An alternative chiral synthesis of Wieland-Miescher ketone mediated by (S)-2-(pyrrolidinylmethyl)pyrro-lidine: Remarkable effects of Br?nsted acid

Article abstract of DOI:10.3987/com-07-s(w)44

The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by (S)-2-(pyrrolidinylmethyl)pyrrolidine to prepare Wieland-Miescher ketone was examined in detail. A remarkable inversion of enantioselectivity was observed when a Br?nsted acid was used as a co-catalyst. Development of the reaction to Robinson annulation was successfully achieved by the use of (S)-2-(pyrrolidinylmethyl)pyrrolidine as a Br?nsted base, followed by trifluoroacetic acid as a Br?nsted acid.

Full text of DOI:10.3987/com-07-s(w)44

HETEROCYCLES, Vol. 74, 2007
637
HETEROCYCLES, Vol. 74, 2007, pp. 637 - 648. © The Japan Institute of Heterocyclic Chemistry
Received, 27th August, 2007, Accepted, 3rd October, 2007, Published online, 4th October, 2007. COM-07-S(W)44
AN ALTERNATIVE CHIRAL SYNTHESIS OF WIELAND-MIESCHER
KETONE MEDIATED BY (S)-2-(PYRROLIDINYLMETHYL)PYRRO-
LIDINE: REMARKABLE EFFECTS OF BRØNSTED ACID
Yuichi Akahane, Naoko Inage, Takashi Nagamine, Kohei Inomata,* and
Yasuyuki Endo
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai
981-8558, Japan, E-mail: inomata@tohoku-pharm.ac.jp
This paper is dedicated to Professor Ekkehard Winterfeldt on the occasion of his
75th birthday.
Abstract – The enantioselectivity of the intramolecular asymmetric aldol
reaction mediated by (S)-2-(pyrrolidinylmethyl)pyrrolidine to prepare Wieland-
Miescher ketone was examined in detail. A remarkable inversion of
enantioselectivity was observed when a Brønsted acid was used as a co-catalyst.
Development of the reaction to Robinson annulation was successfully achieved
by the use of (S)-2-(pyrrolidinylmethyl)pyrrolidine as a Brønsted base, followed
by trifluoroacetic acid as a Brønsted acid.
Wieland-Miescher ketone (3a), which was prepared by L-proline (L-Pro)-mediated asymmetric
intramolecular aldol reaction of the trione (1a), has been a very useful synthon in total syntheses of a
variety of natural products.1,2 This asymmetric aldol reaction has become known as the
Hajos-Parrish-Eder-Sauer-Wiechert (HPESW) reaction,3,4 and has been widely recognized to involve an
enamine-based mechanism.5,6 In the optimized procedure, HPESW reaction of 1a mediated by L-Pro
afforded (S)-3a in the order of 70% ee.3g Fractional crystallization was required to obtain the optically
pure material. Uda and Hagiwara successfully extended the reaction of 1b by using L-phenylalanine
(L-Phe, 4) as a mediator in the presence of camphorsulfonic acid (CSA) to construct a Wieland-Miescher
ketone analog [(S)-3b] bearing a methyl substituent at C-1 in 83% yield with 80% ee (Scheme 1).7
Recently, Barbas reported L-Pro-mediated asymmetric Robinson annulation between
2-methylcyclohexane-1,3-dione (5) and methyl vinyl ketone (MVK, 6) to afford (S)-3a in 47% yield
accompanied with 76% ee (Scheme 1).8 It has been shown that this synthesis, comprising three reactions
(Michael addition, aldol reaction and dehydration) can be performed as a one-pot synthesis.

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HETEROCYCLES, Vol. 74, 2007
Notwithstanding the variety of substituents, those reactions mediated by L-amino acids afforded products
3 whose absolute configuration at C-4a was invariably S.9 The results suggested us that the use of
unnatural D-amino acid as a reaction mediator would be required, when the preparation of an antipode
(R)-3 would be needed. Therefore, developments of new and alternative routes to provide 3 have been
still required.4
for R = H
1)
O
O
O
CO2H
N
R
H 2
(S)-3a: R = H
(S)-3b: R = Me
4a
2) H+
O
O
1
1a: R = H
1b: R = Me
R
for R = Me
NH2
CSA
CO2H
4
O
O
2 (30 mol%)
(S)-3a
DMSO
rt
O
5
6
89 h
Scheme 1
Recently, we have reported the L-methionine (8, L-Met)- or L-Phe-mediated asymmetric intramolecular
aldol reaction of the trione (7) to prepare a new bicyclic enedione [(R)-9] containing a 7-membered ring.10
During this research, we found that L-Met decomposed to generate a corresponding achiral amine (10) by
through decarboxylation reaction.11 This result means that an amino acid is not always a suitable mediator
for the HPESW reaction (Scheme 2).
NH2
O
O
MeS
CO2H
O
8
NH2
(+)-CSA
+
MeS
DMSO
O
O
7
9
(R)-
10
(99% yield)
(up to 60% ee)
Scheme 2

HETEROCYCLES, Vol. 74, 2007
639
On the other hand, in the area of organocatalysis,12 (S)-2-(pyrrolidinylmethyl)pyrrolidine (11) has been
employed as a new catalyst to achieve highly efficient asymmetric reactions, including intra- and
intermolecular aldol reaction.13 Amine-Brønsted acid catalysis has also been utilized in asymmetric
Diels-Alder reaction and 1,4-addition reaction to construct new chiral centers.14,15 In those reports, an
ammonium moiety produced from amine and Brønsted acid plays a key role in stabilizing the transition
state as a result of hydrogen bonding between catalyst and substrate. However, to our knowledge, there
have been few attempts to use amine catalysts in the HPESW reaction.4f-k Barbas et al reported that
Robinson annulation of 5 and 6 in the presence of a catalytic amount of 11 afforded a trace amount of 3a.8
They noted that the diamine (11) mediated both the Michael addition step of 5 to afford 1a and the aldol
process of 1a to afford β-hydroxyketone (12), but the final dehydration step to afford 3a hardly proceeded
(Scheme 3). However, they did not give details of the absolute configuration or yield of the aldol products
(12) and (3a). Hayashi and co-workers have reported asymmetric intramolecular aldol reactions mediated
by 11 to construct new 6-6 fused bicycles.16 Inspired by that work, we considered that a diamine catalyst
such as 11 would require a hydrogen bonding site to fix the transition state of the aldol reaction and that
the addition of a Brønsted acid would promote both the aldol and the dehydration step. We wish to report
here an alternative chiral synthesis of Wieland-Miescher ketone (3a) using a combination of
(S)-2-(pyrrolidinylmethyl)pyrrolidine (11) and Brønsted acid, and also to report a remarkable inversion of
enantioselectivity due to addition of Brønsted acid.17
N
O
N
11
H
(30 mol%)
3a
5
6
DMSO
rt
O
(trace amount)
OH
12
Scheme 3
We first examined the effects of Brønsted acid on the aldol reaction of the trione (1a) mediated by
diamine (11). All of the reactions were carried out under the same conditions in the presence of a
stoichiometric amount of 11 with 1.0 or 1.5 equiv. of Brønsted acid in DMSO at rt. The results are
compiled in Table 1. First of all, the aldol reaction mediated by 11 without Brønsted acid afforded (S)-3a
in 55% yield with 19% ee (entry 1). The reaction in the presence of acetic acid (AcOH) as a Brønsted acid
showed a shorter reaction time, with a slightly improved yield and better enantioselectivity for (S)-3a
(entry 2). As indicated in Table 1, since the pKa value of AcOH in DMSO is higher than that in H2O, the
expected protonation on the diamine (11) to produce a corresponding ammonium salt might not occur
under the reaction conditions employed.18,19 Interestingly, the aldol reaction using PPTS, which has a

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HETEROCYCLES, Vol. 74, 2007
lower pKa value in DMSO than that of AcOH, afforded (R)-3a in 64% yield with 70% ee. The same
tendency was observed with other organic acids, such as dichloroacetic acid (DCA), (－)-CSA and
p-toluenesulfonic acid (p-TsOH), having lower pKa values in H2O than that of AcOH (entries 4-8). The
reactions shown in entries 4-8 afforded (R)-3a in 64-81% yield with 54-70% ee. The aldol reactions in the
presence of sulfonic acids made the reaction time shorter than in the case of using AcOH. With a stronger
acid than p-TsOH, such as TFA or trifluormethanesulfonic acid (TfOH), the reactions required longer
times to reach completion and afforded (R)-3a in moderate yield with higher ee than that obtained with
sulfonic acids (entries 9-12). These results suggested to us that 1) the combination of diamine (11) and a
stronger Brønsted acid than AcOH inverted the enantioselectivity compared with the reaction using 11
only or the combination of 11 and AcOH, 2) protonation on the diamine (11) to produce the
corresponding ammonium salt was very important for achieving higher ee. Optically pure material of
(R)-3a could be obtained after recrystallization of the product in entry 10. Since the highest ee value was
observed in entry 10, 1.5 equiv. of TFA was selected as an additive for further optimization.
Table 1
11
(1.0 equiv.)
additive
1a
3a
(R)- or (S)-
DMSO
rt
Additive
(equiv.)
Time Yieldc
Eed
(%)
19
Absolute
Entry
pKaa,b
(h)
27
(%)
55
Configuration
1
2
3
4
-
-
S
S
AcOH (1.5)
PPTS (1.5)
DCAe (1.5)
4.76 (12.3)
5.21 (3.4)
1.29
9
4
68
64
81
25
70
70
R
R
12
5
6
(-)-CSA (1.0)
(-)-CSA (1.5)
p-TsOH (1.0)
p-TsOH (1.5)
TFA (1.0)
4
4
68
74
70
75
60
53
58
65
72
54
70
65
77
81
75
80
R
R
R
R
R
R
R
R
−2.6 f (1.6)f
7
8
−1.34
8
4
9
16
48
8
−0.25
10
11
12
TFA (1.5)
TfOH (1.0)
TfOH (1.5)
−14 (0.3)
20
a pKa values of additives measured in H2O.18
b pKa values measured in DMSO are shown in parentheses.19
c Isolated yield.
d Determined by HPLC equipped with a chiral stationary phase column.
e Dichloroacetic acid.
f pKa values of methanesulfonic acid instead of CSA.

HETEROCYCLES, Vol. 74, 2007
641
We next examined the solvent effects in the aldol reaction of 1a. Thus, all of the reactions were carried
out with a stoichiometric amount of diamine (11) in the presence of 1.5 equiv. of TFA in several solvents.
The results are compiled in Table 2. Non-protic polar solvents such as DMF and acetonitrile exhibited the
same tendency as the reaction in DMSO, and afforded (R)-3a in moderate yield with 73-77% ee (entries 2
and 3). Although benzene, a non-polar solvent, also afforded (R)-3a in relatively higher yield than other
solvents, the ee value was only 35% ee.
Table 2
11
(1.0 equiv.)
TFA (1.5 equiv.)
3a
(R)-
1a
solvent
rt
Time Yielda
(h) (%)
48 53
Eeb
(%)
Entry
Solvent
1
2
3
4
DMSO
DMF
81
43
43
47
56
54
75
73
77
35
MeCN
benzene
a Isolated yield.
b Determined by HPLC with a chiral
stationary phase.
Finally, we tried to extend the reaction to Robinson annulation. All of the reactions were carried out under
same conditions utilizing a stoichiometric amount of 11 with or without TFA in several solvents at rt. The
results are summarized in Table 3. The reaction without TFA proceeded to afford (S)-3a in 26% yield
with 20% ee (entry 1). This result means that the diamine (11) mediated Robinson annulation to afford
the antipode of 3a, and that we needed to avoid the competing reactions to obtain (R)- or (S)-3a with and
without Brønsted acid, respectively. However, in preliminary experiments, Robinson annulation did not
proceed when TFA was added at the beginning of the reaction, because the addition of TFA suppressed
the first Michael addition of 5 to MVK (6) in Robinson annulation. Monitoring the reaction in entry 1 by
the use of TLC indicated that a lot of Michael adduct (1a) and only a trace amount of (S)-3a were
observed after 1 h. This result means that 11 acts as a Brønsted base for the first Michael addition step.
Based on this result, we decided to add TFA at 1 h after addition of diamine 11. Although Robinson
annulation of 5 in DMSO required a longer reaction time than the aldol reaction of 1a (entry 9 in Table 1),
(R)-3a was obtained in 47% yield with 75% ee (entry 2 in Table 3). The absolute configuration of the
product (3a) in entry 2 was assigned as R by comparison with the optical rotation of (R)-3a reported
previously.4f Specifically, the optical rotation of product (R)-3a in entry 2 was [α]D –72.2 (benzene, 75%
ee), lit.,4f [α]D -100 (benzene, 100% ee). Almost the same results, except for reaction time, were obtained

642
HETEROCYCLES, Vol. 74, 2007
in DMF and CH3CN (entries 3 and 4 in Table 3) when compared with the results in Table 2 (entries 2 and
3 in Table 2). Other non-protic polar solvents such as THF, dioxane and CH2Cl2 were not suitable
solvents for the Robinson annulation, because lower ee of (R)-3a was observed (entries 5-7). The
reactions both in a non-polar solvent (benzene or toluene) and in a protic polar solvent (MeOH) failed to
achieve high ee of (R)-3a (entries 8-10). As in Barbas’s report, the Robinson annulation of 5 mediated by
L-Pro afforded (S)-3a in 49% yield with 76% ee (entry 11).8 Therefore, we could achieve to develop an
alternative route to provide the antipode (R)-3a without using unnatural D-Pro (entry 1).
Table 3
6
(2.0 eqiv.)
11
(1.0 equiv.)
3a
(R)- or (S)-
5
1a
after 1h
TFA (1.5 equiv.)
solvent
rt
Time Yielda
Eeb
(%)
Absolute
Entry
Solvent
(h)
144
(%)
26
Configuration
1c
2
DMSO
DMSO
DMF
20
S
R
R
R
R
R
R
R
R
R
S
80
90
47
50
56
62
60
69
72
70
40
49
75
67
66
28
43
5
3
4
MeCN
THF
80
5
120
120
130
105
105
72
6
dioxane
CH2Cl2
benzene
toluene
MeOH
7
8
34
33
40
76
9
10
11d, e DMSO
a Isolated yield.
89
b Determined by HPLC equipped with a chiral stationary phase.
c TFA was not added.
d
L-Pro was used instead of 11 and TFA was not added.
e The result was previously reported in ref. 8.
In the aldol reaction of 1a to afford a 6-6 fused bicycle, there exists the possibility of producing four
stereoisomers as a result of two newly generated stereogenic centers. Since we could not isolate the
initially formed β-hydroxy ketones under the conditions using 11 and TFA, dehydration to afford 3a must
occur rapidly. The transition states predicted for all of the stereoisomers are shown in Figure 1. In the
presence of Brønsted acid, the pyrroridinylmethyl moiety in 11 would be protonated to generate a
corresponding ammonium salt. We think that this hydrogen in the ammonium salt could hydrogen-bond

HETEROCYCLES, Vol. 74, 2007
643
to the β-oxygen atom originated from ketone functionality and a nitrogen atom in the enamine moiety to
stabilize the transition state. Among these hydrogen-bonding models, two of the syn (syn, anti:
conformation between olefinic and pyrroridinylmethyl moieties) transition states (16) and (20) are
considered to be slightly higher in energy because of relatively unstable chair-boat conformations in the
6,6-fused-bicycle, resembling bicyclo[3.3.1]nonane, while the anti transition states (13) and (17) have
chair-chair conformations. Kwon et al. reported that a chair-chair conformation in bicyclo[3.3.1]nonane is
more stable than a chair-boat conformation.20,21 They also showed that the free energy difference between
those two conformers in bicyclo[3.3.1]nonane is 2.3-2.5 kcal/mol by means of ab initio and density
functional theory (DFT) calculations. Thus, the aldol reaction should proceed through anti transition
states, (13) and/or (17). In comparison with the trans-anti (cis, trans: cis- or trans-fused carbocycles)
transition state (13) and the cis-anti one (17), 17 appears to be disfavored because of steric repulsion
between a methyl substituent and a pyrrolidine ring. Consequently, the trans-anti transition state (13)
should be most favored, affording the 4aR, 8aS aldol product (14), which would give rise to (R)-3a after
dehydration (Figure 1).
with H+
3a
(R)-
- H2O
O
- H2O
O
N
N
N
H
H
N
4
O
O
O
4a
8a
chair-boat
2
chair-chair
O
O
O
OH
OH
14
15
(4aR, 8aS)-
(4aR, 8aR)-
cis-syn: 16
trans-anti: 13
(most favor)
N
N
O
O
N
H
H
N
O
O
O
O
O
O
OH
OH
19
18
(4aS, 8aS)-
(4aS, 8aR)-
cis-anti: 17
trans-syn: 20
- H2O
- H2O
3a
(S)-
Figure 1
When no Brønsted acid was used, inversion of enantioselectivity was noted with lower ee (Table 1, entry
1). This result indicates that the reaction without an acid could not generate hydrogen bonds and the

644
HETEROCYCLES, Vol. 74, 2007
pyrrolidinylmethyl moiety would be oriented away from the C-C bond forming site. The two favorable
anti-transition states (21) and (22) might have very similar potential energy (Figure 2). In the
non-hydrogen bonding model, there is also the possibility that the aldol reaction proceeds through
syn-type transition states (23) and (24). To date, we have no evidence to suggest which transition state is
more stable, syn or anti. However, the transition states (22) and/or (24) which lead to (S)-3a might be
slightly more favored than the other two, (21) and (23) which lead to (R)-3a. Further investigations into
the effects of Brønsted acid, and calculations of the energy differences of our proposed transition states
are under way.
without H+
N
N
N
N
O
O
O
O
trans-anti: 21
cis-anti: 22
3a
(S)-
3a
(R)-
N
N
N
O
N
O
O
O
trans-syn: 24
cis-syn: 23
Figure 2
In conclusion, we have established an alternative chiral route to provide (R)-3a by using the combination
of (S)-2-(pyrrolidinylmethyl)pyrrolidine and TFA. In the reaction, a remarkable inversion of
enantioselectivity with or without a Brønsted acid was observed. Furthermore, development of the
reaction to Robinson annulation has been succeeded. Under the optimized condition, (R)-3a was obtained
almost same result, except for the enantioselectivity, as the reaction mediated by L-Pro.8 These results
may enable the creation of diverse and efficient organocatalysts for a wide variety of reactions. Further
work on a detail of the reaction mechanism and a development of more efficient mediator for the
reactions is currently in progress.
EXPERIMENTAL
1
Melting points are uncorrected. IR spectra were recorded on a JASCO FT−IR 5000 spectrometer. H

HETEROCYCLES, Vol. 74, 2007
645
NMR spectra and 13C NMR spectra were recorded on a JEOL AX−400 (1H 400 MHz, 13C 100 MHz)
spectrometer and calibrated using trimethysilane as the internal standard. Mass spectra were recorded on a
JEOL DX−303 or a JEOL JMS-MS700 spectrometer. Elemental analysis was done with a Perkin Elmer
CHN-2400 II. Enantiomeric excesses were determined with a Waters HPLC 600 instrument equipped
with a chiral stationary phase column. Optical rotations were measured with a JASCO DIP−370 digital
polarimeter.
Typical procedure of intramolecular aldol reaction of 1a
To a stirred solution of the trione (1a) (147 mg, 0.75 mmol) in DMSO (1.5 mL) was added the amine (11)
(121 μL, 0.75 mmol) and (TFA 86 μL, 1.1 mmol) at rt. The reaction mixture was stirred at rt for 48 h,
then diluted with ethyl acetate (AcOEt), washed with saturated aqueous NaHCO3 and brine, and dried
(MgSO4). The solvent was removed under reduced pressure. The crude product was chromatographed on
silica gel (AcOEt/CH2Cl2/hexane = 1/1/4) to afford (R)-3a 70 mg (53%) as a pale yellow oil. The optical
purity was determined to be 75% ee by HPLC with a chiral stationary phase. HPLC conditions: Chiralcel
OD, 2-propanol/hexane = 1/10 (v/v), flow rate 1.0 mL/min, detected at 254 nm, tR = 14.6 min for (S)-3a,
15.7 min for (R)-3a. Optically pure material was obtained by recrystallization as follows: compound
(R)-3a (200 mg, 82% ee) was recrystallized from Et2O/hexane to afford (R)-3a (55 mg, >99% ee) as
o
o
25
colorless needless. For optically pure (R)-3a: mp 49.5-50 C, lit.,4b 48.5-49 C. [α]D -100 (c 1.00,
25
1
benzene), lit.,4f [α]D -100 (c 1.40, benzene). IR (film) νmax 1714, 1668. H-NMR (400 MHz, CDCl3) δ
1.46 (s, 3H), 1.67-1.78 (m, 1H), 2.10-2.19 (m, 3H), 2.44-2.53 (m, 4H), 2.68-2.77 (m, 2H). 13C-NMR (100
MHz, CDCl3) δ 22.8, 23.2, 29.6, 31.7, 33.5, 37.6, 50.5, 125.8, 165.8, 198.2, 211.0. EIMS (m/z) 178 (M+,
100%). HRMS calcd for C11H14O2 178.0994, found 178.0988. Anal. Calcd for C11H14O2 C, 74.13; H,
7.92. Found C, 74.03; H, 8.16.
Typical procedure of Robinson annulation of 5
To a stirred solution of 2-methylcyclohexane-1,3-dione (5) (96 mg, 0.75 mmol) and the amine (11) (121
μL, 0.75 mmol) in DMSO 1.5 mL was added MVK (6) (122 μL, 1.5 mmol) at rt with stirring. After 1 h,
TFA (86 μL, 1.1 mmol) was added to the mixture, and stirring was continued at rt for 80 h. The mixture
was diluted with AcOEt, washed with saturated aqueous NaHCO3 and brine, and dried (MgSO4). The
solvent was removed under reduced pressure. The crude product was chromatographed on silica gel
(AcOEt/CH2Cl2/hexane = 1/1/4) to afford (R)-3a (63 mg, 47%) as a pale yellow oil. The optical purity
was determined to be 75% ee by HPLC as described above.
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