Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through Cooperative Action of B(C6F5)3, N-Alkylamine and a Zn-Based Catalyst

Article abstract of DOI:10.1021/jacs.8b13757

An efficient and highly enantioselective Conia-ene-type process has been developed. Reactions are catalyzed by a combination of B(C₆F₅)₃, an N-alkylamine and a BOX-ZnI₂ complex. Specifically, through cooperative

Full text of DOI:10.1021/jacs.8b13757

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Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through
Cooperative Action of B(C6F5)3, N-Alkylamine and a Zn-Based Catalyst
Min Cao, Ahmet Yesilcimen, and Masayuki Wasa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13757 • Publication Date (Web): 20 Feb 2019
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Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through Cooperative
Action of B(C6F5)3, N-Alkylamine and a Zn-Based Catalyst
Min Cao, Ahmet Yesilcimen, and Masayuki Wasa*
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Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
RECEIVED DATE (automatically inserted by publisher); wasa@bc.edu
pKa ~10).6-8 With catalysts that are more strongly acidic and/or
Abstract: An efficient and highly enantioselective Conia-
basic and capable of deprotonating less acidic ketones (pKa ~20),
mutual quenching can be an issue.1,2 Consequently, pre-formation
of silicon enolate is needed for enantioeselective R3P/Au-
catalyzed (5-endo-dig) cyclization of ketones (III to IV; Figure
1B).10 Synergetic catalyst systems that promote direct
enantioselective Conia-ene-type processes with mono-carbonyl
compounds remain unprecedented. Herein, we describe
enantioselective direct Conia-ene-type reaction of ketones
promoted by cooperative action of B(C6F5)3, an N-alkylamine and
a chiral Lewis acid co-catalyst (Figure 1C).
ene-type process has been developed. Reactions are
catalyzed by a combination of B(C6F5)3, an N-alkylamine
and a BOX–ZnI2 complex. Specifically, through cooperative
action of B(C6F5)3 and amine, ketones with poorly acidic -
C–H bonds can be converted in situ to the corresponding
enolates. Subsequent enantioselective cyclization involving
a BOX–ZnI2-activated alkyne leads to the formation of
various cyclopentenes in up to 99% yield and 99:1 er.
Cooperative acid/base catalysis may be used to promote an
enantioselective reaction between an in situ generated, acid-
activated electrophile and a base-activated nucleophile.1,2 One of
the key challenges in developing such transformations is to find a
way for bypassing undesirable mutual quenching. Although one
possible solution is to avoid utilizing a combination that exhibits
high affinity (i.e., hard–hard or soft–soft pairing),1,2 this approach
has been confined to cases that involve weakly or moderately
acidic and/or basic catalysts along with substrates that are acid- or
base-sensitive. Development of highly efficient and unquenchable
cooperative catalyst systems that are capable of promoting
enantioselective reactions between relatively unactivated starting
materials stands as a largely unresolved challenge.
The application of frustrated Lewis pairs (FLPs), consisting of
hindered and electronically disparate Lewis acids and Lewis
bases, has recently emerged as an enabling strategy for
overcoming undesirable mutual quenching.3,4 Furthermore, FLPs
that are comprised of Lewis acidic B(C6F5)3 and a Brønsted basic
N-alkylamine catalyst have been shown to promote Mannich-type
and -amination reactions with ketone, ester or amide pro-
nucleophiles (pKa ~20-30).5 An ammonium ion derived from an
N-alkylamine catalyst is thought to serve as a poorly activating
Brønsted acid catalyst;1,2 these methods therefore demand acid-
sensitive electrophiles such as N-Boc-benzaldimines or dimethyl
azodicarboxylate. We reasoned that catalyst systems comprised of
B(C6F5)3, an N-alkylamine and a Lewis acid co-catalyst for
electrophile activation might pave the way for development of
reactions between unactivated pro-nucleophiles and electrophiles.
Enantioselective cycloadditions of 1,3-dicarbonyl compounds
a tethered alkyne moiety (5-exo-dig and 5-endo-dig
with
processes) offer access to valuable five-membered ring structures
that bear an exo-methylene moiety (e.g., I to II; Figure 1A) or
cyclopentene derivatives.6-9 These “direct” Conia-ene-type
reactions can be promoted by cooperative Lewis acid/Lewis acid
catalysts
(e.g.,
Pd/Yb-,
La/Ag-,
Zn/Yb-based),7
or
enantiomerically pure Lewis basic amine/Lewis acid catalysts
(e.g., Cu-, Ag-based).8 Such transformations allow for in situ
generation of an enolate equivalent by Lewis acid or Lewis base
catalyzed deprotonation, in addition to an electrophilic alkyne unit
by Lewis acid activation.4 Nonetheless, the requisite weakly to
moderately acidic and/or basic catalysts render the approach
confined to readily enolizable 1,3-dicarbonyl compounds (e.g., I;
Figure 1. Enantioselective 5-endo-dig cycloadditions.
In contemplating ways to design an enantioselective method
for cyclization of ketones that contain an alkyne unit (1), we
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envisioned a catalyst system that is comprised of a strongly Lewis
The amount of a bis-oxazoline ligand had a notable impact on
efficiency and er. In the absence of L8, under otherwise identical
conditions, rac-2a was isolated in >95% yield;13 as a consequence,
there was diminution in enantioselectivity when 10 mol% of ZnI2
and 8.0 mol% of L8 was used (2a in >95% yield, 92:8 er). On the
other hand, with excess L8 (13 mol%), 2a was obtained in <5%
yield, suggesting that the Lewis basic oxazoline units of L8 can
deactivate B(C6F5)3. Preformed and purified ZnI2/L8 complex
may be used with similar effect.14
acidic B(C6F5)3, a Brønsted basic N-alkylamine, and a chiral
Lewis acid co-catalyst (Figure 1C). By employing structurally and
electronically different organoborane and chiral Lewis acid co-
catalyst that could have overlapping functions, we might be able
to control the ability of B(C6F5)3 to serve as a carbonyl activator,
and use the chiral Lewis acid co-catalyst to elevate alkyne
reactivity (V). We surmised that N-alkylamine could deprotonate
B(C6F5)3-activated ketone of 1, generating an enolate and an
ammonium ion (VI). In the meantime, a chiral Lewis acid co-
catalyst (ML*) would activate the alkyne unit (VI). An ensuing
enantiodetermining 5-endo-dig cyclization of the enolate and the
alkyne would deliver VII. Subsequent protonation of C–ML*
bond by the ammonium ion would afford the desired
cyclopentenyl product 2. One key advantage provided by the
untethered catalyst system would be that efficiency and
stereoselectivity might be optimized through rapid evaluation of
readily accessible Lewis acids, chiral ligands, and N-alkylamines.
1
2
3
4
5
6
7
8
Next, we set out to identify an effective organoborane and
Brønsted base catalysts, and optimize other reaction parameters
(Table 2). Whereas with Et3N, 2a was obtained in >95% yield and
97:3 er (entry 1), none of the desired product could be detected
with DBU as the base (entry 2). With less B(C6F5)3 (7.5 mol%),
PMP (15 mol%), ZnI2/L8 (7.5 mol%), efficiency suffered but not
enantioselectivity (90% yield, 97:3 er; entry 4). Efficiency
improved at 40 °C (entry 5), allowing catalyst loading to be
reduced to 5.0 mol% B(C6F5)3, 10 mol% PMP and 5.0 mol%
ZnI2/L8; under these conditions, 2a was produced in 92% yield
and 97:3 er (entry 6). No product was generated without the
Brønsted base, the organoborane catalyst or the ZnI2/L8 (entries
7–9); the same was the case when the smaller BF3•OEt2 or the less
acidic BPh3 were used (entries 10–11). Thus, the appropriately
acidic B(C6F5)3, sizeable and electron-rich PMP, together with
sterically demanding ZnI2/L8 complex emerged as the most
effective combination.
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To identify an optimal catalyst combination, we probed the
ability of B(C6F5)3, 1,2,2,6,6-pentamethylpiperidine (PMP), and
various chiral Lewis acid/ligand complexes to catalyze the
cyclization of 1-phenylnon-5-yn-1-one 1a (CH2Cl2, 12 h, 22 °C),
to generate 2a (Table 1).11 The combination of 10 mol% ZnI2 and
Ph–PyBOX (L1) or Ph–DBFOX (L2) afforded 2a in 20% and 7%
yield, and 83:17 and 55:45 er, respectively. With Ph–BOX (L3) as
the ligand, the desired product was generated in >95% yield and
89:11 er. Catalysts derived from alkyl-substituted L4 (10% yield
and 75:25 er) and L5 (6% yield, 71:28 er) were less effective.
Evaluation of Ph–BOX ligands with varying 2,2’-substiutents
(cyclopropyl (L6), diisopropyl (L7), and dibenzyl (L8)) led us to
establish that L8 is the most effective, providing 2a in >95 %
yield and 97:3 er.12
Table 2. Evaluation of Reaction Parameters a,b
O
Lewis acid
cat. Bn Bn
O
cat.
O
O
cat. Brønsted base
CH2Cl2, 22 °C, 12 h
N
N
H
Zn
Ph
Ph
n-Pr
H
I
I
n-Pr
ZnI2/L8
Table 1. Evaluation of Bis-oxazoline Ligands a,b
2a
1a
entry
Lewis acid
(mol%)
Brønsted base
(mol%)
ZnI2/L8
yield of 2a
er
10 mol% B(C6F5)3
Me
Me
Me
Me
O
(mol%)
(%)
>95
0
O
N
Me
20 mol% PMP
1
B(C6F5)3 (10)
B(C6F5)3 (10)
B(C6F5)3 (10)
B(C6F5)3 (7.5)
B(C6F5)3 (7.5)
B(C6F5)3 (5.0)
B(C6F5)3 (5.0)
none
NEt3 (20)
DBU (20)
PMP (20)
PMP (15)
PMP (15)
PMP (10)
none
10
97:3
ND
H
10 mol%
ZnI2,
11 mol% L1 L8
n-Pr
H
2
10
n-Pr
CH2Cl2, 22 °C, 12 h
2a
1a
3
10
>95
90
>95
92
0
97:3
97:3
97:3
97:3
ND
4
7.5
7.5
5.0
5.0
5.0
0
Me Me
O
O
O
O
N
O
5c
6c
7
N
O
O
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
L1
L2
L3
2a, 20% yield
83:17 er
2a, 7% yield
55:45 er
2a, >95% yield
89:11 er
8
PMP (10)
PMP (10)
PMP (10)
PMP (10)
0
ND
Me Me
Me Me
O
9
B(C6F5)3 (5.0)
BF3•OEt2 (5.0)
BPh3 (5.0)
0
ND
O
O
O
O
O
N
N
N
N
N
N
10
11
5.0
5.0
0
ND
Ph
Bn
Ph
t-Bu
Bn
t-Bu
0
ND
L4
L5
L6
2a, 85% yield
85:15 er
2a, 10% yield
75:25 er
2a, 6% yield
71:28 er
a Conditions: 1-phenylnon-5-yn-1-one (1a, 0.2 mmol), organoborane, Brønsted base,
b
ZnI2/L8 complex, CH2Cl2 (1.0 mL), under N2, 22 °C, 12 h. Yield was determined
by 1H NMR analysis of unpurified reaction mixtures with mesitylene as the internal
standard. The er values were determined by HPLC analysis of the purified product. c
The reaction mixture was allowed to stir at 40 °C.
i-Pr
i-Pr
O
Bn Bn
with 8.0 mol% L8:
2a, >95% yield
92:8 er
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
A
variety of 1-phenyl ketones with different alkyne
with 13 mol% L8:
2a, <5% yield
97:3 er
L7
L8
substituents proved to be suitable substrates (2a–2i; Table 3).
With 1-phenylhex-5-yn-1-one, containing a terminal alkyne
moiety (R = H), the transformation was inefficient and moderately
enantioselective (10% yield, 70:30 er).15 In contrast, 1-
phenylhept-5-yn-1-one, which bears an internal alkyne (R = Me),
was converted to 2b in 96% yield and 82:18 er. Reactions
involving substrates that carry a larger ethyl, n-propyl, n-butyl,
and iso-butyl substituent, afforded the desired products in >95%
2a, >95% yield
2a, >95% yield
93:7 er
97:3 er
a
Conditions: 1-phenylnon-5-yn-1-one (1a, 0.2 mmol), B(C6F5)3 (10 mol%),
1,2,2,6,6-pentamethylpiperidine (20 mol%), ZnI2 (10 mol%), bis-oxazoline ligand
(11 mol%), CH2Cl2 (1.0 mL), under N2, 22 °C, 12 h. Yield was determined by 1H
b
NMR analysis of unpurified reaction mixtures with mesitylene as the internal
standard. The er values were determined by HPLC analysis of the purified product.
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68:32 er. Studies are underway to enhance the applicability of the
yield and 96:4–97:3 er (2a, 2c–2e). Although benzyl-substituted
approach.
1
2
3
4
5
6
7
8
substrate furnished 2f in 82% yield and 98:2 er, phenyl-
substituted substrate was less efficient (2g, 50% yield, 91:9 er).
As indicated by the formation of 2h (97% yield, 94:6 er) and 2i
(94% yield, 97:3 er), the presence of a carboxylic ester or a
monosubstituted alkene is tolerated.
Table 4. Conia-Ene-Type Reactions with Different Ketones a,b
Bn Bn
B(C6F5)3
NR3
O
7.5 mol%
15 mol%
O
O
O
R
N
I
N
I
H
R1
H
R
R1
Zn
Ph
Ph
R2
CH2Cl2, 40 °C, 12 h
Table 3. Conia-Ene-Type Reactions with Different Alkyne
R2
O
Substituents a,b
7.5 mol%
1j-1s
MeO
2j-2s
O
O
9
H
10
11
12
13
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Br
n-Pr
n-Pr
n-Pr
H
H
2j, 95% yield
93:7 er
2k, 97% yield
97:3 er
2l, 98% yieldc
99:1 er
O
S
O
O
O
H
R2
n-Pr
n-Pr
H
H
2m (R2 = n-Pr)c,d
2o, 99% yield
98:2 er
2p, 99% yield
97:3 er
20% yield, 98:2 er
2n (R2 = Me)c,d
73% yield, 91:9 er
O
O
O
Et
n-Bu
H
n-Pr
n-Pr
n-Pr
H
H
2q, 91% yield
95:5 er
2r, 77% yield
96:4 er
2s, 82% yieldc
80:20 er
a
Conditions: Alkynyl ketone (1j-1l, 1o-1s; 0.2 mmol), B(C6F5)3 (7.5 mol%),
1,2,2,6,6-pentamethylpiperidine (15 mol%), ZnI2/L8 (7.5 mol%), CH2Cl2 (1.0 mL),
b
under N2, 40 °C, 12 h. Yield of isolated and purified product. The er values were
determined by HPLC analysis of the purified product. c 1-Methylpiperidine was used
d
as a Brønsted base catalyst. Alkynyl ketone (1m, 1n; 0.2 mmol), B(C6F5)3 (10
mol%), 1-methylpiperidine (20 mol%), ZnI2/L8 (10 mol%), ClCH2CH2Cl (1.0 mL),
a
under N2, 60 °C, 24 h.
Conditions: Alkynyl ketone (1a-1d, 1h, 1i; 0.2 mmol), B(C6F5)3 (7.5 mol%),
1,2,2,6,6-pentamethylpiperidine (15 mol%), ZnI2/L8 (7.5 mol%), CH2Cl2 (1.0 mL),
under N2, 40 °C, 12 h. Yield of isolated and purified product. The er values were
determined by HPLC analysis of the purified product. Alkynyl ketone (1e-1g; 0.2
mmol), B(C6F5)3 (10 mol%), 1,2,2,6,6-pentamethylpiperidine (20 mol%), ZnI2/L8
b
Bn Bn
c
B(C6F5)3
PMP
O
2.5 mol%
5.0 mol%
O
O
O
N
I
N
I
(10 mol%), ClCH2CH2Cl (1.0 mL), under N2, 60 °C, 24 h.
H
Zn
Ph
Ph
CH2Cl2, 40 °C, 24 h
n-Pr
We then investigated reactions with different aryl- and alkyl-
substituted ketones (Table 4). 2-Methoxyphenyl- and 4-
bromophenyl-substituted ketones gave 2j (95% yield, 93:7 er) and
2k (97% yield, 97:3 er), respectively. The process involving
indanone derivative did not afford 2l when PMP was employed as
a Brønsted base catalyst, probably because it is too hindered to
deprotonate a tertiary C–H bond within a B(C6F5)3-activated
ketone. In the case of using less hindered 1-methylpiperidine, 2l,
which possesses an -quaternary carbon center was produced in
98% yield and 99:1 er. Tetralone-derived 2m was formed
inefficiently (20% yield) but in 98:2 er, perhaps an indication of
severe steric repulsion between the n-propyl substituent and the
tetralone ring. Thus, we were able to convert a Me-substituted
substrate to 2n in 73% yield and 91:9 er. Thiophene-substituted
2o (99% yield, 98:2 er) and furan-substituted 2p (99% yield, 97:3
er) provide further evidence regarding the approach’s notable
scope. Transformations with alkyl ketones were similarly
effective, as represented by 2q (91% yield, 95:5 er) and 2r (77%
yield, 96:4 er). Cyclopentanone derivative 2s was generated with
1-methylpiperidine as the Brønsted base, but in diminished er
(82% yield, 80:20 er).
H
n-Pr
2.5 mol%
2a, 1.4 g
1a, 1.5 g
94% yield, 97:3 er
O
B(C6F5)3
N Me
7.5 mol%
15 mol%
Bn Bn
O
O
O
H
N
I
N
I
Zn
Ph
Ph
CH2Cl2, 22 °C, 12 h
H
H
H
7.5 mol%
4a, 98% yield
3a
68:32 er
Scheme 1. Scale-up experiments and 5-exo-dig cycloaddition of 3a
To summarize, we have designed an efficient and
enantioselective Conia-ene-type reaction by implementing the
cooperative action of a three-component catalyst system, which
consists of a pair of Lewis acids and a Brønsted basic amine. We
show that by tuning of different features of Lewis acids that
possess overlapping functions, it is possible to engage Lewis acid
catalysts to serve as an activator of a carbonyl group or an
activator of electron-rich alkyne. Accordingly, efficiency and
stereoselectivity of C–C bond forming reactions between in situ
generated enolate and chiral Lewis acid-activated alkyne can be
conveniently enhanced without significant loss in er, which might
arise due to intervention by an achiral Lewis acid component. The
principles outlined herein, entailing separate and independently
operational Lewis acidic co-catalysts and a Brønsted base catalyst,
The method is readily scalable. Treatment of 1.5 g (7.0 mmol)
of 1a with 2.5 mol% B(C6F5)3, 5.0 mol% PMP and 2.5 mol%
ZnI2/L8 (CH2Cl2, 24 h, 40 °C) afforded 2a in 94% yield (6.6
mmol, 1.4 g) and 97:3 er (Scheme 1). Moreover, we discovered
that cycloaddition of 1-phenylhept-6-yn-1-one (3a) (5-exo-dig) is
facilitated by B(C6F5)3, 1-methylpiperidine and ZnI2/L8 to deliver
exo-methylene-substituted cyclopentane 4a in 98% yield but just
provide
a rational framework for further development of
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2017, 139, 9598. (c) Shang, M.; Cao, M.; Wang, Q.; Wasa, M.
processes involving weakly acid- and/or base-sensitive substrates.
Studies aimed at achieving these objectives are in progress.
Enantioselective Direct Mannich-Type Reaction Catalyzed by Frustrated
Lewis Acid/Brønsted Base Complexes. Angew. Chem., Int. Ed. 2017, 56,
1333813526.
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2
3
4
5
6
7
8
Author Information
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Carbonyl Compounds. Synthesis 1975, 1, 119. (b) Hack, D.; Blümel, M.;
Chauhan, P.; Philipps, A. R.; Enders, D. Catalytic Conia-ene and related reactions.
Chem. Soc. Rev. 2015, 44, 60596093.
(7) (a) Corkey, B. K.; Toste, F. D. Catalytic Enantioselective Conia-Ene
Reaction. J. Am. Chem. Soc. 2005, 127, 1716817169. (b) Matsuzawa, A.;
Mashiko, T.; Kumagai, N.; Shibasaki, M. La/Ag Heterobimetallic
Corresponding Author
*wasa@bc.edu
Notes
The authors declare no competing financial interest.
Acknowledgements. Financial support was provided by the NIH
(GM-128695) and Boston College. We thank Professor Amir H.
Hoveyda (Boston College) for helpful discussions. We also thank Dr.
Bo Li and Dr. Malte S. Mikus (Boston College) for X-ray
crystallographic analysis.
Cooperative Catalysis:
A Catalytic Asymmetric Conia-Ene Reaction.
Angew. Chem., Int. Ed. 2011, 123, 77587761. (c) Suzuki, S.; Tokunaga,
E.; Reddy, D. S.; Matsumoto, T.; Shiro, M.; Shibata, N. Enantioselective
5-endo-dig Carbocyclization of β-Ketoesters with Internal Alkynes
Employing a Four Component Catalyst System. Angew. Chem., Int. Ed.
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Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) (a) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J.
Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective
Conia-Ene reaction. J. Am. Chem. Soc. 2009, 131, 91409141. (b) Shaw,
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Intermediates
Enantioselective
in
Chiral
Bis(oxazoline)copper(II)-Catalyzed
and Theoretical
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1-phenylhex-5-yn-1-one, see the SI.
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