Copper-Catalyzed Enantiotopic-Group-Selective Allylation of gem-Diborylalkanes

Article abstract of DOI:10.1021/jacs.0c11750

We report a copper-catalyzed enatiotopic-group-selective allylation of gem-diborylalkanes with allyl bromides. The combination of copper(I) bromide and H8-BINOL derived phosphoramidite ligand proved to be the most effective catalytic system to provide various enantioenriched homoallylic boronate esters, containing a boron-substituted stereogenic center that is solely derived from gem-diborylalkanes, in good yields with high enantiomeric ratios under mild conditions. Experimental and theoretical studies have been conducted to elucidate the reaction mechanism, revealing how the enatiotopic-group-selective transmetalation of gem-diborylalkanes with chiral copper complex occurs to generate chiral α-borylalkyl-copper species for the first time. Additional synthetic applications to the synthesis of various chiral building blocks are also included.

Full text of DOI:10.1021/jacs.0c11750

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Copper-Catalyzed Enantiotopic-Group-Selective Allylation of gem-
Diborylalkanes
Minjae Kim,∥ Bohyun Park,∥ Minkyeong Shin, Suyeon Kim, Junghoon Kim, Mu-Hyun Baik,*
and Seung Hwan Cho*
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ABSTRACT: We report a copper-catalyzed enatiotopic-group-
selective allylation of gem-diborylalkanes with allyl bromides. The
combination of copper(I) bromide and H8−BINOL derived
phosphoramidite ligand proved to be the most effective catalytic
system to provide various enantioenriched homoallylic boronate
esters, containing a boron-substituted stereogenic center that is solely
derived from gem-diborylalkanes, in good yields with high
enantiomeric ratios under mild conditions. Experimental and
theoretical studies have been conducted to elucidate the reaction
mechanism, revealing how the enatiotopic-group-selective trans-
metalation of gem-diborylalkanes with chiral copper complex occurs
to generate chiral α-borylalkyl-copper species for the first time. Additional synthetic applications to the synthesis of various chiral
building blocks are also included.
diborylmethane as a nucleophile in the presence of chiral
copper/NHC catalytic system. Niu reported an alternative
strategy for the enantioselective coupling of diborylmethane
with allylic electrophiles in the presence of iridium and silver as
cocatalysts.5d These processes showed limited scope with
respect to gem-diborylalkanes, and only diborylmethane was
employed as the coupling reagent. In addition, the reactions
delivered homoallylic boronate esters, bearing a carbon
stereogenic center solely derived from allylic electrophiles
but not from nucleophiles, namely, gem-diborylalkanes.
Therefore, the discovery of a more broadly applicable catalytic
system that expands the scope of reactants with regard to the
gem-diborylalkanes is desirable but has remained an
unmatched challenge thus far.
Herein, we describe an enantiotopic-group-selective cou-
pling of gem-diborylalkanes with allylic electrophiles catalyzed
by copper (Scheme 1c). This method provides homoallylic
boronate esters that contain a boron-substituted carbon
stereogenic center derived from prochiral gem-diborylalkanes
with high enantiomeric purity. Extensive experimental and
computational studies provide the first mechanistic insight into
how the enantiotopic-group-selective transmetalation of gem-
INTRODUCTION
■
The development of an efficient catalytic reaction for preparing
enantioenriched organoboron compounds received consider-
able attention over the past decades because they can serve as
versatile intermediates in the synthesis of a range of natural
products and pharmaceuticals.1 Thus, various enantioselective
approaches to accessing these compounds have been reported
including hydrogenation of vinyl boronates, hydroboration,
conjugate addition, allylic borylation, and cross-couplings.2
Recently, copper-catalyzed enantiotopic-group-selective cou-
plings of gem-diborylalkanes with suitable electrophiles
emerged as a powerful complementary strategy to afford
enantioenriched organoborons.3,4 In these processes, chiral α-
borylalkyl-copper species, generated by enantiotopic-group-
selective transmetalation of gem-diborylalkanes with copper
catalysts that carry chiral phosphine ligands could readily react
with electrophiles including carbonyls and imines (Scheme
1a). However, a mechanistic understanding of the enantio-
topic-group-selective transmetalation of gem-diborylalkanes
with chiral copper complex has thus far been elusive.
Furthermore, this protocol is restricted primarily to CO or
CN electrophiles, and the reaction with other electrophiles
such as allylic functionalities has rarely been reported.5
Received: November 9, 2020
Published: January 4, 2021
In our continuing explorations of catalytic enantiotopic-
group-selective coupling of gem-diborylalkanes,3,6 we recently
disclosed the copper-catalyzed chemo- and regioselective
coupling of gem-diborylalkanes with allyl chlorides.5a Sub-
sequently, Hoveyda5b and Fu5c independently reported
enantioselective variants of similar reactions employing
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competitive SN2 reaction of 1e with in situ generated α-
borylcarbanion.8 The absolute stereochemistry of the major
enantiomer of 3c was determined as S after oxidation of
B(nep) to a known compound.9
Scheme 1. Copper-Catalyzed Enantioselective Coupling of
gem-Diborylalkanes with Allylic Electrophiles
Substrate Scope. With the optimized conditions in hand,
the scope of allyl bromides was explored using 2c as a coupling
reagent (Table 2a). Allyl bromides bearing methyl-, hexyl-, and
cyclohexyl group as a substituent at C2-position furnished 3c−
3f in good yields and er. Substrates containing an ester, a
protected amine, a tert-butyldimethylsilyl (TBS)-protected
ether or a trimethylsilyl (TMS) group resulted in the formation
of 3g−3j with good to high selectivity. Furthermore, 4- bromo-
2-(bromomethyl)but-1-ene was successfully reacted with 2c,
leaving the bromo group intact (3k) for further elaborations.
Reactions of allyl bromides bearing alkenyl moiety smoothly
underwent the allylation, affording 3l and 3m in good
efficiency. Whereas CuH-catalyzed coupling of alkenes with
allylic electrophiles has been well-established,10 the reaction
scope is rather limited especially for substrates containing
additional alkene substituent because of competitive hydro-
cupration. Therefore, our developed protocol offers an
attractive alternative to CuH-catalyzed allylation of alkenes.
Various C2-aryl-substituted allyl bromides bearing electroni-
cally neutral, donating, or withdrawing substituents led to
products 3n−3r in good yields with high er. Naphthyl- and
heteroaryl-containing 3-bromoprop-1-ene readily engaged in
the reaction leading to 3s and 3t. 2-Bromo-substituted and
simple allyl bromides also underwent the allylation, delivering
3u and 3v. Next, we investigated the scope of gem-
diborylalkanes under the standard reaction conditions.
Reactions of gem-diborylpropane and gem-diboryl-3-phenyl-
propane with 1e yielded 4a and 4b in good to moderate yields
with good er. gem-Diborylalkanes bearing a TBS-protected
alcohol and alkenes led to 4c−4e in good efficiencies. 2-
Bromo-substituted and simple allyl bromides also proceeded to
complete the coupling with various gem-diborylalkanes to give
corresponding products 4f−4i. Interestingly, the reaction of 2-
phenylallyl bromide and complex gem-diborylalkanes contain-
ing pinacolato groups, derived from lithocholic acid and liquid
crystal,11 furnished 4j and 4k in good yields with high
stereoselectivity.
Mechanistic Studies. To understand how the enantio-
topic-group-selective transmetalation occurs between gem-
diborylalkanes and copper catalyst, we performed quantum
mechanical calculations based on density functional theory
(DFT). The theoretical investigation utilizes gem-diborylalkane
2c as a representative substrate, L5 as the ligand bound to
copper, and LiOtBu as the base. Figure 1 shows the calculated
free energy profile of the enantiotopic-group-selective trans-
metalation to furnish chiral copper species C. The reaction
model starts from CuOtBu, which is formed by ligand
exchange of CuBr. Once tBuO−Cu(L5) is formed to
accommodate the gem-diborylalkane substrate, two mecha-
nistic scenarios of transmetalation can be imagined. One
involves the assistance of LiOtBu as marked in blue and red
trajectories, while the other excludes participation of the base
as shown in the black dotted line. Our calculations indicate
that LiOtBu renders the transmetalation much more viable. As
illustrated in Figure 1, LiOtBu first binds to the tBuO−Cu(L5)
intermediate to form a cyclic Lewis acid−base pair, A, which
can act as a bridge during the C−B bond cleavage and Cu−C
bond formation between the copper complex and 2c when
traversing what could be best characterized as an open
diborylalkanes with chiral copper catalyst proceeds. Further
synthetic transformations of the obtained enantioenriched
homoallylic boronate esters are also demonstrated.
RESULTS AND DISCUSSIONS
■
Optimization Studies. We tested the reaction of 2-
benzylallylic electrophiles (1) and gem-diborylethane bearing a
pinacolato moiety (2a) in the presence of CuBr as a catalyst,
(R)-BINOL-derived phosphoramidite as a ligand (L1), and
LiOtBu as a base. Although no reaction took place when 2-
benzylallyl acetate (1a) was employed as an electrophile
(Table 1, entry 1), the reactions of 2a with tert-butyl-(2-
benzylallyl)carbonate (1b) or diethyl-(2-benzylallyl)-phos-
phate (1c) afforded desired allylation product 3a in low to
high yields (entries 2 and 3) with poor enantiomeric ratios
(er). The er of 3a was increased up to 70:30 when (2-
(chloromethyl)allyl)benzene (1d) was used as an electrophile
(entry 4), and (2-(bromomethyl)allyl)benzene (1e) gave 3a
with a slightly higher er (entry 5).7 Next, we surveyed the
effect of an amino group of (R)-BINOL-derived phosphor-
amidite ligands (L2−L4) and found them to have negligible or
negative effects on the er (entries 6−8). Pleasingly, subjecting
the (R)-H8−BINOL-based phosphoramidite (L5) as a ligand
afforded 3a in good yield with 95:5 er (entry 9).
Spirobiindanediol (L6) or TADDOL-derived phosphoramidte
(L7) ligand displayed lower efficiencies (entries 10 and 11).
To improve the enantioselectivity further, substituent effects of
boronate ester were subsequently examined. While gem-
diborylalkane containing 1,3-propanediolato group(2b)
showed low efficiency and selectivity (entry 12), the
employment of gem-diborylalkane having neopentylglycolato
group (2c) delivered 3c in good yields with the highest er
(entry 13) found in this series. Increasing the reaction
temperature to 50 °C shortened the reaction time (12 h),
even though 3c was obtained in a slightly decreased er (entry
14). Using NaOtBu (entry 15) or KOtBu (entry 16) instead of
LiOtBu gave 3c in low to poor er, probably because of the
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a
Table 1. Evaluation of Reaction Conditions
a
The reaction was performed on 0.20 mmol scale with CuBr (5.0 mol %), ligand (10 mol %), and base (2.0 equiv) in THF at room temperature for
b
c
1
30 h. The yield of 3 was determined by H NMR using 1,1,2,2-tetrachloroethane as an internal standard. Enantiomeric ratios (er) were
determined by HPLC. The reaction was conducted at 50 °C for 12 h.
d
S
R
transition state, A-TS and A-TS, at 27.4 and 29.0 kcal/mol,
respectively. If LiOtBu is not added, then the closed transition
undergo only a minor distortion to reach the transition state
structure worth 15.7 and 7.6 kcal/mol, respectively. The
interaction energies are −73.6 and −65.8 kcal/mol to afford
the final electronic transition state energies of −23.0 and −22.3
kcal/mol, respectively, giving preference to SA-TS. As the
distortion−interaction analysis reveals, the interaction energy
difference is the most important factor determining the
enantioselectivity. This inequality of interaction energy is
easily understood considering the structural difference between
the two transition states.
S
state, A-TS′, must be utilized giving rise to a notably higher
barrier of 31.7 kcal/mol. Note that the association of LiOtBu
to the catalyst is modeled considering the presence of
(LiOtBu)4, a cubane-type cluster, often adopted in quantum
chemical modeling of reactions with the metal alkoxide
bases.12
The energy difference between SA-TS and RA-TS is
responsible for the observed product selectivity and was
further investigated using the distortion−interaction analysis as
summarized in Figure 2.13 Starting from the fully relaxed
structures of 2c and A as the reference state, the energies
required to distort the structures to what is found in the
transition state are calculated separately. These calculations
afford the distortion energy. On letting these two distorted
fragments interact with each other, the transition state energies
can be reached. As illustrated in Figure 2a, the gem-
diborylalkane substrate must undergo a substantial structural
Figure 2b,c illustrates the structures of the two transition
S
states and reveals that in A-TS the 2c substrate orientation
avoids unfavorable steric interactions with the copper complex,
because the sterically demanding portion of 2c points away
from the L5 ligand. In contrast, the methyl functionality of the
R
B(nep) group points directly at L5 in A-TS and does not
allow 2c substrate to approach the Cu-center as closely as in
SA-TS, reflected in a C−Cu distance of 2.56 Å in RA-TS, which
S
is 0.29 Å longer than 2.27 Å found in A-TS. This structural
S
difference explains the weaker interaction energy found for RA-
TS, as discussed above. This rationale is also in line with the
change, accounting for 34.9 and 35.9 kcal/mol in A-TS and
RA-TS, respectively. In comparison, copper complex A has to
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a b
,
Table 2. Substrate Scope of Allyl Bromides and gem-Diborylalkanes
a
The reaction was performed on 0.2 mmol scale with CuBr (5.0 mol %), L5 (10 mol %), and LiOtBu (2.0 equiv) in THF at room temperature for
b
c
30 h. In all cases, isolated yields are indicated. Enantiomeric ratios (er) were determined by HPLC. Isolated yield after oxidation of boron group
is given.
experimental observation that sterically bulkier B(pin) and
B(nep) (Table 1, entries 9 and 13) show a better er than the
less-bulky B(pro) (Table 1, entry 12). Note that the solution
phase free energies were estimated to be +24.4 and +25.9 kcal/
mol, respectively. Thus, the entropy and solvation energies
spectral analysis of the isotope pattern showed that the
10B(pin)-containing (S)-6 remained in excess quantities after
the transformation.14 Conversely, the treatment of (S)-L5
instead of (R)-L5 as a ligand under the reaction conditions
gave the product (R)-6 in 8:92 er. The boron isotope
distribution found in (R)-6 is consistent with the natural
distribution, showing an excess of 11B.9 On the basis of the
assumption that the C−C bond forming process takes place
with retention of configuration at the carbon of chiral α-
borylalkyl-copper, the observed isotopic composition of the
product suggests that the transmetalation between (S)-10B-5
and chiral copper species occurs in a stereoinvertive fashion,
which is in good agreement with our DFT calculations.
S
R
increase the preference for A-TS over A-TS, slightly.
In order to find additional support for the proposed
transmetalation event between gem-diborylalkane and the
chiral copper species, we performed the allylation reaction by
subjecting isotopically chiral (S)-10B-5, prepared by a known
literature procedure,6a in the presence of (R)-L5 or (S)-L5, as
summarized in Scheme 2. When (S)-10B-5 and allyl bromide
were treated in the presence of CuBr, (R)-L5, and LiOtBu in
THF, coupled product (S)-6 was obtained in 92:8 er. Mass
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Scheme 2. Mass Spectral Analysis of the Reaction Using
Isotopically Enantioenriched gem-Diborylalkane (S)-10B-5
with Allyl Bromide
After the enantiotopic-group-selective transmetalation oc-
curs, subsequent dissociation of tBuO−B(nep) and LiOtBu
from B gives chiral α-borylalkyl-copper intermediate C located
at −8.1 kcal/mol. To gain further insight for C−C bond
formation of chiral copper intermediate C with allyl bromide,
we performed the reaction by treatment of deuterated 2-phenyl
allyl bromide 1p-d2 or cinnamyl bromide 7. When deuterated
1p-d2 and 2c were used as substrates under the standard
reaction conditions, a 4:1 mixture of 3n-d2 and 3n′-d2 was
produced (Scheme 3a). Furthermore, using 7 and 2c as
Scheme 3. Experiments to Examine the Origin of
Regioselectivity
Figure 1. Free energy profile of the reaction mechanism. Dotted
traces represent relatively unfavored reaction pathways. Geometry
optimization, vibration, and solvation energy calculations were
conducted with B3LYP-D3/LACVP** level of theory. Single-point
energies were re-evaluated with B3LYP-D3/cc-pVTZ(-f) level of
theory.
substrates also gave the products 8 and 9 with ratios of 3:1
(Scheme 3b) with good optical purity. These experimental
results suggested that both SN2′ and SN2-like processes could
be involved at the C−C bond formation event by the attack of
the chiral α-borylalkyl-copper species C to the 3- or 1-position
of the allyl bromide.15
Synthetic Applications. The enantioenriched homoallylic
boronate esters that we obtained could be transformed into
other enantioenriched building blocks by further elaborations
(Scheme 4a). Oxidation of the boron group of 4g gave
homoallylic alcohol 10. Product 3c underwent one-carbon
homologation with ClCH2Li, affording γ-alkenyl boronate
S
Figure 2. (a) Distortion−interaction analysis diagram for A-TS and
RA-TS. Asterisk indicates distorted fragments. Optimized structures
for (b) SA-TS and (c) RA-TS. Unimportant hydrogen atoms are
omitted for clarity.
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a
nate esters in good yields with good to high enantiopurity. We
also demonstrate that gem-diborylalkanes derived from
complex molecules can be used to carry out allylations with
good stereoselectivity. Combining experimental and theoretical
studies, the mechanism is revealed for the enantiotopic-group-
selective transmetalation between gem-diborylalkanes and
chiral copper complex to generate a chiral α-borylalkyl-copper
species, which subsequently undergoes C−C bond formation
with allyl bromides. Further studies to develop enantio- and
diastereoselective versions of the reaction coupling gem-
diborylalkanes with allylic electrophiles are currently underway
in our laboratory.
Scheme 4. Synthetic Utility
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11750.
Experimental procedures, characterization data, 1H
NMR, 13C NMR, and HPLC spectra for new
compounds. Cartesian coordinates of DFT-optimized
structures, calculations, and computational details
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Mu-Hyun Baik − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea; Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Republic of Korea; orcid.org/0000-0002-8832-
8187; Email: mbaik2805@kaist.ac.kr
Seung Hwan Cho − Department of Chemistry, Pohang
University of Science and Technology (POSTECH), Pohang
37673, Republic of Korea; orcid.org/0000-0001-5803-
4922; Email: seunghwan@postech.ac.kr
a
Reaction conditions: (a) NaBO3·4H2O, THF/H2O, rt, 3 h. (b)
LiCH2Cl, THF, −78 °C to rt, 3 h. (c) TsNHNH2, NaOAc, THF/
H2O, 80 °C, 24 h. (d) cat. Pd(OAc)2, phenylacetylene, THF, 70 °C,
24 h. (e) cat. Grubbs II, CH2Cl2, 50 °C, 6 h. (f) H2N-DABCO,
KOtBu, THF, 80 °C, 1 h, then 2-NO2−C6H4SO2Cl, Et3N, 0 °C to rt,
1 h. (g) K2CO3, allyl bromide, MeCN, 50 °C, 24 h.
ester 11. Enantioenriched secondary alkylboronate ester 12
could be efficiently synthesized by the reduction of alkene with
TsNHNH2 and NaOAc. Sonogashira cross-coupling of 3u with
phenylacetylene yielded 1,3-enyne 13. Ring-closing metathesis
of 4e using the second generation Grubbs catalyst furnished
enantioenriched cyclic homoallyl boronates 14.
Authors
Minjae Kim − Department of Chemistry, Pohang University of
Science and Technology (POSTECH), Pohang 37673,
Republic of Korea
Bohyun Park − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea; Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Republic of Korea; orcid.org/0000-0003-0552-
8763
Minkyeong Shin − Department of Chemistry, Pohang
University of Science and Technology (POSTECH), Pohang
37673, Republic of Korea
Suyeon Kim − Department of Chemistry, Korea Advanced
Institute of Science and Technology (KAIST), Daejeon
34141, Republic of Korea; Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science (IBS), Daejeon
34141, Republic of Korea; orcid.org/0000-0002-7032-
1147
Junghoon Kim − Department of Chemistry, Pohang
University of Science and Technology (POSTECH), Pohang
37673, Republic of Korea
The utility of the enantioenriched homoallylic boronate
ester could also be demonstrated by the synthesis of a chiral
piperidine derivative, which presents a ubiquitous core
structure in myriad piperidine alkaloids (Scheme 4b).16 After
achieving stereospecific amination of B(nep) moiety with
H2N-DABCO under the reaction conditions developed by Liu
and co-workers,17 nosyl protection of the amine group afforded
enantioenriched homoallylic amine 15 in good yield without
erosion of er. Subsequent N-alkylation of 15 with allyl bromide
and ring-closing metathesis yielded enantioenriched cyclic
homo homoallylic amine 16, which can be readily converted to
piperidine alkaloids such as (+)-sedamine, (−)-sedridine,
(−)-ehtylnorlobelol, and (+)-coniine by known procedures.18
CONCLUSION
■
We have developed a copper-catalyzed enantiotopic-group-
selective allylation of gem-diborylalkanes with various allyl
bromides. The substrate scope is very broad, and a range of
gem-diborylalkanes and allyl bromides undergoes the coupling,
thereby providing various enantioenriched homoallylic boro-
Complete contact information is available at:
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by Copper(I)-Catalyzed 1,2-Addition of 1,1-Bis[(pinacolato)boryl]-
alkanes to Imines. Angew. Chem., Int. Ed. 2017, 56, 11584−11588.
(d) Murray, S. A.; Liang, M. Z.; Meek, S. J. Stereoselective Tandem
Bis-Electrophile Couplings of Diborylmethane. J. Am. Chem. Soc.
2017, 139, 14061−14064. (e) Kim, J.; Hwang, C.; Kim, Y.; Cho, S. H.
Improved Synthesis of β-Aminoboronate Esters via Copper-Catalyzed
Diastereo- and Enantioselective Addition of 1,1-Diborylalkanes to
Acyclic Arylaldimines. Org. Process Res. Dev. 2019, 23, 1663−1668.
(f) Kim, J.; Shin, M.; Cho, S. H. Copper-Catalyzed Diastereoselective
and Enantioselective Addition of 1,1-Diborylalkanes to Cyclic
Ketimines and α-Imino Esters. ACS Catal. 2019, 9, 8503−8508.
Author Contributions
∥M.K. and B.P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Samsung Science and Technology
Foundation under Project Number SSTF-BA1701-11. M.-H.B.
thanks the Institute for Basic Science in Korea for the financial
support (IBS-R10-A1). We thank a reviewer for insightful
mechanistic suggestions.
́
(4) For reviews, see (a) Miralles, N.; Maza, R. J.; Fernandez, E.
Synthesis and Reactivity of 1,1-Diborylalkanes Towards C−C Bond
Formation and Related Mechanisms. Adv. Synth. Catal. 2018, 360,
1306−1327. (b) Nallagonda, R.; Padala, K.; Masarwa, A. gem-
Diborylalkanes: Recent Advances in Their Preparation, Trans-
formation and Application. Org. Biomol. Chem. 2018, 16, 1050−
1064. (c) Wu, C.; Wang, J. Geminal Bis(boron) Compounds: Their
Preparation and Synthetic Applications. Tetrahedron Lett. 2018, 59,
2128−2140.
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