Chausset-Boissarie, L., Ghozati, K., LaBine, E., Chen, J. L. -Y.,
Aggarwal, V. K., & Crudden, C. M. (2013). Enantiospecific,
Regioselective Cross-Coupling Reactions of Secondary Allylic Boronic
Esters.
Chemistry - A European Journal
,
19
(52), 17698-17701.
https://doi.org/10.1002/chem.201303683
Peer reviewed version
Link to published version (if available):
10.1002/chem.201303683
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This is the accepted version of the following article: Chausset-Boissarie, L., Ghozati, K., LaBine, E., Chen, J. L.-
Y., Aggarwal, V. K. and Crudden, C. M. (2013), Enantiospecific, Regioselective Cross-Coupling Reactions of
Secondary Allylic Boronic Esters. Chem. Eur. J., 19: 17698–17701,
which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/chem.201303683/abstract.
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1
Enantiospecific, regioselective cross-coupling reactions of secondary allylic
boronic esters
Laetitia Chausset-Boissarie, Kazem Ghozati, Emily LaBine, Jack L.-Y. Chen, Varinder K. Aggarwal*
and Cathleen M. Crudden*
This paper is dedicated to Professor Scott E. Denmark on the occasion of his 60
th
birthday
Asymmetric cross coupling reactions in which stereochemistry-
bearing CC bonds are created are still in their infancy. Considering
the wealth of compounds that can be prepared by cross-coupling
methodologies, and the importance of synthetic methods leading to
enantiomerically enriched products, this is a surprising reality.
Advances in this area have occurred in the past few years, in the
realm of enantioselective or enantiospecific cross couplings of chiral
electrophiles
[1]
In the area of cross coupling of stereodefined nucleophiles, Crudden
originally reported the enantiospecific cross coupling of chiral
enantiomerically enriched benzylic boronic esters (eq. 1).
[2]
[3]
Similar reaction conditions were shown by Aggarwal
[4]
to be
applicable to tertiary propargylic boronic esters (eq. 2) and by
Crudden to allylic boronates in racemic form (eq. 3).
[5]
Elegant
examples of stereospecific cross couplings of unrelated chiral
organoboronic esters have followed from Suginome, Hall and
Molander,
[6]
and recent advances have been reported in the
stereospecific Stille cross coupling.
[7]
[8]
Herein, we address the question of enantiospecificity, isomeric
composition and mechanism in the coupling of enantiomerically
enriched versions of allylic boronic esters such as 6 and related
derivatives. We demonstrate that the coupling proceeds with almost
perfect stereoretention in all cases, and high -selectivity with
several classes of substrates. The method provides a valuable
addition to the cross coupling of allylic organometallics such as
organosilanes,
[9]
where introduction of chirality in the starting
materials can be challenging. Remarkably, this is the first report of
the coupling of chiral, non-racemic allylic organoboron species,
[10]
a
readily available class of substrates.
[11]
After brief optimization, conditions for the cross coupling of allylic
boronic esters were found, with small but significant changes from
the previously described coupling procedure
[2]
for benzylic boronic
esters. Most importantly, with the addition of only two equivalents
of PPh
3
relative to Pd, the reaction proceeded in high yield with
virtually complete enantiospecificity.
In addition to providing good yields and high selectivities for
substrates similar to those previously reported in racemic form,
[5]
equally good results were obtained regardless of the geometry of the
olefin (Entries 12) and branched aliphatic substituents were well
tolerated (entry 3). Interestingly, although yields were lower, even
trisubstituted allyl boronic esters were reactive (entry 4). Entry 5
describes the only example in which there is an aromatic substituent
on the vinyl group and this is the only example where the cross-
coupling proceeds with (albeit moderate) -selectivity. The same
propensity for styrene-containing substrates to react with -
selectivity was observed in previous work, and in these cases,
selectivities for -arylation of 8:92 (nBu in place of CH
2
CH
2
Ph) and
18:82 (nHex in place of CH
2
CH
2
Ph) were observed.
[5]
The rationale
for the -selectivity in these cases is discussed in an overall
mechanistic context below.
We next embarked on the synthesis of enantiomerically enriched
versions of allylic boronic esters using Aggarwal lithiation-
borylation methodology. For example, (Z)-10 was prepared in 80%
yield with a 98:2 e.r. (eq. 5).
[11c, 12]
[] Dr. L. Chausset-Boissarie, Dr. J.L.-Y. Chen, Prof. V.K.
Aggarwal
School of Chemistry
University of Bristol
BS8 1TS, UK 1
E-mail: V.aggarwal@bristol.ac.uk
Homepage:
www.bris.ac.uk/chemistry/research/organic/aggarwal-group
Dr. Kazem Ghozati, Ms. E. LaBine, Prof. C.M. Crudden
Department of Chemistry
Queen's University
Kingston, Ontario, Canada, K7L 3N6
E-mail: Cathleen.crudden@chem.queensu.ca
Homepage: www.cruddengroup.com
Prof. C.M. Crudden
Institute of Transformative Bio-Molecules (WPI-ITbM),
Nagoya University, Chikusa,
Nagoya 464-8602, Japan
www.itbm.nagoya-u.ac.jp
[] CMC acknowledges the Natural Sciences and
Engineering Research Council for support of this work in
terms of a discovery grant, an accelerator grant and a
research tools grant. VKA thanks the Swiss National
Foundation for a fellowship (LCB), and the European
Research Council (ERC grant no. 246785) for financial
support.
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
2
Table 1. Effect of substrate structure on regioselectivity of the cross-
coupling reaction.
a
Entry
Compound
γ:α
b
E:Z
c
Yield (%)
d
1
E-6
97:3
99:1
65
2
Z-6
92:8
99:1
70
3
Z-7
91:9
99:1
77
e
4
8
92:8
99:1
40
5
9
39:61
86:14
28
e
[a] PhI (1 eq), Pd(dba)
2
(5%), PPh
3
(10%), Ag
2
O (1.5 eq), DME (0.1
M), 90 °C, 16 h. [b] ratio determined by GC and/or
1
H NMR; [c]
E:Z ratio for the major isomer. [d] Isolated yield of major isomer
unless otherwise stated. [e] Isolated as mixture of regioisomers.
Boronic esters (E)-10, (E)-13, and (E)-14 were prepared in a similar
manner in high yield and selectivity.
[11c, 12]
However, the synthesis
of (E)-15, which requires the lithiation and homologation of a
benzylic carbamate, is significantly more challenging, as the
lithiated derivative is configurationally unstable even at low
temperature, leading to racemic products.
[13]
Hoppe has shown that under thermodynamic control, bisoxazoline
ligands are effective with this class of carbamate, and we found that
the combination of this ligand with the more reactive neopentyl
glycol boronic ester provided the desired chiral allylic boronate
(R,E)-15 with 96% enantioselectivity.
[14]
Having secured access to all of our key substrate classes in
enantiomerically enriched form, we then examined the
enantiospecificity of the coupling reaction. All of the substrate
classes investigated reacted with virtually complete
enantiospecificity (Table 2). The (Z)-allylic boronates 10 and 13
gave the -products with high E selectivity. In contrast, the (E)-
allylic boronate 10 gave the -product with lower E selectivity
although high E selectivity was restored with the more hindered i-Pr
substituent. The E/Z selectivity is governed by A
1,3
strain between
the R
1
and R
2
Table 2. Regio and enantiospecificity in the Suzuki-Miyaura cross
coupling of enantiomerically enriched allylic boronic esters.
Compound
γ:α
b
E:Z
b
Yield
c
e.r.
(S.M.)
d
e.s.
(%)
e
R,Z-10
83:17
94:6
75
f
98:2
96
R,E-10
94:6
78:22
81
98:2
100
R,Z-13
90:10
99:1
77
f
96:4
96
R,E-14
92:8
99:1
71
96:4
100
R,E-15
98:2
99:1
78
98:2
100
[a] See Table 1 footnote for conditions. [b] γ:α ratio determined by
1
H
NMR, and E:Z selectivity is given for the major regioisomer. [c]
Isolated yield (%) of major isomer unless otherwise stated. [d] e.r. of
the starting material. [e] Enantiospecificity = e.e. product/e.e. starting
material. [f] Isolated as mixtures of γ and α products.
Electronic effects with respect to the aryl halide were then explored
in the cross-coupling of allylic boronic ester (R,Z)-13 (96:4 e.r.). As
shown in Table 3, electron neutral or electron rich aryl iodides gave
the desired product in good yield and high isomeric purity favoring
the (E)--product (Table 3, entries 1-3). Electron poor aryl iodides
resulted in decreased yields but still reacted with high
enantiospecificities (Table 3, entries 4-6).
Table 3. Electronic effects in the Suzuki-Miyaura cross coupling of
aryl iodides with boronic ester (R,Z)-13.
a
Entry
R
γ:α
E:Z
a
Yield(%)
b
e.s. (%)
c
1
H
90:10
99:1
77
96
2
Me
91:9
99:1
72
93
3
OMe
85:15
99:1
72
96
4
COCH
3
90:10
99:1
60
96
5
Br
90:10
99:1
42
93
6
CF
3
91:9
99:1
42
93
[a] See notes to Table 1. [b] Isolated as mixture of γ and α products.
[c] Enantiospecificity, determined by chiral HPLC analysis, e.e.
product/e.e. starting material.
The two most likely mechanisms for transmetalation are anti- and
syn-S
E
isomers
of the product.
[9]
Mechanistic studies on the Suzuki-Miyaura
reaction
[15]
point to likely pathways that involve a B-O-Pd linkage
Ph
BPin
H
3
C
Ph
BPinCH
3
BPin
CH
3
Ph
BPin
CH
3
H
3
C
Ph
BPin
Ph
Conditions
a
R
2
R
1
BPin
R
3
R
1
R
2
(6)
R
3
R
1
Ph
R
3
Ph
R
2
+
PhI
BPin
CH
3
Ph
BPin
H
3
C
Ph
BPin
CH
3
BPin
nPr
Ph
BPin
nPr
3
(A, Scheme 1) prior to transmetalation, such that the syn-S
E
intramolecular transmetalation would be predicted. This leads
ultimately to organopalladium intermediate B, which subsequently
undergoes reductive elimination generating the -product.
Scheme 1. Mechanism for the formation of both the - and γ-isomers
In order to test this hypothesis, the absolute stereochemistry of the
products was determined and was found to correlate with olefin
stereochemistry.
[16]
Thus, (R,E)-10 was shown to give (S,E)-17a,
whilst cross coupling of the geometrical isomer (R,Z)-10 gave (R,E)-
17a (Scheme 2). This is consistent with a syn-S
E
transmetalation.
The involvement of -allyl intermediates in the transformation was
considered next.
[17]
-bonded transmetalated
intermediate B to the isomeric organopalladium intermediate C,
could occur prior to reductive elimination. If this isomerization
occurred fully, the ratio of-cross coupled products would be
solely dependent on the relative rate of reductive elimination from
intermediates B or D (Scheme 1).
Scheme 2. Absolute configuration of products and the relationship to
mechanism of transmetalation
To test the involvement of -allyl intermediate C, we prepared a
selectively deuterated allylic boronic ester, 18, in which the steric
and electronic effects of the two substituents are equivalent.
Subjecting 18 (90:10 mixture of D-isomers) to our standard
conditions gave an 85:15 (±5%) ratio in favor of product 19a,
indicating that reductive elimination is faster than isomerization via
-allyl intermediate C (eq. 8). Indeed, it appears that on the order of
95% of the transmetalated intermediate A proceeds to product
without isomerization through C.
The synthesis of a deuterated diphenyl substituted version of 18 was
not possible due to facile borotropic shifts, making a conclusive
statement on the mechanism of the reaction for these particular
substrates difficult. However, the observation that different starting
materials in which an aryl group is present on either end of the
allylic unit give the same major product (eqs. 9, 10) suggests that -
allyl intermediates are more prevalent in these cases. Conjugation of
the double bond with the aromatic ring presumably provides the
driving force for the selectivity observed. As shown in eqs 9 and
10, although the same product is obtained starting from either (E)-15
or (E)-20,
[18]
the selectivity starting from (E)-20 is markedly lower.
conjugation which now out-competes k
re
(B), resulting in the -
product being major.
[19]
In conclusion, we have described the first enantioselective Suzuki-
Miyaura cross-coupling of chiral, enantioenriched secondary allylic
boronic esters. The reaction proceeds with high -regioselectivity
and high retention of chirality. Mechanistic studies show that the
reactions proceed via -selective transmetalation followed by
reductive elimination; the latter process competing with
-allyl intermediate. Deuterium labeling
studies show that direct reductive elimination is faster than
formation of a -allyl intermediate for alkyl substituted allylic
boronates. In addition to the synthetic utility of this transformation,
the reaction provides the first independent confirmation that the
transmetalation of boronic esters proceeds via a syn pathway, in
accord with mechanistic studies that show the importance of the B
OPd linkage for facile transmetalation.
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R
2
R
3
H
H
B(OR)
2
R
1
O
Pd
L
n
Ar
H
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1
PdL
n
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PdArL
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g
-product
H R
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-product
H R
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PdArL
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syn-S
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)
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R,E-17a
S,E-17a
PhI
Pd/Ag
2
O
PhI
Pd/Ag
2
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R,E-10
R,Z-10
4
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[16] Note that this was accomplished by RuO
4
oxidation. See supporting
information for details.
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Catalysed Enantioselective Allylic Substitution in Organic Synthesis;
Springer: Berlin, 2012; b) Szabo proposes an alternative mechanism for
-selective arylations of allylic boronic esters which involve
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inconsistent with such a mechanism in our system.
[18] Derivatives of 20 in which the alkyl group are n-Bu and n-Hex also give
alpha-selective couplings (ref 5).
[19] It is also possible that the styrene unit in 20 somehow promotes -
selective transmetalation but it is not possible to differentiate between
these two possibilities.
