A catalytic asymmetric electrocyclization-protonation reaction

Article abstract of DOI:10.1002/adsc.200800623

The first enantioselective Bronsted acidcatalyzed electrocyclization-protonation reaction has been developed which provides a number of different cyclopentenones in good yields and with high enantioselectivities. The stereodetermining step of this asymmet

Full text of DOI:10.1002/adsc.200800623

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DOI: 10.1002/adsc.200800623
A Catalytic Asymmetric Electrocyclization-Protonation Reaction
Magnus Ruepinga,* and Winai Ieawsuwana
a
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical Biology, Goethe University Frankfurt am
Main, Max-von-Laue Strasse 7, 60438 Frankfurt, Germany
Fax : (+49)-69-798-29248; e-mail: M.Rueping@chemie.uni-frankfurt.de
Received: October 11, 2008; Published online: January 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800623.
Abstract: The first enantioselective Brønsted acid-
catalyzed electrocyclization-protonation reaction
has been developed which provides a number of
different cyclopentenones in good yields and with
high enantioselectivities. The stereodetermining
step of this asymmetric Nazarov cyclization reaction
is an asymmetric Brønsted acid-catalyzed kinetic
protonation.
electrocyclization reaction we were, for instance, able
to prepare valuable alkyl- and aryl-substituted cyclo-
pentenones in good yields and with excellent enantio-
selectivities (Scheme 1).[5]
In this first organocatalytic electrocyclization reac-
tion the activation of the divinyl ketone A is achieved
by a catalytic protonation through a chiral phosphoric
acid diester 1[6,7] or chiral N-triflylphosphoramide cat-
alyst 2[8,9] resulting in the formation of adduct B. Sub-
sequent conrotatory 4p electrocyclization leads to the
oxyallyl cation C which upon elimination of a proton
forms the enolate D. Protonation of this enolate re-
sults in the formation of the desired cyclopentenone
Keywords: Brønsted acids; cascade reaction; cyclo-
pentenone; domino reaction; Nazarov reaction; or-
ganic catalysis
E
and the regenerated Brønsted acid catalyst
(Figure 1).
The mechanistic considerations of the asymmetric
The Nazarov reaction[1] is an electrocyclic reaction Brønsted acid-catalyzed Nazarov reaction of 2,3-di-
and is one of the most versatile methods in organic
ACHTUNGTRENsNUGN ubstituted divinyl ketone derivatives 3 illustrate that
synthesis to rapidly access cyclopentenones which are the key step in these reactions consists of an enantio-
the key structural element of numerous natural prod- selective electrocyclization reaction. The subsequent
ucts.[2] In general, the Nazarov reaction involves the diastereoselective kinetic protonation of intermediate
transformation of a divinyl ketone to a cyclopent- D results in the cis-cyclopentenones 4 as the major
ACHTUNGTRENNUNGenone by activation of Brønsted or Lewis acids. How- products (Scheme 2a). The cis-cyclopentenones can
ever, to date only a few asymmetric variants have readily be transformed into the corresponding trans-
been described of which most require the use of products without loss of enantiomeric purity. Howev-
chiral metal complexes.[3,4] Within this context and er, in the case of 2-substituted derivatives 5 the ster-
based on our previous work in the field of asymmetric eodetermining step of the asymmetric Nazarov cycli-
Brønsted acid catalysis, we recently developed the zation is different. In this case the key step of the
first metal-free highly enantioselective Nazarov cycli- overall transformation to 2-substituted cyclopent-
zation. Applying this newly developed organocatalytic
Scheme 1. Enantioselective Brønsted acid-catalyzed Nazarov cyclization.
78
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Adv. Synth. Catal. 2009, 351, 78 – 84

A Catalytic Asymmetric Electrocyclization-Protonation Reaction
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Table 1. Influence of solvent on the enantioselectivity of
Brønsted acid-catalyzed protonation.
Entry[a]
Solvent
Time
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Toluene
CF3Ph
Benzene
CHCl3
CH2Cl2
CCl4
ClCH2CH2Cl
CH3CN
n-Bu2O
EtOAc
MeOH
1 h
1 h
1 h
30 min
30 min
1 h
15 min
1 h
85
96
87
89
93
92
96
88
30
60
28
47
26
44
53
43
42
34
5
Figure 1. Catalytic cycle of the Brønsted acid-catalyzed Naz-
arov reaction.
ACHTUNGTRENNUNGenones 6 is a Brønsted acid-catalyzed enantioselective
protonation of intermediate D (Scheme 2b).[4,10–12]
Given the importance of cyclopentenones in organ-
ic synthesis together with our recently developed
enantioselective organocatalytic Nazarov reaction[5]
and carbonyl activations,[8] we decided to examine a
Brønsted acid-catalyzed enantioselective cyclization-
protonation reaction. This would not only be the first
organocatalytic enantioselective protonation within
the Nazarov reaction but, more importantly, would
provide direct and fast access to optically active 2-
substituted cyclopentenones (Scheme 2b).
9
10
11
2 h
2 h
5 h
12
12
4
[a]
Reaction conditions: 5a (0.113 mmol), 5 mol% 2a in sol-
vent at room temperature.
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary
column.
[b]
[c]
periments showed that the reactivities and selectivi-
Hence, our initial investigation of the enantioselec- ties are strongly dependent on the solvent. While re-
tive protonation concentrated on the evaluation of actions in polar solvents gave almost no selectivities
various solvents in the N-triflylphosphoramide (2a)- (Table 1, entries 8–11), both better reactivities and se-
catalyzed transformation of divinyl ketone 5a to the lectivities were observed if aromatic and halogenated
corresponding cyclopentenone 6a (Table 1). These ex- solvents were employed (entries 1–7). This tendency
Scheme 2. Origin of enantioselectivity in the Brønsted acid-catalyzed asymmetric synthesis of cyclopentenones: a) for 2,3-
disubstituted divinyl ketones enantioselection is induced by an asymmetric electrocyclization followed by a diastereoselective
kinetic protonation and b) in the case of 2-substituted divinyl ketones through the new Brønsted acid-catalyzed enantioselec-
tive protonation.
Adv. Synth. Catal. 2009, 351, 78 – 84
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79

Magnus Rueping and Winai Ieawsuwan
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Table 2. Assessment of catalyst loading and solvent concen-
tration.
vent of choice for the organocatalytic Nazarov cycli-
zation-enantioselective protonation sequence.
Further examination of the enantioselective cycliza-
tion-protonation reaction focused on the catalyst
loading and solvent concentration (Table 2). While a
decrease in catalyst loading and concentration result-
ed in longer reaction times no significant changes
with regard to enantioselection were observed. How-
ever, decreasing the temperature had a considerable
impact on the enantioselectivity (Table 2, entry 6).
In further experiments aiming to improve the enan-
tioselectivities we decided to apply different chiral N-
triflylphosphoramide catalysts 2a–l in this asymmetric
Brønsted acid-catalyzed protonation reaction. While
the reaction could be catalyzed by all Brønsted acids
employed, the N-triflylphosphoramides with sterically
more demanding residues in the 3,3-position of the
BINOL skeleton provided better enantioselectivities
(Table 3, entries 1 and 2). Therefore, we decided to
vary the sulfonamide residue of the phenanthryl-sub-
stituted catalyst 2a (Table 3, entries 9–11). Interesting-
ly, catalyst 2i (R=p-CF3-C6H4) showed better selec-
tivities but considerably lower reactivities. Introduc-
tion of longer fluorinated alkyl chains (catalysts 2j
Entry[a]
x
M [mol/
Time Yield
[%][b]
ee
[mol%] L]
[%][c]
1
2
3
4
5
5
2
1
5
5
0.057
1.5 h
92
53
51
53
52
53
64
0.227
0.113
0.113
0.113
0.113
30 min 96
2 h
4 h
92
85
5
30 min 96
3 h 70
6[d]
[a]
Reaction conditions: 5a (0.113 mmol), x mol% 2a in
CHCl3 at room temperature.
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary
column.
[b]
[c]
[d]
At 08C.
is in agreement with our earlier observations on and k) did not result in improved selectivities. Re-
Brønsted acid-catalyzed reactions where halogenated cently we found that, for certain Brønsted acid-cata-
and aromatic solvents typically gave superior re- lyzed transformations, the octahydro-BINOL-phos-
sults.[5,7,8] Thus chloroform was identified as the sol- phoric acid diesters gave superior results. Hence, we
Table 3. Chiral N-triflylphosphoramides in the catalytic enantioselective protonation.
Entry[a]
Ar
R
Time [h]
Yield [%][b]
ee [%][c]
1[e]
2
3
4
5
9-phenanthryl (2a)
anthracenyl (2b)
2-naphthyl (2c)
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
4-CF3-C6H4
C8F17
C4F9
CF3
3
5
5
5
2
5
4
5
72
72
72
20
70
69
68
60
75
66
38
31
10
61
47
96
64
53
42
54
28
35
40
40
86
63
60
75
1-naphthyl (2d)
4-NO2-C6H4 (2e)
3,5-(CF3)2-C6H3 (2f)
4-Ph-C6H4 (2g)
6
7
8
phenyl (2h)
9[d]
10[d]
11[d]
12[e]
9-phenanthryl (2i)
9-phenanthryl (2j)
9-phenanthryl (2k)
[H8]-9-phenanthryl (2l)
[a]
Reaction conditions: 5a (0.113 mmol), 5 mol% 2 in CHCl3 at 58C.
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary column.
Room temperature.
[b]
[c]
[d]
[e]
At 08C.
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A Catalytic Asymmetric Electrocyclization-Protonation Reaction
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Table 4. Evaluation of the reaction temperature.
Table 5. Scope of the Brønsted acid-catalyzed enantioselec-
tive protonation.
Entry[a]
Temp. [oC]
Time [h]
Yield [%][b]
ee [%][c]
Entry[a]
Product
Yield
[%][b]
ee
1
2
3
4
0
20
20
18
18
96
83
40
24
75
78
80
81
[%][c]
À10
À20
À30
1
2
3
4
5
6a 83
78
70
70
76
78
[a]
Reaction condition: 5a (0.113 mmol), 5 mol% 2l in
CHCl3.
[b]
[c]
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary
column.
6b 44
6c 72
6d 71
6e 79
prepared the corresponding N-triflylphosphoramide
2l and applied it in the catalytic enantioselective pro-
tonation. Pleasingly, we obtained the cyclopentenone
6a in good yields and with an enantiomeric excess of
75% ee (Table 3, entry 12).
Our earlier studies showed that Brønsted acid-cata-
lyzed carbonyl activations are strongly dependent on
reaction temperature. Hence, we decided to evaluate
the reaction temperature employing catalyst 2l. These
experiments demonstrated that higher enantioselec-
tivities could be obtained at lower temperature (81%
ee at À308C), however, the cyclopentenone was iso-
lated in only 24% yield (Table 4, entry 4). The best
temperature for the Brønsted acid-catalyzed enantio-
selective electrocyclization-protonation reaction was
found to be À108C, and the product 6a was obtained
in 83% yield and with 78% enantiomeric excess.
With the optimized conditions in hand we explored
the scope of the Brønsted acid-catalyzed asymmetric
Nazarov cyclization via enantioselective protonation
of various dienones 5 (Table 5). In general, it was pos-
sible to successfully transform differently substituted
dienones 5a–i into the corresponding products, where-
by alkyl- and benzyl-substituted cyclopentenones 6a–i
were obtained in good isolated yields and with high
enantioselectivities (67–78% ee).[13]
6
7
8
6f 81
6g 93
6h 87
6i 49
71
67
71
67
9
In summary, we have developed the first enantiose-
lective Brønsted acid-catalyzed electrocyclization-pro-
tonation reaction which provides a number of differ-
ent cyclopentenones in good yield and with high
enantioselectivities (67–78% ee). Special features of
our newly developed organocatalytic Brønsted acid-
catalyzed protonation are the low catalyst loadings as
well as the mild reaction conditions. Further studies
to improve the scope and selectivities and the applica-
tion in the synthesis of biologically active compounds
and natural products are currently under investiga-
tion.
[a]
Reaction conditions: substrate 5a–i, 5 mol% 2l in CHCl3
(0.1M).
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary
column.
[b]
[c]
Adv. Synth. Catal. 2009, 351, 78 – 84
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81

Magnus Rueping and Winai Ieawsuwan
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1 mLminÀ1): major enantiomer: tR =31.29 min; minor enan-
tiomer: tR =27.83 min.
Experimental Section
(S)-6-Ethyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6c): colorless oil; 1H NMR (300 MHz, CDCl3): d=
4.08–4.00 (m, 2H), 2.55 (tdd, J=1.7, 6.3, 17.4 Hz, 1H), 2.28
(t, J=6.3 Hz, 2H), 2.25–2.17 (m, 1H), 2.06 (ddd, J=1.8, 1.8,
17.4 Hz, 1H), 1.95–1.84 (m, 2H), 1.84–1.70 (m, 1H), 1.44–
1.26 (m, 1H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=202.86, 150.66, 144.36, 66.76, 44.75, 32.22, 24.39,
General Remarks
Unless otherwise stated, all commercially available com-
pounds were used as provided without further purification.
Solvents for chromatography were technical grade and dis-
tilled prior to use. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel aluminum plates
with F-254 indicator, visualized by irradiation with UV light.
Column chromatography was carried out using silica gel
Merck 60 (particle size 0.063–0.200 mm). 1H NMR and
13C NMR spectra were recorded on a Bruker AM 250 or
AV 300 spectrometer in CDCl3. Chemical shifts (d) are
given in ppm, coupling constants (J) in Hz. Mass spectra
(MS-EI, 70 eV) were conducted on a GC-MS Shimadzu
QP2010 (column: Equityꢁ-5, length ꢂ I.D. 30 mꢂ0.25 mm,
df 0.25 mm, lot # 28089-U, Supelco). IR spectra were record-
ed on a Jasco FT/IR-420 spectrometer and are reported in
terms of frequency of absorption (cmÀ1). Elemental analysis
(C, H, N) were recorded on a Perkin–Elmer Elemental An-
alyzer 2400 CHN. Substrates 5a–i were prepared according
to the reported procedure.[4]
˜
24.06, 21.63, 11.15; IR (neat): n=2960, 2929, 2875, 1704,
1648, 1461, 1402, 1292, 1168, 1116, 1076, 1051, 952 cmÀ1; EI-
MS: m/z (relative intensity)=166 (24) [M]+C, 151 (5), 138
(100), 132 (7), 120 (8), 110 (28), 95 (23), 81 (14), 79 (15), 67
(33); [a]rD:t:: +40.0 (c 1.0, CHCl3, 70% ee); HPLC (conditions
AD-H column, n-hexane/2-propanol=95/5, flow rate=
0.6 mLminÀ1): major enantiomer: tR =21.28 min; minor en-
antiomer: tR =19.88 min.
(S)-6-Propyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6d): colorless oil; 1H NMR (250 MHz, CDCl3): d=
4.07–4.00 (m, 2H), 2.55 (tdd, J=1.6, 6.2, 17.4 Hz, 1H), 2.32–
2.22 (m, 1H), 2.27 (t, J=6.2 Hz, 2H), 2.05 (ddd, J=1.7, 1.7,
17.4 Hz, 1H), 1.96–1.82 (m, 2H), 1.81–1.65 (m, 1H), 1.45–
1.14 (m, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (63 MHz,
CDCl3): d=203.06, 150.62, 144.08, 66.79, 43.37, 33.66, 32.86,
˜
24.09, 21.68, 20.34, 14.05; IR (neat): n=2956, 2934, 2874,
1758, 1451, 1382, 1183, 1144, 1065, 1033, 958, 938 cmÀ1; EI-
MS: m/z (relative intensity)=180 (6) [M]+C, 151 (5), 138
(100), 120 (5), 110 (24), 95 (12), 91 (7), 82 (8), 81 (8), 79 (8),
67 (15), 55 (13); [a]r:t:: +40.4 (c 1.0, CHCl3, 76% ee); HPLC
(conditions AD-H cDolumn, n-hexane/2-propanol=99/1, flow
rate=1 mLminÀ1): major enantiomer: tR =32.58 min; minor
enantiomer: tR =35.13 min.
General Pocedure for Nazarov Cclization
The substrate 5 was suspended in chloroform (0.1M) in a
screw-capped test-tube and allowed to stir at À108C for
10 min. The catalyst 2l (5 mol%) was added to the solution
and the reaction mixture was stirred at À108C for 20–96 h.
The reaction mixture was purified by column chromatogra-
phy on silica gel (ethyl acetate/hexane as eluent) to afford
the cyclopentenone 6.
(S)-6-Nonyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6a): colorless oil; 1H NMR (250 MHz, CDCl3): d=
4.07–4.00 (m, 2H), 2.54 (tdd, J=1.6, 6.2, 17.4 Hz, 1H), 2.32–
2.20 (m, 3H), 2.05 (ddd, J=1.6, 1.6, 17.4 Hz, 1H), 1.95–1.83
(m, 2H), 1.82–1.67 (m, 1H), 1.37–1.07 (m, 15H), 0.81 (t, J=
6.6 Hz, 3H); 13C NMR (63 MHz, CDCl3): d=203.07, 150.68,
144.06, 66.81, 43.63, 32.89, 31.93, 31.55, 29.65, 29.60, 29.54,
(S)-6-Hexyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6e): colorless oil; 1H NMR (250 MHz, CDCl3): d=
4.07–4.00 (m, 2H), 2.55 (tdd, J=1.6, 6.2, 17.4 Hz, 1H), 2.32–
2.19 (m, 1H), 2.27 (t, J=6.2 Hz, 2H), 2.05 (ddd, J=1.8, 1.8,
17.4 Hz, 1H), 1.94–1.83 (m, 2H), 1.83–1.67 (m, 1H), 1.38–
1.08 (m, 9H), 0.81 (t, J=6.7 Hz, 3H); 13C NMR (63 MHz,
CDCl3): d=203.06, 150.64, 144.07, 66.78, 43.59, 32.86, 31.70,
˜
31.51, 29.27, 27.05, 24.10, 22.61, 21.68, 14.07; IR (neat): n=
2929, 2857, 1758, 1454, 1376, 1174, 1068 cmÀ1; EI-MS: m/z
(relative intensity)=222 (6) [M]+C, 151 (21), 138 (100), 123
(4), 110 (16), 95 (8), 82 (5), 81 (5), 79 (6), 67 (3), 55 (11);
anal. calcd. for C14H22O2: C 75.63, H 9.97; found: C 75.78, H
10.07; [a]rD:t:: +33.9 (c 1.0, CHCl3, 78% ee); HPLC (condi-
tions: OD-H column, n-hexane/2-propanol=95/5, flow
rate=1 mLminÀ1): major enantiomer: tR =13.87 min; minor
enantiomer: tR =11.74 min.
˜
29.34, 27.14, 24.13, 22.72, 21.71, 14.16; IR (KBr): n=2956,
2918, 2851, 1698, 1649, 1463, 1399, 1289, 1169, 1112, 1068,
949, 722 cmÀ1; EI-MS: m/z (relative intensity)=264 (19)
[M]+C, 193 (4), 179 (14), 165 (85), 152 (100), 138 (14), 123
(11), 111 (30), 95 (13), 81 (12), 69 (14), 67 (14); anal. calcd.
for C17H28O2: C 77.22, H 10.67; found: C 76.96, H 10.57;
[a]rD:t:: +31.8 (c 1.0, CHCl3, 78% ee); HPLC (conditions OD-
H
column, n-hexane/2-propanol=95/5, flow rate=
1 mLminÀ1): major enantiomer: tR =12.90 min; minor enan-
tiomer: tR =10.53 min.
(S)-6-Benzyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6f): colorless oil; 1H NMR (250 MHz, CDCl3): d=
7.25–7.17 (m, 2H), 7.17–7.08 (m, 3H), 4.10–3.94 (m, 2H),
3.20 (dd, J=3.6, 13.4 Hz, 1H), 2.66–2.54 (m, 1H), 2.46 (dd,
J=10.6, 13.4 Hz, 1H), 2.39 (tdd, J=1.6, 6.0, 17.4 Hz, 1H),
2.21 (t, J=6.3 Hz, 2H), 2.10 (ddd, J=1.8, 1.8, 17.4 Hz, 1H),
1.91–1.79 (m, 2H); 13C NMR (63 MHz, CDCl3): d=201.91,
150.61, 144.70, 139.40, 128.91, 128.48, 126.36, 66.86, 44.91,
(S)-6-Methyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-
one (6b): colorless oil; 1H NMR (250 MHz, CDCl3): d=
4.07–4.00 (m, 2H), 2.63 (tdd, J=1.7, 6.2, 17.4 Hz, 1H), 2.39–
2.28 (m, 1H), 2.27 (t, J=6.2 Hz, 2H), 1.97 (ddd, J=1.8, 1.8,
17.4 Hz, 1H), 1.92–1.83 (m, 2H), 1.13 (d, J=7.5 Hz, 3H);
13C NMR (63 MHz, CDCl3): d=203.52, 150.23, 143.83,
˜
37.16, 32.09, 24.10, 21.63; IR (neat): n=3025, 2923, 1707,
˜
66.79, 38.04, 34.91, 24.08, 21.67, 16.55; IR (neat): n=2937,
2875, 1758, 1631, 1453, 1282, 1180, 1069, 1002, 936 cmÀ1; EI-
MS: m/z (relative intensity)=152 (100) [M]+C, 137 (39), 124
(30), 109 (23), 96 (35), 95 (34), 81 (29), 68 (47), 67 (54), 53
(32); [a]rD:t:: +12.7 (c 1.0, CHCl3, 70% ee); HPLC (conditions
OD-H column, n-hexane/2-propanol=98/2, flow rate=
1648, 1495, 1454, 1402, 1291, 1167, 1113, 1071, 955, 752,
701 cmÀ1; EI-MS: m/z (relative intensity)=228 (100) [M]+C,
211 (8), 199 (4), 184 (6), 172 (4), 156 (8), 151 (12), 137 (31),
128 (10), 115 (10), 109 (17), 91 (50), 77 (8), 65 (13); anal.
calcd. for C15H16O2: C 78.92, H 7.06; found: C 78.78, H 6.97;
82
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A Catalytic Asymmetric Electrocyclization-Protonation Reaction
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[a]rD:t:: +68.4 (c 1.0 in CHCl3, 71% ee); HPLC (conditions
OD-H column, n-hexane/2-propanol=95/5, flow rate=
1 mLminÀ1): major enantiomer: tR =29.76 min; minor enan-
tiomer: tR =26.62 min.
Acknowledgements
We gratefully acknowledge Evonik Degussa GmbH as well
as the DFG (Priority Programme Organocatalysis) for finan-
cial support.
(S)-6-(4-Chlorobenzyl)-3,4,5,6-tetrahydrocyclopenta[b]-
1
pyran-7(2H)-one (6g): pale yellow oil; H NMR (300 MHz,
CDCl3): d=7.19–7.13 (m, 2H), 7.08–7.02 (m, 2H), 4.08–3.94
(m, 2H), 3.11 (dd, J=2.8, 12.6 Hz, 1H), 2.61–2.53 (m, 1H),
2.50 (dd, J=10.0, 12.6 Hz, 1H), 2.40 (tdd, J=1.7, 6.0,
17.5 Hz, 1H), 2.21 (t, J=6.2 Hz, 2H), 2.05 (ddd, J=1.8, 1.8,
17.5 Hz, 1H), 1.90–1.79 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=200.41, 149.66, 143.57, 136.73, 131.17, 129.27,
References
[1] I. N. Nazarov, I. I. Zaretskaya, Izv. Akad. Nauk SSSR,
Ser. Khim. 1941, 211.
[2] Reviews on the Nazarov cyclization: a) K. L. Haber-
mas, S. E. Denmark, T. K. Jones, Org. React. 1994, 45,
1–158; b) S. E. Denmark, in: Comprehensive Organic
Synthesis Vol. 5, (Eds.: B. M. Trost, I. Flemming), Per-
gamon, Oxford, 1991, p 51; c) A. J. Frontier, C. Colli-
son, Tetrahedron 2005, 61, 7577; d) H. Pellissier, Tetra-
hedron 2005, 61, 6479; e) M. A. Tius, Eur. J. Org.
Chem. 2005, 2193.
[3] Metal-catalyzed enantioselective Nazarov reactions:
a) G. Liang, S. N. Gradl, D. Trauner, Org. Lett. 2003, 5,
4931; b) V. K. Aggarwal, A. J. Belfield, Org. Lett. 2003,
5, 5075; c) I. Walz, A. Togni, Chem. Commun. 2008,
4315; for enantioselective tandem Nazarov-flurorina-
tion reaction, see: d) J. Nie, H.-W. Zhu, H.-F. Cui, M.-
Q. Hua, J.-A. Ma, Org. Lett. 2007, 9, 3053; e) H.-F. Cui,
K.-Y. Dong, G.-W. Zhang, L. Wang, J.-A. Ma, Chem.
Commun. 2007, 2284; for tandem Nazarov cyclization-
Michael addition, see: f) M. Janka, W. He, I. E. Hae-
dicke, F. R. Fronczek, A. J. Frontier, R. Eisenberg, J.
Am. Chem. Soc. 2006, 128, 5312.
[4] For the leading work on the enantioselective electro-
cyclization-protonation, see: G. Liang, D. Trauner, J.
Am. Chem. Soc. 2004, 126, 9544.
[5] The first enantioselective Brønsted acid-catalyzed Naz-
arov cyclization using chiral N-triflylphosphoramides:
M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J.
Nachtsheim, Angew. Chem. 2007, 119, 2143; Angew.
Chem. Int. Ed. 2007, 46, 2097.
[6] a) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal.
2006, 348, 999; b) T. Akiyama, Chem. Rev. 2007, 107,
5744; applications: c) T. Akiyama, J. Itoh, K. Yokota,
K. Fuchibe, Angew. Chem. 2004, 116, 1592; Angew.
Chem. Int. Ed. 2004, 43, 1566; d) D. Uraguchi, M.
Terada, J. Am. Chem. Soc. 2004, 126, 5356; e) S. Hof-
mann, A. M. Seayad, B. List, Angew. Chem. 2005, 117,
7590; Angew. Chem. Int. Ed. 2005, 44, 7424; f) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J.
Am. Chem. Soc. 2006, 128, 84; g) M. Terada, K. Sori-
machi, D. Uraguchi, Synlett 2006, 133; h) M. Terada, K.
Machioka, K. Sorimachi, Angew. Chem. 2006, 118,
2312; Angew. Chem. Int. Ed. 2006, 45, 2254; i) S.
Mayer, B. List, Angew. Chem. 2006, 118, 4299; Angew.
Chem. Int. Ed. 2006, 45, 4193; j) J. Itoh, K. Fuchibe, T.
Akiyama, Angew. Chem. 2006, 118, 4914; Angew.
Chem. Int. Ed. 2006, 45, 4796; k) S. Hoffmann, M. Nic-
oletti, B. List, J. Am. Chem. Soc. 2006, 128, 13074;
l) N. J. A. Martin, B. List, J. Am. Chem. Soc. 2006, 128,
13368; m) T. Akiyama, H. Morita, K. Fuchibe, J. Am.
Chem. Soc. 2006, 128, 13070; n) X.-H. Chen, X.-Y. Xu,
H. Liu, L.-F. Cun, L.-Z. Gong, J. Am. Chem. Soc. 2006,
128, 14802; o) H. Liu, L.-F. Cun, A. Q. Mi, Y. Z. Jiang,
˜
127.56, 65.84, 43.61, 35.32, 30.88, 23.06, 20.59; IR (KBr): n=
2926, 1704, 1645, 1491, 1406, 1291, 1166, 1091, 1069, 1013,
952, 805 cmÀ1; EI-MS: m/z (relative intensity)=264 (33)
[M]+C (C15H1537ClO2), 262 (100) [M]+C (C15H1535ClO2), 245
(9), 233 (4), 218 (6), 199 (4), 190 (7), 181 (5), 165 (5), 151
(17), 137 (48), 125 (52), 115 (18), 109 (30), 91 (13), 89 (17),
79 (13), 77 (12); anal. calcd. for C15H15ClO2: C 68.57, H
5.75; found: C 68.69, H 5.96; [a]r:t:: +51.2 (c 1.0, CHCl3,
67% ee); HPLC (conditions ODD-H column, n-hexane/2-
propanol=90/10, flow rate=1 mLminÀ1): major enantio-
mer: tR =21.88 min; minor enantiomer: tR =18.29 min.
(S)-6-(4-Methoxybenzyl)-3,4,5,6-tetrahydrocyclopenta[b]-
pyran-7(2H)-one (6h): colorless oil; 1H NMR (250 MHz,
CDCl3): d=7.04 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H),
4.10–3.93 (m, 2H), 3.71 (s, 3H), 3.11 (dd, J=3.5, 13.4 Hz,
1H), 2.62–2.51 (m, 1H), 2.44 (dd, J=10.2, 13.4 Hz, 1H),
2.38 (dd, J=6.1, 17.5 Hz, 1H), 2.21 (t, J=6.2 Hz, 2H), 2.09
(dd, J=1.7, 17.5 Hz, 1H), 1.91–1.79 (m, 2H); 13C NMR
(63 MHz, CDCl3): d=202.03, 158.14, 150.61, 144.69, 131.29,
129.85, 113.84, 66.82, 55.27, 45.06, 36.20, 31.96, 24.07, 21.61;
˜
IR (KBr): n=2992, 2963, 2931, 2873, 2834, 1698, 1644, 1612,
1512, 1440, 1401, 1289, 1246, 1166, 1113, 1057, 1030, 948,
816 cmÀ1; EI-MS: m/z (relative intensity)=258 (46) [M]+·C,
207 (11), 150 (4), 121 (100), 115 (4), 108 (7), 91 (10), 77
(11); anal. calcd. for C16H18O3: C 74.39, H 7.02; found: C
74.14, H 6.99; [a]rD:t:: +61.5 (c 1.0, CHCl3, 71% ee); HPLC
(condition: OD-H column, n-hexane/2-propanol=90/10,
flow rate=0.6 mLminÀ1): major enantiomer: tR =38.22 min;
minor enantiomer: tR =34.48 min.
(S)-6-(3,4-Dimethoxybenzyl)-3,4,5,6-tetrahydrocyclopen-
ta[b]pyran-7(2H)-one (6i): white solid (mp. 106–1098C);
1H NMR (250 MHz, CDCl3): d=6.74–6.61 (m, 3H), 4.10–
3.94 (m, 2H), 3.79 (s, 6H), 3.10 (dd, J=3.2, 13.0 Hz, 1H),
2.64–2.54 (m, 1H), 2.48 (dd, J=9.8, 13.0 Hz, 1H), 2.40 (dd,
J=6.0, 17.5 Hz, 1H), 2.21 (t, J=6.0 Hz, 2H), 2.10 (dd, J=
1.7, 17.5 Hz, 1H), 1.92–1.80 (m, 2H); 13C NMR (63 MHz,
CDCl3): d=202.05, 150.65, 148.85, 147.56, 144.78, 131.81,
120.87, 112.10, 111.10, 66.82, 55.91, 55.88, 45.05, 36.70, 31.97,
˜
24.08, 21.60; IR (neat): n=2917, 2838, 1697, 1643, 1517,
1455, 1417, 1261, 1158, 1141, 1113, 1070, 1025, 948, 883, 802,
734 cmÀ1; EI-MS: m/z (relative intensity)=288 (37) [M]+C,
151 (100), 138 (5), 107 (8), 91 (6), 77 (5); anal. calcd. for
C17H20O4: C 70.81, H 6.99; found: C 70.69, H 7.26; [a]rD:t::
+46.3 (c 1.0, CHCl3, 67% ee); HPLC (conditions AS-H
column,
n-hexane/2-propanol=80/20,
flow
rate=
0.6 mLminÀ1): major enantiomer: tR =51.54 min; minor en-
antiomer: tR =58.33 min.
Adv. Synth. Catal. 2009, 351, 78 – 84
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asc.wiley-vch.de
83

Magnus Rueping and Winai Ieawsuwan
COMMUNICATIONS
L.-Z. Gong, Org. Lett. 2006, 8, 6023; p) M. Terada, K.
Sorimachi, J. Am. Chem. Soc. 2007, 129, 292; q) Q.
Kang, Z.-A. Zhao, S.-L. You, J. Am. Chem. Soc. 2007,
129, 1484; r) G. Li, Y. Liang, J. C. Antilla, J. Am.
Chem. Soc. 2007, 129, 5830; s) J. Zhou, B. List, J. Am.
Chem. Soc. 2007, 129, 7498; t) M. Terada, K. Machioka,
K. Sorimachi, J. Am. Chem. Soc. 2007, 129, 10336;
u) E. B. Rowland, G. B. Rowland, E. Rivera-Otero,
J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 12084;
v) M. J. Wanner, R. N. S. v. d. Haas, K. R. d. Cuba,
J. H. v. Maarseveen, H. Hiemstra, Angew. Chem. 2007,
119, 7629; Angew. Chem. Int. Ed. 2007, 46, 7485; w) J.
Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z. Gong, Angew.
Chem. 2008, 120, 2492; Angew. Chem. Int. Ed. 2008, 47,
2458; x) S. Xu, Z. Wang, X. Zhang, X. Zhang, K. Ding,
Angew. Chem. 2008, 120, 2882; Angew. Chem. Int. Ed.
2008, 47, 2840; y) M. Sickert, C. Schneider, Angew.
Chem. 2008, 120, 3687; Angew. Chem. Int. Ed. 2008, 47,
3631; z) D. S. Giera, M. Sickert, C. Schneider, Org.
Lett. 2008, 10, 4259.
[8] a) M. Rueping, B. Nachtsheim, S. A. Moreth, M. Bolte,
Angew. Chem. 2008, 120, 603; Angew. Chem. Int. Ed.
2008, 47, 593; b) M. Rueping, T. Theissmann, A. Kuen-
kel, R. M. Koenigs, Angew. Chem. 2008, 120, 6903;
Angew. Chem. Int. Ed. 2008, 47, 6798.
[9] First synthesis and application of chiral triflylphosphor-
amides: a) D. Nakashima, H. Yamamoto, J. Am. Chem.
Soc. 2006, 128, 9626; b) P. Jiao, D. Nakashima, H. Ya-
mamoto, Angew. Chem. 2008, 120, 2445; Angew. Chem.
Int. Ed. 2008, 47, 2411; c) D. Enders, A. A. Narine, F.
Toulgoat, T. Bisschops, Angew. Chem. 2008, 120, 5744;
Angew. Chem. Int. Ed. 2008, 47, 5661.
[10] For Brønsted acid-catalyzed enantioselective protona-
tions: a) M. Rueping, T. Theissmann, S. Raja, J. W.
Bats, Adv. Synth. Catal. 2008, 350, 1001; b) C. H.
Choen, H. Yamamoto, J. Am. Chem. Soc. 2008, 130,
9246.
[11] For reviews on enantioselective protonations, see a) L.
Duhamel, P. Duhamel, J. C. Plaquevent, Tetrahedron:
Asymmetry 2004, 15, 3653; b) C. Fehr, Angew. Chem.
1996, 108, 2726; Angew. Chem. Int. Ed. Engl. 1996, 35,
2566; c) A. Yanagisawa, H. Yamamoto, in: Comprehen-
sive Asymmetric Catalysis, (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, Vol.
3, pp 1295; d) J. Eames, N. Weerasooriya, J. Chem. Res.
Synop. 2001, 2.
[12] Examples for the tautomerization of enols, see: a) O.
Piva, J.-P. Pete, Tetrahedron Lett. 1990, 31, 5157; b) O.
Piva, R. Mortezaei, F. Henin, J. Muzart, J.-P. Pete, J.
Am. Chem. Soc. 1990, 112, 9263; c) C. Fehr, Angew.
Chem. 2007, 119, 7249; Angew. Chem. Int. Ed. 2007, 46,
7119; for the protonation of lithium enolates with or-
ganic acids, see d) C. Fehr, J. Galindo, Angew. Chem.
1994, 106, 1967; Angew. Chem. Int. Ed. Engl. 1994, 33,
1888; e) A. Yanagisawa, T. Kikuchi, T. Watanabe, T.
Kuribayashi, H. Yamamoto, Synlett 1995, 372; f) E.
Vedejs, A. W. Kruger, J. Org. Chem. 1998, 63, 2792;
g) K. Nishimura, M. Ono, Y. Nagaoka, K. Tomioka,
Angew. Chem. 2001, 113, 454; Angew. Chem. Int. Ed.
2001, 40, 440; for the protonation of silyl enolates, see:
h) K. Ishihara, M. Kaneeda, H. Yamamoto, J. Am.
Chem. Soc. 1994, 116, 11179; i) K. Ishihara, S. Naka-
mura, M. Kaneeda, H. Yamamoto, J. Am. Chem. Soc.
1996, 118, 12854; j) C. Fehr, J. Galindo, I. Farris, A.
Cuenca, Helv. Chim. Acta 2004, 87, 1734; k) A. Yanagi-
sawa, T. Touge, T. Arai, Angew. Chem. 2005, 117, 1570;
Angew. Chem. Int. Ed. 2005, 44, 1546; l) T. Poisson, V.
Dalla, F. Marsais, G. Dupas, S. Oudeyer, V. Levacher,
Angew. Chem. 2007, 119, 7220; Angew. Chem. Int. Ed.
2007, 46, 7090.
[7] Selected examples on asymmetric chiral counter-ion
catalysis employing BINOL phosphoric acids from our
laboratory: a) M. Rueping, C. Azap, E. Sugiono, T.
Theissmann, Synlett 2005, 2367; b) M. Rueping, E. Su-
giono, C. Azap, T. Theissmann, M. Bolte, Org. Lett.
2005, 7, 3781; c) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. 2006, 118, 6903; Angew.
Chem. Int. Ed. 2006, 45, 6751; d) M. Rueping, A. P. An-
tonchick, Angew. Chem. 2007, 119, 4646; Angew.
Chem. Int. Ed. 2007, 46, 4562; e) M. Rueping, T.
Theissmann, A. P. Antonchick, Synlett 2006, 1071; f) M.
Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. 2006, 118, 3765; Angew. Chem. Int. Ed. 2006, 45,
3683; g) M. Rueping, E. Sugiono, C. Azap, Angew.
Chem. 2006, 118, 2679; Angew. Chem. Int. Ed. 2006, 45,
2617; h) M. Rueping, C. Azap, Angew. Chem. 2006,
118, 7996; Angew. Chem. Int. Ed. 2006, 45, 7832; i) M.
Rueping, E. Sugiono, T. Theissmann, A. Kuenkel, A.
Kçckritz, A. Pews-Davtyan, N. Nemati, M. Beller, Org.
Lett. 2007, 9, 1065; j) M. Rueping, E. Sugiono, F. R.
Schoepke, Synlett 2007, 1441; k) M. Rueping, E. Sugio-
no, S. A. Moreth, Adv. Synth. Catal. 2007, 349, 759;
l) M. Rueping, A. P. Antonchick, Org. Lett. 2008, 10,
1731; m) M. Rueping, A. P. Antonchick, Angew. Chem.
2008, 120, 5920; Angew. Chem. Int. Ed. 2008, 47, 5836;
n) M. Rueping, A. P. Antonchick, Angew. Chem. 2008,
120, 10244; Angew. Chem. Int. Ed. 2008, 47, 10090;
o) for an example of a chiral counter ion strategy in
asymmetric transition metal catalysis with silver cations
and chiral phosphoric acid catalysts: M. Rueping, A. P.
Antonchick, C. Brinkmann, Angew. Chem. 2007, 119,
7027; Angew. Chem. Int. Ed. 2007, 46, 6903.
[13] The absolute configuration of the products was as-
signed as (S) by comparison with literature data.[4]
84
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Adv. Synth. Catal. 2009, 351, 78 – 84