Regioselective α-Addition of Deconjugated Butenolides: Enantioselective Synthesis of Dihydrocoumarins

Article abstract of DOI:10.1002/anie.201700437

The enantioselective α-addition of deconjugated butenolides has rarely been exploited, in contrast to the well-studied γ-addition of deconjugated butenolides. In this study, an unprecedented asymmetric α-addition/transesterification of deconjugated butenolides with ortho-quinone methides generated in situ afforded a series of functionalized 3,4-dihydrocoumarins containing two contiguous stereogenic centers with excellent diastereo- and enantioselectivity. DFT calculations suggested that the rarely observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic dienolate and the electrophilic ortho-quinone methide.

Full text of DOI:10.1002/anie.201700437

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201700437
German Edition: DOI: 10.1002/ange.201700437
Organocatalysis
Regioselective a-Addition of Deconjugated Butenolides:
Enantioselective Synthesis of Dihydrocoumarins
Bo Wu, Zhaoyuan Yu, Xiang Gao, Yu Lan,* and Yong-Gui Zhou*
Abstract: The enantioselective a-addition of deconjugated
butenolides has rarely been exploited, in contrast to the well-
studied g-addition of deconjugated butenolides. In this study,
an unprecedented asymmetric a-addition/transesterification of
deconjugated butenolides with ortho-quinone methides gen-
erated in situ afforded a series of functionalized 3,4-dihydro-
coumarins containing two contiguous stereogenic centers with
excellent diastereo- and enantioselectivity. DFT calculations
suggested that the rarely observed regioselectivity was due to
the distortion energy that resulted from the interaction between
Scheme 1. Regioselectivity in asymmetric addition reactions of decon-
jugated butenolides.
the nucleophilic dienolate and the electrophilic ortho-quinone
methide.
B
utenolide scaffolds are ubiquitous structural fragments in
reactions of deconjugated butenolides would diversify the
asymmetric reaction types of deconjugated butenolides.
ortho-Quinone methides (o-QMs) are a pivotal class of
highly reactive intermediates in both biological processes[7]
and organic synthesis.[8] A range of catalytic asymmetric
processes of o-QMs have been successfully developed on the
basis of transition-metal catalysis and organocatalysis.[9–11]
During our studies on the utilization of o-QMs,[12] we focused
on bifunctional organocatalytic reactions of o-QMs generated
in situ. We previously reported the bifunctional squaramide-
catalyzed enantioselective annulation of o-QMs generated in
situ with active methylene compounds bearing a cyano
group.[12e,f] Considering that g-substituted deconjugated bute-
nolides have been widely employed as nucleophilic reagents
in asymmetric organocatalytic addition reactions, we envi-
sioned that the combination of g-substituted deconjugated
butenolides with o-QMs generated in situ could enable the
synthesis of chiral O-containing heterocycles by an asymmet-
ric annulation reaction.
The reaction of deconjugated butenolides with o-QMs can
proceed through two possible pathways. According to pre-
vious reports,[3–6] the nucleophilic addition tends to occur at
the g-position of deconjugated butenolides. Subsequently, the
negatively charged oxygen atom attacks the electron-defi-
cient unsaturated lactone through Michael addition followed
by protonation to afford a fused butyrolactone 5 (Scheme 2,
path A). Another pathway is the a-addition of deconjugated
butenolides with the o-QM generated in situ, followed by
intermolecular transesterification to give 3,4-dihydrocoumar-
ins 3 (Scheme 2, path B). Herein, we report an unprecedented
a-addition/transesterification reaction of g-substituted decon-
jugated butenolides with o-QMs generated in situ from 2-(1-
tosylalkyl)phenols. This asymmetric annulation provided
streamlined and enantioselective access to functionalized
3,4-dihydrocoumarins containing two contiguous tertiary
stereogenic centers: an essential scaffold in various natural
products and pharmaceutical molecules.[13] Additionally,
biologically active molecules, natural products, and synthetic
drugs.[1] Owing to the prevalence and significance of buteno-
lides, the development of streamlined strategies for the
construction of optically active butenolide-containing com-
pounds has attracted considerable attention.[2] Deconjugated
butenolides have emerged as versatile synthons for the
construction of butenolide derivatives. A base can deproto-
nate deconjugated butenolides to generate highly active
dienolate intermediates, which could react with electrophiles
at different positions to give products of g- or a-addition
(Scheme 1). Recently, great progress has been made in
asymmetric g-addition of g-substituted deconjugated buteno-
lides to afford g,g-disubstituted butenolides. Various trans-
formations involving asymmetric allylic alkylation,[3] a vinyl-
ogous Mannich reaction,[4] and vinylogous Michael addition
reactions[5] of g-substituted deconjugated butenolides have
been documented. In contrast to the well-studied g-addition
of deconjugated butenolides, a-addition reactions have been
far less exploited.[6] In 2003, Egorova and Timofeeva reported
the a-addition of deconjugated butenolides to a,b-unsatu-
rated ketones to give the racemic a-addition products (with
respect to the butenolide).[6b] To the best of our knowledge,
the asymmetric a-addition of deconjugated butenolides is still
unknown. Hence, the development of asymmetric a-addition
[*] B. Wu, X. Gao, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences
Dalian 116023 (P.R. China)
E-mail: ygzhou@dicp.ac.cn
Z. Yu, Prof. Y. Lan
School of Chemistry and Chemical Engineering
Chongqing University
Chongqing 400030 (P.R. China)
E-mail: lanyu@cqu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700437.
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Table 1: Optimization of the reaction conditions.[a]
Scheme 2. Possible pathways for the asymmetric annulation of decon-
jugated butenolides with o-QMs.
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11[e]
12[f]
13[g]
4a
4a
4a
4a
4a
4b
4c
4d
4e
4 f
p-xylene
toluene
benzene
CHCl3
DCE
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
12
12
24
18
24
18
24
40
40
40
60
120
144
97
94
97
94
97
97
97
91
73
94
97
97
97
3.9:1
4.6:1
4.9:1
6.2:1
4.6:1
7.3:1
8.4:1
8.0:1
2.7:1
1.0:1
8.3:1
8.1:1
9.2:1
91/78
92/81
93/81
96/82
92/86
97/80
73/38
66/33
23/2
20/20
97/75
97/67
97/69
theoretical studies based on DFT calculations provided
important insight into the origin of the observed unusual
regioselectivity.
To test the viability of our proposed protocol, we chose 2-
(1-tosylalkyl)naphthol 1a and a-angelica lactone (2a) as
model substrates. This reaction was conducted under our
previously reported reaction conditions.[12e] Pleasingly, the
reaction proceeded smoothly to completion in 12 h, and 3,4-
dihydrocoumarin 3a containing two contiguous tertiary
stereogenic centers was isolated in 97% yield with excellent
enantioselectivity, albeit with moderate diastereoselectivity
(3.9:1; Table 1, entry 1). Hence, the main challenge was to
improve the diastereoselectivity. Various solvents were exam-
ined extensively, and it was found that the solvent had
a crucial effect on the diastereoselectivity. Chloroform proved
to be the most favorable solvent in view of enantioselectivity
and diastereoselectivity (entries 2–5). Subsequently, a series
of bifunctional organocatalysts were evaluated. Cinchona
alkaloid based squaramide catalysts gave higher enantiose-
lectivity and lower diastereoselectivity in comparison with
thiourea catalysts. The quinine-based squaramide catalyst 4b
was the most efficient catalyst in overall terms (97% ee, d.r.
7.3:1; entries 6–10). Finally, the effect of the temperature was
also explored. When the reaction temperature was decreased,
the diastereoselectivity was improved slightly, and the enan-
tioselectivity could be maintained with a longer reaction time.
When the reaction was conducted with 4b in chloroform at
308C, the desired 3,4-dihydrocoumarin adduct was delivered
with 97% ee and d.r. 9.2:1 (Table 1; entries 11–13).
4b
4b
4b
[a] Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), 4
(0.01 mmol), Na2CO3 (0.12 mmol), solvent (1.5 mL), 608C. [b] Yield of
the isolated mixture of the two diastereoisomers. [c] The diastereomeric
ratio was determined by H NMR spectroscopy. [d] The ee value was
determined by HPLC on a chiral stationary phase. [e] The reaction was
carried out at 508C. [f] The reaction was carried out at 408C. [g] The
reaction was carried out at 308C. DCE=1,2-dichloroethane.
1
However, possibly owing to steric hindrance, the presence of
an ortho substituent on the aromatic ring resulted in
a diminished d.r. value, and product 3d was obtained with
d.r. 6.2:1. The reaction of 2-(1-tosylalkyl)sesamol 1k with a-
angelica lactone delivered the desired product 3k with good
enantioselectivity and moderate diastereoselectivity. In the
case of 5-methoxy-2-(phenyl(tosyl)methyl)phenol, the reac-
tion gave the corresponding dihydrocoumarin 3l with 89% ee,
albeit with low diastereoselectivity and in moderate yield,
when the reaction temperature was increased to 608C.
Unfortunately, when 2-(phenyl(tosyl)methyl)phenol was
used as the substrate, none of the desired product was
obtained; only a side product was obtained.[14] For 2-(1-
tosylalkyl)phenols, electron-donating substituents on the
phenolic ring were necessary for the reaction to proceed,
possibly for stabilization of the o-QM intermediate.[9c,10f,11b,g,h]
Furthermore, a series of deconjugated butenolides with
different g substituents were transformed successfully with
After establishing optimal reaction conditions, we next
sought to examine the scope and generality of the current a-
addition/transesterification of o-QM precursors 1 with g-
substituted deconjugated butenolides 2. For 2-(1-tosylalkyl)-
naphthols 1a–j, the electronic properties of the substituent on
the aromatic ring R1 had only marginal influence on the
enantioselectivity and diastereoselectivity of the reaction.
2
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excellent enantioselectivity. Good diastereoselectivity was
observed for g-alkyl-substituted deconjugated butenolides,
whereas the diastereoselectivity decreased for the corre-
sponding g-phenyl-substituted deconjugated butenolide.
Finally, the annulation of 2-(1-tosylalkyl)naphthol 1a with
5-(3-nitrophenyl)furan-2(3H)-one proceeded well with mod-
erate diastereoselectivity to give 3q. The absolute config-
uration of the product (+)-3a was unambiguously determined
to be S,S by X-ray crystallographic analysis.[15]
We performed a control experiment to determine whether
an o-QM intermediate was involved in the reaction. When the
presynthesized stable o-QM intermediate 1k-Awas subjected
to the standard conditions, the reaction proceeded success-
fully with good enantioselectivity and moderate diastereose-
lectivity [Eq. (1)]. This result is in accordance with the
annulation of the 2-(1-tosylalkyl)sesamol substrate 1k and a-
angelica lactone 2a (Scheme 3).
To properly understand the origin of the observed
unprecedented regioselectivity and enantioselectivity, we
carried out density functional theory (DFT) calculations.
The full Gibbs free energy profiles of the annulation of 2-(1-
tosylalkyl)naphthol 1a with a-angelica lactone (2a) under the
catalysis of quinine-based squaramide 4b were calculated,[16]
and the calculations suggested that the regioselectivity and
enantioselectivity were determined by the nucleophilic-addi-
tion step. We therefore focused on this key step. The
nucleophilic addition may take place by two reaction
modes: a- and g-addition. We located eight transition-state
structures for a-addition and g-addition to identify the most
plausible reaction profile. When the relative free energies of
all transition states for a-addition were compared, the
transition state 11-ts-SS was found to be optimal, with the
lowest activation free energy of 2.1 kcalmolÀ1 (Figure 1a).
When the nucleophilic addition occurs at the g-position of a-
angelica lactone (2a), transition state 21-ts-SSR has the
lowest activation free energy of 4.0 kcalmolÀ1 (Figure 1b).
The calculated activation energy of 11-ts-SS (a-addition) is
1.9 kcalmolÀ1 lower than that of 21-ts-SSR (g-addition), thus
indicating that regioselective a-addition is favored, which is
consistent with the experimental results. To gain more insight,
we employed a distortion/interaction model, in which the
activation energy is separated into distortion energy and
interaction energy[17] (DE°act = DE°dist + DE°int). The differ-
ence in interaction-energy terms (DE°int) between 11-ts-SS
and 21-ts-SSR is only 2.1 kcalmolÀ1. However, the difference
in distortion-energy terms (DE°dist) between the two transi-
tion states is 4.6 kcalmolÀ1, thus suggesting that distortion
energy plays an important role in the observed regioselectiv-
ity. Furthermore, the C1-C2-C3-C4 dihedral angle in 11-ts-SS
is 15.28, which is 10.78 smaller than that in 21-ts-SSR, thus
correlating well with the distortion-energy difference
Scheme 3. Scope of the reaction. Reaction conditions: 1 (0.10 mmol),
2 (0.12 mmol), 4b (0.01 mmol), Na2CO3 (0.12 mmol), CHCl3 (1.5 mL),
308C. Yields are for the isolated mixture of the two diastereoisomers.
[a] The reaction was carried out at 608C. Bn=benzyl.
between the two transition states. Therefore, the better
conjugation in the 2-(1-tosylalkyl)naphthol moiety leads to
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a lower energy barrier in the a-addition step. Our calculated
enantioselectivity for this reaction is also consistent with
experimental observations.
In summary, we have developed an unprecedented
enantioselective a-addition of deconjugated butenolides, as
opposed to the well-studied asymmetric g-addition of decon-
jugated butenolides. The asymmetric a-addition/transesteri-
fication of g-substituted deconjugated butenolides with ortho-
quinone methides that were generated in situ afforded a series
of functionalized 3,4-dihydrocoumarins containing two con-
tiguous stereogenic centers in high yields with excellent
diastereo- and enantioselectivity. Theoretical studies based on
DFT calculations revealed that the observed regioselectivity
was due to the distortion energy that resulted from the
interaction between the nucleophilic dienolate and the
electrophilic ortho-quinone methide. Further efforts are
currently under way toward the application of this method-
ology in organic synthesis.
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (21532006 and 21372220) and the Strategic
Priority Program of Chinese Academy of Sciences
(XDB17020300) is acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · butenolides ·
dihydrocoumarins · nucleophilic addition ·
ortho-quinone methides
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[14] See the Supporting Information for details. When sodium
carbonate was used as the base, the reaction did not occur.
With potassium carbonate as the base, only a side product was
obtained.
[15] CCDC 1450126 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
[16] See Figure S1 in the Supporting Information for the full Gibbs
free energy profiles of the reaction.
[17] a) K. Kitaura, K. Morokuma, Int. J. Quantum Chem. 1976, 10,
325; b) D. H. Ess, K. N. Houk, J. Am. Chem. Soc. 2007, 129,
10646; c) A. E. Hayden, K. N. Houk, J. Am. Chem. Soc. 2009,
131, 4084; d) A. G. Green, P. Liu, C. A. Merlic, K. N. Houk, J.
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Manuscript received: January 14, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
B. Wu, Z. Yu, X. Gao, Y. Lan,*
Y.-G. Zhou*
&&& — &&&
Regioselective a-Addition of
Deconjugated Butenolides:
Enantioselective Synthesis of
Dihydrocoumarins
The alpha… but not the gamma: The a-
addition of deconjugated butenolides has
rarely been exploited, in contrast to their
well-studied g-addition. Now an unpre-
cedented asymmetric a-addition/trans-
esterification of deconjugated buteno-
lides with ortho-quinone methides gener-
ated in situ from 2-(1-tosylalkyl)phenols
has been developed for the synthesis of
functionalized 3,4-dihydrocoumarins
containing two contiguous stereogenic
centers (see scheme).
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!