Diastereoselective and Enantioselective Conjunctive Cross-Coupling Enabled by Boron Ligand Design

Article abstract of DOI:10.1021/jacs.8b09909

Enantio- and diastereoselective conjunctive cross-coupling of β-substituted alkenylboron "ate" complexes is studied. Whereas β-substitution shifts the chemoselectivity of the catalytic reaction in favor of the Suzuki-Miyaura product, use of a boronic este

Full text of DOI:10.1021/jacs.8b09909

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Communication
Diastereoselective and Enantioselective Conjunctive
Cross-Coupling Enabled by Boron Ligand Design
Jesse Myhill, Christopher A. Wilhelmsen, Liang Zhang, and James P. Morken
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09909 • Publication Date (Web): 30 Oct 2018
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Diastereoselective and Enantioselective Conjunctive Cross-Coupling
Enabled by Boron Ligand Design
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Jesse A. Myhill, Christopher A. Wilhelmsen, Liang Zhang, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
Supporting Information Placeholder
In these situations, multistep organic synthesis is often re-
quired for construction of the stereochemical dyad of inter-
est.3 Our group has been developing a catalytic conjunctive
cross-coupling reaction that converts vinylboron "ate" com-
plexes and electrophiles to enantiomerically-enriched sec-
ondary or tertiary alkylboronic esters bearing a single stere-
ocenter (eq. 1, Scheme 1).4 To address the problem of ben-
zhydryl construction as outlined above, we questioned
whether b-substituted alkenylboronic esters might engage in
conjunctive cross-coupling and deliver compounds that bear
vicinal stereogenic centers (eq. 2). In this report, we de-
scribe the development of this process and provide insight
about how the structure of boron ligands can tip the reaction
outcome in favor of the conjunctive coupling product or the
classic Suzuki-Miyaura product.
ABSTRACT: Enantio- and diastereoselective conjunctive
cross-coupling of b-substituted alkenylboron "ate" com-
plexes is studied. While b substitution shifts the chemose-
lectivity of the catalytic reaction in favor of the Suzuki-
Miyaura product, use of a boronic ester ligand derived from
acenaphthoquinone allows the process to favor the conjunc-
tive product, even with substituted substrates.
Configurationally-defined benzhydryl stereocenters are
important structural motifs that appear in a broad array of
natural products and therapeutic agents.1 Accordingly, a va-
riety of catalytic methods have been developed to target their
construction.2 While recent advances in benzylic cross-cou-
pling have provided important tools to target these features,
an added synthetic challenge arises when benzylic stereo-
centers are sited adjacent to additional stereogenic centers.
Preliminary efforts to employ b-substituted alkenyl boro-
nates in conjunctive cross-coupling reactions revealed a pro-
cess that is dominated by direct Suzuki-Miyaura cross-cou-
pling. For instance, in contrast to the conjunctive cross-cou-
pling with the unsubstituted vinylB(neo)-derived "ate" com-
plex 1a which occurs in 84% yield and 97:3 er (Scheme 1,
eq. 3), when styrenylB(neo) was converted to the derived
"ate" complex 1b and subjected to coupling with p-anisyltri-
flate, 1 mol% Pd(OAc)2 and 1.2 mol% Mandyphos (L), only
13% of the conjunctive coupling product 2b was obtained,
with stilbene derivative 3b being the predominant product.
The disparate reaction outcomes with 1a and 1b as substrate
may be understood by consideration of competing catalytic
reaction pathways. Mechanistic studies intimate that the
metal-induced metallate rearrangement which underlies the
conjunctive coupling occurs by metal-alkene binding (A,
equation 1, box),4f followed by simultaneous RM migration
and C-Pd bond formation at Cb. In contrast, recent studies
of transmetallation from organoboronic acid derivatives to
bis(phosphine)Pd complexes suggests that the direct Suzuki-
Miyaura reaction could arise by either (a) an open transition
state originating from a palladium alkene complex where C-
Pd bond formation occurs at Ca with concomitant rupture of
the C-B bond (B, shaded box, Scheme 1)5, or (b) association
of Pd with a boronic ester oxygen (C), which is then fol-
lowed by transmetallation reaction through a closed four-
centered transition state involving a five-coordinate Pd com-
plex.6 For the reaction of substrate 1b, the added substitution
at the b carbon of the alkene (R=H→Ph) would serve to in-
hibit conjunctive coupling as it requires Pd-C bond for-
mation at a more hindered site. However, transmetallation
Scheme 1. Conjunctive Cross-Coupling of
Alkenylboronates
b
-Substituted
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through either B or C, ultimately leading to C-Pd bond for-
in the direct transmetalation process is provided by the reac-
tion with hydrocarbon-based ligand L7 (9-BBN) wherein the
metallate shift-based path operates to the near exclusion of
the Suzuki-Miyaura reaction.
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mation at Ca, would be relatively unaltered by the addition
of b-substituents on the alkenyl group. Thus, the net effect
of alkene b-substitution is to disfavor the metallate shift rel-
ative to the direct transmetalation reaction and thereby alter
the course of the reaction. Following this analysis, it was
considered that alternate ligand sets on the boron atom that
selectively interfere with either Pd(II)-oxygen binding or
that hinder access to Ca might reestablish the metallate shift
as a major reaction pathway.
Considering the observations in entries 1-6 of Table 1, we
sought ligands that are both readily accessible and also ef-
fectively shield the oxygen atom and/or Ca without blocking
access to the alkene Cb. As shown in entry 8, ligand L8
(termed "mac"), readily prepared by methylation of
acenaphthoquinone (vide infra), appears to satisfy these re-
quirements, delivering the conjunctive product in good yield
and enantioselectivity. Of note, the reaction chemoselectiv-
ity could be enhanced by conducting the reaction at 40 °C
and in the presence of CsF; under these conditions the con-
junctive coupling product is formed in 76% isolated yield,
>20:1 dr, and with 99:1 enantioselectivity.
9
To investigate the effect of boron ligands on the chemose-
lectivity of the coupling reaction in equation 2, we converted
a series of styrenyl boronic esters to the derived "ate" com-
plexes and subjected them to coupling with Pd(OAc)2 and
MandyPhos ligand (Sp,Sp-L). As depicted in Table 1, with
relatively unencumbered ligands on boron such as L1 (neo-
pentyl glycol) or L2 (cis-1,2-cyclopentane diol) the Sukuzi-
Miyaura product remains the predominant reaction product.
However, when the boron center is more encumbered such
as with L3 (pinacol) and L4, the proportion of conjunctive
cross-coupling (C3) product was increased, consistent with
the notion that hindered access to either the oxygen atom or
Ca may retard the rate of the direct transmetalation reaction
relative to metallate shift. It can also be noted that chemose-
lectivity with boron centers bearing even more highly en-
cumbered ligands (L5, L6) begins to suffer, an outcome we
consider might be due to hindered olefin binding. Lastly,
support for the notion that the oxygen atom may be involved
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Diol 4 is readily available from acenaphthoquinone by a
single-step diastereoselective (4.3:1 dr) carbonyl addition
reaction employing trimethylaluminum in toluene,7 followed
by crystallization of the diol from ethyl acetate solvent.
Conversion of boronic acids to derived B(mac) esters is
readily accomplished by esterification in the presence of cat-
alytic FeCl3.8 In contrast to common boronic ester ligands
(i.e. pinacol, neopentylglycol), when the B(mac) derivatives
are converted to the four coordinate "ate" complexes, the is-
sue of stereoisomerism arises and it was considered that this
feature might pose a complication for selective and efficient
catalytic coupling reactions. To study the properties of
B(mac) "ate" complexes, the addition of phenyllithium to n-
butylB(mac) in THF-d8 at room temperature was analyzed
Table 1. Effect of Boron Ligand on Chemoselectivity in
Conjunctive Coupling Reactions.a
1
by H NMR analysis. As shown in Scheme 2b, the kinetic
addition product appeared to arise from addition of the nu-
cleophile cis relative to the vicinal methyl groups forming
trans-6 in a 5:1 ratio.9 Of note, stirring the reaction for 30
minutes at 60 °C resulted in a 2:1 diastereomer ratio, and
after 12 hours an equilibrium 1:1 ratio of the isomers was
observed. Importantly, when reaction partners are reversed
such that of n-BuLi was added to PhB(mac), an inverted
entry
BL2
L1 (neo)
L2
C3:SM C3 yield
1:5.8 13 (10) >20:1 99:1
1:>20 <5 nd nd
dr
er
1
2
Scheme 2. Methylated Acenaphthoquinone (mac) as a
Ligand for Boronic Esters.
3
L3 (pin)
L4
1:2
35(30)
>20:1 98:2
>20:1 99:1
>20:1 nd
4
1.7:1
1:2
56(46)
30
5
L5
6
L6
1:3
20
>20:1 nd
7
L7 (9-BBN) >20:1 92(75)
>20:1 67:33
>20:1 99:1
>20:1 99:1
8
9b
L8 (mac)
L8 (mac)
2.5:1
4.2:1
75(70)
83(76)
(a) Yields are by 1H NMR versus an internal standard, yield in pa-
rentheses is after isolation. For entry 7, yield is of the derived al-
cohol; for the others, yield is of the boronic ester. Enantiomer ratio
of derived alcohol was determined by SFC analysis on a chiral sta-
tionary phase and in comparison to authentic enantiomer mixture.
1
Diastereomer ratio determined by analysis of the H NMR spec-
trum. (b) Reaction at 40 °C and with 1 equiv CsF.
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Table 2. Pd/MandyPhos-Catalyzed Conjunctive Coupling of
b
-Substituted B(mac)-Derived "Ate" Complexes.a
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(a) Yields are isolated yields of purified material and represent and average yield of two different experiments. Enantiomer ratios was
determined by SFC analysis on a chiral stationary phase and are in comparison to authentic racemic materials. Diastereoselectivity deter-
mined by analysis of the 1H NMR spectrum. For reactions of organobromide electrophiles, an equivalent of KOTf was added. (b) Reaction
at 60 °C. (c) Reaction conducted with 2% Pd and 2.2% L1.
initial kinetic ratio (ca. 1:12.5) results, but the same thermo-
dynamic ratio is achieved upon heating (see Supporting In-
formation for details). These experiments suggest that dia-
stereomeric "ate" complexes should be interconverting dur-
ing the course of reaction and that the configuration of these
species will likely be inconsequential to conjunctive cou-
plings.
with several different migrating groups, with electron-rich
migrating groups giving higher yields than those that are
electron-poor. Surprisingly, under the current conditions,
"ate" complexes containing alkyl migrating groups did not
engage in the conjunctive coupling pathway and provided
direct Suzuki-Miyaura coupling products instead. With re-
spect to the substituent at the b-carbon of the alkenyl boro-
nate, substrates containing electron-rich and electron-defi-
cient arenes, as well as those containing alkyl groups were
found to participate in the reaction. While an electron-rich
b-substituent appeared to increase the conversion of the re-
action, it also resulted in more competition from the Suzuki-
Miyuara pathway (23; 1:1 conjunctive:Suzuki). Substrates
with electron-deficient b-substituents furnished less Suzuki-
Miyaura reaction, but required higher temperatures for the
conjunctive process to proceed (24, 4:1 conjunctive:Suzuki).
Lastly, while substrates with b-alkyl substitution (16-22)
gave only modest yields, they reacted with outstanding se-
lectivity and furnished products that would be otherwise dif-
ficult to access with single-step catalytic processes.
With ready access to B(mac)-derived substrates and an un-
derstanding of their properties, these compounds were ex-
amined in conjunctive coupling reactions. As depicted in
Table 2, the reaction can operate with both electron-rich and
electron-poor electrophiles and, after oxidative work-up,
provides the derived secondary alcohols with high diastere-
oselectivity (>20:1 dr) and enantioselectivity (generally
above 98:2 er.). While substrates with heteroatom-contain-
ing functional groups do not pose an inherent problem, di-
minished yield was observed with electron-deficient electro-
philes, an outcome that arises from competitive Suzuki-
Miyaura coupling reactions (in general for Table 2, the re-
maining mass balance is comprised of Suzuki-Miyaura prod-
ucts). Fortunately, even with these substrates the stereoin-
duction remains high. It should also be noted that a substrate
with a hindered migrating alkenyl group, reacted with anom-
alously low enantioselectivity, an observation that has been
made in other systems.4a,c Examination of both aryl triflate
and aryl bromide electrophiles showed that both electro-
philes could be employed to furnish to conjunctive product;
however, bromide electrophiles required the addition of
KOTf to ameliorate the inhibitory activity of bromide salts4b
and provided diminished product yields relative to their tri-
flate counterparts. The reaction was also found to operate
Although B(mac)-derived products are stable to column
chromatography, they are poorly soluble in many organic
solvents such that for the purposes of Table 2, it was most
convenient to oxidize the coupling products and isolate the
corresponding alcohols. To learn about other transfor-
mations of the B(mac) derivatives, a larger scale coupling
reaction was undertaken and the reaction product examined.
As shown in Scheme 3, a gram-scale coupling provided sec-
ondary boronic ester 26 with reaction efficiency and selec-
tivity comparable to smaller scale reactions in Table 2. Con-
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Scheme 3. Synthetic Transformations of AlkylB(mac) Scheme 4. Construction of (+)-Obtusafuran by Conjunc-
Page 4 of 6
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Derivatives.
tive Cross-Coupling.
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alkenylboronic esters. This process employs an encumbered
diolato ligand to control the reaction of alkenylboron "ate"
complexes, tipping the reaction in favor of a metallate shift-
based pathway rather than direct transmetalation. Further
studies on the mechanistic origin of chemoselectivity with
B(mac) derived "ate" complexes will be reported in due
course.
sistent with the observations in Table 2, purified intermedi-
ate 26 underwent oxidation efficiently, providing alcohol 2b
in outstanding yield and selectivity. Also noteworthy, is that
direct amination10/Boc protection of 26 furnished carbamate
27 in excellent yield and as a single diastereomer. Lastly, it
was found that B(mac)-derivate 26 underwent efficient mod-
ified Matteson homologation11 to furnish primary B(mac)
derivative 28 as a single diastereomer.
■ ASSOCIATED CONTENT
Supporting Information. Procedures, characterization
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
The diastereoselective conjunctive coupling establishes
strategically-useful functional group arrays in ways that are
not straightforward to access by contemporary asymmetric
synthesis. This feature is illustrated by the application of the
conjunctive coupling to the synthesis of obtusafuran12
(Scheme 4). While this target was previously prepared by a
convenient enantioselective ketone reduction and cycliza-
tion, construction of the requisite ketone starting material re-
quired five steps of chemical synthesis.13 Employing trans-
2-propenylB(mac) in a conjunctive coupling with PhLi and
aryl bromide 29, furnished 30 in excellent yield and stere-
oselection. Subsequent oxidative cyclization14 and deprotec-
tion provided the target in just three synthesis steps (two re-
action vessels) from simple starting materials.
■ AUTHOR INFORMATION
Corresponding Author
*morken@bc.edu
ORCID
James P. Morken 0000-0002-9123-9791
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGEMENTS
This work was supported by the NIH (R35-
GM1217140). We thanks Solvias for a generous dona-
tion of MandyPhos ligands.
■ REFERENCES
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OMe
OH
B(mac)
RM B(mac)
cat. Pd/L
E
+
E-X
RM
64%
99:1 er
Me
O
R
N
Me
R
Li
Ph
Me
OMe
Boc
N
OMe
OH
OH
OH
Ph
Ph
(+)-obtusafuran
>99:1 er
58%
99:1 er
51%
99:1 er
Ph
Cl
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