7, 56.1, 56.0, 21.1; IR (Film) 3446, 2965, 1601, 1507, 1464, 1263, 1224 (cm-
1
+
); HRMS (EI-magnetic sector) m/z: [M] Calcd for C H FO 316.1475; Found 316.1475.
1
9
21
3
(
±)-(2R,3R,E)-5-(4-Chlorophenyl)-3-(3,4-dimethoxyphenyl)pent-4-en-2-ol
[syn-(±)-
1
0j]. From a solution of syn-(±)-7a15 (63.0 mg, 0.297 mmol) in DCM, trans-2-[4-
chlorophenyl]vinylboronic acid 8d (81.2 mg, 0.445 mmol) and InBr (210.5 mg, 0.594 mmol),
3
following the general procedure, syn-(±)-10j was obtained. Chromatographic purification
(
hexanes/EtOAc 3:1) provided syn-(±)-10j (80.7 mg, 0.242 mmol, dr = 95:5) as a colorless oil.
1
H NMR (400 MHz, CDCl ) δ 7.30 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.84 (d, J
3
=
8.0 Hz, 1H), 6.79 (dd, J = 8.0, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.46-6.47 (m, 2H), 4.01-
4
.09 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.26-3.30 (m, 1H), 1.77 (d, J = 3.6 Hz, 1H), 1.14 (d, J
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8
9
1
3
1
=
6.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 149.1, 147.9, 135.5, 134.1, 133.0, 131.5,
3
1
30.5, 128.6, 127.5, 119.9, 111.5, 111.4, 70.9, 57.6, 56.09, 56.05, 21.2; IR (Film) 3469, 2964,
-1
+
1590, 1513, 1489, 1463, 1258 (cm ); HRMS (FAB-magnetic sector) m/z: [M] Calcd for
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
C H ClO 332.1179; Found 332.1172.
1
9
21
3
(±)-(2R,3R,E)-5-([1,1'-Biphenyl]-4-yl)-3-(3,4-dimethoxyphenyl)pent-4-en-2-ol [syn-(±)-
0k]. From a solution of syn-(±)-7a15 (15.2 mg, 0.0716 mmol) in DCM, trans-2-[4-
1
biphenyl]vinylboronic acid 8e (24.1 mg, 0.107 mmol) and InBr (50.8 mg, 0.143 mmol),
3
following the general procedure, syn-(±)-10k was obtained. Chromatographic purification
(
hexanes/Et O 4: 1 to 2:1) provided syn-(±)-10k (18.4 mg, 0.0491 mmol, dr = 95:5) as a white
2
1
solid. mp 95 °C; H NMR (400 MHz, CDCl ) δ 7.53-7.59 (m, 4H), 7.40-7.47 (m, 4H), 7.31-
3
7
.34 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H),
6.58 (d, J = 15.6 Hz, 1H), 6.51 (dd, J = 15.6, 8.0 Hz, 1H), 4.03-4.09 (m, 1H), 3.90 (s, 3H), 3.86
13
1
(
s, 3H), 3.31 (dd, J = 8.0, 7.6 Hz, 1H), 1.87 (brs, 1H), 1.15 (d, J = 6.4 Hz, 3H); C{ H} NMR
(
100 MHz, CDCl ) δ 149.0, 147.8, 140.6, 140.2, 135.9, 134.2, 132.4, 129.8, 128.8, 127.3, 127.2,
3
126.9, 126.7, 119.9, 111.4, 111.3, 70.9, 57.8, 56.10, 56.06, 21.1; IR (Film) 3440, 2964, 1591,
-1
+
1
3
513, 1486, 1463, 1260 (cm ); HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O
25 26 3
74.1882; Found 374.1883.
(
±)-(2R,3R,E)-3-(3,4-Dimethoxyphenyl)-5-(p-tolyl)pent-4-en-2-ol [syn-(±)-10l]. From a
solution of syn-(±)-7a15 (18.4 mg, 0.0867 mmol) in DCM, trans-2-[4-
methylphenyl]vinylboronic acid 8f (21.1 mg, 0.130 mmol) and InBr (61.5 mg, 0.173 mmol),
3
following the general procedure, syn-(±)-10l was obtained. Chromatographic purification
(
hexanes/EtOAc 2:1 to 1:1) provided syn-(±)-10l (13.5 mg, 0.0432 mmol, dr = 95:5) as a
1
colorless oil. H NMR (400 MHz, CDCl ) δ 7.28 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H),
3
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4
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5
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6
6
1
.84 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.0, 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.52 (d, J =
5.6 Hz, 1H), 6.40 (dd, J = 15.6, 8.4 Hz, 1H), 3.99-4.05 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H),
1
3
1
3.26 (dd, J = 8.4, 7.6 Hz, 1H), 2.32 (s, 3H), 1.92 (brs, 1H), 1.13 (d, J = 6.4 Hz, 3H); C{ H}
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
NMR (100 MHz, CDCl ) δ 149.0, 147.7, 137.3, 134.3, 134.1, 132.8, 129.2, 128.6, 126.2, 119.9,
3
1
11.4, 111.2, 70.9, 57.9, 56.08, 56.06, 21.4, 21.0; IR (Film) 3437, 2927, 1590, 1512, 1463,
-1
+
1418, 1261 (cm ); HRMS (EI-magnetic sector) m/z: [M] Calcd for C H O 312.1725; Found
2
0
24
3
3
12.1726.
(±)-(2R,3R,E)-3-(3,4-Dimethoxyphenyl)-5-(4-methoxyphenyl)pent-4-en-2-ol [syn-(±)-
1
0m]. From a solution of syn-(±)-7a15 (18.0 mg, 0.0848 mmol) in DCM, trans-2-[4-
methoxyphenyl]vinylboronic acid 8g (22.6 mg, 0.127 mmol) and BF ·OEt (0.013 mL, 0.103
3
2
mmol), following the general procedure, syn-(±)-10m was obtained. Chromatographic
purification (hexanes/EtOAc 3:1) provided syn-(±)- 10m (11.0 mg, 0.0335 mmol, dr = 95:5)
1
as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.32 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz,
3
2
H), 6.83 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.49 (d,
J = 15.6 Hz, 1H), 6.30 (dd, J = 15.6, 8.8 Hz, 1H), 3.98-4.07 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H),
13
1
3
.80 (s, 3H), 3.25 (dd, J = 8.8, 8.0 Hz, 1H), 1.92 (brs, 1H), 1.13 (d, J = 6.4 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 159.1, 149.0, 147.7, 134.5, 132.4, 129.7, 127.5, 127.4, 119.9, 114.0,
3
1
11.5, 111.3, 70.9, 58.0, 56.11, 56.10, 55.5, 21.0; IR (Film) 3437, 2927, 1590, 1512, 1463,
-1
+
1
418, 1261 (cm ); HRMS (EI-magnetic sector) m/z: [M + H] Calcd for C H O 328.1675;
20 24 4
Found 328.1672.
(±)-(1R,2R)-1-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)propan-2-ol [syn-(±)-10n].
15
From a solution of syn-(±)-7a (66.4 mg, 0.313 mmol) in DCM, 4-methoxyphenylboronic acid
8
h (71.3 mg, 0.469 mmol) and BF ·OEt (0.077 ml, 0.626 mmol), following the general
3 2
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The Journal of Organic Chemistry
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procedure, syn-(±)-10n was obtained. Chromatographic purification (hexanes/EtOAc 6:1 to 3:1)
1
provided syn-(±)-10n (69.0 mg, 0.228 mmol, dr = 92:8) as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.29 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.82 (dd, J = 8.0, 2.0 Hz, 1H), 6.78
3
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
2
2
3
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3
3
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4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
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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
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3
4
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7
8
9
0
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6
7
8
9
0
(d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.41-4.49 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78
1
3
1
(
s, 3H), 3.70 (d, J = 8.4 Hz, 1H), 1.62 (d, J = 3.2 Hz, 1H), 1.20 (d, J = 6.0 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 158.3, 148.7, 147.4, 135.4, 133.5, 129.5, 119.8, 114.2, 111.5, 111.2,
3
0.3, 59.2, 55.97, 55.95, 55.4, 21.6; IR (Film) 3517, 2930, 1607, 1509, 1463, 1244, 1142 (cm-1);
7
+
HRMS (EI-magnetic sector) m/z: [M] Calcd C H O 302.1518; Found 302.1519.
1
8
22
4
(±)-(R)-1,1-Bis(3,4-dimethoxyphenyl)propan-2-ol [(±)-10o]. From a solution of syn-(±)-
1
5
7
a (63.4 mg, 0.298 mmol) in DCM, 3,4-dimethoxyphenylboronic acid 8i (81.4 mg, 0.447
mmol) and BF ·OEt (0.074 ml, 0.596 mmol), following the general procedure, (±)-10o was
3
2
obtained. Chromatographic purification (hexanes/EtOAc 3:1 to 3:2) provided (±)-10o (70.6 mg,
1
0
.212 mmol) as a colorless oil. H NMR (400 MHz, CDCl ) δ 6.95 (dd, J = 8.4, 2.0 Hz, 1H),
3
6
.87 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.4, 1.6 Hz, 1H), 6.79 (d, J =
8.4 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 4.40-4.47 (m, 1H), 3.86 (s, 3H), 3.854 (s, 3H), 3.850 (s,
13
1
3
H), 3.84 (s, 3H), 3.68 (d, J = 8.4 Hz, 1H), 1.72 (brs, 1H), 1.20 (d, J = 6.0 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 149.0, 148.7, 147.8, 147.5, 135.2, 134.0, 120.1, 119.8, 112.1, 111.5,
3
1
1
3
11.4, 111.2, 70.3, 59.7, 55.98, 55.97, 21.5; IR (Film) 3516, 2931, 1589, 1509, 1463, 1415,
-1
+
240 (cm ); HRMS (FAB-magnetic sector) m/z: [M] Calcd C H O 332.1624; Found
1
9
24
5
32.1629.
(±)-(1S,2R)-1-(2,4-Dimethoxyphenyl)-1-(3,4-dimethoxyphenyl)propan-2-ol [syn-(±)-
0p]. From a solution of 1,2-diol syn-(±)-7a15 (63.0 mg, 0.297 mmol) in DCM, 2,4-
1
dimethoxyphenylboronic acid 8j (81.0 mg, 0.445 mmol) and BF ·OEt (0.073 ml, 0.594 mmol),
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