Carbohydrate/DBU Cocatalyzed Alkene Diboration: Mechanistic Insight Provides Enhanced Catalytic Efficiency and Substrate Scope

Article abstract of DOI:10.1021/jacs.7b12316

A mechanistic investigation of the carbohydrate/DBU cocatalyzed enantioselective diboration of alkenes is presented. These studies provide an understanding of the origin of stereoselectivity and also reveal a strategy for enhancing reactivity and broadening the substrate scope.

Full text of DOI:10.1021/jacs.7b12316

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Article
On the Carbohydrate/DBU Co-Catalyzed Alkene Diboration: Mechanistic
Insight Provides Enhanced Catalytic Efficiency and Substrate Scope
Lu Yan, Yan Meng, Fredrik Haeffner, Robert Leon, Michael P. Crockett, and James P. Morken
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Feb 2018
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On the Carbohydrate/DBU Co-Catalyzed Alkene Diboration:
Mechanistic Insight Provides Enhanced Catalytic Efficiency and
Substrate Scope
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Lu Yan, Yan Meng, Fredrik Haeffner, Robert Leon, Michael P. Crockett, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
lyzed diboration that allow for an understanding of stereose-
lectivity, and that has facilitated the development of a more
efficient reaction system that has an expanded substrate scope.
ABSTRACT: A mechanistic investigation of the carbohy-
drate/DBU co-catalyzed enantioselective diboration of alkenes
is presented. These studies provide an understanding of the
origin of stereoselectivity and also reveal a strategy for en-
hancing reactivity and broadening the substrate scope.
Preliminary mechanistic experiments on alkene diboration
catalyzed by trans-1,2-cyclohexane diol and related com-
pounds suggested that transesterification of the catalytic diol
with the stoichiometric achiral diboron reagent furnishes 1,2-
1. INTRODUCTION
,
bonded diboron species A (Scheme 2).9 10 Similar to the hy-
,
Catalytic enantioselective 1,2-diboration of alkenes1 2 is a
pothesis put forward by Fernandez, we considered that the
diboron may be activated by association of an alkoxide there-
by furnishing B. Subsequent enantioselective diboration is
accomplished by a singlet-carbenoid-like reaction11 via en-
semble C, followed by internal trap of the derived boracyclic
ate complex D12 to provide E. Ligand exchange then releases
both the product and the catalyst. While computational exper-
iments provided support for the general pathway from A to E,
it was not clear why stereoselection should emerge from the
addition of an alkene to B, nor was the slow step in the cycle
identified such that attempts might be made to improve cata-
lytic efficiency.
valuable strategy for transforming alkenes to a variety of func-
tionalized products.3 Most often, this process operates by
transition-metal based activation of a diboron reagent, fol-
lowed by reaction of a resulting metal-boryl complex with the
unsaturated substrate.4 Alternatively, and aligned with semi-
nal studies by Hoveyda5 on the Lewis-base catalyzed activa-
tion of diboron reagents for nucleophilic conjugate addition
reactions, Fernandez made the remarkable discovery that 1,2-
diboration of unactivated alkenes could be catalyzed by simple
metal alkoxides.6 In an effort to render the metal-free dibora-
tion enantioselective, Fernandez employed two equivalents of
a chiral alkoxide activator, and achieved modest selectivity
(up to 40% ee).6c To render the alkoxide-promoted 1,2-alkene
diboration reactions catalytic and highly enantioselective, we
studied this process in the presence of exogenous diol catalysts
that were proposed to undergo reversible boronic ester ex-
change with the diboron reagent.7 The expectation was that an
appropriate alcohol might a) enhance reactivity of the diboron
nucleus; b) control facial selectivity of the diboration reaction;
c) undergo a second boronic ester exchange to release the
product, thereby rendering the entire process catalytic and
enantioselective. Preliminary studies revealed that cyclic
trans-1,2-diols are ideally suited for this catalysis strategy
with the carbohydrate derivatives TBS-DHG and DHR
(Scheme 1) being readily available, inexpensive, and able to
serve as competent catalysts.8 While preliminary studies re-
vealed an operative system, they also exposed limitations:
long reaction times (24-48 h), high catalyst loading (10-20 mol
%), elevated temperatures (60 °C), and a restricted substrate
scope (inefficient reaction with other than 1-alkenes). In this
Article, we present mechanistic studies on carbohydrate cata-
Scheme 2. Mechanism of Cyclic Diol-Catalyzed Alkene
Diboration
B(neo)
B(neo)
R
R
B2(neo)2
OR
+ RO
B
B
HO
HO
O
O
O
O
O
O
B
B
2 H2neo
(2 equiv)
2 H2neo
(2 equiv)
2
(2 equiv)
A
E
RO
R
R
R
OR
B
O
O
R
2
O
O
B
B
O
B
B
O
B
O
O
2
2
R
D
B
C
2. RESULTS AND DISCUSSION
Overview. Mechanistic studies were first directed to vali-
date the structure of diboron species A as being a 1,2-bonded
compound and to demonstrate that it can engage in enantiose-
lective addition to alkenes. Subsequently, studies on trans-
esterification of B2(neo)2 and trans-cyclic diols were examined
to demonstrate that exchange occurs and that it operates under
catalytic reaction conditions. Kinetic studies established the
turnover-limiting step for catalytic reactions with B2(neo)2 and
provided clues to developing faster processes. These im-
Scheme 1. Glycol-Catalyzed Alkene Diboration
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proved reactions were then subjected to a kinetic analysis and
computational modeling to provide a more complete under-
standing of the process.
glycolato phenyl boronic ester (eq. 1).9a To learn more about
1
2
3
4
5
6
7
8
the composition of diboronic esters derived from the exchange
process with cyclic diols, the complexes were prepared inde-
pendently by an alternate route. Thus, TBS-DHG, DHR, and
TCD were treated with B2(OH)4 under dehydrating reaction
conditions (refluxing toluene, Dean-Stark trap). As depicted
in Scheme 3 (eq. 2-4), these reactions provide access to dibo-
ron compounds that, collectively, have spectral features con-
sistent with 1,2-bonded diboron complexes. Due to the C2
symmetry axis in trans-1,2-cyclohexanediol, the 13C NMR
spectrum of B2(TCD)2 ([1H]13C d: 81.8, 32.9, 24.3 ppm) is
consistent with both 1,1-bonded and 1,2-bonded diboron spe-
cies. However, lack of a symmetry element in TBS-DHG and
DHR results in structural isomerism for 1,2-bonded diboron
species, whereas 1,1-bonded complexes would bear a C2-axis
that would render associated carbohydrate ligands equivalent.
Thus, the presence of two sets of 13C resonances for both
B2(TBS-DHG)2 and B2(DHR)2 is suggestive of 1,2-bonding
mode for these compounds and, by analogy, is considered
likely for TCD as well.
It was anticipated that some mechanistic experiments would
benefit from the use of trans-cyclohexanediol (TCD) in place
of TBS-DHG and DHR, and from the use of alternate solvents.
To demonstrate the impact of these permutations on the reac-
tion outcome, we examined the impact of catalyst and solvent
selection on reaction conditions. As shown in Table 1, it was
found that in comparison to TBS-DHG and DHR, the chiral
diol TCD furnishes diminished yield and only slightly dimin-
ished selectivity suggesting that it can serve as a surrogate for
the carbohydrate-derived catalysts in mechanistic experiments.
It should also be noted that inclusion of diazabicycloundecane
is required for all three catalysts to operate and that reactions
can be conducted in CH2Cl2 and CHCl3 solvents with similar
selectivity suggesting that NMR studies conducted in CDCl3
and CD2Cl2 would bear relevance to the catalytic reaction.
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Table 1.
Impact of Reaction Parameters on Diol-
Catalyzed Diboration of 1-Octene
Scheme 3. Preparation of Carbohydrate-Derived Diboron
Reagents
alcohol catalyst
OH
DBU
HO
HO
CDCl3
O
O
+
OH
B2(neo)2
hexyl
+
hexyl
+
Ph
B
Ph
B
(1)
solvent, 24 h, 23 °C
then NaOH, H2O2
rt
O
O
HO
HO
<5% conversion
Brown and Roy (ref. 9a)
TBSO
O
O
Me
OH HO
HO
O
O
B
HO
HO
HO
OH
OH
OH
HO
DHR
HO
TCD
toluene
B
B
+
(2)
B
TBS-DHG
O
O
HO
TCD
entry
alcohol
% DBU solvent yield (%)a erb
TBSO
1
2
10% TBS-DHG
10
THF
80
96:4
O
O
O
B
O
10% TBS-DHG
none
0
THF
THF
<5
<5
50
40
43
49
n.r.
n.r.
B
O
O
HO
HO
HO
HO
OH
OH
toluene
3
4
5
6
7
10
10
10
10
10
+
(3)
B
B
+
OTBS
O
10% DHR
THF
5:95
7:93
93:7
93:7
O
O
O
O
B
B
10% TCD
THF
OTBS
TBS-DHG
O
O
10% TBS-DHG
10% TBS-DHG
CHCl3
CH2Cl2
TBSO
OTBS
1:1 ratio
Me
(a) Yield determined after purification by silica gel chromatography.
(b) Enantiomer ratio (er) determined by chiral GC analysis of the derived
acetonide.
O
O
O
O
O
B
B
O
HO
HO
HO
OH
OH
toluene
+
(4)
B
B
+
Me
Preparation and characterization of B2(trans-1,2-
diol)2 complexes. To learn more about structures involved
in catalytic diboration, preliminary experiments examined the
products of reaction between B2(neo)2 and TBS-DHG in the
absence of alkene substrate.7 HRMS analysis of this reaction
mixture revealed the presence of B2(TBS-DHG)2 and B2(neo)2,
but not the mixed diboron reagent B2(neo)(TBS-DHG). This
outcome is in contrast to the analogous reaction between
B2(neo)2 and styrenediol which affords B2(neo)2,
B2(styrenediolato)2 as well as the mixed diboronic ester
B2(neo)(styrenediolato) (data not shown). Minimally, this
observation suggests that ligand exchange indeed occurs be-
tween B2(neo)2 and TBS-DHG, but the absence of the mixed
diboron in the exchange reaction with TBS-DHG pointed to
unique behavior of this diol ligand.
O
HO
O
O
O
O
B
B
Me
DHR
O
O
Me
Me
1:1 ratio
While 1,2-bonded diboron species are less common isomers
of diboron species derived from diol ligands, they do have
13
precedent.
The crystal structure of B2(binol)2
and
14
B2(cat)(NMe2)2 show 1,2-bonding although for the latter
compound this bonding mode may arise by kinetic control
during the synthesis. Also of relevance, B2(cat)2 exhibits dy-
namic isomerism, exchanging between 1,1-bonded and 1,2-
bonded upon addition of Lewis basic reagents (DBN, 4-
picoline).15
While significant effort was invested in preparing x-ray
quality crystals of 1,2-bonded diboron complexes derived
from TBS-DHG, DHR, and non-racemic TCD, these efforts
proved fruitless. In contrast, dehydration of B2(OH)4 and rac-
TCD furnished a solid material whose 13C NMR and HRMS
spectra are consistent with a dimer. From this material, x-ray
That transesterification can occur between trans-1,2-diols
and diboron reagents is noteworthy in light of observations by
Brown who found that, because of strain engendered in the
trans-fused bicyclic ring framework, <5% transesterification
occurred between trans-cyclohexanediol (TCD) and ethylene
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quality crystals could be obtained (Figure 1). The crystal of 8.085. For the estimation of the molecular weight, an ex-
ternal calibration curve method developed by Stalke19 was
employed. Using this technique with naphthalene as a refer-
ence, the calculated solution molecular weight for the diboron
complex B2(TBS-DHG)2 in CDCl3 solvent is 536.4 g/mol.
Considering that the molecular weight of B2(TBS-DHG)2 is
543.3 g/mol suggests that, for this diboron compound in chlo-
roform solvent, the monomeric diboron species predominates
over higher-order aggregates.
1
2
3
4
5
6
7
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structure includes two enantiomeric molecules of
B6(TCD)5(ent-TCD) per unit cell, with each molecule com-
posed of three tethered diboron subunits. Each of the diboron
subunits bears a 1,2-bonded TCD group and is tethered by an
additional diol ligand to a neighboring subunit. Of the six
diols ligands in the molecular structure, five are of the same
configuration and the sixth is the opposite. While this species
is clearly unavailable when using non-racemic ligand, the
bonding present in the trimeric structure gives credence to the
importance of 1,2-bonded TCD groups in diboron reagents.
Of note, the B-B bond distances (1.706, 1.721, and 1.724 Å)
are not substantially distorted relative to other diboron com-
pounds (1.720Å for B2(OMe)416; 1.711Å for B2(pin)217).
Equilibria
between
B2(neo)2
and
trans-
9
cyclohexanediol. The experiments described above estab-
lish the likely structure of B2(TCD)2 and related complexes;
however, for effective catalysis to emanate from a cycle that
involves the chiral diboron complex, boronic ester exchange
between the stoichiometric achiral diboron reagent and the
chiral cyclic diol is a necessary prerequisite. To establish the
capacity for such a transesterification under catalytic reaction
conditions, B2(neo)2 was treated with 2 equiv of TCD in THF
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OH
B2(27)2
HO
HO
OH
OH
Toluene
+
B
B
13C δ: 81.8, 32.9, 24.3 ppm
11B δ: 32.7
OH
rac-27
Dean-Stark
HRMS m/z: 251.1631
1
at 60 °C (Scheme 4). When the reaction was examined by H
S
NMR, it was found that exchange indeed occurs and that it
requires the presence of DBU. After 15 h, the reaction
achieves >95% conversion, suggesting that Keq for the ex-
change reaction is >20. Importantly, this exchange could also
be conducted with 10 mol% DBU and it still proceeds to com-
pletion (data not shown). As a control experiment, the reverse
reaction was conducted where B2(TCD)2 was treated with
neopentyl glycol under identical conditions and <5 % conver-
sion was observed.
O
S
R
B
O
O
B
R
R
R
O
O
O
O
O
B
B
O
B
R
R
R
O
R
B
O
R
O
R
Figure 1. Preparation of [B2(rac-trans-cyclohexanediol)2] and
crystal structure analysis of B6(TCD)5(ent-TCD) revealing the
1,2-bonding mode for the trans-cyclohexanediol ligand.
Scheme 4. Equilibrium Between Neopentyl Glycol and
trans-Cyclohexanediol Diboron Reagents
OH
OH
OH
DBU (2 equiv)
Me
Me
+
+
(5)
B2(neo)2
B2(TCD)2
The presence of oligomeric species in rac-TCD-derived di-
boron structures, suggests higher-order species might be both
accessible and relevant to processes involving non-racemic
diols. To measure diffusion coefficients that may be correlat-
ed with molecular weight of complexes in solution, diffusion
ordered spectroscopty (DOSY) NMR18 analysis was per-
formed on B2(TBS-DHG)2. As depicted in Figure 2, CDCl3
was employed as the DOSY NMR solvent and naphthalene
was used as the molecular weight reference for calibration.
The 2D NMR spectrum of B2(TBS-DHG)2 shows that only one
species exists in solution and it exhibits an average diffusion
60 °C, THF-d8
15 h
>95% conversion
OH
TCD
(2 equiv)
(2 equiv)
OH
OH
OH
OH
DBU (2 equiv)
Me
Me
+
+
(6)
B2(TCD)2
B2(neo)2
60 °C, THF-d8
15 h
<5% conversion
H2neo
TCD
(2 equiv)
(2 equiv)
Stoichiometric reactions of chiral diboron com-
plexes and alkenes. With available evidence suggesting
that ligand exchange between B2(neo)2 and trans-cyclic diols
provides 1,2-bonded diboron species, the reaction between
Table 2. Additive Effects in the Addition of B2(TBS-
DHG)2 to 1-Octene
additive
20% DBU
yield (%)a erb
entry
1
2
3
4
5
6
7
<5
43
40
25
30
52
46
n.d.
20% DBU; 20% 1,3-propanediol
20% DBU; 20% n-BuOH
20% DBU; 20% i-PrOH
20% DBU; 20% t-BuOH
20% KOtBu
92:8
90:10
86:14
80:20
73:27
81:19
20% KOMe
Figure 2. DOSY NMR analysis of B2(TBS-DHG)2in comparison
to naphthalene as a molecular weight reference. Analysis was
performed in CDCl3 by 600 MHz 1H NMR.
(a) Yield determined after purification by silica gel chromatography.
(b) Enantiomer ratio (er) determined by chiral GC analysis of the derived
acetonide.
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these chiral complexes and alkenes was examined. As depict- butanol and 1,3-propanediol, affording product with selectivity
1
2
3
4
5
6
7
8
ed in Table 2, when 1-tetradecene was treated with B2(TBS-
DHG)2 at 60 °C for 12 h in the presence of DBU, and the reac-
tion mixture subjected to oxidative work-up, it was found that
no reaction occurred (Table 2, entry 1). However, the addition
of an achiral alcohol to this reaction did serve to promote the
diboration of 1-octene in an enantioselective fashion (entry 2).
Of note, the stereoselectivity is dependent upon the nature of
the added alcohol, with tert-butanol and isopropanol giving
the product in selectivity that is less than that observed in the
catalytic reaction whereas unhindered alcohols, such as 1-
that is comparable to that observed in the catalytic process.
We considered that the function of the added alcohol in these
experiments may be to react with DBU thereby providing an
alkoxide activator for the diboration. Such alkoxide activation
was proposed by Fernandez6 for reactions of alkenes with
achiral diboron reagents and DBU/CH3OH-based alkoxide
activation of B2(pin)2 had been documented by Hoveyda5d;
consistent with these observations, the DBU-alcohol combina-
tion in the stoichiometric process can be replaced with a metal
alkoxide and comparable selectivity is observed (Table 2, en-
try 6, 7).
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Preliminary kinetic analysis of catalytic diboration
with B2(neo)2. Further information about the diol-catalyzed
diboration was obtained by studying the reaction kinetics.
Because of its experimental convenience and because it can
collect data continuously throughout the entire course of the
reaction, calorimetry was chosen for these studies. As depict-
ed in Figure 1a, the diboration of 4-phenyl-1-butene (0.83 M
conc) with B2(neo)2 (1.0 M conc) was monitored by calorime-
try in the presence of either 10 mol% or 15 mol% TBS-DHG
catalyst. While neither process achieved complete conversion,
analysis of the heat flow versus time profile (Figure 3A) indi-
cates a 45% increase in the initial rate at the higher catalyst
loading, suggestive of a first-order dependence of the reaction
rate on catalyst concentration. As depicted in Figure 3b, the
rate of catalytic diboration did not exhibit a significant de-
pendence on initial concentration of alkene, but did appear to
exhibit positive-order dependence on [B2(neo)2] (Figure 3c).
Impact of diboron reagents on catalytic efficiency
and selectivity. The zero-order dependence of reaction rate
on alkene concentration suggests that steps involving boronic
ester exchange rather than the diboration reaction itself are
turnover-limiting. With a first-order dependence upon catalyst
concentration and also a positive-order dependence upon
[B2(neo)2], it was suspected that formation of B2(TCD)2 from
B2(neo)2 and trans-cyclohexanediol was likely the slow step
with the initial association of TCD and B2(neo)2 likely turno-
ver-limiting and association of a second TCD being fast
(Scheme 5). This hypothesis was considered plausible since
dislodging a primary alcohol from B2(neo)2 with a secondary
alcohol from TCD (giving F) is likely to be slow relative to
subsequent intramolecular transesterification giving G and
displacement of monodentate ligands in G with TCD giving
H.
Scheme 5. Proposed Exchange Process for Reaction of
Cyclic Diol Ligands and B2(neo)2
HO
O
O
O
O
OH
OH
slow
O
O
O
O
B
B
+
B
B
OH
F
OH
OH
OH HO
O
O
O
O
fast
OH
O
O
O
O
fast
B
B
+
B
B
OH
(2 equiv)
H
G
Figure 3. Kinetic analysis of TBS-DHG catalyzed diboration of
4-phenyl-1-butene with B2(neo)2 as stoichiometric diboron rea-
gent. Effect of (a) catalyst concentration, (b) alkene concentra-
tion, and (c) diboron concentration.
Effect of diboron reagent structure on reactivity
and selectivity. With experiments suggesting that for-
mation of the chiral 1,2-bonded diboron complex is the turno-
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ver-limiting step of the catalytic cycle, we sought to develop a tion run at 2.0 M vs. 1.5 M results in a 1.30-fold increase in
1
2
3
4
5
6
7
8
more efficient process by employing diboron reagents that
would be prone to more rapid ligand exchange. As depicted in
Table 3, catalytic diboration reactions with varied diboron
reagents were carried out under conditions where conversion
with B2(neo)2 is modest (rt, 12 h, 40% yield). When B2(neo)2
was replaced with B2(ethyleneglycol)2, a compound that
should undergo faster transesterification because of decreased
steric encumbrance and increased strain in the cyclic boronic
ester motif, a significant improvement in the reaction efficien-
cy was observed; however, the reaction suffers from a
measureable decrease in enantioselectivity. Like B2(eg)2, the
catechol group on B2(cat)2 is also readily displaced and this
provides outstanding reactivity. However, presumably due to
facile background reaction, B2(cat)2 furnished racemic prod-
rate); while the plots in Figure 4b and 4c reveal a zero-order
dependence on alkene and DBU concentration.
A
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[B2(pro)2] = 2.0 M
[B2(pro)2] = 1.5 M
8
uct. The reagent B2(pro)2 (entry 4) provided the optimal
combination of both enhanced efficiency while maintaining
high enantioselectivity. It should be noted that, consistent
with the mechanistic proposal described above, more hindered
diboron reagents that likely suffer diminished rates of trans-
esterification, react with severely diminished efficiency (entry
5, 6).
B
Table 3. Effect of Diboron Reagent Structure on the Effi-
ciency and Selectivity of 1-Tetradecene Diborationa
10% TBS-DHG
OH
10% DBU
C12H25
1.0 eq
+
B2(OR)2
1.0 eq
OH
C12H25
THF, rt, 12h
then NaOH/H2O2
diboron
abbrev. yield (%)b erc
entry
[alkene] = 1.25 M
[alkene] = 1.0 M
O
O
B
O
B
B
B
B
1
B2(neo)2
B2(eg)2
B2(cat)2
B2(pro)2
40
75
98
56
96:4
91:9
O
O
O
B
2
3
4
O
O
O
O
B
51:49
95:5
O
O
O
C
O
B
O
O
O
O
B
B
5
6
B2(tmpd)2
B2(pin)2
15
10
81:19
69:31
O
O
O
O
O
O
B
B
12.5% DBU
10% DBU
7.5% DBU
(a) Reactions were performed on 0.2 mmol scale of alkene and at [al-
kene] = 1.0 M. (b) Yield determined after purification by silica gel chro-
matography. (c) Enantiomer ratio (er) determined by chiral GC analysis
of the derived acetonide.
Kinetic analysis of carbohydrate-catalyzed dibora-
tion with B2(pro)2. In addition to exhibiting enhanced reac-
tivity and scope (vide infra), B2(pro)2 has the significant ad-
vantage that it is more soluble in THF solvent than B2(neo)2
and therefore is more amenable to kinetic analysis. Using a
reference set of reaction conditions ([4-phenyl-1-butene] =
1.0 M, [B2(pro)2] = 2.0 M, 10 mol% TBS-DHG, 10 mol%
DBU), calorimetry showed the diboration of 4-phenyl-1-
butene was complete within 4 h and the calorimetric reaction
rate data was corroborated by NMR analysis versus an internal
standard. When the heat flow versus time data was integrated
(Figure 4), it becomes apparent that the reaction approximates
first-order behavior over its entire course. The two plots in
Figure 4a show the effect of diboron concentration on the re-
action rate and are consistent with a first-order dependence
(the 1.33-fold increase in diboron concentration between reac-
Figure 4. Kinetic analysis of TBS-DHG catalyzed diboration of
4-phenyl-1-butene with B2(pro)2. Effect of (a) diboron concentra-
tion, (b) alkene concentration, (c) DBU concentration.
The dependence of reaction rate upon catalyst concentration
was also analyzed by reaction calorimetry (Figure 5) and
clearly show that the reaction is first-order in TBS-DHG with
a reduction in catalyst to 5 mol% loading giving a rate that is
approximately half that of the standard reaction.
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For effective catalysis, reaction through TS-1 must be fa-
1
vored over the analogous reaction between the alkene and
stoichiometric achiral diboron compounds. Along these lines,
calculations performed previously7 suggested that TS-1 is
favored relative to the corresponding transition state originat-
ing from 1,1-bonded B2(neo)2. To learn more about back-
ground reaction rates for both 1,1- and 1,2-bonded B2(pro)2
and to better understand rate acceleration and stereoinduction
with TCD, TBS-DHG, and DHR, additional computational
investigations were undertaken. Calculations were performed
with Gaussian 09 and optimized with M06-2X21 density func-
tional and 6-31+G* basis set using PCM solvation model
(THF). Thus, the transition state energies were calculated 1,1-
bonded and 1,2-bonded transition states derived from TCD,
1,3-propanediol, and ethylene glycol (Figure 7). As the results
indicate, the relative TS energy for 1,2-bonded TCD (TS-1A)
is far lower in energy than the TS for 1,1-bonded TCD (TS-
1B) as well as both 1,1 and 1,2-bonded propanediol (TS-1C
and TS-1D). TS-1A is also lower in energy than both transi-
tion states that would arise from B2(eg)2 as a stoichiometric
reagent (TS-1E, TS-1F), although the difference in catalyzed
(TS-1A) and background (TS-1E) energy is less in the latter
case suggesting that competing background reaction would
likely be more problematic when B2(eg)2 is employed as a
reagent. Of note, observations in Table 3 (entry 2) indicate
lower reaction enantioselectivity with B2(eg)2, in line with
calculations.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Kinetic analysis of diboration of 4-phenyl-1-butene
with B2(pro)2 catalyzed by TBS-DHG.
Origin of rate acceleration and stereoinduction in
trans-glycol catalyzed diboration. A. Rate Accelera-
tion. Previous computational studies carried out by DFT
methods provided support for a mechanism involving reaction
of an alkene with 1,2-B2(TCD)2•OMe by a two-step mecha-
nism involving initial rupture of the B-B bond (TS-1, Figure
6) and formation of an anionic boracycle12 tethered to a triva-
lent borate ester (INT). Mechanistically, this first step appears
to be isoelectronic with cyclopropanation involving singlet-
carbenes.11 Subsequent to cycloboration, intramolecular reac-
tion between the trivalent borate and the anionic boracycle
occurs (via TS-2) in a stereoretentive fashion and delivers a
macrocyclic vicinal diboronate (PDT); ligand exchange be-
tween this species and propanediol would release the 1,2-
glycol catalyst from the reaction product. Of note, the calcu-
ated barrier for TS-1 is too high for a reaction that occurs at
room temperature. Moreover, the energy of TS-1 suggests it
should be kinetically relevant, which is inconsistent with ki-
netic data. Part of this error arises because calculations over-
estimate the decrease in translational entropy for association of
ethylene with the diboron precursor.20 Thus, subsequent cal-
culations have focused on relative comparisons of similar tran-
sition states where systematic errors are expected to cancel.
Me
Me
Me
O
O
O
O
O
O
B
O
O
O
O
B
O
B
B
B
B
O
O
O
O
Me
Me
Me
ΔG≠rel = 14.7 kcal/mol
ΔG≠rel = 10.4 kcal/mol
ΔGrel = 5.2 kcal/mol
TS-1B
TS-1D
TS-1F
Me
Me
Me
O
O
O
O
O
O
O
O
O
B
B
B
B
B
B
O
O
O
O
O
O
Me
Me
Me
ΔG≠rel = 0 kcal/mol
ΔG≠rel = 9.9 kcal/mol
ΔGrel = 0.5 kcal/mol
TS-1A
TS-1C
TS-1E
Figure 7. Comparison of relative transition state energies for
cycloboration employing TCD, ethylene glycol and 1,3-
propanediol ligands in both the 1,1 and 1,2 bonding modes. To
make meaningful comparison of transition states, the total energy
for each ensemble was compared relative to the ensemble for TS-
1A (ensemble energy includes the calculated transition state ener-
gy and the ground state energy for non-participating diols; see
Supporting Information for additional discussion). Calculations
performed with M06-2x/6-31+G*.
H
H
H
H
OMe
B
O
B
H
H
O
H
H
O
O
OMe
B
B
H
H
O
O
H
TS-1
H
O
OMe
O
-
B
B
O
O
H
H
H
31.0
H
O
O
OMe
TS-2
-
B
B
Consistent with preferred 1,2-bonding mode for TCD in the
ground state diboron structure, the six-membered ring in TCD
imposes significant strain that penalizes the 1,1-bonding mode
in transition state TS-1B, thereby favoring TS-1A. It is note-
worthy that when this strain element is removed in the case of
the B2(eg)2, the 1,2-bonded TS-1E is still favored over 1,1-
bonded TS-1F suggesting a general preference for 1,2-bonded
transition states in the alkoxide promoted diboration, even in
the absence of strain. With 1,3-propane diol as ligand, the
benefit of 1,2-bonding in transition state TS-1C appears to be
offset by strain in the seven membered rings and thus neither
the 1,1- or 1,2-bonding mode allows B2(pro)2-based back-
ground reaction to effectively compete with the catalyzed re-
action through TS-1A.
33.5
O
O
2.3
B2(TCD)2•OMe
O
O
INT
24.9
PDT
B2(TCD)2•OMe
TS-1
INT
Figure 6. Calculated reaction mechanism for alkene dibora-
tion with B2(TCD)2.
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1
Journal of the American Chemical Society
The origin of transition state stabilization with 1,2-bonded
The two lower energy structures are distinguished from each
other by a DDG≠ of 0.27 kcal/mol, a number which appears
reasonable given the lower selectivity observed in reactions
promoted with potassium methoxide as activator (Table 2)
instead of 1,3-propanediol/DBU. Examination of the TS-
major and TS-minor does not reveal a clear difference in
steric effects between the two structures; however, a key dis-
tinguishing feature is that the O2 oxygen atom in the higher
energy structure (TS-minor) is positioned in such a way that
its non-bonding electrons are directed towards the alkene sub-
stituent, whereas the alkene substituent in the lower energy
structure is situated over an oxygen (O1) whose lone pairs are
directed away from the olefin substituent. This difference in
lone pair orientation can be discerned from the electrostatic
potential surface calculated for the most favored transition
structure (TS-major); from perspective B (inset Figure 9), the
electron density associated with the O(2) oxygen encroaches
on the substrate more than the electron density associated with
O(1) simply as a result of orientation, and this is expected to
provide an energetic preference for locating the small vinylic
H over O(2) and the larger alkyl group over O(1).
versus 1,1-bonded diolato ligands merits comment. Analysis
of 11B NMR chemical shifts in non-coordinatign chloroform
solvent for compounds that are 1,2-bonded (11B d B2(TCD)2 =
32.05 ppm; B2(TBS-DHG)2 = 32.7 ppm) are consistently
downfield relative to 1,1-bonded compounds (11B d B2(neo)2 =
28.4 ppm; B2(pin)2 = 30.7 ppm, B2(pro)2 = 28.3 ppm), suggest-
ing decreased O→B p bonding in the 1,2 bonding mode likely
as a result of less effective orbital overlap.22 Similarly, abbre-
viated transition state structures I and J shown in Figure 8
reveal a substantial difference in the orientation of the diolato
oxygen atom lone pair electrons. For the 1,2-bonded transi-
tion state J, much of the lone pair electron density is directed
away from the breaking B-B bond, whereas in the 1,1-bonded
complex I, the breaking B-B bond bisects the oxygen lone
pairs. It was considered that during the course of bond reor-
ganization in the cycloboration, the B-B bond cleaves in a
manner that that leads to increased electron density on boron
atom BA and, due to orbital orientation, the 1,1-bonding mode
may suffer enhanced electron-electron repulsion relative to the
1,2-bonding mode. To gain an understanding of the magni-
tude of this effect, we computed the ground state energy of
conformers of the boryl anion (HO)2B⊖. As depicted in Figure
8, of the two conformers, structure K (reflective of the 1,1-
bonding mode) is found to be 2.8 kcal/mol higher in energy
than L, a feature consistent with destabilization of the 1,1-
bonded transition state relative to the 1,2 mode.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
G. Scope of diboration: Terminal Alkenes. With an
appreciation of reaction mechanism and noting enhanced rates
with B2(pro)2, we explored the scope of glycol catalyzed enan-
tioselective diborations with both TBS-DHG and DHR cata-
lysts. For consistently high reaction efficiency, we employed
two equiv of B2(pro)2 and allowed reactions to proceed for 12
h (Table 4). Generally, high enantioselectivities and high
yields were observed regardless of the nature of the olefin
substituent: 1-octene, 1-tetradecene, and vinylcyclohexene
furnished the corresponding diols in approximately 95:5 enan-
tiomer ratios and 97%, 95%, 84% yield respectively (products
1, 2, and 3). Allyl- and homoallyl benzene derivatives also
undergo the diboration reaction smoothly resulting in for-
mation of the diol products in good yield and good enantiose-
lectivity (products 4-7). Heterocycle-containing alkenes such
as furan, Boc-protected indole, thiophene and pyridine-
containing substrates, afforded diol products in similarly good
yield and enantioselectivity (8-11). Similarly, TBDPS protect-
ed allylic alcohol and homoallylic alcohols, survive the dibo-
ration/oxidation (12, 13) as to carbonyl-based functional
groups such as ketone and ester derivatives (14, 15). Alkyl
bromides also appear to be non-problematic (16) as are com-
pounds containing pre-existing stereocenters (products 18, 19).
Aromatic alkenes appear to be one type of substrates that did
not react with high selectivity (19). Of note, the diboron in-
termediate in the synthesis of 13 could be isolated in 79%
R
R
H
B
H
O
O
O
H
H
O
O
O
O
O
O
O
BB
BA
O
B
BB
O
BA
O
O
ΔG = +2.8 kcal/mol
I
J
K
L
Figure 8. General comparison of 1,1- and 1,2-bonded transition
states in metal-free diboration.
B. Stereoinduction. According to the energy profile de-
picted in Figure 6, the stereochemical outcome of the carbo-
hydrate-catalyzed diboration would appear to arise from the
facial selectivity with which a prochiral alkene engages in TS-
1. As depicted in Figure 9, four different reaction pathways
were calculated for the addition of propene to 1,2-
B2(TCD)2•OMe. Perhaps unsurprisingly in light of anticipated
steric effects, the two transition states in which the alkene
substituent is directed towards the activating alkoxy group
(transition structures TS-M and TS-N) are highest in energy.
Figure 9. Calculated transition states for reaction of 1,2-B2(TCD)2•OMe with propene leading to enantiomeric reaction products. The
inset structures depict and alternate perspective of the lowest energy transition state along with an electrostatic potential surface that sug-
gests a possible origin of stereocontrol in diboration reactions.
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Page 8 of 11
yield and separated from the catalyst, which could be recov- tion operates on non-functionalized hydrocarbons (20, 21) as
1
2
3
4
5
6
7
8
ered in 96% yield (see Supporting Information for details).
Lastly, it should be noted that DHR catalyzed reactions is gen-
erally just as efficient as TBS-DHG catalyzed process, fur-
nishing diol 1, 3, 5, 7, 10, 13, 16 in similarly good yield and
good enantioselectivity. corresponding
well as those bearing adjacent oxygenated functional groups
(22, 23, 25-27). From the data, it appears that electron-
withdrawing allylic substituents decrease alkene reactivity (cf.
20, 23, 24) such that with an allylic benzoate, no detectable
diboration was observed. The reactivity enhancement ob-
served with B2(pro)2 also extends to indene and dihydronaph-
thalene, substrates that exhibit low reactivity with B2(neo)2 as
reagent. Importantly, these cyclic Z-alkenes, as well as prod-
uct 30 from an acyclic Z-alkene precursor, provide additional
support for the stereospecific cycloboration mechanism pro-
posed for this reaction.
Internal Alkenes. Internal alkenes are less reactive than
mono-substituted olefins under carbohydrate-catalyzed reac-
tion conditions. Indeed, with more hindered substrates, dibo-
ration with B2(neo)2 required heating to 60 °C and use of the
Cs2CO3 as the base. When the more reactive reagent B2(pro)2
is used, however, the reaction may be conducted at lower tem-
peratures and with DBU as the base, and under these milder
conditions appears to suffer from less background non-
selective reaction. As depicted in Table 5, useful yields and
selectivity could be obtained from carbohydrate catalyzed
diboration of internal alkenes if 10% catalyst was employed
with 3 equivalents of diboron reagent at 40 °C. A modest
improvement in yield was also noted when the reaction was
conducted in ethyl acetate solvent versus THF solvent. Under
these reaction conditions a collection of functionalized disub-
stituted alkenes were examined. As noted in Table 2, the reac-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Enantioselective Diboration of Internal Alkenes
with B2(pro)2 and Carbohydrate-Derived Catalysts
10% TBS-DHG
10% DBU
OH
O
O
O
O
R2
R1
1.0 eq
OH
B
B
OH
+
R
ethyl acetate, 40 °C
12 h, 4Å MS;
then NaOH/H2O2
R2
3.0 equiv
OH
TBDPSO
OH
OH
n-Bu
n-Bu
Et TBDPSO
n-Pr
n-Bu
Me
OH
20
OH
21
OH
OH
22
23
89%, 92:8 er
83%, 90:10 er
91%, 92:8 er
53%, 93:7 er
Table 4. Enantioselective Diboration of 1-Alkenes with
B2(pro)2 and Carbohydrate-Derived Catalysts
OH
OBn OH
OBz
OH
OBn OH
BzO
n-Pr
OH
OTBS
n-Bu
Et
OH
OH
OH
24
<5 %
25
26
78%, 91:9 er
27
74%, 91:9 er
92%, 91:9 er
OH
OH
OH
OH
OH
TBDPSO
OH
Et
28
73%, 93:7 er
29
75%, 90:10 er
30
65%, 68:32 er
(a) Conditions: [alkene]=1.0 M, 0.2 mmol scale. Yield refers to the iso-
lated yield of the purified reaction product. Enantiomer ratio determined
by chromatography with a chiral stationary phase (see Supplementary
Material for details).
G. Practical features of carbohydrate-catalyzed
diboration. As the examples above suggest, carbohydrate-
catalyzed diboration reactions are markedly accelerated by the
use of B2(pro)2 in place of B2(neo)2 and B2(pin)2. Moreover,
due to its high solubility in water, removal of 1,3-propanediol
from reaction products is easily accomplished by an aqueous
wash and this makes product purification far easier than when
neopentyl glycol or pinacol-derived boron reagents are em-
ployed. In spite of these attractive features, a use of B2(pro)2
is limited by the fact that it is less commonly available than
other diboron reagents.8 To address this, we have examined
the direct preparation of B2(pro)2 from B2(OH)4 and 1,3-
propane diol. As depicted in Scheme 6, it was found that heat-
ing a mixture of B2(OH)4 and 1,3-propanediol for 6 h in tolu-
ene with a Dean-Stark trap to remove water, followed by
evaporation of the solvent provided B2(pro)2 of sufficient puri-
ty to be used directly in diboration. Moreover, it was deter-
mined that the reaction in the presence of the DHR catalyst
was sufficiently rapid that it could proceed to completion
within 12 h at room temperature and with only 1.5 equivalents
of diboron reagent. Subsequent to buffered (pH=7) oxidation
with H2O2, aqueous wash to remove 1,3-propanediol, and puri-
fication provided the product 1,2-diol in 93% yield on 20
mmol scale reaction.
(a) Conditions: [alkene]=1.0 M, 0.2 mmol scale. Yield refers to the iso-
lated yield of the purified reaction product. Enantiomer ratio determined
by chromatography with a chiral stationary phase (see Supplementary
Material for details).
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Journal of the American Chemical Society
Scheme 6. Single Vessel Catalytic Enantioselective Dibora-
1
tion with B2(OH)4 as Reagent
2
3
4
OH
toluene
Dean-Stark
150 °C
B2(OH)4
+
(30 mmol)
OH
see: (f) Lee, Y.; Jang, H. Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 18234-18235.
5
6
7
8
10% DHR
10% DBU
OH
O
O
O
B
O
(2) Non-asymmetric alkene diboration: (a) Baker, R. T.; Nguyen,
P.; Marder, T. B.; Westcott, S. A. Angew. Chem. Int. Ed. 1995, 34,
1336. (b) Iverson, C. N.; Smith, M. R. Organometallics 1997, 16,
2757. (c) Ishiyama, M.; Miyaura, N. Chem. Commun. 1997, 689. (d)
Marder, T. B.; Norman, N. C.; Rice, C. R. Tetrahedron Lett. 1998, 39,
155. (e) Mann, G.; John, K. D.; Baker, R. T. Org. Lett. 2000, 2, 2105.
(f) Lillo, V.; Mata, J.; Ramírez, J.; Peris, E.; Fernández, E. Organo-
metallics 2006, 25, 5829. (g) Dai, C.; Robins, E. G.; Scott, A. J.;
Clegg, W.; Yufit, D. S.; Howard, J. A. K.; Marder, T. B. Chem.
Commun. 1998, 1983. (h) Nguyen, P.; Coapes, R. B.; Woodward, A.
D.; Taylor, N. J.; Burke, J. M.; Howard, J. A. K.; Marder, T. B. J.
Organomet. Chem. 2002, 652, 77. (i) Ramírez, J.; Corberán, R.;
Sanaú, M.; Peris, E.; Fernández, E. Chem. Commun. 2005, 3056. (j)
Corberán, R.; Ramírez, J.; Poyatos, M.; Perisa E.; Fernández E. Tet-
rahedron: Asymmetry 2006, 17, 1759. (k) Lillo, V.; Mas-Marzá, E.;
Segarra, A. M.; Carbó, J. J.; Bo, C.; Peris, E.; Fernández, E. Chem.
Commun. 2007, 3380. (l) Lillo, V.; Fructos, M. R.; Ramírez, J.; Díaz
Requejo, M. M.; Pérez, P. J.; Fernández, E. Chem. Eur. J. 2007, 13,
2614. (m) Ramírez, J.; Mercedes, S.; Fernández, E. Angew. Chem.,
Int. Ed. 2008, 47, 5194. For recent review, see: (n) Neeve, E. C.;
Geier, S. J.; Mkhalid, I. A.; Westcott, S. A.; Marder, T. B. Chem. Rev.
2016, 116, 9091.
OH
B
+
hexyl
hexyl
ethyl acetate, 22 °C
4AMS, 12 h;
then H2O2
1.5 equiv
(used directly)
(20 mmol)
93% yield (2.73 g)
94:6 er
pH=7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. CONCLUSION
The glycol/DBU co-catalyzed diboration of alkenes is an ef-
ficient, enantioselective reaction that employs simple catalysts
and reagents to convert unsaturated hydrocarbons into useful
chiral building blocks. Importantly, with B2(pro)2 as a reagent,
the reaction occurs in a reasonable time course and applies to
both terminal and internal alkenes. Of note, the waste streams
arising from the diboration/oxidation process employing
B2(pro)2 as the reagent are 1,3-propanediol and boric acid, both
of which are relatively innocuous. Thus, the catalytic dibora-
tion process described herein would appear to be an appealing
method for the enantioselective transformation of olefins.
ASSOCIATED CONTENT
Supporting Information
(3) For recent strategies that result in selective functionalization of
vicinal diboronates, see: (a) Mlynarski, S. N.; Schuster, C. H.;
Morken, J. P. Nature 2014, 505, 386. (b) Fawcett, A.; Nitsch, D.; Ali,
M.; Bateman, M.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. Int.
Ed., 2016, 55, 14663. For a review, see: (c) Xu, L.; Zhang, S.; Li, P.
Chem. Soc. Rev. 2015, 44, 8848.
Procedures, characterization and spectral data. The Supporting
Information is available free of charge on the ACS Publications
website.
AUTHOR INFORMATION
Corresponding Author
(4) Mechanism of metal-catalyzed diboration: (a) Ishiyama, T.;
Matsuda, N.; Murata, M.; Ozawa, F.; Suzuki, A.; Miyaura, N. Organ-
ometallics 1996, 15, 713. (b) Clegg, W.; Lawlor, F. J.; Marder, T.
B.; Nguyen, P.; Norman, N. C.; Orpen, A. G.; Quayle, M. J.; Rice, C.
R.; Robins, E. G.; Scott, A. J.; Souza, F. E. S.; Stringer, G.; Whittell,
G. R. J. Organomet. Chem. 1998, 550, 183. (c) Iverson, C. N.; Smith,
M. R. III Organometallics 1996, 15, 5155. (d) Thomas, R. L.; Souza,
F. E. S.; Marder, T. B. J. Chem. Soc., Dalton 2001, 1650. (e) Ishiya-
ma, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. J. Am. Chem. Soc.
1993, 115, 11018. (f) Iverson, C. N.; Smith, M. R. J. Am. Chem. Soc.
1995, 117, 4403. (g) Lesley, G.; Nguyen, P.; Taylor, N. J., Marder, T.
B. Organometallics 1996, 15, 5137. For recent review, see: (h)
Westcott, S. A.; Fernández, E. Adv. Organomet. Chem. 2015, 63, 39.
(5) (a) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 7253. (b) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2012, 134, 8277. (c) Wu, H.; Radomkit, S.;
O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 8277.
(d) Wu, H.; Garcia, J. W.; Haeffner, F.; Radomkit, S.; Zhugralin, A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2015, 137, 10585.
*morken@bc.edu
ORCID
James P. Morken 0000-0002-9123-9791
Funding Sources
This work was supported by the NIH (GM-59417).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Mr. Max Deaton is acknowledged for experimental assistance
and Dr. Bo Li (Boston College) for X-ray crystallography.
(6) (a) Bonet, A.; Pubill-Ulldemolins, C.; Bo, C.; Gulyás, H.; Fer-
nández, E. Angew. Chem. Int. Ed., 2011, 50, 7158. (b) Miralles, N.;
Cid, J.; Cuenca, A. B.; Carbó, J. J.; Fernández, E. Chem. Commun.
2015, 51, 1693. (c) Bonet, A.; Sole, C.; Gulyás, H.; Fernández, E.
Org. Biomol. Chem., 2012, 10, 6621.
REFERENCES
(7) Fang, L.; Yan, L.; Haeffner, F.; Morken, J. P. J. Am. Chem.
Soc. 2016, 138, 2508.
(8) TBS-DHG, DHR, and B2(pro)2 used in this study are being
commercialized by Aldrich chemical (TBS-DHG: catalog no. 901235;
DHR: 901237; B2pro2: 901464). TBS-DHG and DHR are readily
synthesized from corresponding dehydroglycal derivatives (See Sup-
plementary Material). For a previous synthesis of TBS-DHG, see:
Groaning, M. D.; Rowe, B. J.; Spilling, C. D. Tetrahedron Lett. 1998,
39, 5485.
(9) For seminal studies on boronic ester exchange, see: (a) Roy, C.
D.; Brown, H. C. J. Organomet. Chem. 2007, 692 784. Selected stud-
ies in catalytic boron activation by boronate exchange: (b) Wu, T. R.;
Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244. (c) Pellegrinet, S.
C.; Goodman, J. M. J. Am. Chem. Soc. 2006, 128, 3116. (d) Lou, S.;
(1) Catalytic enantioselective alkene diboration: (a) Morgan, J. B.;
Miller, S. P.; Morken, J. P., J. Am. Chem.Soc. 2003, 125, 8702. (b)
Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem.
2005, 70, 9538-9544. (c) Kliman, L. T.; Mlynarski, S. N.; Morken, J.
P. J. Am. Chem. Soc. 2009, 131, 13210-13211. (d) Coombs, J. R.;
Haefner, F.; Kliman, L. T.; Morken, J. P. J. Am. Chem. Soc. 2013,
135, 11222. (e) Toribatake, K.; Nishiyama, H. Angew. Chem. Int. Ed.
2013, 52 11011. For asymmetric double hydroboration of alkynes,
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Page 10 of 11
1
2
3
4
5
6
7
8
9
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660. (e)
(13) (a) Clegg, W.; Johann, T. R. F.; Marder, T. B.; Norman, N. C.;
Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908. (f) Lu-
an, Yi, Schaus, S. E. J. Am. Chem. Soc. 2012, 134, 19965. (g) Sim-
mons, E. M.; Mudryk, B.; Lee, A. G.; Qiu, Y.; Razler, T. M.; Hsiao,
Y. Org. Proc. Res. Dev. 2017 asap; 10.1021/acs.oprd.7b00253. (h)
Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem. Int. Ed.,
2010, 49, 7096. (i) Kodama, T.; Moquist, P. N.; Schaus, S. E. Org.
Lett, 2011, 13, 2011. (j) Bishop, J. A.; Lou, S.; Schaus, S. E. Angew.
Chem. Int. Ed., 2009, 48, 4337. (k) Lou, S.; Moquist, P. N.; Schaus, S.
E. J. Am. Chem. Soc. 2007, 129, 15398. (l) Paton, R. S.; Goodman, J.
M.; Pellegrinet, S. C. Org. Lett., 2009, 11, 37. (m) Barnett, D. S.;
Moquist, P. N.; Schaus, S. E. Angew. Chem. Int. Ed., 2009, 48, 8679.
(n) Jiang, Y.; Schaus, S. E. Angew. Chem. Int. Ed., 2017, 56, 1544.
(10) For reviews of aligned processes that employ boronic or bo-
rinic esters as catalysts in exchange-based cycles, see: (a) Taylor, M.
S. Acc. Chem. Res. 2015, 48, 295. (b) Dimitrijević, E.; Taylor, M. S.
ACS Catal. 2013, 3, 945. (c) Zheng, H.; Hall, D. G. Aldrichimica
Acta 2014, 47, 41.
(11) For reviews on carbene cyclopropanation reactions, see: (a)
Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341. (b)
Davies, H. M.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (c)
Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev.
2003, 103, 977.
(12) Three-membered boracyclic ate complexes have precedent,
see: (a) Kropp, M.; Bhamidapaty, K.; Schuster, G. B. J. Am. Chem.
Soc. 1988, 110, 6252. (b) Kropp, M. A.; Baillargeon, M.; Park, K. M.;
Bhamidapaty, K.; Schuster, G. B. J. Am. Chem. Soc. 1991, 113, 2155.
(c) Khusainova, L. I.; Khafizova, L. O.; Tyumkina, T. V.; Dzhemilev,
U. M. Russ. J. Org. Chem. 2015, 51, 1517. (d) Khusainova, L. I.;
Khafizova, L. O.; Tyumkina, T. V.; Ryazanov, K. S. J. Organomet.
Chem. 2017, 832, 12. (d) Braunschweig, H.; Claes, C.; Damme, A.;
Deibenberger, A.; Dewhurst, R. D.; Horl, C.; Kramer, T. Chem.
Comm. 2015, 51, 1627. (e) Denmark, S. E.; Nishide, K.; Faucher, A.
M. J. Am. Chem. Soc. 1991, 113, 6675. (f) Rao, Y-L.; Chen, L. D.;
Mosey, N. J.; Wang, S. J. Am. Chem. Soc. 2012, 134, 11026.
Orpen, A. G.; Peakman, T. M.; Quayle, M. J.; Rice, C. R.; Scott, A. J.
J. Chem. Soc., Dalton Trans., 1998, 1431. (b) Alibadi, M. A. M.;
Batsanov, A. S.; Bramham, G.; Charmant, J. P. H.; Haddow, M. F.;
MacKay, L.; Mansell, S. M.; McGrady, J. E.; Norman, N. C.; Roffey,
A.; Russell, C. A. Dalton Trans., 2009, 5348.
(14) Lesley, M. J. G.; Norman, N. C.; Orpen, A. G.; Starbuck, J.
New J. Chem., 2000, 24, 115.
(15) Cade, I. A.; Chau, W. Y.; Victorica-Yrezabal, I.; Ingleson, M.
J. Dalton Trans., 2015, 44, 7506.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Brain, P. T.; Downs, A. J.; MacCallum, P.; Rankin, D. W. H.;
Robertson, H. E.; Forsyth, G. A. J. Chem. Soc., Dalton Trans. 1991,
1195.
(17) Noth, H. Z. Naturforsch., Teil B, 1984, 39, 1463.
(18) (a) Morris, K. F.; Johnson, C. S. J. Am. Chem. Soc. 1992, 114,
3139. (b) Barjat, H.; Morris, G. A.; Swanson, A. G.; Williams, S. C.
R. J. Magn. Reson. Ser. B. 1995, 108, 170. (c) Cohen, Y.; Avram, L.;
Fish, L. Angew. Chem. Int. Ed. 2005, 44, 520. (d) Johnson Jr., C. S.
Prog. Nucl. Magn. Res. Spectr. 1999, 34, 203. (e) Poppler, A. C.;
Meinholz, M. M.; Fabhuber, H.; Lange, A.; John, M.; Stalke, D. Or-
ganometallics, 2012, 31, 42.
(19) (a) Neufeld, R.; Stalke, D. Chem. Sci., 2015, 6, 3354. (b)
Bachmann, S.; Neufeld, R.; Dzemski, M.; Stalke, D. Chem. Eur. J.
2016, 22, 8462. (c) Neufeld, R.; Teuteberg, T. L.; Herbst-Itmer, R.;
Mata, R. A.; Stalke, D. J. Am. Chem. Soc. 2016, 138, 4796. (d)
Neufeld, R.; John, M.; Stalke, D. Angew. Chem. Int. Ed. 2015, 54,
6994.
(20) For an overview of this phenomena, see: (a) Zhou, H.-X.;
Gilson, M. K. Chem. Rev. 2009, 109, 4092. For a discussion of error
in DFT calculation of solution entropy, see: (b) Plata, R. K.; Single-
ton, D. A. J. Am. Chem. Soc. 2015, 137, 3811.
(21) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(22) Wrackmeyer, B. Annu. Rep. NMR Spectrosc. 1988, 20, 61.
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OH
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kinetics
TBSO
DOSY NMR
DFT
crystallography
O
OH
OH
hexyl
10%
97%, 95:5 er
OH
10% DBU
OH
Et
alkene
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TBDPSO
B2(pro)2
7
91%, 92:8 er OH
THF or ethyl acetate
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4AMS, 12 h; then [O]
BocN
OH
OH
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scalable
commercial reagents
commercial catalysts
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85%, 97:3 er
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