Enantioselective preparation and chemoselective cross-coupling of 1,1-diboron compounds

Article abstract of DOI:10.1038/nchem.1150

The simplicity, efficiency and generality of the transition-metal-catalysed Suzuki-Miyaura cross-coupling reaction has led to its application in the preparation of a wide variety of organic compounds. Cross-coupling of alkylboron derivatives, however, remains a major challenge, in particular with regard to stereochemical control. Here, we describe the preparation and reaction of highly optically enriched 1,1-diboron compounds. A catalytic asymmetric conjugate borylation of β 2-boronylacrylates provided geminal diboronate products that feature two distinct boronyl units, in 99% enantiomeric excess. Chemoselective cross-coupling of one-boronyl unit, a trifluoroborate salt, occurred stereospecifically via inversion of its configuration to generate enantioenriched benzylic or allylic boronates. The difficult transmetallation in the Suzuki-Miyaura catalytic reaction cycle is believed to be facilitated by a stabilization effect from the second boronyl unit, and internal coordination by the oxygen of the proximal carboxyester. We also explored subsequent functionalization of the second boronyl unit.

Full text of DOI:10.1038/nchem.1150

ARTICLES
PUBLISHED ONLINE: 25 SEPTEMBER 2011 | DOI: 10.1038/NCHEM.1150
Enantioselective preparation and chemoselective
cross-coupling of 1,1-diboron compounds
Jack Chang Hung Lee1, Robert McDonald2 and Dennis G. Hall1
*
The simplicity, efficiency and generality of the transition-metal-catalysed Suzuki–Miyaura cross-coupling reaction has led
to its application in the preparation of a wide variety of organic compounds. Cross-coupling of alkylboron derivatives,
however, remains a major challenge, in particular with regard to stereochemical control. Here, we describe the preparation
and reaction of highly optically enriched 1,1-diboron compounds. A catalytic asymmetric conjugate borylation of
b-boronylacrylates provided geminal diboronate products that feature two distinct boronyl units, in 99% enantiomeric
excess. Chemoselective cross-coupling of one-boronyl unit, a trifluoroborate salt, occurred stereospecifically via inversion
of its configuration to generate enantioenriched benzylic or allylic boronates. The difficult transmetallation in the Suzuki–
Miyaura catalytic reaction cycle is believed to be facilitated by a stabilization effect from the second boronyl unit, and
internal coordination by the oxygen of the proximal carboxyester. We also explored subsequent functionalization of the
second boronyl unit.
ross-coupling reactions have become ubiquitous in the elab- group for cross-coupling of the other one, suggesting promise for
oration of carbon–carbon bonds in synthetic organic chem- the stereospecific cross-coupling of optically pure 1,1-diboronyl
C
istry1–4. These reactions have been widely studied, developed esters. We therefore realized that the carbon atom of 1,1-diboronyl
and utilized for the generation of novel organic molecules in the esters could be made stereogenic through the use of two different
pharmaceutical, agrochemical and materials industries. Indeed, boronate adducts (Fig. 1b). To date, however, there have been no
the significance of this class of reactions was recognized in the attri- known examples of optically enriched 1,1-diboronyl esters.
bution of the 2010 Nobel Prize in Chemistry to Richard Heck, Herein, we report the first preparation of an optically pure 1,1-
Ei-ichi Negishi and Akira Suzuki for their contributions in develop- diboronyl compound, together with its use in stereoselective
ing palladium-catalysed cross-coupling reactions. Efficient catalysts cross-coupling chemistry. Beyond their fundamental importance
and conditions exist for the preparation of unsaturated compounds in the field of stereochemistry, these findings are significant from
by coupling of sp2- and sp-hybridized carbon centres. Although a practical standpoint. In addition to the potential of delivering opti-
coupling of sp3 centres using the Suzuki–Miyaura cross-coupling cally enriched diarylmethane units via sequential cross-couplings
of primary alkylboranes is also well known5, it is only recently of both boronyl units, it is also possible to plan sequential cross-
that notable advances have been reported for the coupling of coupling/allylation, cross-coupling/oxidation or cross-coupling/
organoboronates6–8
. The comparatively slow development of 1,2-addition sequences towards the construction of a variety of
cross-coupling methodology with alkylboronates is associated with synthetically valuable enantioenriched intermediates.
difficulties such as slow transmetallation9 and side reactions like
b-hydride elimination and protodeboronation. These issues add Results and discussions
more complications to the significant challenge of stereoselective Preparation of optically enriched 1,1-diboronyl compounds.
cross-coupling of alkylboron derivatives. In spite of these hurdles, Based on our recent report describing the preparation of optically
it has now become possible to conduct stereoselective cross- pure boronic esters via a copper-catalysed conjugate addition of
couplings through either a dynamic kinetic resolution of secondary organomagnesium reagents onto 1,8-diaminonaphthalenyl (dan)
alkyl halides10–13, stereospecific cross-coupling of optically pure 3-boronyl enoate 1a16, we envisioned that an asymmetric
alkyl triflate14, or a stereospecific cross-coupling of secondary conjugate borylation of 1 with B2pin2 could deliver the desired,
alkylboronates. The first stereospecific cross-coupling of optically chiral 1,1-diboronyl ester
2
with high enantioselectivity
enriched benzylic boronates was demonstrated by Crudden and (Table 1)17. By screening known reaction conditions18–20, the
co-workers6. Suginome and co-workers extended those findings to protocol developed by Yun and co-workers quickly allowed access
a-(acylamino)benzylboronic esters7. More recently, Molander and to the desired 3,3-diboronyl carboxyester 2a with good yield,
co-workers provided the first example of stereospecific cross-coupling albeit with a low enantioselectivity when (R)–(S)-Josiphos 4 was
of a non-benzylic, secondary alkylboron derivative (Fig. 1a)8.
used as the ligand (entry 2, Table 1). A more thorough evaluation
An attractive, logical evolution of this powerful approach would of various chiral diphosphine ligands was therefore conducted.
consist in achieving stereospecific coupling of optically pure 1,1- Taniaphos 5 was found to be ineffective, whereas (R)-tol-BINAP
diboronyl esters (that is, geminal alkyl diboronic esters)15. Shibata 6 afforded a much improved enantiomeric excess (e.e.) at 79%
and co-workers recently demonstrated that achiral 1,1-diboronyl (Table 1, entries 3 and 4, respectively). The enantioselectivity
esters undergo cross-coupling in a chemoselective fashion, affording could be improved to 82% using Walphos 7 (Table 1, entry 5).
only the mono-coupled product (as a racemate). These important Following
a
systematic evaluation of commercial chiral
results suggest that one boronyl unit can serve as an activating ferrocene-type ligands, we were delighted to find that the
1Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada, 2X-ray Crystallography Laboratory, Department of Chemistry,
University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. e-mail: dennis.hall@ualberta.ca
*
894
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1150
ARTICLES
a
b
Crudden
Ar1I (1 equiv.)
Pd2(dba)3 (8 mol%), PPh3 (1 equiv.)
Ag2O (1.5 equiv.)
Shibata's approach
PdAr
O
O
Ar1
HBpin
Ar
B
THF
Rh catalyst
Ar
Ar
O
O
B
B
O
R
B
(1.5 equiv.)
O
O
R
Suginome
O
Ar1Br (1.2 equiv.)
O
BX2
BY2
t-Bu
HN
Ar
t-Bu
HN
Ar
Stabilized α−B−Pd(II)
Pd(dba)2 (5 mol%), XPhos (10 mol%)
K2CO3 (3 equiv.), H2O (2 equiv.)
O
O
B
O
RO
intermediate
O
O
(5 steps)
1) B2pin2
Ar1
B
Toluene
Current approach
Suginome and Molander's approach
O
Ar
Y
Y
B
Molander
O
Ar1Cl (1 equiv.)
O
O
CuCl, Josiphos
NaOtBu
MeOH, THF
R2N
O
(10 mol%), XPhos (20 mol%)
K2CO3 (3 equiv.)
Pd(OAc)2
R2N
KF3B
R2N
R2N
Facilitated transmetallation from
intramolecular coordination
CPME/H2
O
2) KHF2 ,CH3CN
Ar1
Figure 1 | Suzuki–Miyaura cross-coupling reactions with enantioenriched secondary alkyl boronate derivatives. a, Recent advances using either benzylic
boronates or b-boronyl amide as the cross-coupling partners. Crudden and co-workers successfully cross-coupled optically enriched pinacol boronate with
retention of stereochemistry6. Suginome and Molander’s groups, on the other hand, cross-coupled optically enriched pinacol boronates and trifluoroborate
salts with an inversion of stereochemistry7,8. All of the above methods, however, are restricted to the use of substrates that are either benzylic boronates or
that have a strongly coordinating amide b to the boron atom. b, Current approach using the strong stabilization from the a-boronyl–Pd(II) intermediate
discovered by Shibata and co-workers15 and the intramolecular carbonyl coordination to further expand the concept of stereoselective cross-coupling
reactions. CPME, cyclopentylmethyl ether.
Table 1 | Optimization of reaction conditions for the preparation of chiral 3,3-diboronyl carboxyesters.
O
O
B
B
(1.1 equiv.)
O
O
O
H
O
O
N
O
B
H
RO
B
N
CuCl (3 mol%), ligand (3 mol%)
NaOt-Bu (3 mol%), MeOH (2 equiv.)
RO
B
HN
HN
THF, r.t.
2a–b
1a–b (1 equiv.)
Ligands:
CF3
F3C
Fe
Ph2P
PPh2
PPh2
O
PPh2
PCy2
PPh2
Ph2P
PPh2
Ptol2
Ptol2
CF3
Fe
Ph2P
Fe
P
Fe
NMe2
CF3
8 (R)-(R)-Walphos (CF3)
3 DPEphos
4 (R)-(S)-Josiphos
5 (S)-(S)-Taniaphos
6 (R)-tol-BINAP
7 (R)-(R)-Walphos
Entry
R
Ligand
Product
Yield (%)
e.e. (%)*
1
Me, 1a
Me, 1a
Me, 1a
Me, 1a
Me, 1a
Me, 1a
CH2(o-Br)C6H4, 1b
3
4
5
6
7
8†
8†
2a
2a
2a
2a
2a
2a
2b
90
86
88
91
74
88
81
0
213
0
279
82
99
99
2
3
4
5
6
7
Reaction conditions: RB(dan) (0.5 mmol), CuCl (15
mmol), Ligand (15 mmol), NaOt-Bu (15 mmol), B2pin2 (0.55 mmol), MeOH (1.0 mmol) in THF (1 ml) at room temperature. *Measured by chiral HPLC.
Configuration assigned by X-ray crystallographic analysis of compound 2b. †Solvias SL-W001-1.
trifluoromethyl-substituted Walphos ligand 8 provided the desired space group P1. The high quality of the diffraction data and the
enantioenriched 3,3-diboronyl carboxyester 2a with 99% e.e. presence of a bromine atom in the molecule allowed its absolute
(Table 1, entry 6). This enantioenriched 3,3-diboronyl configuration to be reliably determined using anomalous
carboxyester 2a is stable to silica column chromatography and dispersion methods, and the final value of the Flack absolute
could be recrystallized from hot methanol to give X-ray quality structure parameter21–23 was determined to be 0.016(6).
crystals, which were successfully analysed by X-ray diffraction
(Fig. 2). The absolute stereochemistry of 3,3-diboronyl Chemoselective cross-coupling of optically enriched 1,1-
carboxyester 2a, when using (R)–(R)-CF3-Walphos 8, was diboronyl compounds. The X-ray crystallographic structure of 2a
assigned the (R) configuration based on X-ray crystallography of revealed that the carbonyl oxygen of the methyl ester is much
brominated derivative 2b. Compound 2b crystallized in the chiral closer to the boron atom of the pinacolate unit (distance of
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1150
ARTICLES
desired cross-coupled product as a racemate, implying that the
reaction went through a transient intermediate that lost its
stereochemical integrity. Because trifluoroborate salts are known
to be potent cross-coupling partners, we prepared the
corresponding trifluoroborate salt 9 from the 3,3-diboronyl
carboxyester 2a in hand. Using conditions similar to the method
developed by Molander and co-workers8, we were pleased to
isolate product 10a stereoselectively, with preservation of
stereochemical integrity (Table 2, entry 1). The absolute
configuration of 10a was confirmed to be (R) by comparison with
the reported optical rotation of the corresponding alcohol27.
Combining this result with the (R) stereochemistry of 3,3-
diboronyl carboxyester 2a (vide supra), it can be concluded that
the observed cross-coupling product 10a underwent a complete
inversion of stereochemistry, similar to that observed in the
Suginome and Molander examples7,8. A screening of various
ligands indicated that XPhos was the most effective in promoting
the cross-coupling reactions (Table 2, entries 3–5). The
temperature and stoichiometry of the diboronyl substrate 9 also
C7
C9
C6
C10
C8
C5
O3
O4
C13
C14
C12
B1
C16
C15
N1
C11
N2
C20
O1
B2
C19
C17
C3
C18
O2
C2
C1
C4
Figure 2 | X-ray crystallographic structure of chiral 3,3-diboronyl
carboxyester 2a.
2.94 Å) than to the boron atom of the Bdan unit (distance of play very important roles in ensuring high yields, resulting in 78%
4.41 Å). These data suggest that the boron pinacolate could be the product formation when the reaction was executed in toluene at
active unit participating in the subsequent Suzuki–Miyaura cross- 80 8C with 1.5 equiv. of the 3,3-diboron reagent (Table 2, entries
coupling reaction. Moreover, the longer B–O bond lengths 6 and 7). After changing the electrophile from phenyl iodide to
(1.376 Å and 1.369 Å) compared to the standard B–O bond phenyl bromide, the reaction yield could be further improved to
lengths of tricoordinate pinacol esters (usually ꢀ1.31–1.32 Å)24 92% (Table 2, entry 8), and it was later found that only 1.2 equiv.
are indicative of a weaker p-overlap between the oxygens of the of the 3,3-diboron reagent was needed to achieve a high yield
boronic ester and the boron atom in 2a. This comparison further of the cross-coupled product (Table 2, entry 9). The main
supports the possibility for coordination between the carbonyl by-product observed in these cross-coupling reactions is the
oxygen of the methyl ester and the boron atom. In addition, the protodeboronated product, so a slight excess of the diboron
torsional angles of the boron pinacolate unit between C6–O4–B1– reagent is necessary to ensure a high yield for the coupling
O3 and C5–O3–B1–O4 are 13.758 and 4.818, respectively. These process. This remarkable result constitutes another advance in the
data suggest that the boron pinacolate is slightly distorted from Suzuki–Miyaura cross-coupling of alkyl boronates. Indeed, in
planarity, possibly because of the coordination with the carbonyl their previous communication8, Molander and co-workers
oxygen. On the other hand, the torsional angles for the Bdan mentioned that a direct cross-coupling reaction with a b-boronyl
unit, B2–N1–N2–C11 and B2–N1–N2–C19, are 4.08 and 3.78, carboxy ester was not possible, and a stronger coordinating amide
respectively, indicate that the Bdan unit is nearly trigonal planar. was necessary. Consequently, our results with 3,3-diboronyl
These observations and the reported inertness of the Bdan unit in carboxyesters demonstrate that a strong cooperative effect is at
cross-coupling reactions25,26 made us confident that the pinacol play, which facilitates the transmetallation step through both the
boronate unit could be cross-coupled selectively. We then initiated coordination of the methyl ester to the boron atom and the
model cross-coupling experiments with the 3,3-diboronyl stabilization of the a-borylated, Pd(II) intermediate (Fig. 1).
carboxyester 2a. Although we were able to obtain the desired
product in good yield, under all conditions attempted (see Scope of chemo- and stereoselective cross-coupling of 3,3-
Supplementary Information) we were only able to obtain the diboronyl carboxyester 9. Using this optimized procedure, we
Table 2 | Optimization of reaction conditions for the cross-coupling of 3,3-diboronyl carboxyester 9.
I
(1 equiv.)
O
BF3K
Pd(OAc)2 (10 mol%)
Ligand (20 mol%)
K2CO3 (3 equiv.)
H
O
N
H
O
B
HN
O
O
KHF2
N
O
B
O
B
MeCN
HN
Toluene/H2O (1:0.1), Temp.
O
B(dan)
2a
9
10a
(91%)
Entry
Equiv. (9)
Temp. (8C)
Ligand
Yield (%)
e.e. (%)*
1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
1.2
95
95
95
95
95
80
80
80
80
XPhos
XPhos
SPhos
RuPhos
Pt-Bu3
XPhos
XPhos
XPhos
XPhos
39
23†
24
13
37
53
78
92‡
89‡
99
2
3
4
5
6
7
8
9
ND
ND
ND
ND
ND
ND
99
99
Reaction conditions: RBF3K (0.11–0.15 mmol), phenyl iodide (0.1 mmol), Pd(OAc)2 (10 mmol), Ligand (20 m
mol), K2CO3 (0.3 mmol) in toluene (1 ml) and H2O (0.1 ml) at the indicated temperature. †CPME was
used as the solvent. ‡Phenyl bromide was used as the electrophile. *The e.e. of 10 was measured by chiral HPLC. The absolute configuration was assigned by comparison with the optical rotation of the
corresponding alcohol27. ND ¼ Not Determined.
896
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Table 3 | Reaction scope for the cross-coupling of 3,3-diboronyl carboxyester 9.
RBr (1.0 equiv.)
O
BF3K
O
R
Pd(OAc)2 (10 mol%)
XPhos (20 mol%)
K2CO3 (3 equiv.)
H
H
N
N
O
B
O
B
HN
HN
Toluene/H2O (1:0.1) 80 °C
9 (1.2 equiv.)
99% e.e.
10
Entry
RBr
Product Yield e.e.
Entry
RBr
Product Yield e.e.
Entry
RBr
Product Yield e.e.
(%)
(%)*
(%)
(%)*
(%)
(%)*
Br
Br
1
10b
83
99
6
10g
85
97
10†
10k
66
95
Br
EtO
OEt
Br
Br
Br
2
10c
86
99
7
10h
0
–
11†
10l
81
99
CO2Me
CO2Me
F
NC
Br
Br
Br
3
4
5
10d
10e
10f
85
88
84
99
99
98
8
9
10i
10j
79
71
97
97
12†
13†
10m
10n
51
91
TMS
Cl
Br
Br
Br
33
88
S
Ph
MeO
Br
F3C
Reaction conditions: RBF3K (0.12–0.15 mmol), phenyl bromide (0.1 mmol), Pd(OAc)2 (10
by chiral HPLC. †1.5 equiv of RBF3K was used.
mmol), XPhos (20 mmol), K2CO3 (0.3 mmol) in toluene (1 ml) and H2O (0.1 ml) at 80 8C. *The e.e. of 10 was measured
examined the scope of substrates for cross-coupling reactions with Mechanistic proposal for the cross-couplings. The mechanism of
the 3,3-diboronyl carboxyester 9. Most of the coupling reactions these stereospecific cross-coupling reactions probably follows a
with aryl electrophiles proceeded efficiently, leading to high yields pathway similar to that suggested previously by Suginome,
and almost complete enantiomeric inversion while tolerating Molander and Shibata7,8,15. Subsequent to the oxidative addition of
various functional groups (Table 3, entries 1–6). Surprisingly, a Pd(0) into the C–X bond, the resulting intermediate is surmised to
nitrile-substituted electrophile did not fare well and afforded a readily transmetallate by inversion of configuration with the borate
mixture of protodeboronated side products (Table 3, entry 7). It is to provide a s-alkyl–Pd(II)Ar intermediate through a transition
interesting to note here that when the aromatic ring system bears structure 13 (Fig. 3a). This key transmetallation step is known to be
a nitrile group such as in 10h, the Bdan unit is no longer stable notoriously difficult for alkyl boronates due to potential b–H
and protodeboronation product is observed. The reaction tolerates elimination and protodeboronation side reactions. Despite this
various ortho- or meta-substituted aryl electrophiles, demonstrating apprehension, the desired cross-coupled products were obtained in
that sterics is not a major factor in these cross-coupling reactions high yields. Thus, we believe that the second boronyl unit, Bdan,
(Table 3, entries 1 and 6). Furthermore, naphthalene derivatives stabilizes the a-B–Pd(II) intermediate (see Fig. 1b) in a manner
or heteroaromatics such as thiophene can also undergo the similar to Shibata’s work with bis-pinacolates, even though the
desired reactions to give the corresponding products 10i and 10j 1,8-diaminonaphthalene protecting group partially suppresses
in good yields (Table 3, entries 8 and 9). To our satisfaction, not the Lewis acidity of the boron atom. In addition, the facile
only aryl electrophiles, but also alkenyl electrophiles, could be transmetallation step is also probably facilitated by internal
cross-coupled with the diboronyl reagent. This approach coordination between the carbonyl oxygen and the boron atom in
constitutes a new way of preparing enantioenriched a-substituted 13 (Fig. 3a). This internal coordination becomes much more
allylic boronates28–32, which can undergo carbonyl allylation evident in the trifluoroborate salt 9 than in pinacolate 2, probably
reactions to form valuable carbon–carbon bonds (Table 3, entries due to the formation of the boronic acid intermediate reported to
10–13)33–35. Coupling of 9 with alkenyl electrophiles, however, is be the active species in cross-coupling reactions of trifluoroborate
slower than cross-coupling reactions with aryl electrophiles. The salts40. The dual stabilization effect greatly facilitates the
reaction requires 1.5 equiv. of the diboron reagent and tends to transmetallation step for the 1,1-diboronic ester. The resulting
lead to lower product yields (Table 3, entries 10–13). A s-alkyl–Pd(II)Ar could then undergo reductive elimination to afford
particularly interesting example is the cross-coupling reaction of products 10 while regenerating the Pd(0) catalyst.
diboron reagent
9 with 2-trimethylsilyl-bromoethene. The
resulting product represents a Type I double allylation reagent Applications of the cross-coupled products. To demonstrate the
that is capable of undergoing sequential allylation or oxidation versatility of the products obtained in these stereospecific cross-
reactions leading to different functionalities (Table 3, entry 12)36–39
.
couplings, we then attempted the second cross-coupling with the
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1150
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a
Equation 1
b
Br
a) 2M H2SO4
pinacol, THF
b) Pyrrolidine
1,2,4-triazole, DBU
toluene, 95 °C
Pd(OAc)2 (10 mol%)
XPhos (20 mol%)
O
K2CO3 (3 equiv.)
+
+
Y
O
O
Y
H
O
O
B
N
BF3K
N
O
B(dan)
c) KHF2, MeCN
CPME/H2O (1:0.15)
95 °C
Bdan
Pd(Ar)L
10a
11a
12a
(74%, >95% e.e.)
X
(62% over 3 steps)
13
Equation 2
O
O
PhCHO
TFA
2M H2SO4
pinacol
O
O
Ph
OH
O
B
O
O
B(dan)
THF
Toluene, r.t.
O
12k
(83%, >25:1 E/Z, 97% e.e.)
10k
11k
(92%)
Figure 3 | Proposed transition state for the stereospecific cross-coupling reaction of 3,3-diboronyl carboxyester 9 and applications of mono cross-coupled
products 10. a, Proposed transition state (Y ¼ F or OH) for the key transmetallation step with inversion of stereochemistry during the cross-coupling reaction.
The transition state is believed to be stabilized both by the neighbouring empty p-orbital from the boron atom and the coordination effect from the oxygen of
the carboxyester. b, Equation 1: iterative cross-coupling sequence for the synthesis of enantioenriched diarylmethane units 12a. This enantioenriched
diarylmethane core structure is an important pharmacophore and the approach presented here demonstrates a potential method for diversity-oriented
synthesis towards the discovery of various pharmaceuticals. Equation 2: carbonyl allylboration reaction to synthesize enantioenriched homoallylic alcohol 12k.
The resulting enantioenriched homoallylic alcohol moiety is a common entity in various biologically active natural products, thus demonstrating the
importance of the optically enriched 1,1-diboronyl compounds 2 and 9 synthesized in this study.
chiral boronate 10 acquired from the first coupling. However, it was difficult mechanistic step in cross-coupling reactions of alkyl boro-
not possible to cross-couple the boronate 10a directly, even after nates. The cross-coupling reactions reported herein represent a rare
transforming the 1,8-diaminonaphthalene protecting group to the example of the successful use of non-benzylic secondary alkylboro-
trifluoroborate salt. We found it necessary to transform the nates, which occur with preservation of stereochemical integrity.
carboxyester to the amide to effect the desired reaction. As shown The resulting enantioenriched benzylic or allylic boronates can
in Fig. 3b (equation 1), following the conversion of the Bdan unit undergo a plethora of reactions including a second iterative cross-
to the boronic acid pinacol ester, we applied the protocol coupling, carbonyl allylation and oxidation reactions. These appli-
developed by Yang and Birman to form the corresponding cations highlight the versatility of chiral boronates and
amide41. Trifluoroborate salt formation afforded 11a, and this demonstrate the numerous synthetic possibilities associated with
compound could be cross-coupled successfully with enantioenriched 1,1-diboronyl compounds.
p-bromotoluene to afford the enantioenriched diarylmethane 12a.
Methods
The enantioenriched diarylmethane core structure is an important
3,3-Diboronyl carboxyester 2a. CuCl (1.5 mg, 15 mmol), Solvias SL-W001-1
pharmacophore, and 1,1-diboryls could serve as a universal
ligand 8 (10 mg, 15 mmol) and NaOtBu (1.4 mg, 15 mmol) were dissolved in dry
template for their synthesis42. Our method represents a new way tetrahydrofuran (THF, 0.4 ml) and stirred at room temperature for 30 min before
the addition of bis-pinacolato diboron (140 mg, 0.550 mmol) in THF (0.3 ml). The
reaction was stirred further for 10 min, and boronate 1a (126 mg, 0.500 mmol) was
then added with THF (0.3 ml) followed by dropwise addition of MeOH (41 ml,
1.00 mmol). After 12 h of stirring, the reaction mixture was evaporated in vacuo and
to prepare these synthetic intermediates where both of the aryl
groups can be assembled through simple cross-coupling reactions
with readily available aryl bromides.
Another synthetically valuable application of the mono cross-
purified directly by silica column chromatography (EtOAc/hexanes ¼ 1:4) to give 2a
(167 mg, 88%) as a white solid. The product could be recrystallized from hot MeOH
to give X-ray quality crystals (72%) (see Supplementary Information).
coupled products is the subsequent allylboration reaction. Once the
Bdan group was removed to provide access to allyl boronic acid
pinacol ester 11k, a Brønsted-acid-catalysed allylboration reaction
could be achieved to afford the homoallylic alcohol 12k43,44. The
e.e., as measured by chiral high-performance liquid chromatography
(HPLC) analysis, wasfound to be fully retained in the alcohol product
12k (equation 2, Fig. 3b). Based on the excellent enantiomeric reten-
tion and the E/Z ratio, the reaction most likely proceeded through
the expected chair-like transition state35,45–48. All these preliminary
applications demonstrate the potential value of enantioenriched
3,3-diboronyl carboxyesters as intermediates in organic synthesis.
In summary, we have reported the first syntheses of enantiomeri-
cally pure 3,3-diboronyl carboxyesters and shown their intriguing
physical properties through X-ray crystallographic analysis. We
have demonstrated that the enantioenriched diboronyl esters can
be cross-coupled chemoselectively and stereoselectively with
various organic electrophiles. Both the coordination of the carbonyl
oxygen to the boron atom and the stabilization provided by the
second boronyl unit in the a-B–Pd(II) complex are thought to
assist the transmetallation process, thus facilitating this notoriously
General procedure for stereoselective cross-coupling reactions with 3,3-diboronyl
carboxyester 9. Pd(OAc)2 (10 mmol), XPhos (20 mmol), K2CO3 (0.30 mmol),
aromatic or alkenyl bromide (0.10 mmol) and 1,1-diboronyl ester 9 (0.12 or
0.15 mmol) were stirred in toluene (1.0 ml) and H2O (0.10 ml) at 80 8C for 6 h. The
reaction mixture was then cooled and evaporated in vacuo. The crude reaction
mixture was purified with column chromatography to afford the purified product.
X-ray crystallographic data. CCDC 816515 contains the crystallographic data for
compound 2a. CCDC 826384 contains the crystallographic data for compound 2b.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received 6 June 2011; accepted 16 August 2011;
published online 25 September 2011; corrected after print
10 May 2013
References
1. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of
organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).
2. Bellina, F., Carpita, A. & Rossi, R. Palladium catalysts for the Suzuki cross-coupling
reaction: an overview of recent advances. Synthesis 15, 2419–2440 (2004).
898
NATURE CHEMISTRY | VOL 3 | NOVEMBER 2011 | www.nature.com/naturechemistry
© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1150
ARTICLES
3. Rudolph, A. & Lautens, M. Secondary alkyl halides in transition-metal-catalyzed
cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).
4. Molander, G. A. & Canturk, B. Organotrifluoroborates and monocoordinated
palladium complexes as catalysts—a perfect combination for Suzuki–Miyaura
coupling. Angew. Chem. Int. Ed. 48, 9240–9261 (2009).
5. Chemler, S. R., Trauner, D. & Danishefsky, S. J. The b-alkyl Suzuki–Miyaura
cross-coupling reaction: development, mechanistic study, and applications in
natural product synthesis. Angew. Chem. Int. Ed. 40, 4544–4568 (2001).
6. Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. Cross coupling
reactions of chiral secondary organoboronic esters with retention of
configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).
32. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of
allylboronates bearing a tertiary or quaternary b-substituted stereogenic
carbon by NHC-Cu-catalyzed substitution reactions. J. Am. Chem. Soc.
132, 10634–10637 (2010).
33. Denmark, S. E. & Fu, J. Catalytic enantioselective addition of allylic
organometallic reagents to aldehydes and ketones. Chem. Rev. 103,
2763–2793 (2003).
34. Hall, D. G. Lewis and Brønsted acid catalyzed allylboration of carbonyl
compounds: from discovery to mechanism and applications. Synlett 11,
1644–1655 (2007).
35. Lachance, H. & Hall, D. G. Allylboration of Carbonyl Compounds. Organic
Reactions 1–574 (Wiley, 2008).
7. Ohmura, T., Awano, T. & Suginome, M. Stereospecific Suzuki–Miyaura coupling
of chiral a-(acylamino)benzylboronic esters with inversion of configuration.
J. Am. Chem. Soc. 132, 13191–13193 (2010).
36. Roush, W. R. & Grover, P. T. Diisopropyl tartrate (1)-g-(dimethyl-
phenylsilyl)allylboronate, a chiral allylic alcohol b-carbanion equivalent
for the enantioselective synthesis of 2-butene-1,4-diols from aldehydes.
Tetrahedron Lett. 31, 7567–7570 (1990).
´
8. Sandrock, D., Jean-Gerard, L., Chen, C. Y., Dreher, S. D. & Molander, G. A.
Stereospecific cross-coupling of secondary alkyl b-trifluoroboratoamides.
J. Am Chem. Soc. 132, 17109–17110 (2010).
9. Zou, G. & Falck, J. R. Suzuki–Miyaura cross-coupling of lithium n-alkylborates.
Tetrahedron Lett. 42, 5817–5819 (2001).
10. Zhou, J. R. & Fu, G. C. Cross-couplings of unactivated secondary alkyl halides:
room-temperature nickel-catalyzed Negishi reactions of alkyl bromides and
iodides. J. Am. Chem. Soc. 125, 14726–14727 (2003).
11. Zhou, J. R. & Fu, G. C. Palladium-catalyzed Negishi cross-coupling reactions of
unactivated alkyl iodides, bromides, chlorides, and tosylates. J. Am. Chem. Soc.
125, 12527–12530 (2003).
12. Saito, B. & Fu, G. C. Enantioselective alkyl–alkyl Suzuki cross-couplings of
unactivated homobenzylic halides. J. Am. Chem. Soc. 130, 6694–6695 (2008).
13. Son, S. & Fu, G. C. Nickel-catalyzed asymmetric Negishi cross-couplings
of secondary allylic chlorides with alkylzincs. J. Am. Chem. Soc. 130,
2756–2757 (2008).
37. Hunt, J. A. & Roush, W. R. 4,5-Diisopropyl-b-[(1)-[(3′-
menthofuryl)dimethylsilyl]allyl]-1,3,2- dioxaborolane, an improved chiral
reagent for the anti a-hydroxyallylation of aldehydes: application to the
enantioselective synthesis of (2)-swainsonine. J. Org. Chem. 62,
1112–1124 (1997).
38. Flamme, E. M. & Roush, W. R. Enantioselective synthesis of 1,5-anti- and
1,5-syn-diols using a highly diastereoselective one-pot double allylboration
reaction sequence. J. Am. Chem. Soc. 124, 13644–13645 (2002).
39. Binanzer, M., Fang, G. Y. & Aggarwal, V. K. Asymmetric synthesis of allylsilanes
by the borylation of lithiated carbamates: formal total synthesis of
(–)-decarestrictine D. Angew. Chem. Int. Ed. 49, 4264–4268 (2010).
40. Butters, M., Harvey, J., Jover, J., Lennox, A., Lloyd-Jones, G. & Murray, P. Aryl
trifluoroborates in Suzuki–Miyaura coupling: the roles of endogenous aryl
boronic acid and fluoride. Angew. Chem. Int. Ed. 49, 5156–5160 (2010).
41. Yang, X. & Birman, V. B. Acyl transfer catalysis with 1,2,4-triazole anion.
Org. Lett. 11, 1499–1502 (2009).
14. He, A. & Falck, J. R. Stereospecific Suzuki cross-coupling of alkyl a-cyanohydrin
triflates. J. Am. Chem. Soc. 132, 2524–2525 (2010).
42. Fessard, T. C., Andrews, S. P., Motoyoshi, H. & Carreira, E. M. Enantioselective
preparation of 1,1-diarylethanes: aldehydes as removable steering groups for
asymmetric synthesis. Angew. Chem. Int. Ed. 46, 9331–9334 (2007) and
references therein.
43. Yu, S. H., Ferguson, M. J., McDonald, R. & Hall, D. G. Brønsted acid-catalyzed
allylboration: short and stereodivergent synthesis of all four eupomatilone
diastereomers with crystallographic assignments. J. Am. Chem. Soc. 127,
12808–12809 (2005).
44. Elford, T., Yu, S. H., Arimura, Y. & Hall, D. G. Triflic acid-catalyzed additions of
2-alkoxycarbonyl allylboronates to aldehydes. Study of scope and mechanistic
investigation of the reaction stereochemistry. J. Org. Chem. 72,
1276–1277 (2007).
45. Li, Y. & Houk, K. N. Transition structures for the allylboration reactions of
formaldehyde by allylborane and allylboronic acid. J. Am. Chem. Soc. 111,
1236–1240 (1989).
15. Endo, K., Ohkubo, T., Hirokami, M. & Shibata, T. Chemoselective and
regiospecific Suzuki coupling on a multisubstituted sp3-carbon in 1,1-
diborylalkanes at room temperature. J. Am. Chem. Soc. 132, 11033–11035 (2010).
16. Lee, J. C. H. & Hall, D. G. Chiral boronate derivatives via catalytic
enantioselective conjugate addition of Grignard reagents on 3-boronyl
unsaturated esters and thioesters. J. Am. Chem. Soc. 132, 5544–5545 (2010).
17. Gao, M., Thorpe, S. B. & Santos, W. L. sp2–sp3 hybridized mixed diboron:
synthesis, characterization, and copper-catalyzed b-boration of a,b-unsaturated
conjugated compounds. Org. Lett. 11, 3478–3481 (2009).
18. Lee, J. E. & Yun, J. Catalytic asymmetric boration of acyclic a,b-unsaturated
esters and nitriles. Angew. Chem. Int. Ed. 47, 145–147 (2008).
19. Sim, H. S., Feng, X. & Yun, J. Copper-catalyzed enantioselective b-boration of
acyclic enones. Chem. Eur. J. 15, 1939–1943 (2009).
20. Feng, X. & Yun, J. Conjugate boration of b,b-disubstituted unsaturated esters:
asymmetric synthesis of functionalized chiral tertiary organoboronic esters.
Chem. Eur. J. 16, 13609–13612 (2010).
21. Flack, H. D. On enantiomorph-polarity estimation. Acta. Crystallogr. A39,
876–881 (1983).
46. Kennedy, J. W. J. & Hall, D. G. Dramatic rate enhancement with preservation of
stereospecificity in the first metal-catalyzed additions of allylboronates. J. Am.
Chem. Soc. 124, 11586–11587 (2002).
47. Carosi, L. & Hall, D. G. Catalytic enantioselective preparation of alpha-
substituted allylboronates. One-pot addition to functionalized aldehydes
and a route to chiral allylic trifluoroborate salts. Angew. Chem. Int. Ed. 46,
5913–5915 (2007).
22. Flack, H. D. & Bernardinelli, G. Absolute structure and absolute configuration.
Acta. Crystallogr. A55, 908–915 (1999).
23. Flack, H. D. & Bernardinelli, G. Reporting and evaluating absolute-structure and
absolute-configuration determinations. J. Appl. Cryst. 33, 1143–1148 (2000).
24. Ho, O. C. et al. ((Trityloxy)methyl)boronic esters. Organometallics 14,
2855–2860 (1995).
25. Noguchi, H., Hojo, K. & Suginome, M. Boron-masking strategy for the selective
synthesis of oligoarenes via iterative Suzuki2Miyaura coupling. J. Am.
Chem. Soc. 129, 758–759 (2007).
´
´
48. Althaus, M., Mahmood, A., Ramon Suarez, J., Thomas, S. P. & Aggarwal, V. K.
Application of the lithiation-borylation reaction to the preparation of
enantioenriched allylic boron reagents and subsequent in situ conversion into
1,2,4-trisubstituted homoallylic alcohols with complete control over all elements
of stereochemistry. J. Am. Chem. Soc. 132, 4025–4028 (2010).
26. Noguchi, H., Shilda, T., Chou, C-M. & Suginome, M. Differentially protected
benzenediboronic acids: divalent cross-coupling modules for the efficient
synthesis of boron-substituted oligoarenes. Org. Lett. 10, 377–380 (2008).
27. Xu, C. & Yuan, C. Candida Rugosa lipase-catalyzed kinetic resolution of
b-hydroxy-b-arylpropionates and d-hydroxy-d-aryl-b-oxo-pentanoates.
Tetrahedron 61, 2169–2186 (2005).
28. Gao, X. & Hall, D. G. 3-Boronoacrolein as an exceptional heterodiene in the
highly enantio- and diastereoselective Cr(III)-catalyzed three-component
[4þ2]/allylboration. J. Am. Chem. Soc. 125, 9308–9309 (2003).
29. Carosi, L. & Hall, D. G. Catalytic enantioselective preparation of a-substituted
allylboronates: one-pot addition to functionalized aldehydes and a route to chiral
allylic trifluoroborate reagents. Angew. Chem. Int. Ed. 46, 5913–5915 (2007).
30. Lessard, S., Peng, F. & Hall, D. G. a-Hydroxyalkyl heterocycles via chiral allylic
boronates: Pd-catalyzed borylation leading to a formal enantioselective
isomerization of allylic ether and amine. J. Am. Chem. Soc. 131, 9612–9613 (2009).
31. Ito, H., Ito, S., Sasaki, Y., Matsuura, K. & Sawamura, M. Copper-catalyzed
enantioselective substitution of allylic carbonates with diboron: an efficient route to
optically active a-chiral allylboronates. J. Am. Chem. Soc. 129, 14856–14857 (2007).
Acknowledgements
This research was generously funded by the Natural Sciences and Engineering Research
Council (NSERC) of Canada, and the University of Alberta. J.C.H.L. thanks the University
of Alberta for a Queen Elizabeth II Graduate Scholarship. The authors are grateful to M.
Ferguson of the X-ray Crystallographic Laboratory (analysis of 2a) and to the Spectral
Services staff at the University of Alberta, Department of Chemistry. The authors thank
Solvias AG (H. Steiner and H.-U. Blaser) for a generous gift of chiral ligands.
Author contributions
J.C.H.L. performed the experiments. R.M. performed the X-ray crystallographic analysis of
2b. D.G.H. directed the project. The manuscript was co-written by J.C.H.L. and D.G.H.
Additional information
The authors declare no competing financial interests. Supplementary information
and chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to D.G.H.
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CORRIGENDUM
Enantioselective preparation and chemoselective cross-coupling of
1,1-diboron compounds
Jack Chang Hung Lee, Robert McDonald and Dennis G. Hall
Nature Chemistry 3, 894–899 (2011); published online 25 September 2011; corrected afer print 10 May 2013.
In the version of this Article originally published, in Table 1, the ferrocene-based ligands 4, 5, 7 and 8 should have had 1,2-substituted
cyclopentadienyl rings rather than 1,3-substituted. is error has been corrected in the HTML and PDF versions of this Article.
© 2013 Macmillan Publishers Limited. All rights reserved.