Asymmetric Bronsted acid-catalyzed Nazarov cyclization of acyclic α-alkoxy dienones

Article abstract of DOI:10.1002/asia.201200391

A Bronsted acid-catalyzed asymmetric Nazarov cyclization of acyclic α-alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Bronsted acid-catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities. I've got 5 on it! An enantioselective Bronsted acid-catalyzed Nazarov cyclization of acyclic α-alkoxy dienones that affords optically active cyclopentenones in good yields and excellent enantiomeric excess has been developed. Copyright

Full text of DOI:10.1002/asia.201200391

DOI: 10.1002/asia.201200391
Asymmetric Brønsted Acid-Catalyzed Nazarov Cyclization of Acyclic
a-Alkoxy Dienones
Sadiya Raja,* Winai Ieawsuwan, Vadim Korotkov, and Magnus Rueping*[a]
Abstract: A Brønsted acid-catalyzed asymmetric Nazarov cyclization of acyclic a-
alkoxy dienones has been developed. The reaction offers access to chiral cyclopen-
tenones in a highly enantioselective manner. The reaction is complementary to our
previously reported Brønsted acid-catalyzed electrocyclization reactions, which
provided differently substituted optically active cyclopentenones with a fused tet-
rahydropyrane ring in good yields and with excellent enantioselectivities.
Keywords: asymmetric synthesis ·
Brønsted acids · electrocyclizations ·
Nazarov reaction · organocatalysis
Introduction
Cyclopentenones are valuable building blocks in the synthe-
sis of natural products and biologically active compounds.
Important natural products such as jasmonoids, prostaglan-
dins, and cyclopentanoid antibiotics contain these structural
units.[1] Owing to the great importance of cyclopentenones
in organic chemistry, different methods have been devel-
oped for their synthesis. Successful approaches include vari-
ous intramolecular reactions such as aldol reactions, Wittig-
ꢀ
type reactions, 1,5-C H insertions, as well as intermolecular
cyclization strategies using transition metals.[2] The Nazarov
reaction is a 4p-electron conrotatory cyclization of a penta-
dienyl cation and is one of the most versatile methods for
the synthesis of cyclopentenones.[3] Generally, the divinyl
ketone involved in the transformation, is activated by
a Brønsted or a Lewis acid (Scheme 1a). So far, only a few
catalytic asymmetric versions have been described and they
mainly rely on chiral metal complexes as catalysts.[4,5] Re-
cently, we developed the first organocatalytic asymmetric
version of the Nazarov cyclization.[6] The Brønsted acid-cat-
alyzed reaction[7] developed by our research group provides
access to optically active 2,3-disubstituted cyclopentenones 2
in good yields and high enantioselectivities (Scheme 1b).
Furthermore, we have described a Brønsted acid-catalyzed
electrocyclization/protonation reaction that yields cyclopen-
Scheme 1. Enantioselective Brønsted acid-catalyzed Nazarov reactions.
tanones 4 in good yields and high enantioselectivities
(Scheme 1c).[8] More recently, we succeeded in developing
an organocatalyzed asymmetric domino electrocyclization/
bromination reaction, which offers access to highly function-
alized trans-4,5-substituted 5-bromocyclopentenone deriva-
tives
5
with high to excellent enantioselectivities
(Scheme 1d).[9]
Regarding the mechanism of the organocatalyzed Naza-
rov cyclization, the chiral 2,2ꢀ-dihydroxy-1,1ꢀ-binaphthyl
(BINOL)-derived N-triflyl phosphoramide catalyst[10,11] acti-
vates the divinyl ketone A by a catalytic protonation. Subse-
quent conrotatory 4p electrocyclization gives the oxyallyl
cation C, which leads to the enolate D after proton elimina-
tion. Protonation of the enolate results in the formation of
[a] Dipl.-Chem. S. Raja, Dr. W. Ieawsuwan, Dr. V. Korotkov,
Prof. M. Rueping
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-8092665
E-mail: magnus.rueping@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200391.
Chem. Asian J. 2012, 00, 0 – 0
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FULL PAPER
Scheme 4. Brønsted acid-catalyzed Nazarov cyclization using acyclic
ether 6a.
hydroxyenone 8a, in a 1:1 ratio (Scheme 4). However, when
7a was treated with acid, the a-hydroxyenone 8a was ob-
tained. Therefore, we decided to isolate 8a after acidic hy-
drolysis.
In our previous studies on asymmetric Nazarov cycliza-
tions, the enantioselectivities were strongly dependent on
the reaction media employed. Thus, our first examination
focused on varying the solvent in the reaction of divinyl
ketone 6a to a-hydroxyenone 8a. The best result with re-
spect to selectivity was obtained when the reaction was per-
formed in chloroform at room temperature (Table 1, en-
Scheme 2. Proposed mechanism for the Brønsted acid-catalyzed Nazarov
cyclization.
the desired enantioenriched cyclopentenone E and regener-
ates the catalyst (Scheme 2). The stereodetermining step for
the conversion of 2,3-substituted dienone derivatives 1 to cy-
clopentenones 2 (Scheme 1b) is the enantioselective electro-
cyclization reaction, a process followed by a diastereoselec-
tive kinetic protonation, which furnishes the cis-cyclopente-
nones 2 with high enantioselectivities. In contrast, the ster-
eodetermining step for the generation of optically active 2-
Table 1. Evaluation of different solvents and catalyst loadings.
substituted cyclopentenones
4
(Scheme 1c) involves
a Brønsted acid-catalyzed enantioselective protonation of
intermediate D.
Entry[a]
Solvent
ee [%][b]
1
CHCl3
CHCl3
CHCl3
CH2Cl2
Benzene
Toluene
MeOH
nBu2O
72
76
77
48
72
65
6
32
2[c]
3[d]
4
In our previous work, we focused on cyclic ethers as sub-
strates of type 1 and 3. Cyclopentenones fused with cyclic
ethers are not particularly suitable as structural units for the
synthesis of natural products. Therefore, we attempted to
cleave the ether moiety after cyclization, but without suc-
cess. Thus, we became interested in studying the Nazarov
5
6
7
8
9
MeCN
ClCH2CH2Cl
CHCl3
Racemate
30
81
cyclization of divinyl ketones using acyclic ethers
6
(Scheme 3).[11]
10
11[e]
[a] Reaction conditions: 6a (0.11 mmol), 2 mol% of 10a in solvent at RT.
Prior to treatment with conc. HCl. [b] Enantiomeric excess was deter-
mined by HPLC. [c] Using 5 mol% of 10a. [d] Using 10 mol% of 10a.
[e] Using 5 mol% of the H8 derivative 11a.
Scheme 3. Brønsted acid-catalyzed Nazarov cyclization using acyclic
ethers.
tries 1–3). Comparable or slightly lower selectivities were
observed in aromatic solvents, for example, benzene and tol-
uene (Table 1, entries 5 and 6). In polar solvents, a very low
level of stereocontrol was achieved. Accordingly, chloroform
was the solvent of choice. With regard to the catalyst load-
ing, the best result in terms of selectivity was achieved with
5 mol% of 10a. Neither lower loadings (2 mol%) nor
higher loadings (10 mol%) enhanced the enantioselectivity
(Table 1, entries 1 and 3). A slightly better selectivity was
observed with the H8-BINOL-derived N-triflylphosphora-
mide derivative 11a (Table 1, entry 11).
Results and Discussion
We started our experimental investigations by subjecting di-
vinyl ketone 6a to the cyclization reaction in the presence
of strongly acidic achiral N-triflylphosphoramide 9 as a cata-
lyst. Interestingly, in this case we observed the formation of
two different cyclization products, cyclopentenone 7a and a-
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Asymmetric Brønsted Acid-Catalyzed Nazarov Cyclization of Acyclic a-Alkoxy Dienones
Table 2. Evaluation of different ether substrates and catalysts.
Table 3. Evaluation of acids for the transformation of cyclopentenone
into diketone.
Entry[a]
Acid
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
HCl (conc.)[d]
HCl (conc.)[e]
HCl (conc.)[f]
HCl (conc.)
HCl (2N)
4
2
36
24
24
24
91
59
42
80
–
31
27
71
69
–
Entry[a]
6
R
11
Ar
ee [%][b]
1
2
3
4
5
6
7
8
6a
6b
6c
6c
6c
6c
6c
6c
6c
6c
6c
Et
11a
11a
11a
11b
11c
11d
11e
11 f
11g
11h
11i
9-phenanthryl
9-phenanthryl
9-phenanthryl
1-naphthyl
81
82
89
76
72
50[c]
81
50
60
56
57
nPr
iBu
iBu
iBu
iBu
iBu
iBu
iBu
iBu
iBu
HCl (6N)
71
89
[a] Reaction conditions: 7c in 0.5 mL CH2Cl2, 1 mL acid HCl (conc:
37%). [b] Yield of the isolated product after column chromatography.
[c] Enantiomeric excess was determined by HPLC. [d] At 808C in micro-
wave. [e] At 908C in microwave. [f] At 408C in microwave.
2-naphthyl
p-OMe-C6H4
9-anthracenyl
phenyl
3,5-(CF3)2-C6H3
p-F-C6H4
9
10
11
p-tBu-C6H4
selectivity (89% ee, Table 3, entry 6). Under the optimized
reaction conditions we investigated the scope of the Brønst-
ed acid-catalyzed enantioselective Nazarov cyclization of 4-
aryl-substituted divinyl ketones 6c–k (Table 4).
[a] Reaction conditions: 6 (0.123 mmol), 5 mol% 11 in CHCl3 at RT.
Prior to treatment with conc. HCl. [b] Enantiomeric excess was deter-
mined by HPLC. [c] Opposite enantiomer was obtained.
In general, differently substituted a-hydroxyenones 8
were obtained in moderate to good yields and with excellent
enantioselectivities of up to 99% ee (Table 4). With regard
to the mechanism, we assume that the highly enantioselec-
tive cyclization starts with activation of divinyl ketone 6 by
the Brønsted acid catalyst. The oxyallyl cation, which is
formed during the conrotatory 4p electrocyclization is stabi-
lized by the iBu group. A subsequent protonation of the
generated enolate leads to the corresponding cyclopente-
none 7, which isomerizes in the presence of acid into a-hy-
droxyenone 8.
Next, we decided to prepare differently substituted enol
ethers to establish which groups are suitable to improve the
selectivity (Table 2 entries 1–3). We observed that the reac-
tion proceeded with good enantiocontrol in all cases, with
the best selectivity (89% ee) for 8a being obtained with di-
vinyl ketone 6c that bears an iBu group. In further experi-
ments, we examined the Nazarov cyclization of 6c in the
presence of catalytic amounts of chiral N-triflylphosphora-
mides 11a–i (Table 2, entries 3–11). The survey revealed
that large aromatic substituents in the 3,3’-positions of the
BINOL backbone provided better enantioselectivities. How-
ever, the best result was obtained with catalyst 11a (Ar=9-
phenanthryl; Table 2, entry 3). Interestingly, the opposite
enantiomer was obtained when the reaction was performed
in the presence of catalyst 11d (Ar=p-OMe-C6H4; Table 2,
entry 6).
As previously mentioned, both products 7 and 8 are ob-
tained in the asymmetric reaction. To isolate our desired
product 8a we concentrated on finding the appropriate reac-
tion conditions for the conversion of chiral cyclopentenone
7c into the corresponding a-hydroxyenone 8a (Table 3).
Apart from various acids tested, the temperature and the
acid concentration were also varied. These experiments re-
vealed that both temperature and acid concentration have
a considerable impact on the reactivity and enantioselectivi-
ty. While better selectivities for 8a could be obtained at
room temperature, higher yields were obtained when the re-
actions were run in the presence of strong acids at high tem-
peratures. We observed that using concentrated acid caused
a dramatic decrease in enantioselectivity (Table 3, entries 1
and 2).
Conclusions
In summary, we have presented a new Brønsted acid-cata-
lyzed asymmetric Nazarov cyclization of a-alkoxy divinyl
ketones to afford optically active cyclopentenones. This effi-
cient electrocyclization reaction proceeds under mild reac-
tion conditions and leads to various substituted aromatic a-
hydroxyenones with excellent enantioselectivities (88–99%
ee). Further studies to expand the generality of asymmetric
Brønsted acid-catalyzed Nazarov reactions are in prog-
ress.[12]
Experimental Section
General procedure for preparation of divinyl ketone 6
tBuLi (20.5 mL, 1.6m in pentane, 33 mmol) was slowly added to a solution
of isobutyl vinyl ether (4.5 mL, 34.6 mmol) in tetrahydrofuran (THF;
30 mL) at ꢀ788C and the resulting reaction mixture was allowed to
warm to 08C over 1 h. Afterwards, a solution of morpholine enamide
(4 g, 17.3 mmol) in THF (50 mL) was added dropwise and the mixture
was stirred at ꢀ788C for 1 h. The reaction mixture was quenched with
brine and the aqueous phase was extracted with ethyl acetate (3ꢂ
Thus, the reaction was conducted using 6 N HCl at room
temperature. Under these reaction conditions, the a-hydrox-
yenone 8a was furnished in a good yield with high enantio-
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Magnus Rueping, Sadiya Raja et al.
FULL PAPER
Table 4. Scope of the Nazarov cyclization.
135.9, 135.6, 129.7, 128.5, 128.3, 91.5, 74.5, 27.9, 19.3, 13.9 ppm; IR (KBr):
n˜ =3058, 2961, 1736, 1660, 1467, 1383, 1290, 1193, 1050, 776, 697 cmꢀ1
MS-EI: m/z (%): 244.3 (2), 188.1 (100), 173.1 (48), 145 (85).
;
(E)-4-Isobutoxy-2-methyl-1-p-tolyl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 42%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.29–7.17 (m, 5H), 4.68 (d, J=2.5 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H),
3.42(d, J=6.5 Hz, 2H), 1.97 (d, J=1.1 Hz, 3H), 1.94–1.87 (m, 1H),
0.85 ppm (d, J=6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=193.1,
159.9, 141.3, 138.5, 135.4, 133.7, 130.1, 129.3, 90.7, 74.4, 28.3, 21.4, 19.5,
14.3 ppm; IR (KBr): n˜ =3025, 2961, 1735, 1607, 1469, 1384, 1292, 1192,
816 cmꢀ1; MS-EI m/z (%): 159.2 (96), 145.2 (100), 131.2 (45).
Entry[a]
Product
Yield[b]
71
ee [c]
1
8a
8b
8c
8d
8e
8 f
8g
89
(E)-1-(4-Fluoro-phenyl)-4-isobutoxy-2-methyl-penta-1,4-dien-3-one
2
3
4
5
6
7
48
43
63
40
43
44
93
92
91
91
99
92
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 54%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.29–7.17 (m, 5H), 4.68 (d, J=2.5 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H), 3.42
(d, J=6.5 Hz, 2H), 1.97 (d, J=1.1 Hz, 3H), 1.94–1.87 (m, 1H), 0.85 ppm
(d, J=6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=194.0, 164.2,158.9,
140.1, 131.6, 131.5, 115.6, 115.4, 91.5, 74.5, 27.8, 19.3, 13.9 ppm; IR (KBr):
n˜ =2926, 2852, 1743, 1600, 1449, 1235, 1154, 902, 835 cmꢀ1; MS-EI m/z
(%): 262.3 (3), 206.2 (63), 178 (90), 135 (93).
(E)-1-(4-Bromo-phenyl)-4-isobutoxy-2-methyl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 62%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.29–7.17 (m, 5H), 4.68 (d, J=2.5 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H),
3.42(d, J=6.5 Hz, 2H), 1.97 (d, J=1.1 Hz, 3H), 1.94–1.87 (m, 1H),
0.85 ppm (d, J=6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=159.4,
138.7, 138.2, 137.4, 134.6, 129.8, 91.4, 74.5, 28.3, 19.4, 14.2 ppm; IR (KBr):
n˜ =3469, 2962, 2874, 1716, 1586, 1486, 1385, 1290, 1193, 1071, 948, 820,
516 cmꢀ1; MS-EI m/z (%): 225.1(36), 185.1 (35), 116.2 (35), 57.4 (100).
(E)-1-(4-Chloro-phenyl)-4-isobutoxy-2-methyl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 58%; yellowish oil; 1H NMR (CDCl3, 400 MHz): d=
7.28–7.23 (m, 5H), 4.74 (s, 1H), 4.44 (s, 1H), 3.47(d, J=6.4 Hz, 2H), 2.00
(s, 3H), 1.98–1.93 (m, 1H), 0.85 ppm (d, J=6.7 Hz, 6H); 13C NMR
(CDCl3, 75 MHz): d=193.8, 158.7, 139.5, 136.1, 134.4, 134.2, 130.9, 128.6,
91.7, 74.6, 28.0, 19.5, 14.2 ppm; IR (KBr): n˜ =3459, 2958, 1741, 1651,
1489, 1386, 1312, 1188, 1090, 823, 699 cmꢀ1; MS-EI m/z (%): 179.2 (13),
115 (36), 57.5 (100).
8
9
8h
8i
42
53
99
88
(E)-4-Isobutoxy-2-methyl-1-(4-trifluoromethyl-phenyl)-penta-1,4-dien-3-
one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 38%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.71 (d, J=7.8 Hz, 1H), 7.61–7.32 (m, 4H), 4.93 (d, J=2.7 Hz, 1H), 4.6
(d, J=2.7 Hz, 1H), 3.57 (d, J=6.6 Hz, 2H), 2.14–2.03 (m, 1H), 1.91 (d,
J=1.4 Hz, 3H), 0.98 ppm (d, J=6.7 Hz, 6H); 13C NMR (CDCl3,
75 MHz): d=158.1, 137.2, 131.6, 130.3, 127.9, 125.9, 92.8, 74.7, 29.1, 27.8,
19.3, 13.9 ppm; IR (KBr): n˜ =3446, 2966, 1740, 1670, 1469, 1382, 1315,
1165, 1061, 951, 771 cmꢀ1; MS-EI m/z(%): 255.2 (13), 213.2 (99), 199.2
(95), 185 (36), 145 (19).
[a] Reaction conditions: 1) substrates 6c–k, 5 mol% 11a in CHCl3 at RT
for 48 h; 2) 6 N HCl, 08C!RT in CH2Cl2. [b] Yield of the isolated prod-
uct after column chromatography. [c] Enantiomeric excess was deter-
mined by HPLC.
(E)-4-Isobutoxy-2-methyl-1-naphthalen-2-yl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:60). Yield: 46%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.29–7.17 (m, 5H), 4.68 (d, J=2.5 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H), 3.42
(d, J=6.5 Hz, 2H), 1.97 (d, J=1.1 Hz, 3H), 1.94–1.87 (m, 1H), 0.85 ppm
(d, J=6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=193.2, 159.8, 144.5,
141.2, 136.5, 133.9, 133.6, 133.4, 131.3, 129.9, 127.3, 126.9, 126.6, 123.7,
121.1, 90.9, 74.5, 28.2, 19.3, 14.3 ppm; IR (KBr): n˜ =3490, 2961, 1736,
1660, 1466, 1382, 1292, 1192, 1050, 821, 747 477 cmꢀ1; MS-EI m/z (%):
294.2 (43), 238.2 (98), 195.1 (100), 167 (61).
20 mL). The combined organic phases were dried over Na2SO4, filtered,
and evaporated in vacuo. The crude product was purified by column
chromatography on silca gel to afford the divinyl ketone 6.
(E)-4-Isobutoxy-2-methyl-1-phenyl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:40). Yield: 44%; yellowish oil; 1H NMR (CDCl3, 300 MHz): d=
7.29–7.17 (m, 5H), 4.68 (d, J=2.5 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H), 3.42
(d, J=6.5 Hz, 2H), 1.97 (d, J=1.1 Hz, 3H), 1.94–1.87 (m, 1H), 0.85 ppm
(d, J=6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=194.2, 158.9, 141.3,
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Asymmetric Brønsted Acid-Catalyzed Nazarov Cyclization of Acyclic a-Alkoxy Dienones
(E)-1-Benzo
G
(R)-4-(4-Bromo-phenyl)-2-hydroxy-3-methyl-cyclopent-2-enone (8d)
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:60). Yield: 52%; yellowish oil; H NMR (C6D6, 400 MHz): d=7.46
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:5). White solid; m.p.: 133–1358C; 1H NMR (CDCl3, 400 MHz): d=
7.30 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 5.48 (brs, 1H), 3.77 (d,
J=6.4 Hz, 1H), 2.93 (dd, J=19.2, 6.6 Hz, 1H), 2.29 (d, J=19.2 Hz, 1H),
1.79 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=201.5, 149.5, 144.8,
140.3, 133.0, 129.1, 128.6, 44.324, 42.1, 12.6 ppm; IR (KBr): n˜ =3335,
2924, 2854, 1697,1652, 1461, 1215, 759 cm-1; MS-EI m/z(%): 289.0 (23)
[M]+·, 271.0 (45) [M-H2O]+·, 261.0 (74), 211.0 (100); ½aꢁ2D5 =ꢀ11.4 (c=0.5
in MeOH); HPLC conditions: OD-H column, n-hexane/2-propanol=
98:2, flow rate=0.5 mLmin-1, major enantiomer: tR =53.76 min; minor
enantiomer: tR =44.91 min
1
(s, 1H), 6.84 (s, 1H), 6.69–6.66 (m, 1H), 6.54 (d, J=8.1 Hz, 1H), 5.23 (s,
2H), 4.91 (d, J=2.3 Hz, 1H), 4.27 (d, J=2.3 Hz, 1H), 3.24 (d, J=6.3 Hz,
2H), 2.07 (d, J=1.3 Hz, 3H), 1.79 (m, 1H), 0.79 ppm (d, J=6.7 Hz, 6H);
13C NMR (CDCl3, 75 MHz): d=193.0, 159.9, 148.3, 141.1, 134.7, 130.5,
125.2, 110.0, 108.6, 101.3, 90.6, 74.5, 28.3, 19.5, 14.3 ppm; IR (KBr): n˜ =
2965, 1640, 1600, 1488, 1317, 1250, 1060, 929, 830, 761 cmꢀ1; MS-EI m/z
(%): 288.3 (27), 232.3 (64), 189.2 (65), 159.2 (60), 103.3 (100).
(E)-4-Isobutoxy-1,2-diphenyl-penta-1,4-dien-3-one
The product was purified by column chromatography (EtOAc/cyclohex-
ane 1:60). Yield: 48%; yellowish oil; 1H NMR (C6D6, 400 MHz): d=
7.28–7.25 (m, 2H), 7.07–7.02 (m, 5H), 6.87–6.85 (m, 3H), 5.17 (d, J=
2.4 Hz, 1H), 4.26 (d, J=2.4 Hz, 1H), 3.10 (d, J=6.4 Hz, 2H), 1.69–1.61
(m, 1H), 0.72 ppm (d, J=6.7 Hz, 6H); 13C NMR (C6D6, 75 MHz): d=
191.7, 159.5, 140.7, 138.8, 136.9, 135.5, 130.7, 129.9, 128.8, 92.2, 74.6, 28.2,
19.4 ppm; IR (KBr): n˜ =3475, 3058, 2961, 1732, 1670, 1492, 1383, 1292,
1200, 1123, 697 cmꢀ1; MS-EI m/z (%): 306.2 (52), 250.3 (22), 232.3 (13),
178.2 (65), 131.3 (91), 105 (100).
(R)-4-(4-Fluoro-phenyl)-2-hydroxy-3-methyl-cyclopent-2-enone (8e)
White solid, m.p.: 174–1768C; 1H NMR (400 MHz, CDCl3): d=7.10–6.99
(m, 4H), 5.49 (brs, 1H), 3.78 (d, J=6.46 Hz, 1H), 2.93 (dd, J=19.2,
6.5 Hz, 1H), 2.29 (d, J=19.3 Hz, 1H), 1.78 ppm (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d=201.6, 149.8, 144.9, 143.9, 134.8, 130.3, 127.5,
125.4, 44.6, 41.9, 12.6 ppm; IR (KBr): n˜ =3330, 2922, 1697, 1507, 1401,
1358, 1226, 1122, 927, 825, 669 cmꢀ1; MS-EI m/z (%): 206.1 (100), 191.1
(49), 177.1 (75), 163.1 (47); ½aꢁ2D5 =ꢀ4.3 (c=0.2 in MeOH); HPLC condi-
tions: AD-H column, n-hexane/2-propanol=95:5, flow rate=
0.5 mLminꢀ1, major enantiomer: tR =26.49 min, minor enantiomer: tR =
24.56 min.
General procedure for Nazarov cyclization
A mixture of catalyst 11a (5 mol%) and divinylketone 6 (0.24 mmol) in
CHCl3 (1.2 mL) was placed in a screw-capped test tube equipped with
a stirring bar. The resulting solution was stirred for 48 h at room temper-
ature. The solvent was then exchanged to CH2Cl2 and at 08C 6 N HCl
(1 mL) was added dropwise. The resulting mixture was allowed to warm
to room temperature and stirred for 48 h. The crude reaction mixture
was directly charged on silica gel and purified by column chromatogra-
phy to afford the cyclopentenone 8.
(R)-2-Hydroxy-3-methyl-4-(4-trifluoromethyl-phenyl)-cyclopent-2-enone
(8 f)
White solid; m.p.: 182–1858C; 1H NMR (CDCl3, 400 MHz): d=7.68 (d,
J=7.9 Hz, 1H), 7.51 (t, J=15.1, 7.5 Hz, 1H), 7.36 (t, J=15.2, 7.6 Hz,
1H), 7.12 (d, J=7.8 Hz, 1H), 5.50 (brs, 1H), 4.30 (d, J=6.9 Hz, 1H),
2.97 (dd, J=18.2, 6.2 Hz, 1H), 2.23 (d, J=19.2 Hz, 1H), 1.81 ppm (s,
3H); 13C NMR (CDCl3, 62.5 MHz): d=201.4, 150.1, 144.0, 132.7, 127.4,
126.0, 125.9, 42.7, 39.8, 12.5 ppm; IR (KBr): n˜ =3325, 2923, 1700, 1653,
1399, 1153, 1107, 1035, 932, 772, 659 cmꢀ1; MS-EI m/z (%): 256.0 (100),
159.1 (60); ½aꢁ2D5 =ꢀ15.2 (c=0.2 in MeOH); HPLC conditions: OD-H
(R)-2-Hydroxy-3-methyl-4-phenyl-cyclopent-2-enone (8a)[5b]
White solid, m.p.: 104–1078C; 1H NMR (CDCl3, 400 MHz): d=7.34–7.12
(m, 5H), 5.68 (brs, 1H), 3.80 (d, J=6.5, 1H), 2.93 (dd, J=19.2, 6.5 Hz,
1H), 2.35 (d, J=20.0 Hz, 1H), 1.80 ppm (s, 3H); 13C NMR (CDCl3,
62.5 MHz): d=202.2, 149.5, 145.9, 141.7, 128.9, 127.3, 127.1, 44.9, 42.3,
12.6 ppm; IR (KBr): n˜ =3332, 2918, 2853, 1693, 1511, 1403, 1351, 1122,
column, n-hexane/2-propanol=90:10, flow rate=1.0 mLminꢀ1
enantiomer: tR =57.89 min; minor enantiomer: tR =38.22 min.
, major
928, 814 cmꢀ1
;
MS-EI m/z (%): 188.2 (100); ½aꢁ2D5 =ꢀ8.6 (c=1.2 in
(R)-2-Hydroxy-3-methyl-4-naphthalen-1-yl-cyclopent-2-enone (8g)
MeOH); HPLC conditions: AD-H column, n-hexane/2-propanol=90:10,
flow rate=1.0 mLminꢀ1, major enantiomer: tR =30.84 min; minor enan-
tiomer: tR =25.91 min.
White solid, m.p.: 127–1308C; 1H NMR(CDCl3, 400 MHz): d=7.83–7.79
(m, 3H), 7.61 (s, 1H), 7.52–7.45 (m, 2H), 7.17 (dd, J=8.4, 1.7 Hz, 1H),
3.94 (d, J=6.4 Hz, 1H), 2.97 (dd, J=19.2, 6.6 Hz, 1H), 2.41 (d, J=
19.3 Hz, 1H), 1.80 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=202.4,
149.7, 146.4, 139.0, 133.4, 132.6, 128.9, 127.6, 127.5, 126.3, 125.8, 124.6,
(R)-2-Hydroxy-3-methyl-4-p-tolyl-cyclopent-2-enone (8b)
White solid, m.p.: 119–1218C; 1H NMR (CDCl3, 400 MHz): d=7.13 (d,
J=7.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 5.68 (brs, 1H), 3.75 (d, J=
6.4 Hz, 1H), 2.90 (dd, J=19.2, 6.5 Hz, 1H), 2.35–2.30 (m, 4H), 1.80 ppm
(s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=202.1, 149.2, 145.8, 138.6,
136.8, 129.6, 127.1, 44.5, 42.3, 21.0, 12.6 ppm; IR (KBr): n˜ =3330, 2920,
2853, 1693, 1511, 1403, 1353, 1120, 928, 815, 668 cmꢀ1; MS-EI m/z (%):
202.1 (100), 187.1 (76), 159.1 (72); ½aꢁ2D5 =ꢀ14.4 (c=0.7 in MeOH);
HPLC conditions: AD-H column, n-hexane/2-propanol=95:5, flow
rate=0.5 mLminꢀ1, major enantiomer: tR =21.25 min; minor enantiomer:
tR =25.07 min.
45.0, 42.2, 12.7 ppm; IR (KBr): n˜ =3339, 2921, 2852, 1739, 1653, 1440,
25
1360, 1227, 1117, 858, 750, 675 cmꢀ1; MS-EI m/z (%): 238.0 (100); ½aꢁD
=
ꢀ8.6 (c=0.4 in MeOH); HPLC conditions: AD-H column, n-hexane/2-
propanol=98:2, flow rate=0.5 mLminꢀ1
57.94 min; minor enantiomer: tR =47.91 min.
,
major enantiomer: tR =
(R)-4-BenzoACTHNUTRGNE[UNG 1,3]dioxol-4-yl-2-hydroxy-3-methyl-cyclopent-2-enone (8h)
White solid, m.p.: 125–1278C; 1H NMR (CDCl3, 400 MHz): d=6.75 (d,
J=7.9 Hz, 1H), 6.61 (dd, J=7.8 and 1.6 Hz, 1H), 6.55 (d, J=1.6 Hz,
1H), 5.95 (s, 2H), 5.67 (brs, 1H), 3.71 (d, J=6.4 Hz, 1H), 2.90 (dd, J=
19.2, 6.5 Hz, 1H), 2.29 (d, J=19.3 Hz, 1H), 1.80 ppm (s, 3H); 13C NMR
(CDCl3, 62.5 MHz): d=201.8, 149.2, 148.3, 146.7, 145.3, 135.5, 120.6,
(R)-4-(4-Chloro-phenyl)-2-hydroxy-3-methyl-cyclopent-2-enone (8c)
White solid, m.p.: 163–1668C; 1H NMR (CDCl3, 400 MHz): d=7.45 (d,
J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 5.58 (brs, 1H), 3.76 (d, J=
6.5 Hz, 1H), 2.93 (dd, J=19.3, 6.6 Hz, 1H), 2.28 (d, J=19.2 Hz, 1H),
1.79 ppm (s, 3H); 13C NMR (CDCl3, 62.5 MHz): d=201.6, 149.6, 144.8,
140.2, 132.9, 129.1, 128.6, 44.3, 42.0, 12.5 ppm; IR (NaCl): n˜ =cmꢀ1; MS-
EI m/z (%): 323.7 (21) [M]+·, 321.7 (14) [M]+·, 20 9.8 (25), 207.8 (25),
129.0 (100), 85.9 (90); ½aꢁ2D5 =ꢀ19.5 (c=0.5 in MeOH); HPLC conditions:
108.5, 107.1, 101.1, 44.7, 42.2, 12.5 ppm; IR (KBr): n˜ =3319, 2924, 2855,
25
1701, 1652, 1450, 1216, 759 cmꢀ1; MS-EI m/z (%): 232.1 (100); ½aꢁD
=
ꢀ48.3 (c=0.45 in MeOH); HPLC conditions: OJ-H column, n-hexane/2-
propanol=90:10, flow rate=0.5 mLminꢀ1
38.39 min; minor enantiomer: tR =62.13 min.
, major enantiomer: tR =
(R)-2-Hydroxy-3,4-diphenyl-cyclopent-2-enone (8i)[5b]
AD-H column, n-hexane/2-propanol=98:2, flow rate=0.5 mLminꢀ1
major enantiomer: tR =70.49 min; minor enantiomer: tR =56.98 min.
,
White solid, m.p.: 145–1478C; 1H NMR (CDCl3, 400 MHz): d=7.75 (m,
2H), 7.33–7.24 (m, 4H), 7.20–7.16 (m, 4H), 6.10 (brs, 1H), 4.49 (d, J=
6.9 Hz, 1H), 3.09 (dd, J=19.3, 6.9 Hz, 1H), 2.38 ppm (d, J=19.3 Hz,
1H); 13C NMR (CDCl3, 62.5 MHz): d=201.9, 149.1, 143.3, 139.4, 132.8,
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Magnus Rueping, Sadiya Raja et al.
FULL PAPER
129.1 129.0, 128.8, 128.4, 127.0, 126.9, 42.5, 41.6 ppm; IR (KBr): n˜ =3293,
2921, 2853, 1682, 1624, 1451, 1389, 1281, 1134, 740, 690 cmꢀ1; MS-EI m/z
(%): 250.1 (100), 221.1 (35); ½aꢁ2D5 =ꢀ19.2 (c=0.6 in MeOH); HPLC con-
ditions: AD-H column, n-hexane/2-propanol=95:5, flow rate=
0.5 mLminꢀ1, major enantiomer: tR =24.72 min; minor enantiomer: tR =
42.76 min.
B. O. Ashburn, A. K. Basak, W. F. Bow, D. A. Vicic, M. A. Tius,
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[7] For reviews on Brønsted acid catalysis, see: a) T. Akiyama, Chem.
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Acknowledgements
The authors acknowledge the DFG (Programme Organocatalysis) for fi-
nancial support.
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[12] During the preparation of this manuscript an elegant application of
this method for synthesis of roseophilin was reported, see: D. J.
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Received: May 1, 2012
Published online: && &&, 0000
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

FULL PAPER
Organocatalysis
Sadiya Raja,* Winai Ieawsuwan,
Vadim Korotkov,
Magnus Rueping*
&&&& — &&&&
Asymmetric Brønsted Acid-Catalyzed
Nazarov Cyclization of Acyclic a-
Alkoxy Dienones
I’ve got 5 on it! An enantioselective
Brønsted acid-catalyzed Nazarov cycli-
zation of acyclic a-alkoxy dienones
that affords optically active cyclopen-
tenones in good yields and excellent
enantiomeric excess has been devel-
oped.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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