Asymmetric Catalytic Enantio- and Diastereoselective Boron Conjugate Addition Reactions of α-Functionalized α,β-Unsaturated Carbonyl Substrates

Article abstract of DOI:10.1021/acs.orglett.6b01998

An efficient catalytic system has been established for the asymmetric boron conjugate addition of B₂pin₂ onto α-functionalized (involving C, N, O, and Cl) α,β-unsaturated carbonyls under mild, neutral conditions involving Cu[(S)-(R)-ppfa]Cl, AgNTf₂, and alcohols. The dual additives of AgNTf₂ and alcohols were found to play crucial roles for achieving high catalytic activity and enantio- and diastereoselectivity (up to 98% ee and 70:1 dr).

Full text of DOI:10.1021/acs.orglett.6b01998

Letter
pubs.acs.org/OrgLett
Asymmetric Catalytic Enantio- and Diastereoselective Boron
Conjugate Addition Reactions of α‑Functionalized α,β-Unsaturated
Carbonyl Substrates
Jian-Bo Xie,*,†,‡ Siqi Lin,† Shuo Qiao,† and Guigen Li†,§
†Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
‡New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates
§Institute of Chemistry & BioMedical Sciences (ICBMS), Nanjing University, Nanjing 210093, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient catalytic system has been established for
the asymmetric boron conjugate addition of B2pin2 onto α-
functionalized (involving C, N, O, and Cl) α,β-unsaturated carbonyls
under mild, neutral conditions involving Cu[(S)-(R)-ppfa]Cl,
AgNTf2, and alcohols. The dual additives of AgNTf2 and alcohols
were found to play crucial roles for achieving high catalytic activity
and enantio- and diastereoselectivity (up to 98% ee and 70:1 dr).
Scheme 1. Copper-Catalyzed Boron Conjugate Additions to
α-Substituted α,β-Unsaturated Substrates
n the past several decades, enantio- and diastereoselective
Icatalysis has been one of the most challenging topics in
chemical synthesis,1 particularly for those examples involving
the control of multiple stereogenic centers in a concise
manner.2 Recently, asymmetric catalytic boron conjugate
additions to α,β-unsaturated carbonyl compounds has attracted
much attention3 due to the importance of its resulting chiral β-
substituted boron products that are versatile building blocks for
chemical synthesis and drug development.4 For example, the
resulting carbon−boron bonds can be readily transformed into
C−O, C−N, and C−C bonds through many reactions, such as
1,2-migration4i,j and Suzuki−Miyaura cross-coupling.4c,h Even
though progress has been made on asymmetric catalytic boron
conjugate additions, its use on α-substituted α,β-unsaturated
substrates still faces a serious challenge as shown by the
following: (1) the reactivity of trisubstituted alkene substrates
has been substantially diminished with known catalytic systems
(see Scheme S1); (2) nonstereospecific protonation compli-
cates its diastereoselective control; and (3) it lacks mild, neutral
conditions to avoid or minimize epimerization and the
formation of side products. Therefore, successful examples on
such reactions were quite rare (Scheme 1).5
So far, the work on asymmetric catalytic β-boration of α,β-
unsaturated substrates has been mainly focused on the use of
copper catalysts under alkaline conditions.3 However, these
conditions would not favor the diastereoselective boron
conjugate additions onto α-substituted α,β-unsaturated com-
pounds. For example, the previous work by Lillo5a or by He5b
could only achieve low dr values or no diastereoselectivity,
which were very likely affected by the racemization on the α-
positions of the carbonyl products under alkaline conditions.
Thus, to achieve both high enantio- and diastereoselectivity,
mild and neutral conditions should be used. In this paper, we
report an efficient, general, and mild catalytic system for
asymmetric boron conjugate additions to α-substituted α,β-
unsaturated substrates that contain various functional moieties
(C, N, O, and halogen) on their α-positions. It is worth noting
that these α-functionalized α,β-unsaturated starting materials
can be readily obtained via well-known and classical methods,
such as condensation reactions, Wittig−Horner reaction, and
halogenation.
Recently, we have found that the complex of CuOTf and
Josiphos catalyzed the boron conjugate addition to chalcone
with high yield and enantioselectivity by using MeOH as an
additive in the absence of any base.6 Unfortunately, no reaction
was observed when the α-substituted enone 1a was used under
the same catalytic conditions, which was probably due to the
increased steric hindrance. Careful screening of the chiral
ligands (Scheme S1) showed that only the aminophosphine
ligands (S)-(R)-ppfa (L1) afforded the desired product with
high yields and diastereoselectivity but low enantioselectivity
Received: July 9, 2016
© XXXX American Chemical Society
A
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(98% conv, 24:1 dr, 47% ee, with 5 equiv MeOH, 10 mol % of
CuOTf, and 12 mol % of L1), and the syn isomer was the main
product (Table 1, entry 2). This might be because, compared to
counterion (which should decrease dimerization) instead of
−OTf might enhance the reactivity and thus enantioselectivity.
Moreover, according to the HSAB theory, the “harder acid”
CuNTf2 might favor the coordination of the “hard base” amino
ligand. On the basis of the above consideration, the anion-
exchange reagent, AgNTf2, was added in situ to the CuCl
complex with L1 without further separation (AgCl precipitated
as dark solid). Fortunately, we found that the resulting catalyst
showed much higher enantioselectivity (80% ee) over the
CuOTf/ligand. Further study on the amount of MeOH
indicated that 10 equiv of MeOH was the optimal amount
for good enantioselectivity (82% ee, entries 5−8). Encouraged
by the influence of MeOH on the reactivity and selectivity, we
screened other alcohol additives, including phenols with CuCl/
ligand and AgNTf2 (entries 9−17). While both the pKa and
steric bulk of the additives might contribute to the reactivity
and selectivity, the results seemed to lack distinct patterns or
trends. To simplify the analysis, we compared the results of
TFE (CF3CH2OH, 99% conv, 11:1 dr, 93% ee) to the results of
EtOH (95% conv, 20:1 dr, 87% ee), as their sizes are similar.
We then concluded that the lower pKa of the additive had a
positive effect on the enantioselectivity and reactivity but a
negative effect on the diastereoselectivity (entries 9 and 14).
When the pKa of the additive was further decreased [HFIP,
(CF3)2CHOH], a dramatic change in the diastereoselectivity
occurred as the anti isomer became the dominant product
(1:1.2 dr, entry 15). Finally, we compared the substitution
groups on the N atom of the ligand and found that L1 was
superior to L2 and L3 for improving the enantioselectivity
(entries 18 and 19). With the optimized conditions in hand
(TFE as additive, L1 as ligand), we found that the catalyst was
quite effective (entries 20 and 21) and the results could be
suitably maintained (89%, 90% ee, 14:1 dr) with 1 mol % of
catalyst. Notably, the reaction was very clean, and no side
products were observed for any of the studied cases.
a
Table 1. Optimization of Reaction Conditions
The scope of α-alkyl-substituted starting materials was then
screened with 5 mol % (conditions A) or 10 mol % (conditions
B) catalyst under the optimized conditions (Scheme 2). Good
to excellent enantioselectivities (79−98% ee) were achieved for
all cases, while the syn diastereomer was obtained as the major
product for each case. The highest diastereoselectivity was
obtained with o-Cl substrate 1c (70:1 dr, likely due to the ortho
effect or contribution of Cl−B to the conformation). For some
substrates with increased steric hindrance (1n−p), increased
loading of catalyst, ligand, and additive (condition B) was used
to achieve high yields with excellent enantioselectivities. For the
substrate with a larger alkyl group on the α-position (1n), the
syn product (2n) was generated with a relatively lower dr ratio
of 3.2:1 and 94% ee (syn) and 93% ee (anti), respectively.
When the β-position was substituted with a methyl group
rather than an aryl group, a moderate dr value was also
obtained (2q, 3.1:1 dr). The cyclic product 2r can also be
formed in quantitative yield and good diastereoselectivity
(12:1) with 79% ee for the major syn product. The absolute
configuration of the product was determined by single-crystal
X-ray diffraction analysis of anti-2k, which was obtained in the
presence of HFIP with 1:1.5 dr (syn/anti, Scheme 3).
a
General reaction conditions: 1a (0.192 mmol), B2pin2 (4 equiv),
CuCl (10 mol %), chiral ligand (20 mol %), AgNTf2 (10 mol %), 4 Å
molecular sieves (∼70 mg), toluene (2.5 mL), additives were added
with indicated amount. Determined by H NMR analysis of crude
product. Determined by HPLC. CuOTf (10 mol %) was used; no
AgNTf2. 12 mol % of L1 was used. L2 was used. L3 was used.
mol % of catalyst was used. 1 mol % of catalyst was used with 2 equiv
of B2pin2.
b
1
c
d
e
f
g
h
5
i
phosphine that could form π-backbonding or oxazoline ligand,
the use of the amino ligand could increase the electron density
of Cu and thus the nucleophilicity of boron that is bonded to
Cu. We then investigated other means to increase the
enantioselectivity. While increased loading of L1 could slightly
enhance the enantioselectivity (54% ee, with 20 mol % L1,
entry 3), the use of more MeOH (12 equiv) significantly
harmed the reactivity (35% conv, entry 4). Surprisingly, only
the racemic product was obtained when 1 equiv of MeOH was
added (entry 1). We assume that the use of more MeOH might
help the coordination of the chiral ligand to the active copper
species.
Given the mild, neutral conditions, a wide scope of α-
functionalized α,β-unsaturated carbonyls were examined
(Scheme 4). For the α-amino-substituted unsaturated ester 3,
In our previous work,6 we proposed that the catalyst
dimerization7 might contribute to the low reactivity. Thus,
the use of a weaker Lewis base (−NTf2 compared to −OTf) as
the high pKa and bulky additive, BuOH, gave the highest dr
t
values for syn products. When the tert-butyl ester (3d) was
applied, the dr could be increased to 16:1, with 97% ee. α-
B
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Scheme 2. α-Alkyl Substrates
Scheme 4. α-Functionalized Substrates
oxidation with m-CPBA gave the hydroxylated product 9 in
83% yield with 15:1 dr and 78% ee.
A plausible mechanism for the diastereoselectivity is
proposed in Scheme 5. First, we assume that there is an O-
Scheme 3. Absolute Configuration of anti-2k by X-ray Study
Scheme 5. Plausible Mechanism for the Diastereoselective
Control
donation to the B atom in the enolate transition state, which is
then protonated with the alcohol additives. There are two main
possible pathways, and one is via protonation from the C-
terminal of the enolate (pathway a). In this case, the syn
product was favored because of the relatively lower steric
hindrance on the H side. Thus, the more bulky alcohol
additives could give higher dr for the syn products. The other is
via protonation from the O-terminal of the enolate with H+
(pathway b). In this case, the thermodynamic product would be
favored as the proton has little steric effect on the kinetic
selectivity. Thus, the low pKa additives tend to induce the more
thermodynamically stable product (in our case, the anti
product; see the equilibrium experiment in Scheme 5).
Moreover, the steric effect of the bulky ligand might influence
the diastereoselectivity as well. The protonation usually tends
to occur through pathway a because of the steric hindrance at
Methoxy and α-chloro substrates (5 and 7) were also
investigated. A good chemical yield (89%) was obtained for
syn-6 product with 94% ee and 4.9:1 dr. For the halogenated
substrate 7, a higher loading of CuCl (20 mol %) with 24 mol
% of chiral ligand was required because the elimination
byproduct ClBpin released the harmful chloride anion into the
reaction and poisoned the Cu catalyst (the resulting CuCl was
catalytically inert). A small amount of byproducts (E)-10 and
11 (∼12%) was observed, while the desired product 8 was
obtained with high diastereoselectivity (15:1 dr). Further
C
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the O-terminal, making it easier to control the syn selectivity
(up to 70:1, 2c) over the anti selectivity (only up to 1:1.7, 4b)
with the alcohol additives. This is further supported by the
equilibrium experiment that showed that a higher dr for anti
product (1:3.9 dr for 2a) could be achieved. The thermody-
namic stability could be explained by the crystal structure of
anti-2k, in which the B atom and the O atom of the carbonyl
group have a relatively short distance (2.7 Å). The aryl group
and the methyl group are aligned on the trans positions, which
is thermodynamically favorable. This equilibrium reaction
provides a facile method for the preparation of anti products.
When the steric hindrance on the α-position was increased (for
example, comparing 1n to 1a) or the steric hindrance on the O-
terminal side of the enolate was decreased (for example,
comparing 3a to 3d), pathway b would be more favored; this
significantly decreased the diastereoselectivity for syn products.
The influence of the additives on the diastereoselectivities for
1n and 3b was investigated, and the results were in agreement
with the mechanism (Table S1).
By simple oxidation with NaBO3, the borated product syn-2a
(92% ee, 50:1 dr) could be transformed to the chiral alcohol
syn-12 with slightly higher ee (94% ee) and lower dr (14:1 dr).
This was followed by stereospecific reduction, and the
enantioenriched diol epimers (13 and 14) with three
stereogenic centers could be efficiently and stereodivergently
obtained (see Scheme S2). For example, Bu4NBH4 in acetic
acid8a gave anti diol 13 in about 80% yield (16:1 dr), while
DIBAL8b gave syn diol 14 in 95% yield (19:1 dr).
In summary, we have developed a strategy of obtaining
enantioenriched products bearing two adjacent stereogenic
centers with various functional groups by an enantio- and
diastereoselective boron conjugate addition to α-substituted
α,β-unsaturated compounds using a copper catalyst. In fact, the
diastereoisomers of the products could be stereodivergently
synthesized by changing the additives or simple transformation
with base. The influence of steric bulk and pKa of the additives
on the diastereoselectivity was investigated. The boron
conjugate addition product was used for the synthesis of
epimers of 1,3-diol, which contain three stereogenic centers.
We expect the enantio- and diastereoselective control of the
conjugate addition product of α-substituted α,β-unsaturated
compounds could be applied to broader substrate scope and
more reactions, as the enantioenriched products with various
functional groups could be synthesized concisely.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NIH
(R33DA031860) and the Robert A. Welch Foundation (D-
1361). We thank Dr. Daniel Unruh (Texas Tech University)
for the X-ray diffraction analysis. We thank Dr. Patrick
Commins (New York University Abu Dhabi) for critical
reading of the manuscript and helpful comments.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01998.
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AUTHOR INFORMATION
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■
Corresponding Author
*E-mail: nkjbxie@gmail.com.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.6b01998
Org. Lett. XXXX, XXX, XXX−XXX