Catalytic Asymmetric Diels-Alder Reaction of Quinone Imine Ketals: A Site-Divergent Approach

Article abstract of DOI:10.1002/anie.201410957

The catalytic asymmetric Diels-Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl-substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels-Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3-alkyl quinone imine ketals from the inherently favored unsubstituted C=C bond to the disfavored alkyl-substituted C=C bond.

Full text of DOI:10.1002/anie.201410957

Angewandte
Chemie
DOI: 10.1002/anie.201410957
Diels–Alder Reactions
Catalytic Asymmetric Diels–Alder Reaction of Quinone Imine Ketals:
A Site-Divergent Approach**
Takuya Hashimoto, Hiroki Nakatsu, and Keiji Maruoka*
Abstract: The catalytic asymmetric Diels–Alder reaction of
quinone imine ketals with diene carbamates catalyzed by
axially chiral dicarboxylic acids is reported herein. A variety of
primary and secondary alkyl-substituted quinone derivatives
which have not been applied in previous asymmetric quinone
Diels–Alder reactions could be employed using this method.
More importantly, we succeeded in developing a strategy to
divert the reaction site in unsymmetrical 3-alkyl quinone imine
=
ketals from the inherently favored unsubstituted C C bond to
=
the disfavored alkyl-substituted C C bond.
F
or decades, the quinone-based Diels–Alder reaction has
been widely used in the synthesis of complex molecules, as it
expediently generates functionalized cis-decalin structures
from readily available materials.[1] Asymmetric catalysis has
been recognized as an ideal way to promote this transfor-
mation enantioselectively. Chiral Lewis acid catalysis has
played a central role in this regard,[2] while a couple of
organocatalytic methods have also emerged in the last few
years.[3] However, the uniqueness of quinones, having two
carbonyl oxygen atoms as the coordination site of a catalyst
Figure 1. Use of methyl quinone and its derivatives in catalytic
asymmetric Diels–Alder reactions. Boc=tert-butoxycarbonyl; Tr=trityl;
Bn=benzyl.
=
and two C C bonds as the reaction site, poses a critical
challenge. Namely, the complex selectivity issue (endo/exo,
site, enantio-, and regioselectivities) must be solved in face of
a variety of possible transition states. To simplify the issue,
this research field has been developed by using carefully
selected quinones bearing substituents to mask or direct the
coordination and reaction sites sterically and/or electroni-
cally. As a result, simple methyl-1,4-benzoquinone and other
primary and secondary alkyl-substituted quinones have not
been successfully utilized in this reaction (Figure 1a).[4] The
only reported solution to this issue has employed 3-methyl
quinone monoketal which has one carbonyl group and
decreases the number of possible catalyst–substrate com-
plexes (Figure 1b).[5] The reaction occurs at the inherently
coordination of the catalyst is advantageous compared with
quinones. Although the use of quinone imine ketals as
electrophiles in chiral Brønsted acid catalysis has been
recently developed by us and others,[7] these studies utilize
quinone imine ketals as aryl group equivalents and there has
been no report wherein a stereogenic center is set in a quinone
imine ketal. This study led us to establish a highly enantio-
selective Diels–Alder reaction between a variety of 3-alkyl
quinone imine ketals and diene carbamates catalyzed by
axially chiral dicarboxylic acids (R)-1 (Figure 1c).[8] More-
over, we disclosed that the reaction site can be reversed to the
=
more-reactive unsubstituted C C bond.
=
Cognizant of the above issue, we became interested in the
development of catalytic asymmetric Diels–Alder reactions
using quinone imine ketals as quinone surrogates.[6] It was
anticipated that the presence of the singular lone pair for the
more-hindered C C bond (Figure 1c, left). This site-diver-
gent strategy enabled the synthesis of cycloadducts having an
all-carbon quaternary stereocenter while leaving the less-
hindered C C bond for later transformation.
[9,10]
=
This coun-
ter-intuitive selectivity will be explained by considering the
E/Z isomerization of the imino functionality which acts as
a fluxional directing group.
In the initial study, several conventional dienes were
examined to understand the reactivity of simple, unfunction-
alized quinone imine ketals 2 and 5 for Diels–Alder reaction
by using axially chiral dicarboxylic acid catalyst (R)-1.[11]
Diene carbamate 3a[12] was found to be a good reaction
partner from which the cycloadduct could be obtained in good
yield [Eq. (1) and (2)]. We decided to focus our efforts on the
[*] Dr. T. Hashimoto, H. Nakatsu, Prof.Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502, (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT (Japan). H.N. thanks a Grant-in-Aid for the
Research Fellowship of JSPS for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410957.
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use of this diene in the reaction given the importance of
nitrogen-functionalized cis-decalin systems as represented by
antibiotic tetracycline and its analogues,[13] as well as the lack
of precedent of using diene carbamate in catalytic asymmetric
quinone-based Diels–Alder reactions.[14,15] Optimization of
the reaction conditions resulted in the identification of two
catalyst systems which gave either exo or endo cycloadducts
with high enantioselectivities. (R)-1a catalyzed the reaction
of N-Boc quinone imine ketal 2 with diene carbamate 3a to
give the exo cycloadduct 4 as the major product [Eq. (1)],
whereas the reaction of N-Bz quinone imine ketal 5 (Bz =
benzoyl) catalyzed by (R)-1c provided the endo cycloadduct
6a with high stereoselectivities [Eq. (2)].
to exhibit a general activity,[17] although the catalyst needed to
be fine-tuned to attain high enantioselectivity for each diene
carbamate. The reactions with dienes having a methyl group
at the 2- and/or 3-positions gave endo cycloadducts 6b, 6c,
and 6e, respectively, with high enantioselectivities. A phenyl
group could also be attached to the diene to afford 6d in 79%
yield with 82% ee. Use of trans-4-methyl diene resulted in the
formation of 6 f in low yield and selectivity presumably as
a result of the steric repulsion between the dimethyl ketal
moiety and the 4-methyl group.
We next turned our focus to N-Bz 3-methyl quinone imine
ketal 7 (Table 2), with the expectation that the less-hindered
=
C C bond would react exclusively. While the reaction with
diene 3a catalyzed by (R)-1c predominantly gave the
expected site isomer A, albeit in low yield and low ee, we
also identified a small portion of isomer B which formed from
=
the reaction occurring at the methyl-substituted C C bond
(Table 2, entry 1). Both A and B were identified as endo cy-
cloadducts. Surprisingly, the proportion of this sterically
disfavored isomer B with an all-carbon quaternary center
increased further by use of the disilyl catalyst (R)-1d
(entry 2), even in consideration of the fact that some of
isomer A further aromatized by the elimination of metha-
nol.[6] This observation motivated us to establish procedures
which provide each site isomer selectively with high enantio-
selectivity. The substrate was first replaced with more robust
and less congested ethylene glycol ketal 8a.[5] A substantial
increase of the yield and enantioselectivity was achieved
albeit with poor site selectivities (entries 3 and 4). With
substrate 8a in hand, we then carried out a catalyst screening.
It was found that isomer A could be obtained selectively with
good enantioselectivity by use of (R)-1a or 1b (entries 5
and 6). Further modification of the reaction conditions led to
the formation of the cycloadduct in good yield with a site
selectivity of 85:15 (A:B) and 90% ee (entry 7). While the use
With these results in hand, we first looked into the
applicability of other substituted diene carbamates[16] using N-
Bz quinone imine ketal 5 (Table 1). For this purpose, it was
necessary to re-evaluate the catalysts employed. For example,
when (R)-1c was used as the catalyst in the reaction using 3-
methyl diene carbamate, the product was obtained with only
15% ee. Catalysts 3,3’-disilyl-substituted (R)-1d–f were found
Table 2: Optimization of the reaction conditions.[a]
Table 1: Scope of diene carbamate substrates.[a]
Entry
1
R3
Ar
A:B
% yield % ee
1
2
3
4
5
6
1c Me
1d Me
Ph (7)
Ph (7)
80:20
52:48[b]
62:38
48:52
80:20
84:16
85:15
10
35
46
34
52
60
73
62
70
54
11/–
3/10
1c (CH2)2 Ph (8a)
1d (CH2)2 Ph (8a)
1a (CH2)2 Ph (8a)
1b (CH2)2 Ph (8a)
1b (CH2)2 Ph (8a)
57/À77
53/27
80/À72
87/À82
90/À83
49/88
44/92
68/À50
7[c]
8[c]
9[c,d]
1d (CH2)2 3,5-Ph2C6H3 (9a) 33:67
1d (CH2)2 3,5-Ph2C6H3 (9a) 18:82
10[c,d] 1b (CH2)2 3,5-Ph2C6H3 (9a) 84:16
[a] Reaction conditions: Quinone imine ketal (0.10 mmol), 3a
(0.15 mmol), and (R)-1 (0.005 mmol). The combined yield of A and B is
given. The ee values were determined by HPLC analysis on a chiral
stationary phase. [b] The ratio of (A and aromatized product of A):B.
[c] Performed with 3a (0.25 mmol). [d] Performed at 08C.
[a] Reaction conditions: 5 (0.10 mmol), 3 (0.25 mmol), and (R)-1
(0.005 mmol). The yield of the isolated product is given. The ee values
were determined by HPLC analysis on a chiral stationary phase.
MS4A=molecular sieves (4 ꢀ).
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of bulkier catalysts gave more of isomer B in general,[18] we
were unable to further improve the site selectivity toward B
by the catalyst screening. We therefore turned our attention
to a substrate with a different N-aroyl group. We employed
3,5-diphenylbenzoyl quinone imine ketal 9a in combination
with (R)-1d, with which isomer B was obtained in a ratio of
33:67 (A:B) with high enantioselectivity (entry 8). The site
selectivity and the enantioselectivity were further optimized
at 08C (entry 9). At lower temperature, the reaction slowed
down considerably while the site- and enantioselectivities
remained unchanged (data not shown). It should be noted
that the use of the isomer-A-selective catalyst (R)-1b for this
quinone imine ketal reagent indeed led to the formation of
isomer A (entry 10), underlying the critical role of the catalyst
for controlling the site selectivity.
out at a lower temperature with a higher catalyst loading to
outcompete the uncatalyzed reaction. Quinone imine ketals
bearing an aryl or alkynyl group were converted into the
corresponding cycloadducts 10h and 10i with good enantio-
selectivities by use of (R)-1a as the optimal catalyst. The
endo selectivity was retained irrespective of the electronic
and steric differences of the substituent. Quinone imine ketals
having a 2-substituent were far less reactive and required
higher temperature to give the products with low enantio-
selectivities (data not shown).
We then examined the substrate scope of the site-
divergent Diels–Alder reaction, which gives cycloadducts 11
with an all-carbon quaternary center (Table 4). The reactions
Table 4: Site-divergent Diels–Alder reaction.[a]
With the optimized conditions in hand, we examined the
scope of the quinone imine ketal substrate for the reactions
=
taking place at the unsubstituted C C bond (Table 3).
Primary and secondary alkyl chains were both tolerated as
the substituent at the 3-position to give cycloadducts
10b–e with high enantioselectivities. Attachment of an
electron-donating methoxy group gave 10 f in good yield
and with a good enantioselectivity. As for the use of 3-chloro
quinone imine ketal to give 10g, the reaction had to be carried
Table 3: Scope of quinone imine ketal substrates.[a]
[a] Reaction conditions: 9 (0.10 mmol), 3 (0.25 mmol), and (R)-1d
(0.005 mmol). The combined yield of the site isomers is given. The
ee values were determined by HPLC analysis on a chiral stationary phase.
[b] The ratio of 11 and its site isomer determined by 1H NMR
spectroscopic analysis of the crude material. [c] Performed with (R)-1d
(15 mol%).
between several dienes and 3-methyl quinone imine ketal 9a
were investigated, which afforded compounds 11b–d in
uniformly high enantioselectivities. As for other quinone
imine ketals, primary-alkyl-substituted derivatives generally
gave cycloadducts 11e and 11 f with high stereoselectivities.
When bulkier alkyl-, aryl-, or heteroatom-substituted sub-
strates were employed, the catalyst system could not over-
[a] Reaction conditions: 8 (0.10 mmol), 3a (0.25 mmol), and (R)-1b
(0.005 mmol). Combined yield of the site isomers is given. The ee values
were determined by HPLC analysis on a chiral stationary phase. [b] The
ratio of 10 and its site isomer was determined by 1H NMR spectroscopic
analysis of the crude material. [c] endo/exo=9.4:1. [d] Performed with 3a
(0.50 mmol) and (R)-1b (10 mol%) at À208C. [e] Reaction carried out
using (R)-1a. TBS=tert-butyldimethylsilyl.
=
come the innate reactivity at the less-hindered C C bond
(data not shown). One noteworthy substrate is 3-alkynyl
quinone imine ketal from which cycloadducts 11g and 11h
were obtained with fairly good site selectivities and enantio-
selectivities.
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As expected from the above experiments, 3,5-dimethyl
quinone imine ketal also reacted smoothly with diene 3a to
give endo cycloadduct 13 in good yield and enantioselectivity
[Eq. (3)].
Received: November 11, 2014
Revised: January 20, 2015
Published online: && &&, &&&&
Keywords: asymmetric catalysis · Brønsted acids ·
.
carboxylic acids · Diels–Alder reactions · quinones
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This site divergence can be explained by taking the
E/Z isomerization of quinone imine ketals into consideration.
Rapid interconversion of the E and Z isomers at the reaction
temperature was confirmed by NMR spectroscopy experi-
ments (see the Supporting Information). The estimated
energy barrier for the isomerization was around 10 kcalmolÀ1
in the absence of the catalyst. Although additional exper-
imental and theoretical support is required to be conclusive,
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into different site isomers A and B via transition states TS1
and TS2, respectively (Figure 2).[19] The use of the bulky 3,3’-
disilyl catalyst (R)-1d in combination with 3,5-diphenylben-
zoyl quinone imine ketal would destabilize TS1 sterically,
thereby diverting the pathway via TS2 to give compound B.
Accordingly, the geometry of the imine is considered to be
acting as a fluxional directing group to promote the reaction
at the more congested reaction site.
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Figure 2. The origin of the site selectivity for the products obtained
from the Diels–Alder reaction of quinone imine ketals.
As the capability of asymmetric catalysis expands, the
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also considered as a parameter to be optimized.[9,10] However,
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quinone imine ketal Diels–Alder reaction serves as an
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Communications
Diels–Alder Reactions
T. Hashimoto, H. Nakatsu,
K. Maruoka*
&&& — &&&
Catalytic Asymmetric Diels–Alder
Reaction of Quinone Imine Ketals: A Site-
Divergent Approach
Here or there? Axially chiral dicarboxylic
acids serve as the catalyst in the Diels–
Alder reaction between quinone imine
ketals and diene carbamates. A strategy is
also developed to divert the reaction site
in unsymmetrical 3-alkyl quinone imine
ketals from the inherently favored
=
unsubstituted C C bond to thedisfavored
=
alkyl-substituted C C bond.
6
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