Diastereo- and Enantioselective 1,4-Difunctionalization of Borylenynes by Catalytic Conjunctive Cross-Coupling

Article abstract of DOI:10.1002/anie.202001580

Enantioselective conjunctive cross-coupling of enyne-derived boronate complexes occurs with 1,4 addition of the electrophile and migrating group across the π system. This reaction pathway furnishes α-boryl allenes as the reaction product. In the presence of a chiral catalyst, both the central and axial chirality of the product can be controlled during product formation.

Full text of DOI:10.1002/anie.202001580

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Accepted Article
Title: Diastereo- and Enantioselective 1,4-Difunctionalization of
Borylenynes by Catalytic Conjunctive Cross-Coupling
Authors: James Patrick Morken, Chunyin Law, Elton Kativhu, and
Johnny Wang
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Diastereo- and Enantioselective 1,4-Difunctionalization of
Borylenynes by Catalytic Conjunctive Cross-Coupling
Chunyin Law, Elton Kativhu, Johnny Wang and James P. Morken*[a]
Abstract: Enantioselective conjunctive cross-coupling of enyne-
derived boronate complexes occurs with 1,4 addition of the
electrophile and migrating group across the p system. This reaction
pathway furnishes a-boryl allenes as the reaction product. In the
presence of a chiral catalyst, both the central and axial chirality of the
product can be controlled during product formation.
Allenes are important structural motifs that are found in a
number of natural products1 and often find use as synthetic
intermediates.2 Accordingly, a substantial body of work has been
dedicated to the enantioselective synthesis of axially chiral
allenes.3,4 Because of their ability to undergo cyclization to afford
5
biologically-relevant oxygenated heterocycles
,
particular
attention has been paid to the synthesis of chiral substituted a-
allenols. These compounds have been prepared by the
stereospecific SN2’ reaction between organocuprates and
propargylic alcohols, and by the transition-metal catalyzed
coupling of propargylic epoxides and organic nucleophiles. In
both cases, the axial chirality of the allenes arises by transfer of
axial chirality from the starting materials to the products.6 More
recently, Ma reported an elegant copper-catalyzed synthesis of a-
allenols by coupling aldehydes and terminal alkynes wherein the
axial chirality is controlled by the ligand on the copper complex.7
Despite these advances in the catalytic synthesis of a-allenols,
there is still a lack of catalytic methods that allow for a-allenol
construction with catalyst-based control of both axial and central
chirality. Indeed, to the best of our knowledge, the Mukaiyama-
type aldol reaction reported by List is the only method where a
catalyst controls both axial and central chirality of a-allenols
during the formation of the product. 8 Herein, we report the
application of catalytic conjunctive cross-coupling to the synthesis
of a-allenyl boronates, which are direct precursors not only to a-
allenols, but also an array of other compounds. Of note, the
processes reported herein occur catalytically, and in a highly
enantioselective and diastereoselective fashion.
Scheme 1. Issues pertaining to the control of both axial and central
chirality in catalytic construction of chiral allenes.
that activation of A might occur by alkyne activation (C, inset
Scheme 1), such that 1,2 boronate rearrangement would form the
allenyl palladium intermediate (D). Upon reductive elimination,
this sequence would generate allenyl boronic ester B.
In
practice, selective reaction by this pathway was found to face
several challenges: first, unlike activation of simple alkenyl
boronates where the chiral Pd complex directly binds to a
prochiral alkene substrate, the Pd complex in C is further removed
from the incipient stereogenic center such that effective
stereoinduction is more challenging. Second, while activation of
ate complex is proposed to occur by alkyne activation (C→D),
activation of the substrate might also occur through alkene
association (E→F) and this can lower the chemoselectivity of the
process. Moreover, competitive if interconversion between D and
F is faster than reductive elimination, then competitive activation
of the alkene may also lower the stereoselectivity.
The reaction design we undertook involves a conjunctive cross-
coupling9 reaction of an enyne-derived boronate complex (A,
Scheme 1) with an electrophile under the influence of a Pd
catalyst to give allene-containing boronic ester B. It was expected
[*]
M. Law, E. Kativhu, J. Wang, Prof. J. P. Morken
Department of Chemistry
To initiate our investigation of the conjunctive coupling with
Boston College
2609 Beacon Street, Chestnut Hill, MA 02467, USA
E-mail: morken@bc.edu
enynyl boronates, trans-borylenyne
1
was subjected to
conjunctive coupling with mol% Pd(OAc)2, 3.6 mol%
3
MandyPhos ligand L1, and phenyl triflate. As shown in Scheme
2, this process indeed delivered the allene-containing product 2
in acceptable levels of enantioselectivity and yield; however, the
reaction diastereoselectivity was poor (Scheme 2). A survey of
phosphine ligands and reaction conditions (see SI) did not
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202001580
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improve the outcome. It was reasoned that the two diastereomers
in this reaction would originate from competing syn- and anti-
periplanar migrations (I and II, Scheme 2) and with trans enyne-
derived boronate, the Pd complex may be situated too far from
the incipient stereogenic center to control the topological course
of the 1,2 shift. To address this issue, we considered reaction of
cis enyne-derived boronates. As depicted in III and IV (Scheme
2), this alternate olefin configuration would bring the four-
coordinate boron center in closer proximity to the alkyne-bound
palladium catalyst, such that anti-periplanar migration (I) would be
favored in order to avoid steric repulsions between the migrating
group and Pd catalyst.
Table 1. Conjunctive coupling of aryl enynyl boronate complexesa
3% Pd(OAc)2
3.6 (S,S)-L1
pentyl
Ph
(pin)
B
(pin)B
Ph
!
Ph
PhOTf
THF, 55 °C, 15 h
pentyl
H
2
79% yield
92:8 er, 3:1 dr
1
trans enynes:
L1Pd Ph
little interaction
RM
L1Pd Ph
H
H
L2B
RM
Ph
L2B
Ar2P
Fe
R
H
R
H
NMe2
PAr2
I (anti)
II (syn)
Ph
cis enynes:
NMe2
L1Pd Ph
L1Pd Ph
RM
H
H
H
(S
,S)-L1
H
Ar = 4-methoxy-3,5-xylyl
R
R
BL2
L2B
III (anti)
IV (syn)
RM
Scheme 2. Preliminary observation in conjunctive coupling with
enyne-derived boronate 1 and an analysis of the impact of alkene
stereochemistry on the reaction.
In practice, the use of cis-enyne-derived boronates10 led to
significantly enhanced diastereoselectivity, while retaining high
enantioselectivity and product yield in the conjunctive cross-
coupling reaction. As depicted in Table 1, a number of
electrophiles and migrating groups were examined with the cis-
enyne substrate, and yields and selectivities are generally good.
Of note, aryl bromides could be used as the electrophile and
provide comparable yield and selectivity to the aryl triflates. The
reaction operates with both electron-rich (3) and electron-poor (6)
arene electrophiles, providing the corresponding a-allenols upon
oxidative workup. An alkenyl electrophile also reacted with
reasonable selectivity to furnish the enallene product (8). Also of
note, heterocycles such as furan and indole derivatives can be
employed as the electrophile (9, 10) or migrating group (14, 15)
and alkyne substituents other than a pentyl group can be
employed (16, 17).
(a) Yields are isolated yield of product and reflect an averaged outcome of two
experiments. Diastereoselectivity (dr) determined by 1H NMR analysis of the
unpurified reaction product and 13C NMR analysis of purified compounds;
enantioselectivity (er) determined by chiral SFC analysis.
The conditions employed for aryl migration in Table 1 proved to
be ineffective for alkyl migration, providing products with inferior
enantio- and diastereoselectivity. In an attempt to improve the
outcome for this important class of products, we examined other
achiral boron ligands that might alter catalyst–substrate steric
interactions. As depicted in Table 2, whereas the pinacol-derived
boronate provided the product in 3:1 dr and in a near-racemic
fashion (18), the larger "mac"-derived substrate provided the
product (19) in enhanced enantioselectivity.
Probing this
alternate ligand framework, it was found that the secondary
alcohol derived ligand, "hac", provided the product (20) in both
high enantio- and diastereoselectivity. With the "hac" ligand, the
modest yield of 20 was due to competitive direct transmetallation,
providing Suzuki-Miyaura coupling products. Inspired by a
previous report9g, it was found that the direct transmetallation
could be minimized by adding steric encumbrance near the
boronate oxygen ligands that might prevent O–Pd interaction11
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required for transmetallation. Thus, the 3,7-dimethyl substituted
"hac*" ligand provided the desired product 21 in acceptable yield
and both high enantio- and diastereoselectivity.
in the coupling reaction, along with sodium or potassium triflate to
sequester the halide which is an inhibitor of couplings.9b With
these conditions, it was found that simple aliphatic groups can
migrate in the coupling reaction (22, 23) and that the reaction can
easily process side chains containing alkene (24), silyl ether (26),
acetal (27), and alkyne (28) functional groups as well as a
secondary migrating carbon atom (25), although a tert-butyl group
failed to migrate under these conditions.
Table 2. Influence of the boron ligand on conjunctive coupling with
aliphatic migrating groups a
3% Pd(OAc)2
3.6 (S,S)-L1
pentyl
Ph
n-Bu
(RO)2B
pentyl
B(OR)2
+
!
PhOTf
C(sp2)-Br/KOTf
THF, 55 °C, 15 h
n-Bu
As alluded to in the introduction, activation of the enyne-derived
boronate might occur through either alkene or alkyne activation,
with interconversion of vinyl and propargyl palladium complexes
providing a route for both activation modes to deliver the allene
product. Insight into the dynamic features of this process was
gained through the reaction of a more hindered boronate. As
depicted in Scheme 3, when cyclohexyl-substituted boronate 29
was subjected to the reaction conditions, alkyne product 31 was
produced in addition to expected allene 30. Of note, the
enantioselectivity of compounds 30 and 31 is significantly
different. Because the p-s-p isomerization that would interconvert
alkenyl palladium complex V and propargyl palladium VI is known
to be stereospecific12, the divergent stereoselectivity observed in
30 and 31 suggests that these products are unlikely to arise from
a rapidly interconverting common intermediate, but rather are
formed by distinct reaction pathways, mostly likely involving
alkyne versus alkene activation as depicted in Scheme 3.
H
B(OR)2:
Me
Me
Me Me
Me Me
Me
Me
O
H
H
H
H
O
O
O
O
O
O
O
B
B
B
B
18, 60%
19, 62%
20, 15%
21, 60%
3:1 dr, 56:44 er
(OR)2 = pin
15:1 dr, 68:31 er
(OR)2 = mac
>20:1 dr, 92:8 er
(OR)2 = hac
>20:1 dr, 92:8 er
(OR)2 = hac*
(a) Yields are isolated yield of product and reflect an averaged outcome of two
experiments. Diastereoselectivity (dr) determined by 1H NMR analysis of the
unpurified reaction product and 13C NMR analysis of purified compounds;
enantioselectivity (er) determined by chiral SFC analysis.
With an effective strategy for alkyl migration in conjunctive
coupling with enyne-derived boronates, other substrates were
examined in this reaction (Table 3). Because of the limited
availability of functionalized alkyllithium reagents and their
impractical synthesis on a laboratory scale, conditions were
developed for use of more easily accessible alkyl Grignard
reagents in the conjunctive coupling reaction. While a detailed
optimization is described in the Supporting Information, critical
features are the use of 14 equivalents of DMSO to stabilize the
boronate complex, along with the use of CsF to improve reactivity
OH
3% Pd(OAc)2
Cy
Ph
Li
3.6 (S,S)-L1
PhOTf
OH
Ph
Ph
Cy
B(pin)
!
Ph
+
Ph
THF, 55 °C, 15 h
then NaOH, H2O2
H
Cy
30, 52% y
>20:1 dr, 90:10 er
31, 20% y
>20:1 dr, 59:41 er
29
Ph PdL1
Ph PdL1
H
H
Table 3. Conjunctive coupling of enynyl boronates derived from
aliphatic Grignard reagentsa
H
H
!
30
31
(pin)B
Cy
Cy
Cy
(pin)B
Ph
RM
V
X
Ph PdL1
Ph
PdL1
H
H
H
H
Cy
(pin)B
Ph
(pin)B
VI
Ph
Scheme 3. Origin of chemoselectivity in conjunctive coupling of
enyne-derived boronates.
To assess the utility of the obtained a-allenols in oxygenated
heterocycle synthesis, we first examined a AuCl3-catalyzed
cyclization13 reaction to afford 2,5-dihydrofuran compound 32
(Scheme 4). This reaction was found to occur with excellent
preservation of the stereochemical integrity of the stereogenic
center in the starting material and established a second
stereogenic center with a high level of selectivity (>20:1 dr). In a
second reaction, it was found that the allenol substrate could
undergo stereoselective epoxidation followed by intramolecular
epoxide opening to afford tetrahydrofuranone 33.14 In both cases,
(a) Yields are isolated yield of product and reflect an averaged outcome of two
experiments. Diastereoselectivity (dr) determined by 1H NMR analysis of the
unpurified reaction product and 13C NMR analysis of purified compounds.
Enantioselectivity (er) determined by chiral SFC analysis. NaOTf used for
RMgCl, KOTf added for RMgBr.
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the reactions proceeded with transfer of axial chirality to central
chirality, forming a new quaternary stereogenic center with
stereocontrol.
synthesis of a-borylallenes from simple achiral borylenynes. Both
aliphatic and aromatic groups can migrate in this process, but they
require different boron ligands for the realization of both high yield
and stereoselectivity. Further studies on the applications of this
method in synthesis of natural products are underway.
pentyl
OH
10% AuCl3
THF
78% y
>20:1 dr
93:7 er
!
Ph
(1)
Ph
Ph
Ph
Ph
O
Me
H
32
Acknowledgements
O
pentyl
Ph
OH
m-CPBA
55% y
>20:1 dr
92:8 er
!
(2)
Ph
Ph
We thank Prof. Yao Fu (USTC) for sharing procedures for the
preparation of cis enyne-containing boronic esters and we thank
Prof. Jay Siegel (Tianjin University) for providing substituted
acenapthoquinones used in the preparation of hac*. This work
was supported by a grant from the US National Institutes of Health
(NIGMS GM-R35-127140).
O
CH2Cl2
Me
H
33
Scheme 4. Construction of tetrahydrofuran derivatives from a-
allenols.
In conclusion, we have reported a catalytic conjunctive coupling
reaction that allows for the enantio- and diastereoselective
Keywords: Boron • Cross-Coupling • Palladium • Catalysis
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Chunyin Law, Elton Kativhu, Johnny
Wang, and James P. Morken*
Page No. – Page No.
Diastereo- and Enantioselective 1,4-
Difunctionalization of Borylenynes by
Catalytic Conjunctive Cross-Coupling
Chiral Allenes: 1,4-Addition of the migrating group and electrophile across an
enyne-derived boronate complex occurs during the course of Pd-catalyzed
conjunctive cross-coupling. This process generates chiral allenyl boronic esters
with control of both axial and central chirality.
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