Asymmetric Domino Reaction of α,β-Unsaturated Aldehydes and α-Acyl α,β-Unsaturated Cyclic Ketones Catalyzed by Diphenylprolinol Silyl Ether

Article abstract of DOI:10.1021/acs.orglett.0c03190

An asymmetric domino reaction combining vinylogous Michael reaction, hydration of aldehyde, and oxy-Michael reaction proceeds with α,β-unsaturated aldehydes and α-acyl α,β-unsaturated cyclic ketones in the presence of diphenylprolinol silyl ether to afford tetrahydrochromane derivatives with excellent enantioselectivity. After the domino reaction, addition of Wittig reagent and acid in the same reaction vessel promoted a second domino reaction incorporating retro oxy-Michael reaction, isomerization, and Wittig reaction to afford chiral functionalized cyclic 1,3-diene derivatives with excellent enantioselectivity. Overall, six reaction steps proceed in a one-pot procedure.

Full text of DOI:10.1021/acs.orglett.0c03190

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Letter
Asymmetric Domino Reaction of α,β-Unsaturated Aldehydes and
α‑Acyl α,β-Unsaturated Cyclic Ketones Catalyzed by
Diphenylprolinol Silyl Ether
Yujiro Hayashi,* Yurina Suga, and Nariyoshi Umekubo
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ABSTRACT: An asymmetric domino reaction combining vinyl-
ogous Michael reaction, hydration of aldehyde, and oxy-Michael
reaction proceeds with α,β-unsaturated aldehydes and α-acyl α,β-
unsaturated cyclic ketones in the presence of diphenylprolinol silyl
ether to afford tetrahydrochromane derivatives with excellent
enantioselectivity. After the domino reaction, addition of Wittig
reagent and acid in the same reaction vessel promoted a second
domino reaction incorporating retro oxy-Michael reaction, isomer-
ization, and Wittig reaction to afford chiral functionalized cyclic 1,3-diene derivatives with excellent enantioselectivity. Overall, six
reaction steps proceed in a one-pot procedure.
he Michael reaction is one of the most useful carbon−
T
carbon bond-forming reactions in organic synthesis,1 and
recently the application of organocatalysts2 has been extended
to include asymmetric catalytic Michael variants.3 The
vinylogous Michael reaction is a further extension of the
classical Michael reaction, wherein an additional double bond
is involved; here also, organocatalysts have been used to
catalyze the reaction efficiently.4
Our group5 and Jørgensen’s group6 have independently
developed diphenylprolinol silyl ether7 as an effective organo-
catalyst for the asymmetric Michael reaction of α,β-unsaturated
aldehyde with active methylene compounds, such as nitro-
alkanes8 and malonates.9 Recently, we reported that the
asymmetric Michael reaction of α,β-unsaturated aldehyde with
a nonactivated ketone, such as cyclohexanone, proceeded in a
highly enantioselective manner in the presence of two amine
catalysts, diphenylprolinol silyl ether and 4-hydroxyproline (eq
1).10 We also reported the domino Michael/Michael reaction
reaction.13 We then became interested in using 2-acetyl-
cyclohex-2-en-1-one (1) as an alternative Michael donor.
As 1 is a functionalized cyclohexene derivative possessing
two carbonyl groups, an alkene, and a methyl ketone moiety,
the product would also inherit useful functional groups.
Moreover, we wanted to explore the reactivity of this
compound because it possesses both nucleophilic and
electrophilic moieties (Scheme 1), and it has several acidic
of ethyl 4-oxo-2-pentenoate, which was successfully applied for
the pot- and time-economical synthesis of Corey lactone (eq
2).11 Recently, we developed the Michael reaction of 3-hexene-
2,5-dione and α,β-unsaturated aldehyde and reported the one-
pot synthesis of chiral hydrindanes using diphenylprolinol silyl
ether (eq 3).12 As shown in these three examples, we found
that the ketone moiety is a suitable nucleophile in the Michael
Received: September 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03190
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
enantioselectivity (98% ee) (eq 5). The relative structure of
6a was determined based on the analysis of the NMR coupling
constant and NOE signals (see the SI).
Scheme 1. Possible Reaction Products
Considering that tetrahydrochromane derivative 3a was
obtained in good yield with excellent enantioselectivity, the
generality of this reaction was investigated (Table 1). With
protons at the α′-, α″-, and γ-positions at which a range of
reactions might proceed. One possible path is a Michael
reaction at either the α′- or α″-position of 1 as a Michael
donor. A vinylogous Michael reaction can also occur when a
reaction takes place at the γ-position of cyclohexanone.14 It is
known that 1,3-diketone is not a useful Michael donor in
reactions with α,β-unsaturated aldehydes catalyzed by
diphenylprolinol silyl ether, because of the retro-Michael
reaction, and the product is generally afforded with low
enantioselectivity.15 If the retro reaction proceeds in the case
of the vinylogous Michael reaction, its enantioselectivity is also
a concern. Compound 1 is known to act as a suitable Michael
acceptor because the alkene moiety is activated with two good
electron-withdrawing groups.16 In spite of these possible
competing reaction pathways, we investigated the reaction of
1 and found that vinylogous Michael reaction is the dominant
reaction path, as will be described in this communication.
Cinnamaldehyde (2a) was selected as a model α,β-
unsaturated aldehyde, and a mixture of 1 and 2a was treated
with diphenylprolinol silyl ether in CH2Cl2 in the presence of
H2O (3.0 equiv) and benzoic acid (0.2 equiv).17 The reaction
proceeded at room temperature to give tetrahydrochromane
derivative 3a (1:1 diastereoisomeric mixture) and diene 4a in
67% and 13% yield, respectively (eq 4). The enantioselectiv-
Table 1. Generality in the Synthesis of Tetrahydrochromane
Derivative 3
a
b
b
c
time
(h)
yield of 3
yield of 4
ee
entry
R
(%)
(%)
(%)
1
2
3
4
5
Ph (2a)
1.5
1
2
3
2
67
70
73
70
81
13
25
21
21
19
98
>99
>99
>99
99
p-BrC6H4 (2b)
o-BrC6H4 (2c)
p-MeOC6H4 (2d)
2-furyl (2e)
a
Unless otherwise shown, reactions were performed using 1 (0.45
mmol), α,β-unsaturated aldehyde 2 (0.30 mmol), organocatalyst
(0.060 mmol), water (0.90 mmol), and benzoic acid (0.060 mmol) in
b
CH2Cl2 (0.30 mL) at room temperature for the indicated time. Yield
c
of the isolated product. Enantiomeric excess of the products 3 and 4,
which were determined by HPLC analysis over a chiral solid phase
after converting 3 and 4 to α,β-unsaturated ester 7.
respect to the β-substituent of α,β-unsaturated aldehyde, in
addition to the phenyl group, electron-withdrawing p-
bromophenyl and o-bromophenyl and electron-rich p-methox-
yphenyl substituents were also suitable, affording 3 in good
yield in almost enantiopure form. The reaction also proceeded
successfully with furyl-substituted α,β-unsaturated aldehyde as
substrate to afford the product in 81% yield with 99% ee.
Under acidic conditions, the formation of an equilibrium
between 3a, 4a, and 5a is presumed, wherein 5a (which was
not observed directly) would be converted into more
thermodynamically stable intermediates 3a and 4a. This idea,
which is supported by TLC analysis showing the formation of
4a, leads to the conclusion that conversion of tetrahydrochro-
mane derivative 3a into diene 4a is driven through a retro oxy-
Michael reaction under acidic conditions. Removal of 4a from
the equilibrium mixture through reaction with another reagent
would drive the system toward product formation under the
equilibrium conditions and both 3a and 4a would be converted
into the same product compound in good yield. Using this
hypothesis, we examined a range of compatible reactions using
3a as a starting material and found that Wittig reaction under
acid conditions was suitable (eqs 7 and 8): When 3a was
treated with Wittig reagent (ethyl 2-(triphenylphosphoranyl-
idene)acetate), in the presence of benzoic acid,19 retro oxy-
Michael reaction followed by isomerization of the double bond
ities of both 3a and 4a were excellent (both 98% ee).18
Compounds 3a and 4a are presumably generated as follows:
The reaction takes place at the γ-position of cyclohexenone 1
to afford the Michael product 5a, which then reacts with water,
followed by an oxy-Michael reaction to afford 3a. Compound
4a would be generated by isomerization of 5a. The identical
enantioselectivity of 3a and 4a is evidence that these
compounds are generated from the same intermediate 5a.
These results indicate that 1 reacts as a Michael donor, and
that the vinylogous Michael reaction proceeds selectively at the
γ-position of 1. Compound 3a was obtained as a mixture of
two diastereomers, which was treated with Et3SiH in the
presence of BF3·OEt2 to afford tetrahydrochromane derivative
6a in 66% yield as a single isomer with excellent
B
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Table 2. Generality of Domino Reaction of Cyclic α-Acyl
α,β-Unsaturated Cyclic Ketones and α,β-Unsaturated
a
Aldehydes
and Wittig reaction proceeded to afford cyclohexadiene
derivative 7a in 50% yield. Acid was crucial for this reaction;
without acid, the yield was low.
Cyclohexadiene derivative 7a was obtained from 1 and 2a in
a two-pot reaction sequence: In the first pot, a domino reaction
of vinylogous Michael reaction, hydration, and oxy-Michael
reaction (1 + 2a → 3a + 4a) proceeded, and a domino
reaction of retro oxy-Michael reaction, isomerization, and
Wittig reaction (3a + 4a → 7a) proceeded in the second pot.
Given that we are positing the importance of pot-economy in
synthesis,11,20 we examined the feasibility of combining the
two-pot reaction sequence into a one-pot reaction. After
optimizing the reaction conditions, we established a one-pot
transformation from 1 and 2a into 7a (Scheme 2) involving
Scheme 2. One-Pot Synthesis of Cyclohexadiene Derivative
7a
a
Unless otherwise shown, reactions were performed using α,β-
unsaturated aldehyde (0.30 mmol), acyl cycloalkene derivative (0.45
mmol), organocatalyst (0.060 mmol), water (0.90 mmol), and
benzoic acid (0.060 mmol) in CH2Cl2 (0.30 mL) at room
temperature. After the first reaction, Ph3P=CHCO2Et (0.90 mmol)
and benzoic acid (0.24 mmol) were added. Isolated yield of diene was
indicated. Enantiomeric excess of the products was determined by
the reaction of 1 and 2a in the presence of diphenylprolinol
silyl ether and benzoic acid (0.2 equiv) for 1.5 h at room
temperature. After the first domino reaction, Wittig reagent
and benzoic acid (0.8 equiv) were added to the same reaction
vessel. The second domino reaction then proceeded to afford
the desired diene 7a in good yield (70%) with excellent
enantioselectivity (98% ee) in a one-pot operation.
After determining the optimal reaction conditions, the
generality of the reaction was investigated; the results are
summarized in Table 2. Compound 1 reacted with a range of
β-aryl-substituted α,β-unsaturated aldehydes efficiently, with
either electron-rich substituents, such as p-tolyl and p-
methoxyphenyl, or electron-withdrawing substituents, such as
p-fluorophenyl, p-cholorophenyl, p-bromophenyl, m-bromo-
phenyl, and o-bromophenyl, affording the corresponding
b
HPLC analysis over a chiral solid phase. The reaction was conducted
at 40 °C.
cyclohexadiene derivatives in good yield with excellent
enantioselectivity. Naphthalene was also a good substituent
on the substrate, and the reaction also proceeded well in the
case of heteroaromatic derivatives such as furan. In addition to
aryl and heteroaryl substituents, ethoxycarbonyl was also found
to be a suitable substituent, providing the desired diene
derivative in 54% yield with good enantioselectivity. In the case
of β-alkyl substituted α,β-unsaturated aldehyde such as 5-
phenylpent-2-enal is not a suitable substrate, affording a
complex mixture.
C
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Focusing on the substituent at the 2-position of cyclo-
hexenone as a Michael donor, in addition to an acetyl group
(1), benzoyl, pent-4-enoyl, and 5-trimethylsilylpent-4-ynoyl
were also found to be compatible substituents, affording
cyclohexadiene derivatives featuring several functional groups
in good yield with excellent enantioselectivity. Although the
cyclopentenone derivative afforded a complex mixture, the
reaction of the cycloheptenone derivative proceeded to afford
the product with excellent enantioselectivity.
AUTHOR INFORMATION
Corresponding Author
■
Yujiro Hayashi − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai, Miyagi 980-8578, Japan;
orcid.org/0000-0002-1838-5389;
Email: yujiro.hayashi.b7@tohoku.ac.jp
Authors
Yurina Suga − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai, Miyagi 980-8578, Japan
Nariyoshi Umekubo − Department of Chemistry, Graduate
School of Science, Tohoku University, Sendai, Miyagi 980-
8578, Japan
The reaction also proceeded on a larger scale (1 mmol),
affording 7l with same excellent enantioselectivity.21
As a demonstration of the synthetic potential of the diene
derivative 7l, the cyclohexadienol moiety was successfully
converted into the corresponding phenol moiety under Swern
oxidation conditions to afford 8 in 61% yield (eq 10).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03190
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
JP20H04801 in Hybrid Catalysis for Enabling Molecular
Synthesis on Demand and JP19H05630.
Considering the conversion of cyclohexadienol moiety into
phenol, this reaction can be regarded as an asymmetric
Michael reaction or Friedel−Crafts reaction of o-acyl phenol
derivative to α,β-unsaturated aldehydes.
The absolute configuration of 7l was determined using the
modified Mosher method22 after conversion into 9 using the
Tamao−Fleming reaction23 (Figure 1, see SI for details).
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03190.
Experimental procedures and analytical data (PDF)
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E
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