Catalytic asymmetric inverse-electron-demand oxa-diels-alder reaction of in situ generated ortho-quinone methides with 3-methyl-2-vinylindoles

Article abstract of DOI:10.1002/anie.201500215

The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels-Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r.; 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels-Alder reaction.

Full text of DOI:10.1002/anie.201500215

Angewandte
Chemie
DOI: 10.1002/anie.201500215
Cycloaddition
Catalytic Asymmetric Inverse-Electron-Demand Oxa-Diels–Alder
Reaction of In Situ Generated ortho-Quinone Methides with 3-Methyl-
2-Vinylindoles**
Jia-Jia Zhao, Si-Bing Sun, Sai-Huan He, Qiong Wu, and Feng Shi*
In memory of Professor Carlos F. Barbas III
Abstract: The first catalytic asymmetric inverse-electron-
demand (IED) oxa-Diels–Alder reaction of ortho-quinone
methides, generated in situ from ortho-hydroxybenzyl alco-
hols, has been established. By selecting 3-methyl-2-vinylindoles
as a class of competent dienophiles, this approach provides an
efficient strategy to construct an enantioenriched chroman
framework with three adjacent stereogenic centers in high
yields and excellent stereoselectivities (up to 99% yield, > 95:5
d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl
alcohols as precursors of dienes and 3-methyl-2-vinylindoles as
dienophiles, as well as the hydrogen-bonding activation mode
of the substrates met the challenges of a catalytic asymmetric
IED oxa-Diels–Alder reaction.
C
atalytic, enantioselective Diels–Alder (DA) reactions
belong to the most fundamental and powerful tools in
constructing enantioenriched six-membered ring systems.[1]
Particularly, catalytic asymmetric inverse-electron-demand
(IED) hetero-DA reactions have proven to be efficient and
atom-economical methods for the synthesis of six-membered
heterocycles with perfect regio- and stereoselectivities
(Scheme 1).[2] As a result, elegant developments have been
achieved in the research area of catalytic asymmetric IED
aza-DA reactions,[1a,2a,b] which employed 1-azadienes (Sche-
me 1a)[3] or 2-azadienes (Scheme 1b)[2e–h,4] as electron-defi-
cient dienes to react with electron-rich dienophiles in the
presence of either chiral metal catalysts or organocatalysts.
These well-developed approaches afforded nitrogenous het-
erocycles such as tetrahydropyridines and tetrahydroquino-
lines in excellent stereoselectivities. However, in sharp
contrast, the catalytic asymmetric IED oxa-DA reactions
are underdeveloped in spite of the fact that this class of
transformation will efficiently build up oxygen-containing
Scheme 1. Profile of catalytic asymmetric hetero-Diels–Alder reactions.
EDG=electron-donating group, EWG=electron-withdrawing group.
heterocyclic frameworks with multiple stereogenic cen-
ters.[2a,5] So far, only a few enantioselective IED oxa-DA
reactions have been reported, and they predominantly utilize
a,b-unsaturated carbonyl compounds as diene components to
perform cycloadditions with electron-rich alkenes (Sche-
me 1c).[2a,6] Despite these creative works, great challenges
still exist in the catalytic asymmetric IED oxa-DA reactions.
The first one is the limited scope of dienes and dienophiles,
which is mainly confined to a,b-unsaturated carbonyl com-
pounds and vinyl ethers.[2a,6a–k] The second one is the limited
catalyst system and activation mode, which is dominated by
metal/chiral ligands,[2a,6a–i] and only a small number of trans-
formations employed chiral amines as organocatalysts to
activate aldehydes as dienophiles through enamine catal-
ysis.[2a,6l–n] Therefore, the development of catalytic asymmetric
IED oxa-DA reactions, especially those utilizing other types
of dienes and dienophiles based on different catalytic
activation modes, is of great significance.
[*] J.-J. Zhao, S.-B. Sun, S.-H. He, Prof. Dr. F. Shi
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, School of Chemistry and Chemical Engineering
Jiangsu Normal University, Xuzhou, 221116 (China)
E-mail: fshi@jsnu.edu.cn
Recently, ortho-hydroxybenzyl alcohols have emerged as
active reaction partners in asymmetric catalysis for their
characteristic of being readily converted into ortho-quinone
methide (o-QM) intermediates[7] in the presence of a Brønsted
acid (Scheme 2),[8] and should serve as a suitable diene for
catalytic asymmetric IED oxa-DA reactions. However, pre-
vious reports on catalytic enantioselective transformations of
ortho-hydroxybenzyl alcohols only included conjugate addi-
Dr. Q. Wu
School of Chemistry and Chemical Engineering
Xuzhou Institute of Technology (China)
[**] This work was supported by NSFC (21372002 and 21232007), Open
Foundation of Jiangsu Key Laboratory (K201314), PAPD, and the
QingLan project of Jiangsu Province.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500215.
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Communications
and the two substrates, but also bring a biologically important
indole moiety to the constructed chroman core.
Herein, we report the first catalytic asymmetric IED oxa-
DA reaction of in situ generated o-QMs and 3-methyl-2-
vinylindoles, thus leading to highly diastereo- and enantiose-
lective construction of the chroman scaffold with three
adjacent stereogenic centers (up to > 95:5 d.r., 99.5:0.5 e.r.).
This transformation utilized ortho-hydroxybenzyl alcohols as
precursors of dienes and 3-methyl-2-vinylindoles as dieno-
philes, both of which are new substrates for catalytic
asymmetric IED oxa-DA reactions. In addition, the hydro-
gen-bonding activation mode of the catalyst to the substrates
has been little reported in catalytic asymmetric IED oxa-DA
reactions.
Scheme 2. Previous works on catalytic asymmetric reactions involving
ortho-hydroxybenzyl alcohols.
Initially, the reaction of ortho-hydroxybenzyl alcohol (1a)
and the 3-methyl-2-vinylindole 2a in the presence of
10 mol% of the CPA 4a in chloroform at 258C was utilized
to test our hypothesis (Scheme 4). The IED oxa-DA reaction
tions (Scheme 2a)[8b–d] and stepwise cyclizations (Scheme 2
b).[8e,f] During the preparation and submission of this manu-
script, Schneider and co-workers reported an elegant tandem
cyclization using highly reactive cyclic enamides as nucleo-
philes (Scheme 2c).[8g,h] In spite of this progress, olefins of
relatively low reactivity, that is, having no activating groups
=
directly linking to the C C bond, have not yet been employed
in reactions with ortho-hydroxybenzyl alcohols.[9] The accom-
plishment of such a reaction would result in the enantiose-
lective cycloaddition of this substrate class, thus achieving the
catalytic asymmetric IED oxa-DA reaction. This transforma-
tion is highly desirable, but challenging because of the great
demand in developing highly enantioselective procedures.
Inspired by the challenges in catalytic asymmetric IED
oxa-DA reactions and in view of the biological importance of
chiral chroman derivatives,[10] we design a chiral phosphoric
acid[11] (CPA) catalyzed asymmetric IED oxa-DA reaction of
o-QMs generated in situ from ortho-hydroxybenzyl alcohols
(Scheme 3). Our previous work on indole-related enantiose-
Scheme 4. Catalysts and model reaction employed to optimize the
reaction conditions. DCE=1,2-dichloroethane.
proceeded smoothly to generate the chroman product 3aa in
good diastereoselectivity (85:15 d.r.) but with a low enantio-
selectivity (60:40 e.r.). To improve the enantioselectivity, this
reaction was further subjected to catalyst screening and
reaction conditions optimization by changing solvent, tem-
perature, additives, and reagents ratio (see the Supporting
Information for details). At last, the optimal reaction
conditions were established by using the CPA 4e as a catalyst
in dichloroethane (DCE) at 258C, thus leading to 3aa in an
excellent stereoselectivity of 95:5 d.r. and 96:4 e.r.
With the optimal reaction conditions in hand, we then
carried out the investigation on the substrate scope of ortho-
hydroxybenzyl alcohols (1) by the catalytic asymmetric IED
oxa-DA reactions with 2a. As shown in Table 1, this protocol
was applicable to a wide range of ortho-hydroxybenzyl
alcohols (1) with different R/R1 groups, and delivered the
desired chroman derivatives 3 bearing multiple stereogenic
centers in generally high yields and excellent stereoselectiv-
ities. Basically, both aromatic (entries 1–7) and aliphatic
(entries 8–12) groups could be successfully employed as part
of the substrates 1, which smoothly participated in the
reactions in good yields and high stereoselectivities. In
detail, a variety of phenyl groups with electronically neutral
Scheme 3. Design of a catalytic asymmetric IED oxa-DA reaction of in
situ generated o-QMs and 3-methyl-2-vinylindoles.
lective transformations[12] stimulated us to select 3-methyl-2-
vinylindoles as dienophiles because the introduction of
a methyl group at the C3-position of 2-vinylindoles could
enable this class of substrates to act as dienophiles rather than
dienes. In addition, the indole moiety will not only facilitate
the formation of dual hydrogen bonds between the catalyst
2
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Table 1: Substrate scope of the ortho-hydroxybenzyl alcohols 1.[a]
Table 2: Substrate scope of the 3-methyl-2-vinylindoles 2.[a]
Yield [%][b]
d.r.[c]
e.r.[d]
Entry
3
R/R1 (1)
Yield [%][b]
d.r.[c]
e.r.[d]
Entry
3
R (2)
1
2
3
4
5
6
7
8
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
Ph/H (1a)
88
60
77
81
99
99
84
97
82
83
82
89
67
75
72
93
50
95:5
>95:5
89:11
89:11
86:14
86:14
88:12
>95:5
>95:5
>95:5
>95:5
93:7
93:7
93:7
95:5
88:12
86:14
96:4
95:5
96:4
96:4
92:8
94:6
95:5
99:1
98:2
98:2
96:4
99:1
97:3
94:6
94:6
95:5
98:2
1
2
3
4
5
6
7
8
9
3hb
3hc
3hd
3he
3hf
3hg
3hh
3hi
p-MeC6H4 (2b)
m-MeC6H4 (2c)
o-MeC6H4 (2d)
p-FC6H4 (2e)
o-FC6H4 (2 f)
m-ClC6H4 (2g)
p-BrC6H4 (2h)
Me (2i)
99
99
99
99
99
99
80
71
68
95:5
95:5
98:2
99.5:0.5
99:1
99:1
99:1
99:1
99:1
96:4
98:2
p-FC6H4/H (1b)
m-FC6H4/H (1c)
p-ClC6H4/H (1d)
p-MeC6H4/H (1e)
m-MeC6H4/H (1 f)
m-MeOC6H4/H (1g)
Me/H (1h)
n-pentyl/H (1i)
n-hexyl/H (1j)
iBu/H (1k)
cyclopropyl/H (1l)
Ph/4-F (1m)
Ph/4-Cl (1n)
Ph/4-Br (1o)
Ph/4-MeO (1p)
Me/4-Br (1q)
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
9
3hj
Et (2j)
10
11
12
13
14
15
16
17
[a] Unless otherwise indicated, the reaction was carried out at the
0.05 mmol scale and catalyzed by 10 mol% 4e in DCE (2 mL) at 258C for
12 h. The molar ratio of 1h/2 was 1:1. [b] Yield of isolated product.
[c] The d.r. value was determined by 1H NMR spectroscopy. [d] The
e.r. value was determined by HPLC.
ities (entries 1–7). Notably, this approach could be applied to
the 2-vinylindoles 2i,j bearing terminal alkyl groups such as
methyl or ethyl, thus affording products 3hi,hj in good yields
and excellent stereoselectivities (entries 8 and 9). This scope
offers more chances for obtaining structurally diverse chro-
mans with high optical purity.
[a] Unless otherwise indicated, the reaction was carried out at the
0.05 mmol scale and catalyzed by 10 mol% 4e in DCE (2 mL) at 258C for
12 h. The molar ratio of 1/2a was 1:1. [b] Yield of isolated product.
[c] The d.r. value was determined by 1H NMR spectroscopy. [d] The
e.r. value was determined by HPLC.
The absolute configuration of 3pa (99.5:0.5 e.r. after
recrystallization) was unambiguously determined to be
(2R,3S,4R) by single-crystal X-ray diffraction analysis (in
Scheme 5).[13] The absolute configuration of the other prod-
(entry 1), poor (entries 2–4), and rich (entries 5–7) substitu-
ents could be utilized in the reaction without significant
difference in enantioselectivity (94:6 to 96:4 e.r.) except for
the substrate 1e (92:8 e.r.). More importantly, a series of alkyl
groups including linear (entries 8–10), branched (entry 11),
and cyclic (entry 12) ones proved to be competent R
substituents, and gave the products 3ha–la in overall excellent
yields and perfect stereoselectivities. It should be noted that
in previous catalytic enantioselective transformations, the R
groups of ortho-hydroxybenzyl alcohols were almost aroma-
tic,[8c–g] and aliphatic R groups have scarcely been utilized. In
our case, both aromatic and aliphatic R groups work well, and
the latter was superior to the former with regard to
stereoselectivity (entries 8–12 versus 1–7). The applicability
of various R groups provides a good opportunity for
synthesizing optically pure chromans with structural diversity.
Besides, the R1 group linked to the phenyl ring could be
varied from electron-withdrawing to electron-donating sub-
stituents (entries 13–17), thus providing the products 3 in
good yields and good to excellent stereoselectivities.
Then, the use of various 3-methyl-2-vinylindoles (2) was
examined by the catalytic asymmetric IED oxa-DA reactions
with the ortho-hydroxybenzyl alcohol 1h. As shown in
Table 2, a series of 3-methyl-2-vinylindoles with various
terminal substituents including aromatic and aliphatic ones
served as suitable substrates in the reaction, thus offering the
indole-substituted chromans 3 in high yields and perfect
stereoselectivities. For terminal phenyl groups, both electron-
rich and electron-poor substituents at different positions of
the phenyl ring uniformly delivered excellent stereoselectiv-
Scheme 5. Suggested transition state.
ucts 3 were assigned by analogy. On the basis of the
experimental results, we suggested a possible transition state
to explain the stereochemistry of this catalytic asymmetric
IED oxa-DA reaction. As exemplified by the formation of
product 3pa (Scheme 5), the CPA 4e simultaneously forms
two hydrogen bonds with 3-methyl-2-vinylindole and the o-
QM, which was generated in situ from ortho-hydroxybenzyl
alcohol, thus facilitating the stereoselective IED oxa-DA
reaction to give the experimentally observed (2R,3S,4R)-3pa.
The excellent stereoselectivity is attributed to the dual
hydrogen-bonding activation mode and the chiral environ-
ment created by 4e. In all of the experiments (Tables 1 and 2),
only two diastereomers of 3 with unchanged trans-geometry
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=
of the original C C bond were detected with high d.r. values.
Besides, TLC revealed that the reaction was very clean, and
no other intermediate product or byproduct was generated.
Moreover, the intercepting reaction[4b] using indole as a nucle-
ophilic trapping reagent disclosed that no desired interrupted
product was generated (see the Supporting Information for
details). These results indicated that there is a high possibility
that the reaction undergoes a concerted pathway.[14]
To verify the suggested activation mode, a control experi-
ment using the N-methyl-protected 3-methyl-2-vinylindole
2k as a substrate was performed under the standard reaction
conditions [Eq. (1)]. As expected, no reaction occurred, and
In summary, we have established the first catalytic
asymmetric IED oxa-DA reaction of o-QMs generated
in situ from ortho-hydroxybenzyl alcohols. By selecting 3-
methyl-2-vinylindoles as a class of competent dienophiles, this
approach provides an efficient strategy to construct the
enantioenriched chroman framework with three adjacent
stereogenic centers in high yields and excellent stereoselec-
tivities. The utilization of ortho-hydroxybenzyl alcohols as
precursors of dienes and 3-methyl-2-vinylindoles as dieno-
philes, as well as the hydrogen-bonding activation mode of the
catalyst to the substrates met the challenges of the catalytic
asymmetric IED oxa-DA reaction. In addition, this reaction
also represents the first highly enantioselective construction
of a chroman scaffold involving an indole moiety, which can
be applicable to a variety of substrates, thus offering a good
opportunity for the synthesis of biologically important chiral
chroman derivatives with structural diversity.
À
thus demonstrated that the N H group of 2-vinylindoles
played a crucial role in the reactivity of the reaction.
Moreover, we investigated the effect of Z/E configuration
of the substrates 2 on the reaction by utilizing (Z)-2a as
a reaction component [Eq. (2)]. Very interestingly, this
Received: January 9, 2015
Revised: January 30, 2015
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cycloaddition ·
.
enantioselectivity · heterocycles · organocatalysis
reaction generated the product 3ha in a moderate yield and
excellent stereoselectivity, and it had the same relative and
absolute configuration as the product produced from (E)-2a
(Table 1, entry 8). At the same time, a small amount of (E)-2a
was observed, by TLC, in the reaction mixture along with
some remaining (Z)-2a. This phenomenon indicated that (Z)-
2a could be transformed into (E)-2a during the reaction
process, and ultimately took part in the reaction to afford 3ha
with the observed configuration. Furthermore, this result
implied that utilizing the Z/E mixture of 2 would not affect
the stereoselectivity of the reaction, thus avoiding the arduous
isolation of the Z/E isomers of 2. Indeed, when (Z/E)-2a was
employed in the reaction under the standard reaction
conditions, the desired product 3ha was obtained in a high
yield (92%) and with a perfect stereoselectivity of greater
than 95:5 d.r. and 99:1 e.r. [Eq. (3)].
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4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Cycloaddition
J.-J. Zhao, S.-B. Sun, S.-H. He, Q. Wu,
F. Shi*
&&&& — &&&&
Catalytic Asymmetric Inverse-Electron-
Demand Oxa-Diels–Alder Reaction of
In Situ Generated ortho-Quinone
Three in a row: The title reaction of ortho-
quinone methides, generated in situ from
ortho-hydroxybenzyl alcohols, has been
established. By selecting 3-methyl-2-
vinylindoles as a class of competent
dienophiles, this approach provides an
efficient strategy to construct enantio-
enriched chroman frameworks with three
adjacent stereogenic centers in high
yields and excellent stereoselectivities.
CPA=chiral phosphoric acid.
Methides with 3-Methyl-2-Vinylindoles
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!