Chiral Phosphoric Acid Dual-Function Catalysis: Asymmetric Allylation with α-Vinyl Allylboron Reagents

Article abstract of DOI:10.1002/anie.202000039

We report a dual function asymmetric catalysis by a chiral phosphoric acid catalyst that controls both enantioselective addition of an achiral α-vinyl allylboronate to aldehydes and pseudo-axial orientation of the α-vinyl group in the transition state. The reaction produces dienyl homoallylic alcohols with high Z-selectivities and enantioselectivities. Computational studies revealed that minimization of steric interactions between the alkyl groups of the diol on boron and the chiral phosphoric acid catalyst influence the orientation of α-vinyl substituent of the allylboronate reagent to occupy a pseudo-axial position in the transition state.

Full text of DOI:10.1002/anie.202000039

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Chiral Phosphoric Acid Dual-Function Catalysis: Asymmetric
Allylation with α-Vinyl Allylboron Reagents
Authors: Shang Gao, Meng Duan, Ken Houk, and Ming Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000039
Angew. Chem. 10.1002/ange.202000039
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10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chiral Phosphoric Acid Dual-Function Catalysis: Asymmetric
Allylation with α-Vinyl Allylboron Reagents
Shang Gao,[a], # Meng Duan,[b], # K. N. Houk,*[b] and Ming Chen*[a]
Dedicated to Professor William R. Roush
Abstract: We report a dual function asymmetric catalysis by a chiral
phosphoric acid catalyst that controls both enantioselective addition
of an achiral α-vinyl allylboronate to aldehydes and pseudo-axial
orientation of the α-vinyl group in the transition state. The reaction
produces dienyl homoallylic alcohols with high Z-selectivities and
have been developed to generate homoallylic alcohols with high
enantioselectivities.10-13 Reactions with enantioenriched, α-
substituted allylboronate can also form homoallylic alcohols
asymmetrically.14,15 These reactions typically proceed through
chirality transfer, and the enantiopurity of the starting boron
reagents will dictate the enantiomeric excess of the alcohol
products. Compared to well-developed allylation with reagents
that lack the α-substituent, allylation with these α-substituted
allylboron reagents, however, has received much less attention.
enantioselectivities.
Computational
studies
revealed
that
minimization of steric interactions between the alkyl groups of the
diol on boron and the chiral phosphoric acid catalyst influences the
orientation of α-vinyl substituent of the allylboronate reagent to
occupy a pseudo-axial position in the transition state.
Me
Me
OH
OH
O
B
R’CHO
Me
Me
Introduction
R
+
R’
R’
O
1
R
2
3
R
The asymmetric addition of allylmetal reagents to carbonyl
compounds is a widely adopted method for the synthesis of
acyclic alcohols with high enantiopurity.1 Over the past thirty
years, many useful allylmetal reagents, including catalytic
variants, have been developed.2-5 Among these available
reagents, allylboron compounds are particularly useful.6 It is
well-established that carbonyl addition with allylboron reagents
proceeds by way of the cyclic Zimmerman-Traxler transition
state to give homoallylic alcohol products,7 and stereochemical
outcomes of these reactions are highly predictable. While chiral,
nonracemic allylboranes are valuable for the syntheses of
enantioenriched homoallylic alcohols,8 recent studies have
shown that allylboronates are also highly useful reagents for
asymmetric allylation because of their low toxicities and
remarkable stabilities toward oxygen and moisture.
Me
Me
Me
Me
H
O
B
Me
Me
Me
Me
O
B
R
H
R’
O
O
2
3
O
H
O
R’
H
H
R
TS-1
TS-2
Scheme 1. Allyl addition to aldehydes with α-substituted allylboronates
The major challenge in asymmetric allylation with α-
substituted allylboronates is to control the stereoselectivity of the
reactions besides enantioselective preparation of such reagents.
Scheme 1 shows the reaction of α-substituted allylboronate
reagent 1 with an aldehyde. Two products can be generated
from this reaction via two competing transition states, TS-1 and
TS-2. In TS-1, the α-substituent R occupies a pseudo-equatorial
position, which leads to the formation of product 2 with an E-
olefin unit. This transition state typically suffers a gauche
interaction between the pseudo-equatorially oriented R group
and the pinacol unit of allylboronate 1. On the other hand, the α-
substituent R was placed in a pseudo-axial position in TS-2 to
Several strategies are available for enantioselective
carbonyl allylation with allylboronate reagents. Chiral auxiliary
based allylboronates are conventional reagents to produce
enantioenriched homoallylic alcohols.9 However, it is inevitable
that a stoichiometric amount of chiral auxiliaries are required for
these reactions. In comparison, catalytic carbonyl addition with
achiral allylboronates, pinacol allylboronate for instance, in the
presence of
a chiral, nonracemic catalyst represents a
form product
3 with Z-olefin geometry. In this case, the
significant advance in allylation chemistry. Elegant studies of
allylboration using either chiral Lewis or Brønsted acid catalysts
nonbonding A1,3 allylic strain is developed between the H atom
and the pseudo-axially oriented R group in TS-2. As shown by
early studies from the Hoffmann group,16 when R is not a polar
group (R ≠ Cl, Br, OR1, NR1R2), the energies of these two
competing transition states are very close to each other.
Consequently, the reaction generally provides a mixture of
products 2 and 3 with low selectivity (~1:2 in many cases).
Therefore, the development of a general approach to proper
control the orientation of the α-substituent of reagent 1 in the
transition state is an important objective.
[a]
[b]
Shang Gao, Professor Ming Chen
Department of Chemistry and Biochemistry
Auburn University, Auburn, AL 36849, United States
E-mail: mzc0102@auburn.edu
Meng Duan, Professor K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, California 90095, United States
E-mail: houk@chem.ucla.edu
# These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
OH OH
An elegant example of E-selective allylation with α-
substituted allylboronates was recently disclosed by the
Aggarwal group.17 By using a three-step reaction sequence,
homoallylic alcohols 2 were obtained with high E-selectivities
from reagent 1. 11B NMR studies showed that the reaction
proceeded via the intermediacy of an allylborinate that is
substantially more reactive than allylboronates 1. More
importantly, the steric repulsion between the α-substituent (R
group) and the pinacol moiety is greatly relieved in the transition
state. Consequently, the α-substituent (R group) was positioned
in the pseudo-equatorial position to give homoallylic alcohols 2
with high E-selectivities.
MeO
HO2C
Me
HO2C
Me
CO2H
Me
HO
Me
CO2H
bongkrekic acid
linieodolide B
Me
n-Hexyl
O
Me
O
Me
OH
S
Me
OH
O
H
OH OH
O
N
H
Me
O
O
O
Me Me Me
OH
OH
O
OH
H
thuggacin A
Me
ascospiroketal B
HO
OH OH
OH OH OH OH
O
O
Me
Me
Me
HO
OH
O
B
Me
Me
Me
R’CHO
catalyst
OH
O
O
1
R’
Me
O
R
O
R
3
Me
R = nonpolar group
Me
O
marinisporolide C
macrolactin A
R’
R’
cat
R’
R’
H
Figure 1. Selected natural products containing a (Z)-homoallylic alcohol unit
OH
O
B
R’
R’
O
B
RCHO
R’
R’
R
O
R
O
O
5
catalyst
H
6
Results and Discussion
TS-A
readily available achiral reagent
highly Z-selective and enantioselective
enantioselectivity and olefin geometry controlled by a single catalyst
Reaction Development: We began our studies by examining
the reaction between allylboronate 5a22 and benzaldehyde in the
absence of any catalyst. As shown in Scheme 3, the reaction
produced a 1:1 mixture of Z-isomer (±)-6a and E-isomer (±)-7a.
The data suggest that the two competing transition states TS-3
and TS-4 have very similar energies. Either pseudo-axial (TS-3)
or pseudo-equatorial (TS-4) placement of the α-vinyl group of
reagent 5a does not have a significant impact on the energy of
transition state of the reaction, presumably due to minimal
gauche interactions between the small vinyl group and pinacol
diol unit on boron.
Scheme 2. Proposed Z-selective allylboration with α-substituted allylboronates
In comparison, proper control of the α-substituent (R
group) of reagent 1 in the pseudo-axial position in the transition
state (e.g., TS-2, Scheme 1) will produce Z-homoallylic alcohols
3. While aldehyde allylation with a polar group (R = Cl, Br, OR1,
NR1R2)18 substituted allylboronates proceeds with good Z-
selectivity, the development of highly Z-selective allylation is
challenging when the α-substituent is a nonpolar group (top
panel, Scheme 2).19-21 In connection with an ongoing synthesis
project, we became interested in developing new methods for Z-
selective allylation with α-substituted allylboronates. We report
herein catalytic asymmetric aldehyde allylation with α-vinyl
allylboronate 5 that delivers homoallylic alcohols 6 with high Z-
selectivities and enantioselectivities (bottom panel, Scheme 2).
Compared to aldehyde allylation with chiral nonracemic α-
substituted allylboron reagents (e.g., 1) that proceeds via
chirality transfer, a salient feature of the reaction we developed
is that reagent 5 is achiral and readily available, and the chiral
catalyst controls both the enantioselection of allyl addition and
more importantly, the axial orientation of the α-vinyl group in the
transition state (TS-A, Scheme 2). DFT computation studies
were conducted to probe the origin of enantioselectivity and Z-
selectivity of the reaction. In addition, Z-dienyl homoallylic
alcohol 6 is a common structural motif in many bioactive natural
products (Figure 1). The approach we developed offers a
straightforward method to access this structural entity from
reagent 5 and a corresponding aldehyde substrate.
We were intrigued whether or not the addition of a chiral
catalyst can bias the orientation of vinyl group in the transition
state. Pioneered by Antilla and coworkers,12 chiral phosphoric
acids such as (R)-A (Scheme 4)23 have been shown to catalyze
the reaction of aldehydes with a variety of boron reagents.24-26
The origin of enantioselection was elucidated by computational
studies conducted by the Houk and the Goodman groups.27
Me
Me
OH
OH
PhCHO, rt
O
B
Me
Me
Ph
+
Ph
O
4 Å MS, toluene
(±)-6a
(±)-7a
(±)-6a:(±)-7a = 1:1, 93%
5a
Me
Me
Me
Me
H
H
O
B
Me
Me
O
B
Me
Me
6a
7a
O
Ph
O
O
Ph
O
H
H
TS-3
TS-4
Scheme 3. Allylboration with α-vinyl allylboron 5a in the absence of a catalyst
This article is protected by copyright. All rights reserved.

10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
OH
OR
B
OH
OR
B
R’CHO
R’CHO
In our recent report on chiral phosphoric acid-catalyzed
asymmetric allenylation,26b we found that proper choice of the
diol unit of propargyl boronate is crucial to the enantioselectivity
of the reaction. As shown in Scheme 5, the addition of reagent
D-1 to benzaldehyde produced allenic alcohol E in 94 % yield
with 99% ee. When the pinacol moiety of D-1 was replaced with
benzopinacol or 2,2-dimethyl-1,3-propanediol (reagent D-2 or D-
3), the enantiomeric excess of product E decreased to 6% or
11% ee. The significant change in enantiopurity of E indicates
that the diol unit on boron is essential to the facial selective
addition of propargylboron reagent D to the aldehyde substrate,
presumably due to the interactions between the diol group of D
and the acid catalyst (R)-A. Based on these data, we postulated
that modifying the diol unit of α-vinyl substituted allylboronate 5
might impact the E/Z selectivity of the reaction of aldehydes with
reagent 5, while maintaining high level of enantioselection.
OR
OR
R’
R’
(R)-A
(R)-A
R
R
1
B
4
3
a)
b)
TS-6
TS-5
O
O
O
O
P
P
O
O
O
O
H
H
H
H
RO
RO
R’
R’
Ar
Ar
Ar
Ar
B
B
H
H
O
O
OR
OR
H
R
Figure 2. Stereochemical models for chiral phosphoric acid (R)-A catalyzed
allylboration with reagent B or 1
Based on the reported model, Figure 2a shows the favored
reaction pathway (TS-5) of allylboronate B with an aldehyde
substrate. By analogy, we speculated that the reaction of α-
substituted allylboronate 1 with an aldehyde substrate should
proceed through transition state TS-6 shown in Figure 2b, with
pseudo-axial placement of the α-substituent, R group, to give
product 3. The competing transition state leading to the E-olefin
product would have the R group in the pseudo-equatorial
position, and nonbonding steric interaction between the R group
of reagent 1 and the Ar group of the catalyst will be developed.
Therefore, we decided to choose chiral phosphoric acid (R)-A as
the catalyst for aldehyde addition with boronate 5a, aiming for Z-
selective allylboration.
(R)-A (5 mol %)
PhCHO, -45 °C
OH
i-Pr
OR
B
Me
●
i-Pr
Ph
OR
Me
4 Å MS, toluene
i-Pr
D
E
O
O
O
P
Me
Ph
Ph
Me
Me
OH
i-Pr
Me
O
B
O
O
Me
Me
Ph
B
B
O
O
O
Ph
i-Pr
(R)-A
i-Pr
D-1
E: 94%, 99% ee
D-2
E: 75%, 6% ee
D-3
E: 88%, 11% ee
Scheme 5. Impact on enantioselectivity of chiral phosphoric acid-catalyzed
allenylation with propargylic boronates D bearing different diols
In the event, 5 mol % of phosphoric acid (R)-A was added
to the reaction of 5a with benzaldehyde at −45 ºC in toluene.
Disappointedly, only a 2:1 mixture of 6a and 7a was formed,
slightly favoring the Z-isomer 6a (Scheme 4). One encouraging
aspect of this reaction, however, is that the enantiomeric excess
of 6a is 93% ee.28 These data indicate that the acid catalyst (R)-
A enables highly face selective allyl addition to benzaldehyde.
However, it is not able to control the orientation of the α-vinyl
group in the transition state presumably because two competing
transition states that led to the formation of 6a and 7a have a
similar level of energy in the presence of phosphoric acid (R)-A.
To test our hypothesis, allylboronates 5b-h with different
diol units were synthesized.22 Allylation of benzaldehyde with
these boronates in the absence of phosphoric acid catalyst were
examined first. In all cases, ~1:1 mixture of racemic alcohol (±)-
6a and (±)-7a was obtained. These data indicate that there is no
inherent pseudo-equatorial or pseudo-axial bias of the α-vinyl
group of allylboronates 5b-h in the allylation transition states.
Next, asymmetric allylation of benzaldehyde with 5b-h in the
presence of 5 mol % phosphoric acid (R)-A were examined. As
summarized in Table 1, allylation with boronate 5b bearing an
ethyl analog of pinacol group provided a 16:1 mixture of 6a and
7a in 92% yield (entry 2) with Z-isomer 6a as the major product.
The enantiomeric excess of 6a was determined to be 94% ee.
Encouraged by this initial success, we anticipated that the
reaction with boronate 5c, a propyl analog of pinacol boronate
5a, should have an even better selectivity. Indeed, excellent Z-
selectivity was observed in the reaction with allylboronate 5c.
Homoallylic alcohol 6a was formed as the only product (Z:E >
30:1) in 86% yield with 95% ee (entry 3). We discovered that
further increasing steric bulk of the diol group significantly
decreases the rate of allylation. For example, the reaction with
boronate 5d (the i-Pr analog of 5a) proceeded with very low
conversion (< 5%, entry 4). Reaction of allylboronate 5e with
cyclopentyl groups gave a 12:1 mixture of 6a and 7a in 82%
yield with 95% ee for 6a (entry 5). High Z-selectivity was also
Me
(R)-A (5 mol %)
PhCHO, -45 °C
Me
OH
OH
O
B
Me
Me
Ph
+
Ph
O
4 Å MS, toluene
6a
i-Pr
7a
5a
6a:7a = 2:1, 86%
i-Pr
i-Pr
O
O
O
P
OH
i-Pr
i-Pr
(R)-A
i-Pr
Scheme 4. Chiral phosphoric acid-catalyzed allylation with reagent 5a
This article is protected by copyright. All rights reserved.

10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. Evaluation of Z/E selectivity in chiral phosphoric acid catalyzed
allylboration with reagents 5a-h bearing different diols
Table 2. Scope of aldehyde for asymmetric allylboration catalyzed by chiral
phosphoric acid (R)-Aa,b
R’
R’
(R)-A (5 mol %)
OR’
OH
(R)-A (5 mol %)
OH
OH
OH
PhCHO, -45 °C
O
B
RCHO, -45 °C
R’
OR’
+
Ph
B
R
Ph
R’
O
+
R
4 Å MS, toluene
4 Å MS, toluene
5a-h
6a
7a
7
6
62-98%, 90-97% ee
5c or 5f
OH
OH
OH
entry
boronate
6a:7a
% yield (6a+7a)
% ee (6a)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
2:1
16:1
> 30:1
N.D.
12:1
25:1
1.5:1
2:1
86
92
86
< 5
82
86
80
83
93
94
O2N
EtO
95
6a, 86%, 95% ee
Z:E > 30:1c
6b, 79%, 97% ee
Z:E = 27:1c
6c, 83%, 97% ee
Z:E = 25:1
N.D.
95
OH
OH
OH
95
5g
5h
N.D.
N.D.
Cl
Br
I
6d, 82%, 95% ee
Z:E = 19:1
6e, 78%, 97% ee
Z:E = 20:1
6f, 93%, 96% ee
Z:E = 16:1
Me
Et
n-Pr
i-Pr
Me
Et
n-Pr
i-Pr
O
O
O
O
Me
Me
Et
Et
n-Pr
n-Pr
i-Pr
i-Pr
OH
OH
OH
B
B
B
B
O
O
O
O
O2N
Br
MeO
5a
5b
5c
5d
Me
Me
Me
Me
6g, 82%, 94% ee
Z:E = 15:1
6h, 98%, 95% ee
Z:E = 17:1
6i, 75%, 95% ee
Z:E > 30:1c
Me
O
Me
O
O
O
B
B
B
B
O
OH
OH
OH
O
O
O
H
H
Cl
Cl
O
O
5e
5g
5h
5f
Reaction conditions: allylboronate 5 (0.12 mmol), benzaldehyde (0.1 mmol),
phosphoric acid (R)-A (5 mol %), 4 Å MS, toluene, −45 °C, 48 h. Yields of
isolated products are listed. The ratios of 6a and 7a were determined by 1H
NMR analysis of the crude reaction mixture. The enantiomeric excess of 6a
was determined by modified Mosher ester analysis
Br
6j, 83%, 95% ee
Z:E = 21:1
6k, 79%, 93% ee
Z:E = 16:1
6l, 86%, 95% ee
Z:E = 16:1
OH
OH
OH
O
Me
Ph
observed for the reaction with allylboronate 5f (the cyclohexyl
analog), affording 6a in 86% yield with 25:1 Z-selectivity and
95% ee (entry 6). Intriguingly, the enantiomeric excess of the
minor product E-isomer 7a is only 50% ee in the reaction with 5f.
Reactions of benzaldehyde with allylboronates 5g-h that have a
chiral, nonracemic diol group on boron were also conducted in
the presence of acid catalyst (R)-A. Interestingly, both cases
gave very low Z/E selectivities (entries 7 and 8). Overall, these
data showed that the trend for Z-selectivities in chiral phosphoric
acid-catalyzed reactions with boronates 5 correlates well with
respect to the size of diol group on boron: methyl << cyclopentyl
< ethyl < cyclohexyl < propyl. However, in the case of boronates
with a sterically very demanding diol group, the rate of allylation
decreases significantly. Meanwhile, in the absence of the acid
catalyst, the 1:1 Z/E selectivity in these reactions with
allylboronates 5a-h indicates that the size of diol unit does not
have any apparent impact on orientation of the α-vinyl group in
the transition states. Collectively, these data suggest that the
observed Z/E selectivities in chiral phosphoric acid-catalyzed
reactions are likely the results of intricate interactions between
the acid catalyst and the diol group on boron.
6m, 78%, 90% ee
Z:E > 30:1c
6n, 90%, 95% ee
Z:E > 30:1c
6o, 83%, 95% ee
Z:E = 25:1c
OH
OH
OH
O
BocN
S
6p, 62%, 95% ee
Z:E > 30:1c
6q, 75%, 95% ee
Z:E > 30:1c
6r, 90%, 94% ee
Z:E = 16:1
OH
OH
OH
Pr
Ph
6s, 77%, 90% ee
Z:E > 30:1c
6t, 72%, 92% ee
Z:E = 23:1c
6u, 81%, 95% ee
Z:E > 30:1c
[a] Reaction conditions: allylboronate 5f (0.12 mmol, 1.2 equiv), aldehyde (0.1
mmol, 1.0 equiv), phosphoric acid (R)-A (5 mol %), 4 Å molecular sieves (50
mg) toluene (0.3 mL), −45 °C. [b] Yields of isolated products are listed; the Z/E
ratios were determined by 1H NMR analysis of the crude reaction mixture;
enantiomeric excesses were determined by modified Mosher ester analysis.
[c] Reactions were conducted with 5c.
aldehydes. Homoallylic alcohol products 6 were obtained in
good yields with high Z-selectivities and enantiomeric excess.
For instance, reactions of aromatic aldehydes with an electron-
donating or withdrawing group at the para-position provided
alcohols 6b-c in 79-83% yields with 25-27:1 Z-selectivity and 97%
ee. Aromatic aldehydes bearing a halogen atom at para-position
are suitable substrates for the reaction, and alcohols 6d-f were
Substrate Scope: With optimal reaction conditions in hand, the
scope of aldehyde that underwent enantioselective allylboration
with allylboronate 5c or 5f was explored.29 As summarized in
Table 2, the reaction worked well with a broad scope of
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10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
obtained in 78-93% yields with 16-20:1 Z-selectivities and 95-97% Double Stereodifferentiation Reaction with Enantioenriched
ee. Similar results were achieved with meta-substituted aromatic
aldehydes, affording products 6g-i in 75-98% yields with 15-30:1
Z-selectivities and 94-95% ee. Aldehydes with other substitution
patterns also reacted with boronate 5 to give alcohols 6j-k in 79-
83% yields with 16-21:1 Z-selectivities and 93-95% ee. The
reactions of allylboronate 5 with α,β-unsaturated aldehydes
proceeded to furnish products 6l-o in 78-90% yields with 16-30:1
Aldehydes: Double stereodifferentiation reaction is a useful
strategy to form diastereomeric products with high selectivities
from enantioenriched starting materials.30 Depending on the
inherent bias of enantioenriched substrates, these reactions may
proceed under catalyst/reagent control or substrate control. To
probe whether diastereomeric alcohol products can be obtained
selectively by utilizing acid catalyst (R)-A or (S)-A, studies on
reactions of enantioenriched aldehydes 8a-c with allylboronate
5c or 5f were conducted. As shown in Table 3, in the presence
of 5 mol % of catalyst (R)-A, the reaction of (S)-perillaldehyde
(8a) with 5f occurred to give product 9a in 83% yield with 11:1 Z-
selectivity. When (S)-A was used as the catalyst, diastereomer
10a was obtained in 78% with 23:1 Z-selectivity. Aldehyde 8b
reacted with allylboronate 5c in the presence of acid (R)-A to
give product 9b in 71% yield with > 30:1 Z-selectivity and
diastereoselectivity. The Z-selectivity and diastereoselectivity
were equally remarkable (> 30:1) when (S)-A was employed as
the catalyst, affording 10b in 75% yield. Similar results were
achieved in the case of the enantiomeric aldehyde 8c; alcohol
9c and 10c were obtained in 78-82% yields with excellent Z-
selectivities and diastereoselectivities (> 30:1) by employing acid
(R)-A or (S)-A separately. Therefore, through the combination of
enantiomeric aldehydes and catalysts, all four diastereomeric
products (9b-c, 10b-c) were obtained with high Z-selectivities
and diastereoselectivities.31 The data suggest that these
reactions proceeded under complete catalyst-control in all cases.
Z-selectivities and 90-95% ee. Aldehydes that contain
a
heterocycle reacted with boronate 5 to give products 6p-r in 62-
90% yields with high Z-selectivities and 94-95% ee. Moreover,
several representative aliphatic aldehydes also reacted with
boronate 5. Homoallylic alcohol products 6s-u were isolated in
72-81% yields with 23-30:1 Z-selectivities and 90-95% ee.
Table 3. Double stereodifferentiation reactions of enantioenriched aldehydes
with reagent 5 catalyzed by chiral phosphoric acids (R)-A or (S)-Aa
R’
R’
(R)-A (5 mol %)
OH
OH
O
B
or (S)-A (5 mol %)
R’
R’
R
or
R
O
RCHO (8a-c), -45 °C
9
10
4 Å MS, toluene
5c or 5f
OH
OH
Me
Me
with 5f, 5 mol % (R)-A
9a, 83%, dr > 30:1
Z:E = 11:1
with 5f, 5 mol % (S)-A
10a, 78%, dr > 30:1
Z:E = 23:1
OH
OH
O
OH
OH
VO(acac)2, TBHP
PMBO
PMBO
CH2Cl2, 0 °C to rt, 24 h
Me
Me
6u
11, 53%, dr = 7:1
with 5c, 5 mol % (R)-A
9b, 71%, dr > 30:1
Z:E > 30:1
with 5c, 5 mol % (S)-A
10b, 75%, dr > 30:1
Z:E > 30:1
OTBS
OTBS
HO
OH
OH
OH
Grubbs I catalyst
CH2Cl2, rt, 1 h
BocN
PMBO
Me
PMBO
BocN
12
13, 66%
Me
OH
OH
with 5c, 5 mol % (R)-A
9c, 78%, dr > 30:1
Z:E > 30:1
with 5c, 5 mol % (S)-A
10c, 82%, dr > 30:1
Z:E > 30:1
1. (dIpc)2BH, THF, rt, 1 h
then NaOH, H2O2
OH
OTBS
O
O
O
2. TBAF, THF, rt, 3 h
14
H
PMBO
H
PMBO
H
15, 57%
Me
Me
Me
OH OH
8a
8b
8c
Me
OH
H
O
O
i-Pr
i-Pr
O
H
i-Pr
i-Pr
O
OH
OH
Me
H
i-Pr
i-Pr
HO
attenol B
attenol A
O
O
O
O
O
P
P
OH
O
OH
i-Pr
Scheme 6. Transformation of reaction products
i-Pr
i-Pr
i-Pr
(R)-A
i-Pr
i-Pr
(S)-A
Product Derivatization: The alcohol products obtained from the
reaction contain a conjugated diene unit that can undergo a
variety of transformations. As depicted in Scheme 6, hydroxyl
directed epoxidation of 6u using VO(acac)2 gave epoxide 11 in
[a] Reaction conditions: allylboronate 5f (0.12 mmol), aldehyde 8 (0.1 mmol),
phosphoric acid (R)-A or (S)-A (5 mol %), diastereoselectivities and Z/E ratios
were determined by 1H NMR analysis of crude reaction mixtures.
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10.1002/anie.202000039
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53% yield with 7:1 dr.32 Epoxidation of the terminal alkene group
was not detected. Cross-metathesis of TBS ether 12 with (Z)-2-
butene-1,4-diol in the presence Grubbs 1st generation catalyst
provided alcohol 13 in 66% yield with high E-selectivity.33
Regioselective hydroboration/oxidation of the terminal alkene in
14 followed by TBS deprotection with TBAF gave diol 15 in 57%
yield. This structure entity is an important structural motif of
several nature products such as attenols A and B (Scheme 6).34
To further demonstrate the synthetic utility of the develped
method, synthesis of the C1-15 fragment of macrolactin A was
also conducted (please see Supporting Information for details).
(R)-A (5 mol %)
PhCHO, -45 °C
OH
O
B
OH
Ph
6a, 95% ee
O
+
Ph
4 Å MS, toluene
5f
7a, 50% ee
6a:7a = 25:1
O
*
O
P
*
O
O
P
O
O
O
O
H
H
6a
7a
H
O
H
O
B
B
Ph
O
O
Ph
O
O
H
H
TS-9
TS-10
Computational Studies
To better understand the origins of observed Z/E selectivity
and enantioselectivity of the reaction, density functional theory
(DFT)
calculations
at
the
M06-2X/6-311+G(d,p)-
CPCM(toluene)//B3LYP/6-31G(d) level of theory35 using
Gaussian 09 were performed. The uncatalyzed allylation of
benzaldehyde with boronate 5f was studied first. As shown in
Figure 3, the activation free energies of the transition states (TS-
7, TS-8) leading to (±)-6a and (±)-7a are identical, as found
experimentally.
C1
H1
C3
C2
! = -7.7 °
OH
OH
TS-9: ΔG≠ = 10.1 kcal/mol
PhCHO
O
Ph
Ph
B
+
O
4 Å MS, toluene
(±)-6a
(±)-7a
(±)-6a: (±)-7a = 1:1
5f
C1
H1
C3
C2
2.40 Å
TS-7: ΔG≠ = 16.7 kcal/mol
TS-8: ΔG≠ = 16.7 kcal/mol
! = -4.9 °
Figure 3. Optimized transition states of uncatalyzed allylation of benzaldehyde
with boronate 5f
TS-10: ΔG≠ = 10.9 kcal/mol
Figure 4. Axial view of transition states TS-9 and TS-10. The bond lengths are
in Ångstrom.
Next, we explored enantioselective allylboration of
benzaldehyde with boronate 5f in the presence of phosphoric
acid (R)-A using the model developed by the Goodman and the
Houk groups.27 As shown in Figure 4, the addition of boronate 5f
to benzaldehyde leads to product 6a via transition state TS-9
with the vinyl group occupying the pseudo-axial position, while
the reaction via transition state TS-10 with the vinyl group
occupying the pseudo-equatorial position produces alcohol 7a.
Energetically, transition state TS-10 is less favorable than
transition state TS-9 by 0.8 kcal/mol, in reasonable agreement
with the observed Z-selectivity.36 Closely examining the
geometries of these two transition states TS-9 and TS-10
revealed that the vinyl group of allylboronate 5f in TS-10 is
orientated toward isopropyl groups of the acid catalyst (R)-A.
The shortest H−H non-bonding distance between the isopropyl
group and the vinyl group is 2.40 Å (Figure 4), which results in a
steric repulsion between these two groups. Such a destabilizing
interaction is not present in TS-9. Moreover, one of the two
isopropyl groups at the ortho position of the acid catalyst (R)-A
in TS-10 rotated with a dihedral angle of −4.9° (C1-C2-C3-H1,
highlighted in green in Figure 4) to minimize steric interactions.
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10.1002/anie.202000039
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By contrast, the dihedral angle (C1-C2-C3-H1) is −7.7° in TS-9,
TS-9, which indicates that hydrogen bond strength in TS-11 is
weaker than that in TS-9. The different hydrogen bond strengths
therefore influence the electrophilicity of the boron atom of
allylboronate 5f. Consequently, this results in longer C−C and
C−B bond distances in TS-11 (2.26 Å and 1.80 Å) compared to
those in TS-9 (2.20 Å and 1.79 Å). Therefore the chiral
phosphoric acid catalyzed allylboration reaction proceeds
through the more compact and energetically more favored
transition state TS-9 to give alcohol product 6a with high
enantioselectivity.
suggesting the acid catalyst adopts
a
less favorable
conformation in TS-10. All these factors contribute to the energy
difference between transition states TS-9 and TS-10, which
ultimately leads to the observed Z-selectivity in these reactions.
The chiral phosphoric acid (R)-A also dictates the
enantioselective addition of boronate 5f to aldehydes (re-face
attack to give 6a). As shown in Figure 5, the energy of optimized
transition state TS-9 is 2.7 kcal/mol lower than that of TS-11 (si-
face attack to give ent-6a), in good agreement with the
experimentally observed enantioselectivity (95% ee).
The reaction also produced a minor product 7a with E-
To better elucidate the origin of observed enantioselectivity, olefin geometry in 50% ee. We also investigated the origin of its
we performed a distortion/interaction analysis of the transition
states.37 The structures of TS-9 and TS-11 are divided into three
fragments: catalyst (R)-A, benzaldehyde, and the allylboronate
(Figure 5). The calculated distortion energy of TS-11 is 2.1
kcal/mol lower than that of TS-9, while the interaction energy of
TS-11 is 4.6 kcal/mol higher than that of TS-9. Therefore, the
overall energy of TS-11 is 2.5 kcal/mol higher than TS-9 based
on the distortion/interaction analysis model, indicating transition
state TS-9 is more favorable than TS-11.
formation and enantioselectivity. As shown in Figure 5, the H-
bond distances in TS-10 and TS-12, which lead to the formation
of 7a and ent-7a, respectively, are shorter than those in TS-11
because of the orientation of the vinyl group in transition state
TS-11. Therefore, TS-10 and TS-12 are energetically more
favorable than TS-11. The energy difference between TS-10 and
TS-12, however, is only 0.5 kcal/mol, which is consistent with
the 50% ee of 7a observed experimentally.
Conclusion
In summary, we developed
a highly Z-selective and
enantioselective aldehyde allylation with achiral α-vinyl
allylboronate reagents. Chiral phosphoric acid (R)-A serves a
dual-function catalyst: controlling both enantioselective aldehyde
addition and pseudo-axial orientation of the α-vinyl group of the
allylboron reagent in the transition state.38 The origins of
observed enantioselectivity and Z-selectivity are elucidated by
DFT computation studies. Moreover, the results represent a
significant advancement of the chemistry of chiral Brønsted acid
catalysts by defining their ability to enhance the
diastereochemical control (Z-selectivity) through reagent
development while maintaining high enantioselectivity. Synthetic
applications of the method will be reported in due course.
1.80
1.79
2.20
1.63
2.13
1.71
2.26
2.25
6a
ent-6a
TS-9: ΔG≠ = 10.1 kcal/mol
TS-11: ΔG≠ = 12.8 kcal/mol
1.80
1.64
1.79
2.19
1.65
2.11
Acknowledgements
2.18
Financial support provided by Auburn University (to M.C.) is
gratefully acknowledged. We are grateful to the National
Science Foundation (CHE-1764328 to K.N.H) for financial
support of this work. Calculations were performed on the
Hoffman2 cluster at UCLA and the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by the National Science Foundation (OCI-1053575).
2.18
ent-7a
TS-12: ΔG≠ = 11.4 kcal/mol
7a
TS-10: ΔG≠ = 10.9 kcal/mol
Figure 5. Side view of transition states TS-9 to TS-12. The bond lengths are in
Ångstrom.
Keywords: Chiral Phosphoric Acid • α-Vinyl Allylboronate •
Dual-Function Catalysis
The origin of different interaction energies can be
visualized from optimized geometries of the transition states. As
illustrated in Figure 5, the vinyl group is oriented toward the left
side in TS-11. Such an arrangement results in longer H-bonds
(1.71 and 2.25 Å) in the benzaldehyde, allylboronate and
catalyst complex in TS-11 to accommodate the vinyl group. By
contrast, these H-bonds are 1.63 and 2.13 Å, respectively, in
[1]
a) H. Lachance, D. G. Hall, Org. React. 2008, 73, 1; b) C.-H. Ding, X.-L.
Hou, Chem. Rev. 2011, 111, 1914; c) M. Yus, J. C. González-Gómez,
F. Foubelo, Chem. Rev. 2011, 111, 7774; d) M. Yus, J. C. González-
Gómez, F. Foubelo, Chem. Rev. 2013, 113, 5595; e) Science of
Synthesis: Advances in Organoboron Chemistry towards Organic
Synthesis, 2019, E. Fernández, Ed.; Thieme: Stuttgart.
This article is protected by copyright. All rights reserved.

10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
[2]
a) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853; b) S.
Yamasaki, K. Fujii, R. Wada, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2002, 124, 6536; c) R. Wada, K. Oisaki, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2004, 126, 8910; d) R. Yazaki, N. Kumagai, M.
Shibasaki, J. Am. Chem. Soc. 2009, 131, 3195; e) R. Yazaki, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 5522; f) S.-L.
Shi, L.-X. Xu, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2010, 132, 6638; g) X.-F. Wei, X.-W. Xie, Y. Shimizu, M. Kanai, J. Am.
Chem. Soc. 2017, 139, 4647.
[13] a) D. L. Silverio, S. Torker, T. Pilyugina, E. M. Vieira, M. L. Snapper, F.
Haeffner, A. H. Hoveyda, Nature 2013, 494, 216; b) K. Lee, D. L.
Silverio, S. Torker, F. Haeffner, D. W. Robbins, F. W. van der Mei, A. H.
Hoveyda, Nat. Chem. 2016, 8, 768; c) D. W. Robbins, K. Lee, D. L.
Silverio, A. Volkov, S. Torker, A. H. Hoveyda, Angew. Chem., Int.
Ed. 2016, 55, 9610; d) F. W. van der Mei, C. Qin, R. J. Morrison, A. H.
Hoveyda, J. Am. Chem. Soc. 2017, 139, 9053; e) N. W. Mszar, M. S.
Mikus, S. Torker, F. Haeffner, A. H. Hoveyda, Angew. Chem., Int. Ed.
2017, 56, 8736.
[3]
[4]
a) J. Feng, Z. A. Kasun, M. J. Krische, J. Am. Chem. Soc. 2016, 138,
5467; b) I. S. Kim, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc. 2008,
130, 6340; c) I. S. Kim, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc.
2008, 130, 14891; d) I. S. Kim, S. B. Han, M. J. Krische, J. Am. Chem.
Soc. 2009, 131, 2514; e) J. R. Zbieg, E. Yamaguchi, E. L. McInturff, M.
J. Krische, Science 2012, 336, 324.
[14] a) C. Diner, K. J. Szabó, J. Am. Chem. Soc. 2017, 139, 2; b) L. Carosi,
H. Lachance, D. G. Hall, Tetrahedron Lett. 2005, 46, 8981; c) F. Peng,
D. G. Hall, Tetrahedron Lett. 2007, 48, 3305; d) M. Chen, D. H. Ess, W.
R. Roush, J. Am. Chem. Soc. 2010, 132, 7881; e) M. Chen, W. R.
Roush, Org. Lett. 2010, 12, 2706; f) M. Chen, W. R. Roush, J. Am.
Chem. Soc. 2011, 133, 5744; g) M. Chen, W. R. Roush, Org. Lett. 2013,
15, 1662.
a) M. Holmes, L. A. Schwartz, M. J. Krische, Chem. Rev. 2018, 118,
6026; b) E. L. McInturff, E. Yamaguchi, M. J. Krische, J. Am. Chem.
Soc. 2012, 134, 20628; c) L. M. Geary, S. K. Woo, J. C. Leung, M. J.
Krische, Angew. Chem. Int. Ed. 2012, 51, 2972; d) F. Meng, F.
Haeffner, A. H. Hoveyda, J. Am. Chem. Soc. 2014, 136, 11304; e) Y.
Yang, I. B. Perry, G. Lu, P. Liu, S. L. Buchwald, Science 2016, 353,
144; f) K. D. Nguyen, D. Herkommer, M. J. Krische, J. Am. Chem. Soc.
2016, 138, 5238; g) Y. Xiong, G. Zhang, J. Am. Chem. Soc. 2018, 140,
2735; h) R. Y. Liu, Y. Zhou, Y. Yang, S. L. Buchwald, J. Am. Chem.
Soc. 2019, 141, 2251; i) C. Li, R. Y. Liu, L. T. Jesikiewicz, Y. Yang, P.
Liu, S. L. Buchwald, J. Am. Chem. Soc. 2019, 141, 5062; j) S. Gao, M.
Chen, Chem. Sci. 2019, 10, 7554; k) S. Gao, M. Chen, Chem. Commun.
2019, 11199.
[15] For selected references on aldehyde allylboration with enantioenriched,
α-substituted allylboronates: a) R. Stürmer, K. Ritter, R. W. Hoffmann,
Angew. Chem., Int. Ed. 1993, 32, 101; b) N. F. Pelz, A. R. Woodward,
H. E. Burks, J. D. Sieber, J. P. Morken, J. Am. Chem. Soc. 2004, 126,
16328; c) G. Y. Fang, V. K. Aggarwal, Angew. Chem. Int. Ed. 2007, 46,
359; d) L. Carosi, D. G. Hall, Angew. Chem., Int. Ed. 2007, 46, 5913; e)
H. E. Burks, S. Liu, J. P. Morken, J. Am. Chem. Soc. 2007, 129, 8766;
f) M. Binanzer, G. Y. Fang, V. K. Aggarwal, Angew. Chem. Int. Ed.
2010, 49, 4264; g) M. Althaus, A. Mahmood, J. R. Suarez, S. P.
Thomas, V. K. Aggarwal, J. Am. Chem. Soc. 2010, 132, 4025; h) L. T.
Kliman, S. N. Mlynarski, G. E. Ferris, J. P. Morken, Angew. Chem. Int.
Ed. 2012, 51, 521; i) M. J. Hesse, S. Essafi, C. G. Watson, J. N. Harvey,
D. Hirst, C. L. Willis, V. K. Aggarwal, Angew. Chem., Int. Ed. 2014, 53,
6145.
[5]
[6]
a) J. W. A. Kinnaird, P. Y. Ng, K. Kubota, J. L. Leighton, J. Am. Chem.
Soc. 2002, 124, 7920; b) K. Kubota, J. L. Leighton, Angew. Chem. Int.
Ed. 2003, 42, 946; c) H. Kim, S. Ho, J. L. Leighton, J. Am. Chem.
Soc. 2011, 133, 6517.
[16] For α-alkyl substituted allylboronate, the Z/E selectivity is 2:1 typically
for aldehyde allylation. a) R. W. Hoffmann, U. Weidmann, J. Organomet.
Chem. 1980, 195, 137; b) M. Andersen, B. Hildebrandt, G. Koester, R.
W. Hoffmann, Chem. Ber. 1989, 122, 1777; c) R. W. Hoffmann, J. J.
Wolff, Chem. Ber. 1991, 124, 563. For computational studies: d) C.
Gennari, E. Fioravanzo, A. Bernardi, A. Vulpetti, Tetrahedron 1994, 50,
8815.
a) J. W. J. Kennedy, D. G. Hall, J. Am. Chem. Soc. 2002, 124, 11586;
b) T. Ishiyama, T. Ahiko, N. Miyaura, J. Am. Chem. Soc. 2002, 124,
12414; c) V. Rauniyar, D. G. Hall, J. Am. Chem. Soc. 2004, 126, 4518;
d) K. Sakata, H. Fujimoto, J. Am. Chem. Soc. 2008, 130, 12519; e) M.
Chen, W. R. Roush, J. Am. Chem. Soc. 2013, 135, 9512; f) S. Gao, M.
Wang, M. Chen, Org. Lett. 2018, 20, 7921; g) J. Chen, S. Gao, M.
Chen, Org. Lett. 2019, 21, 4638; h) J. Liu, S. Gao, M. Chen,
Tetrahedron 2019, 75, 4110; i) S. Gao, J. Chen, M. Chen, Chem. Sci.
2019, 10, 3637; j) J. Liu, S. Gao, M. Chen, Org. Process Res. Dev.
2019, 23, 1659; k) J. Chen, S. Gao, M. Chen, Org. Lett. 2019, 21, 8880;
l) J. Chen, S. Gao, M. Chen, Org. Lett. 2019, 21, 9893.
[17] a) J. L.-Y. Chen, H. K. Scott, M. J. Hesse, C. L. Willis, V. K. Aggarwal, J.
Am. Chem. Soc. 2013, 135, 5316; b) J. L.-Y. Chen, V. K. Aggarwal,
Angew. Chem. Int. Ed., 2014, 53, 10992.
[18] For carbonyl addition with α-hetero atom substituted allyl boronates, the
selectivity Z/E is > 10:1 in general. a) R. W. Hoffmann, B. Landmann,
Angew. Chem. Int. Ed. 1984, 23, 437; b) E. Beckmann, D. Hoppe,
Synthesis 2005, 217; c) F. Berree, N. Gernigon, A. Hercouet, C. H. Lin,
B. Carboni, Eur. J. Org. Chem. 2009, 329; d) S. Touchet, A. Mace, T.
Roisnel, F. Carreaux, A. Bouillon, B. Carboni, Org. Lett. 2013, 15, 2712.
e) R. J. Morrison, F. W. van der Mei, F. Romiti, A. H. Hoveyda, J. Am.
Chem. Soc. 2020, 142, 436.
[7]
[8]
a) H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79, 1920;
b) R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 1982, 21, 555.
a) H. C. Brown, P. K. Jadhav, J. Am. Chem. Soc. 1983, 105, 2092; b) H.
C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 293; c) H. C.
Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919; d) C. H. Burgos,
E. Canales, K. Matos, J. A. Soderquist, J. Am. Chem. Soc. 2005, 127,
8044; e) E. Canales, K. G. Prasad, J. A. Soderquist, J. Am. Chem.
Soc. 2005, 127, 11572.
[19] a) M. Shimizu, H. Kitagawa, T. Kurahashi, T. Hiyama, Angew. Chem.
Int. Ed. 2001, 40, 4283; b) T. Miura, J. Nakahashi, M. Murakami,
Angew. Chem. Int. Ed. 2017, 56, 6989; c) T. Miura, J. Nakahashi, W.
Zhou, Y. Shiratori, S. G. Stewart, M. Murakami, J. Am. Chem. Soc.
2017, 139, 10903; d) T. Miura, J. Nakahashi, T. Sasatsu, M. Murakami,
Angew. Chem., Int. Ed. 2019, 58, 1138.
[9]
a) W. R. Roush, A. E. Walts, L. K. Hoong, J. Am. Chem. Soc.
1985, 107, 8186; b) W. R. Roush, R. L. Halterman, J. Am. Chem.
Soc. 1986, 108, 294; c) W. R. Roush, K. Ando, D. B. Powers, A. D.
Palkowitz, R. L. Halterman, J. Am. Chem. Soc. 1990, 112, 6339; d) E. J.
Corey, C.-M. Yu, D.-H. Lee, J. Am. Chem. Soc. 1990, 112, 878; e) H.
Lachance, X. Lu, M. Gravel, D. G. Hall, J. Am. Chem.
Soc. 2003, 125, 10160.
[20] a) E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644;
b) J. Kister, A. C. DeBaillie, R. Lira, W. R. Roush, J. Am. Chem. Soc.
2009, 131, 14174; c) S. M. Winbush, W. R. Roush, Org. Lett. 2010,
12, 4344.
[10] a) V. Rauniyar, D. G. Hall, Angew. Chem. Int. Ed. 2006, 45, 2426; b) V.
Rauniyar, H. Zhai, D. G. Hall, J. Am. Chem. Soc. 2008, 130, 8481; c) V.
Rauniyar, D. G. Hall, J. Org. Chem. 2009, 74, 4236.
[21] a) J. Pietruszka, Schöne, N. Angew. Chem. Int. Ed. 2003, 42, 5638; b)
J. Pietruszka, N. Schöne, W. Frey, L. Grundl, Chem. Eur. J. 2008, 14,
5178; c) Y. Gehrke, C. A. Berg, R. Vahabi, J. Pietruszka, Eur. J. Org.
Chem. 2016, 2413.
[11] a) S. Lou, P. N. Moquist, S. E. Schaus, J. Am. Chem. Soc. 2006, 128,
12660; b) D. S. Barnett, P. N. Moquist, S. E. Schaus, Angew. Chem. Int.
Ed. 2009, 48, 8679; c) R. Alam, T. Vollgraff, L. Eriksson, K. J. Szabó, J.
Am. Chem. Soc. 2015 137, 11262.
[22] Reagents 5 can be easily prepared in two steps from CH2Cl2. Please
see SI for details. For related references, see: a) R. W. Hoffmann, B.
Landmann, Chem. Ber. 1986, 119, 1039; b) H. C. Brown, M. V.
Rangaishenvi, S. Jayaraman, Organometallics 1992, 11, 1948.
[12] P. Jain, J. C. Antilla, J. Am. Chem. Soc. 2010, 132, 11884.
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RESEARCH ARTICLE
[23] a) T. Akiyama, J. Itoh, D. Yokota, K. Fuchibe, Angew. Chem., Int. Ed.
2004, 43, 1566; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004,
126, 5356. For selected reviews, see: c) T. Akiyama, Chem. Rev. 2007,
107, 5744; d) M. Terada, Chem. Commun. 2008, 4097; e) T. Akiyama,
K. Mori, Chem. Rev. 2015, 115, 9277.
Pozo, P. H. S. Paioti, S. A. Gonsales, X. Li, F. W. W. Hartrampf, A. H.
Hoveyda, J. Am. Chem. Soc. 2019, 141, 17952.
[24] a) T. Miura, Y. Nishida, M. Morimoto, M. Murakami, J. Am. Chem. Soc.
2013, 135, 11497; b) C. A. Incerti–Pradillos, M. A. Kabeshov, A. V.
Malkov, Angew. Chem. Int. Ed. 2013, 52, 5338; c) Y. Huang, X. Yang,
Z. Lv, C. Cai, C. Kai, Y. Pei, Y. Feng, Angew. Chem. Int. Ed. 2015, 54,
7299; d) P. Barrio, E. Rodriguez, K. Saito, S. Fustero, T. Akiyama,
Chem. Commun. 2015, 51, 5246; e) S. Gao, M. Chen, Org. Lett. 2018,
20, 6174. (f) T. Miura, N. Oku, M. Murakami, Angew. Chem. Int. Ed.
2019, 58, 14620. (g) S. Gao, M. Chen, Org. Lett. 2020, 22, 400.
[25] a) P. Jain, H. Wang, K. N. Houk, J. C. Antilla, Angew. Chem., Int. Ed.
2012, 51, 1391; b) L. R. Reddy, Org. Lett. 2012, 14, 1142; c) M. Chen,
W. R. Roush, J. Am. Chem. Soc. 2012, 134, 10947; d) M. Wang, S.
Khan, E. Miliordos, M. Chen, Org. Lett. 2018, 20, 3810.
[26] a) L. R. Reddy, Chem. Commun. 2012, 48, 9189; b) M. Wang, S. Khan,
E. Miliordos, M. Chen, Adv. Synth. Catal. 2018, 360, 4634.
[27] a) M. N. Grayson, S. C. Pellegrinet, J. M. Goodman, J. Am. Chem. Soc.
2012, 134, 2716; b) H. Wang, P. Jain, J. C. Antilla, K. N. Houk, J. Org.
Chem. 2013, 78, 1208; c) M. N. Grayson, J. M. Goodman, J. Am. Chem.
Soc. 2013, 135, 6142; d) M. N. Grayson, Z. Yang, K. N. Houk, J. Am.
Chem. Soc. 2017, 139, 7717.
[28] a) J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512; b) I.
Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 1991,
113, 4092; c) T. R. Hoye, C. S. Jeffrey, F. Shao, Nat. Protoc. 2007, 2,
2451.
[29] The rate of hydrolysis of borate products derived from the reaction of
aldehydes with boronate 5c can be slow depending on the structure of
aldehyde. In these cases, boronate 5f was used for allylboration. The
borate products from these reactions were readily hydrolyzed to give
alcohol products.
[30] a) S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. Int.
Ed. Engl. 1985, 24, 1; b) M. Chen, W. R. Roush, J. Am. Chem. Soc.
2012, 134, 3925.
[31] S. Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2017, 139, 5627.
[32] a) E. D. Mihelich, K. Daniels, D. J. Eickhoff, J. Am. Chem. Soc. 1981,
103, 7690; b) R. W. Bates, R. Fernández-Moro, S. V. Ley, Tetrahedron
Lett. 1991, 32, 2651.
[33] a) A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2017, 125, 11360; b) G. C. Vougioukalakis, R. H. Grubbs,
Chem. Rev. 2010, 110, 1746.
[34] N. Takada, K. Suenaga, K. Yamada, S.-Z. Zheng, H.-S. Chen, D.
Uemura, Chem. Lett. 1999, 1025.
[35] a) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157; b) Y. Zhao,
D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215; c) M. Cossi, N. Rega,
G. Scalmani, V. J. Barone, Comput. Chem. 2003, 24, 669; d) V. Barone,
M. Cossi, J. Phys. Chem. A 1998, 102, 1995; e) A. D. Becke, J. Chem.
Phys. 1993, 98, 5648; f) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B
1988, 37, 785.
[36] Various DFT methods were benchmarked against experiment with the
def2-tzvpp basis set: ΔΔGǂ (kcal/mol): M062X (0.9), M062X-D3 (0.7),
M11 (0.8), PBE0 (1.0), TPSSh (1.2), Exp (1.5). The calculated energy
difference between TS-10 and TS-9 is in reasonable agreement with
the observed Z-selectivity.
[37] a) F. M. Bickelhaupt, K. N. Houk, Angew. Chem. Int. Ed. 2017, 56,
10070; b) D. H. Ess, K. N. Houk, J. Am. Chem. Soc. 2008, 130, 10187.
c) D. H. Ess, K. N. Houk, J. Am. Chem. Soc. 2007, 129, 10646.
[38] For selected references on dual-function catalysis: a) D. R. Li, A.
Murugan, J. R. Falck, J. Am. Chem. Soc. 2008, 130, 46; b) T. A. Davis,
J. C. Wilt, J. N. Johnston, J. Am. Chem. Soc. 2010, 132, 2880; c) T.
Yukawa, B. Seelig, Y. Xu, H. Morimoto, S. Matsunaga, A. Berkessel, M.
Shibasaki, J. Am. Chem. Soc. 2010, 132, 11988; d) L. Albrecht, G.
Dickmeiss, F. C. Acosta, C. Rodríguez-Escrich, R. L. Davis, K. A.
Jørgenson, J. Am. Chem. Soc. 2012, 134, 2543; e) F. Romiti, J. del
This article is protected by copyright. All rights reserved.

10.1002/anie.202000039
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
R’
R’
OH
Shang Gao,[a], # Meng Duan,[b], #
K. N. Houk,*[b] and Ming
Chen*[a]
(R)-A (5 mol %)
RCHO, -45 °C
A dual function asymmetric
catalysis by a chiral phosphoric
acid catalyst that controls both
enantioselective addition of an
achiral α-vinyl allylboronate to
aldehydes and pseudo-axial
orientation of the α-vinyl group
in the transition state is
O
R’
R’
R
B
O
4 Å MS, toluene
Highly Z-selective
Highly enantioselective
Page No. – Page No.
i-Pr
i-Pr
Chiral Phosphoric Acid Dual-
Function Catalysis:
Asymmetric Allylation with α-
Vinyl Allylboron Reagents
i-Pr
O
O
O
developed.
P
OH
i-Pr
i-Pr
i-Pr
(R)-A
This article is protected by copyright. All rights reserved.