Enantioselective α-alkenylation of aldehydes with boronic acids via the synergistic combination of copper(II) and amine catalysis

Article abstract of DOI:10.1021/ja406356c

The enantioselective α-alkenylation of aldehydes has been accomplished using boronic acids via the synergistic combination of copper and chiral amine catalysis. The merger of two highly utilized and robust catalytic systems has allowed for the development

Full text of DOI:10.1021/ja406356c

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Communication
Enantioselective #-Alkenylation of Aldehydes with Boronic Acids
via the Synergistic Combination of Copper(II) and Amine Catalysis
Jason M Stevens, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja406356c • Publication Date (Web): 28 Jul 2013
Downloaded from http://pubs.acs.org on July 29, 2013
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Enantioselective α-Alkenylation of Aldehydes with Boronic Acids via the
Synergistic Combination of Copper(II) and Amine Catalysis
Jason M. Stevens and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
dmacmill@princeton.edu
RECEIVED DATE
Scheme 1. Proposed Mechanism for Aldehyde α-Alkenylation.
Abstract: The enantioselective α-alkenylation of aldehydes has
been accomplished using boronic acids via the synergistic
combination of copper and chiral amine catalysis. The merger of
two highly utilized and robust catalytic systems has allowed for
the development of a mild and operationally trivial protocol for
the direct formation of α-formyl olefins employing common
building blocks for organic synthesis.
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trans-
B(OH)2
XB(OH)2
2
metalation
Y
boronic acid
3
Y
CuIIX2
1
XCuII
CuIIX2
1/2 O2
Copper
CuIX
Synergistic catalysis has emerged in recent years as a powerful
concept for the design of new chemical reactions in organic
chemistry.1 The use of two discrete catalysts that simultaneously
activate orthogonal reaction partners (e.g. electrophile and
nucleophile) enables a significant opportunity to dramatically
lower the HOMO–LUMO gap for any desired bimolecular
transformation. Indeed, the resulting levels of rate accelerations
and mechanistic discrimination allow for the discovery of new
chemical reactions between otherwise benign substrates. Our lab
has recently applied the synergistic catalysis paradigm to the
development of several new asymmetric bond formations that
were previously elusive, namely, the enantioselective α-
trifluoromethylation,2 α-arylation,3 α-alkenylation,4 and α-
oxidation5 of aldehydes. As part of these ongoing efforts in dual
catalysis, we recently sought to merge the broad utility of chiral
enamine catalysis with the capacity of transition metals,
Catalytic Cycle
Y
CuIX
X2CuIII
9
4
Merging Copper
Catalysis with
Enantiofacial
Coupling Step
DFT-7
X
Organocatalysis
X
Cu
Y
O
Me
O
Me
8
N
N
N
1-Nap
1-Nap
t-Bu
t-Bu
Organocatalytic
Cycle
N
Y
6
R
R
Simultaneous Dual Catalytic Activation: Strategy for Reaction Development
O
Me
E
LUMO
N
O
■
■
■
Catalyst specific activation of
nucleophile and electrophile
O
1-Nap
Y
cat-B
cat-A
E
t-Bu
•TFA
N
H
H
H
Enhanced reactivity and selectivity
over mono-catalytic protocols
ΔE
R
R
aldehyde
enantioenriched
catalyst 5
Nu
α-vinyl aldehyde
Nu
Enables design of new reactions
HOMO
specifically CuII, to undergo transmetalation with vinyl boronic
acids to form highly electrophilic CuIII–olefin intermediates (after
a subsequent oxidation step). By targeting the merger of catalytic
systems that presently enjoy widespread use, yet employ practical
and economical substrates and catalysts, we presumed that these
technologies would allow new operationally convenient bond-
forming processes to be developed that could not be accessed
Synergistic Catalysis: In Concert Activation of Aldehydes and Boronic Acids
chiral
O
amine
HO
X
Cu(II)X2
N
B
Cu
X
H
catalyst
OH
R
R
stable
aldehyde
activated
nucleophile
stable
boronic acid
activated
electrophile
using mono-catalysis mechanisms.
Specifically, the
enantioselective α-alkenylation of carbonyls has been a long-
standing problem in chemical synthesis that has only recently
begun to come to fruition.6-8 Herein, we describe a mild, room
temperature protocol for the enantioselective α-alkenylation of
aldehydes with boronic acids9 using readily available, bench-
stable catalysts and reagents through the successful application of
synergistic copper(II)-organocatalysis.
Enantioselective α-Alkenylation of Aldehydes with Boronic Acids
O
O
chiral
R
HO
R
amine catalyst
H
B
H
R
OH
Cu(II) catalyst
R
enantioenriched
α-alkenyl aldehyde
aldehyde
boronic acid
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Table 1. Evaluation of Dual Copper and Amine Catalysts.
Table 2. Scope of Enantioselective α-Alkenylation of Aldehydes.a,b,c
1
2
3
4
20 mol% 5•TFA
O
O
HO
O
O
O
Me
Me
Me
30 mol% Cu(OAc)2
B
Ph
N
N
N
H
Ph
H
OH
4 Å mol. sieves
O2, EtOAc
Me
Me
Me
Me
Me
Me
C6H13
R
N
H
N
H
N
H
aldehyde
boronic acide
α-alkenyl aldehyde
23 °C, 10 h
Me
Me
Me
5
6
10
11
5
7
O
O
1
2
8
9
H
H
20 mol% amine cat.
Copper catalyst
O
O
HO
Me
B
Ph
H
Ph
H
10
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60
OH
4 Å mol. sieves
O2, EtOAc
23 °C, 10 h
C6H13
C6H13
octanal
boronic acid
α-alkenyl aldehyde
72% yield, 93% ee
74% yield, 90% ee
3d
4d
yield (%)a
ee (%)b
O
O
entry
amine cat.
none
Copper catalyst (mol%)
H
H
1
2
Cu(OAc)2 (20 mol%)
none
0
--
10
10
10
10
10
10
10
10
10
11
•
•
•
•
•
•
•
•
•
•
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
0
--
3
Cu(OTf)2 (20 mol%)
Cu(OMe)2 (20 mol%)
Cu(OTFA)2 (20 mol%)
Cu(Oi-Bu)2 (20 mol%)
CuOAc (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (20 mol%)
Cu(OAc)2 (30 mol%)
Cu(OAc)2 (30 mol%)
Cu(OAc)2 (30 mol%)
26
45
47
50
42
58
69
73
69
77
84
82
78
82
84
86
86
86
93
93
N
Ts
4
73% yield, 90% ee
67% yield, 85% ee
5
6
O
O
O
O
O
O
5
7
9
6
7
H
H
H
H
H
H
8
9c
10c
11c
12c
N(Phth)
OTBS
69% yield, 94% ee
75% yield, 93% ee
5 • TFA
8d
aYields determined via 1H NMR analysis vs. Bn2O standard.
bDetermined by chiral HPLC analysis of the corresponding alcohol.
cPerformed with 2.0 equiv. MeB(OH)2.
2( )
Design Plan. From the outset, we questioned whether a
transient and highly electrophilic d8-organocopper(III) species,
which have shown a remarkable propensity for reactions with π-
nucleophiles,3-4,10 could undergo productive and enantioselective
coupling with nucleophilic enamines generated through chiral
amine catalysis. As outlined in Scheme 1, we proposed that an
oxidase-style mechanism (as first delineated by Stahl11 for the
Chan–Evans–Lam reaction)12 could be employed to generate a
transient electrophilic organocopper(III) species 4 from a simple
TIPS
CO2Et
76% yield, 94% ee
72% yield, 94% ee
10
Et
boronic acid substrate (Scheme 1).
More precisely, the
84% yield, 92% ee
82% yield, 91% ee
transmetalation of copper(II) catalyst 1 with a boronic acid would
furnish organocopper(II) 3 which, after oxidation by copper(II),
would deliver the desired alkenylcopper(III) 4. Thereafter, the
HOMO-activated enamine 6, generated through a concomitant
organocatalytic cycle, would intercept organocopper(III) 4 to
access the critical dual catalysis intermediate (enamine-
organocopper(III) complex 7),13 which after reductive elimination,
would furnish α-alkenyl iminium 8 and the corresponding
copper(I) salt 9. Regeneration of each catalyst would be
accomplished through hydrolysis of iminium 8 and single-electron
oxidation of the copper(I) salt 9 under an oxygen atmosphere,
while delivering the enantioenriched α-alkenyl aldehyde product.
With respect to enantiocontrol, computational studies predict that
the Si-face of this enamine will be shielded by the naphthyl ring
of the imidazolidinone framework, leaving the Re-face accessible
to electrophilic attack (see DFT-7). Importantly, we recognized
that if such a synergistic mechanism could be realized then
boronic acids, one of the most prevalent building blocks in
organic chemistry, would become a viable and practical substrate
for the enantioselective α-functionalization of simple aldehydes.
aAbsolute configuration assigned by chemical correlation or analogy.
bIsolated yield of the corresponding alcohol. cEnantiomeric excess
determined by chiral HPLC analysis of the corresponding alcohol. d25
mol% 5•TFA. ePerformed with 2.0 equiv. MeB(OH)2.
the proposed coupling of aldehydes and boronic acids under the
simultaneous action of copper and aminocatalysis is indeed
feasible. Furthermore, a survey of copper salts (entries 3–8)
revealed that copper(II) acetate was the optimal metal catalyst in
terms of reactivity and enantioselection when employed in concert
with commercially available amine catalyst 10 (entry 8, 58%
yield, 86% ee). Further improvements in reaction efficiency were
realized via the use of higher copper loadings (30 mol%) in
combination with the addition of methylboronic acid as a reaction
supplement to deliver the desired α-vinyl adduct in 73% yield
(entry 10, 86% ee). The success of methylboronic acid as a
suitable additive for this protocol presumably arises from the in
situ formation of mixed boronic anhydrides,14-18 a species from
which boron to copper transmetalation is accelerated.18 Finally,
an evaluation of 5•TFA, 10•TFA, and 11•TFA (entries 10–12)
revealed that organocatalysts 5•TFA and 11•TFA provide superior
levels of enantiocontrol (entries 11 and 12, 93% ee); however, the
Results. As shown in Table 1, we were delighted to find that
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Table 3. Scope of the Alkenyl Boronic Acid Component.a,b,c
Scheme 2. Synergistic Catalysis Enabled Synthesis of Complex
1
Structures from Commercially Available Building Blocks.
2
3
4
5
20 mol% 5•TFA
I
Me
O
O
1. 5•TFA, Cu(OAc)2
NaClO , NaH PO
4
O
HO
R
30 mol% Cu(OAc)2
HO
C3H7
R
2.
3. I(pyr)2BF4, HBF4
2
2
B
B
H
H
H
C3H7
O
O
4 Å mol. sieves
O2, EtOAc
OH
OH
C6H13
C6H13
Me
52% yield, 94% ee
octanal
boronic acidf
α-alkenyl aldehyde
23 °C, 10 h
6
7
! rapid and facile access to structural
8
9
diversity, potentially natural products
O
O
1
2
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
O
10
11
12
13
14
15
16
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60
C6H13
C6H13
I
Me
I
O
Pr
76% yield, 96% ee
76% yield, 95% ee
O
O
Me
O
O
O
O
62% yield,
91% ee
52% yield,
90% ee
O
Me
O
blastmycinone
3
4
Me
Me
F
90% ee).19 Remarkably, given the context of a multi-catalytic
system, diverse heteroatom-containing functionalities, including
protected amines, alcohols, and esters, do not interfere with the
reactivity of either the metal or organocatalyst (entries 4–7, 67–
76% yield, 85–94% ee). Moreover, a variety of aldehydes
containing pendent alkyne and alkene functional handles are
excellent substrates for this coupling protocol (entries 8–10, 72–
84% yield, 91–94% ee).
C6H13
C6H13
80% yield, 95% ee
77% yield, 93% ee
O
O
5
6
3
(
)
Cl
OTBS
C6H13
C6H13
76% yield, 96% ee
81% yield, 96% ee
As shown in Table 3, a broad spectrum of alkenylboronic acids
can be successfully employed as substrates in this enantioselective
aldehyde α-alkenylation transformation. For example, alkyl
substituted alkenylboronic acids were found to be excellent
substrates (entries 1–4, 76–80% yield, 93–96% ee), tolerating 1°,
2°, and 3° substitution at the allylic position of the alkenylboronic
acid. Notably, the 3-phenylpropenylboronic acid adduct (entry 4)
did not undergo olefin isomerization to the corresponding enal or
styrene regioisomers in the presence of the copper transition metal
catalyst. The boronic acid component can also tolerate halide and
heteroatom functionalities (entries 5 and 6), a chemoselectivity
feature that will be important in the use of these synthons in
complex molecule construction. Moreover, a wide range of
electronically diverse styrenylboronic acids were found to be
compatible with these synergistic catalysis conditions. For
example, electron-poor styrene substrates proved to be excellent
coupling partners, achieving and maintaining high levels of
enantiopurity, despite the increased potential for these adducts to
undergo in situ racemization (entries 7–9, 67–77% yield, 91–93%
ee). Furthermore, electron-neutral and electron-rich styrenes20
were also found to furnish the α-vinyl formyl adducts with
excellent levels of efficiency and enantiocontrol (entries 10–12,
70–73% yield, 92–94% ee). To demonstrate operational utility,
we have executed our α-alkenylation reaction on a 10 mmol scale
to prepare 1.7 g of (E)-2R-(2-phenyleth-1-en-1-yl)octan-1-ol in
72% yield and in 92% ee (cf. Table 3, entry 10, 73% yield, 93%
ee).
CF3
F
7d
9e
11e
8e
10e
12e
O
O
C6H13
C6H13
67% yield, 91% ee
77% yield, 93% ee
O
O
F
C6H13
C6H13
71% yield, 91% ee
73% yield, 93% ee
Me
OMe
O
O
C6H13
C6H13
71% yield, 94% ee
70% yield, 92% ee
aAbsolute configuration assigned by chemical correlation or analogy.
bIsolated yield of the corresponding alcohol. cEnantiomeric excess
determined by chiral HPLC analysis of the corresponding alcohol. d30
mol% 5•TFA. e25 mol% 5•TFA. fPerformed with 2.0 equiv. MeB(OH)2.
superior efficiencies demonstrated by amine 5•TFA in
combination with Cu(OAc)2 defined this system as the optimal
synergistic protocol for aldehyde vinylation.
As outlined in Table 2, we have found that a broad range of
formyl components are suitable for this enantioselective coupling
with boronic acids. Of particular importance is the facility with
which propionaldehyde can be employed (entry 1, 72% yield,
93% ee), a substrate which enables modular access to diverse
propionate motifs of utility in macrolide total syntheses.
Additionally, arene functionality on the aldehydic component is
well tolerated (entry 2, 74% yield, 90% ee). Sterically demanding
β-branched products were also generated in high yield and
excellent enantioselection (entries 3 and 4, 67–73% yield, 85–
To highlight the value of this new enantioselective vinylation
reaction, we have demonstrated that this protocol can be used to
accelerate the production of a diverse series of enantioenriched
iodolactones,21 potentially valuable intermediates en route to
natural products containing γ-butyrolactone motifs (Scheme 2).21-
22
These stereochemically rich heterocycles were prepared from
their corresponding α-alkenyl aldehydes via a short two-step
sequence involving aldehyde oxidation followed by iodo-
lactonization23 without loss in enantiopurity. The rapid
development of molecular complexity obtained via this
3
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(13) DFT calculations for the enamine were performed with the use of
B3LYP/6-311+G(2d,2p)// B3LYP/6-31G(d). Copper was not included in
the calculation.
(14) It has been proposed that the Chan–Evans–Lam reaction proceeds
through boroxines formed in situ through dehydration in the presence of
molecular sieves: See Ref. 12b.
(15) For a perspective on boroxines and their applications, see: Korich, A. L.;
Iovine, P. M. Dalton Trans. 2010, 39, 1423.
(16) It was found that the reaction proceeds in 64% yield using 1 equiv. of the
preformed trans-2-styrylboroxine.
(17) NMR analysis of a mixture of styrylboronic acid and trimethylboroxine
in the presence of 4 Å mol. sieves in anhydrous d6-acetone show three
distinct vinyl boroxine resonances that vary proportionally with the
amount of added trimethylboroxine. See supporting information.
(18) For a detailed discussion on boron to copper transmetalation for oxidase
mechanisms, see Ref. 11b and references therein.
(19) This result is complementary to enantioselective α-vinylation studies via
organo-SOMO catalysis, which was unsuccessful with carbocyclic
substrates. See Ref. 6a.
(20) This result is complementary to enantioselective α-vinylation with
electron-rich styrenyliodonium salts, which exhibit poor stability: (a)
Thielges, S.; Bisseret, P.; Eustache, J. Org. Lett. 2005, 7, 681. (b) See
Ref. 4.
(21) For the preparation and stereochemical analysis of 5-membered
iodolactones via iodolactonization, see: Den Hartog, T.; Maciá, B.;
Minaard, A.; Feringa, B. L. Adv. Synth. Catal. 2010, 352, 999.
(22) For a review, see: (a) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005,
9, 285. For recent examples in the natural product literature, see: (b)
Rodrigues, A. M. S.; Theodoro, P. N. E. T.; Eparvier, V.; Basset, C.;
Silva, M. R. R.; Beauchêne, J.; Espíndola, L. S.; Stien, D. J. Nat. Prod.
2010, 73, 1706. (c) Zhang, J.; Tang, X.; Li, J.; Li, P.; de Voogd, N. J.; Ni,
X.; Jin, X.; Yao, X.; Li, P.; Li, G. J. Nat. Prod. 2013, 76, 600.
(23) Barluenga, J.; Alvarez-Pérez, M.; Rodriguez, F.; Fañanás, F. J.; Cuesta, J.
A.; Garía-Granda, S. J. Org. Chem. 2003, 68, 6583.
straightforward procedure is further underscored by the value and
convenience of employing bench-stable and readily available
catalysts and starting materials. An epoxy-lactonization variant of
the sequence is currently being employed for the total synthesis of
blastmycinone.
1
2
3
4
5
6
7
8
In conclusion, we have demonstrated the capacity of amine and
copper catalysis to be combined in a synergistic fashion to allow
the enantioselective construction of α-vinyl aldehydes. The scope
of this new dual catalysis transformation has been found to be
extensive in both the aldehyde and vinyl boronic acid coupling
partners. We previously described asymmetric, organocatalytic α-
alkenylation protocols that employ either vinyl potassium
trifluoroborate salts6a or vinyl iodonium salts4 as coupling
partners. Importantly, the dual catalysis strategy described herein
offers a major practical advantage over existing methods, as it has
enabled boronic acids, one of the most pervasive building blocks
in organic chemistry, to become a viable and practical substrate
for electrophilic additions in the context of enamine catalysis.
Application of this new methodology to the synthesis of
stereochemically complex β-iodo-γ-butyrolactones, has been
accomplished in a concise three-step sequence.
9
10
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Acknowledgement. Financial support was provided by the
NIHGMS (R01 GM103558-01) and kind gifts from Merck,
Amgen and AbbVie.
Supporting Information Available. Experimental procedures
and spectral data are provided.
References
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Synergistic Catalysis: In Concert Activation of Aldehydes and Boronic Acids
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