Asymmetric intramolecular oxa-Michael reactions of cyclohexadienones catalyzed by a primary amine salt

Article abstract of DOI:10.1002/anie.201206977

Michael brings the rings: An asymmetric intramolecular oxa-Michael reaction involving iminium activation has been developed. This reaction provides enantioenriched 1,4-dioxane derivatives with up to 99 % yield and 98 % ee. The method allows for concise and stereoselective access to stereodiverse, complex tetracyclic compounds containing a bicyclo[2.2.2]octan-2-one backbone with multiple chiral centers. Copyright

Full text of DOI:10.1002/anie.201206977

Angewandte
Chemie
DOI: 10.1002/anie.201206977
Asymmetric Catalysis
Asymmetric Intramolecular Oxa-Michael Reactions of
Cyclohexadienones Catalyzed by a Primary Amine Salt**
Wenbin Wu, Xin Li, Huicai Huang, Xiaoqian Yuan, Junzhu Lu, Kailong Zhu, and Jinxing Ye*
Since the first example of oxa-Michael addition of an alcohol
to a conjugate acceptor was reported by Loydl in 1878,[1] oxa-
Michael reactions have been the subject of increasing interest
from synthetic organic chemists as one of the most efficient
and directed methods for carbon–oxygen bond formation.[2]
Generally, the nucleophiles involved in the reactions are
alcohols, phenols, oximes, and hydrogen peroxide. Compared
with other more reactive nucleophiles, oxa-Michael reactions
involving alcohols still remain challenging owing to a rever-
sible addition step and the poor nucleophilicity of alco-
hols.[2b,c] Tandem oxa-Michael reactions, where the reversible
intermediates are immediately transformed into the final
products, are effective in solving the first problem.[3] Whereas,
the main strategies used to overcome the poor nucleophilicity
of oxygen atoms are: 1) Deprotonation by strong bases to
enhance their nucleophilicity.[4] 2) Activation of the conjugate
acceptor by Lewis acids, transition metal complexes, or
amines to lower the LUMO level.[5] 3) A bifunctional
activation pathway is employed, using a chiral phosphoric
acid or a tertiary amine thiourea as catalyst.[8a–c]
As a key reaction step, oxa-Michael reactions were
frequently applied in the total synthesis of complex natural
products.[6] Thus far, few organocatalytic enantioselective
oxa-Michael reactions have been reported.[7] The first organo-
catalytic intramolecular oxa-conjugate addition of an alcohol
to a chiral a,b-unsaturated ketone was accomplished by Hong
et al. in the total synthesis of psymberin.[6k] Despite this, only
a few organocatalytic asymmetric oxa-Michael reactions of
a,b-unsaturated ketones have been reported.[8]
desymmetrization of cyclohexadienones had been
reported.[11] In 2010, You and co-workers reported the
Brønsted acid-catalyzed desymmetrization of cyclohexadie-
nones by intramolecular oxa-Michael reaction through
bifunctional activation,[8b] which leads to highly enantio-
enriched addition products in excellent yield (Scheme 1).
Scheme 1. Brønsted acid-catalyzed enantioselective intramolecular oxa-
Michael reaction.
Intrigued by these elegant reports, we envisaged that the
intramolecular oxa-Michael reaction of cyclohexadienones
might be realized through iminium-based activation
(Scheme 2, pathway I).[12] Simultaneously, a background reac-
tion could proceed when Brønsted acids were employed as
Because of their wide range of biological activity, oxygen-
containing heterocycles such as tetrahydropyrans, benzo-
pyran, xanthones, g-butyrolactones, and 1,4-dioxanes, which
can be synthesized from alcohols through oxa-Michael
reactions, can often be found in natural products.[9] As
a practical synthon, 1,4-dioxanes could be easily synthesized
through the desymmetrization of cyclohexadienones.[10] Until
very recently, only a few examples of the asymmetric
Scheme 2. General reaction design.
additives (pathway II). Herein, we report a highly enantiose-
lective intramolecular oxa-Michael reaction catalyzed by an
inexpensive and easily prepared chiral primary amine salt.
Moreover, the gentle reaction conditions are more compat-
ible with the functional or protecting groups of the substrates
and can avoid potential side reactions, which could expand its
range of applications in total synthesis.
Choosing compound 7a, with the smallest group (methyl)
in the 4 position, as a model substrate with which to optimize
the reaction conditions, we focused our initial studies on
a series of easily prepared chiral primary amines. No oxa-
Michael products were obtained when the reaction was
catalyzed only by a primary amine (Table 1, entry 3). Using
the benzoic acid salts of either (R,R)-1,2-cyclohexanediamine
or 9-amino(9-deoxy)epi-quinine, led to the desired product in
[*] W. Wu, X. Li, H. Huang, X. Yuan, J. Lu, K. Zhu, Prof. Dr. J. Ye
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University of
Science and Technology
130 Meilong Road, Shanghai 200237 (China)
E-mail: yejx@ecust.edu.cn
[**] This work was supported by the Innovation Program of Shanghai
Municipal Education Commission (11ZZ56), the National Natural
Science Foundation of China (21272068), the Fundamental
Research Funds for the Central Universities, and the Shanghai
Committee of Science and Technology (11DZ2260600).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206977.
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Table 1: Screening of chiral amine catalysts and acidic additives.[a]
After slight modification of the reaction parameters (for
details, see the Supporting Information), including changing
the solvent, lowering the reaction temperature, increasing the
catalytic salt loading, and prolonging the reaction time, 95%
conversion and 95% ee were finally achieved (entries 14–16).
Entries 11, 12, 16, and 17 indicate that the chiral amine is
essential for stereoinduction in the products.
Entry
Cat.
Solvent
Acid
Conv. [%][b]
ee [%][c]
After the optimized conditions had been established, the
substrate scope was investigated. To make this method more
practical, we used chiral DPEN, which was commercially
available in both enantiomeric forms for most of our work. As
summarized in Scheme 3, the reaction was tolerant of alkyl,
alkoxy, electron-withdrawing, or electron-donating substitu-
ents on the aromatic groups in the 4 position of cyclohex-
1
2
3
4
5
6
7
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
PhCO2H
PhCO2H
none
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
N-Boc-l-Phe
N-Boc-l-Pro
N-Boc-l-Pro
N-Boc-d-Pro
N-Boc-l-Pro
N-Boc-l-Pro
N-Boc-l-Pro
N-Boc-l-Pro
N-Boc-l-Pro
82
78
<5
54
62
50
60
58
98
82
80
80
0
>99
60
50
60
n.d.
0
0
18
À44
À33
À94
72
85
84
n.d.
82
95
95
4
2a
2a
2b
2c
3
4
5
6
2a
2a
2a
none
2a
2a
2a
(Æ)-2a
8[d]
9[d]
10
11[e]
12[e]
13
14[e]
15[e,f]
16[g]
17[g]
95
95
[a] Reaction conditions: catalyst (10 mol%) and acid (20 mol%) in
CH2Cl2 (0.5m) at room temperature for 24 h. [b] Determined by GC
analysis. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] Catalyst (20 mol%) and acid (20 mol%). [e] Catalyst (10 mol%) and
acid (10 mol%). [f] Reaction at 08C for 72 h. [g] Catalyst (15 mol%) and
acid (15 mol%) at 08C for 96 h.
good conversion and moderate ee (entries 1 and 7). When the
reaction was catalyzed by the benzoic acid salt of (1R,2R)-
diphenylethylenediamine (DPEN), 60% ee was obtained.
The enantioselectivity dropped significantly when the reac-
tion was catalyzed by catalysts derived from (R,R)-DPEN:
primary/tertiary amine catalyst 2b, primary amine/hydrogen
bonding catalyst 2c and catalyst 3 (entries 4–6). With these
moderate results in hand, we introduced a tert-butyl group
into the catalyst scaffold,[13] and the resulting catalyst 6
showed excellent stereocontrolling ability in regulating the
enantioselectivity (À94% ee).
With the intention of using inexpensive and simple
catalysts to improve the reaction efficiency, a series of
weakly acidic organic additives were screened for coordina-
tion with (R,R)-DPEN to improve the ee while simultane-
ously avoiding the background reaction. The results showed
that the reaction was sensitive to different acidic additives
(for details, see the Supporting Information). When N-Boc-l-
proline (Boc = tert-butoxycarbonyl) was employed, the ee
increased to 72% (entry 10). After varying the quantity of
acidic additives, 85% ee and 80% conversion (entry 11) were
Scheme 3. Organocatalytic enantioselective intramolecular oxa-Michael
reaction. Reaction conditions: (R,R)-DPEN (15 mol%) and N-Boc-l-
Pro (15 mol%) in toluene (0.5m) at 08C for 96–120 h. [a] Catalyst 6
(20 mol%) and N-Boc-l-Phe (20 mol%) in CH2Cl2 (0.5m) at room
temperature for 48 h. [b] o-fluorobenzoic acid was used. [c] 7p was
prepared from (R)-1,2-propylene glycol. Yields shown are of isolated
products. Enantiomeric excesses were determined by HPLC analysis
on a chiral stationary phase. The diastereomeric ratios were deter-
mined by 1H NMR spectroscopy of the crude reaction mixture.
achieved without
(entry 13).
a
detectable background reaction
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adienone. It has been reported that the alkyl group at the
4 position of the cyclohexadienone has a great influence on
the enantioselectivity (Me, 94% ee; Et, 78% ee; iPr, 61%
ee).[8b] Herein, the enantioselectivities were greatly improved
and the alkyl-substituted substrates (8a–8e) were expanded:
R = Me, 95% ee; Et, 91.5% ee; nPr, 98% ee; iPr, 83% ee;
nBu, 85% ee. Different aromatic-substituted substrates were
suitable for the intramolecular oxa-Michael reaction, and lead
to the desired products in 73–95% yield and 92–97% ee (8 f–
8k). The reaction of the substrates with alkoxy substituents in
the 4 position of cyclohexadienone proceeded quite well, with
81–95% yield and 91–96% ee (8l–8o), which has not
previously been reported. The ee of product 8p, with the
introduction of one methyl group in the 3 position, decreased
slightly to 62:38 d.r. When the chiral center at C3 possessed an
R configuration, 8r was obtained in 99% ee and > 20:1 d.r.
Product 8s, with a triple-ring structure, was synthesized with
50% yield and 70% ee. When the reaction was carried out on
a larger (1.008 g) scale, the desired product 8a was obtained in
high yield and high enantioselectivity. Some experiments
were conducted using 6 and N-Boc-l-phenylalanine as
catalysts; the products were obtained in excellent yields and
moderate to good enantioselectivities: R = Me, À94% ee;
nBu, À55% ee; 4-Br-C6H4, À90% ee; MeO, À96% ee; BnO,
À92% ee. Crystals of bromide product 8k were obtained for
single-crystal X-ray analysis, and the result revealed a 4aS,8aS
configuration (see the Supporting Information).[17]
Scheme 5. Application of the oxa-Michael reaction product. A) Catalyst
10a (10 mol%) in EtOAc (0.5m) at room temperature for 72 h.
B) Catalyst 10b (10 mol%). C) Potassium carbonate (10 mol%) in
EtOAc/MeOH=1:1 (0.5m) at room temperature for 24 h.
5-substituted 3-pyrrolidin-2-ones to a,b-unsaturated keto-
nes,[13g] we used 15 mol% each of 13a and N-Boc-l-Trp as
catalysts and kept the temperature at 358C for 3 days,
whereupon the desired single-step addition product (42%
yield) was detected (Scheme 6); however, almost no product
Subsequently, we tried to apply the above catalytic system
to synthesize intramolecular oxa-Michael reaction products
with various ring sizes. A significant drop in chemical yields
and enantioselectivities was observed in the synthesis of five
and seven-membered ring products 8s and 8t in preliminary
studies (Scheme 4).
Scheme 4. Ring sizes of the oxa-Michael reaction products.
As a Michael acceptor, 1,4-dioxane derivative 8l was
applied in a conjugate addition with nitromethane for the
synthesis of ketones with three chiral centers.[14] The reaction
was catalyzed by 10a and its diastereomer 10b, which gave
entirely different results (Scheme 5). Interestingly, the ee
remained high when potassium carbonate was used as
a catalyst. The results indicate that the addition step is
highly sensitive to steric effects in the g-position. Single-
crystal X-ray analysis of 11 revealed a 4aS,8R,8aS config-
uration (see the Supporting Information).[17]
There are few examples where organocatalytic diastereo-
selective synthesis was attained by changing reaction con-
ditions, including catalysts, ligands, and additives, as well as by
modifying substrates.[15] Herein, we have realized the diaste-
reoselective synthesis of tetracyclic compounds with strong
structural rigidity, starting from the same chiral molecule. In
keeping with our previous vinylogous Michael addition of
Scheme 6. Diastereoselective synthesis of tetracyclic compounds con-
taining a bicyclo[2.2.2]octan-2-one backbone.
was generated when the reaction was catalyzed by 13b. When
the temperature was elevated to 508C, diastereomeric
tandem Michael–Michael reaction products were acquired
when catalyzed by 13a and its diastereomer 13b
(Scheme 6).[16] X-ray analyses of products 15a and 15b are
shown in the Supporting Information.[17] This result is
particularly noteworthy, as it provides concise and stereose-
lective access to stereodiverse, complex tetracyclic com-
pounds with multiple chiral centers, which could be useful
in the total synthesis of complex natural products.
In summary, we have disclosed a primary-amine-salt-
catalyzed asymmetric intramolecular oxa-Michael reaction
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through iminium-based activation, which provides enantioen-
riched 1,4-dioxane derivatives with excellent results (up to
99% yield and 98% ee). Further exploration provided
a useful, concise, and stereoselective access to stereodiverse,
complex tetracyclic compounds containing bicyclo-
[2.2.2]octan-2-one backbone with multiple chiral centers.
Experimental Section
Catalyst 2a (0.15 mmol, 0.15 equiv) and N-Boc-l-Pro (0.15 mmol,
0.15 equiv) were added to a solution of 7 (1.0 mmol, 1.0 equiv) in
toluene (2.0 mL). The reaction mixture was stirred at 08C for 4–
5 days and then the solvent was removed under vacuum. The residue
was purified by silica gel chromatography to yield the desired
product.
Received: August 29, 2012
Revised: September 16, 2012
Published online: December 20, 2012
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Keywords: asymmetric catalysis · cyclohexadienones ·
iminium activation · Michael addition · primary amine salt
.
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