Chemoselective Umpolung of Enals for Asymmetric Homoenolate Cross-Annulation of Enals and Aldehydes Catalyzed by N-Heterocyclic Carbene

Article abstract of DOI:10.1021/acs.orglett.9b03509

An asymmetric homoenolate cross-annulation of enals and aldehydes with high enantioselectivity is realized by NHC-catalyzed chemoselective umpolung of enals. The reaction proceeds in a highly chemoselective manner, selectively generating the conjugated Br

Full text of DOI:10.1021/acs.orglett.9b03509

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemoselective Umpolung of Enals for Asymmetric Homoenolate
Cross-Annulation of Enals and Aldehydes Catalyzed by
N‑Heterocyclic Carbene
Ryuji Ide,†,# Ryuji Kyan,‡,# Thien Phuc Le,§ Yuya Kitagawa,† Kohei Sato,†,§ Nobuyuki Mase,†,‡,§,∥
and Tetsuo Narumi*,†,‡,§,∥
†Course of Applied Chemistry and Biochemical Engineering, Department of Engineering, Graduate School of Integrated Science and
Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
‡Graduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
§Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku,
Hamamatsu, Shizuoka 432-8561, Japan
∥Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
S
* Supporting Information
ABSTRACT: An asymmetric homoenolate cross-annulation
of enals and aldehydes with high enantioselectivity is realized
by NHC-catalyzed chemoselective umpolung of enals. The
reaction proceeds in a highly chemoselective manner,
selectively generating the conjugated Breslow intermediates
from enals rather than aldehydes, enabling the homoenolate
addition of enals to aldehydes in preference to competing acyl
anion-mediated reactions. Enantioenriched substituted γ-
butyrolactones are formed in good yields with high
enantioselectivities.
atalytic generation of homoenolate equivalents from α,β-
unsaturated aldehydes (enal) by N-heterocyclic carbenes
toward conjugated Breslow intermediates also react with NHC
to generate undesired Breslow intermediates that would
undergo competing acyl anion-mediated reactions such as
benzoin9 and Stetter10 reactions. In addition, circumstances in
which the use of aldehydes with reactivity lower than that of
enals is undesirable have often been found, because of either a
decreased overall efficiency or homodimerization of the
enals.2b,11 For these reasons, enantioselective homoenolate
cross-annulation with aldehydes requires not only the control
of stereoselective homoenolate addition to aldehydes but also
the chemoselective generation of conjugated Breslow inter-
mediates from enals. To date, a few reports on the NHC-
catalyzed enantioselective homoenolate annulation employing
aldehydes have been published,11,12 but only low to modest
yields and enantioselectivities have been observed.
In this report, we describe an NHC-catalyzed enantiose-
lective γ-butyrolactone formation, directly from enals and aryl
aldehydes, through the chemoselective generation of con-
jugated Breslow intermediates. A newly designed NHC catalyst
with an (ethoxydiphenyl)methyl group that shows unique
reactivity toward enals allows the chemoselective generation of
conjugated Breslow intermediates, facilitating a stereoselective
homoenolate addition. Importantly, this catalysis avoids the
C
(NHCs) enables the formation of unique bonds at the β-
carbonyl carbon, producing a variety of carbocycles and
heterocycles in a single step from easily available starting
materials.1 Although significant progress has been made since
two seminal reports on the diastereoselective additions of
homoenolates to aldehydes,2 enantioselective cross-annula-
tions with carbonyl electrophiles affording enantioenriched γ-
butyrolactones remain a significant challenge.3 Current
methods include cooperative catalysis with a Lewis acid,
Brønsted acid, or hydrogen bond donor for activating carbonyl
electrophiles4 and promoting the enantioselective annulations
with highly activated ketones such as isatins,5 trifluoromethyl
ketones,2a,6 acyl phosphonates,7 or α-ketoesters8 to give the
functionalized γ-butyrolactones with high enantioselectivity
(Figure 1a). Because the addition of NHC to these ketones is
reversible, these homoenolate systems can suppress the
competing reactions derived from ketones. Thus, NHC
essentially reacts only with the enal to generate a conjugated
Breslow intermediate, which can be trapped stereoselectively
with reactive ketone electrophiles to provide the corresponding
γ-butyrolactones.
A long-standing goal in this area is the highly enantiose-
lective annulation with reactive aldehyde electrophiles,
including aryl aldehydes that were used in the initial reports2
(Figure 1b). The aldehydes that show sufficient reactivity
Received: October 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03509
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Letter
a
Table 1. Catalyst Optimization
d
d
conversion
yield
c
er
er
b
b
entry precatalyst
(%)
(%)
dr
(cis)
(trans)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C9
C9
C9
90
>95
14
>95
>95
>95
94
>95
>95
>95
>95
12
38
10
44
62
51
43
45
80
45
76
1.9:1
2.2:1
1.1:1
3.8:1
2.7:1
1.2:1
2.2:1
1.8:1
1.7:1
2.0:1
1.7:1
62:38
51:49
91:9
62:38
85:15
98:2
88:12
93:7
93:7
−
−
−
−
77:23
96:4
−
Figure 1. Enantioselective homoenolate annulation (a) employing
ketone electrophiles and (b) employing aldehyde electrophiles (this
work).
−
need for an additive or co-catalyst to increase the yield and
selectivity, providing direct access from enals and aldehydes to
chiral substituted γ-butyrolactones in good yields and high to
excellent enantioselectivities.
9
10
11
90:10
89:11
88:12
e
f
92:8
93:7
a
Reaction conditions: cinnamaldehyde (0.30 mmol, 1.0 equiv),
Our study began with the identification of a potential
catalyst structure for the asymmetric homoenolate cross-
annulation of cinnamaldehyde and methyl terephthalaldehy-
date. Several NHC catalysts (10 mol %) in the presence of
DBU (40 mol %) in CHCl3 were screened (Table 1 and the
Supporting Information). The aminoindane-based precatalyst
(C1)13 showed sluggish reactivity, affording many products,
including the desired annulation product (1a) in a 1.9:1
diastereomeric ratio (dr) with preferable formation of the cis
isomer, and with a 62:38 enantiomeric ratio (er) (Table 1,
methyl terephthalaldehydate (0.60 mmol, 2.0 equiv), 40 mol %
b
DBU, and 0.2 M CHCl3 at 25 °C for 24 h. Conversion and dr were
c
determined by 1H NMR analysis of the crude mixture. The yield is a
1
combined yield of both diastereomers and determined by H NMR
analysis of the crude mixture utilizing tert-butylanisole as an internal
standard. er was determined by chiral HPLC analysis. With 1.0
equiv of methyl terephthalaldehydate. With 5 mol % precatalyst.
d
e
f
enantioselectivity were achieved with catalyst C9 with an EtO
group in place of the fluorine, affording the product in 80%
yield with a 93:7 er for 1a-cis and a 90:10 er for 1a-trans (entry
9). NMR analysis of the reaction with C9 revealed that acyl
anion-derived products such as benzoin and Stetter products
could not be observed until the cinnamaldehyde had been
consumed, indicating that the conjugated Breslow intermedi-
ates were generated chemoselectively. The reaction with an
equimolar amount of methyl terephthalaldehydate furnished
1a in 45% yield and similar selectivity with a trace amount of
cinnamaldehyde-derived butyrolactone via homodimerization
after 24 h (entry 10). Decreasing the catalyst loading to 1 mol
% proved to be unreactive, but the reaction with the 5 mol %
catalyst loading gave the products in 76% yield with
comparable selectivities (entry 11). After screening the bases,
Lewis acids,17 and solvents (see the Supporting Information),
we have found lactone formation in high yield and with high
enantioselectivity is facilitated by a combination of catalyst C9
and DBU in CHCl3 at 25 °C.
entry 1). Using a morpholine-based precatalyst (C2),5b,8c,14
a
slightly increased yield was obtained without any increase in
stereoselectivity (entry 2). The pyrrolidine-based precatalyst
(C3)8c was found to improve the enantioselectivity, delivering
the product in a 91:9 er, albeit with a low diastereoselectivity
(entry 3). On the basis of the encouraging results of
pyrrolidine-based scaffolds, we began to optimize the structure
of C3. First, we speculated that the large steric bulk of the TBS
ether group of C3 could underlie the low reactivity. As
expected, using C4,15 which lacks the TBS ether group,
increased the chemical yield and diastereoselectivity but
decreased the enantioselectivity (entry 4). The introduction
of a fluorine group to subject the phenyl group(s) positioned
close to the reaction site to the fluorine gauche effect16 led to
the recovery of the enantioselectivity (85:15 er) for the cis
isomer with the trans isomer in a 77:23 er (entry 5).
Modification of the aryl groups of C5 was effective for the
enantioselectivity, and catalyst C6 with 3,5-bis-
(trifluoromethyl)phenyl groups furnished 1a-cis in a 98:2 er
and 1a-trans in a 96:4 er (entry 6). Though several of the
fluorine-type catalysts provide high enantioselectivity, the
reactivity decreased with the aryl groups, giving the product
in lower yields (entries 7 and 8). High levels of reactivity and
With the optimal conditions in hand, we investigated the
substrate scope of the substituted enals, employing methyl
terephthalaldehydate as the electrophile (Scheme 1). The
reaction is tolerant of various functionalities, including
bromide, chloride, ether, and esters. A single ortho substitution
B
DOI: 10.1021/acs.orglett.9b03509
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a
Scheme 1. Scope of Asymmetric Homoenolate Cross-Annulation
a
Reaction conditions: enal (0.30 mmol), arylaldehyde (0.60 mmol), 40 mol % DBU, and 0.2 M CHCl3 at 25 °C for 24 h. The yield is a combined
1
yield of both diastereomers and determined by H NMR analysis of the crude mixture utilizing tert-butylanisole as an internal standard. In
parentheses, the isolated yield is shown after preparative HPLC for the analytical sample. dr was determined by H NMR analysis of the crude
1
mixture. er was determined by chiral HPLC analysis.
led to the diastereoselectivity and enantioselectivities that were
higher than those of cinnamaldehyde, as o-bromo-substituted
γ-butyrolactone (1b) is formed in 72% yield with a 4:1 dr and
a 97:3 er. On the other hand, a meta substitution resulted in
lower yields with comparable selectivities (1e and 1f),
probably due to the reactivity of meta substitution being
lower than those of other substitutions. The enals with a para
substituent were also eligible to stereoselectively provide the
corresponding γ-butyrolactones (1g−1j), except the nitro
substitution. Additionally, γ-butyrolactones with a heteroar-
omatic ring were obtained in good yields and high
enantioselectivities (1l). Unfortunately, using an enal with an
alkyl group instead of an aromatic ring failed to provide the
desired products (1m).
Next, we examined the substrate scope of the aryl aldehydes.
Replacement of the ester with a trifluoromethyl group gave 1n
in 73% yield with a 1.8:1 dr and a 95:5 er. Similarly, 4-bromo
and 4-chloro substitutions afforded the corresponding γ-
butyrolactones (1o and 1p, respectively) in moderate yields
with high enantioselectivity, but 4-fluoro substitution resulted
in no reaction (1q). The absolute stereochemistry at the
stereogenic centers of 1o was determined by X-ray
crystallography. It is noteworthy that the diastereoselectivity
of the reaction with 2,4-bis(trifluoromethyl)benzaldehyde was
completely reversed, affording the corresponding γ-butyrolac-
tones (1r) in 68% yield with a 1:16 dr and a 85:15 er. Under
these conditions, heteroaromatic aldehyde and aliphatic
aldehydes were not productive (see the Supporting Informa-
tion). These results suggested the reaction is highly sensitive to
the reactivity of aryl aldehydes, which is consistent with the
previous reports.2
To gain some insight into the observed chemoselectivity in
the annulation reaction with catalyst C9, several mechanistic
studies were conducted. The fact that the reactivity observed in
these annulations is highly dependent on the substituents of
the diphenylmethyl group on the catalyst raises the possibility
that those substituents may play a key role in the chemo-
selective induction. To evaluate this, the rates of the
consumption of each aldehyde in the presence of 5 mol %
catalyst C4 or C9 were evaluated by NMR spectroscopy.
Figure 2 shows the time course of each reaction of
cinnamaldehyde and methyl terephthalaldehydate in terms of
the consumption of the starting materials. In the presence of
catalyst C4 with a diphenylmethyl group that shows low levels
of reactivity and enantioselectivity, reaction of cinnamaldehyde
with C4 follows an exponential decay, in which the time to
reach 10% consumption is ∼60 min (Figure 2a). In contrast, a
different reactivity against cinnamaldehyde can be observed for
C
DOI: 10.1021/acs.orglett.9b03509
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
between enals and aldehydes. The result is the formation of the
cross-annulation products with high enantioselectivity over the
dimerization products. Our laboratory is currently studying the
mechanism of this transformation for the observed stereo-
selectivity and chemoselectivity and is also expanding the
utility of the identified catalyst with a pendant alkoxy group to
additional asymmetric NHC catalysis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03509.
Experimental details and characterization data for all
new compounds as well as crystal data and data
collection parameters (PDF)
Accession Codes
CCDC 1903388−1903389 contain the supplementary crys-
tallographic 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: narumi.tetsuo@shizuoka.ac.jp.
ORCID
Figure 2. Kinetic profiles of substrate consumption with C4 or C9.
(a) Consumption of cinnamaldehyde and (b) consumption of
alaldehyde. Standard conditions: precatalyst (0.0175 mmol),
cinnamaldehyde or methyl terephthalaldehydate (0.350 mmol), and
DBU (0.070 mmol) in CDCl3 (0.5 M) at 25 °C.
Tetsuo Narumi: 0000-0003-2412-4035
Author Contributions
#R.I. and R.K. contributed equally to this work.
Notes
catalyst C9 with an (ethoxydiphenyl)methyl group that shows
high levels of reactivity and enantioselectivity. The con-
sumption of cinnamaldehyde was slower than that for C4, and
the rate of decrease becomes much slower after 10 min. To our
surprise, ∼80% of cinnamaldehyde remained even after 60
min, but only a trace amount of the lactone products can be
detected. For the methyl terephthalaldehydate (Figure 2b),
while the reaction with catalyst C4 was too fast to be measured
by NMR, the reaction with C9 resulted in consumption of
methyl terephthalaldehydate that was slower than that for C4.
A comparison of the time courses of the reactions with C4 and
C9 revealed that the catalyst reactivity against two types of
aldehydes is significantly affected by the substituents of the
diphenylmethyl group and that introduction of an EtO group
decreases the reactivity against both aldehydes. In particular,
the unique reactivity of C9 against cinnamaldehyde demon-
strates that the reaction with enals of conjugated Breslow
intermediates derived from C9 does not occur easily, resulting
in the suppression of the undesired reactions, including enal
dimerizations. Efforts to elucidate the effects of the EtO group
on chemoseletivity are currently under investigation.18
In summary, we have developed an NHC-catalyzed
asymmetric homoenolate annulation of two types of aldehyde
species. Although the diastereoselectivity is modest, the
reaction proceeds with readily available enals and aldehydes
under mild conditions and allows for a direct and efficient
access to enantiomerically enriched substituted γ-butyrolac-
tones. The NHC-catalyzed asymmetric process presented here
highlights the chemoselective generation of the conjugated
Breslow intermediates, controlling the difference in reactivity
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” (26105721) and in part by a
Grant-in-Aid for Young Scientists (A) (16H06217) from The
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. R.K. is grateful for the Amano Institute of
Technology scholarship. The authors are grateful to Dr.
Hiroyuki Takemoto (Shizuoka University) for the assistance
with the accurate mass measurement and Dr. Hiroyasu Sato
(Rigaku) for the assistance with X-ray analysis.
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E
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