A novel design of roof-shaped anthracene-fused chiral prolines as organocatalysts for asymmetric Mannich reactions

Article abstract of DOI:10.1016/j.tetasy.2006.11.010

A new class of artificial anthracene-fused chiral proline catalysts has been synthesized from the Diels-Alder adduct of anthracene and maleic anhydride via lithiation/carboxylation of 6 as a key step. Chiral resolution of racemic amino acids was carried o

Full text of DOI:10.1016/j.tetasy.2006.11.010

Tetrahedron: Asymmetry 17 (2006) 2963–2969
A novel design of roof-shaped anthracene-fused chiral prolines
as organocatalysts for asymmetric Mannich reactions
Aika Sasaoka,a Md. Imam Uddin,a Ai Shimomoto,a Yoshiyasu Ichikawa,a
Motoo Shirob and Hiyoshizo Kotsukia,*
aLaboratory of Natural Product Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
bX-ray Research Laboratory, Rigaku Corporation, Matsubara-cho, Akishima, Tokyo 196-8666, Japan
Received 22 August 2006; accepted 7 November 2006
Abstract—A new class of artificial anthracene-fused chiral proline catalysts has been synthesized from the Diels–Alder adduct of anthra-
cene and maleic anhydride via lithiation/carboxylation of 6 as a key step. Chiral resolution of racemic amino acids was carried out
through the formation of diastereomeric esters with (ꢀ)-menthol. The absolute configuration of the chiral amino acid was determined
by X-ray crystallographic analysis. The utility of the catalyst was confirmed by effecting asymmetric three-component Mannich reactions
between aldehyde, ketone, and amine (yield up to 76%, ee up to 90%).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cene because of its rigid roof-shaped framework for the
selective shielding of one side of a catalyst center,6 since
some successful examples have been reported of efficient
asymmetric catalysts or chiral auxiliaries containing such
a molecular architecture.7
Asymmetric organocatalysis is now recognized as an impor-
tant tool for preparing enantiomerically enriched organic
molecules due to its operational simplicity, high efficiency,
and environmentally friendly processes.1 Accordingly,
numerous approaches have been used to devise new
chiral organocatalysts and novel systems in unusual reaction
media (water, ionic liquid, etc.), and to apply this method
to natural product synthesis. In this rapidly expanding
research area, proline and its derivatives occupy a pivotal
position due to their ready availability in either enantiomeric
form, ease of handling, and broad applicability since they
were described by List et al.2,3 However, there are still some
limitations, particularly with regard to the reactivity and
selectivity of asymmetric transformations through proline-
based catalysis. Therefore, the discovery of more powerful
proline-like catalysts is required.4
We describe here our own contribution to the development
of new anthracene-fused chiral proline catalysts 1 and 2,
and their use in asymmetric three-component Mannich
reactions.8
COOH
COOH
NH
NH
1
2
2. Results and discussion
In our continuing research on the development of organo-
catalytic asymmetric synthesis,5 we focused on the design
of new proline-like catalysts that are more efficient than
proline itself. We sought to incorporate planar steric hin-
drance in close proximity to the proline core skeleton. As
a consequence, we used a Diels–Alder strategy with anthra-
The synthesis of a new class of anthracene-fused proline
catalysts 1 and 2 began with Diels–Alder adduct 3,9 which
was readily available from anthracene and maleic anhy-
dride (Scheme 1). Treatment of 3 with an equimolar
amount of p-methoxybenzylamine (PMBNH2) in hot
THF produced the desired N-PMB-protected imide 4 in
an almost quantitative yield. LAH-reduction followed by
protective-group transformation cleanly provided N-Boc-
protected isoindole 6 (66% yield over two steps). The
*
Corresponding author. Tel.: +81 88 844 8298; fax: +81 88 844 8359;
e-mail: kotsuki@kochi-u.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.010

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A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
O
O
O
NPMB
NR
b, c
a
O
O
4
3
5 R = PMB
6 R = Boc
Li
N
COOH
NBoc
O
d
e
f
O
7
8
COO(–)-menth
COO(–)-menth
NH
COO(–)-menth
NH
5
6
3
1
3
3a
9a
9a
NBoc
1
3a
g
8
+
4
9
7
6
9
4
8
7
5
9
10
11
h
h
2
1
Scheme 1. Reagents and conditions: (a) p-MeOC6H4CH2NH2, THF, reflux, 6 h, 100%; (b) LiAlH4, THF, reflux, 12 h, 98%; (c) H2, Boc2O, 10% Pd(OH)2/
C, abs EtOH, rt, 15 h, 67%; (d) sec-BuLi, TMEDA, THF, ꢀ78 ꢁC, 4 h; (e) CO2 (gas), ꢀ78 ꢁC, 3 h, 100% (2 steps); (f) (ꢀ)-menthol, DCC, DMAP, CH2Cl2,
rt, 16 h, 80%; (g) TFA, CH2Cl2, rt, 3 h, 91%; (h) 1.0 M aq NaOH, MeOH, 45 ꢁC, 16 h, then SiO2 column, 73%.
crucial attachment of a carboxyl function onto 6 was suc-
cessfully achieved by using Beak’s protocol: N-Boc-direc-
ted lithiation/carboxylation.10 Thus, lithiation using sec-
BuLi/TMEDA in dry THF at ꢀ78 ꢁC for 5 h provided
the a-lithioamide intermediate 7, which on exposure to
bubbling CO2 (gas) gave the desired carboxylic acid 8 in
an excellent yield.
Finally, alkaline hydrolysis of the menthyl ester of 10 gave
the end product, anthracene-fused proline catalyst 1,
22
½aꢁD = +57.6 (c 0.62, MeOH), in an enantiomerically pure
Based on its behavior in TLC and NMR, compound 8 exists
as a diastereomeric mixture of endo- and exo-isomers.
Fortunately, however, we found that the endo-isomer could
be readily isomerized into the more stable exo-isomer after
the following experiments.
Since initial attempts to enzymatically resolve racemic 8
after conversion to the corresponding methyl ester deriva-
tives were not successful,11 we decided to use the diastereo-
meric esters. Thus, treatment of 8 with (ꢀ)-menthol with
the aid of DCC/DMAP gave menthyl ester 9 in 80% yield.
At this stage, the side chain was isomerized quite smoothly.
TFA-promoted deprotection of the N-Boc group gave
nearly equal amounts of free amine 10 and 11 in a com-
bined yield of 91%. Compounds 10 and 11 were isolated
by silica gel column chromatography: 10 as a colorless
22
gum, ½aꢁD = +20.9 (c 1.62, MeOH) and 11 as mica crystals,
22
mp 159–161 ꢁC, ½aꢁD = ꢀ93.1 (c 1.41, MeOH).
The stereochemistry of 11 was fully determined by X-ray
crystallographic analysis, and the absolute configuration
of the mother skeleton was unambiguously established to
be (1R,3aS,9aR) (Fig. 1). This result leads to the conclusion
that diastereomer 10 should have the (1S,3aR,9aS)-
configuration.
Figure 1. The ORTEP drawing of compound 11.

A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
2965
Table 1. Asymmetric three-component Mannich reactions between ketone, p-anisidine, and aldehydea
OMe
PMP
R'
O
O
20 mol% 1
O
HN
+
+
rt
H
R'
R
R
NH2
Entry
Product
Time (h)
Yieldb (%)
eec (%)
PMP
O
HN
1d
2e
3
0.5
0.5
0.5
71
76
76
56
65
75
12
PMP
PMP
O
O
HN
4f
5g
6
0.5
0.5
0.5
76
56
62
68
54
64
13
HN
14
PMP
PMP
O
O
HN
15
HN
7g
8g
9g
2
3
2
54
59
65
90
90
84
16
NO2
PMP
O
HN
17
PMP
O
O
O
HN
18
PMP
HN
10g
3
3
72 (dr > 19:1)h
79
86
OH
19
PMP
O
HN
11g
67 (dr > 17:1)h
OMe
NO2
20
a Unless otherwise noted, all reactions were conducted at rt in pure ketone (5 mL) using aldehyde (0.5 mmol) and p-anisidine (0.55 mmol) in the presence
of 20 mol % of 1.
b Isolated yield.
c Determined by chiral HPLC analysis.
d At 0 ꢁC in the presence of 5 mol % of 1.
e 10 mol % of 1 was used.
f 20 mol % of 2 was used as the catalyst.
g The reaction was conducted in DMSO/ketone = 4:1.
h Determined by NMR.

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A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
form in 73% yield. In the same manner, catalyst 2,
½aꢁD = ꢀ57.6 (c 1.31, MeOH), was obtained from 11.
moisture-sensitive compounds were introduced via syringe
or cannula through a rubber septum. All melting points
were measured on a Yanagimoto MP-S3 micro-melting
point apparatus and are uncorrected. The NMR spectra
were recorded on a JEOL LA 400 (400 MHz for 1H
NMR analysis and 100 MHz for 13C NMR analysis)
instrument in CDCl3 unless otherwise stated and are
reported in parts per million (d) downfield from TMS as
an internal standard. The infrared spectra were measured
with a JASCO FTIR-5300 or FTIR-460plus Fourier
Transform Infrared Spectrophotometer and are reported
in wavenumbers (cmꢀ1). Optical rotations were mea-
sured on a JASCO DIP-370 polarimeter. HPLC analysis
was carried out using a Hitachi L-6200 HPLC system.
22
The overall sequence in the above strategy requires only
seven steps from the starting anhydride 3 and the product
is relatively easy to access in multigram quantities. In addi-
tion, one of the favorable points of this work is the ready
availability of either enantiomer of the catalysts, which
provides a highly flexible way to conduct research on
organocatalytic asymmetric synthesis.
By analogy to previously established examples using L-pro-
line as a catalyst,8 the utility of the newly formed anthra-
cene-fused chiral proline catalysts was then tested in
asymmetric three-component Mannich reactions between
ketone donors, p-anisidine, and aldehyde acceptors. The
results are summarized in Table 1.
Thin-layer chromatography (TLC) was conducted using
Merck Kieselgel 60F-254 plates (0.25 mm). Fuji silicia
BW-300 was used for column chromatography, and
Merck Kieselgel (230–400 mesh) was used for flash
chromatography.
A
mixture of isovaleraldehyde (1 equiv), p-anisidine
(1.1 equiv), and catalyst 1 (20 mol %) in pure acetone was
subjected to the standard conditions (entry 3).12 After 30
min at room temperature, the reaction was completed and
the N-PMP-protected b-amino ketone 12 was obtained in
76% yield with 75% ee. The absolute configuration of 12 was
determined to be (R) by comparison with that of the authen-
tic sample prepared by L-proline catalysis. Slight decreases in
enantioselectivity were observed at a lower loading of the
catalyst or at lower temperatures (entries 1 and 2 vs entry 3).
4.2. N-(p-Methoxybenzyl)-4,9[10,20]benzeno-3a,4,9,9a-tetra-
hydro-1H-benz[f]isoindole-1,3(2H)-dione 4
To a solution of 39 (5.53 g, 20 mmol) in dry THF (60 mL)
was added p-methoxybenzylamine (2.74 g, 20 mmol) at
room temperature, and the mixture was refluxed for 6 h.
After the reaction was complete, the mixture was filtered,
and the precipitate was dried in vacuo to give 4 (7.91 g,
100%) as a white solid. Rf 0.29 (hexane/EtOAc = 2:1);
mp 224–226 ꢁC (from CHCl3–hexane); FTIR (KBr) m
On the other hand, the use of catalyst 2 gave (S)-enantiomer
13 (entry 4). The general applicability of the present method
was established by Mannich reactions using isobutyralde-
hyde, pentanal, p-nitrobenzaldehyde, 2-naphthaldehyde,
and 2-furaldehyde as an aldehyde component (entries
5–9). Other ketones (hydroxyacetone and methoxyacetone)
were also used as a donor, and with p-anisidine and
aldehyde furnished the desired products 19 and 20 in high
regio-, diastereo-, and enantioselectivities (entries 10 and 11).
1
1773, 1707, 1615, 1516, 1250, 1034; H NMR d 3.20 (2H,
s), 3.76 (3H, s), 4.20 (2H, s), 4.76 (2H, s), 6.65 (2H, d,
JAB = 8.4 Hz), 6.70 (2H, d, JAB = 8.4 Hz), 6.97 (2H, dd,
J = 5.4, 3.2 Hz), 7.14–7.17 (4H, m), 7.35 (2H, dd, J = 4.6,
3.2 Hz); 13C NMR d 41.5, 45.4 (·2), 46.8 (·2), 55.2, 113.7
(·2), 124.2 (·2), 124.8 (·2), 126.6 (·2), 127.0 (·2), 127.3,
129.3 (·2), 138.4 (·2), 141.7 (·2), 158.8, 176.5 (·2). Anal.
Calcd for C26H21NO3: C, 78.97; H, 5.35; N, 3.54. Found:
C, 78.95; H, 5.59; N, 3.76.
3. Conclusion
In summary, we have developed an efficient synthetic path-
way for the construction of anthracene-fused chiral proline
catalysts 1 and 2 via a seven-step conversion from Diels–
Alder adduct 3. The utility of this novel class of artificial
catalysts was exemplified by applying it to asymmetric
Mannich-type reactions that provide chiral b-amino ketone
compounds. Although the catalytic activities of 1 and 2 do
not exceed our expectations, the present system offers sev-
eral advantages, including easy construction of the cata-
lysts and short reaction times. Further studies to improve
the catalyst design and to apply this approach to other
types of asymmetric transformations are now in progress.
4.3. N-(p-Methoxybenzyl)-4,9[10,20]benzeno-1,3,3a,4,9,9a-
hexahydro-1H-benz[f]isoindole 5
To a suspension of LiAlH4 (1.02 g, 26.9 mmol) in dry THF
(60 mL) at 0 ꢁC was added 4 (3.95 g, 10 mmol) in dry THF
(140 mL), and the mixture was gently refluxed overnight.
After cooling, the mixture was carefully quenched by the
addition of a minimum amount of water, dried (K2CO3),
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (hexane/
EtOAc = 4:1) to give 5 (3.31 g, 98%) as a yellowish gum.
Rf 0.28 (hexane/EtOAc = 2:1); FTIR (neat) m 1613, 1512,
1464, 1244, 1036; 1H NMR d 1.71 (2H, dd, J = 9.0,
6.6 Hz), 2.68 (2H, m), 2.80 (2H, m), 3.17 (2H, s), 3.78
(3H, s), 4.09 (2H, s), 6.77 (2H, d, J = 8.5 Hz), 6.97 (2H,
d, J = 8.5 Hz), 7.07 (2H, dd, J = 5.4, 3.2 Hz), 7.14 (2H,
J = 5.4, 3.2 Hz), 7.20–7.24 (4H, m); 13C NMR (CDCl3) d
44.3 (·2), 47.3 (·2), 55.2, 56.9 (·2), 59.5, 113.4 (·2),
123.6 (·2), 125.6 (·2), 125.6 (6) (·2), 125.6 (7) (·2),
128.2, 129.8 (·2), 141.9 (·2), 144.1 (·2), 158.5. Anal. Calcd
4. Experimental
4.1. General
All reactions were performed in an oven-dried glassware
under a positive pressure of nitrogen or argon. Air- and

A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
2967
for C26H25NOÆH2O: C, 81.01; H, 7.06; N, 3.63. Found: C,
80.70; H, 7.19; N, 3.88.
and the mixture was stirred at room temperature for
16 h. After the reaction was complete, the mixture was
concentrated, and the insoluble substance was removed
by filtration. Evaporation of the solvent gave a crude
product, which was purified by column chromatography
on silica gel (CHCl3/MeOH = 99:1) to afford 9 (4.36 g,
80%; an inseparable 1:1 diastereomeric mixture) as a white
solid. Rf 0.53 (hexane/acetone = 2:1); mp 179–185 ꢁC
(from hexane); FTIR (KBr) m 1730, 1703, 1468, 1399,
4.4. N-(tert-Butoxycarbonyl)-4,9[10,20]benzeno-1,3,3a,4,9,9a-
hexahydro-1H-benz[f]isoindole 6
To a solution of 5 (3.53 g, 9.6 mmol) in abs EtOH (50 mL)
were added Boc2O (3.14 g, 14.4 mmol) and 10% Pd(OH)2/
C (100 mg), and the mixture was stirred under H2 at room
temperature for 15 h. The catalyst was removed by filtra-
tion through Celite, and the crude product was recrystal-
lized from CH2Cl2–hexane to give 6 (2.24 g, 67%; a ca.
3:1 mixture of amide rotamers) as a white solid (minor
rotamer peaks denoted by an *). Rf 0.41 (hexane/
EtOAc = 2:1); mp 211–215 ꢁC (from CHCl3–hexane);
1
1175; H NMR d 0.71 (3H, m), 0.86 (6H, d, J = 6.4 Hz),
0.90–1.15 (2H, m), 1.21 and 1.24 (total 9H, s), 1.32–1.50
(2H, m), 1.62–1.70 (3H, m), 1.78–1.96 (2H, m), 2.72 (2H,
m), 3.17–3.19 and 3.37–3.50 (total 2H, m), 3.85 and 3.98
(total 1H, s), 4.17 and 4.21 (total 1H, s), 4.41 (1H, m),
4.66 (1H, m), 7.11–7.13 (4H, m), 7.26–7.34 (4H, m); 13C
NMR (major peaks; Boc carbonyl is missing) d 16.1,
20.8, 21.9, 23.2, 26.0, 28.1 (·3), 31.3, 34.1, 40.7, 42.9,
46.9, 49.0 (·2), 49.1 (·2), 63.2, 74.9, 79.3, 123.6, 123.7,
123.8, 126.0, 126.1, 126.2 (·2), 126.5, 139.4, 139.7, 142.1,
143.1, 172.6. Anal. Calcd for C34H43NO4ÆH2O: C, 74.56;
H, 8.28; N, 2.56. Found: C, 74.77; H, 8.21; N, 2.83.
1
FTIR (KBr) m 1691, 1470, 1418, 1175, 1115; H NMR d
1.29 (9H, s), 2.73 (2H, br s), 2.90 (1H, d, J = 10.2 Hz),
3.01 (1H, d, J = 10.2 Hz), 3.39 (2H, m), 4.17 (2H, d,
J = 13.7 Hz), 7.09 (2H, dd, J = 5.4, 3.2 Hz), 7.11 (2H,
dd, J = 5.8, 2.9 Hz), 7.24–7.29 (4H, m); 13C NMR d 28.3
(·3), 43.4*, 44.2*, 48.4 (·6), 48.6*, 77.2*, 78.8, 123.6 (·4),
125.1*, 125.6*, 125.9 (·4), 126.1*, 126.2*, 140.2 (·4),
143.2*, 143.5*, 153.3. Anal. Calcd for C23H25NO2: C,
79.51; H, 7.25; N, 4.03. Found: C, 79.26; H, 7.53; N, 4.06.
4.7. 4,9[10,20]Benzeno-1,3,3a,4,9,9a-hexahydro-1H-
benz[f]isoindole-1-carboxylic acid (ꢀ)-menthyl ester
10 and 11
4.5. N-(tert-Butoxycarbonyl)-4,9[10,20]benzeno-
1,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole-1-carboxylic
acid 8
To a solution of 9 (2.06 g, 3.9 mmol) in dry CH2Cl2
(40 mL) at 0 ꢁC was added trifluoroacetic acid (TFA;
3.0 mL, 40.4 mmol), and the mixture was stirred at room
temperature for 3 h. After being quenched by the addition
of aq NaOH, the mixture was extracted with EtOAc. The
extracts were dried (K2CO3) and concentrated. The crude
product was purified repeatedly by column chromato-
graphy on silica gel (hexane/EtOAc = 2:1) to give 10
(762 mg, 46%) and 11 (758 mg, 45%).
To a solution of 6 (3.0 g, 8.63 mmol) in dry THF (36 mL)
at ꢀ78 ꢁC were added N,N,N0,N0-tetramethylethylen-
diamine (TMEDA; 1.5 mL, 9.94 mmol), and sec-BuLi
(0.98 M in cyclohexane; 10 mL, 9.8 mmol). The mixture
was stirred at ꢀ78 ꢁC for 4 h and CO2 gas was then bub-
bled into the reaction mixture. After being stirred for 3 h,
the mixture was carefully quenched by the addition of aq
NH4Cl to make the solution acidic (pH ca. 4). The organic
layer was separated and the aqueous layer was extracted
with EtOAc (30 mL · 3). The combined extracts were
washed with saturated NaCl, dried (Na2SO4), and concen-
trated. The crude product was purified by column chroma-
tography on silica gel (hexane/EtOAc = 1:1) to afford 8
(3.38 g, 100%) as a white solid. Rf 0.24 (hexane/
EtOAc = 1:1); mp 235–238 ꢁC (from CHCl3–hexane);
Compound 10: colorless gum; Rf 0.41 (hexane/
22
EtOAc = 2:1); ½aꢁD = +20.9 (c 1.62, MeOH); FTIR (neat)
m 3316, 1732, 1458, 1179; 1H NMR d 0.75 (3H, d,
J = 6.8 Hz), 0.91 (6H, d, J = 6.8 Hz), 0.95–1.12 (2H, m),
1.45–1.51 (2H, m), 1.58–1.80 (4H, m), 1.86 (1H, ddt,
J = 16.0, 7.1, 2.7 Hz), 1.98 (1H, m), 2.36 (1H, dd,
J = 11.5, 5.6 Hz), 2.70 (2H, m), 3.10 (1H, d, J = 5.6 Hz),
3.15 (1H, dd, J = 11.5, 7.4 Hz), 4.12 (1H, d, J = 2.7 Hz),
4.34 (1H, d, J = 2.7 Hz), 4.73 (1H, dt, J = 10.9, 4.3 Hz),
7.07–7.12 (2H, m), 7.13–7.17 (2H, m), 7.23–7.30 (4H, m);
13C NMR d 16.4, 20.7, 22.0, 23.6, 26.4, 31.4, 34.2, 40.9,
46.8, 47.1, 47.7 (·2), 50.1, 51.9, 63.7, 74.7, 123.6, 123.8,
125.5, 125.7, 125.8, 126.0, 126.2 (6), 126.2 (7), 140.9,
141.1, 143.4, 144.1, 173.1. Anal. Calcd for C29H35NO2Æ
H2O: C, 77.82; H, 8.33; N, 3.13. Found: C, 77.46; H,
8.27; N, 3.39.
1
FTIR (KBr) m 3441, 1732, 1692, 1399; H NMR d 1.40
and 1.42 (total 9H, s), 2.74 (1H, t, J = 10.1 Hz), 2.93
(1H, m), 3.13 (1H, m), 3.77 (1H, m), 4.14 (1H, br), 4.52
(1H, br s), 4.62 (1H, br), 7.06–7.28 (8H, m); 13C NMR
(major peaks; Boc carbonyl is missing) d 28.3 (·3), 44.9
(·2), 46.2 (·3), 59.9, 80.1, 123.7, 123.8, 125.7, 125.9 (8),
126.0 (3), 126.3, 126.5, 127.3, 141.4, 143.8 (·2), 143.9,
171.2. Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44; N,
3.58. Found: C, 73.31; H, 6.63; N, 3.63.
Compound 11: mica crystals; Rf 0.38 (hexane/
4.6. N-(tert-Butoxycarbonyl)-4,9[10,20]benzeno-
1,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole-1-carboxylic
acid (ꢀ)-menthyl ester 9
To a solution of 8 (4.04 g, 10.3 mmol), N,N0-dicyclohexyl-
carbodiimide (DCC; 3.61 g, 17.5 mmol), and 4-dimethyl-
aminopyridine (DMAP; 370 mg, 3.0 mmol) in dry CH2Cl2
(150 mL) was added (ꢀ)-menthol (1.75 g, 11.2 mmol),
EtOAc = 2:1);
mp
159–161 ꢁC
(from
hexane);
22
½aꢁD = ꢀ93.1 (c 1.41, MeOH); FTIR (KBr) m 3322, 1725,
1
1456, 1233, 1181; H NMR d 0.77 (3H, d, J = 7.1 Hz),
0.92 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.8 Hz), 0.87–
1.13 (2H, m), 1.26 (1H, m), 1.43–1.57 (2H, m), 1.71–1.76
(2H, m), 1.96–2.04 (2H, m), 2.27 (1H, dd, J = 11.5,
7.8 Hz), 2.65 (1H, br), 2.69 (1H, ddd, J = 10.8, 7.8,
3.0 Hz), 2.78–2.85 (1H, m), 3.07 (1H, d, J = 7.6 Hz), 3.27

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A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
(1H, dd, J = 11.5, 8.1 Hz), 4.11 (1H, d, J = 2.8 Hz), 4.34
(1H, d, J = 2.7 Hz), 4.76 (1H, dt, J = 11.0, 4.5 Hz), 7.03–
7.11 (2H, m), 7.13–7.18 (2H, m), 7.20–7.22 (1H, m),
7.23–7.27 (2H, m), 7.30–7.33 (1H, m); 13C NMR d 16.1,
21.0, 22.0, 23.2, 26.3, 31.4, 34.2, 40.8, 47.1 (6), 47.2 (0),
47.4, 47.5, 49.9, 52.3, 63.6, 74.7, 123.6 (·2), 125.7, 125.8,
125.8 (8), 125.9 (2), 126.2, 126.3, 140.1, 141.3, 143.6,
144.2, 173.2. Anal. Calcd for C29H35NO2: C, 81.08; H,
8.21; N, 3.26. Found: C, 79.97; H, 8.64; N, 3.45.
4.11. General procedure for anthracene-fused proline-cata-
lyzed asymmetric Mannich reactions
A suspension of 1 (29 mg, 0.1 mmol), p-anisidine (67 mg,
0.55 mmol), and an aldehyde (0.5 mmol) in 5 mL of pure
ketone (or DMSO/ketone = 4:1) was stirred at room tem-
perature for 30–120 min. The mixture was worked up by
filtration to remove the insoluble materials, concentrated,
and purified by column chromatography on silica gel
(hexane/EtOAc = 4:1 to 2:1). In the reactions in DMSO–
ketone, the mixture was quenched by the addition of
phosphate buffer solution (pH 7.4) and extracted with
EtOAc. The extracts were dried (MgSO4), concentrated,
and purified by column chromatography on silica gel (hex-
ane/EtOAc = 4:1 to 2:1). The enantiomeric purity of the
substance was determined by chiral HPLC analysis.
4.8. X-ray crystal structure determination of compound 11
A colorless platelet crystal of C29H35NO2 with approxi-
mate dimensions of 0.80 · 0.40 · 0.05 mm, mounted in a
loop, was used for the X-ray study. All measurements were
made on a Rigaku RAXIS-RAPID Imaging Plate diffrac-
tometer with graphite monochromated Mo-Ka radiation.
The structure was solved by direct methods (SIR97) and
expanded using Fourier techniques (DIRDIF94). The non-
hydrogen atoms were refined anisotropically. Hydrogen
atoms were included but not refined. The final cycle of
full-matrix least-squares refinement was based on 4010
observed reflections and 289 variable parameters and
converged with unweighted and weighted agreement factors
of R = 0.063 and Rw = 0.101. Crystal data: C29H35NO2,
M = 429.60, crystal system: orthorhombic, space group:
4.11.1. (R)-4-(4-Methoxyphenylamino)-6-methylheptan-2-
one 12. Yellow oil, 76%, ee = 75%. FTIR (neat) m 3367,
1709, 1618, 1512, 1241; 1H NMR d 0.91 (3H, d,
J = 6.6 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.32 (1H, ddd,
J = 14.0, 8.1, 5.9 Hz), 1.47 (1H, ddd, J = 14.0, 8.3,
6.3 Hz), 1.74 (1H, m), 2.12 (3H, s), 2.55 (1H, dd,
J = 16.4, 6.3 Hz), 2.65 (1H, dd, J = 16.4, 4.9 Hz), 3.37
(1H, br), 3.74 (3H, s), 3.81 (1H, m), 6.57 (2H, m), 6.77
(2H, m); 13C NMR d 22.3, 22.9, 25.0, 31.0, 44.7, 48.0,
49.1, 55.7, 115.0 (·4), 141.3, 152.1, 208.6. HPLC: Daicel
Chiralpak AS, k = 315 nm, 10% i-PrOH/hexane, flow
rate = 0.5 mL/min, major tR (R-enantiomer) 16.08 min,
minor tR (S-enantiomer) 20.08 min.
˚
P212121 (#19). Lattice parameters: a = 7.1814 (2) A,
3
˚
˚
˚
b = 8.6301(3) A,
c = 38.797(1) A,
V = 2404.5(1) A ,
Z = 4, Dcalc = 1.187 g/cm3, F(000) 928.00, l(Mo-Ka)
0.73 cmꢀ1. CCDC-626851 contains the supplementary crys-
tallographic data for this complex. These data are available
free of charge via www.ccdc.cam.ac.uk/data_request/cif.
4.11.2. (S)-4-(4-Methoxyphenylamino)-5-methylhexan-2-one
14. Yellow oil, 56%, ee = 54%. FTIR (neat) m 3376, 1709,
1618, 1513, 1236; 1H NMR d 0.90 (3H, d, J = 6.8 Hz), 0.96
(3H, d, J = 7.1 Hz), 1.93 (1H, m), 2.14 (3H, s), 2.53 (1H,
dd, J = 15.9, 7.1 Hz), 2.58 (1H, J = 15.9, 5.4 Hz), 3.36
(1H, br), 3.65 (1H, dt, J = 7.1, 5.4 Hz), 3.74 (3H, s), 6.58
(2H, m), 6.76 (2H, m); 13C NMR: d 18.4, 18.8, 30.6, 31.2,
45.2, 55.8, 56.2, 114.9 (·4), 141.6, 152.1, 208.5. HPLC: Dai-
cel Chiralpak AS, k = 315 nm, 15% i-PrOH/hexane, flow
rate = 0.5 mL/min, major tR (S-enantiomer) 16.14 min,
minor tR (R-enantiomer) 23.31 min.
4.9. (1S,3aR,9aS)-4,9[10,20]Benzeno-1,3,3a,4,9,9a-hexa-
hydro-1H-benz[f]isoindole-1-carboxylic acid 1
To a solution of 10 (180 mg, 0.42 mmol) in MeOH (5 mL)
was added aq NaOH (1.0 M; 2.5 mL, 2.5 mmol), and the
mixture was stirred at 45 ꢁC for 16 h. Evaporation of the
solvent gave a crude product, which was purified by col-
umn chromatography on silica gel (CHCl3/MeOH = 4:1)
to give pure 1 (89 mg, 73%) as a white solid. Rf 0.19
22
4.11.3. (R)-4-(4-Methoxyphenylamino)octan-2-one 15.
Yellow oil, 62%, ee = 64%. FTIR (neat) m 3366, 1709, 1512,
1237; H NMR d 0.88 (3H, t, J = 7.5 Hz), 1.23–1.43 (4H,
(CHCl3/MeOH = 4:1); mp 261–265 ꢁC; ½aꢁ = +57.6 (c
0.62, MeOH); FTIR (KBr) m 3434, 1735,D 1675, 1198,
1140; 1H NMR (CD3OD) d 2.26 (1H, dd, J = 11.7,
9.5 Hz), 2.73 (1H, m), 2.90 (1H, m), 3.04 (1H, d,
J = 9.3 Hz), 3.46 (1H, dd, J = 11.7, 8.3 Hz), 4.28 (1H, d,
J = 2.7 Hz), 4.58 (1H, d, J = 2.7 Hz), 7.09–7.14 (2H, m),
7.19–7.24 (2H, m), 7.28–7.37 (3H, m), 7.46–7.50 (1H, m);
13C NMR (CD3OD) d 45.2, 47.1, 47.7, 48.0, 50.0, 65.2,
124.9, 125.2, 127.3 (9) (·2), 127.4 (4), 127.7, 127.8, 127.9,
141.7, 141.8, 144.1, 144.2, 172.7. Anal. Calcd for
C19H17NO2Æ0.6H2O: C, 75.52; H, 6.07; N, 4.64. Found:
C, 75.14; H, 6.38; N, 4.58.
1
m), 1.53 (2H, m), 2.13 (3H, s), 2.57 (1H, dd, J = 16.4,
6.4 Hz), 2.65 (1H, dd, J = 16.4, 5.4 Hz), 3.38 (1H, br),
3.72 (1H, m), 3.74 (3H, s), 6.57 (2H, m), 6.76 (2H, m);
13C NMR d 14.0, 22.6, 28.4, 30.9, 34.9, 47.9, 51.0, 55.8,
115.0 (·2), 115.1 (·2), 141.3, 152.2, 208.4. HPLC: Daicel
Chiralpak AD, k = 315 nm, 2% i-PrOH/hexane, flow
rate = 0.5 mL/min, major tR (S-enantiomer) 24.04 min,
minor tR (R-enantiomer) 27.26 min.
4.11.4.
(S)-4-(4-Nitrophenyl)-(4-methoxyphenylamino)-
butan-2-one 16. Yellow oil, 54%, ee = 90%. FTIR (neat)
m 3361, 1713, 1600, 1512, 1346, 1239; 1H NMR d 2.15
(3H, s), 2.94 (2H, d, J = 6.4 Hz), 3.69 (3H, s), 4.28 (1H,
br), 4.85 (1H, t, J = 6.4 Hz), 6.46 (2H, m), 6.69 (2H, m),
7.55 (2H, d, J = 8.8 Hz), 8.17 (2H, d, J = 8.8 Hz); 13C
NMR d 30.7, 50.7, 54.7, 55.6, 55.7, 114.8 (·2), 115.4 (·2),
4.10. (1R,3aS,9aR)-4,9[10,20]Benzeno-1,3,3a,4,9,9a-hexa-
hydro-1H-benz[f]isoindole-1-carboxylic acid 2
Compound 2 was also prepared in the same manner as
22
for 1: mp 262–265 ꢁC; ½aꢁD = ꢀ57.6 (c 1.31, MeOH).

A. Sasaoka et al. / Tetrahedron: Asymmetry 17 (2006) 2963–2969
2969
116.4, 124.0 (·2), 127.4 (·2), 140.1, 150.6, 152.8, 206.1.
HPLC: Daicel Chiralpak AD, k = 280 nm, 50% i-PrOH/
hexane, flow rate = 0.5 mL/min, major tR (S-enantiomer)
17.36 min, minor tR (R-enantiomer) 14.38 min.
as well as by a Special Research Grant for Green Science
from Kochi University. We also thank the Asahi Glass
Foundation, for the financial support of this work.
4.11.5. (S)-4-(2-Naphthyl)-(4-methoxyphenylamino)-butan-
2-one 17. Light yellow solid, 59%, ee = 90%. FTIR
(KBr) m 3386, 1709, 1512, 1238; H NMR d 2.12 (3H, s),
References
1
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(3H, m), 7.78–7.83 (4H, m); 13C NMR d 30.8, 51.4, 55.5,
55.6, 114.7 (·2), 115.4 (·2), 124.4, 125.1, 125.8, 126.2,
127.7, 127.9, 128.7, 132.8, 133.4, 140.2, 140.9, 152.4,
207.2. HPLC: Daicel Chiralpak AS-H, k = 315 nm, 15%
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18. Yellow oil, 65%, ee = 84%. FTIR (neat) m 3362, 1712,
1618, 1513, 1239; H NMR d 2.15 (3H, s), 2.97 (1H, dd,
´
Palomo, C.; Oiarbide, M.; Garcıa, J. M. Chem. Eur. J. 2002,
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1
J = 16.4, 6.1 Hz), 3.02 (1H, dd, J = 16.4, 6.1 Hz), 3.73
(3H, s), 3.96 (1H, br), 4.91 (1H, t, J = 6.1 Hz), 6.15 (1H,
d, J = 3.3 Hz), 6.27 (1H, dd, J = 3.3, 2.0 Hz), 6.63 (2H,
m), 6.75 (2H, m), 7.32 (1H, m); 13C NMR d 30.7, 47.3,
49.6, 55.6, 106.4, 110.3, 114.7 (·2), 115.9 (·2), 140.5,
141.6, 152.9, 154.9, 206.8. HPLC: Daicel Chiralpak AS-
H, k = 315 nm, 10% i-PrOH/hexane, flow rate = 1.0 mL/
min, major tR (R-enantiomer) 25.83 min, minor tR (S-enan-
tiomer) 35.55 min.
4.11.7.
(3S,4R)-3-Hydroxy-4-phenyl-(4-methoxyphenyl-
amino)butan-2-one 19. Colorless solid, 72% (dr >19:1),
ee = 79%. FTIR (KBr) m 3381, 1714, 1619, 1513, 1241;
1H NMR d 2.33 (3H, s), 3.68 (3H, s), 3.77 (1H, d,
J = 2.8 Hz), 4.34 (1H, br), 4.43 (1H, t, J = 2.8 Hz), 4.90
(1H, br s), 6.50 (2H, m), 6.68 (2H, m), 7.23–7.38 (5H,
m); 13C NMR d 25.2, 55.6, 59.1, 80.8, 114.8 (·2), 115.1
(·2), 127.0 (·2), 127.6, 128.7 (·2), 139.3, 140.1, 152.4,
207.4. HPLC: Daicel Chiralpak AD, k = 254 nm, 8%
i-PrOH/hexane, flow rate = 1.0 mL/min, minor tR (3R,4S-
enantiomer) 14.56 min, major tR (3S,4R-enantiomer)
20.30 min.
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M.; Spanevello, R. A.; Suarez, A. G. Tetrahedron Lett. 2004,
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´
8. For reviews of proline-catalyzed asymmetric Mannich reac-
´
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phenylamino)butan-2-one 20. Yellow oil, 67% (dr >17:1),
ee = 86%. FTIR (neat) m 3379, 1717, 1605, 1514, 1347,
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1
1243; H NMR d 2.23 (3H, s), 3.32 (3H, s), 3.68 (3H, s),
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3.81 (1H, d, J = 2.5 Hz), 4.59 (1H, br), 4.86 (1H, d,
J = 2.5 Hz), 6.45 (2H, m), 6.67 (2H, m), 7.53 (2H, m),
8.18 (2H, m); 13C NMR d 27.3, 55.6, 59.3, 59.9, 89.8,
114.9 (·2), 115.1 (·2), 115.6, 123.8 (·2), 128.1 (·2), 139.5,
147.9, 152.7, 209.5. HPLC: Daicel Chiralpak AD,
k = 280 nm, 5% i-PrOH/hexane, flow rate = 0.5 mL/min,
minor tR (3R,4S-enantiomer) 49.04 min, major tR (3S,4R-
enantiomer) 54.48 min.
11. Sturmer, R.; Scha¨fer, B.; Wolfart, V.; Stahr, H.; Kazmaier,
¨
U.; Helmchen, G. Synthesis 2001, 46–48.
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Acknowledgments
This work was supported in part by a Scientific Research
on Priority Areas (18037053 and 18032055) from MEXT,