Enantioselective Allylation of Alkenyl Boronates Promotes a 1,2-Metalate Rearrangement with 1,3-Diastereocontrol

Article abstract of DOI:10.1021/jacs.1c01242

Alkenyl boronates add to Ir(π-allyl) intermediates with high enantioselectivity. A 1,2-metalate shift forms a second C-C bond and sets a 1,3-stereochemical relationship. The three-component coupling provides tertiary boronic esters that can undergo multiple additional functionalizations. An extension to trisubstituted olefins sets three contiguous stereocenters.

Full text of DOI:10.1021/jacs.1c01242

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Enantioselective Allylation of Alkenyl Boronates Promotes a 1,2-
Metalate Rearrangement with 1,3-Diastereocontrol
Colton R. Davis, Irungu K. Luvaga, and Joseph M. Ready*
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ABSTRACT: Alkenyl boronates add to Ir(π-allyl) intermediates with high enantioselectivity. A 1,2-metalate shift forms a second
C−C bond and sets a 1,3-stereochemical relationship. The three-component coupling provides tertiary boronic esters that can
undergo multiple additional functionalizations. An extension to trisubstituted olefins sets three contiguous stereocenters.
a
Table 1. Optimization of Ligand and Reaction Conditions
ulticomponent couplings generate complex molecular
1−3
Marchitectures from simple substrates.
Enantioselec-
Scheme 1. C−C Bond Formation from Boronate
Intermediates
a
1a was preformed using PhLi (1.0 equiv), Et2O, 0 °C−r.t., 30 min.
[Ir(COD)Cl]2 (2.5 mol %) + 10 mol % of the ligand in THF. Isolated
yields after oxidation via treatment of boronic ester with NaOH and
H2O2. The er of the major diastereomer as determined by HPLC
b
analysis. The dr was determined by 1H NMR. 1.0 equiv of LiCl was
c
added. The reaction was performed in the absence of a catalyst.
d
Linear cinnamyl tert-butyl carbonate was used as the electrophile.
Received: February 1, 2021
Published: March 23, 2021
tive variants are particularly valuable, especially when multiple
stereocenters are set in a single operation.4,5 Within the field of
multicomponent couplings, organoboronic esters have played a
prominent role.6−12 They are widely available and generally
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a
Scheme 2. Scope of Allylic Carbonates
a
All reactions were conducted in THF (0.3 M) using 2-isopropenylboronic acid, pinacol ester (0.3 mmol), PhLi (0.3 mmol), [Ir(COD)Cl]2 (2.5
mol %), (S)-L1 (10 mol %), allylic carbonates (0.63 mmol), and LiCl (0.3 mmol). Yields of the isolated and purified material after oxidation by
treatment of boronic ester with NaOH and H2O2. The er of the major diastereomer as determined by HPLC analysis. The dr was determined by
1H NMR.
display good air and moisture stability.13,14 Furthermore,
incorporation of organoboronic esters provides a functional
handle for further diversification.15
multicomponent coupling. However, the Morken group found
that a vinyl boronate complex generated 1,1-disubstitued
alkenyl boronic esters rather than allylated products in the
presence of allyl acetate and a palladium catalyst (Scheme
1c).42 This vinylidenation was proposed to occur via an inner-
sphere mechanism wherein addition of the ate complex to a
PdII(π-allyl) intermediate was followed by a β-hydride
elimination. We speculated that the use of a 1,1-disubstitued
alkenyl boronate complex would prevent this pathway and
provide access to allylation products. However, several
attempts with a variety of ligands and allylic alcohol derivatives
in the presence of a palladium catalyst provided poor reactivity
and little observable product (see the Supporting Information
for details).
We questioned if an alternative metal could promote an
outer-sphere mechanism and provide the desired allylation
coupling product. In this context, iridium-catalyzed allylic
substitution reactions accommodate a wide variety of
nucleophiles and electrophiles to provide branched allylic
alkylation products with high regioselectivity (Scheme
1d).43−47 Herein we describe a multicomponent coupling
involving alkenyl boronates and Ir(π-allyl) intermediates that
provides tertiary boronic esters and forms nonadjacent
stereocenters in an enantio- and diastereoselective manner
(Scheme 1e).
Some of the most valuable transformations of organoboronic
esters involve 1,2-metalate shifts from anionic “ate” complexes.
1,2-Migration from boron to an adjacent electrophilic sp3
hybridized center generally results in expulsion of a leaving
group, most notably in the Matteson homologation (Scheme
1a).16 Alternatively, alkenyl boronates utilize an external
electrophilic activator to promote the 1,2-metalate shift
(Scheme 1a). For example, halogenation of olefins can induce
a metalate rearrangement in the Zweifel olefination17−20 or
Aggarwal arylation.21−23 Similarly, a dearomatizing 1,2-
migration onto heterocyclic rings can be induced via the N-
acylation of pyridines.24,25 Finally, radical addition to alkenyl
boronates can initiate a 1,2-metalate rearrangement.26−28
π-Acidic late transition-metal complexes, such as PdII and
NiII, can induce a 1,2-migration of an alkyl or aryl fragment of
an alkenyl boronate. The conjunctive cross-coupling of vinyl
boronate complexes with aryl triflates features inner-sphere
activation of vinyl boronates with a Pd(aryl)+ intermedi-
ate.29−34 In related studies, our group developed an
enantioselective coupling of indole boronates with allylic
acetates to set multiple contiguous stereocenters (Scheme
1b).35−41 This process may occur via a stepwise process
involving an enantioselective allylation followed by a
diastereoselective 1,2-metalate rearrangement.
We first exposed alkenyl ate complex 1a (Table 1) to various
allylic alcohol derivatives in the presence of several iridium
complexes (see the Supporting Information for details). Key
findings of the optimization process are highlighted in Table 1.
We sought to broaden the scope of this asymmetric
allylation to include less reactive alkenyl boronic esters in a
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a
Scheme 3. Scope of Alkenyl Boronates
a
All reactions were conducted in THF (0.3 M) using boronic ester (0.3 mmol), 2-bromopropene (0.3 mmol), t-BuLi (0.6 mmol), [Ir(COD)Cl]2
(2.5 mol %), (S)-L1 (10 mol %), ( )-2a (0.63 mmol), and LiCl (0.3 mmol). Yields of the isolated and purified material after oxidation by
treatment of boronic ester with NaOH and H2O2. The er of the major diastereomer as determined by HPLC analysis. The dr was determined by
b
c
1H NMR. Tertiary boronic esters required extended oxidation times with poor conversion to the corresponding alcohol. Reactions were
d
conducted using either isopropenyllithium (0.3 mmol) or α-lithiostyrene (0.3 mmol) and the corresponding boronic ester (0.3 mmol). Reactions
were conducted using oganolithium (0.3 mmol) and the corresponding 1,1-disubstituted alkenylboronic ester (0.3 mmol).
Typically, the organoboronic ester product was oxidized to the
alcohol derivative, although isolation of the organoboron
product is possible (see Scheme 4). The best results were
obtained with Carreira’s phosphoramidite ligand, (S)-L1.48−51
Our initial attempt with 1.1 equiv of ( )-2a in the presence of
[Ir(COD)Cl]2 and (S)-L1 provided alcohol 3 in 68% yield and
4:1 dr, with the major diastereomer displaying 82:18 er (entry
1). We speculated that ( )-2a might be undergoing a kinetic
resolution under the reaction conditions.52−56 Accordingly,
upon increasing the carbonate loading to 2.1 equiv, we
obtained product 3 in improved yields and enantioselectivity
(entry 2). Addition of LiCl57 further improved the yield and
dr, with the major diastereomer now displaying excellent er
(entry 3). Absence of the catalyst (entry 4) and use of the
linear cinnamyl tert-butyl carbonate provided no observed
product (entry 5). Catalysts featuring Feringa’s phosphor-
amidite ligands (S,S,Sa)-L2 and (S,S,Sa)-L3 provided only
modest yields, no diastereoselectivity, and poor er (entries 6,
7).
We next explored the scope of secondary allylic carbonates
that were compatible with these reaction conditions (Scheme
2). Under optimized conditions, consistently high yields,
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a
Scheme 4. Synthetic Transformations of Tertiary Boronic
Ester
Scheme 5. Mechanistic Studies
a
a
The reaction was conducted in THF (0.3 M) using 2-
isopropenylboronic acid, pinacol ester (4.0 mmol), PhLi (4.0
mmol), [Ir(COD)Cl]2 (2.5 mol %), (S)-L1 (10 mol %), ( )-2a
(8.2 mmol), and LiCl (4.0 mmol). The er of the major diastereomer
as determined by HPLC analysis of the gram-scale reaction of 41 after
1
oxidation. The dr was determined by H NMR. All yields refer to
b
c
isolated yields of the purified material. KHF2. Vinyl lithium, then I2,
d
e
a
and then NaOMe. ArLi and then NBS. ArLi, then 2,2,2-
All reactions were conducted on a 0.3 mmol scale using PhLi (0.3
mmol), 2-isopropenylboronic acid, pinacol ester (0.3 mmol),
[Ir(COD)Cl]2 (2.5 mol %), ligand (10 mol %), secondary phenyl
carbonate (0.63 mmol), and LiCl (0.3 mmol). Isolated yields after
oxidation by treatment with NaOH and H2O2. The er of the major
diastereomer as determined by HPLC. The dr was determined by 1H
NMR.
f
trichloroethyl chloroformate, and then NaOH/H2O2. BH3·DMS
and then NaOH/H2O2.
enantioselectivities, and diastereoselectivities were observed
with electron-donating (4, 5) and electron-withdrawing groups
(6−9). Likewise, ortho-substituted aryl secondary allylic
carbonates 10 and 11 were compatible. The 3-methoxyphenyl
carbonate (12) displayed excellent yield and selectivity, while
the bulkier 2-naphthyl-derived carbonate (13) reacted with
improved dr and similar er. Carbonates featuring heterocycles
such as 2-thiophene or 3-indole (14, 15) provided similarly
high selectivity. Aliphatic secondary carbonates failed to
provide the desired product under the current reaction
conditions.
Alkenyl ate species can be accessed either through addition
of lithium reagents to alkenyl boronic esters or through
addition of alkenyl lithium reagents to RB(pin) substates. We
adopted the latter approach to further explore the scope of the
coupling by virtue of the wide commercial availability of
boronic esters (Scheme 3a). We first synthesized bis-aryl,
tertiary alcohols from the addition of aryl boronic esters to
preformed α-lithiostyrene. Both electron-withdrawing (16)
and electron-donating (17) aryl boronic esters were tolerated
with moderate to high yields, excellent enantioselectivities, and
modest diastereoselectivities. The stability of an aryl bromide
under the reaction conditions involving organolithium species
is noteworthy. Addition of boronic esters to preformed
isopropenyllithium allowed us to explore a wide range of aryl
and alkyl boronic esters. With regards to para-substituted
boronic esters, high yields and selectivities were observed with
both electron-donating (18, 19, 20) and electron-withdrawing
groups (21, 22). Methyl and fluoro groups were accom-
modated in the ortho position (23, 24), with somewhat higher
enantio- and diastereoselectivity being observed with the
fluorinated substrate. Bulkier 2-naphthylboronic esters (25,
26) also provided the desired product in excellent yield and
stereoselectivity. Heterocyclic boronic esters (27, 28, 29)
provided the desired products in high yields, with excellent er
and dr. Interestingly, 3-furylboronic ester provided low yields
of the desired product 30 due to a dearomatizing 1,2-
migration, which provided dihydrofuran 31 in 50% yield as a
1:1 mixture of unassigned diastereomers.21 The anticipated
alkenyl addition product 30 and the dihydrofuran 31 were
both recovered with 98:2 er. Finally, we explored the scope of
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(Scheme 5a).61 We also isolated cinnamyl tert-butyl ether 48,
which could arise from the decomposition of the IrIII(π-allyl)
intermediate derived from the less reactive enantiomer of the
carbonate.53,54 To further illustrate this mechanistic hypoth-
esis, the reaction was probed with enantioenriched carbonate
(S)-2a using either (S)-L1 or (R)-L1 (Scheme 5b). Ligand
(S)-L1 provided the desired product in 96% yield with
excellent stereoselectivity and no observable byproduct.
Alternatively, ligand (R)-L1 provided the three-component
coupling product in only 32% yield with greatly diminished
enantioselectivity. The linear cinnamyl ether 48 was obtained
in comparable yields. Lastly, enantioenriched carbonate (S)-2a
was coupled with boronate 1b in the presence of achiral ligand
L4 to obtain the product in quantitative yield with a slight drop
in the er compared to (S)-2a (Scheme 5b). From these results,
a proposed mechanism of the pathway is shown in Scheme 5c.
First, the racemic allylic carbonate undergoes a kinetic
resolution by the Ir(phosphoramidite) complex to provide
diastereomeric IrIII(π-allyl) intermediates 49 and 50, wherein
kS > kR. Loss of carbon dioxide renders the oxidative addition
step irreversible. The IrIII(π-allyl) intermediates can then either
react with alkenyl boronate to form the desired product or
react with tert-butoxide to form ether 48.
Quantitative assessment of the various reaction pathways
accessible to the IrIII(π-allyl) intermediates will require
additional investigation, but qualitative conclusions can be
drawn with existing data. The rate of product formation from
the fast-reacting enantiomer (kmat) is much faster than the rate
of ether formation (kether). This conclusion arises from the
observation that little ether was observed when optically active
substrate (S)-2a reacted in the presence of the matched ligand.
Alternatively, the rate of product formation from the slower-
reacting enantiomer (kmis) is similar to the rate of etherification
(k′ether) because the mismatched reaction formed ether 48 and
the coupled product in similar yields. Moreover, π−σ−π
isomerization of the IrIII(π-allyl) complex is slower than the
matched reaction (kmat > kisom) based on the modest drop in
optical activity observed using the enantioenriched substrate
and the achiral ligand L4 (Scheme 5b). However, the
mismatched reaction of (S)-2a in the presence of (R)-L1
proceeded with substantial epimerization to give the same
major enantiomer of product as from (R)-2a, indicating that
kisom ∼ kmis. Taken together, the results indicate the chiral
ligand (S)-L1 affects the enantioselectivity of the reaction
through effects on both the oxidative addition step and the
addition of the alkenyl boronate nucleophile.
a
Scheme 6. Setting Three Contiguous Stereocenters
a
The reaction was conducted on a 0.3 mmol scale using 2-bromo-2H-
chromene (0.3 mmol), s-BuLi (0.3 mmol), boronic ester (0.3 mmol),
[Ir(COD)Cl]2 (2.5 mol %), (S)-L1 (10 mol %), ( )-2a (0.63 mmol),
and LiCl (0.3 mmol). Yields of the isolated and purified material after
oxidation by treatment of boronic ester with NaOH and H2O2. The er
of the major diastereomer as determined by HPLC analysis. The dr
1
determined by H NMR.
alkyl-derived ate complexes. Primary (32, 33), secondary (34),
and tertiary (35) boronic esters all coupled cleanly and
selectively. Coupling products derived from tertiary boronic
esters often provided poor conversion to the alcohol (35)
during oxidation.
Diastereomeric products could be accessed by switching the
migrating group and the olefin substituent (Scheme 3b). For
example, addition of isopropenyllithium to phenyl boronic
ester provided 36 from R2 = Ph as the migrating organic
fragment. Alternatively, addition of methyllithium to 2-boryl
styrene provided the diastereomeric product 37 as a
consequence of R1 = Me now participating in the migration
step. We have demonstrated this flexibility with aryl−alkyl (36,
37), alkyl−alkyl (38, 39), and aryl−aryl (40, 3) derived
tertiary alcohols with similar yields and enantioselectivities of
the major diastereomer in each case.
To explore the synthetic utility of asymmetric allylation, the
coupling reaction was executed on a gram-scale to provide
tertiary boronic ester 41 in 88% yield and 8:1 dr and 95:5 er
(Scheme 4). Next, synthetic transformations were performed
on boronic ester 41 to demonstrate the compatibility of these
compounds for derivatizations. Oxidation of 41 followed by
iodoetherification of the tertiary alcohol provided crystalline
iodide 42, which established absolute and relative stereo-
chemistry. Other useful synthetic intermediates were prepared,
such as the trifluoroborate salt (43)58 and diene (44).59 The
boronic ester was arylated to provide both the furan (45)21
and pyridine (46)25 using transition-metal-free cross-coupling
chemistry. Finally, hydroboration/oxidation provided diol 47.
In all cases, good to excellent yields were obtained with
retention of stereochemistry.
Mechanistic Considerations. The Carreira group has
investigated the mechanisms of allylic substitution reactions
catalyzed by Ir[(S)-L1] complexes.60 However, the addition of
alkenyl boronates to Ir(π-allyl) intermediates and the
associated metalate shift gave rise to some interesting
mechanistic questions. To determine if the racemic carbonate
was undergoing a kinetic resolution, we conducted the
allylation using ate complex 1b and isolated both the product
36 and the unreacted starting material (Scheme 5). Recovered
carbonate (R)-2a was isolated in 97:3 enantioselectivity,
indicating that an efficient kinetic resolution had occurred
To gain insight into the diastereoselectivity of the reaction,
we investigated trisubstituted boronate 1d to form three
contiguous stereocenters (Scheme 6).35,62,63 Under optimized
conditions, product 51 (R = n-Bu) was isolated in 65% yield as
a 1:1 mixture of diastereomers, both of which display 99:1 er.
Likewise, 52 (R = Me) was obtained in similar yield and
stereoselectivity. In both diastereomers of both products,
irradiation of the benzopyran methine showed an NOE signal
corresponding to the OH hydrogen, while we observed no
correlation between the butyl or methyl group with the
adjacent sp3-hybridized methine. The NMR data is bolstered
by an X-ray crystal of 52a. This evidence suggests the
surprising conclusion that both diastereomers result from a cis
addition of the migrating R group and the allyl fragment across
the olefin, with the diastereomers arising from opposite facial
selectivity. Understanding the mode of addition for disub-
stituted alkenyl boronate complexes is an ongoing effort.
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(4) Cho, H. Y.; Morken, J. P. Catalytic Bismetallative Multi-
component Coupling Reactions: Scope, Applications, and Mecha-
nisms. Chem. Soc. Rev. 2014, 43, 4368−4380.
Conclusions. In summary, we have showcased a three-
component coupling of organolithium reagents, organoboronic
esters, and secondary allylic aryl carbonates. Significant
findings include (1) expansion of the scope of suitable
nucleophiles to engage Ir(π-allyl) intermediates to include
alkenyl boronates; (2) the establishment of two new C−C
bonds and two nonadjacent stereocenters in a single operation;
and (3) the ability to set three contiguous stereocenters using
trisubstituted ate complexes. Ongoing work seeks to better
understand the addition of alkenyl ate complexes into Ir(π-
allyl) intermediates and the generality of this reaction in the
formation of multiple stereocenters.
(5) Zhu, J.; Bienaymé, H.; Eds.; Multicomponent Reactions; Wiley-
VCH Verlag GmbH & Co. KGaA: 2005; 468 pp, DOI: 10.1002/
3527605118.
(6) For representative MCRs involving organoboron reagents, see
refs 6−9 Patel, S. J.; Jamison, T. F. Catalytic Three-Component
Coupling of Alkynes, Imines, and Organoboron Reagents. Angew.
Chem., Int. Ed. 2003, 42, 1364−1367.
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Tetrasubstituted Olefins by the Palladium-Catalyzed Three-Compo-
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01242.
Experimental procedures, characterization data, spectra,
and crystal data for 42 and 52a (PDF)
(10) For representative MCRs which contain organoboronic esters,
see refs 10 and 11 Sardini, S. R.; Brown, M. K. Catalyst Controlled
Regiodivergent Arylboration of Dienes. J. Am. Chem. Soc. 2017, 139,
9823−9826.
(11) Logan, K. M.; Sardini, S. R.; White, S. D.; Brown, M. K. Nickel-
Catalyzed Stereoselective Arylboration of Unactivated Alkenes. J. Am.
Chem. Soc. 2018, 140, 159−162.
Accession Codes
CCDC 2060331 and 2068375 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(12) Kanti Das, K.; Manna, S.; Panda, S. Transition Metal Catalyzed
Asymmetric Multicomponent Reactions of Unsaturated Compounds
using Organoboron Reagents. Chem. Commun. 2021, 57, 441−459.
(13) Lennox, A. J. J.; Lloyd-Jones, G. C. Selection of Boron Reagents
for Suzuki-Miyaura Coupling. Chem. Soc. Rev. 2014, 43, 412−443.
(14) Matteson, D. S. Functional Group Compatibilities in Boronic
Ester Chemistry. J. Organomet. Chem. 1999, 581, 51−65.
(15) Sandford, C.; Aggarwal, V. K. Stereospecific Functionalizations
and Transformations of Secondary and Tertiary Boronic Esters. Chem.
Commun. 2017, 53, 5481−5494.
AUTHOR INFORMATION
■
Corresponding Author
Joseph M. Ready − Department of Biochemistry, UT
Southwestern Medical Center, Dallas, Texas 75390-8548,
United States; orcid.org/0000-0003-1305-9581;
Email: Joseph.Ready@UTSouthwestern.edu
(16) Matteson, D. S. Boronic Esters in Asymmetric Synthesis. J. Org.
Chem. 2013, 78, 10009−10023.
Authors
Colton R. Davis − Department of Biochemistry, UT
Southwestern Medical Center, Dallas, Texas 75390-8548,
United States
Irungu K. Luvaga − Department of Biochemistry, UT
Southwestern Medical Center, Dallas, Texas 75390-8548,
United States
(17) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. A Convenient
Stereoselective Synthesis of Substituted Alkenes via Hydroboration-
Iodination of Alkynes. J. Am. Chem. Soc. 1967, 89, 3652−3653.
(18) Zweifel, G.; Polston, N. L.; Whitney, C. C. A Stereoselective
Synthesis of Conjugated Dienes from Alkynes via the Hydroboration-
Iodination Reaction. J. Am. Chem. Soc. 1968, 90, 6243−6245.
(19) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C.
Stereoselective Introduction of Olefinic Side Chains onto Cyclic
Systems via the Hydroboration-Iodination of Alkynes. J. Am. Chem.
Soc. 1971, 93, 6309−6311.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01242
Notes
(20) Armstrong, R. J.; Aggarwal, V. K. 50 Years of Zweifel
Olefination: A Transition-Metal-Free Coupling. Synthesis 2017, 49,
3323−3336.
(21) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V.
K. Enantiospecific sp2-sp3 Coupling of Secondary and Tertiary
Boronic Esters. Nat. Chem. 2014, 6, 584−589.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding was received from the Welch Foundation (I-1612)
and the NIH (R01 CA216863 J.M.R; T32GM127216 C.R.D.).
(22) Aichhorn, S.; Bigler, R.; Myers, E. L.; Aggarwal, V. K.
Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic
Esters by a 1,2-Metalate Rearrangement/1,3-Borotropic Shift
Sequence. J. Am. Chem. Soc. 2017, 139, 9519−9522.
(23) Bigler, R.; Aggarwal, V. K. ortho-Directing Chromium Arene
Complexes as Efficient Mediators for Enantiospecific C(sp2)-C(sp3)
Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2018, 57, 1082−
1086.
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