Facile access to functionalized chiral secondary benzylic boronic esters: Via catalytic asymmetric hydroboration

Article abstract of DOI:10.1039/c8sc05613g

Allylic and homoallylic phosphonates bearing an aryl or heteroaryl substituent at the γ- or δ-position undergo rhodium-catalyzed asymmetric hydroboration by pinacolborane to give functionalized chiral secondary benzylic boronic esters in yields up to 86% and enantiomer ratios up to 99:1. Compared to minimally-functionalized terminal and 1,1-disubstituted vinyl arenes, there are relatively few reports of efficient catalytic asymmetric hydroboration (CAHB) of more highly functionalized internal alkenes. Phosphonate substrates bearing a variety of common heterocyclic ring systems, including furan, indole, pyrrole and thiophene derivatives, as well as those bearing basic nitrogen substituents (e.g., morpholine and pyrazine) are tolerated, although donor substituents positioned in close proximity of the alkene can influence the course of the reaction. Stereoisomeric (E)- and (Z)-substrates afford the same major enantiomer of the borated product. Deuterium-labelling studies reveal that rapid (Z)- to (E)-alkene isomerization accounts for the observed (E/Z)-stereoconvergence during CAHB. The synthetic utility of the chiral boronic ester products is illustrated by stereospecific C-B bond transformations including stereoretentive electrophile promoted 1,2-B-to-C migrations, stereoinvertive S_E2 reactions of boron-ate complexes with electrophiles, and stereoretentive palladium- and rhodium-catalyzed cross-coupling protocols.

Full text of DOI:10.1039/c8sc05613g

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Chakrabarty, H.
Palencia, M. D. Morton, R. O. Carr and J. M. Takacs, Chem. Sci., 2019, DOI: 10.1039/C8SC05613G.
This is an Accepted Manuscript, which has been through the
Volume
7 Number 1 January 2016 Pages 1–812
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 8
Chemical Science
View Article Online
DOI: 10.1039/C8SC05613G
Journal Name
ARTICLE
Facile Access to Functionalized Chiral Secondary Benzylic Boronic
Esters via Catalytic Asymmetric Hydroboration
Suman Chakrabarty,a Hector Palencia,b Martha D. Morton,a,c Ryan O. Carr,a and James M. Takacs*,a,c
Received 00th January 20xx,
Accepted 00th January 20xx
Allylic and homoallylic phosphonates bearing an aryl or heteroaryl substituent at the γ- or -position undergo rhodium-
catalyzed asymmetric hydroboration by pinacolborane to give functionalized chiral secondary benzylic boronic esters in
yields up to 86% and enantiomer ratios up to 99:1. Compared to minimally-functionalized terminal and 1,1-disubstituted
vinyl arenes, there are relatively few reports of efficient catalytic asymmetric hydroboration (CAHB) of more highly
functionalized internal alkenes. Phosphonate substrates bearing a variety of common heterocyclic ring systems, including
furan, indole, pyrrole and thiophene derivatives, as well as those bearing basic nitrogen substituents (e.g., morpholine and
pyrazine) are tolerated, although donor substituents positioned in close proximity of the alkene can influence the course of
the reaction. Stereoisomeric (E)- and (Z)-substrates afford the same major enantiomer of the borated product. Deuterium-
labelling studies reveal that rapid (Z)- to (E)-alkene isomerization accounts for the observed (E/Z)-stereoconvergence during
CAHB. The synthetic utility of the chiral boronic ester products is illustrated by stereospecific C-B bond transformations
including stereoretentive electrophile promoted 1,2-B-to-C migrations, stereoinvertive SE2 reactions of boron-ate complexes
with electrophiles, and stereoretentive palladium- and rhodium-catalyzed cross-coupling protocols.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Prior work: CAHB of -aryl methylidenes & , -bisaryl trisubstituted alkenes

 
Introduction
O
EtO P
EtO
CH2
Ph
O
EtO P
EtO
Me
CAHB
Bpin
Chiral alkyl boronic esters possess a unique blend of
benchtop stability and the potential to undergo a variety of C–
B bond transformations via stereospecific 1,2-migration from an
in-situ generated boron “ate-complex” rendering them
especially versatile intermediates for asymmetric synthesis.1,2
Ar
Ar
Ph
(R,R)-T1
O
O
O
Me
Me
P O
Me
1
(R)-2: 4:1 rr
O
(81%, 97:3 er)
Ar
Ar
(R,R)-T1:
(Ar = 3,5-Me2C6H3)
Ph
Ph
Ph
O
CAHB
O
EtO P
EtO
Metal-catalyzed
asymmetric
protoboration3
and
Bpin
X
EtO P
EtO
(R,R)-T1
Ph
hydroboration4,5 of alkenes are among the most common
approaches for the preparation of chiral alkyl boronic esters.
While catalytic asymmetric hydroboration (CAHB) of minimally-
functionalized terminal and 1,1-disubstituted vinyl arenes (e.g.
simple substituted styrene derivatives) have been extensively
investigated,6 there are relatively few reports using more highly
functionalized di- or trisubstituted internal alkenes.7 The latter
have been a focus of our research into CAHB. Herein, we
disclose that 1,2-disubstituted allyl phosphonates bearing an
aryl substituent at the γ-position are efficient substrates and
provide facile access to functionalized chiral, secondary benzylic
and related α-aryl boronic esters.8
O
O
Ph
(R)-4: 3:1 rr
(60%, 97:3 er)
P N
(E)-3
Bn
X
This work: CAHB of -aryl 1,2-disubstituted alkenes

(R)-B1: X = Ph
(R)-B2: X = H
Ph
O
EtO P
EtO
pinB
O
EtO P
Ph
O
EtO P
EtO
EtO
(E)-5a
or
CAHB
oxidation
Ph
OH
(R)-B1
O
EtO P
EtO
O
EtO P
EtO
Ph
Bpin
(82%, 96:4 er)
Ph
(Z)-5a
(S)-6a: >20:1 rr
We previously reported that methylidene substrates
bearing β-phenyl substitution undergo efficient rhodium-
Figure 1: Directed-CAHB of allylic phosphonate-functionalized vinyl arenes varying
in substitution pattern. Standard CAHB conditions: 1 mol% Rh(nbd)2BF4 or 0.5
mol% [Rh(cod)Cl]2/1 mol% AgBF4, 1 mol% (R,R)-T1 or (R)-B1, 1.1 eq. pinacolborane
(pinBH), 3 h, rt. Oxidation conditions: NaBO3.4H2O/H2O.
a. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska
68588-0304, USA.
catalyzed CAHB with pinacolborane (pinBH) to give chiral
tertiary boronic esters via regioselective β-boration. For
example, 1 affords (R)-2 (81%) in a 97:3 enantiomer ratio (er);
the β: regioisomer ratio (rr) is 4:1 or greater under the
conditions described in Figure 1.5a Similarly, the trisubstituted
alkene (E)-3, bearing phenyl substituents at both the β- and γ-
b. Department of Chemistry, University of Nebraska-Kearney, Kearney, Nebraska
68849, USA.
c. Nebraska Center for Integrated Biomolecular Communication (NCIBC), University
of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304, USA.
Corresponding author e-mail: jtakacs1@unl.edu
Electronic Supplementary Information (ESI) available: [Experimental Procedures
and Characterization Data & Spectral Data]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 8
ARTICLE
Journal Name
positions, undergoes preferential β-boration (3:1 rr) to afford often necessitating its use in excess, a stoichiometric amount of
View Article Online
the chiral, tertiary boronic ester product (R)-4 (60%, 97:3 er).5a pinBH is usually enough for complete CAHB of these allylic
DOI: 10.1039/C8SC05613G
We now report that 5a and related substrates bearing a phosphonates.
phenyl, aryl or heteroaryl substituent at the γ-position undergo
The choice of chiral ligand is, of course, critical to the
preferential γ-boration to afford new chiral, secondary benzylic success of CAHB.12 As indicated in Figure 1, rhodium catalyst
boronic esters. The benzylic regiochemistry presumably arises systems incorporating the TADDOL-derived chiral cyclic
from the favorable formation of a rhodium π-benzyl complex of monophosphite (R,R)-T1 give efficient enantioinduction for β-
the substrate in the course of reaction.9 We were surprised to aryl methylidene substrate 1 and the β,γ-bisaryl trisubstituted
find that the alkene stereochemistry does not impact the alkene (E)-3. Its use with 5a gives (S)-6a in good yield (81%, after
overall regio- or stereochemical course of the reaction. Both (E)- oxidation), but with only a low level of enantioinduction (64:36
and (Z)-5a afford the same γ-borated product 6a in greater than er). In contrast, the BINOL-derived phosphoramidite (R)-B1
20:1 rr using (R)-B1; C–B bond oxidation using NaBO3.4H2O affords high levels of regiocontrol and enantioselectivity.13
affords the known chiral alcohol10 shown (82%, 96:4 er).
Scope of Aryl and Heteroaryl Substrates. Figure 2
summarizes results obtained for a series of substrates 5b–t in
which the nature of the aromatic ring appended at the γ-
position varies. In addition to the major γ-boration product 6
and the minor regioisomeric β-boration product 7, alkene
reduction (i.e., 8) typically comprises the remaining 5-15% of
the product mixture. The latter reaction mode arises from a
competing catalytic cycle and is the subject of ongoing studies;14
it will not be discussed further here. Herein, we focus on the
regio- and enantioselectivity of the rhodium-catalyzed
hydroboration mode.15
Results and Discussions
Two alternative rhodium catalyst precursors are used in
this study. A 1:1 combination of [Rh(nbd)2BF4/(R)-B1] can be
replaced by an in situ generated 1:1 [Rh(cod)BF4/(R)-B1]
catalyst formed by treating [Rh(cod)Cl]2 with AgBF4 and the
chiral ligand. The catalysts afford near identical results, but the
latter protocol is more economical. While pinBH is known to
undergo relatively facile rhodium-catalyzed degradation,11 thus
[1 mol% Rh(nbd)2BF4] or
[0.5 mol% [Rh(cod)Cl]2/1 mol% AgBF4]
O
EtO P
EtO
O
EtO P
EtO
Bpin
O
EtO P
EtO
O
EtO P
EtO
O
Ar
Ar
Ar
+
+
Ar
OH
1 mol% (R)-B1
EtO P
EtO
Ar
Oxidation
Bpin
NaBO3.4H2O
pinBH (1.1-2 eq.), r. t., 3-12 h
(R/S)-6
-boration product
(major regioisomer)
7
8
(R/S)-9
5
xx
xx
reduced product
(ca. 5-15%)
-boration product

(minor regioisomer)

Isolated yield reported
Enantiomer ratio (er)
determined
Inseparable mixture of CAHB products
Regioisomer ratio (rr) of 6:7 is determined via 31P NMR analysis of the crude reaction mixture
CH3
CF3
F
OMe
O
O
O
O
O
EtO P
EtO
EtO P
EtO
EtO P
EtO
EtO P
EtO
EtO P
EtO
OMe
Bpin
Bpin
Bpin
Bpin
Bpin
(S)-6b: >20:1 rr
(S)-6c: >20:1 rr
(S)-6d: 11:1 rr
(S)-6e: 10:1 rr
(S)-6f: >20:1 rr
(S)-9b: 84%, 97:3 er
(S)-9c: 78%, 97:3 er
(S)-9d: 71%, 94:6 er
(S)-9e: 77%, 94:6 er
(S)-9f: 83%, 98:2 er
Boc
O
N
N
N
N
MeO
O
O
O
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
EtO P
EtO
Bpin
Bpin
Bpin
Bpin
Bpin
(S)-6h:b 9:1 rr
(S)-6i:a,b >20:1 rr
(S)-6j:a,b 12:1 rr
(S)-6k:a,b >20:1 rr
(S)-6g: >20:1 rr
(S)-9g: 70%, 94:6 er
(S)-9h: 72%, 94:6 er)
(S)-9i: 67%, 92:8 er
(S)-9j: 55%, 94:6 er
(S)-9k: 68%, 91:9 er
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
N Boc
S
N
Boc
N
Boc
S
Bpin
Bpin
Bpin
Bpin
Bpin
(S)-6l:a >20:1 rr
(S)-6m:a,b >20:1 rr
(R)-6n:a >20:1 rr
(S)-6o: >20:1 rr
(S)-9o: 83%, 85:15 er
(S)-6p: >20:1 rr
9p: 80%, 95:5 er
(S)-9l: 78%, 96:4 er
(S)-9m: 86%, 99:1 er
(R)-9n: 85%, 80:20 er
(S)-
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
O
Me
S
O
O
Bpin
Bpin
Bpin
Bpin
(S)-6q: 5:1 rr
(S)-9q: 65%, 89:11 er
(S)-6r: 6:1 rr
(S)-9r: 76%, 83:17 er
(S)-6s: >20:1 rr
(S)-9s: 82%, 84:16 er
(S)-6t: 4:1 rr
(S)-9t: 55%, 79:21 er
Figure 2: Substrate scope for CAHB of γ-aryl allylic phosphonates. Note: a Two equivalents of pinacolborane were used. b Reaction carried out for 12 hours.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 8
Chemical Science
View Article Online
DOI: 10.1039/C8SC05613G
Journal Name
ARTICLE
A range of donor and acceptor substituents are well- illustrate a caveat for substrates bearing multiple donor groups
tolerated with relatively minor fluctuations in regio- and/or in proximity to the alkene or bear relatively bulky aromatic ring
enantioselectivity. For example, the 4-methylphenyl derivative systems. Using the Birman benzotetramisole (BTM)17 chiral
5b and the 4-trifluoromethylphenyl derivative 5c undergo γ- acylation catalyst, a kinetic resolution (KR) strategy was
boration with high regioselectivity (>20:1 rr) yielding 9b (84%, employed to confirm the absolute configuration assignments
97:3 er) and 9c (78%, 97:3 er) after oxidation of the for several of the previously unreported chiral secondary
corresponding secondary benzylic boronic esters (i.e., 6b and benzylic alcohols 9 prepared via CAHB. As shown in Figure 3A,
6c). The 4-fluorophenyl (5d) and 4-methyoxyphenyl (5e) the (S)-BTM-catalyzed acylation of a racemic sample of (±)-9a
derivatives exhibit somewhat lower levels of γ:β regioselectivity with 0.5 equivalents of isobutyric anhydride results in the rapid
(6d–e, 10-11:1 rr) and enantioselectivity affording 9d (71%, 94:6 acylation of (S)-9a to (S)-10a and recovery of the known (R)-9a
er) and 9e (77%, 94:6 er), respectively. In contrast, the 3- unreacted alcohol.
methoxyphenyl derivative 5f and 3,4-methylenedioxyphenyl
A
General Scheme for kinetic resolution via acylation using benzotetramisole (BTM)
.
derivative 5g again exhibit higher regioselectivity (6f-g: >20:1 rr)
leading to 9f (83%, 98:2 er) and 9g (70%, 94:6 er), after
oxidation. The 2-methoxyphenyl derivative 5h exhibits reduced
regioselectivity (6h: 9:1 rr), but otherwise good conversion to
yield 9h (72%, 94:6 er).16 The 4-dimethylamino, morpholine,
and pyrazine derivatives 5i–k demonstrate the viability of
substrates bearing basic nitrogen functionality; 9i–k are
obtained in moderate to good yields (55-68%) and up to 94:6 er.
In addition to demonstrating tolerance for basic nitrogen in
several of the substrates described in Figure 2, it is pleasing to
see that substrates incorporating some heteroaromatic ring
systems also undergo efficient CAHB, albeit with some unusual
variation in regio- and/or enantioselectivity. For example, the
Boc-protected indole derivative 5l exhibits high -
regioselectivity (6l, >20:1 rr) with good enantioinduction after
oxidation to 9l (78%, 96:4 er). Similarly, the 3-substituted N-
Boc-protected pyrrole derivative 5m is both highly
regioselective (6m, >20:1 rr) and highly enantioselective; the er
obtained for 9m (86%, 99:1 er) is the highest obtained among
the substrates tested. However, the results obtained for CAHB
of the 2-substituted N-Boc-protected pyrrole derivative 5n
differ markedly. The regioselectivity of 6n (>20:1 rr) is excellent.
However, the level of enantioselectivity for 9n (85%, 80:20 er)
is not only much lower but results from hydroboration with the
opposite sense of π-facial selectivity compared to most other
substrates (vide infra); (R)-9n is the major product.
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
KR
(R)
(S)
Ph
Ph
Ph
OH
+
(S)-BTM
O
O
OH
(±)-9a
(R)-9a
31P NMR 32.88 ppm

(S)-
10a
Kinetic Resolution (KR) Conditions:
S
31P NMR 30.95 ppm

N
isobutyric anhydride (0.5 eq)
(S)-BTM (5 mol%)
Hunig's Base (1.0 eq)
N
Ph
CDCl3 (Substrate conc. = 0.1 M)
(
S)-Benzotetramisole (BTM)
B. 31P NMR analysis for assignment of absolute configuration via KR
O
EtO P
EtO
Ph
(iPrC=O)2O
(iPrC=O)2O
OH
(S)-(-)-9a
(S)-BTM
(R)-BTM
9a
10a
9a
10a
C. Absolute configuration assignments of benzyl alcohol products containing
heterocyclic ring systems via KR
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
N-Boc
S
O
OH
OH
OH
(S)-9m (99:1 er)
(R)-BTM: 2% conv. (12 h)
(S)-BTM: 27% conv. (12 h)
(S)-9o (85:15 er)
(R)-BTM: 4% conv. (1 h)
(S)-BTM: 30% conv. (1 h)
(S)-9r (83:17 er)
(R)-BTM: 6% conv. (12 h)
(S)-BTM: 41% conv. (12 h)
The 3- and 2-substituted thiophene substrates (i.e., 5o and
5p) exhibit high regioselectivity leading to 6o and 6p (>20:1 rr),
respectively. However, the 3-substituted thiophene 5o affords
9o (83%, 85:15 er) with only modest levels of stereocontrol,
while the 2-substituted thiophene 5p gives 9p (80%, 95:5 er)
with good stereocontrol. The 2-substituted benzothiophene 5q
gives both lower levels of regiocontrol (6q, 5:1 rr) and
enantioselectivity for 9q (65%, 89:11 er). The corresponding
furan derivatives 5r–t give similar results.
O
EtO P
EtO
O
O
Me
EtO P
EtO
EtO P
EtO
N
Boc
S
O
OH
OH
OH
(R)-9n (80:20 er)
)-BTM: 21% conv. (12 h)
(S)-BTM: 3% conv. (12 h)
(S)-9p (95:5 er)
)-BTM: 2% conv. (1 h)
(S)-BTM: 31% conv. (1 h)
(S)-9s (84:16 er)
)-BTM: 3% conv. (12 h)
(S)-BTM: 14% conv. (12 h)
(
R
(
R
(
R
Figure 3: Stereochemical assignments based on kinetic resolution.
Alcohol 9 and ester 10 are readily differentiated by 31P NMR
spectroscopy providing a convenient protocol for the rapid
Stereochemical Assignments. The variable regio- and
stereochemical results obtained with heteroaryl derivatives
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 8
ARTICLE
Journal Name
determination of absolute configuration of these previously significant erosion of enantiopurity. Using the same conditions,
View Article Online
DOI: 10.1039/C8SC05613G
unreported chemical entities (Figure 3B). As demonstrated by cross-coupling of (S)-6a with 4-iodoanisole yields (S)-13 (60%,
the 31P NMR stack-plot, (S)-9a (96:4 er) is more rapidly acylated 77:23 er, 80% sr). The latter is useful, since we were unable to
using (S)-BTM than with (R)-BTM. Using this method, we prepare 13 via the 1,2-B-to-C migration protocol. An alternative
assigned the absolute configurations for the -hydroxy rhodium-catalyzed cross-coupling procedure reported by
heteroaryl products obtained via CAHB/oxidation (Figure 3C). Aggarwal23 effects the stereoretentive addition of (S)-6a to 4-
For example, the 3-substituted pyrrole derivative 9m (99:1 er), nitrobenzaldehyde to afford aryl ketone (S)-14 (74%, 94:6 er)
synthesized via CAHB/oxidation using (R)-B1, undergoes more after oxidation; the latter cross-coupling proceeds with only
rapid (S)-BTM-catalyzed acylation to 10m (27% conversion in 12 slight erosion of enantiopurity over two steps.
O
EtO P
EtO
h) compared to (R)-BTM-catalyzed acylation (2% conversion in
Ph
12 h). The relative rates are consistent with predominant (S)-
configuration of 9m. In contrast, the 2-pyrrole derivative 9n
(80:20 er), also prepared via CAHB/oxidation, undergoes
relatively sluggish (S)-BTM-catalyzed acylation to 10n compared
to (R)-BTM-catalyzed acylation. The results indicate that
predominantly (R)-9n is formed from the 2-substituted pyrrole
by CAHB with (R)-B1. We speculate that the N-Boc moiety in the
latter acts as an alternative directing group in the rhodium-
catalyzed hydroboration thereby switching the sense of alkene
π-facial selectivity. Although one might reasonably expect that
2-subsituted thiophene and furan derivatives behave similarly,
the data summarized in Figure 3c indicate that (S)-9o-p and (S)-
9r-s are the major stereoisomers produced via CAHB/oxidation.
In our prior studies of phosphonate-directed CAHB, we
illustrated the synthetic utility of chiral bifunctional tertiary
(R)-11
O
O
EtO P
EtO
79%, 95:5 er
EtO P
EtO
Ph
O
Ph
N
N
a
(R)-16
55%, 94:6 er
(S)-12
c
g
or
b
O
EtO P
EtO
b: 68%, 96:4 er
OMe
Ph
Ph
Bpin
(Aggarwal condition)
c: 55%, 70:30 er (73% sr)
(Crudden condition)
(S)-6a (96:4 er)
d
f
O
O
EtO P
EtO
Ph
EtO P
EtO
e
(S)-13
60%, 77:23 er
(80% sr)
O
EtO P
EtO
Ph
OMe
organoboron
derivatives
through
thiophosphonate
(S)-15
95%, 95:5 er
olefination5b chemistry and -oxophosphonate active ester5a
chemistry as well as through a number of stereospecific C–B
bond transformations. Here, we focus on the use of (S)-6a (96:4
er) in stereoretentive and stereoinvertive C-B bond
transformations via intermediate boron-ate complexes (Figure
4). Stereoretentive cross-coupling with carbanions derived from
electron rich vinyl and aromatic derivatives via electrophile-
promoted 1,2-B-to-C migration of a boron-ate complex is
generally facile under conditions reported by Aggarwal.2b, 2e For
example, treatment of (S)-6a with excess vinyl magnesium
bromide followed by I2 and sodium methoxide affords the vinyl
derivative (R)-11 (79%, 95:5 er) in high levels of
stereoretention.2e Similarly, reaction of (S)-6a with 2-
lithiobenzofuran followed by NBS affords the gem-bisaryl
product (S)-12 (68%, 96:4 er) with essentially complete
enantiospecificity.2b
O
*sr = % stereoretention
% major enantiomer
O2N
(S)-14
74%, 94:6 er
(product)
=
% major enantiomer
x 100
(starting material)
Reagents and Conditions: (a) i. Excess CH2=CHMgBr, THF, -78 oC to rt; ii. I2/MeOH,
-78 oC; iii. NaOMe/MeOH; iv. Na2S2O3 (aq.); (b) i. benzofuran-2-yllithium, THF, -78
oC; ii. NBS, THF, -78 oC; iii. Na2S2SO3 (aq.); (c) 2-iodobenzofuran, Ag2O,
Pd2(dba)3/PPh3, THF, 60 oC; (d) 4-iodoanisole, Ag2O, Pd2(dba)3/PPh3, THF, 60 oC; (e)
i. 4-nitrobenzaldehyde, [Rh(cod)Cl]2, KHF2, dioxane/H2O ; ii. TEMPO, TCCA, CH2Cl2;
(f) (3,5-bis(trifluoromethyl)phenyl)lithium, THF, -78 oC to -40 oC; ii.
rt.; iii. NaHCO3 (aq.). (g) i. (3,5-
bis(trifluoromethyl)phenyl)lithium, THF, -78 oC to -40 oC; ii. 4-
Methoxybenzenediazonium tetrafluoroborate, 0 oC iii. NaHCO3 (aq.)
Cycloheptatrienyl tetrafluoroborate
,
Figure 4: Product utility illustrated by stereoretentive and stereoinvertive C-B
bond transformations.
The palladium-catalyzed cross-coupling of chiral boronic
esters has attracted recent interest both due to its synthetic
utility and the interesting mechanistic issue of stereoretention18
or stereoinversion;19 the outcome is often dependent upon
participation or non-participation of polar substituents in the
substrate.20,21 Benzylic boronic esters are rather unique in the
context of palladium-catalyzed cross-coupling. Only the
protocol recently introduced by Crudden22 is reportedly
effective. Its efficiency varies, but in favorable constructs, the
latter proceeds with 84-94% stereoretention (sr). Thus, the
outcome for the bifunctional substrate (S)-6a (96:4 er) was
uncertain. In our hands, cross-coupling with 2-iodobenzofuran
under the [Pd2(dba)3/PPh3/Ag2O] conditions reported by
Crudden gives (S)-12 (55%, 70:30 er, 73% sr); cross-coupling
proceeds with predominant stereoretention, albeit with
Aggarwal reported that ate-complexes of secondary boronic
esters react with strong electrophiles via a stereoinvertive SE2
mechanism.2f We find that the intermediate boron-ate complex
formed by addition of (3,5-bis(trifluoromethyl)phenyl) lithium
to (S)-6a (96:4 er) readily reacts with cycloheptatrienyl
tetrafluoroborate to effect the net C-B to C-C bond substitution
to give (S)-15 (95%, 95:5 er) in excellent yield. Similarly, the net
stereoinvertive C-B to C-N bond substitution is accomplished by
treating the in situ generated boron ate-complex with 4-
methoxybenzenediazonium tetrafluoroborate to give the diazo
compound (R)-16 (55%, 94:6 er).
Additional Substrate Scope and Some Key Mechanistic
Insights. The question naturally arises as to whether the
phosphonate directing group is unique in promoting -boration
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
with these vinyl arene substrates. That appears not to be the deuteration as determined by mass spectral ViaewnAarltyicsleisO.nliInne
case (Figure 5A); the corresponding benzylamide substrate (E)- contrast, CAHB/oxidation of (Z)-5a usingDpOinI:B1D0.1a0f3f9o/rCd8sS:C3005%613oGf
17 undergoes regioselective (7:1 rr) amide-directed CAHB using non-deuterated (3S)-9a; 47% of a mixture of diastereomeric
(R)-B1 to afford the analogous -borated benzylic ester (S)-18 monodeuterated products 2-d-(2S,3S)-9a; and 2-d-(2R,3S)-9a
(78%, 94:6 er).24
and 21% of the dideuterated product 2,2-d2-(3S)-9a. The
The one-carbon homolog of (E)-5a, that is, the γ,δ- dideuterated product presumably arises by the reaction of 2-d-
unsaturated phosphonate substrate (E)-19, reacts under the (E)-5a with pinBD. The latter, when generated in situ via
standard conditions to afford predominantly (>20:1 rr) δ- isomerization of (Z)-5a as described above, also generates an
borated benzylic boronic ester (S)-20 (79%, 94:6 er) after equivalent amount of pinBH that can react competitively to give
oxidation (Figure 5B). Furthermore, as was noted for (E)- and the observed diastereomeric monodeuterated product and an
(Z)-5a, the same major enantiomer of 20 is formed independent increased amount of the non-deuterated product as is
of the substrate alkene geometry; (Z)-19 also affords (S)-20 observed. See the SI for more detailed mechanistic schemes.
(81%, 94:6 er). The ability to start with pure (E)-, pure (Z)- or an
A. (Z)- to (E)-substrate isomerization is observed under standard CAHB conditions:
(E/Z)-mixture and arrive at the same product is a practical
O
EtO P
EtO
H
O
EtO P
EtO
H
O
EtO P
EtO
1 mol% Rh(nbd)2BF4
1 mol% (R)-B1
advantage but raises mechanistic questions. We previously
reported that the amide-directed CAHBs of (E)- and (Z)-
trisubstituted alkenes proceed with the same sense of -facial
selectivity and therefore lead to diastereomers.5f Those results
would have suggested that (E)- and (Z)-19 (and similarly (E)- and
(Z)-5a) should lead to enantiomers not the same product.
Ph
H
Ph
(S) Ph
+
0.4 eq. pinBH
3 h, r t.
H OH
H
(Z)-5a
(90:10 Z:E)
(3S)-9a
30%, 95:5 er
(E)-5a
Recovered isomerized
alkene
Starting E/Z-Mixture
Recovered E/Z-Mixture
(E)-H (E)-H
(Z)-H
(Z)-H
A. Analogous amide substrate undergoes efficient CAHB using B1
O
O
CAHB

Ph
Ph
Ph
N
H
Ph
N
H
(R)-B1
Bpin
(E)-17
(S)-18: 7:1 rr (78%, 94:6 er)
B. One-carbon homologous substrates perform with similar efficiency:
Same major enantiomer obtained from (E)- and (Z)-substrates
B. Different distriubutions of deuterated products are obtained when isomeric (E)-
or (Z)-substrates react with PinBD under standard CAHB conditions:

% formed from
EtO
EtO P
CAHB with (R)-B1
O
EtO P
EtO
Ph
H H
(S) Ph
CAHB
(top face)

(E)-5a: 17%
(Z)-5a: 30%
>20:1 rr
(79%, 94:6 er)
O
pinBH
(E)-19
H OH
(3S)-9a
EtO
EtO P
O
EtO P
EtO
H
(E)

Ph
Ph
O
Bpin

EtO
EtO P
H
O
EtO P
EtO
(S)-20
H D
(S) Ph
CAHB with (R)-B1

CAHB
(top face)
(E)-5a
O
Ph
(S)
>20:1 rr
(81%, 94:6 er)
(E)-5a: 83%
(Z)-5a: 47%
(Z)-19a
pinBD
H OH
2-d-(2S,3S)-9a
(Z)-5a
O
EtO P
EtO
D H
(S) Ph
CAHB
pinBD
CAHB
(top face)
Figure 5: The influence of other structural variations on the directed CAHB of 1,2-
disubstituted alkenes. Note: Yield and er were determined after oxidation to the
corresponding alcohols. a Z:E ratio = 4:1.
(R)
pinBH
H OH
O
EtO P
EtO
D
(E)
2-d-(2R,3S)-9a
Ph
The origin of (E/Z)-isomer stereoconvergence is resolved
based on the results of CAHB of (Z)-5a using a limiting amount
of pinBH (Figure 6A) and deuterium labelling via CAHB of (E)-
and (Z)-5a with pinBD (Figure 6B). With respect to the first test,
a sample enriched in (Z)-isomer of 5a (90:10 Z:E) is subjected to
the otherwise standard CAHB conditions, but using a limiting
amount of pinBH (0.4 equiv.), leading to partial boration and
recovered alkene. The 1H NMR spectral windows for the starting
and recovered E/Z-mixtures of 5a shown in Figure 6A indicate
that (Z)-5a is essentially completely converted to the (E)-isomer
under the reaction conditions, thus providing a mechanism by
which the two isomers lead to the same product.
Figure 6B shows the results of deuterium labelling. CAHB of
(E)- and (Z)-5a using pinBD affords different distributions of
non-, isomeric mono- and di-deuterated products.
CAHB/oxidation of (E)-5a using pinBD yields essentially a single
monodeuterated product 2-d-(2S,3S)-9a (83%) accompanied by
the non-deuterated (3S)-9a (17%) with no apparent di-
O
EtO P
EtO
H
D D
CAHB
(top face)
(S) Ph
2-d-(E)-5a
(E)-5a: 0%
(Z)-5a: 21%
pinBD
H OH
2,2-d2-(3S)-9a
Figure 6: Mechanistic studies indicating the origin of (E/Z)-stereoconvergent CAHB
arises via Z to E isomerization under the reaction conditions.
Some Current Limitations. The attempted CAHB of several
related phosphonates reveal some current limitations of the
[Rh(nbd)2BF4/B1] catalyst system (Figure 7). (i) The vinyl (i.e.,
-unsaturated) phosphonate (E)-21 is largely recovered
unchanged when subjected to the standard CAHB conditions.
(ii) The trisubstituted variants (E)-22 and (E)-23 react only
sluggishly under the standard conditions. (iii) In contrast to the
vinylarene substrate (E)-5a, similar internal alkenes bearing an
alkyl rather than aryl/heteroaryl γ-substituent (e.g., (E)-24)
undergo predominantly -boration, albeit with modest regio-
and enantioselectivity with the standard catalyst system. (iv)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 8
ARTICLE
Journal Name
The -unsaturated vinyl arene (E)-25 affords the
corresponding benzylic boronic ester upon CAHB but again with
only modest regioselectivity, yield, and enantiopurity. It should
be noted, however, that these results can only be said to reflect
limitations of the [Rh(nbd)2BF4/B1] catalyst system; systematic
catalyst optimizations have not been carried out for these
substrates.
Acknowledgements
Funding from the NIH National Institutes of General Medical
Sciences (R01 GM100101) is gratefully acknowledged. We thank
Dr. Jian Zhang, Dr. Jingshi Lu and Mr. Nicholas Armada for
View Article Online
DOI: 10.1039/C8SC05613G
assistance
in
preparing
(Z)-5a
and
(Z)-19
via
photoisomerization.25
O
EtO P
EtO
O
EtO P
EtO
O
EtO P
EtO
Me



Ph
Ph
Ph



Notes and references
1
Me
(E)-21
Reacts sluggishly
(E)-22
Reacts sluggishly
23
(E)-
For leading examples, see (a) J. Wu, P. Lorenzo, S. Zhong, M.
Ali, C. P. Butts, E. L. Myers and V. K. Aggarwal, Nature, 2017,
547, 436; (b) B. S. L. Collins, C. M. Wilson, E. L. Myers and V. K.
Aggarwal, Angew. Chem., Int. Ed., 2017, 56, 11700; (c) J.
Schmidt, J. Choi, A. T. Liu, M. Slusarczyk and G. C. Fu, Science,
2016, 354, 1265; (d) C.M. Crudden, C. Ziebenhaus, J. P. G.
Rygus, K. Ghozati, P. J. Unsworth, M. Nambo, S. Voth, M.
Hutchinson, V. S. Laberge, Y. Maekawa and D. Imao, Nat.
Commun., 2016, 7, 11065; (e) S. C. Matthew, B. W. Glasspoole,
P. Eisenberger and C. M. Crudden, J. Am. Chem. Soc., 2014,
136, 5828.
For selected examples, see: (a) L. Zhang, G. J. Lovinger, E. K.
Edelstein, A. A. Szymaniak, M. P. Chierchia and J. P. Morken,
Science, 2016, 351, 70; (b) A. Bonet, M. Odachowski, D.
Leonori, S. Essafi and V. K. Aggarwal, Nat. Chem., 2014, 6, 584;
(c) M. Burns, S. Essafi, J. R. Bame, S. P. Bull, M. P. Webster, S.
Balieu, J. W. Dale, C. P. Butts, J. N. Harvey and V. K. Aggarwal,
Nature, 2014, 513, 183; (d) C. G. Watson, A. Balanta, T. G.
Elford, S. Essafi, J. N. Harvey and V. K. Aggarwal, J. Am. Chem.
Soc., 2014, 136, 17370; (e) R. P. Sonawane, V. Jheengut, C.
Rabalakos, R. Larouche-Gauthier, H. K. Scott and V. K.
Aggarwal, Angew. Chem., Int. Ed., 2011, 50, 3760. (f) R.
Larouche-Gauthier, T. G. Elford and V. K. Aggarwal, J. Am.
Chem. Soc., 2011, 133, 16794. For reviews, see: (g) C.
Sandford and V. K. Aggarwal, Chem. Commun., 2017, 53,
5481; (h) R. J. Armstrong and V. K. Aggarwal, Synthesis, 2017,
49, 3323; (i) D. Leonori and V. K. Aggarwal, Angew. Chem., Int.
Ed., 2015, 54, 1082.
For key examples, see (a) B. Liu, H-H. Wu and J. Zhang, ACS
Catal., 2018, 8, 8318; (b) Y. Cai, X-T. Yang, S-Q. Zhang, F. Li, Y-
Q. Li, L-X. Ruan, X. Hong and S-L. Shi, Angew. Chem., Int. Ed.,
2018, 57, 1376; (c) L. Chen, X. Zou, H. Zhao and S. Xu, Org.
Lett., 2017, 19, 3676; (d) C. Jarava-Barrera, A. Parra, A. Lopez,
F. Cruz-Acosta, D. Collado-Sanz, D. J. Cardenas and M.
Tortosa, ACS Catal., 2016, 6, 442; (e) H. Lee, B. Y. Lee and J.
Yun, Org. Lett., 2015, 17, 764; (f) Z. T. He, Y. S. Zhao, P. Tian,
C. C. Wang, H. Q. Dong and G. Q. Lin, Org. Lett., 2014, 16,
1426; (g) A. Parra, L. Amenos, M. Guisan-Ceinos, A. Lopez, J. L.
G. Ruano and M. Tortosa, J. Am. Chem. Soc., 2014, 136, 15833;
(h) J. C. H. Lee, R. McDonald and D. G. Hall, Nat. Chem., 2011,
3, 894; (i) Y. Sasaki, C. Zhong, M. Sawamura and H. Ito, J. Am.
Chem. Soc., 2010, 132, 1226; (j) Y. Lee and A. H. Hoveyda, J.
Am. Chem. Soc., 2009, 131, 3160; (k) J. M. O’Brien, K. S. Lee
and A. H. Hoveyda, J. Am. Chem. Soc., 2010, 132, 10630; (l) I-
H. Chen, L. Yin, W. Itano, M. Kanai and M. Shibasaki, J. Am.
Chem. Soc., 2009, 131, 11664.
Reacts sluggishly
O
EtO P
EtO
O
EtO P
EtO


Ph
Ph


(E)-24
(E)-25
Major product = boronate

60% yield ( : = 1:3), 75:25 er
Major product = boronate

47% yield ( : = 2.5:1), 88:12 er
 
 
Figure 7: Current limitations of the methodology.
2
Conclusions
While the regioselective, CAHBs of minimally-
functionalized terminal and 1,1-disubstituted vinyl arenes (e.g.
simple substituted styrene derivatives) have been investigated
rather extensively and quite successfully, there are relatively
few reports using more highly functionalized di- or
trisubstituted internal alkenes. We find that the rhodium-
catalyzed CAHBs of allylic and homoallylic phosphonates
derived from internal vinyl arenes give facile access to
functionalized chiral secondary benzylic boronic esters. A range
of substrates including some bearing heteroaromatic ring
systems of interest in medicinal chemistry, such as furan,
indole, morpholine, pyrazine, pyrrole and thiophene
derivatives, can be accommodated. The absolute configurations
of selected chiral secondary benzylic boronic ester products
were confirmed or assigned via kinetic acylation of the
corresponding benzylic alcohols using the BTM acylation
catalyst highlighting the potential for other donor substituents
in proximity of the alkene to influence the stereochemical
course of the reaction. Stereoretentive and stereoinvertive C-B
bond transformation protocols highlight the versatility of this
methodology. We find that palladium-catalyzed cross-coupling
under the conditions reported by Crudden proceeds mostly
with stereoretention. Diastereomeric substrates, for example,
(E)- and (Z)-5a and (E)- and (Z)-16, give the same borated
product stereochemistry. Mechanistic studies reveal that (Z)- to
(E)-alkene isomerization occurs rapidly under the reaction
conditions. This observation along with deuterium
incorporation data provides a reasonable explanation for the
origin of (E/Z)-stereoconvergence during CAHB.
3
4
5
For selected examples, see: (a) W. J. Jang, S. M. Song, J. H.
Moon, J. Y. Lee and J. Yun, J. Am. Chem. Soc., 2017, 139,
13660; (b) J. R. Smith, B. S. L. Collins, M. J. Hesse, M. A.
Graham, E. L. Myers and V. K. Aggarwal, J. Am. Chem. Soc.,
2017, 139, 9148; (c) Y. Xi and J. F. Hartwig, J. Am. Chem. Soc.,
2016, 138, 6703; (d) N. Hu, G. Zhao, Y. Zhang, X. Liu, G. Li and
W. Tang, J. Am. Chem. Soc., 2015, 137, 6746.
(a) S. Chakrabarty and J. M. Takacs, ACS Catal., 2018, 8, 10530;
(b) S. Chakrabarty and J. M. Takacs, J. Am. Chem. Soc., 2017,
139, 6066; (c) G. L. Hoang and J. M. Takacs, Chem. Sci., 2017,
8, 4511; (d) V. M. Shoba, N. C. Thacker, A. J. Bochat and J. M.
Conflicts of interest
The authors declare no conflicts of interest.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
Takacs, Angew. Chem., Int. Ed., 2016, 55, 1465; (e) G. L.
enantioselectivity determined after oxidation (74%, 91:9 er);
View Article Online
Hoang, Z. D. Yang, S. M. Smith, R. Pal, J. L. Miska, D. E. Perez,
see the SI.
L. S. W. Pelter, X. C. Zeng and J. M. Takacs, Org. Lett., 2015, 17 V. B. Birman and X. Li., Org. Lett., 2006D, O8,I:11305.1103. 9/C8SC05613G
17, 940; (f) S. M. Smith and J. M. Takacs, J. Am. Chem. Soc., 18 For examples of stereoretentive cross-coupling of chiral
2010, 132, 1740; (g) S. M. Smith, N. C. Thacker and J. M.
Takacs, J. Am. Chem. Soc., 2008, 130, 3734.
Selected examples of CAHB of 1,1-disubstituted vinyl arenes:
(a) Z. Wang, Z. He, R. Zhang, G. Zhang, G. Xu, Q. Zhang, T. Xiong
secondary organoboron derivatives, see Ref. 5c, 5e and (a) T.
P. Blaisdell and J. P. Morken, J. Am. Chem. Soc., 2015, 137,
8712; (b) M. Daini and M. Suginome, J. Am. Chem. Soc., 2011,
133, 475.
6
and Q. Zhang, Org. Lett., 2017, 19, 3067; (b) H. Zhang and Z. 19 For examples of stereoinvertive cross-coupling of chiral
Lu, ACS Catal., 2016, 6, 6596; (c) L. Zhang, Z. Zuo, X. Wan and
Z. J. Huang, J. Am. Chem. Soc., 2014, 136, 15501; (d) R.
Corberan, N. W. Mszar and A. H. Hoveyda, Angew. Chem., Int.
Ed., 2011, 50, 7079; (e) C. Mazet and D. Gerard, Chem.
Commun., 2011, 47, 298.
For CAHB of 1,2-disubstituted vinyl arenes, see: (a) G. L.
Hoang, S. Zhang and J. M. Takacs, Chem. Commun., 2018, 54,
4838; (b) D. Noh, S. K. Yoon, J. Won, J. Y. Lee and J. Yun, Chem.
Asian J., 2011, 6, 1967. For CAHB of trisubstituted internal
alkenes (bearing alkyl/aryl substituents), see ref. 5a, 5b, 5d
and 5f.
secondary organoboron derivatives, see: (a) J. C. H. Lee, H.-Y.
Sun and D. G. Hall, J. Org. Chem., 2015, 80, 7134; (b) L. Li, S.
Zhao, A. Joshi-Pangu, M. Diane and M. R. Biscoe, J. Am. Chem.
Soc., 2014, 136, 14027; (c) J. C. Lee, R. McDonald and D. G.
Hall, Nat. Chem., 2011, 3, 894; (d) T. Awano, T. Ohmura and
M. Suginome, J. Am. Chem. Soc., 2011, 133, 20738; (e) D. L.
Sandrock, L. Jean-Gerard, C. Chen, S. D. Dreher and G. A.
Molander, J. Am. Chem. Soc., 2010, 132, 17108; (f) T. Ohmura,
T. Awano and M. Suginome, J. Am. Chem. Soc., 2010, 132,
13191.
7
8
20 For ligand-controlled stereoretentive and stereoinvertive
cross-coupling of chiral secondary organoboron derivatives,
see: S. Zhao, T. Gensch, B. Murray, Z. L. Niemeyer, M. S.
Sigman and M. R. Biscoe, Science, 2018, 362, 670.
Other recent methods for synthesizing chiral secondary
benzylic/α-aryl boronic esters: (a) Z. Tao, K. A. Robb, J. L.
Panger and S. E. Denmark, J. Am. Chem. Soc., 2018, 140,
15621; (b) J. Guo, B. Cheng, X. Shen and Z. Lu, J. Am. Chem. 21 For a perspective on enantiospecific and iterative Suzuki-
Soc., 2017, 139, 15316; (c) C. Margarita and P. G. Andersson,
J. Am. Chem. Soc., 2017, 139, 1346; (d) C. H. Basch, K. M. Cobb
Miyaura cross-couplings, see: J. P. G. Rygus and C. M.
Crudden, J. Am. Chem. Soc., 2017, 139, 18124.
and M. P. Watson, Org. Lett., 2016, 18, 136; (e) H. M. Nelson, 22 D. Imao, B. W. Glasspoole, V. S. Laberge and C. M. Crudden. J.
B. D. Williams, J. Miro´ and F. D. Toste, J. Am. Chem. Soc.,
2015, 137, 3213; (f) C. Sun, B. Potter and J. P. Morken, J. Am. 23 A. Ros and V. K. Aggarwal, Angew. Chem., Int. Ed., 2009, 48,
Chem. Soc., 2014, 136, 6534; (g) X. Feng, H. Jeon and J. Yun, 6289.
Angew. Chem., Int. Ed., 2013, 52, 3989; (h) A. Guzman- 24 The 3,3'-bisphenyl substituents in ligand B1 play a significant
Am. Chem. Soc., 2009, 131, 5024.
Martinez and A. H. Hoveyda, J. Am. Chem. Soc., 2010, 132,
10634.
D. R. Edwards, Y. B. Hleba, C. J. Lata, L. A. Calhoun and C. M.
Crudden, Angew. Chem., Int. Ed., 2007, 46, 7799.
role in determining regioselectivity. B2, the analogous BINOL-
derived phosphoramidite derived from the parent BIONOL
ring system, gives a slight preference for β-boration (ca 2:1 rr)
with (E)-14. Using B2, -unsaturated amides afford -
borated benzylic boronic esters in excellent yields and
enantioselectivities; see: Ref. 7a.
9
10 Y. H. Zhang, C. F. Xu, J. F. Li and C. Y. Yuan, Chin. J. Chem., 2003,
21, 883.
11 S. A. Westcott, H. P. Blom and T. B. Marder, Inorg. Chem., 25 J. Lu, B. Pattengale, Q. Liu, S. Yang, W. Shi, S. Li, J. Huang and
1993, 32, 2175.
J. Zhang, J. Am. Chem. Soc., 2018, 140, 13719.
12 Our recent studies on rhodium-catalyzed CAHB of
functionalized alkene substrates focus on using the simple
and readily available TADDOL- and BINOL-derived chiral
phosphites and phosphoramidites. Our studies consistently
find that these two privileged ligand scaffolds tend to be
complementary in their effectiveness; in part, the choice of
TADDOL- or BINOL-derived ligands hinges on the alkene
substitution pattern.
13 The parent BINOL-derived ligand B2 gives a similar yield and
regioselectivity but lower enantioselectivity for (S)-9a (90:10
er); see the SI for ligand screening data.
14 (a) V. M. Shoba and J. M. Takacs, J. Am. Chem. Soc., 2017, 139,
5740; (b) N. G. Leonard and P. J. Chirik, ACS Catal., 2018, 8,
342; see also reference 8b.
15 The regioisomeric γ- and β-boronic esters 6 and 7 often
proved difficult to separate by chromatography on silica gel.
Thus, the 6:7 ratio is determined via 31P NMR analysis of crude
reaction mixture. The isolated yield of the major γ-
regioisomer and its er are obtained after oxidation.
16 It is worth noting that unlike our previous work on 1,1-
disubstituted alkenes (Ref. 5a) in which ortho-substitution of
the arene leads to a change in regioselectivity, substrates
bearing 2-substituted arenes in this series of 1,2-disubstituted
internal vinylarenes do not significantly impact the
regioselectivity. For example, in addition to 5h, the 2-
methylphenyl derived substrate 5 (Ar = 2-methylphenyl) also
undergoes regioselective γ-boration (13:1 rr) to afford 6 (Ar =
2-methylphenyl) but with a relatively modest level of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Chemical Science
Page 8 of 8
Table of Contents Entry
View Article Online
Allylic and homoallylic phosphonates undergo
asymmetric hydroboration yielding chiral boronic
DOI: 10.1039/C8SC05613G
esters (yields up to 86%, enantiomer ratios up to 99:1).
O
P
O
P
EtO
Ar
EtO
Ar
Bpin
Rh
EtO
EtO
pinacolborane
E or Z
A subset of the Ar-groups from substrate scope:
S
O
Me
S
O
N
Boc
Boc
N
O
N
N
N Boc
N
Boc